Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:12][PH3+].[CH2:21]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[C:26]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:25]=1[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:22].O>C1COCC1>[Si:33]([O:32][C:26]1[C:27](/[CH:28]=[CH:12]\[C:11]2[CH:10]=[C:9]([O:8][CH3:7])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:30][CH:31]=[C:24]([O:23][CH2:21][CH3:22])[C:25]=1[O:40][Si:41]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:42])[CH3:43])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CCOc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
n-Butyl lithium (0.85 mL, 1.36 mmol, 1.6 M in hexanes) was added dropwise over 10 min to a solution of 3,4,5-trimethoxybenzylphosphonium bromide (0.58 g, 1.12 mmol) in THF (7 mL) at −10° C. The reaction mixture was stirred at this temperature for 15 min then cooled to −70 C and a solution of 35 (0.47 g, 1.14 mmol) in THF (3 mL) was added and the reaction mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was cooled to 0° C. and water was added. The reaction mixture was extracted with TBME (3×) and the organic phase was washed successively with water and brine, dried (Na2SO4) and concentrated in vacuo to give crude product (0.67 g). Purification by column chromatography (SiO2 2:98 EtOAc:cyclohexane+1% Et3N) gave 36 (0.21 g, 34%) as an 89:11 mixture of Z:E isomers.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:50][CH2:51][C@@H:52]([NH2:57])[C@@H:53]([CH3:56])[CH2:54][CH3:55])([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:29])[NH:57][C@H:52]([CH2:51][O:50][Si:33]([C:46]([CH3:48])([CH3:47])[CH3:49])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:53]([CH3:56])[CH2:54][CH3:55])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC[C@H](C)[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC[C@H](C)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (2.00 g, 4.29 mmol) (obtained as described in Reference Example 2(1)) in benzene (100 ml) was added a solution of 0.67M (1S,2S)-1-(t-butyldiphenylsilyloxymethyl)-2-methylbutylamine-trimethylaluminium in benzene (12.9 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux overnight. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (200 ml) were added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 30 minutes. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→1:3) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[(1S,2S)-1-(t-butyldiphenylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.89 g, yield 57%) as a pale brown solid.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:19]([C:21](=[O:23])[CH3:22])[CH:20]=1.[OH-].[K+].Cl>CCO>[ClH:14].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:19]([C:21](=[O:23])/[CH:22]=[CH:1]/[C:3]2[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=2)[CH:20]=1
Reactant: CC(=O)c1cc(Cl)ccc1N1CCN(C)CC1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2ccc(Cl)cc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)cc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 163.5 %

Procedure:
A mixture of 4-formylcinnamic acid (397 mg, 2.25 mmol), 1-[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (obtained as described in Preparation 10, 570 mg, 2.25 mmol) and 1.7 M KOH (2.66 ml) in EtOH (25 ml) was stirred at 0° C. for 3 h and then acidified with 10% HCl. The solution was concentrated until formation of a yellow precipitate. The solid was filtered to give 823 mg of (E)-3-(4-{(E)-3-[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[N:13]1([C:17]([C:19]2[N:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[C:28]([CH:39]=[C:40]([C:42](=[O:51])[NH:43][C:44]4[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=4)[CH:41]=3)[O:29][CH:30]([CH2:36][CH2:37][OH:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:21][CH:20]=2)=[O:18])[CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[N:13]1([C:17]([C:19]2[N:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[C:28]([CH:39]=[C:40]([C:42](=[O:51])[NH:43][C:44]4[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=4)[CH:41]=3)[O:29][CH:30]([CH2:36][CH2:37][O:38][S:2]([CH3:1])(=[O:4])=[O:3])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:21][CH:20]=2)=[O:18])[CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)C(CCO)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCOS(C)(=O)=O)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
Methanesulfonyl chloride (13 L, 0.16 mmol) and triethylamine (34 μL, 0.24 mmol) were added to a solution of ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-hydroxy-butanoate (Intermediate 28) (65 mg, 0.12 mmol) in DCM (5 mL) at 0° C. under nitrogen. The reaction was allowed to warm to RT and stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate (10 mL) and brine (10 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (10 mL). The combined organics were dried (MgSO4), concentrated under reduced pressure and the residue purified by column chromatography on silica eluting with 0-10% methanol/DCM to give product (29 mg, 42%). 1H NMR δ (300 MHz, CDCl3) 1.23-1.30 (3H, m), 2.33-2.46 (4H, m), 2.56 (3H, s), 3.03 (3H, s), 4.22-4.29 (4H, m), 4.44-4.49 (2H, m), 4.71 (2H t), 4.87-4.91 (1H, m), 6.81 (1H t), 7.21 (1H t), 7.29 (1H t), 7.38-7.41 (1H, m), 8.13 (2H d), 8.34 (1H d), 8.42 (1H, s), 9.51 (1H, s); m/z 615 (M+H)+.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[Cl:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O>[Cl:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:10]=1[CH2:11][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[S:2](=[O:4])(=[O:3])[NH:5][C:6]1=[O:7]
Reactant: Fc1cccc(Cl)c1CNc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: O=C1NS(=O)(=O)c2ccccc2N1Cc1c(F)cccc1Cl
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
A solution of chlorosulfonylisocyanate (5.04 mL, 57.9 mmol) in nitroethane (100 mL) was cooled to approximately −40° C. and a solution of N-(2-chloro-6-fluorobenzyl)aniline (10.5 g, 44.6 mmol) in nitroethane (80 mL) added dropwise over approximately 10 min. The mixture was stirred at −40° C. for 10 min, then rt for 1 h, before the addition of further chlorosulfonylisocyanate (1.94 mL, 22.3 mmol) and stirring for 30 min at rt. Aluminium chloride (8.32 g, 62.4 mmol) was added and the mixture heated at reflux for 30 min, before cooling to rt and cautious addition to stirred ice-H2O (approximately 300 mL). After stirring for 15 min, the title compound (11.8 g, 34.6 mmol) was isolated by filtration.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[CH:5]=[C:6]([N+:14]([O-])=O)[C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:8][CH:9]=1>>[NH2:14][C:6]1[C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:8][CH:9]=[C:4]([CH3:3])[CH:5]=1
Reactant: Cc1cnc(S(N)(=O)=O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cnc(S(N)(=O)=O)c(N)c1
Reaction time: 12 h

Procedure:
3.46 g of reduced iron and 0.53 g of ammonium chloride are added to a solution of 2.17 g of 5-methyl-3- nitropyridine-2-sulfonamide in 60 cm3 of water/alcohol (EtOH/H2O : 1/1) solution. The mixture is brought to reflux for 20 minutes and then filtered while hot. The filtrate is concentrated to a small volume and left at 4° C. for 12 hours. The crystalline precipitate obtained is collected on a filter, washed with water and dried.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CCO>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(C=O)cc3)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(CO)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-Butyl 1′-(4-formylphenyl)-4,4′-bipiperidine-1-carboxylate (72 mg; 0.193 mmol) in EtOH (1 mL) was treated with NaBH4 (8 mg; 0.213 mmol). The solution was stirred at ambient temperature for 1 hr. The reaction was partitioned between iPrOAc and water. The organic was dried over magnesium sulfate, filtered and evaporated to afford the title compound.
Reaction SMILES: [CH2:1]1[O:14][C:13]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)[O:2]1.[CH2:15]=O>CO>[CH3:15][N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:14][C:13]3=[CH:12][C:6]=2[CH2:7][CH2:8]1
Reactant: c1c2c(cc3c1OCO3)CCNCC2
Reactant: C=O
Solvent: CO
Product: CN1CCc2cc3c(cc2CC1)OCO3

Procedure:
19.1 g (0.1 M) of 2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine base was dissolved in 100 ml of methanol and 12 ml of 37% formaldehyde (0.148 moles) added thereto. In a few minutes, a new precipitate began to form with the evolution of heat. To this suspension 5 g of methanol-washed Raney nickel was added and the mixture shaken under 50 lbs. of hydrogen pressure. Uptake of hydrogen was complete in about an hour after which the excess hydrogen was vented, the catalyst removed by filtration, washed and the combined filtrates freed of solvent in the rotary evaporator. To remove the excess formaldehyde, the residue was dissolved in 100 ml of benzene, the solution washed four times with water, then dried, and the solvent distilled leaving a syrup. This was distilled from a small Claisen flask at reduced pressure, to yield three fractions. The fraction showing a boiling point of 166°-167°/mm contained the above-named product.
Reaction SMILES: N1CCCCC1.Br[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>CCCCC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: Brc1cccs1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCCCC
Solvent: O
Product: C[Si](C)(C)C#Cc1cccs1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a mixture of piperidine (10 mL, 93.9 mmol), 2-bromothiophene (3.21 g, 19.7 mmol), and (trimethylsilyl)acetylene (2.13 g, 21.7 mmol) was added Pd(PPh3)4 (0.03 g, 0.026 mmol), followed by CuI (0.01 g, 0.05 mmol) and PPh3 (0.015 g, 0.057 mmol). The reaction mixture was heated at the reflux temperature for 45 min., and was allowed to cool to room temperature. The resulting dark brown slurry was diluted with pentane (20 mL) and water (20 mL) and the aqueous layer was extracted with pentane (2×20 mL). The organic layers were washed with a saturated NH4Cl solution (4 mL) and a 3M HCl solution (4 mL), dried (MgSO4) and concentrated under reduced pressure to give 2-(2-thienyl)-1-trimethylsilylacetylene (2.79 g, 79%) as a reddish brown oil: GC-MS m/z (rel abundance) 180 (M+, 30%); 1H NMR (CDCl3) δ 0.15 (s, 9H), 6.79 (m, 1H), 7.15 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[C:13]([C:15](OCC)=[O:16])[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:16][CH2:15][C:13]1[N:14]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Temperature: 0 °C
Reaction time: 6 h
Yield: 40.5 %

Procedure:
To a stirred solution of ethyl 6-(bis(tert-butoxycarbonyl)amino)picolinate 77 (11.0 g, 33 mmol) in THF (120 mL) under nitrogen was added LiAlH4 (3.80 g, 100 mmol) in THF (60 mL) over a period of 30 min at 0° C. The reaction mixture was stirred at 0° C. for 6 h and carefully quenched by the addition of H2O (2.0 mL) and 10% NaOH solution (4.0 mL) at 0° C. The reaction mixture was filtered and the filtrate was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue purified by chromatography (1:1 petroleum ether:ethyl acetate) to afford 78 (3.0 g, 41% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]([F:12])([F:11])[F:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[C:4]([C:9]([F:12])([F:11])[F:10])=[N:5][CH:6]=[CH:7][CH:8]=2)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: FC(F)(F)c1ncccc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cccnc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of crude 3-(bromomethyl)-2-(trifluoromethyl)pyridine (0.684 g, 2.84 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (0.242 g, 1.70 mmol) in anhydrous ethanol (100 mL) at 0° C. was added triethylamine (1.14 g, 1.57 mL, 11.36 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated, and ether was added to the precipitated triethylamine hydrobromide salt. The solid was filtered and washed with ether several times. The solvent was evaporated to provide a crude residue, which was purified by Combiflash using 0-10% MeOH:dichloromethane. 6-methyl-2-({[2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrimidin-4-ol was obtained as a white solid (0.438 g, 51% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.14 (t, 3H), 2.21 (s, 3H), 2.61 (q, 2H), 4.35 (s, 2H), 6.00 (bs, 1H), 7.69 (s, 1H), 8.31 (s, 1H) 8.45 (s, 1H); M+ 301.5.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1)[CH2:6]2.Br[C:19]1[C:20](=[O:27])[N:21]([CH3:26])[CH:22]=[C:23]([Br:25])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:25][C:23]1[CH:24]=[C:19]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([N:5]3[CH2:6][CH:7]4[N:2]([CH3:1])[CH:3]([CH2:10][O:9][CH2:8]4)[CH2:4]3)=[CH:16][N:15]=2)[C:20](=[O:27])[N:21]([CH3:26])[CH:22]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CN1C2COCC1CN(c1ccc(N)nc1)C2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1C2COCC1CN(c1ccc(Nc3cc(Br)cn(C)c3=O)nc1)C2
Temperature: 105 °C
Reaction time: 8 h

Procedure:
To a solution of 112j (500 mg, 2.1 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (852 mg, 3.2 mmol) in dioxane (100 ml) was added Xantphos (58 mg, 0.1 mmol), Cs2CO3 (2.1g, 6.4 mmol) and Pd2(dba)3 (110 mg, 0.1 mmol). The reaction mixture was stirred at 105° C. overnight. The mixture was cooled to RT, filtered, concentrated, and the crude product was purified through a silica gel column eluting with MeOH:DCM=0 to 1:5 to 112k (500 mg, 46.4%). MS: [M+H]+: 421
Reaction SMILES: [O:1]([CH:5]([CH3:16])[CH2:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[N+:2]([O-:4])=[O:3].[NH2:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][SH:20]>>[C:21]([CH:18]1[CH2:19][S:20][CH:10]([C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][CH2:6][CH:5]([O:1][N+:2]([O-:4])=[O:3])[CH3:16])[NH:17]1)([OH:23])=[O:22]
Reactant: CC(COc1ccccc1C=O)O[N+](=O)[O-]
Reactant: N[C@@H](CS)C(=O)O
Product: CC(COc1ccccc1C1NC(C(=O)O)CS1)O[N+](=O)[O-]
Yield: 30 %

Procedure:
Prepared from 2-(2-nitroxypropoxy)benzaldehyde and cysteine as described in Example XVI. Yield: 30%. Empirical formula: C13H16N2O6S. Molecular weight: 328. Melting point: 127°-130° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][NH:9][C:10](=[O:29])[C@@H:11]([NH:21]C(OC(C)(C)C)=O)[CH2:12][O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1>O1CCOCC1>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10](=[O:29])[C@@H:11]([NH2:21])[CH2:12][O:13][CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(CNC(=O)[C@H](COCC2CCCCC2)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(CNC(=O)[C@@H](N)COCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under cooling with ice, a solution of 4N solution of hydrogen chloride in dioxane (12 ml) was added dropwise to the compound prepared in Example 2 (1180 mg). The solution was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated to give the title compound (920 mg) having the following physical data.
Reaction SMILES: C(OC([N:11]([C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.CCOCC.[BrH:28]>C(O)(=O)C>[BrH:28].[NH2:20][C@H:19]([C:18]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:22])[CH3:21]
Reactant: C[C@H](N)C(=O)N(C(=O)OCc1ccccc1)c1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: C[C@H](N)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
6 g (0.02 mol) of N-benzyloxycarbonyl-L-alanine anilide were dissolved in 30 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred for 1 hour at room temperature. 300 ml of dry ether were then added. An oil precipitated out and was allowed to settle. The solvents were decanted off and the oil was washed with two 150 ml portions of ether, dissolved in a small amount of methanol and an excess of ethyl acetate was added. The product crystallised out, there being obtained 4.0 g (81%) of L-alanine anilide hydrobromide of melting point 244°-247° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3](=O)[CH2:4][C:5]([C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)=O.[NH2:25][NH2:26]>C1(C)C=CC=CC=1>[CH3:21][S:18]([C:14]1[CH:13]=[C:12]([C:9]2[S:8][C:7]([C:5]3[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[NH:26][N:25]=3)=[CH:11][CH:10]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(C(=O)CC(=O)C(F)(F)F)s2)c1
Reactant: NN
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)[nH]n3)s2)c1
Temperature: 100 °C

Procedure:
Into a 100 mL flask was weighed 5.18 g (13.8 mmol) of 4,4,4-Trifluoro-1-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-butane-1,3-dione, 50 mL of toluene, and 450 μL (14.3 mmol) of hydrazine. The resulting solution was heated at 100° C. for 21 h. The reaction was then concentrated in vacuo and was partially purified by silica gel flash chromatography (Jones Flashmaster, 70 g SiO2, gradient elution from 100% hexanes to 20% ethyl acetate over 30 minutes. Appropriate fractions were combined, concentrated in vacuo, and were precipitated from ethyl acetate with hexanes to afford the intermediate 3-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-5-trifluoromethyl-1H-pyrazole as a faintly yellow, semi-crystalline solid, yield: 1.24 g (24%). 1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 7.86 (d, J=8 Hz, 2H), 7.62 (t, J=8 Hz, 1H), 7.45 (d, J=4 Hz, 1H), 7.39 (d, J=4 Hz, 1H), 6.70 (s, 1H), 3.12 (s, 3H); MS (ES): 373 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]([CH3:27])[C:13](=[O:26])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[C:7]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:6]=[CH:5][C:4]=2[N:3]=1.C([O-])(C)(C)C.[Na+].[CH3:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][NH2:51])=[CH:48][CH:47]=1>CN(C1C(C2[C-]=CC=CC=2)=CC=CC=1)C.C1[C@H]2CC(PC3[C@H]4C[C@H](CC4)C3)[C@H](C2)C1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][NH:51][C:2]2[C:11]3[N:12]([CH3:27])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:10]=3[C:9]3[CH:8]=[C:7]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:6]=[CH:5][C:4]=3[N:3]=2)=[CH:48][CH:47]=1
Reactant: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cnc5ccccc5c4)ccc3nc(Cl)c21
Reactant: COc1ccc(CN)cc1
Agent: Cl[Pd+]
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2nc3ccc(-c4cnc5ccccc5c4)cc3c3c2n(C)c(=O)n3-c2ccc(C(C)(C)C#N)cc2)cc1
Temperature: 100 °C

Procedure:
100 mg (0.198 mmol) of 2-[4-(4-chloro-3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile (Example 109b), 27 mg (0.278 mmol) sodium tert-butanolate, 11 mg (0.02 mmol) SK-CC01-A catalyst and 33 mg (0.238 mmol) 4-methoxybenzylamine in 0.4 ml degassed toluene under argon are heated at 100° C. for 22 h. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with CH2Cl2 (2×). The organic layers are washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and evaporated to provide the title compound as a crude brown solid. ES-MS: 605 (M+H)+; analytical HPLC: tret=3.29 minutes (Grad 1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[C:21]([CH3:25])[CH:22]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C#N)CC2)c(C)c1

Procedure:
Using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (399 mg) described in Preparation Example 187 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (275 mg) was obtained.