Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH2:18].[Cl-].[NH4+].[OH-].[NH4+].[CH3:23][N:24](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:18][C:3]1[CH:4]=[C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[N:7][C:2]=1[C:23]#[N:24]
Reactant: Nc1cc(-c2ncccc2C(F)(F)F)cnc1Cl
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1ncc(-c2ncccc2C(F)(F)F)cc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Heat a solution of 6′-chloro-3-trifluoromethyl-[2,3′]bipyridinyl-5′-ylamine (25 g, 0.091 mol; prepared essentially as described in PCT International Application Publication Number WO 03/062209, published on Jul. 31, 2003), zinc cyanide (6.75 g, 0.058 mol), pd2(dba)3 (2.63 g, 2.86 mmol), DPPF (3.16 g, 5.72 mmol) in DMF (250 mL) and water (2.5 mL), under a nitrogen atmosphere, at 120° C. for 1 hour. Cool the reaction to 0° C. and add a solution of saturated ammonium chloride (200 ml), water (200 mL) and concentrated ammonium hydroxide (50 mL). After stirring at 0° C. for 1 hour, filter the yellow precipitate, and wash with water (200 mL) and a 1:1 mixture of ether-hexane (200 mL). Dry the solid in air and then in a vacuum oven to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28]Br)=[CH:23][N:22]=1.[BH4-].[Na+].C(CN)O>C(#N)C.C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:19][CH2:28][CH:27]([OH:30])[C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[N:22][CH:23]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(CBr)c1ccc(Cl)nc1
Reactant: COc1ccc(C(N)Cc2ccccc2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCO
Product: COc1ccc(C(Cc2ccccc2)NCC(O)c2ccc(Cl)nc2)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of α-(3,4-dimethoxyphenyl)-benzenee-thanamine (see Washburn et al., EP 0 659 737 A2 for the preparation of this compound) (257 mg, 1 mmol, 2 eq) in anhydrous acetonitrile (10 mL) is added a solution of 2-chloro-5-(2-bromoacetyl)pyridine (prepared as described in Example 3) (111 mg, 0.5 mmol) at 0° C. under a nitrogen atmosphere. The mixture is allowed to warm to room temperature and stirred for 1 h. To this mixture is added a solution of sodium borohydride (110 mg, 2.9 mmol, 5.8 eq) in abs. ethanol at room temperature. After one hour, the excess sodium borohydride is quenched with 1N HCl to pH 4.0 and then ethanol amine (0.28 mL, 4.5 mmol, 8 eq) is added. After stirring for 10 minutes, the mixture is diluted with ethyl acetate (30 mL). The organic layer is washed with brine, dried over anhydrous sodium sulfate and then concentrated. Purification by silica column gives the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1>>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a flask containing an ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (0.423 g, 1.922 mmol) in 2Me-THF (7.04 ml) was added lithium bis(trimethylsilyl)amide (2.014 ml, 2.014 mmol) dropwise over 10 min. The mixture was stirred for 15 min prior to the addition of a solution of perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see Example 73, Step 1) (0.750 g, 1.831 mmol) in 2Me-THF (3.5 ml). After 1 hr of stirring (ice melt) LC-MS indicated about 65% conversion to product with starting ester and amine present. The mixture was re-cooled to 0° C. and additional LiHMDS (0.5 eq) was added. The mixture was allowed to stir and slowly warm to room temperature overnight. LC-MS indicated about 90% conversion to desired product. The reaction was quenched by the addition of acetic acid (˜2 ml) and the resulting mixture (some precipitate formation) was dried under reduced pressure and purified with a 40 g silicycle HP column ramping EtOAc in heptane (0 to 50%) providing product 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (0.530 g, 1.188 mmol, 64.9% yield) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.71 (s, 3H) 5.11 (s, 2H) 6.69-6.76 (m, 2H) 7.04 (d, J=3.62 Hz, 1H) 7.26-7.33 (m, 2H) 7.42 (d, J=3.62 Hz, 1H) 7.59-7.64 (m, 1H) 7.85 (dd, J=8.95, 1.81 Hz, 1H) 8.21 (d, J=1.76 Hz, 1H) 8.33-8.41 (m, 2H). m/z (ESI) 446.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH:15]3[O:19]CCO3)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:20].[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=[O:19])[C:9]=3[CH2:8][CH2:7][C:6]2=[O:20])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc2c1CCC(=O)N2CCCN1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
1-(3-Bromopropyl)-5-(1,3-dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (790 mg, 2.32 mmol), 4-benzylpiperidine (0.49 ml, 2.79 mmol) and potassium carbonate (142 mg, 1.03 mmol) were added to acetonitrile (15 ml), followed by heating under reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered to remove the insoluble matter. The solid was washed with acetonitrile, and the filtrate and washing were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→ethyl acetate:methanol=50:1). The purified product was concentrated under reduced pressure, and the residue was dissolved in acetone (15 ml). p-Toluenesulfonic acid monohydrate (368 mg) was added, and the resulting mixture was heated under reflux for 2 hours. An aqueous solution of potassium carbonate was added to the reaction mixture, followed by concentration under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain 672 mg (yield: quantitative) of 1-[3-(4-benzylpiperidin-1-yl)propyl]-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([N:12]1[CH2:19][C:18]2[C:14](=[N:15][NH:16][C:17]=2[NH:20][C:21](=[O:31])[C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[C:13]1([CH3:33])[CH3:32])=[O:11].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([N:12]1[CH2:19][C:18]2[C:17]([NH:20][C:21](=[O:31])[C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:41][CH:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)=[O:28])=[CH:29][CH:30]=3)=[N:16][NH:15][C:14]=2[C:13]1([CH3:32])[CH3:33])=[O:11]
Reactant: CC1(C)c2n[nH]c(NC(=O)c3ccc(C(=O)O)cc3)c2CN1C(=O)Nc1c(Cl)cccc1Cl
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CN1CCC(NC(=O)c2ccc(C(=O)Nc3n[nH]c4c3CN(C(=O)Nc3c(Cl)cccc3Cl)C4(C)C)cc2)CC1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of N-[5-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-terephthalamic acid (0.11 g, 0.22 mmol) N,N-diispropylethylamine (0.12 mL, 0.66 mmol) 1-Methyl-piperidin-4-ylamine (0.04 g, 0.34 mmol) in dry CH2Cl2 (20 mL), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.11 g, 0.34 mmol) was added. The reaction was stirred at room temperature over night, the solvent removed under reduced pressure, the residue dissolved in CH2Cl2 (40 mL) and washed with water (1×20 mL) then with saturated sodium hydrogencarbonate aqueous solution (1×20 mL). The organic phase was dried over sodium sulphate, the solvent evaporated in vacuo and the crude product purified by flash chromatography (CH2Cl2/MeOH/NH3 90/10/1) to afford 0.07 g (yield 55%) of the title compound.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:20])[C@H:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH2:8])[CH3:4].[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:20])[C@H:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8][C:30](=[O:31])[CH2:29][NH:28][C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH3:4]
Reactant: CCOC(=O)[C@@H](N)Cc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1cnc2ccccc2c1)NC(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a mixture of 0.637 g (2 mmol) of 3-(3-quinolyl)alanine ethyl ester dihydrochloride, 0.35 g (2 mmol) of N-(tert-butoxycarbonyl)glycine, 0.56 mL (4 mmol) of triethylamine and 16 mL of chloroform was added at 0° C., in one portion, 0.42 g (2 mmol) of dicyclohexylcarbodiimide. The reaction mixture was stirred overnight and the precipitate which formed was removed by filtration. The filtrate was washed twice with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel, using first 1:1 methylene chloride/ethyl acetate and then 1:3 methylene chloride/ethyl acetate as eluents, to give 0.73 g (9.9%) of the title compound as a colorless oil. TLC Rf =0.52 (ethyl acetate); NMR (CDCl3) δ 8.64 (1H, d), 7.9-8.1 (2H, m), 7.9-7.4 (4H, m), 7.1 (1H, bd), 5.46 (1H, bt), 4.9 (1H, m), 4.15 (2H, q), 3.8 (2H, bd), 3.3 (2H, m), 1.37 (9H, s), 1.2 (3H, t). The product has the formula: ##STR118##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[CH2:21](Br)[C:22]#[CH:23].O>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[CH2:23]([O:16][N:15]=[CH:14][C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:11][C:5]1[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1)[C:22]#[CH:21]
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCON=Cc1ccccc1Oc1nc(OC)cc(OC)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 7.1 g of propargyl bromide were dissolved in 100 ml of N,N-dimethylformamide containing 1.4 g of potassium carbonate, and the solution was stirred at 100° C. for 4 hours. After the reaction mixture was allowed to cool down, it was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate=10:1) to obtain 4.8 g of O-(2-propynyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as an oily substance.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[F:37][CH:38]([F:62])[O:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][N:44]=[C:43]2[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.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>[C:33]([NH:32][C:30]([C:8]1[C:6]2=[N:7][C:2]([C:43]3[C:42]4[C:46](=[CH:47][CH:48]=[C:40]([O:39][CH:38]([F:37])[F:62])[CH:41]=4)[NH:45][N:44]=3)=[CH:3][N:4]=[C:5]2[N:10]([C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:9]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
In a round-bottomed flask, 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (530 mg, 1 mmol) and 5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole (470 mg, 1 mmol) were dissolved in DMF (10 mL) under nitrogen. Pd(PPh3)4 (58 mg, 0.05 mmol) and CuI (38 mg, 0.2 mmol) were added and mixture sonicated for 5 min while bubbling nitrogen. The reaction mixture was stirred at 80° C. for 4 hours. The concentrated mixture was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (3:1 to 1:1, v/v) to give N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (410 mg, 64%) as a solid. MS: (M+H)+=643.2; 1H NMR (300 MHz, CDCl3): δ 8.85 (d, 1H, J=2.4 Hz), 8.35 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H,), 7.52-7.48 (m, 1H), 6.51 (t, 1H, J=74.0 Hz), 1.60 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Yield: 77.9 %

Procedure:
Using general procedure A, 4-chloroaniline (640 mg, 5.0 mmol) and 1-Boc-4-piperidone (1.0 g, 5.0 mmol) afforded 4-(4-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.21 g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.Br[CH:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:3]([O:11][CH:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: COC(=O)c1scc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1scc(Br)c1OC(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (1.42 g), tert-butyl 2-bromopropanoate (1.2 mL), potassium carbonate (2.45 g) and DMF (30 mL) was stirred at 50° C. for 2 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the title compound (2.16 g, 99%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:30])=[C:9](/[CH2:28][CH3:29])\[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:30])=[C:9](/[CH2:28][CH3:29])\[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C(CC)=C(/C)c2ccc(Br)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C(CC)=C(/C)c2ccc(Br)cc2)cc1)C(=O)O
Yield: 94.8 %

Procedure:
The title compound was prepared from (Z)-(S)-ethyl 3-{4-[3-(4-bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (Example 98) (475 mg, 1.0 mmol) and sodium hydroxide (1M, 2.0 ml, 2.0 mmol) by a procedure analogous to that described in example 51, yielding (Z)-(S)-3-{4-[3-(4-bromophenyl)-2-ethyl-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid (0.424 g, 95%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([O:16][CH3:17])=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].C[O-].[Na+].[CH:24](OCC)=O.Cl>COCCOC.O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:18]([OH:20])=[CH:19][CH:24]=[N:1]2)=[CH:4][C:5]=1[O:16][CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC=O
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 1-(2-Amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (108 mmol, 29.3 g) in DME (700 ml) was added sodium methoxide (432 mmol, 23.35 g). The mixture was stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was added and the mixture was stirred overnight. (Additional sodium methoxide may be needed if reaction is not complete as monitored by LC/MS.) After the reaction was completion, the mixture was diluted with water (40 ml) and acidified to neutral with 1M HCl. The precipitate was filtered and washed with water, dried in vacuo to afford 22 g (72%) of 7-benzyloxy-6-methoxy-quinolin-4-ol. 1H NMR (CDCl3): 10.7 (1H, br), 7.703 (1H, s), 7.493-7.461 (1H, t), 7.431-7.413 (2H, br d), 7.372-7.333 (2H, t), 7.296-7.283 (1H, d), 6.839 (1H, s), 6.212-6.193 (1H, d), 5.212 (2H, s), 3.965 (3H, s). LC/MS (M+1=282).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)=[O:4].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(O)CCC>[C:24]1([C@H:22]([NH:21][C:20]2[C:15]3[CH:14]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:8][CH:9]=4)[NH:30][C:16]=3[N:17]=[CH:18][N:19]=2)[CH3:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C1CCNCC1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCl)cc3)cc12)c1ccccc1
Solvent: CCCCO
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CN4CCCCC4)cc3)cc12)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 80 mg (0.19 mmol) 2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide in 1.5 ml n-butanol is treated with 47 μl (0.48 mmol) piperidine and then heated to 100° C. for 2 h. The clear solution is cooled and the solvent evaporated. The residue is purified with flash chromatography using a mixture of ethyl acetate/methanol with increasing concentrations of methanol starting with 100:2.5 and ending with 10:1. The title compound is obtained as a colorless powder; m.p. 194-196° C.; MS-ES+: (M+H)+=469.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1>CN(C=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:20][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: NC1CCOCC1
Solvent: CN(C)C=O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NC1CCOCC1
Yield: 81.8 %

Procedure:
A mixture of 5.1 g of 2-fluoro-5-nitrobenzoic acid and 6.21 g of tetrahydro-2H-pyran-4-amine in 5 ml of DMF is irradiated in a microwave field for 15 minutes at 100° C. The mixture is irradiated a second time for 15 minutes at 100° C. The same reaction is repeated on identical amounts of reagents. All the reaction mixtures are pooled and the solvent is evaporated off under reduced pressure. The residue is recrystallized from EtOAc to give 6 g of expected product.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([CH3:24])[N:6]=1)=[O:4].[NH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:16]([N:12]1[C:13]2[C:8](=[C:7]([CH3:24])[N:6]=[C:5]([C:3]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(C)c2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCCC(=O)O)c(O)c2c1ccc(=O)n2Cc1ccccc1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-5-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (18 mg, 0.056 mmol), β-alanine (494 mg, 5.6 mmol) and NaOMe solution (8.9 mL, 4.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., mixture was concentrated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 11.4 mg of the title compound. MS: (+) m/z 382.28 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])(=[O:14])=[O:13].COC(=O)[C@@H](NC(=O)C1C=CC=C(S(Cl)(=O)=O)C=1)CCS(C)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:18]([C:17]1[CH:16]=[C:15]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: COC(=O)[C@H](CCS(C)(=O)=O)NC(=O)c1cccc(S(=O)(=O)Cl)c1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1cccc(S(=O)(=O)Cl)c1
Yield: 28 %

Procedure:
Starting material (17(c)) was prepared as follows. 3,4-Dichlorobenzylamine was coupled with 3-Chlorosulphonylbenzoyl chloride (analogously as for compound (15(a)) in Example 15) to give 3-(3,4-dichloro-benzylcarbamoyl)-benzene-sulfonyl-chloride (17(a)) in 28% yield.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19]([O:20]C)=[N:18][S:17](=[O:23])(=[O:22])[N:16]=2)[N:9]=1)[CH3:3].[OH-].[Na+]>>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19]([OH:20])=[N:18][S:17](=[O:22])(=[O:23])[N:16]=2)[N:9]=1)[CH3:1]
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)Cc1nc(CSCCNC2=NS(=O)(=O)N=C2O)cs1

Procedure:
When a solution of 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide [prepared according to the procedure described in Example 33, Step F] is reacted with sodium hydroxide according to the procedure described in Example 17, Step B, the title compound is produced.