Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]([NH:13][CH:14]=[O:15])=[CH:11][CH:10]=[N:9]1)(=O)=O.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH:14]([N:13]1[C:12]2[N:8]([N:9]=[CH:10][CH:11]=2)[CH2:7][CH2:6]1)=[O:15]
Reactant: CS(=O)(=O)OCCn1nccc1NC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=CN1CCn2nccc21
Reaction time: 3 h
Yield: 107.3 %

Procedure:
To a solution of 1-(2-methylsulfonyloxyethyl)-5-formamidopyrazole (6.2 g) in N,N-dimethylformamide (60 ml) was added 62% sodium hydride (1.03 g) under ice-cooling. The mixture was stirred at the same condition for 3 hours. The reaction mixture was poured into ethyl acetate (300 ml) and the insoluble material was filtered off. The filtrate was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (100 g) using a mixture of diisopropyl ether and ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated in vacuo to give 1-formyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (3.91 g) as crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:28][CH2:27][CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Solvent: C1COCCO1
Product: COc1ccc(CCNc2nc(N)nc(-c3cccs3)c2C#N)cc1

Procedure:
From 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile and 2-(4-methoxyphenyl)ethylamine in dioxane. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:16])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>CN(C=O)C.CS(C)=O>[CH3:3][O:4][C:5](=[O:16])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:8]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COC(=O)Cc1cn(COCC[Si](C)(C)C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a suspension of sodium hydride (326 mg, 8.10 mmol) in DMF (13 mL) at 0° C. was added a solution of (1H-Indol-3-yl)-acetic acid methyl ester (1.0 g, 5.3 mmol) in DMSO (3 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 1 h. The reaction mixture was cooled back down to 0° C., and SEMCl (1.35 mL, 8.41 mmol) was added neat. The reaction mixture was stirred at 0° C. for 15 min and then at rt for 1 h. The reaction mixture was then partitioned between water (200 mL) and diethyl ether (200 mL) followed by further extraction of the water layer with ether (2×200 mL) and drying of the combined organic layers with Na2SO4. After removal of the solvent under reduced pressure, the crude material was purified by flash chromatography (EtOAc/hexanes) giving 1.1 g (70%) of [1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3yl]-acetic acid methyl ester. 1H NMR (400 MHz, CDCl3): 7.65 (d, J=7.8 Hz, 1H), 7.46 (d, J=8.1, 1H), 7.26 (m, 1H), 7.22 (m, 2H), 5.51 (s, 2H), 3.83 (s, 2H), 3.76 (s, 3H), 3.53 (t, J=7.9 Hz, 2H), 0.94 (t, J=7.9 Hz, 2H), 0.0 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: OC/C=C/c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (10.0 g, 39.2 mmol) in dichloromethane (151 mL) cooled to −78° C. was added a solution of diisobutylaluminum hydride (1.0 M in dichloromethane, 82 mL, 82 mmol) dropwise over 15 minutes time. The solution was then stirred for an additional 2 hours followed by the addition of a solution of 10% aqueous sodium hydroxide (250 mL). The mixture was allowed to warm to room temperature, and then the mixture was extracted with dichloromethane. The organic layer was dried and concentrated to afford 8.35 g (100%) of the title compound used directly in the next reaction.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][N:15]2[CH2:22][CH:21]3[O:23][CH:17]([CH2:18][NH:19][CH2:20]3)[CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH:38]([F:40])[F:39])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:39][CH:38]([F:40])[O:37][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][N:19]2[CH2:20][CH:21]3[O:23][CH:17]([CH2:16][N:15]([CH2:14][CH2:13][NH:12][S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:22]3)[CH2:18]2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]([F:36])[F:35]
Reactant: N#Cc1ccc(S(=O)(=O)NCCN2CC3CNCC(C2)O3)cc1
Reactant: FC(F)Oc1ccc(CCBr)cc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(S(=O)(=O)NCCN2CC3CN(CCc4ccc(OC(F)F)c(OC(F)F)c4)CC(C2)O3)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-cyano-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-benzenesulfonamide (0.3 g, 7.5 mmol; see Preparation E above), 4-(2-bromo-ethyl)-1,2-bis(difluoromethoxy)benzene (0.26 g, 9 mmol; see Preparation G above) and potassium carbonate (0.41 g, 30 mmol) was stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered and solvent was evaporated under reduced pressure. The residue was purified by column chromatography, using methanol in chloroform as eluent, to yield the title compound as a white solid. Yield: 0.23 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]CC=C)=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C1COCC1.N1CCOCC1.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>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(N2CCC(C(=O)OCC)CC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
To a solution of 4.74 g of 1-{4-[(allyloxy)carbonyl]phenyl}piperidine-4-carboxylic acid ethyl ester in 75 ml of THF, 2.10 ml of morpholine and 390 mg of tetrakis(triphenylphosphine)palladium were added, and the mixture was stirred at 60° C. for 1.5 hours. After the solvent was evaporated under reduced pressure, EtOAc was added to the residue, and the reaction solution was washed with NaHCO3 aq. three times. To the collected saturated NaHCO3 aq., conc. HCl was added, and the produced precipitate was collected by filtration and dried under reduced pressure to obtain 2.73 g of 4-[4-(Ethoxycarbonyl)piperidin-1-yl]benzoic acid.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:6][C@H:5]([CH:7]=O)[N:4]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:3]1=[O:21].COP([CH2:29][C:30](=[O:38])[CH:31]([CH3:37])[CH2:32][C:33]#[C:34][CH2:35][CH3:36])(=O)OC>>[F:1][C:2]1([F:22])[CH2:6][C@H:5](/[CH:7]=[CH:29]/[CH:30]([OH:38])[CH:31]([CH3:37])[CH2:32][C:33]#[C:34][CH2:35][CH3:36])[N:4]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:3]1=[O:21]
Reactant: COC(=O)c1ccc(CCN2C(=O)C(F)(F)C[C@@H]2C=O)cc1
Reactant: CCC#CCC(C)C(=O)CP(=O)(OC)OC
Product: CCC#CCC(C)C(O)/C=C/[C@H]1CC(F)(F)C(=O)N1CCc1ccc(C(=O)OC)cc1

Procedure:
Methyl 4-(2-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate was prepared by the method described in Example 1, Steps A and B, except that (R)-methyl 4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate (13b) was used instead of (R)-methyl 7-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl) heptanoate (13a) and (±)-dimethyl(3-methyl-2-oxooct-5-yn-1-yl)phosphonate (15bb(i)/15bc(i)) was used instead of (±)-dimethyl(3-methyl-2-oxohept-5-yn-1-yl)phosphonate (15ab(i)/15ac(i)) in Step A.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CN=3)=NOC=2C)=NC=1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Yield: 84.1 %

Procedure:
As described for example 283, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (53 mg, 0.16 mmol) was converted, instead of 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (42 mg, 83%) which was obtained as a white solid. MS: m/e=311.5 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[N:7][CH:8]=[C:9](Br)[CH:10]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[N:7][CH:8]=[C:9]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:10]=1
Reactant: COC(=O)Cc1cc(Br)cnc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Product: COC(=O)Cc1cc(N2CCN(C)CC2)cnc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of (5-Bromo-2-nitro-pyridin-3-yl)-acetic acid methyl ester (472 mg, 1.72 mmol) and N-methylpiperazine (344 mg, 3.44 mmol) is heated for 18 h under an argon atmosphere. TLC analysis indicated complete consumption of starting material. The reaction mixture is cooled to RT, diluted with water and adjusted to pH 8-9 with a saturated aq. NaHCO3 solution. The aqueous phase is extracted three times with methylene chloride and the combined organic layers are washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The crude product is purified by FCC (methylene chloride/MeOH 95:5 to 90:10) to afford the title compound as a yellow solid. 1H NMR (d6-DMSO 400 MHz): δ 2.01 (s, 3H), 2.22-2.26 (m, 4H), 3.24-3.28 (m, 4H), 3.40 (s, 3H), 3.81 (s, 2H), 7.26 (d, J=2 Hz, 1H), 7.97 (d, J=2 Hz, 1H). ES+−MS: 295.3 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][C:14]#[N:15])(=O)=O)=CC=1.Cl.[NH2:22][CH:23](C(OCC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25].[O-]CC.[Na+].Cl>C(O)C.O1CCCC1>[NH2:15][C:14]1[CH:13]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[NH:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OC(=CC#N)c2ccco2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1[nH]c(-c2ccco2)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.3 %

Procedure:
To a solution of 2-cyano-1-(2-furyl)vinyl 4-methylbenzenesulfonate (10.48 g) and diethyl aminomalonate hydrochloride (7.67 g) in a mixed solvent of ethanol (120 mL)-tetrahydrofuran (64 mL) was added dropwise a solution (36.9 mL) of 20% sodium ethoxide in ethanol under ice-cooling. After stirring at room temperature for 12 hrs, the reaction mixture was poured into ice water (350 mL) and adjusted to pH 7 with 1N hydrochloric acid. The organic solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (150 mL×3). The organic layers were combined, washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=3:1→1:1) and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (2.66 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[Br:10][C:11]1[CH:12]=[N:13][N:14]2[CH:19]=[C:18](Br)[CH:17]=[N:16][C:15]=12.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[N:13][N:14]2[CH:19]=[C:18]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:17]=[N:16][C:15]=12
Reactant: Brc1cnc2c(Br)cnn2c1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnn2cc(-c3cccnc3)cnc12
Temperature: 85 °C

Procedure:
A solution of 3-pyridyl boronic acid (1.33 g, 10.8 mmol) and 3,6-dibromopyrazolo[1,5-a]pyrimidine (3.0 g, 10.8 mmol) in DMF (300 mL) and 1M aqueous sodium bicarbonate (22 mL, 22 mmol) was degassed with nitrogen and treated with palladium tetrakistriphenylphosphine (0.63 g, 0.54 mmol) and heated to 85° C. for 16 hours. The reaction was cooled to room temperature and partitioned between water/methylene chloride. The organics were washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (1-5% methanol/methylene chloride) gave 3-bromo-6-pyridin-3-ylpyrazolo[1,5-a]pyrimidine. LC-MS EIMS: m/z 275.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[NH2:31].C(N(CC)C(C)C)(C)C>C1C=CC=CC=1.CN(C)C=O.ClCCl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:8]([NH:31][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][N:25]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cnccn1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2cnccn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.7 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (prepared as in Example 1, 106 mg, 0.41 mmol) in benzene (10 mL) was treated with oxalyl chloride (55 mg, 0.43 mmol), and N,N-dimethylformamide (1 drop). Effervescence was observed. The reaction mixture was stirred for 2 h at 25° C., under nitrogen. The reaction mixture was concentrated, and dissolved in dichloromethane (10 mL) and treated with pyrazin-2-ylamine (42 mg, 0.43 mmol), and N,N-diisopropylethylamine (161 mg, 1.23 mmol). The reaction mixture was stirred at 25° C., under nitrogen for 18 h. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 4 g; 0% to 10% methanol/dichloromethane) to afford (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-N-pyrazin-2-yl-propionamide (5 mg, 3%) as a white solid: LR-ES-MS m/z calculated for C17H22N4O3 [M]+ 330, observed [M+H]+ 331; 1H NMR (400 MHz, CDCl3) δ ppm 1.13-1.23 (m, 2H) 1.48-1.98 (m, 8H) 1.98-2.09 (m, 1H) 3.82 (s, 3H) 3.94 (d, J=17.5 Hz, 1H) 4.03 (d, J=17.5 Hz, 1H) 4.83 (dd, J=9.1, 6.5 Hz, 1H) 5.15 (s, 1H) 8.28 (dd, J=2.6, 1.5 Hz, 1H) 8.33 (d, J=2.6 Hz, 1H) 9.09 (s, 1H) 9.47 (d, J=1.5 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)=[O:4].N([O-])=[O:13].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:11][C:7]1[N:6]=[C:5]([C:3](=[O:4])[CH2:2][OH:13])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(Br)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CO)c1cccc(Br)n1
Reaction time: 14 h

Procedure:
To a solution of 2-bromo-1-(6-bromopyridin-2-yl)ethanone (500 mg, 1.79 mmol) in dimethylformamide (11.5 mL) was added sodium nitrite (124 mg, 1.79 mmol). After 14 hours, the reaction was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), water (2×100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound. 1H NMR (600 MHz, DMSO): δ 7.94 (m, 2H), 7.91 (m, 1H), 5.07 (t, J=5.9 Hz, 1H), 4.85 (d, J=5.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH2:18])C[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].N1CC(N(C)C(=O)OC(C)(C)C)C1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:13][CH:16]([CH2:15][NH2:18])[CH2:17]2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC1CCN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Agent: CN(C(=O)OC(C)(C)C)C1CNC1
Product: NCC1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)C1
Yield: 87 %

Procedure:
Intermediate 5 (65 mg, 0.22 mmol, 87% yield) was prepared as a white powder following the procedure described for Intermediate 4 by replacing tert-butyl piperidin-4-yl-methylcarbamate with tert-butyl azetidin-3-yl-methylcarbamate. LC-MS (ESI) m/z 295 (M+H)+, RT=1.47 min (Method B).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:40])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.2 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.147 mL, 0.147 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 52-(2); 25 mg, 0.049 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the mixture was stirred at room temperature for six hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (20.4 mg, 84%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([N+:46]([O-:48])=[O:47])[CH:39]=1.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([N:53]2[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]2)=[CH:39][C:40]=1[N+:46]([O-:48])=[O:47]
Reactant: CN1CCNCC1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 54.8 %

Procedure:
Pd(OAc)2 (85 mg, 0.38 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (225 mg, 0.57 mmol), K3PO4 (2.26 g, 10.68 mmol), 4-bromo-1-methoxy-2-nitro-benzene (1.77 g, 7.63 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. N-methylpiperazine (1.01 mL, 9.15 mmol) was added and the reaction mixture was refluxed for 72 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 1.05 g (55% yield) of the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=O)C.[CH2:17](Br)[CH2:18][CH2:19]C.[OH-].[K+].C(O)CCC>O.C(Cl)(Cl)Cl>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:17][CH2:18][CH3:19])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CCCCBr
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
5 G. of 1-acetamido-2-nitro-4-thiocyanatobenzene and 2.8 ml. of n-butyl bromide are added to a solution of 4.8 g. of potassium hydroxide in 70 ml. of n-butanol. The mixture is left overnight at room temperature, then diluted with water. 1-Amino-2-nitro-4-n-butylthiobenzene is isolated by extraction with chloroform.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22]>C(O)CC>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: CCCO
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
The title compound is prepared analogously to Example 2 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[(diethylamino)methyl]piperidine to give colorless crystals, Mp. 225°-225.5° C. (n-propanol).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11](C=CC(O)=O)[CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:2]=1.C1(C2C=CC(O)=CC=2)C=CC=CC=1.[H-].[Na+].[Br:41]C1C=C(C=CC=1)CBr>CN(C)C=O.O>[Br:41][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][O:7][C:4]1[CH:5]=[CH:6][C:1]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:2][CH:3]=1
Reactant: O=C(O)C=Cc1cccc(COc2ccc(-c3ccccc3)cc2)c1
Reactant: BrCc1cccc(Br)c1
Agent: Oc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(COc2ccc(-c3ccccc3)cc2)c1
Yield: 95 %

Procedure:
3-(3-(Biphenyl-4-yloxymethyl)phenyl)acrylic acid ##STR3## To a solution of 4-phenylphenol (6.13 g, 36 mmol) in dry N,N-dimethyl-formamide (100 ml) kept under an atmosphere of nitrogen, sodium hydride (1.73 g, 43.2 mmol, 60% dispersion in mineral oil) was added in portions and the reaction mixture was stirred until gas evolution ceased. 3-Bromobenzyl bromide (10.0 g, 39.61 mmol) was added in portions and the reaction mixture was stirred at room temperature for 18 h. To the reaction mixture water (50 ml) was added. The precipitate was filtered off and washed with water (3×100 ml), 96% ethanol (2×30 ml), diethyl ether (2×80 ml), and dried in vacuo at 50° C. for 18 h affording 11.64 g (95 %) of 4-(3-bromo-benzyloxy)biphenyl as a solid.