Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: OC1CCN(C2CNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(O)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.167 g, 0.43 mmol), 1-azetidin-3-ylpiperidin-4-ol (0.1 g, 0.64 mmol) and 4 Å molecular sieves (0.8 g) in DCE (8 mL) was stirred for 6 h at room temperature. Sodium triacetoxyborohydride (0.272 g, 1.28 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 5:95) to give 486 as a yellow solid (0.123 g, 55%). LCMS (Method I): RT=2.31 min, [M+H]+ 532.3. 1H NMR (400 MHz, DMSO-d): δ 8.03-7.99 (m, 1 H); 7.65-7.61 (m, 1 H); 7.27-7.20 (m, 2 H); 4.54 (d, J=4.0 Hz, 1 H); 4.29-4.22 (m, 4 H); 3.86 (s, 2 H); 3.82-3.73 (m, 7 H); 3.42 (t, J=6.5 Hz, 2 H); 3.30-3.27 (m, 3 H); 3.27 (q, J=7.4 Hz, 2 H); 2.96 (t, J=6.5 Hz, 2 H); 2.89-2.86 (m, 1 H); 1.88-1.85 (m, 2 H); 1.71-1.68 (m, 2 H); 1.39-1.35 (m, 2 H); 1.33 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]\[C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(/C=C\c2ccc(S(C)(=O)=O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(CCc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.8 %

Procedure:
To a solution of (3-{4-[(Z)-2-(4-Methanesulfonyl-phenyl)-vinyl]-phenyl}-isoxazol-4-yl)-carbamic acid tert-butyl ester (220 mg, 0.5 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.7 mL, 5 mmol) and 2-nitrobenzenesulfhydrazide (1.0 g, 4.6 mmol). The reaction mixture was stirred for 24 h at rt and then washed with satd NaHCO3 and dried over Na2SO4. Filtration was followed by removal of volatiles over silica gel followed by column chromatography to yield (3-{4-[2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-isoxazol-4-yl)-carbamic acid tert-butyl ester (88 mg, 40%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(S(C)(=O)=O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and (3-methylsulfonylphenyl)boronic acid (Combi-Blocks, San Diego, USA, 26 mg, 0.127 mmol) to give the title compound as a white solid. (HPLC: tR 2.45 min (Method A); M+H=448 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.19-8.11 (m, 2H), 8.02-7.97 (m, 1H), 7.95-7.86 (m, 3H), 7.80-7.74 (m, 1H), 7.64-7.60 (m, 1H), 3.93 (s, 3H), 3.59 (s, 3H), 3.33-3.30 (3H), 1.94 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=3)[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:13]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]4[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=4)[CH2:20][CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2-c2ccc(Cl)cc2)CC1
Temperature: 110 °C
Yield: 52.2 %

Procedure:
Add 4-chlorobenzeneboronic acid (64 mg, 0.41 mmol) to a mixture 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (104 mg, 0.34 mmol), potassium carbonate (113 mg, 0.82 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.002 g, 0.002 mmol) in N,N-dimethylacetamide (2 mL) and water (1 mL). Purge with nitrogen and heat overnight at 110° C. Cool to room temperature add water (10 mL), extract with DCM (3×20 mL) combine and purify using high pH reverse phase HPLC to give 3′-(4-chloro-phenyl)-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (68 mg, 54.2%). MS (ES): m/z=383 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33].[H-].[Na+].[CH3:38]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]([CH3:38])[S:32]([CH3:35])(=[O:33])=[O:34]
Reactant: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2N(C)S(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
To a solution of 1.4 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of DMF was added 229 mg of sodium hydride under ice-cooling, followed by stirring at the same temperature for 10 minutes, and then 0.17 ml of methyl iodide was added thereto, followed by stirring under ice-cooling for 30 minutes. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 545 mg of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[methyl(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colorless amorphous substance.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:12])[N:6]([CH3:11])[N:7]=2)[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][NH:24][C:23](=[O:27])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.N>CS(C)=O.[Cu]I>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:2]2[CH:10]=[CH:9][C:8]3[C:4](=[C:5]([CH3:12])[N:6]([CH3:11])[N:7]=3)[CH:3]=2)[C:23](=[O:27])[CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c2cc(Br)ccc2nn1C
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc2nn1C
Temperature: 150 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
A suspension of 5-bromo-2,3-dimethyl-2H-indazole (1.85 g), 4-(benzyloxy)pyridin-2(1H)-one (1.65 g), potassium carbonate (3.41 g), copper(I) iodide (1.57 g) and N,N′-dimethylethylenediamine (0.73 g) in DMSO (30 ml) was stirred at 150° C. for 3 hr. The reaction mixture was cooled to room temperature, and added to 28% aqueous ammonia, and the obtained precipitates were collected by filtration. The obtained solid was washed with water and diisopropyl ether, and dried under reduced pressure to give the title compound (1.85 g).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][S:13][C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[N:5]1)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([C:6]2[C:7]3[S:13][CH:12]=[CH:11][C:8]=3[C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(-c2nn(C(C)C)c(=O)c3ccsc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)n1nc(-c2ccc(O)cc2)c2sccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A solution of the product from step 2 (1.0 g, 3.3 mmol) in 25 mL of CH2Cl2 was cooled to 0° C. and BBr3 (1M in DCM, 16.7 mL) was added dropwise. The ice-bath was removed and the reaction was stirred at rt for 1 h. The reaction mixture was then poured into 50 mL of ice cold saturated NH4Cl solution with stirring. The resulting solid was collected, washed with water (3×15 mL), and Et2O (2×15 mL) to give the product of step 3 (868 mg, 92%): Mp 256-257° C.; MS m/z 287 (M+H).
Reaction SMILES: C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.[N+:24]([CH3:27])([O-:26])=[O:25].[CH2:28]([O:30][C:31](=[O:48])[CH:32]=[C:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH2:34]1)[CH3:29]>C1COCC1>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1([CH2:27][N+:24]([O-:26])=[O:25])[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH2:34]1)[CH3:29]
Reactant: CCOC(=O)C=C1CCC(CNC(=O)OC(C)(C)C)CC1
Reactant: C[N+](=O)[O-]
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
A sealable reaction tube was charged with 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.16 mL, 0.450 mmol) and THF (1.0 mL) under Argon. Nitromethane (0.23 mL, 4.24 mmol) was added and the reaction stirred at room temperature for 5 min then cooled to 0° C. for 15 min. [4-(tert-Butoxycarbonylamino-methyl)-cyclohexylidene]-acetic acid ethyl ester (0.261 g, 0.878 mmol) in THF (1.5 mL) was added slowly and the reaction stirred at RT for 15 min. The tube was sealed and the reaction heated at 70° C. for 17 hr. The reaction was cooled to room temperature, quenched with 0.5M HCl, and extracted with EtOAc (2×). The combined organic layers were washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated to provide 0.304 g of crude product which was carried to the next step without purification. ESI-MS m/z 359 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:24][C:25]([OH:27])=O)[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22].C[N:29]1CCOCC1.ClC(OCC(C)C)=O.N>O1CCCC1.O>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:24][C:25]([NH2:29])=[O:27])[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22]
Reactant: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(=O)O)c2c(Cl)nc(C)nc21
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(N)=O)c2c(Cl)nc(C)nc21
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
In 4 ml of tetrahydrofuran, 0.47 g of 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetic acid was dissolved. After the reaction mixture was cooled to −15° C., 0.14 g of N-methylmorpholine and 0.19 g of isobutyl chloroformate was added thereto. After the reaction solution was stirred for 5 minutes, 0.085 ml of 28% aqueous ammonia was added thereto. The reaction mixture was warmed up to room temperature and was subsequently stirred overnight. Water was poured into the reaction mixture. The reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform—methanol=50:1) to yield 0.41 g of 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetamide as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1)[NH2:6].CCN([CH:34]([CH3:36])[CH3:35])C(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:21])([F:22])[F:23])=[CH:12][CH:13]=1)[NH:6][C:15]([C:14]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:36]=1[CH2:34][CH3:35])=[O:26]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(C)c1C(=O)N[C@@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)C(=O)OC
Reaction time: 72 h
Yield: 122.8 %

Procedure:
A mixture of the above prepared acid chloride, 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-phenylalanine methyl ester hydrochloride (100 mg, 0.25 mmol) in dichloromethane (5 mL) was treated with DIPEA (0.17 mL, 1.0 mmol) and the resulting light brown solution was stirred for 3 days. The mixture was concentrated, diluted with ethyl acetate, washed with 1 N HCl and brine solution and was dried over magnesium sulfate. Filtration and evaporation afforded a residue, which was purified by silica gel chromatography using a Biotage column (40s) to give N-[(2-ethyl-6-methylphenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester as a white foam (79 mg, 62%). ES-HRMS m/e calcd for C28H29F3NO4 (M+Na) 537.1974, found 537.1972.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH2:14])=[O:13])[C:5](SC)=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>[Ni].C(O)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH2:14])=[O:13])[CH:5]=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]
Reactant: CSc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(N)=O)ccc1C
Agent: [Ni]
Solvent: CCO
Product: Cc1ccc(C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reaction time: 12 h
Yield: 56 %

Procedure:
A mixture of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzamide (0.15 g, 0.00033 mol from step 5), and Raney nickel (0.8 mL, 50% slurry in water) in ethanol (15.0 mL) was refluxed under argon atmosphere. After 12 h, added an additional 0.4 mL of Raney nickel and continued refluxing for another 4 h. The reaction mixture was cooled and the supernatant was decanted off. The catalyst was washed with ethanol, the combined ethanol washings and the supernatant were concentrated under reduced pressure and the resulting residue was purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=406) were combined and concentrated to a small volume (˜20 mL), cooled added 5% sod. bicarbonate (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated to dryness to afford the title compound (0.075 g,) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.31 (s, 1H), 7.94 (dd, 1H. J=2.0 Hz & 8.0 Hz), 7.79 (d, 1H, J=2.0 Hz), 7.62 (m, 1H), 7.53 (m, 1H), 7.02 (m, 2H), 5.59 (m, 2H), and 2.19 (s, 3H); ES-HRMS m/z 406.0774 (M+H calcd for C19H15N3O3F2Cl requires 406.0765); 19F NMR(CD3OD/400 MHz) −111.62 (m) and −115.94 (m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([O:43]C)=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1>[OH-].[Na+].C1COCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([OH:43])=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of compound 6 (37 g) in NaOH (1N, 150 ml), THF (500 ml) and water (500 ml) was stirred at room temperature overnight. The organic solvent was evaporated. The aqueous concentrate was washed with DCM and acidified with HCl (1N, 150 ml). The solvent was evaporated. The residue was stirred in water, filtered off and dried, yielding 32 g (84%) of 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylic acid (compound 7, mp. 174.2° C.).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[Br:13][CH2:14][C:15]1C=CC(C#N)=[CH:17][CH:16]=1.CC(C[AlH]CC(C)C)C.Cl>CCOC(C)=O.CCCCCC.C1COCC1>[Br:13][CH2:14][C:15]1[CH:3]=[CH:2][C:1]([CH:5]=[O:4])=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1ccc(CBr)cc1
Reaction time: 1.5 h

Procedure:
To a THF-toluene (2.4 L-0.24 L) solution of α-bromo-p-tolunitrile (266.4 g, 1.36 mol) maintained at an internal temperature bellow 0° C. was added DIBAL in hexane (1.0 M) (1.49 L, 1.49 mol) over a period of 2 h. After a period of 1.5 h, the reaction mixture was transferred via canula to a 3N HCl solution (8 L) at 0° C. To the resulting suspension EtOAc (4 L) and THF (0.8 L) were added. After stirring, the organic phase was separated and evaporated to give a yellow solid. The solid was stirred in 20% EtOAc in hexane (1.3 L) for 3 hours. After filtration and drying the title compound was obtained. (210 g).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH2:11][C:12](=[O:14])[CH3:13])[CH:10]=1)(=O)C.[OH-].[Na+].Cl>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:15]#[C:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([CH2:11][C:12](=[O:14])[CH3:13])[CH:10]=1
Reactant: CC(=O)Cc1cc(OC(C)=O)ccc1C#Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Cc1cc(O)ccc1C#Cc1ccccc1
Reaction time: 1 h
Yield: 101 %

Procedure:
1-[5-Acetoxy-2-(phenylethynyl)phenyl]-2-propanone (3.3 g, 11 mmole) was dissolved in MeOH (15 mL) and treated with 50% sodium hydroxide solution (1.8 g, 22 mmole) under argon. The reaction was stirred for 1 hr then poured into dilute hydrochloric acid and extracted with diethyl ether. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was dried under vacuum to yield 2.78 g (98%) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH2:4].[C:5]([NH:8][C:9]1[C:10](=[O:23])[C:11]2[C:16]([C:17](=[O:22])[C:18]=1NCC)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=O)[CH3:6]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]1[C:18]2[C:17](=[O:22])[C:16]3[C:11]([C:10](=[O:23])[C:9]=2[N:8]=[C:5]1[CH3:6])=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: NCCCl
Reactant: CCNC1=C(NC(C)=O)C(=O)c2ccccc2C1=O
Solvent: O=CO
Product: Cc1nc2c(n1CCCl)C(=O)c1ccccc1C2=O

Procedure:
A solution of 43 (5 g, 0.02 mol, prepared from 2a and 2-chloroethylamine in an analogous manner to that of 29 below) in formic acid (50 ml) was refluxed for 1 h, and then concentrated. Purification by column chromatography (CHCl3, silica gel), followed by recrystallization from benzene, afforded 21 as yellow crystals. Yield, mp, and spectral data are given in Table 3.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].C[N:17](C)C1C=CC=CC=1>>[NH2:17][C:9]1[C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN(C)c1ccccc1
Reactant: c1ccc(Sc2cccnc2)cc1
Agent: [NH2-]
Agent: [Na+]
Product: Nc1ncccc1Sc1ccccc1

Procedure:
A mixture of 59.1 g. (0.316 mole) of 3-phenylthiopyridine, 14.7 g. (0.318 mole) of sodium amide and 84 gms. of dimethyl aniline is heated at 150°-160° C. for 6 hours. After dilution with 100 ml. of water, the reaction mixture is extracted with chloroform. The combined extracts are washed with water and dried. Evaporation of the solvent in vacuo yields an oily residue. The residue is triturated with three 100 ml. portions of petroleum ether yielding 17 gm. of crude insoluble product. Proton magnetic resonance spectroscopy indicates the material is a 50/50 mixture of 2- and 6-amino derivatives. The isomers are separated on silica gel eluted with 10% ethylacetate 90% methylene chloride affording pure 2-amino 3-(phenylthio) pyridine, m.p. 108°-109° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: ClCCCCBr
Reactant: COc1cccc(O)c1
Product: COc1cccc(OCCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-methoxyphenol and 1-bromo-4-chlorobutane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Reactant: O=C(Cl)c1cccnc1
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2cccnc2)cc1OC

Procedure:
The preparation took place in analogy with Example 15a), starting with 200 mg of 5-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (44) and 168 mg of nicotinoyl chloride*HCl. The following was obtained: 57.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=O)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([N:23]2[C:12](=[O:14])[CH:10]([CH2:9][S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:11][C:24]2=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: S=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1C(CSCc2ccccc2)NC(=S)N1c1ccccc1

Procedure:
When approximately equimolar amounts of S-benzylcysteine, sodium hydroxide, and phenylisothiocyanate was reacted according to the procedure described for the preparation of the compound of Example 2, the title compound herein was obtained.