Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[NH2:3][C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][CH2:12][C:13]([O:15]CC)=O.[OH-].[Na+].Cl>>[Br:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:3][C:13](=[O:15])[CH:12]=[N:11]2
Reactant: CCOC(=O)CNc1cccc(Br)c1N
Agent: Cl
Agent: OO
Agent: [Na+]
Product: O=c1cnc2cccc(Br)c2[nH]1
Temperature: 95 °C
Yield: 38 %

Procedure:
30% H2O2 (14.27 ml, 466 mmol) was added to a mixture of ethyl 2-((2-amino-3-bromophenyl)amino)acetate (12.72 g, 46.6 mmol) in 1 N aq. NaOH (58.2 ml, 58.2 mmol) before it was heated to 95° C. for 2 h in a sealed tube behind a blast shield. After cooling the reaction, 1 N HCl (58 ml) was added, and the precipitated solid was filtered, washed with water, and dried in a vacuum oven (50° C., over the 3 d) to give 8-bromoquinoxalin-2(1H)-one (210d, 38% yield over two steps) as a brown solid. MS (ESI, pos. ion) m/z: 225.0/227.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.B1(C=C)OB([CH:17]=[CH2:18])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CC(=O)OCC.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>[Cl:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([CH:17]=[CH2:18])=[N:3][CH:4]=1
Reactant: COc1cc(Cl)ncc1Cl
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C=Cc1cc(OC)c(Cl)cn1
Temperature: 80 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
To a solution of 2,5-dichloro-4-methoxy-pyridine (730 mg, 4.10 mmol) in DME (16 mL), 2,4,6-trivinylcyclotriboroxane pyridine complex (987 mg, 4.10 mmol) followed by 2 M aq. K2CO3 solution (4 mL) is added. The solution is degassed and put under argon before Pd(PPh3)4 (95 mg, 82 μmol) is added. The mixture is stirred for 18 h at 80° C. The mixture is cooled to rt, diluted with EA (200 mL) and washed with water and sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The remaining brown residue is purified by CC on silica gel eluting with heptane:EA 9:1 to give 5-chloro-4-methoxy-2-vinyl-pyridine (402 mg) as a pale yellow oil; LC-MS: tR=0.53 min, [M+1]+=169.98; 1H NMR (CDCl3): δ 3.98 (s, 3H), 5.52 (d, J=10.5 Hz, 1H), 6.20 (d, J=17.3 Hz, 1H), 6.76 (dd, J=17.3, 10.8 Hz, 1H), 6.88 (s, 1H), 8.41 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]2[N:6]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cc1ccc(-n2c(CC)nc3cc(Cl)c(Cl)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CC(=O)O)cc1
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a stirred solution of ethyl [4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetate (step 3, 1.30 g, 3.4 mmol) in methanol was added 2N aqueous NaOH (3.4 mL) at room temperature. After 1 h, the mixture was concentrated and the residue was diluted in water (200 mL) and the mixture was washed with diethyl ether (100 mL). The aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate/THF (v/v, 1:1, 300 mL). The organic extract was washed with water (200 mL), brine (200 mL), and dried (MgSO4). Removal of solvent gave 1.02 g (86%) of the title compound as a white powder: 1H-NMR (CDCl3) δ 7.94 (1H, s), 7.56-7.45 (4H, m), 7.26 (1H, s), 3.72 (2H, s), 2.72 (2H, q, J=7.3 Hz), 1.22 (3H, t, J=7.5 Hz).
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][C:4]1[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:6]([CH3:12])=[CH:7][C:8]=1[C:9](Cl)=[O:10]>C1COCC1>[CH3:3][C:4]1[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:6]([CH3:12])=[CH:7][C:8]=1[C:9]([NH2:2])=[O:10]
Reactant: Cc1cc(C(=O)Cl)c(C)n1-c1ccccc1C(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)c(C)n1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To conc ammonium hydroxide (28%, 9.8 mL, 70 mmol) at 0° C. was added cautiously a solution of 2,5-dimethyl-1-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carbonyl chloride (2.1 g, 7.0 mmol) in THF (10 mL). After 10 min the reaction mixture was removed from the ice-bath and allowed to stir at ambient temperature. After 1 h the mixture was added to satd NH4Cl (30 mL) and extracted with DCM (3×30 mL). The combined extracts were washed with water (2×50 mL) and brine (50 mL), dried (anhyd Na2SO4) and concentrated under reduced pressure to afford the title compound (1.9 g, 96%) as a pale brown solid, which was used without purification in the next step. 1H-NMR (DMSO-d6) δ 7.98 (1H, d, J=7.8), 7.88 (1H, app t, J=7.8), 7.78 (1H, app t, J=7.8), 7.44 (1H, d, J=7.8), 7.17 (1H, br s), 6.66 (1H, br s), 6.35 (1H, s), 2.07 (3H, s), 1.81 (3H, s).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:47])[NH:6][C:7]2[CH:45]=[CH:44][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH:35]6[CH2:38][N:37]([C:39](=[O:43])[NH:40][CH2:41][CH3:42])[CH2:36]6)[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:46])[CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:4][C:5](=[O:47])[NH:6][C:7]2[CH:45]=[CH:44][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH:35]6[CH2:36][N:37]([C:39](=[O:43])[NH:40][CH2:41][CH3:42])[CH2:38]6)[CH2:29][C:30]([OH:32])=[O:31])=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:46])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CCNC(=O)N1CC(N(CC(=O)OCC)Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)N1CC(N(CC(=O)O)Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 433 (78 mg, 0.118 mmol) in MeOH (3 mL) was added 1N NaOH (0.59 mL, 0.59 mmol) and stirred at RT for 3 h. The mixture was then concentrated, diluted with water and the pH was adjusted to 6-7 by addition of 1N HCl. To the resulting suspension was added MeOH to dissolve the mixture clearly, and purified via Biotage [KP-C18-HS 30 g, gradient 20-95% (methanol/water)]. Title compound 434 was obtained as a white solid (79.5 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.94 (brs, 1H), 8.71 (s, 1H), 8.62-8.57 (m, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.19 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0, 2.0 Hz, 1H), 7.82 (dd, J=14.0, 2.4 Hz, 1H), 7.20 (t, J=9.2 Hz, 1H), 7.09-7.05 (m, 1H), 6.42 (d, J=4.8 Hz, 1H), 6.22 (t, J=5.6 Hz, 1H), 3.84-3.72 (m, 5H), 3.63-3.58 (m, 2H), 3.01-2.94 (m, 2H), 2.86 (s, 2H), 2.59-2.50 (m, 1H), 0.97 (t, J=7.2 Hz, 3H), 0.61-0.56 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 634.60 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].Cl>CO.O1CCCC1.[OH-].[Na+].O>[NH2:21][C:17]1[CH:16]=[C:15]([CH:12]2[C:11]([CH3:23])([CH3:22])[CH2:10][C:9]3[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([Cl:24])[CH:8]=3)[NH:13]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
A mixture of 2-(3-amino-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.8 g, 2.3 mmol) in methanol (50 mL) and tetrahydrofuran (100 mL), 30% sodium hydroxide in water (20 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-amino-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.75 g, 65%) as a brown solid which was used for next step without further purification: LC/MS m/e calcd for C18H19ClN2O2 (M+H)+: 331.82, observed: 331.1.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]3([O:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][O:12]3)[C:6]=2[CH:5]=[N:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[NH:24][CH2:23]2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.[Cu]I>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([C:2]1[C:11]3[CH2:10][CH2:9][CH2:8][C:7]4([O:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][O:12]4)[C:6]=3[CH:5]=[N:4][CH:3]=1)[CH2:23]2
Reactant: CC1(C)COC2(CCCc3c(Br)cncc32)OC1
Reactant: O=C1NCc2cc(Cl)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)COC2(CCCc3c(N4Cc5cc(Cl)ccc5C4=O)cncc32)OC1
Temperature: 150 °C
Yield: 86.2 %

Procedure:
A mixture of 4′-bromo-5,5-dimethyl-6′,7′-dihydro-5′H-spiro[1,3-dioxane-2,8′-isoquinoline](5.0 g, 16 mmol), 5-chloro-2,3-dihydro-isoindol-1-one (2.7 g, 16 mmol), (+)-(1S,1S)-1,2-diaminocyclohexane (0.576 mL, 4.8 mmol), copper (I) iodide (456 mg, 2.4 mmol) and Cs2CO3 (10.4 g, 32 mmol) in dioxane (80 mL) was heated at 150° C. for 4 hours. After cooling to room temperature, it was diluted with water (50 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford a crude product (5.5 g, 86%) as light yellow solid. MS: 399.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([C:28]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:27]=4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Li+]>C(O)C.O>[F:1][C:2]1[CH:12]=[C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([C:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH:27]=4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(-c2ncnc3ccc(-c4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)cc23)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2ncnc3ccc(-c4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)cc23)cc1F
Yield: 72.9 %

Procedure:
0.82 g ethyl 2-fluoro-4-[6-(1-trityl-1H-pyrazol-4-yl)-quinazolin-4-yl]benzoate (compound in Example 752) was dissolved in 30 mL solvent mixture of ethanol and water (2:1), then 0.11 g lithium hydroxide was added thereto, and the mixture was heated for 5 hours under reflux. The reaction solution was neutralized under ice-cooling. The solution was extracted with dichloromethane and recrystallized from ethanol/ether, to give 570 mg of the title compound as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]Br>ClCCl.CCOC(C)=O>[Br:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
Ex-62A: A solution of 2-hydroxy-4-methoxybenzaldehyde (3.03 g, 20 mmol) in 25 mL of dichloromethane was cooled to 0° C. and treated dropwise with a solution of bromine (3.41 g, 21 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at 0° C. for 1.5 hours. The solvent was removed by rotary evaporation to give a residue. The residue was taken up in EtOAc and washed with 3 portions of water. The organic layer was dried over MgSO4. The drying agent was removed by filtration, and solvent was removed by rotary evaporation to give 3.9 g of the desired 5-bromo-2-hydroxy-4-methoxybenzaldehyde as a solid, m.p. 111-115° C.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[S:13]1[C:17]2[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH2:23]>>[NH2:23][C:14]1[S:13][C:17]2[CH:18]=[C:19]([NH:22][C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:20]=[CH:21][C:16]=2[N:15]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccc2nc(N)sc2c1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2nc(N)sc2c1
Yield: 20 %

Procedure:
The title compound was prepared from Boc-Gly-OH and 1,3-benzothiazol-2,6-diamine according to the procedure of EXAMPLE 51. The product was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)=[CH:26]\[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:21][CH:20]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][C:2]#[C:3][C:19]2[CH:20]=[CH:21][C:22](/[C:25](/[C:42]3[CH:43]=[CH:44][C:45]([C:48]([F:49])([F:50])[F:51])=[CH:46][CH:47]=3)=[CH:26]\[CH2:27][O:28][C:29]3[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=3)=[CH:23][CH:24]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Reactant: C#CCN1CCC(O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpiperidin-4-ol (215 mg, 1.55 mmol) and diisopropylamine (0.51 mL, 3.64 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate (450 mg, 0.773 mmol; example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (12 mg, 0.063 mmol) and bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.039 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2-97:3-95:5) yielding methyl (E)-[4-[3-[4-[3-(4-hydroxy-piperidin-1-yl)propynyl]-phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.[OH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.O>CN1CCCC1=O>[OH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:4][CH:3]=2)[CH2:31]1
Reactant: O=C(Nc1ccc(Cl)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: OC1CCNC1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1ccc(N2CCC(O)C2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
A mixture of 0.4 g (1.01 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide, prepared in step 3.1, and 0.81 ml (10.06 mmol) of 3-hydroxypyrrolidine in 1.2 ml of N-methylpyrrolidinone is heated for 20 minutes in a microwave oven regulated at 200° C. under 300 watts. The reaction mixture is then poured into 50 ml of water. A solid is recovered by filtration and purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. The resulting solid is then recrystallized from a mixture of methanol and dichloromethane. 0.22 g of a solid is recovered by filtration and dried under reduced pressure.
Reaction SMILES: Cl.[C:2](=[NH:8])([O:6][CH3:7])[CH2:3][CH2:4][CH3:5].[N:9]#[C:10]N.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>>[C:10]([N:8]=[C:2]([O:6][CH3:7])[CH2:3][CH2:4][CH3:5])#[N:9]
Reactant: N#CN
Reactant: CCCC(=N)OC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CCCC(=NC#N)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
The methyl butyrimidate salt from Example 1 (322 g, 2.34 mol) was dissolved in a 50% aqueous solution of cyanamide (236 g, 2.81 mol) and cooled in an ice bath. Dibasic sodium phosphate (164 g, 1.15 mol) was added to the reaction mixture in portions over a period of 1 hour. The resulting suspension was stirred at room temperature for 2 hours and the liquid decanted from the reaction mixture. The remaining solid was diluted with water (2 L) and extracted with ether (3×600 mL). The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue distilled under high vacuum to afford 258 g of methyl N-cyanobutyrimidate. MS (DEI) 127 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C@H:19]1[CH2:21][O:20]1>CN(C=O)C>[OH:20][C@@H:19]([CH3:21])[CH2:18][N:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]1[CH3:1]
Reactant: CCOC(=O)c1c[nH]c(C)n1
Reactant: C[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C[C@H](C)O)c(C)n1
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 40.4 %

Procedure:
Ethyl 2-methyl-1H-imidazole-4-carboxylate (1.622 mmol, 250 mg) and potassium carbonate (16.22 mmol, 2241 mg) were dissolved in dry DMF (5 ml) under nitrogen atmosphere. (S)-2-methyloxirane (24.32 mmol, 1.723 ml) was added and the resulting mixture was heated to 60° C. and stirred for 5.5 h. More (S)-2-methyloxirane (1 ml) was added and the stirring continued at 60° C. for one additional hour. The solvent was evaporated. The crude product was purified by flash chromatography. 139 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.06 (d, 3H), 1.24 (t, 3H), 2.30 (s, 3H), 3.71-3.89 (m, 4H), 4.18 (q, 2H), 7.73 (s, 1H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O.[CH:29]([NH2:31])=[S:30].[OH-].[Na+]>O1CCOCC1>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:31]=[CH:29][S:30][CH:19]=2)=[CH:23][CH:24]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: NC=S
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: NC=O
Solvent: C1COCCO1
Product: Brc1ccc(-c2cscn2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of phosphorus pentasulfide (24.5 g, 55 mmol) in dioxane (250 ml) was added formamide (28.4 g, 630 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2,4′-dibromoacetophenone (15 g, 54 mmol) in dioxane (100 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with CH2Cl2 to give title compound (12.3 g, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH3:38][N:39]([CH3:49])[C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:39]([CH3:49])[CH3:38])=[O:48])[CH2:47][CH2:46]3)=[O:28])[C@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 709.3 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][N:3]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[NH:5][C:4]1=[O:20].O1CCCC1.C([Li])CCC.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>O>[CH3:31][N:32]([CH2:33][CH2:34][N:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH2:8][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]([O:2][CH3:1])[C:4]1=[O:20])[CH3:36]
Reactant: CON1C(=O)Nc2ccccc2CC1c1ccccc1
Reactant: CN(C)CCCl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CON1C(=O)N(CCN(C)C)c2ccccc2CC1c1ccccc1
Temperature: 25 °C
Yield: 162 %

Procedure:
To a stirred, chilled (-78° C.) solution of (±) -3-methoxy-4-phenyl-1,3,4,5-tetrahydro-2H-1,3-benzodiazepine-2-one (5.0 g, 0.019 mol) of Example 1c and tetrahydrofuran (200 ml) was added n-butyllithium (9.1 ml of a 2.5 M solution in hexanes, 0.023 mol) (nitrogen atmosphere). The solution was stirred and cooled for 50 minutes, then 2-dimethylaminoethylchloride (10.22 .g, 0.095 mol) was added and the solution was allowed to warm to room temperature. The mixture was stirred and heated to 45° C. for 48 hours, with additional 2-dimethylaminoethylchloride added as follows: 16.5 hours, 14.0 g, 0.13 mol; 24 hours, 14.0 g, 0.13 mol. The mixture was then heated to reflux for 2 hours, allowed to cool, and water (400 ml) was added to quench the reaction. The tetrahydrofuran was removed in vacuo and the resulting oily aqueous phase was extracted twice with 250 ml portions of dichloromethane. The combined organic phase was washed twice with water (300 ml portions), once with saturated sodium chloride (200 ml), and was dried (Na2SO4), filtered, and concentrated to give a solid (10.45 g). The solid was purified by preparative HPLC (Waters Associates Prep LC/System 500, silica gel sample loaded in dichloromethane, eluted with 3:1 ethyl acetate:methanol). The appropriate fractions were combined, evaporated, dissolved in dichloromethane, filtered to remove all insoluble material, and concentrated to yield 1.70 g of a solid (26%). The products of several similar reactions were combined and repurified by preparative HPLC, as above, to yield 2.95 g of a solid, which was recrystallized from dichloromethane/ether to afford 2.39 g (26%) of (±) -1-[2-(N,N-dimethylamino)ethyl]-3-methoxy-4-phenyl-1,3,4,5-tetrahydro-2H-1,3-benzodiazepine-2-one,m.p.127°-128° C.