Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17]([C:19]3[C:20]([C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])=[N:21][O:22][C:23]=3[CH3:24])=[O:18])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CN(C=O)C>[C:1]1([NH:7][CH2:8][CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([N:16]3[C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=4[C:20]4=[N:21][O:22][C:23]([CH3:24])=[C:19]4[C:17]3=[O:18])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)N[C@H]1CCC[C@@H](CCNc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n([C@H]1CCC[C@@H](CCNc3ccccc3)C1)c1cccc(Cl)c21
Reaction time: 0.08 h

Procedure:
N-{(1S,3S)-3-[2-(phenylamino)ethyl]cyclohexyl }[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide (54 mg; 0.118 mmol) was dissolved in anhydrous DMF (2 mL) under a dry nitrogen atmosphere at room temperature. When potassium bis(trimethylsilyl)amide (0.5 M in toluene; 572 μL; 2.2 equiv) was added dropwise to this solution, a clear orange color formed. After 5 min, the reaction was chilled in an ice bath, quenched with 1N HCl(aq) (10 mL), and extracted with ethyl acetate (twice). The organic layer was washed with saturated NaCl(aq) (once), dried with Na2SO4(s), filtered, and concentrated to dryness by rotary evaporation. The product was purified by radial chromatography on a 2 mm thick silica gel rotor. A dichloromethane mobile phase was ineffective at purifying the product. Re-chromatography with a 100% hexanes mobile phase followed by a 20% ethyl acetate/hexanes (v/v) mobile phase separated product from impurities. After drying from diethyl ether, an off-white foam (43 mg; 84%) was obtained.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[C:11](NC2C=CN(COCC[Si](C)(C)C)N=2)[CH:10]=C[CH:8]=1)(=O)=O.Cl.Cl[C:29]1[C:30](F)=C(C=C[CH:42]=1)C(N1CCNCC1)=O>C(Cl)(Cl)Cl>[CH:29]([N:12]([CH2:11][CH3:10])[CH:7]([CH3:6])[CH3:8])([CH3:30])[CH3:42]
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cccc(COS(C)(=O)=O)n2)n1
Reactant: O=C(c1cccc(Cl)c1F)N1CCNCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCN(C(C)C)C(C)C

Procedure:
A mixture of 10 mg of 6-(methanesulfonyloxymethyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridin-2-amine, 40 mg of 1-(3-chloro-2-fluorobenzoyl)piperazine hydrochloride obtained in Reference Example 1, 27 μl of N,N-diisopropylethylamine and 1 ml of chloroform was stirred at 60° C. for 5 hours. The reaction solution was diluted with chloroform, and then washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography(eluent: chloroform to chloroform/methanol=20/1) to give the title compound.
Reaction SMILES: Cl[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[OH:4].[Na+].[I-:14]>CC(C)=O>[I:14][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[OH:4]
Reactant: O[C@@H](CCl)c1ccc(Cl)cc1Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O[C@@H](CI)c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
(R)-2-Chloro-(2′,4′-dichlorophenyl)-1-ethanol (1.95 g, 8.65 mmol) was dissolved in 60 mL of anhydrous acetone (4A molecular sieves). Then NaI (7 g, 46.70 mmol) was added to the solution and the solution refluxed for 3 hours under nitrogen. Upon cooling to room temperature, the solution was poured into 160 mL of hexanes/ethyl acetate (3:1), and filtered to remove excess NaI which had precipitated. The filtrate was evaporated to dryness in vacuo, and the residue treated with ether and decanted from the solid NaI. Upon removal of ether, the product was obtained as white solid. Yield: 2.40 g (88%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[NH:37][C:38](=[O:50])[C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:40]=1[F:49].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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.[Pd].COC1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1NC(=O)C1C=CC(C(F)(F)F)=CC=1F>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:26]3[CH:25]=[CH:24][C:23]([NH:37][C:38](=[O:50])[C:39]4[CH:44]=[CH:43][C:42]([C:45]([F:47])([F:48])[F:46])=[CH:41][C:40]=4[F:49])=[C:22]([O:21][CH3:20])[CH:27]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2-c1ccc(C=O)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 85 °C
Yield: 67 %

Procedure:
A mixture of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehyde (0.400 g, 1.09 mmol), N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-(trifluoromethyl)benzamide (0.735 g, 1.20 mmol), palladium tetrakis(triphenylphosphine) (0.127 g, 0.110 mmol), and sodium carbonate (0.279 g, 2.63 mmol) in DME (10 mL) and water (10 mL) was heated at 85° C. for 1 h. Additional N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-(trifluoromethyl)benzamide (0.026 g, 0.059 mmol) was added and the reaction mixture was heated at 85° C. for 4 h. The reaction mixture was cooled to ambient temperature and filtered. The residual solid was washed with methanol (50 mL) and DMF (50 mL), and the combined filtrates were concentrated to afford N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a beige solid (0.402 g, 0.730 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 10.05 (1H, s), 9.96 (1H, d, J=4.0 Hz), 8.62 (1H, d, J=8.4 Hz), 8.46 (1H, s), 8.39 (1H, d, J=6.8 Hz), 8.12 (2H, d, J=8.8 Hz), 8.02-8.03 (1H, m), 7.84-8.00 (1H, m), 7.75-7.77 (1H, m), 7.51 (1H, s), 7.43 (1H, d, J=8.0 Hz), 3.97 (3H, s); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 12.46 min. MS: MH+551.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])C.Cl[C:36]1[N:41]=[CH:40][C:39]([CH2:42][CH2:43][CH3:44])=[CH:38][N:37]=1>>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:36]3[N:41]=[CH:40][C:39]([CH2:42][CH2:43][CH3:44])=[CH:38][N:37]=3)[CH:12]=2)[N:7]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CCCc1cnc(Cl)nc1
Reactant: CCOC(=O)c1c(Cl)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC(C)C)cc1
Product: CCCc1cnc(-c2ccc3c(c2)c(Cl)c(C(=O)O)n3-c2ccc(OC(C)C)cc2)nc1

Procedure:
The title compound was prepared in accordance with Example 35, Method 1, step (d) from 3-chloro-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 35, Method 1, step (c)) and 2-chloro-5-propylpyrimidine, followed by ester hydrolysis in accordance with Example 1(c).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[C@H:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])[CH2:5][C:4]=2[CH:3]=1.[BH4-].[Na+]>>[F:42][C:36]([F:41])([C:37]([F:38])([F:39])[F:40])[CH2:35][CH2:34][CH2:33][S:32][CH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:6]1[CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:19]=[CH:18][C:17]=2[C@@H:16]2[C@@H:7]1[C@H:8]1[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Yield: 64.8 %

Procedure:
Under the conditions of Example 8, 500 mg of 3-hydroxy-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one is reduced with 100 mg of sodium borohydride. 325 mg of the title compound is obtained as oil. [α]D22=−8.7° (c=0.510 in methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1ccc2[nH]nnc2c1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1nnc2ccccc21

Procedure:
Using general procedure 4 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.25 g, 0.95 mmol) and 1,2,3-benzotriazole (0.136 g, 1.14 mmol) gives the title compound.
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:9][C:8]([Br:20])=[C:7]([Cl:21])[N:6]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Br:20][C:8]1[CH:9]=[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([OH:4])=[N:6][C:7]=1[Cl:21]
Reactant: CC(=O)Oc1nc(Cl)c(Br)cc1C#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Oc1nc(Cl)c(Br)cc1C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-bromo-6-chloro-3-((4-fluorophenyl)ethynyl)pyridin-2-yl acetate (5.5 g, 15 mmol) was suspended in MeOH (75 ml) and K2CO3 (4.12 g, 29.8 mmol) was added. The mixture was stirred at rt for 1 h. At this point, LCMS and TLC show no remaining SM. The mixture was then sparged with a balloon of CO for ten minutes and carried onto the following step, carbonylative coupling, without isolation.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C=CC=CC=2C=CC=N1.[H-].[Na+].Br[CH2:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48]>>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:15]=2[N:14]([CH2:45][C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[O:51])[C:13]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: O=C(NC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O)OCc1ccccc1
Agent: C1=Cc2ccccc2NN=C1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)C(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2cc(Cl)ccc21
Yield: 93 %

Procedure:
This was prepared from (3RS)-3-benzyloxycarbonylamino-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (640 mg, 1.46 mmol, prepared by analogy with the Bock benzodiazepine), sodium hydride (62 mg of an 80% dispersion in oil, 2.04 mmol) and 1-bromopinacolone (537 mg, 3 mmol) following the method of Example 1B. The crude product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 30:70 v/v) to afford the title compound (700 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1([CH3:16])[CH2:13][C:12](=[O:14])[O:11][C:10]1=[O:15].[Cl-].[Cl-].[Cl-].[Al+3]>ClC(Cl)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12](=[O:14])[CH2:13][C:9]([CH3:16])([CH3:8])[C:10]([OH:15])=[O:11])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(C)(CC(=O)c1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a chilled solution (ice/water bath) of bromobenzene (7.71 g, 49.1 mmol) and 3,3-dimethyldihydro-2,5-furandione (5.99 g, 46.7 mmol) in dichloroethane (150 mL) was added aluminum trichloride (13.28 g, 99.58 mmol). The ice bath was removed and the reaction mixture was stirred at rt overnight. The mixture was again chilled in an ice/water bath, and then quenched with 1 M aqueous hydrochloric acid. Water (70 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage apparatus, 17:83 ethyl acetate/hexane) to give 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid as a white solid (8.34 g, 63%). LC-MS: ret. time 2.79 min; m/z 284.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.36 (s, 6H), 3.27 (s, 2H), 7.60 (d, 2H), 7.81 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Br.[O-:10][S:11]([O-:13])=[O:12].[Na+:14].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:11]([O-:13])(=[O:12])=[O:10].[Na+:14]
Reactant: BrCc1ccccc1Br
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(=O)([O-])Cc1ccccc1Br
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 155.6 %

Procedure:
A mixture of 1-bromo-2-(bromomethyl)benzene (20 g, 0.08 mol) and Na2SO3 (15 g, 0.12 mol) in methanol/H2O (100 mL/100 mL) was stirred at 85° Celsius for 2.5 hours, concentrated to dryness and dried to give sodium (2-bromophenyl)methanesulfonate (34 g, crude). 1H NMR (300 MHz, DMSO-d6) δ 7.54 (m, 2H), 7.27 (m, 1H), 7.12 (m, 1H), 3.91 (s, 2H).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:16][CH:15]([NH:32][C:33]([N:35]3[CH:39]=[CH:38]N=C3)=[O:34])[C:14]1=[O:40])=[O:11])[CH2:2]2.N[C:42]1[CH:43]=[C:44]([OH:48])C=C[CH:47]=1.C(N(CC)CC)C.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:16][CH:15]([NH:32][C:33]([NH:35][C:39]3[CH:47]=[CH:42][CH:43]=[C:44]([OH:48])[CH:38]=3)=[O:34])[C:14]1=[O:40])=[O:11])[CH2:2]2
Reactant: Nc1cccc(O)c1
Reactant: Cc1cccc2c1N(CC(=O)N1CC3CCC(CC3)C1)C(=O)C(NC(=O)n1ccnc1)N=C2c1ccccc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cccc2c1N(CC(=O)N1CC3CCC(CC3)C1)C(=O)C(NC(=O)Nc1cccc(O)c1)N=C2c1ccccc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixture of (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-3-(imidazol-1-yl)carbonylamino-9-methyl-1H-1,4-benzodiazepin-2-one (250 mg), 3-aminophenol (55 mg) and triethylamine (93 mg) in N,N-dimethylformamide (1 ml) was stirred at 100° C. for 1 hour. After the reaction mixture was allowed to cool to room temperature, ethyl acetate and 1N aqueous hydrochloric acid were added thereto. The separated organic layer was washed with 1N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine successively, and then dried over magnesium sulfate. The solvent was evaporated in vacuo to give a colorless paste, which was washed with diisopropyl ether and collected by filtration to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N ′-(3-hydroxyphenyl)urea (184.0 mg, 68.5% yield) as a crystalline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2.[C:14]12([C:24]3[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:2]4[CH:3]=[C:4]5[C:9](=[CH:10][CH:11]=4)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]5)[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:22]3)[CH2:21]1)[CH2:23]2
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Reactant: COc1ccc(B(O)O)cc1C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 6-bromo-2-naphthaldehyde (1.17 g, 4.98 mmol, see Example 3c), 3-(1-adamantyl)-4-methoxyphenyl boronic acid (1.57 g, 5.48 mmol, prepared in a manner similar to that described in Example 3b.) and potassium carbonate (1.55 g, 11.20 mmol) in 75 mL of toluene and water (4 mL) was degassed with argon for 30 minutes . Tetrakis(triphenyl phosphine)palladium(0) (0.575 g, 0.50 mmol) was added and the mixture heated at reflux for 18 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:CH2Cl2, 3:2 to 1:1) to give 1.6 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthaldehyde (82%) as a solid. 1H NMR (300 MHz; CDCl3): δ 1.80 (s, 6H), 2.10–2.17(m, 9H), 3.90 (s, 3H), 6.99 (d, J=8.1 Hz, 1H), 7.52–7.60 (m, 2H), 7.82 (d, J=8.4 Hz, 1H), 7.95–8.02 (m, 4H), 8.32 (s, 1H), 10.13 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14](I)[CH:13]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([N:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]2=[O:1])[CH:13]=1
Reactant: COC(=O)c1cc(I)cc([N+](=O)[O-])c1
Reactant: Cc1ccnc(O)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-n2ccc(C)cc2=O)cc([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 99.9 %

Procedure:
To a 25 ml round-bottomed flask was added 2-Hydroxy-4-methylpyridine (17.9 mg, 0.164 mmol), 3-Iodo-5-nitro-benzoic acid methyl ester (40 mg, 0.137 mmol), CuI (5.2 mg, 0.027 mmol) and 1,4-dioxane (10 ml). The reaction mixture was stirred for 5 minutes to the dissolve 2-Hydroxy-4-methylpyridine and 3-iodo-5-nitro-benzoic acid methyl ester, after which 1,10-phenanthroline (9.84 mg, 0.055 mmol) was added, followed by K3PO4 (174 mg, 0.082 mmol). The reaction mixture was flushed with N2, and heated to 110° C. for 24 hours. After cooling to room temperature, the mixture was diluted with H2O, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give 3-(4-Methyl-2-oxo-2H-pyridin-1-yl)-5-nitro-benzoic acid methyl ester (39.45 mg, 61%) as light yellow solid. MS (M+H)=289.
Reaction SMILES: [CH:1]([CH:4]([C:15]#[N:16])[C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)([CH3:3])[CH3:2].CO[CH2:19][CH2:20][C:21]#[N:22].C[O-].[Na+].O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([C:4]([C:15]#[N:16])([CH:1]([CH3:3])[CH3:2])[CH2:19][CH2:20][C:21]#[N:22])[CH:14]=[CH:13][C:10]=1[O:11][CH3:12]
Reactant: COCCC#N
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)(CCC#N)C(C)C)cc1OC
Temperature: 85 °C

Procedure:
438.4 g (2 mol) of α-isopropyl-veratryl cyanide and 204.2 g (2.4 mol) of 3-methoxypropionitrile are dissolved in 400 ml of dimethylformamide, 36 ml of a 5.5 molar solution of sodium methylate are added, and the mixture is heated to 85° C. for 1/2 hour. After cooling, water is added to the reaction mixture and the reaction product separates by crystallisation. Recrystallised from methanol/water, the product melts at 97° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3I)[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([CH3:47])([CH3:46])[CH2:44][OH:45])=[CH:39][C:38]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[C:38]3[CH:39]=[C:40]([C:43]([CH3:47])([CH3:46])[CH2:44][OH:45])[CH:41]=[CH:42][C:37]=3[O:36][CH3:35])[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C(C)(C)CO)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)CO)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 23; 30 mg; 0.049 mmol) was treated with 2-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-1-ol (intermediate 26; 20 mg; 0.065 mmol), 1-1′-bis(di tert-butylphosphino)ferrocene palladium dichloride (3.2 mg; 0.0049 mmol), 1 N K2CO3 (1.2 mL) and THF (1.2 mL) as described in Example 38 to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-(2-hydroxy-1,1-dimethylethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a clear glass. LCMS=664.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.86-7.80 (m, 2H), 7.76 (s, 1H), 7.67-7.61 (m, 2H), 7.41-7.37 (m, 2H), 7.21 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 5.38 (d, J=15.5 Hz, 1H), 4.95 (d, J=11 Hz, 1H), 4.09 (d, J=15.5 Hz, 1H), 3.81 (s, 3H), 3.65-3.63 (m, 1H), 3.58-3.55 (m, 1H), 3.41-3.35 (m, 1H), 2.25-2.20 (m, 1H), 1.80-1.72 (m, 1H), 1.28-1.25 (m, 6H), 1.07-1.03 (m, 3H).
Reaction SMILES: [C:1]([S:5]([NH:7][C:8]1([CH:12]([CH2:17][CH3:18])[C:13]([O:15]C)=[O:14])[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([S:5]([NH:7][C:8]1([CH:12]([CH2:17][CH3:18])[C:13]([OH:15])=[O:14])[CH2:9][O:10][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C(=O)OC)C1(NS(=O)C(C)(C)C)COC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C(=O)O)C1(NS(=O)C(C)(C)C)COC1

Procedure:
Methyl 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}butanoate (Preparation 35, 2.89 g, 10.42 mmol) was stirred in methanol (30 mL) and a 1M aqueous solution of sodium hydroxide (30 mL) for 18 hours at room temperature. The reaction was concentrated in vacuo and partitioned between diethyl ether and water. The pH of the aqueous layer was adjusted to pH3 with potassium hydrogen sulphate and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound that was used without purification in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[SH:12])[CH3:2].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[S:12][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[CH3:2]
Reactant: CCOC(=O)c1cc(F)ccc1S
Reactant: O=[N+]([O-])c1ccccc1F
Product: CCOC(=O)c1cc(F)ccc1Sc1ccccc1[N+](=O)[O-]

Procedure:
Thus, in a five-step process: 5-fluoro-2-mercapto-benzoic acid ethyl ester may be reacted with 1-fluoro-2-nitrobenzene to form 5-fluoro-2-(2-nitro-phenylsulfanyl)-benzoic acid ethyl ester; the ethyl ester may be converted to 5-fluoro-2-(2-amino-phenylsulfanyl)-benzoic acid ethyl ester; the aminophenyl compound may be cyclized to form 2-fluoro-10H-dibenzo[b,f][1,4]thiazepin-11-one, that may be converted to 11-chloro-2-fluoro-dibenzo[b,f][1,4]thiazepine, and that may be then reacted with piperazine to form the title compound.