Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([O:13]C(=O)C)=[CH:5]1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na]>CO>[OH:13][C:6]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)Oc1cn(C(C)=O)c2ncccc12
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CO
Product: CC(=O)n1cc(O)c2cccnc21

Procedure:
1-(3-Hydroxy-pyrrolo[2,3-b]pyridin-1-yl)-ethanone 503 is prepared from acetic acid 1-acetyl-1H-pyrrolo[2,3-b]pyridin-3-yl ester 502 by selective removal of the acetate at the 3-position by reaction with sodium in methanol at room temperature typically for 30 minutes to one hour, followed by purification and isolation by conventional means (e.g. extraction and recrystallization).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.[CH3:19][C:20]1[C:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:31]2[CH2:32][CH2:33][N:28]([C:21]3[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=3)[CH2:29][CH2:30]2)=[O:13])=[C:9]([O:16][CH3:17])[CH:8]=1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Yield: 60 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (136 mg) described in Preparation Example 19 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (103 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 87, the title compound (138 mg) was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[C:11]1[C:21](OC)=[O:22]>O1CCCC1>[CH3:7][O:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[C:11]1[CH2:21][OH:22]
Reactant: COCn1cc(-c2ccccc2)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCn1cc(-c2ccccc2)cc1CO
Reaction time: 12 h
Yield: 90.2 %

Procedure:
Lithium aluminum hydride (113 mg, 3.06 mmol) was added portionwise to a stirred solution of methyl 1-(methoxymethyl)-4-phenyl-pyrrole-2-carboxylate (500 mg, 2.04 mmol) in tetrahydrofuran (10 mL) over a period of 15 min at 0° C. The resulting mixture stirred for 12 h and then quenched with ice and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to yield [1-(methoxymethyl)-4-phenyl-pyrrol-2-yl]methanol (400 mg, 91%) as a brown liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>N.CCO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccccc2C#N)CC1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2ccccc2CN)CC1
Reaction time: 2.5 h
Yield: 98.2 %

Procedure:
To a solution of 4-(2-cyano-phenyl)-perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (905 mg, 3.0 mmol) in NH3/EtOH (2M, 15 mL) was added Raney Nickel (5 mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 2.5 h. After this time the mixture was filtered through celite and concentrated to yield the title compound (900 mg). m/z (M+1) 305.31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][C:21]#[N:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]#[N:22])[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: N#CCBr
Product: N#CCN1CCOC(CNC(=O)Nc2ccc(Cl)cc2)C1

Procedure:
Example 46 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and bromoacetonitrile (2.8 μl) to give the title compound (0.0039 g).
Reaction SMILES: FC(F)(F)CCC([N:7]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][C:8]21[CH2:10][CH2:9]2)=O.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>C1COCC1>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:34]([N:7]1[CH:8]2[CH2:9][CH2:10][CH:14]1[CH2:13][N:12]([C:15]1[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=1)[CH2:11]2)=[O:35]
Reactant: COCCOC(=O)Cl
Reactant: O=C(CCC(F)(F)F)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOC(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reaction time: 16 h

Procedure:
4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 4) (0.05 mmol) was dissolved in THF (1.0 mL). Triethylamine (0.12 mmol) and 2-methoxyethyl chloroformate (0.06 mmol) was added. The reaction mixture was left at rt for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [N-]=[N+]=[N-].[ClH:4].[CH2:5]([C:8]1([NH2:18])[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10](C)([CH3:16])[CH2:9]1)C=C>>[ClH:4].[CH3:5][C:8]1([NH2:18])[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]([CH3:16])=[CH:9]1
Reactant: C=CCC1(N)CC(C)(C)CC(C)(C)C1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Product: CC1=CC(C)(N)CC(C)(C)C1
Yield: 60 %

Procedure:
Prepared from azide 39 according to the procedure for compound 11 (Example 3, c). Amine hydrochloride 40 obtained as a colorless solid with 60% yield. 1H NMR (CDCl3, TMS): 0.96 and 1.07 (total 6H, both s, 5,5-CH3); 1.56 (3H, s, 1-CH3); 1.73 (3H, s, 3-CH3); 1.60-2.05 (4H, m, 4,6-CH2); 5.49 (1H, s, C═CH) and 8.27 ppm (3H, br s, NH3+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][C@@H:21]([CH2:23][C:24]([O:26]CC)=[O:25])[C:20]4[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=4[CH2:18][C:17]=3[CH:33]=2)[CH:3]=1.[OH-].[Na+]>CCO>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][C@@H:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20]4[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=4[CH2:18][C:17]=3[CH:33]=2)[CH:3]=1
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(OCCCNc3cc(C)ccn3)cc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2[C@H](CC(=O)O)C3)c1
Reaction time: 18 h
Yield: 82.4 %

Procedure:
A mixture of ethyl (S)-10,11-dihydro-3-[3-(4-methylpyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (2.08 g, 4.69 mmole) and 1.0 N NaOH (7.0 ml, 7.0 mmole) in absolute EtOH (45 mL) was warmed in an oil bath set at 45° C. After 18 hr, the reaction was concentrated on the rotavap and the pH was adjusted to 7 with 1.0 N HCl. The solid precipitate was collected and washed with H2O. Drying overnight afforded the title compound (1.61 g, 82%) as a nearly colorless solid: MS (ES) m/e 417.4 (M+H)+. Anal. Calcd for C26H28N2O3.1.0 H2O: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.63; H, 6.96; N, 6.30.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9])[CH3:2].[Br:13]Br>O1CCOCC1>[Br:13][CH2:11][C:10]([C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:12]
Reactant: CCc1cc(C(C)=O)ccc1F
Reactant: BrBr
Solvent: C1COCCO1
Product: CCc1cc(C(=O)CBr)ccc1F
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(3-ethyl-4-fluoro-phenyl)-ethanone (400 mg, 2.41 mmol) (from Step D) in 1,4-dioxane, bromine (124 μL, 2.41 mmol) was added and the mixture was stirred for 30 minute. at room temperature. The solvent was removed and the residue was chromatographed (5% dichloromethane/hexanes) to give an oil. 317 mg, 54%. 1H NMR(CDCl3, 300 MHz), σ 1.2-1.35 (t, 3H), 2.67-2.80 (q, 2H), 4.42 (s, 2H), 7.03-7.0 (t, 1H), 4.45 (s, 2H), 7.75-7.92 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[O:33][C:32]1=[O:43].[Cl:44]C1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O=P(Cl)(Cl)Cl>[Cl:44][C:39]1[CH:38]=[C:37]([C@H:34]2[O:33][C:32](=[O:43])[N:31]([CH2:30][C:21]3[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=3[C:4]3[CH:5]=[C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=4[CH3:19])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C@H:35]2[CH3:36])[CH:42]=[CH:41][N:40]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccncc4)[C@@H]3C)c2)c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(Cl)c4)[C@@H]3C)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-2-oxo-5-pyridin-4-yl-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (175 mg, 0.296 mmol) in CH2Cl2 (15 mL) at 0° C. under N2, was added 3-chloroperbenzoic acid (146 mg, 0.593 mmol) as a powder. The mixture was stirred at 0° C. for 15 min. Then it was allowed to warm up to room temperature and stirred for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with satd Na2SO3 (1×) followed satd K2CO3 (2×). The organic layer was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue obtained was dissolved in POCl3 (10 mL). The resulting solution was heated at 110° C. under N2 for 2 h. Then it was allowed to warm to room temperature and stirred for 2 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc (50 mL) and water (10 mL) and washed with satd NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (2×40 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give methyl 2″-{[(4S,5R)-5-(2-chloropyridin-4-yl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS calc.=625.2; found=625.0 (M+1)−. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.40 (s, 0.5 H); 8.39 (s, 0.5 H); 7.97 (s, 1 H); 7.90 (t, J=5.8 Hz, 1 H); 7.72 (s, 0.5 H); 7.69-7.63 (m, 1.5 H); 7.48 (d, J=11.8 Hz, 0.5 H); 7.44 (s, 0.5 H); 7.43-7.37 (m, 1 H); 7.32-7.26 (m, 1 H); 7.24 (s, 0.5 H); 7.20 (s, 0.5 H); 7.16 (d, J=2.2 Hz, 0.5 H); 7.14 (d, J=2.2 Hz, 0.5 H); 7.12-7.06 (m, 1.5 H); 7.05 (d, J=5.1 Hz, 0.5H); 5.42 (d, J=8.1 Hz, 0.5H); 5.18 (d, J=8.1 Hz, 0.5 H); 4.92 (dd, J=15.9, 18.5 Hz, 1 H); 4.19 (d, J=15.8 Hz, 0.5 H); 3.99 (d, J=15.8 Hz, 0.5 H); 3.95 (s, 3 H); 3.88 (s, 3 H); 3.81-3.75 (m, 1 H); 2.39 (s, 1.5 H); 2.35 (s, 1.5 H); 0.60 (d, J=6.5 Hz, 1.5 H); 0.49 (d, J=6.5 Hz, 1.5 H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([NH:16][C@H:17]([CH3:20])[CH2:18][OH:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21]NC(=O)CCC(N)=O>CC(O)=O>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([OH:15])[C:12]([Cl:21])=[C:11]([NH:16][C@H:17]([CH3:20])[CH2:18][OH:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CO)Nc1cc(O)nc(SCc2ccccc2)n1
Reactant: NC(=O)CCC(=O)NCl
Solvent: CC(=O)O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2)nc(O)c1Cl
Reaction time: 3 h

Procedure:
The product of Example 1 (0.5 g) was dissolved in AcOH (10 ml), N-chlorosuccinamide (0.23 g) added and stirred for 3 h. The mixture was evaporated and purified by silica gel chromatography (5% methanol/DCM) to yield the title product as a white solid. Yield 0.42 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[Cl:17])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:19]1([CH2:25][C:26]2[S:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:29]2[S:30][C:26]([CH2:25][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[Cl:17])=[O:9]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1Cl
Product: Nc1ncc(-c2ccc(CN3CCOCC3)s2)cc1C(=O)Nc1ccncc1Cl

Procedure:
Reaction of 2-amino-5-bromo-N-(3-chloro-4-pyridyl)pyridine-3-carboxamide with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A33”; HPLC/MS: 1.25 min, [M+H]=343;
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)=[O:12].[OH-].[Na+].Cl>CO>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:10]/[C:11]([C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)/C=C/c2ccc(O)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 4.9 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (1.0 g, 8.19 mmol) and 3,4,5-trimethoxyacetophenone (1.72 g, 8.19 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (1 ml). The mixture was stirred for 24 hours at room temperature, acidified with 2N HCl and extracted with ethyl acetate (3×30 ml). The combined organic phase was dried over anhydrous MgSO4, filtered, and the solvent evaporated in vacuo. The product was purified by column chromatography using hexane/ethyl acetate (7:3) as eluent to afford the title compound as a pale yellow solid (0.125 g, 5%). 1H-NMR (CDCl3) δ 7.8 (1H, d), 7.6 (2H, m), 7.4 (1H, s), 7.25 (2H, m), 6.9 (2H, d), 5.6 (1H, bs) 3.95 (9H, s). Mass Spectrum (FAB) m/e 315 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:19][C:20](=O)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:19]=[C:20]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: O=C(CBr)CCc1ccccc1
Reactant: CCOC(=O)Cc1cc(NC(N)=S)ncc1Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Temperature: 70 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A flask was charged with ethyl 2-(5-bromo-2-thioureidopyridin-4-yl)acetate (2.200 g, 6.914 mmol), 1-bromo-4-phenylbutan-2-one (1.884 g, 8.297 mmol), DIEA (1.806 mL, 10.37 mmol) and ethanol (100 mL). The mixture was heated stirred at 70° C. for 2 hours, then cooled. The reaction was concentrated, and the residue was partitioned between chloroform and dilute sodium bicarbonate solution. The organic phase was washed with dilute sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The solid residue was recrystallized from hexane/ethyl acetate to give the desired product (1.815 g, 58.81% yield) as a yellow solid.
Reaction SMILES: [OH:1][NH:2][C:3]1([C:11]#[N:12])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1.C(=O)([O-])O.[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH2:26][C:27](Cl)=[O:28]>C(OCC)(=O)C.O>[C:11]([C:3]1([N:2]([OH:1])[C:27](=[O:28])[CH2:26][C:20]2[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=2[CH3:18])[CH2:4][CH2:5][N:6]([O:9][CH3:10])[CH2:7][CH2:8]1)#[N:12]
Reactant: CON1CCC(C#N)(NO)CC1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CON1CCC(C#N)(N(O)C(=O)Cc2cc(C)ccc2C)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxyamino-1-methoxy-piperidine-4-carbonitrile (preparation example 11, step 2) (4.0 g, 23.4 mmol) and sodium hydrogen carbonate (3.0 g, 35.7 mmol) in ethyl acetate (35 ml) and water (25 ml) at 0° C. was added a solution of (2,5-dimethyl-phenyl)-acetyl chloride (4.2 g, 23.0 mmol) in ethyl acetate (35 ml) dropwise over one hour. The reaction mixture was stirred at 0° C. for one hour and at room temperature for two hours. The layers of the biphasic system were separated, the aqueous phase extracted with ethyl acetate (3×), the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (gradient ethyl acetate/hexane 1:2→1:1→2:1). Yield: 1.55 g of N-(4-cyano-1-methoxy-piperidin-4-yl)-2-(2,5-dimethyl-phenyl)-N-hydroxy-acetamide (compound P3ii.2) as a white solid, mp 153-156° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O:12][C:13]([C:15]1[C:16](=[O:29])[N:17]([CH3:28])[C:18]2[C:23]([C:24]=1[OH:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][CH:19]=2)=O)C.C(O)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]([C:15]1[C:16](=[O:29])[N:17]([CH3:28])[C:18]2[C:23]([C:24]=1[OH:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][CH:19]=2)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2c(OC)cccc2n(C)c1=O
Reactant: CCNc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN(C(=O)c1c(O)c2c(OC)cccc2n(C)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
N-Ethylaniline (3.0 g, 25 mmol) was dissolved in 80 ml of toluene and about 30 ml of the solvent was distilled off in order to obtain a dry solution. To this boiling solution was added 1,2-dihydro-4hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (2.7 g, 10 mmol). The ethanol formed during the reaction was distilled off together with some toluene for about 4 hours. The reaction mixture was cooled to room temperature. The precipitate was collected, washed with cold toluene and hexane and dried to give the title compound (2.8 g), yield 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.[CH3:18][CH:19]([CH2:34][C:35](=O)[CH3:36])[C:20](=O)[CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O>C1C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]2[N:1]3[C:35]([CH3:36])=[CH:34][C:19]([CH3:18])=[C:20]3[CH2:21][N:22]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:12])[C:3]=2[CH:13]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: CC(=O)CC(C)C(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Yield: 54.3 %

Procedure:
2-Amino-2',5-dichlorobenzophenone (200 mg, 0.752 millimole) and 3-methyl-1-phthalimidohexane-2,5-dione (225 mg, 0.823 millimole) were dissolved in 10 ml of benzene, and 20 mg of p-toluenesulfonic acid was added. The mixture was heated under reflux for 4 hours, and 2 ml of N,N-dimethylformamide was added. The benzene was evaporated under reduced pressure, and 8 ml of ethanol and 0.3 ml of hydrazine hydrate were added. The mixture was heated under reflux for 30 minutes. The ethanol was evaporated under reduced pressure, and 25 ml of benzene was added. The mixture was heated under reflux for 5 minutes. After cooling, the solid was separated by filtration. The filtrate was washed with water and an aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the concentrate was chromatographed on silica gel. The column was first eluted with benzene to recover unchanged 2-amino-2',5-dichlorobenzophenone, and then with benzene-ethyl acetate (49:1) to afford 145 mg of 8-chloro-6-(2-chlorophenyl)-1,3-dimethyl-4H-pyrrolo[1,2-a][1,4]benzodiazepine as yellow crystals in a yield of 54%. The product showed the same spectral data as those of the compound obtained in Example 32.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[C:21]([CH3:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][OH:24]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][OH:24])[C:21]=1[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1c(N)cccc1CO
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1cccc(CO)c1C
Yield: 65.9 %

Procedure:
A solution of 3-butyryl-4-chloro-8-methoxyquinoline (1.32 g, 5 mmol) and 3-amino-2-methylbenzyl alcohol (0.82 g, 6 mmol) in dioxan (25 ml) was heated at reflux for 1.5 hours, then the solvent evaporated. Aqueous sodium bicarbonate was added, the product extracted into dichloromethane, dried and evaporated. Recrystallisation from methanol gave 3-butyryl-4-(3-hydroxymethyl-2-methylphenylamino)-8-methoxyquinoline (1.20 g, 66%), m.p. 186°-188°.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[C:21](=[O:26])[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:2]1([F:1])[CH2:6][NH:5][C@@H:4]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[C:21]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:26])[CH2:3]1
Reactant: CC(C)NC(=O)c1ccc(F)cc1[C@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc(F)cc1[C@H]1CC(F)(F)CN1
Reaction time: 2 h

Procedure:
To a solution of (R)-tert-butyl 4,4-difluoro-2-(5-fluoro-2-(isopropylcarbamoyl)phenyl)pyrrolidine-1-carboxylate (I-50) (203 mg, 0.525 mmol) in DCM (0.4 mL) was added TFA (1 mL). After stirring for 2 hours the mixture was concentrated to dryness, diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried over sodium sulfate and concentrated to dryness to give (R)-2-(4,4-difluoropyrrolidin-2-yl)-4-fluoro-N-isopropylbenzamide (I-51) as a pale brown solid. MS m/z 287.1 (M+H)+. 1-51 was also isolated as a racemic mixture using un-resolved 1-45A and 1-45B from Method A in the above sequence.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]>CO.[Pd]>[NH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([F:1])[CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)c1cc(F)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(N)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 3-fluoro-N-methyl-5-nitrobenzamide (500 mg, 2.52 mmoL) in methanol (7.5 mL) was added Pd/C (30%) and the mixture was stirred at RT for 1 h. The reaction mixture was filtered through Celite® (diatomaceous earth), washed with methanol and concentrated under reduced. Purification by silica gel column chromatography provided 3-amino-5-fluoro-N-methylbenzamide (0.300 g, 75%) as a solid.
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[O:23][CH2:24][C:20]=2[C:19]=1[CH3:28])[CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]1=[O:17].C(O)(C(F)(F)F)=O>>[OH:1][CH:2]([C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[O:23][CH2:24][C:20]=2[C:19]=1[CH3:28])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]1=[O:17]
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2=O)ccc2c1COC2=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(O)CN2CCNCC2=O)ccc2c1COC2=O

Procedure:
The product of Step A was treated with TFA to remove the Boc group. The crude material was dissolved in aqueous sodium bicarbonate, extracted with Chloroform-IPA (3:1) three times, dried over sodium sulfate and concentrated to furnish the title compound (free base). LC-MS (IE, m/z): 291 [M+1]+.