Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3]>C(O)C.[Rh]>[CH2:20]([OH:21])[CH2:19][CH:17]([CH2:16][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[CH3:13])[CH3:18]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Rh]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reaction time: 8 h
Yield: 100 %

Procedure:
Phytol (2.0 g, 6.7 mmol) was dissolved in ethanol, rhodium 5% on alumina was added and mixture was placed under H2 60 psi and shaken overnight. The reaction mixture was filtered and evaporated to give the desired compound as an oil (2.0 g, 100% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[C:6]2[C:7]([CH:13]=[O:14])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1.[CH3:18][Mg]Br.C1COCC1.[Cl-].[NH4+]>C1COCC1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[C:6]2[C:7]([CH:13]([OH:14])[CH3:18])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1
Reactant: COc1ccc(C=O)c2cc(C(F)(F)F)nn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)c2cc(C(F)(F)F)nn12
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
The compound of Example 115 (1.63 g) was dissolved in THF (70.0 mL) in an argon atmosphere. While the solution was kept at −78° C., 0.90 mol/L methyl magnesium bromide/THF solution (8.90 mL) was added dropwise and the mixture was stirred for 1.5 hours as it was allowed to gradually warm to −40° C. Subsequently, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel column chromatography (hexane:ethyl acetate=1:1) afforded the title compound as a white powder (1.64 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(C)O
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1C(C)Oc1ccccc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 36.1 %

Procedure:
To a solution of 1-(4-bromo-2-methylphenyl)ethanol (430 mg, 2 mmol), phenol (184 mg, 2 mmol), triphenylphosphine (655 mg, 2.5 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (505 mg, 2.5 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 4-bromo-2-methyl-1-(1-phenoxyethyl)benzene (210 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=4)=[CH:19][C:14]=3[O:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[CH3:32][NH2:33].CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH:33][CH3:32])[N:22]=4)=[CH:19][C:14]=3[O:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(Oc3ccnc(Cl)n3)ccc21
Reactant: CN
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CNc1nccc(Oc2ccc3c(c2)OCN3C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)n1

Procedure:
A solution of 50 mg (0.106 mMol) 6-(2-chloropyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (4-chloro-3-trifluoromethyl-phenyl)-amide in 1.5 ml THF and 107 μl MeNH2 (2 M in THF; 0.214 mMol) is stirred in a sealed vessel for 24 h at rt. Concentration of the reaction mixture and chromatography (Combi Flash; hexane/EtOAc 4:1-1:1) gives the title compound: MS: [M+1]+=466; HPLC: tRet=13.8; TLC(hexane/EtOAc 1:1): Rf=0.09.
Reaction SMILES: [CH3:1][O:2][C:3](=[N:5][S:6]([N+:9](CC)(CC)[CH2:10][CH3:11])(=[O:8])=[O:7])[O-:4].NCCO>C1COCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:11][CH2:10][NH:9][S:6]1(=[O:8])=[O:7])=[O:4]
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: NCCO
Solvent: C1CCOC1
Product: COC(=O)N1CCNS1(=O)=O
Temperature: 25 °C

Procedure:
To a solution of 1-methoxy-N-triethylammoniosulfonylmethanimidate (Burgess reagent, 12.3 mmol) in THF (10 mL) at 0° C. was added 2-aminoethanol (4.91 mmol). The reaction was allowed to warm to rt and then heated to 90° C. for 8 h. After cooling to rt, the reaction was quenched with saturated aq. NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried (Na2SO4) and concentrated to afford 1,1-dioxo-1λ6-[1,2,5]thiadiazolidine-2-carboxylic acid methyl ester as colorless oil that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:15](N)=[NH:16].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O>[N:1]1[C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[N:16][CH:15]=1
Reactant: N=CN
Reactant: Nc1cnccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Oc1ncnc2cnccc12
Temperature: 150 °C
Yield: 87.6 %

Procedure:
A mixture of 3-amino-isonicotinic acid (32)(26.24 g, 190.0 mmol) and formamidine acetate (39.56 g, 380 mmol) in dimethylacetamide (100 ml) was stirred and heated to 150° C. The reaction was maintained at this temperature with stirring for 12 hours before it was allowed to cool to 25° C. and then basified with sodium bicarbonate solution (5% aqueous) until pH 7-8 was attained. The resultant pale brown solid was removed by filtration, washed with water (20 ml) and dried in a desiccator to give the desired compound (24.50 g, 87.63%) which required no further purification. m/z (LC-MS, ESP): 148 [M+H]+, R/T=1.09 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([O:20]C)[N:14]=[C:13]([O:22]C)[N:12]=2)=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[C:9]([C:11]1[NH:12][C:13](=[O:22])[NH:14][C:15](=[O:20])[C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:10]
Reactant: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(Cl)cc(Cl)c2)n1
Agent: Cl
Product: CC(C)c1c(C(=O)c2cc(Cl)cc(Cl)c2)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 87.3 %

Procedure:
Compound (60) (2.0 g, 5.6 mmol) was refluxed with conc. HCl (30 ml) for 3 hr. After cooling to room temperature, the white precipitate was collected by filtration, washed with cold water, and dried in high vacuo to afford 1.6 g (87%) of the title compound as a white solid. m.p. 252-253° C.; 1H NMR (200 MHz, CDCl3/CD3OD) δ 1.11 (6H, d, J=6.9 Hz), 2.33 (1H, m), 7.61-7.73 (3H, m); HRMS (EI) Calcd. 326.0225, Found 326.0240.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@H:12]([N:16]1[CH2:19][C:18]3([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:17]1)[CH2:11][CH2:10]2.[ClH:32].CO>O1CCOCC1>[ClH:32].[ClH:32].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@@H:12]([N:16]1[CH2:17][C:18]3([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[CH2:19]1)[CH2:11][CH2:10]2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ncccn4)ccc31)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1cnc(-c2ccc3c(c2)CC[C@@H]3N2CC3(CCNCC3)C2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a round-bottomed flask containing tert-butyl 2-[(1R)-5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1d, 177 mg, 0.42 mmol) was added 5 mL of 4N HCl in dioxane. The mixture was stirred for 3 hours at room temperature and 2 mL of methanol was added to solubilize the reaction. After stirring an additional hour, the volatiles were removed under reduced pressure to give the title compound as a brown solid (190 mg, 100%). MS (APCI) 321.4 (M+H)+. 1H NMR (CD3OD) δ 2.14-2.22 (m, 5H), 2.58 (br s, 1H), 3.11 (d, 1H), 3.19-3.23 (m, 5H), 4.12 (d, 1H), 4.21 (s, 2H), 4.45-4.47 (m, 1H), 5.07-5.08 (m, 1H), 7.51 (t, 1H), 7.74 (s, 1H), 8.34-8.40 (m, 2H), 8.94 (d, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23]O)[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH3:32][N:2]([CH3:1])[C:3]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2
Reactant: C1COCCN1
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CN4CCOCC4)no3)c1)=N2

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(3-hydroxymethyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 46) (53 mg, 0.12 mmol) by treatment with SOCl2 (3 eq.) and morpholine (10 eq.) as described in Example 45. Obtained as a yellow solid (33 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])[CH3:2].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1.CCOCC.O>[CH2:1]([O:3][C:4](=[O:10])[C:5](=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:6](=[O:7])[CH2:8][Cl:9])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(=Cc1ccc(Cl)cc1)C(=O)CCl
Reaction time: 5 h
Yield: 23.4 %

Procedure:
25.7 g of 4-chloroacetoacetic acid ethyl ester, 23.9 g of 4-chlorobenzaldehyde, 0.7 ml of piperidine and 18 ml of glacial acetic acid were dissolved in 15 ml of benzene. The solution was boiled for 5 hours, using a water separator, and was allowed to cool, and 300 ml of ether were added. After the mixture had been washed three times with water, it was dried over magnesium sulphate and the solvent was evaporated off. The residue was distilled under a high vacuum. The product obtained was a Z/E mixture in a ratio of 3/1. Yield: 23.4%, boiling point 0.5: 161° to 165°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][N:42]1[CH:46]=[CH:45][CH:44]=[N:43]1.BrCCCBr.N1C=CC=N1.[H-].[Na+]>CN(C=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][CH2:41][N:42]4[CH:46]=[CH:45][CH:44]=[N:43]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCCn1cccn1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCn3cccn3)cc2)c2ccccc21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (75 mg, 0.17 mmol) was dissolved in DMF (1 mL) at room temperature. K2CO3 (47 mg, 0.34 mmol) was added followed by 1-(3-bromopropyl)-pyrazole (64 mg, 0.34 mmol) (prepared from the reaction of 1,3-dibromopropane and pyrazole with sodium hydride in tetrahydrofuran). The reaction was allowed to stir at 70° C. for 3 hrs. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate. Organic layers were washed with brine, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (1/99 methanol/dichloromethane-3/97 methanol/dichloromethane gradient) to afford the product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].[OH:38][CH2:39][C:40](O)=[O:41].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[CH2:30]([O:29][NH:28][C:26]([CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:37])[N:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[NH:1][C:39](=[O:38])[CH2:40][OH:41])[CH:17]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)CO
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: O=C(CO)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl

Procedure:
By condensing (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and hydroxyacetic acid using WSC and HOBt in accordance with Example 1, (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(glycoloylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH2:39])[NH:13]2)=[O:11])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH2:39])[NH:13]1)=[O:11]
Reactant: CC(C)(CCN)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CCN)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 121a (50 mg, 0.08 mmol) was reacted with aqueous HCl solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (29 mg, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]1[CH2:12][CH:6]([CH2:7]1)[C:5]2=[N:13]O.S(Cl)(Cl)=[O:16]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]3[CH2:12][CH:6]([NH:13][C:5]2=[O:16])[CH2:7]3)=[CH:10][CH:11]=1
Reactant: ON=C1c2cc(Br)ccc2C2CC1C2
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C1NC2CC(C2)c2ccc(Br)cc21
Temperature: 25 °C
Yield: 221.6 %

Procedure:
Into a 20-L 4-necked round-bottom flask was placed 6-Bromo-2,3-dihydro-1H-1,3-methano-naphthalen-4-one oxime (790 g, 3.13 mol, 1.00 equiv), 1,4-dioxane (7.5 L), followed by the addition of a solution of thionyl chloride (12000 g, 32.00 equiv) in 1,4-dioxane (7.5 L) dropwise with stirring at 25° C. The resulting solution was stirred at 65° C. for 6 h. This reaction was repeated for 2 more times. The resulting mixture was concentrated under vacuum, diluted with 10 L of DCM and then quenched by the addition of 8 L of water. The resulting solution was extracted with 2×10 L of dichloromethane and the organic layers were combined. The pH value of the solution was adjusted to 7 with sodium bicarbonate (sat.). The organic layer was dried over anhydrous sodium sulfated and concentrated under vacuum. The residue was diluted with 4 L of EA and stirred at reflux for 0.5 h. The solids were collected by filtration and washed with 2×500 mL, of EA. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column eluting with PE:EA (5:1-3:1). This solid was combined with the previous solids to afford 1749 g (74%) of 5-Bromo-9-aza-tricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([C:16]([O:18]C)=[O:17])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[OH-].[Na+]>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([C:16]([OH:18])=[O:17])[CH2:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1Cc2cccc(-c3ccccc3)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1Cc2cccc(-c3ccccc3)c2C1

Procedure:
Methyl 4-bromo-2-indancarboxylate (510 mg), tributylphenyltin (881 mg), a tris(dibenzylideneacetone)dipalladium chloroform complex (41 mg) and tri-2-furylphosphine (19 mg) were dissolved in N-methylpyrrolidone (10 ml), and the mixture was stirred at 70° C. for 3 hours and allowed to cool. To the reaction solution was added a saturated potassium fluoride solution and the solution was stirred at room temperature for 30 minutes followed by filtering through Celite. The filtrate was extracted with ether. The organic layers was washed with saturated aqueous sodium bicarbonate and saturated brine and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled away under a reduced pressure. The resultant residue was purified by column chromatography on silica gel (hexane: ethyl acetate=4:1) to obtain methyl 4-phenyl-2-indancarboxylate. The resultant ester was dissolved in methanol to which 1 N sodium hydroxide was added to hydrolyze. Methanol was distilled away under a reduced pressure. To the resultant residue was added 1 N hydrochloric acid. The product was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled away to obtain the title compound (351 mg) (melting point: 97-102° C.).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[C:20]([C:19]1[CH:22]=[C:23]([CH3:24])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:27][C:26]([CH3:32])([CH3:25])[O:30][C:29]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)#[N:21]
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)nc2)CC1
Yield: 51.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(6-bromopyridine-3-carbonyl)piperazin-1-yl]-5-methylnicotinonitrile (105 mg) described in Preparation Example 131 and 5,5-dimethyloxazolidin-2-one (47 mg) described in Preparation Example 43, the title compound (59 mg) was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6](N(C)C)[CH:5]=[CH:4][CH:3]=1.Br[C:12]1[C:13]([C:24]2[CH:32]=[CH:31][C:30]3[C:26](=[CH:27][N:28]([CH2:33]C)[N:29]=3)[CH:25]=2)=[N:14][S:15][C:16]=1[NH:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[CH3:23])=[O:19].BrC1C(C2C=CC3C(=CN(C)N=3)C=2)=NSC=1NC([C@@H]1C[C@H]1C)=O.[ClH:58]>>[ClH:58].[CH3:33][N:28]1[CH:27]=[C:26]2[C:30]([CH:31]=[CH:32][C:24]([C:13]3[C:12]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:7]=4)=[C:16]([NH:17][C:18]([C@@H:20]4[CH2:22][C@H:21]4[CH3:23])=[O:19])[S:15][N:14]=3)=[CH:25]2)=[N:29]1
Reactant: CN(C)c1cccc(Br)n1
Reactant: CCn1cc2cc(-c3nsc(NC(=O)[C@@H]4C[C@H]4C)c3Br)ccc2n1
Agent: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc3nn(C)cc3c2)c1Br
Agent: Cl
Product: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc3nn(C)cc3c2)c1-c1ccccn1

Procedure:
The following compounds are prepared essentially as described in Example 5 using (6-bromo-pyridin-2-yl)-dimethyl-amine and either (1R,2R)-2-methyl-cyclopropanecarboxylic acid [4-bromo-3-(2-ethyl-2H-indazol-5-yl)-isothiazol-5-yl]-amide or (1R,2R)-2-methyl-cyclopropanecarboxylic acid [4-bromo-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amide. Example 7; is prepared as the free base by omitting treatment with hydrogen chloride.
Reaction SMILES: [O:1]=[C:2]([CH3:22])[CH2:3][C:4]1[C:5](=[O:21])[NH:6][CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=12.[CH2:23](O)[CH2:24][OH:25].B(F)(F)F.CCOCC.[OH-].[Na+]>C1C=CC=CC=1.O>[CH3:22][C:2]1([CH2:3][C:4]2[C:5](=[O:21])[NH:6][CH2:7][CH2:8][CH:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=4)[C:10]=23)[O:25][CH2:24][CH2:23][O:1]1
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=O)=C21
Reactant: OCCO
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CC3(C)OCCO3)=C21

Procedure:
The starting material is prepared as follows: The mixture of 20 g of 1-(2-oxopropyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one, 37.5 ml of ethylene glycol and 0.95 g of boron trifluoride etherate in benzene is refluxed under a water trap for 6 hours. It is cooled and 10 g of sodium hydroxide in 140 ml of water are added rapidly and the mixture is extracted with chloroform. The extract is dried, evaporated and the residue is crystallized from diethyl ether, to yield the 1-(2-methyl-1,3-dioxolan-2-yl-methyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one melting at 192°-194°.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]([C@H:18]2[CH2:23][O:22][CH2:21][C:20](=[O:24])[NH:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=CC=1)([O-])=O.ClCCl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:10][C@@H:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C@@H:18]1[NH:19][C:20](=[O:24])[CH2:21][O:22][CH2:23]1
Reactant: O=C1COC[C@H]([C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: O=C1COC[C@H]([C@@H](O)c2ccccc2)N1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
(S)-((3R)-5-Oxomorpholin-3-yl)(phenyl)methyl 4-nitrobenzoate (Preparation 7, 1.2 g) is treated with dichloromethane (10 mL), ethanol (30 mL) and potassium carbonate (1.0 g). After 2 h, the reaction mixture is filtered and the filtered solid is triturated with ethanol-dichloromethane (3:1 v:v, 3×30 mL). The filtrates are combined and concentrated under reduced pressure. The resulting residue is adsorbed onto silica gel and purified by flash column chromatography (methanol/CH2Cl2, 1-6%) to afford 0.61 g of the title compound. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 7.55, 7.4-7.2, 5.65, 4.61, 3.92, 3.9-3.8, 3.65-3.55, 3.44.