Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].CCN(C(C)C)C(C)C.[Cl:14][S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[F:27])[C:21](Cl)=[O:22])(=[O:17])=[O:16]>C(Cl)Cl>[F:27][C:26]1[CH:25]=[CH:24][C:20]([C:21](=[O:22])[NH:4][CH2:1][C:2]#[CH:3])=[CH:19][C:18]=1[S:15]([Cl:14])(=[O:17])=[O:16]
Reactant: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: C#CCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC(=O)c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Propargylamine (0.67 mL, 10.5 mmol) and DIEA (1.83 mL, 10.5 mmol) in DCM (10 mL) were added dropwise to 3-(chlorosulfonyl)-4-fluorobenzoyl chloride (2) in DCM (10 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 15 minutes. The reaction was washed with 2N HCl and brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep) to give product as an oil (2.52 g, 87%).
Reaction SMILES: [CH2:1]([N:8]([CH:27]([CH3:29])[CH3:28])[C:9]1[CH:26]=[N:25][C:12]2[CH2:13][N:14](CC3C=CC=CC=3)[CH2:15][CH2:16][O:17][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]([CH:27]([CH3:29])[CH3:28])[C:9]1[CH:26]=[N:25][C:12]2[CH2:13][NH:14][CH2:15][CH2:16][O:17][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(Cc1ccccc1)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(Cc1ccccc1)c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of N,8-dibenzyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (2.55 g) in methanol (20 mL) was added 20% Pd(OH)2/C (260 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2 hr. 20% Pd(OH)2/C (500 mg) was further added, and the mixture was stirred under a hydrogen atmosphere at 50° C. for 4 hr. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (1.95 g, quantitative) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([N:23]1[C:27]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:26][C:25]([CH:32]=O)=[N:24]1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([N:23]1[C:27]([CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:26][C:25]([CH2:32][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[N:24]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1C(C)(C)C
Yield: 74.5 %

Procedure:
Compound 52 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].C([O:17][CH:18]1[CH:22]([N:23]2[C:27]3[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=3[N:25]=[C:24]2Br)[CH2:21][CH:20]([CH2:35][O:36]C(=O)C)[CH:19]1[O:40]C(=O)C)(=O)C>CN(C)C=O>[Cl:32][C:30]1[C:29]([Cl:33])=[CH:28][C:27]2[N:23]([CH:22]3[CH:18]([OH:17])[CH:19]([OH:40])[CH:20]([CH2:35][OH:36])[CH2:21]3)[C:24]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:25][C:26]=2[CH:31]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCC1CC(n2c(Oc3ccccc3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Phenol (72 mg, 0.77 mmol) and anhydrous potassium carbonate (106 mg, 0.77 mmol) were stirred in dry N,N-dimethylformamide (5 mL) under nitrogen for 1.0 hour. (±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (400 mg, 0.770 mmol) was added and the mixture stirred at 80° C. (oil bath) for 18 hours. Volatiles were removed in vacuo and the residue partitioned between chloroform and water. The chloroform layer was dried (sodium sulfate) and volatiles evaporated. The residual oil was stirred in 4N ammonia in methanol (30 mL) at ambient temperature for 18 hours. Evaporation and chromatography of the residue on silica gel with elution by 2% methanol-chloroform gave (±)-(1R*, 2S*, 3S*, 5S*)-5-(5,6-dichloro-2-phenoxy-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as white solid foam from ethyl acetate (215 mg, 68%); 1H-NMR(DMSO-d6)δ: 7.98 and 7.71 (both s, 2, aromatic CH), 7.6-7.3 (m, 5, C6H5), 5.07 (d, J=6.4 Hz, 1, OH), 5.0-4.75 (m overlapping t at 4.95, J=3.1 Hz, total 2, NCH and OH), 4.71 (d, J=3.9 Hz, 1, OH), 4.5-4.35 (m, 1, OCH), 3.9-3.8 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.3-1.9 (m, 3, CH2 and CH); mass spectrum (CI): 409 (M+1).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]4[O:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34]>O1CCOCC1>[ClH:34].[NH:23]1[CH2:24][CH2:25][O:26][C@@H:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:11][N:10]=3)=[O:13])=[CH:20][CH:19]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc(-c4ccccc4)[nH]n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1cc(-c2ccccc2)[nH]n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of (S)-tert-butyl 2-(4-(5-phenyl-1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (120 mg, 268 μmol, Eq: 1.00) in dioxane (0.5 ml) was added 4M-HCl in dioxane (1.00 ml, 4.01 mmol, Eq: 15). The reaction mixture was stirred at 60° C. for 2 h. To the mixture was then added 10 ml of dioxane and the suspension was filtered off, washed with ether and dried under in high vacuum to give the target compound as a white solid (82.3 mg, 79.9%). MS (ISP): 349.2 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])[OH:4].[CH3:17][S:18](O)(=[O:20])=[O:19]>CO>[CH3:17][S:18]([O:4][CH:3]([CH2:2][NH2:1])[C:5]1[CH:10]=[C:9]([S:11](=[O:13])(=[O:14])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)O
Reactant: COc1ccc(S(N)(=O)=O)cc1C(O)CN
Solvent: CO
Product: COc1ccc(S(N)(=O)=O)cc1C(CN)OS(C)(=O)=O

Procedure:
Starting from (+)-α-aminomethyl-2-methoxy-5-sulphamoylbenzenemethanol treated with 1 equivalent of methanesulphonic acid in 2M solution in methanol, recrystallization in methanol and diethyl ether and drying in a desiccator under vacuum over phosphorus pentoxide, (+)-α-aminomethyl-2-methoxy-5-sulphamoylbenzenemethanol methanesulphonate was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[C:7]([NH:9][C:10]1[C:11]([NH:16][C:17]([O:19][CH:20](C2CCNCC2)[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:8])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[C:7]([NH:9][C:10]1[C:11]([NH:16][C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:23][CH2:22]2)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(Nc1ccccc1NC(=O)c1cccc([N+](=O)[O-])c1)OC(c1ccncc1)C1CCNCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2ccccc2NC(=O)OCC2CCN(c3ccncc3)CC2)c1
Yield: 23 %

Procedure:
A mixture of N1-(3-nitrobenzoyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl)-1,2-benzenediamine (370 mg, 0.78 mmol) and 5% palladium-on-carbon (200 mg) in ethanol (10 mL) was placed under an atmosphere of hydrogen (1 atm). After consumption of the starting material, the mixture was filtered through diatomaceous earth and the filtrate concentrated in vacuo. Recrystallization (methanol/diethyl ether) yielded 40 mg (12%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:26][C:27]([OH:29])=O)[C:13]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH:53]12[CH2:61][CH2:60][CH:57]([CH2:58][CH2:59]1)[CH2:56][NH:55][CH2:54]2.Cl>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:53]12[CH2:61][CH2:60][CH:57]([CH2:58][CH2:59]1)[CH2:56][N:55]([C:27]([CH2:26][N:14]1[C:15]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([CH2:19][CH3:20])=[N:18][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C:13]1=[O:30])=[O:29])[CH2:54]2
Reactant: C1CC2CCC1CNC2
Reactant: CCC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)O)c2c(C)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-1-carboxymethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.22 g), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (642 mg), 1-hydroxybenzotriazole (453 mg), 3-azabicyclo[3.2.2]nonane (419 mg) and triethylamine (1.55 ml) in N,N-dimethylformamide (30 ml) was stirred at room temperature overnight. Ethyl acetate and 0.1N aqueous hydrochloric acid were added to the reaction mixture, which was stirred for several minutes. The separated organic layer was washed with 1N aqueous hydrochloric acid, water twice, a saturated aqueous solution of sodium bicarbonate and brine, successively, and then dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was triturated in diisopropyl ether and collected by filtration to afford (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.23 g, 79.9%) as a crystalline powder.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2([CH2:19][C:20]([OH:22])=[O:21])O>ClCCl>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12]/[C:13]/2=[CH:19]\[C:20]([OH:22])=[O:21]
Reactant: O=C(O)CC1(O)CCc2c(Cl)cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C1\CCc2c(Cl)cccc21
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Trifluoroacetic acid (25.1 mL) was added to a stirred, chilled (ice-methanol bath) solution of 2-(4-chloro-1-hydroxy-1-indanyl)acetic acid (10.4 g, 0.05 mol) in dichloromethane (230 mL). After 30 min, the mixture was concentrated in vacuo. Dichloromethane was added to the residue and the mixture was concentrated in vacuo to give 6.5 g (68%) of a white solid. Recrystallization of 0.98 g from acetonitrile: 2-propanol mixtures gave 0.62 g of a white solid: m.p., 233°-234° C.; NMR (DMSO-d6): d12.15 (br, 1H, COOH), 7.30-7.81 (m, 3H, Ar), 6.41 (s, 1H, =CH), 3.00-3.06, 3.19-3.22 (2m's, 4H, 2×CH2), steady-state nOe; irradiation at 6.41 d, observed 19.7% nOe at 7.79.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:14][N:15]=[N+:16]=[N-:17])([F:13])[CH2:10][C@H:9]1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@](O)(COS(C)(=O)=O)C[C@H]1C(=O)NCC1C=CC=C(Cl)C=1F)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([CH2:14][N:15]=[N+:16]=[N-:17])([F:13])[CH2:10][C@H:9]1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@](F)(CN=[N+]=[N-])C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: CC(C)(C)OC(=O)N1C[C@@](O)(COS(C)(=O)=O)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Product: CC(C)(C)OC(=O)N1C[C@](F)(CN=[N+]=[N-])C[C@H]1C(=O)NCc1cccc(Cl)c1F

Procedure:
was obtained using the same protocols as described in Scheme B15 step A and B for the preparation of (2S,4R)-4-azidomethyl-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester starting from (2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-methanesulfonyloxy methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared from (2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as described scheme B13). MS (LC/MS): 474.1/476.2 [M+H]+, 472.1 [M−H]−; tR (HPLC conditions f): 2.180 min, 19F NMR (100 MHz, DMSO-d6) δ (ppm): −120, −150.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:17]=[C:16]([Cl:18])[C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:19])[CH:7]=1)(=[O:5])[CH3:4]>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([Cl:19])[C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:16]([Cl:18])[CH:17]=1)=[O:5]
Reactant: BrBr
Reactant: COC(=O)COc1c(Cl)cc(C(C)=O)cc1Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1c(Cl)cc(C(=O)CBr)cc1Cl
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of bromine (0.77 ml) in chloroform (10 ml) was added dropwise over 15 minutes to a stirred solution of the product from step (i) (4.16 g) in chloroform (40 ml) at 25° C. The temperature was raised to 40° C. for 1 hour and then stirring continued for a further 18 hours at ambient temperature. The solvent was removed in vacuo and the residual oil purified by flash chromatography on silica, eluting with dichloromethane, to give a crystalline solid. Recrystallisation from methanol gave methyl 4-bromoacetyl-2,6-dichlorophenoxyacetate, 1.88 g, as white crystals: m.p. 89°-90° C.; NMR (d6DMSO) δ 8.06 (2H, s), 4.93 (2H, s), 4.82 (2H, s), 3.72 (3H, s); m/e 355/357 (M+H)+, 1 Br pattern; calculated for C11H9BrCl2 O4 : C, 37.1; H, 2.3. found: C, 36.8; H, 2.4%.
Reaction SMILES: O=[C:2]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:5].C(OCC)(=O)C>CN(C=O)C.C1C=CC=CC=1>[CH:20]1[CH:19]=[CH:18][C:17]([CH:16]=[C:3]([C:4]2[O:5][C:9](=[O:10])[C:8]3[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[C:2]2[O:27][C:26](=[O:28])[C:25]3[C:24](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:23]=2)=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound 11 (4.0 g, 9.3 mmol) was mmol) was dropwise added under ice cooling. To the mixture, 8 drops of dry DMF was further added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed, and the residue was extracted with chloroform. The extract was washed with 1N.HCl, saturated aqueous NaCl soluticn, 4% NaHCO3 aqueous solution, and saturated aqueous NaCl solution and dried over MgSO4. The solvent was evaporated to give a pale yellow solid. The resultant product was dissolved in a mixed solution of benzene:ethyl acetate=1:1 and applied on a silica gel column for chromatography (developing solvent, benzene:ethyl acetate - 1:1). After removing the solvent from the eluent containing 2,2'-phenylethenilidene-bis(3,1-benzoxazine-4-one) [Compound 52], the residue was crystallized from isopropyl ether to give the Compound 52 in white solid (3.0 g, yield, 82%), which was recrystallized from the mixed solvent of benzene and n-hexane to give white crystal (2.5 g, yield, 68%). m.p., 214°-215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.C(O)(=O)C>O>[O:22]=[C:19]1[CH:20]=[CH:21][N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=3)=[CH:6][CH:7]=2)[CH:17]=[CH:18]1
Reactant: O=c1ccocc1
Reactant: CC1SC(=O)NN=C1c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC1SC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A stirred mixture of 5-(4-aminophenyl)-6-methyl-3H,6H -1,3,4-thiadiazine-2-one (0.54 g). 4H-pyran-4-one (0.26 g), glacial acetic acid (0.15 g) and water (20 ml) was heated under reflux for 24 hours to give a solid. 0.54 g. Recrystallisation from aqueous ethanol gave the title compound, 0.28 g, which darkened at 265° C. and sublimed at 273-275° C.
Reaction SMILES: [Br:1][C:2]1(Br)[CH:11]([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[C:3]1=[O:14].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>CC#N>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[C:3]=1[OH:14]
Reactant: Cc1ccc2c(c1)CC(C)C(Br)(Br)C2=O
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: CC#N
Product: Cc1ccc2c(O)c(Br)c(C)cc2c1
Temperature: 25 °C

Procedure:
A solution of 2,2-dibromo-3,6-dimethyl-3,4-dihydronaphthalen-1(2H)-one (61.2 g, 184 mmol) in MeCN (1.5 L) was cooled to −40° C. internal temperature using a dry ice/acetone bath. 1,8-Diazabicycloundec-7-ene (41.6 mL, 279 mmol) was added as a solution in MeCN (150 mL) and the reaction was allowed to warm to room temperature overnight. The majority of the reaction solvent was removed in vacuo and the residue taken up in EtOAc (1 L) and washed with 0.5 M HCl (1 L). The resulting aqueous layer was extracted with several portions of EtOAc and the combined organics were washed with brine. Following drying over anhydrous MgSO4 and concentration in vacuo, the resulting residue was absorbed directly onto 200 g silica gel and eluted on Isco silica gel column chromatography (0-20% EtOAc/hex) to afford 2-bromo-3,6-dimethylnaphthalen-1-ol. LCMS-ESI+ (m/z): [M]+ calcd for C12H11BrO: 251.1. found: 251.4.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]C1C=NC=CC=1)[CH2:4][CH2:3]2.Br[C:50]1[S:51][CH:52]=[CH:53][N:54]=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:50]1[S:51][CH:52]=[CH:53][N:54]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Brc1nccs1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3nccs3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-bromothiazole (0.015 g, 0.091 mmol) was used in place of 3-bromopyridine. The product was isolated after reverse phase preparative HPLC purification using Prep HPLC Method 7 as a beige solid (12.8 mg, 18% yield) bis TFA salt. LCMS: m/e 656.4 (M+H)+, 2.38 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.91 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 7.08 (d, J=3.7 Hz, 1H), 6.68 (d, J=4.0 Hz, 1H), 5.28 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.74 (br. s., 1H), 3.69 (dd, J=9.9, 5.3 Hz, 1H), 3.43-3.36 (m, 1H), 2.13 (dd, J=17.2, 6.3 Hz, 1H), 2.05 (d, J=15.0 Hz, 1H), 2.01-1.79 (m, 6H), 1.73 (s, 4H), 1.70-1.46 (m, 8H), 1.46-1.27 (m, 6H), 1.27-1.22 (m, 2H), 1.22-1.10 (m, 2H), 1.07 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)=[C:9]=[S:10].[CH3:23][N:24]1[CH2:29][CH2:28][C:27]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)([C:30]#[N:31])[CH2:26][CH2:25]1.ClCCl.CC(C)=O>C1COCC1.CC(C)=O>[NH:31]=[C:30]1[C:27]2([CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[N:32]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)[C:9](=[S:10])[N:8]1[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:20])([F:22])[F:21])[CH:12]=1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: Cc1ccc(NC2(C#N)CCN(C)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C23CCN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
Triethylamine (0.02, 0.2 mmol) was added to a solution of 1a (0.228 g, 1 mmol) and 27a (0.114 g, 0.5 mmol) in dry THF (2 ml). The reaction mixture was stirred at room temperature for 20 h and then concentrated to yield a dark residue which was subjected to flash chromatography (dichloromethane/acetone, 90:10, and then acetone) to afford 27b (0.059 g, 0.13 mmol, 26%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)=O)=[CH:4][C:3]=1[O:24][CH3:25].[CH3:26][C:27]([S@:30]([NH2:32])=[O:31])([CH3:29])[CH3:28]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)=[N:32][S@@:30]([C:27]([CH3:29])([CH3:28])[CH3:26])=[O:31])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: CC(C)(C)[S@](N)=O
Reactant: COc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Solvent: C1CCOC1
Product: COc1cc(C(=N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a solution of (4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone (16 g, 43 mmol) in THF (70 mL) was added Ti(OEt)4 (15 g, 65.9 mmol), followed by the addition of (R)-2-methylpropane-2-sulfinamide (5.86 g, 48.3 mmol). The reaction mixture was heated at reflux for 16 h, allowed to cool to room temperature and quenched by addition of saturated NaCl. The resulting mixture was filtered and the organic solvent was removed under reduced pressure. The residue was purified by ISCO chromatography using hexanes/EtOAc (10-50%) to afford (R)-N-((4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide as an oil (15 g, 75%). LCMS: RT=4.01 min, [M+H] 468.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).