Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:24])=[CH:10][C:11]=3[C:12]([N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)=[N:13][C:4]=2[CH:3]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:24])=[CH:10][C:11]=3[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:29])[C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)=[N:13][C:4]=2[CH:3]=1
Reactant: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sc(C)cc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sc(C)cc32)CCN1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine (S)-7-chloro-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (33.3 g, 85.2 mmol) and 1,2-dichloroethane (DCE, 500 mL). Add formaldehyde (37% wt. in water, 6.91 g solution, 2.56 g, 85.2 mmol) in one portion and stir at ambient temperature for 5 minutes. Add sodium triacetoxyborohydride (3.41 g, 16.1 mmol) in portions over 5-10 minutes, keeping the pot temperature below 25° C. Stir at ambient temperature overnight. Add saturated aqueous sodium bicarbonate (333 mL). Stir for 15 minutes, and then separate layers. Extract the aqueous layer with methylene chloride (250 mL). Wash the combined organic layers with water (3×333 mL), dry over sodium sulfate, and then concentrate ins vacuo to a residue (>100% recovery). Purify the residue by flash column chromatography, eluting with (100% CH2Cl2 to 93/7 CH2Cl2/MeOH) 91.2% recovery of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 1.49 (m, 1H), 1.82 (m, 1H), 2.13 (m, 2H), 2.20 (s, 3H), 2.27 (s, 3H), 2.74 (m, 2H), 2.98 (bt, 1H), 3.19 (s, 3H), 3.32 (m, 2H), 3.77 (bm, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C[O-].[Na+:31]>CO>[Na+:31].[C:22]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:9]2)=[CH:4][CH:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2ccc(S(=O)(=O)O)cc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 3.75 g (16.8 mmol) of 7-amino-naphthalene-2-sulfonic acid (compound 1) was added 20 mL each of pyridine and acetic anhydride. The reaction was allowed to stir at ambient temperature for 24 hours. The black reaction was cooled in an ice bath and then 45 mL of methanol was added slowly. After 1 hour, a solution of sodium methoxide (425 mg of sodium in 10 mL methanol) was added. A precipitate formed. The suspension was allowed to stir for 2 hours and then the solid was collected by vacuum filtration and was washed with ethyl acetate. This provided 4.4 g of compound 130.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1([Cl:14])[CH2:9][C:8]1([CH3:13])[C:10](Cl)=[O:11]>[OH-].[Na+]>[Cl:6][C:7]1([Cl:14])[CH2:9][C:8]1([CH3:13])[C:10]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:11]
Reactant: NCC(=O)O
Reactant: CC1(C(=O)Cl)CC1(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C(=O)NCC(=O)O)CC1(Cl)Cl
Reaction time: 0.5 h
Yield: 74 %

Procedure:
2.0 g (0.027 mol) of glycine are dissolved in 7 ml of 4 N NaOH and 2,2-dichloro-1-methylcyclopropanecarbonyl chloride and 6.5 ml of 4 N NaOH solution are added in portions at 5 to 10° C., while cooling with ice, the pH being kept>8. The mixture is subsequently stirred for 30 minutes, the aqueous phase is extracted twice with ether and acidified to about pH 2 with 1 N HCl and the precipitate formed is filtered off with suction. After drying, 4.5 g (74% of theory) of N-(2,2-dichloro-1-methylcyclopropanoyl)-glycine of melting point 139-140° C. are obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][OH:13].C(N(CC)CC)C.[CH3:21][O:22][C:23]([CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])=[O:24].Cl>C1COCC1.O>[OH:13][N:12]([CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:23]([O:22][CH3:21])=[O:24]
Reactant: COC(=O)CCCC(=O)O
Reactant: ONCc1ccc2ccccc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCCC(=O)N(O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Into a solution of 52 mg (0.3 mmol) of 2-naphthylmethylhydroxylamine in THF (5 ml) and water (1 ml) was added 30 mg (0.3 mmol) of triethylamine, and then a solution of 49 mg (0.3 mmol) of acid chloride of 4-methoxycarbonylbutanoic acid in THF (1 ml), followed by stirring at room temperature for 30 minutes. 1N-HCl (5 ml) was added and the desired product was extracted with methylene chloride. The extract was successively washed with water, aqueous NaCl, and then dried over anhydrous magnesium sulfate to give a purified product, which was then subjected to silica gel column chromatography to obtain 58 mg (64%) of the desired product.
Reaction SMILES: C(OC([C@@:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:29])[C@H:9]([NH:16][C@@H:17]1[CH2:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[CH2:20][NH:19][C:18]1=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:10]1([C@@H:9]([NH:16][C@@H:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH2:20][NH:19][C:18]2=[O:28])[C@H:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[OH:29])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)[C@](O)(c1ccccc1)[C@H](N[C@@H]1Cc2ccccc2CNC1=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCc2ccccc2C[C@H]1N[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 478 mg (1.01 mmol) of 4(R)-[[t-butoxycarbonyl][(1R,2S)-1,2-diphenyl-2-hydroxyethyl]]amino-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one (Example 1, Step B) in 5 mL of methylene chloride at room temperature was treated with 0.5 mL of trifluoroacetic acid. The mixture was stired at room temperature for 3 hours then all volatiles removed under vacuum. The residue was dissolved in 5 mL of water and the solution made basic (pH 10-11) by the addition of solid sodium carbonate. The mixture was extracted with chloroform (5×) and the combined extracts dried over anhydrous potassium carbonate, filtered and solvents removed under vacuum to give 372 mg (1.00 mmol, 99%) of 4(R)-[[(1R,2S)-1,2-diphenyl-2-hydroxyethyl]]amino-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one which was used in the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][N:24]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=O)(C)(C)C.Cl>CCOC(C)=O>[C:38]([O:37][C:35](=[O:36])[CH2:34][N:24]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])[CH2:23][C@@H:9]1[CH2:10][C@@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:12][NH:8]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CN(CC(=O)OC(C)(C)C)Cc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2CN[C@H](CN(CC(=O)OC(C)(C)C)Cc3cc(F)ccc3F)C2)cc1
Yield: 75.7 %

Procedure:
397 mg (0.67 mmol) (2S,4R)-2-[[tert-butoxycarbonylmethyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester were treated with 4.2 ml 1N HCl in EtOAc at RT. The reaction mixture was concentrated and tituration with ether yielded 250 mg (76%) (2S,4R)-[(2,5-difluoro-benzyl)-[4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl]-amino]-acetic acid tert-butyl ester as light brown solid, which was transformed to (2S,4R)-2-[[tert-butoxycarbonylmethyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid butyl ester according to example 4b by treatment with butyl chloroformate.
Reaction SMILES: [O-]S(C(F)(F)[F:6])(=O)=O.F[N+]1C(Cl)=CC=CC=1Cl.[F:18][C:19]1[C:36]([NH:37][S:38]([CH2:41][CH2:42][CH3:43])(=[O:40])=[O:39])=[CH:35][CH:34]=[C:33]([F:44])[C:20]=1[C:21]([NH:23][C:24]1[CH:25]=[C:26]2[CH:32]=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1)=[O:22]>CC#N.CCOC(C)=O>[F:18][C:19]1[C:36]([NH:37][S:38]([CH2:41][CH2:42][CH3:43])(=[O:40])=[O:39])=[CH:35][CH:34]=[C:33]([F:44])[C:20]=1[C:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:32]([F:6])=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1)=[O:22]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(F)c3c2)c1F
Temperature: 60 °C
Yield: 25.9 %

Procedure:
1-Fluoro-2,6-dichloropyridinium triflate (31 mg, 0.1 mmol) was added to 2,6-difluoro-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (39 mg, 0.1 mmol) in MeCN (4 mL). The mixture was heated at 60° C. for 18 hours and then cooled to room temperature. The mixture was then diluted with EtOAc, washed with brine, dried over MgSO4 and concentrated. The crude product was purified using silica gel chromatography (ISCO) using 5% MeOH in CH2Cl2 as eluent, and subsequently reverse phase HPLC to give 2,6-difluoro-N-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (10.7 mg, 26%). 1H NMR (400 MHz, d6-DMSO) δ 11.51 (s, 3H), 10.97 (s, 3H), 9.77 (s, 3H), 8.41 (s, 6H), 7.70-7.38 (m, 6H), 7.26 (t, J=8.5, 3H), 3.45-2.96 (m, 32H), 2.50 (s, 57H), 2.36-2.09 (m, 1H), 1.77 (dd, J=7.5, 15.1, 6H), 1.00 (t, J=7.4, 9H); m/z (LC-MS) M+1=413.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:47]=[CH:46][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:45])([C:41]([F:44])([F:43])[F:42])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[CH:20][CH:19]=1>O1CCOCC1>[F:40][C:37]([F:38])([F:39])[C:36]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][CH:23]([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:16])=[CH:47][CH:46]=3)[CH2:28][CH2:27]2)=[CH:35][CH:34]=1)([OH:45])[C:41]([F:44])([F:43])[F:42]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 26.5 %

Procedure:
Phenyl pyridin-4-ylcarbamate (1.680 mmol, 0.36 g) was added to a stirred solution of 2-(4-((4-(4-aminobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.120 mmol, 0.5 g) in dioxane (20 mL) and the mixture heated in a microwave for 10 minutes at 130° C. followed by 5 minutes at 130° C. The mixture was washed with water (10 mL) and the organic phase dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by HPLC and concentrated under reduced pressure to afford the title compound (168 mg). MS (ESI) m/z 567.5 [M+H]+
Reaction SMILES: C([CH:5]([O:28][SiH](C)C)[C:6]1[C:7]([CH:25]2[CH2:27][CH2:26]2)=[N:8][C:9]([CH:22]([CH3:24])[CH3:23])=[C:10]([CH2:19][O:20][CH3:21])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:25]1([C:7]2[C:6]([CH2:5][OH:28])=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:10]([CH2:19][O:20][CH3:21])=[C:9]([CH:22]([CH3:24])[CH3:23])[N:8]=2)[CH2:26][CH2:27]1
Reactant: COCc1c(C(C)C)nc(C2CC2)c(C(O[SiH](C)C)C(C)(C)C)c1-c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: COCc1c(C(C)C)nc(C2CC2)c(CO)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.7 g (12.8 mmol) of the crude product from Example 148 are dissolved in absolute tetrahydrofuran. After addition of 12.8 ml of tetrabutylammonium fluoride solution (1M in THF) the mixture is stirred overnight at room temperature. 50 ml of saturated sodium hydrogen carbonate solution are then added and the mixture is extracted several times with methylene chloride. The combined organic phases are dried with sodium sulphate, concentrated and chromatographed over silica gel (eluent: petroleum ether/ethyl acetate 713).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH:9]([NH:10]C(OC(C)(C)C)=O)[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6]1)[CH:2]=[CH2:3].Cl.CO.CCOC(C)=O>C1COCC1.O1CCOCC1.C([O-])(O)=O.[Na+]>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([NH2:10])[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1CN(C(=O)OCc2ccccc2)CC1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a solution of 21.3 g (56.6 mmol) of benzyl 3-(allyloxy)-4-[(tert-butoxycarbonyl)amino]pyrrolidine-1-carboxylate in 125 mL of THF was added 250 mL of 4 N HCl in dioxane solution. The reaction mixture was stirred at room temperature for 2 h, concentrated under reduced pressure to give an oil residue. This residue was redissolved in 200 mL of saturated NaHCO3 aqueous solution. The mixture was adjusted to pH 7-8, then was extracted with ethyl acetate twice (100 mL×2). The combined extracts were washed with brine, dried over Na2SO4, evaporated under reduced pressure to give an oil residue. Chromatography on silica gel column with 5% MeOH-EtOAc provided the title compound (10.5 g, 68%). MS (M+H)+ 277.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]#[N:6].OO.C(=O)([O-])[O-:23].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]([NH2:6])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(F)c(Oc2ccc(C=O)cc2)c(F)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(Oc2ccc(C=O)cc2)c(F)c1
Yield: 99 %

Procedure:
Hydrolysis of the compound of step 1 using hydrogen peroxide and potassium carbonate in DMSO as described previously afford the above compound in 99% yield.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].[CH3:13][S:14]([N:17]([CH2:32][CH2:33][Cl:34])[N:18]([S:28]([CH3:31])(=[O:30])=[O:29])C(OC1C=CC=CC=1)=O)(=[O:16])=[O:15]>>[CH3:13][S:14]([N:17]([CH2:32][CH2:33][Cl:34])[N:18]([S:28]([CH3:31])(=[O:30])=[O:29])[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3])(=[O:15])=[O:16]
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Product: COc1ccc(OC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O)cc1

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-methoxyphenoxy)carbonyl]hydrazine (compound 10g) was prepared by reacting compound 2 with 4-methoxyphenyl chloroformate using a procedure similar to the one employed for compound 10d. The product was recrystallized from ethanol, and the yield was about 30.0% by weight. The Mp of the product was approximately 119-121° C. 1H NMR (CDCl3): δ 7.1 and 6.9 (4H, 2d, aromatic H), 3.6-4.2 (4H, m, CH2CH2Cl), 3.8 (3H, s, OCH3), 3.5 and 3.2 (6H, 2s, 2 CH3SO2).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:13][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)NCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-bromo-pyridine-2-carbaldehyde (1.06 g, 5.73 mmol) in dry CH2Cl2 (30 mL) was added isopropylamine (0.51 mL, 6.02 mmol). The mixture was stirred at RT and under N2 for 30 min followed by the addition of NaBH(OAc)3 (2.42 g, 11.46 mmol) and HOAC (1.3 mL, 22.92 mmol). The resulting cloudy light-yellow solution was stirred at RT and under N2 for 15 h. A 10% solution of Na2CO3 (50 mL) was added to the mixture and stirred for 30 min. The organic phase was separated, washed with H2O, brine, dried over MgSO4 and concentrated to afford a light yellow-oil without further purification. MS m/z: 229.1 (M+H). Calc'd for C9H13BrN2: 228.03.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[OH-:22].[Na+]>>[O:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:22])[CH:7]=3)[CH:13]=[CH:12][N:11]=2)[CH2:16][CH2:17]1
Reactant: [OH-]
Reactant: Fc1cc(-c2ccnc(NC3CCOCC3)c2)ccn1
Agent: Cl
Agent: [Na+]
Product: O=c1cc(-c2ccnc(NC3CCOCC3)c2)cc[nH]1
Temperature: 95 °C
Yield: 98 %

Procedure:
2′-Fluoro-N-(tetrahydro-2H-pyran-4-yl)-4,4′-bipyridin-2-amine (0.64 g, 2.3 mmol) was combined with 1M HCl (25 mL, 25 mmol) and heated to 95° C. for 3 hours. Upon cooling, the mixture was neutralized (pH 7-8) with of 1M NaOH (25 mL). The resulting slurry was cooled to 0° C. and filtered. The solids were washed with water and dried to give 4-(2-(tetrahydro-2H-pyran-4-ylamino)pyridin-4-yl)pyridin-2(1H)-one (0.62 g, 2.3 mmol, 98% yield) as a solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH:10]([CH2:20][OH:21])[CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N:22]([CH2:25][CH2:26][O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])=[C:23]=[O:24]>ClCCl.[Sn]>[CH2:14]([O:13][P:12]([CH2:11][CH:10]([CH2:20][O:21][C:23](=[O:24])[NH:22][CH2:25][CH2:26][O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: CCOP(=O)(CC(CO)CP(=O)(OCC)OCC)OCC
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: [Sn]
Solvent: ClCCl
Product: C=C(C)C(=O)OCCNC(=O)OCC(CP(=O)(OCC)OCC)CP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A solution of 2-hydroxymethyl-1,3-propylene-bisphosphonic acid tetraethylester (4.8 g, 13.8 mmol) in anhydrous dichloromethane (6.0 ml) was added to a 1% solution of the tin catalyst Metatin 712 in anhydrous dichloromethane (4.0 ml). Then isocyanatoethyl-methacrylate (1.96 ml, 13.8 mmol) was added dropwise, and the reaction mixture was stirred for 3 h at room temperature. After concentrating in vacuo the obtained crude product was purified by column chromatography (eluent: ethyl acetate/methanol 95:5). 6.0 g (86% yield) of the product was obtained as a colorless oil.
Reaction SMILES: O[C:2]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:4]=2[CH2:3]1.Cl>CC(O)=O.[Pd]>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:4]2[CH2:3][CH:2]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][C:5]=2[CH:13]=1
Reactant: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Cc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.3 %

Procedure:
10% Pd/C (242 mg, 0.23 mmol) was added to a solution of ethyl (±)-10,11-dihydro-10-hydroxy-3-methoxy-5H-dibenzo [a,d]cycloheptene-10-acetate (741.1 mg, 2.27 mmol) and conc. HCl (0.19 mL, 2.27 mmol) in glacial AcOH (23 mL), and the mixture was shaken on a Parr apparatus at RT under H2 (50 psi). After 6 h, the reaction was filtered through celite®, and the filter pad was washed with EtOAc. The filtrate was concentrated, and the residue was reconcentrated from toluene. The resulting faintly yellow, oily residue was chromatographed (silica gel, 20% EtOAc/hexanes) to afford the title compound as a colorless oil (643.6 mg, 91%): TLC Rf 0.57 (20% EtOAc/hexanes); 1H NMR (250 MHz, CDCl3) δ 7.05-7.22 (m, 4H), 7.01 (d, J=8.2 Hz, 1H), 6.76 (d, J=2.7 Hz, 1H), 6.67 (dd, J=8.2, 2.7 Hz, 1H), 4.30 (d, J=15.0 Hz, 1H), 4.11-4.25 (m, 2H), 3.85 (d, J=15.0 Hz, 1H), 3.70-3.90 (m, 1H), 3.77 (s, 3H), 3.31 (dd, J=15.0, 4.1 Hz, 1H), 2.93 (dd, J=15.0, 9.2 Hz, 1H), 2.64 (dd, J=15.6, 5.0 Hz, 1H), 2.52 (dd, J=15.6, 9.3 Hz, 1H), 1.27 (t, J=7.1 Hz, 3H); FTIR (CCl4) 1734, 1611, 1504,1285, 1263, 1155, 1044 cm-1 ; MS (ES) m/e 333.0 (M+Na)+, 328.0 (M+NH4)+, 311.0 (M+H)+, 265.0 (M+H-EtOH)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH:46]6[CH2:49][CH2:48][CH2:47]6)[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH:46]6[CH2:49][CH2:48][CH2:47]6)[CH:42]=[CH:43][N:44]=5)=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CC4CCC4)cc2)CCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CC4CCC4)cc2)CCN3CC(C)C)cc1
Yield: 67 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclobutylmethylimidazol-2-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (640 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (342 mg) in dichloromethane (15 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and an aqueous solution of sodium thiosulfate was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclobutylmethylimidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (439 mg) (Compound 361) as yellow amorphous.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.C(O)C.C(=O)([O-])O.[Na+].[NH2:18][C:19]1[N:20]=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=1>Br.O>[F:27][C:25]([F:26])([F:28])[C:23]1[CH:22]=[N:21][N:20]2[CH:8]=[CH:9][N:18]=[C:19]2[N:24]=1
Reactant: Nc1nncc(C(F)(F)F)n1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cnn2ccnc2n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 22.5 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (2.30 ml, 14.8 mmol) in concentrated hydrobromic acid (0.73 ml) and water (0.73 ml) was heated at reflux for 2 h, then poured into ethanol (25 ml). The solution was neutralised to pH 7 with solid sodium hydrogencarbonate, then filtered. To the filtrate was added 3-amino-5-trifluoromethyl-1,2,4-triazine (1.0079 g, 6.14 mmol) and the mixture was stirred at 60° C. for 20 h, then 80° C. for 23 h. The mixture was evaporated in vacuo, and the residue was purified by flash chromatography (silica gel, 35-50% EtOAc/isohexane) to give 0.2593 g (22%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 8.20 (1H, d, J 0.8 Hz), 8.30 (1H, d, J 0.9 Hz), 8.73 (1H, s).