Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:39])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]3([CH3:35])[CH2:34][O:33][CH2:32]3)[NH:17][CH:16]2[C:36](O)=[O:37])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[CH2:43][O:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:45][C@H:44]([CH2:43][OH:42])[CH2:46][CH2:47][NH:48][C:36]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:39])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]2([CH3:35])[CH2:32][O:33][CH2:34]2)[NH:17]1)=[O:37]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(CC2NC(C(=O)NCC[C@H](O)CO)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Yield: 48.2 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 112c (0.5 g, 0.84 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.73 mL, 4.2 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.23 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[O:20]COC)=[O:9])([CH3:6])[CH3:5]>C(O)(C)C.O1CCCC1.Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5]
Reactant: COCOc1c(C(=O)NC(C)(C)C(=O)OC)ccc2c1CCCC2
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2c(c1O)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
1.023 g 2-[(1-methoxymethoxy-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester was dissolved in a mixture of isopropanol (8 ml), tetrahydrofurane (8 ml) and HCl conc. (4 ml). It was stirred at room temperature for one hour. The mixture was concentrated in vacuo, then 20 ml of ethyl acetate and 30 ml of water were added to the residue. The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo to afford 0.857 g of 2-[(1-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].Cl[CH2:13][S:14][CH3:15]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:13][S:14][CH3:15]
Reactant: CSCCl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCOc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.2 %

Procedure:
To a solution of 2,4-dichloro-phenol (10 g, 61.35 mmol) in dry DMF (100 mL) was added NaH (2.06 g, 85.89 mmol, 60% in mineral oil). The mixture was stirred for 30 min. at room temperature followed by dropwise addition of chloro-methylsulfanyl-methane (5.65 mL, 67.48 mmol) and stirring was continued for 16 hrs at ambient temperature. The reaction was quenched by addition of water (150 mL) and extracted with diethyl ether (2×100 mL). The combined organic phases were washed with saturated aq. ammonium chloride (2×100 mL), dried (Na2SO4), filtered and evaporated in vacuo afforded 17 g crude 2,4-dichloro-1-methylsulfanylmethoxy-benzene which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[Cl:28])[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16]C(=O)C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(S(N)(=O)=O)C=CC=CC=1.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[Cl:28])[CH:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16][C:39]([C:40]([CH3:43])([CH3:42])[CH3:41])=[O:44])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)NCCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: NS(=O)(=O)c1ccccc1
Product: CC(CCCNC(=O)C(C)(C)C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 86 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl)-N-[4-[[(1,1-dimethylethyl)carbonyl]amino]-1-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-4-(acetylamino)butyl]benzenesulfonamide by reacting 4-chloro-N-[2,5-dichlorophenyl]-N-[R]-1-methyl-4-aminobutyl]benzenesulfonamide with pivaloyl chloride. Yield=86%; MS (ESI+), 505 (M+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.C([Li])CCC.[CH:40]([OH:43])([CH3:42])[CH3:41]>>[CH:40]([O:43][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)([CH3:42])[CH3:41]
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CC(C)O
Agent: [Li]CCCC
Product: CC(C)Oc1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 20 (30 mg, 0.06 mmol) with 2 equivalents each of n-butyl lithium and isopropyl alcohol by the procedure described in Reference Example 6 and 7 to afford the title compound: HPLC/MS: m/e=521 (M++1); Rt=4.93 min. 1H-NMR 400 MHz (CDCl3): δ 1.33 (d, J=6 Hz, 6H), 5.02-5.09 (m, 1H), 6.90-6.94 (m, 1H), 7.04-7.10 (m, 1H), 7.12-7.28 (m, 7H), 7.35 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][S:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1ccc(SCCCCN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(SCCCCNS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
To a solution of 7.2 g of 4-[4-(acetamido)phenylthio]butaneamine (Example 70) in 100 ml of dichloromethane containing 8 ml of triethylamine is added 6.2 g of 4-methylbenzenesulfonyl chloride. The mixture is then stirred under reflux for six hours. The solvents are removed in vacuo. The residue is triturated with 2 portions of 100 ml of water. The insoluble portion is recrystallized from aqueous ethanol. Initially, the product precipitates as an oil, but after standing, crystals are obtained, m.p. 104°-105° C.; yield, 6.6 g.
Reaction SMILES: [CH3:1][C:2]12[CH2:9][O:8][C:5]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)([O:6][CH2:7]1)[O:4][CH2:3]2.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH3:1][C:2]12[CH2:3][O:4][C:5]([C:10]3[O:11][C:12]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=3)([O:6][CH2:7]1)[O:8][CH2:9]2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC12COC(c3ccco3)(OC1)OC2
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C23OCC(C)(CO2)CO3)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
2-(4-Methyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)furan (2.0 g, 10.2 mmol) was dissolved in THF (20 ml) and the solution was cooled to −78° C. n-Buli (1.6M solution in hexanes, 7.7 ml, 12.32 mmol) was added and the mixture stirred at −78° C. for 30 min, allowed to warm to 0° C. for 20 min. and then recooled to −78° C. The tributyltin chloride (3.5 ml, 4.68 g, 14.4 mmol) was added and stirring was continued at −78° C. for 15 min. The mixture was allowed to warm gradually to room temperature and stirring continued for three days. The reaction was quenched by the addition of water, and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), and concentrated in vacuo to give the title compound as a yellow oil (4.7 g, 9.7 mmol, 95%); δH [2H6]DMSO 6.52 (1H,d), 6.38 (1H,d), 3.96 (6H,s), 0.77-1.63 (30H,m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)=[O:1]
Reactant: OCc1ccc(-c2cccc3cncn23)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(-c2cccc3cncn23)cc1

Procedure:
A solution of 5-(p-hydroxymethylphenyl)imidazo[1,5-a]pyridine (0.52 g) in 10 ml of methylene chloride is refluxed with 5.2 g of activated manganese dioxide for 24 h. An additional 5.2 g of manganese dioxide is added and the reaction mixture is refluxed an additional 6 h, filtered, and the solvent is evaporated to yield 5-(p-formylphenyl)-imidazo[1,5-a]pyridine, m.p. 144°-146°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
With cooling on ice, an anhydrous N,N-dimethylformamide (DMF) solution (70 ml) of 1H-indole-2-carboxylic acid ethyl ester (45 g, 0.238 mol) was added dropwise to a solution of 50% sodium hydride (13.7 g, 0.286 mol) in anhydrous N,N-dimethylformamide (DMF) (90 ml). After one and half hour of stirring with cooling on ice, the reaction mixture was warmed to room temperature, and then stirred for one hour. After cooling on ice, an anhydrous N,N-dimethylformamide (DMF) solution of benzenesulfonyl chloride (50.4 g) was added dropwise, and the resulting mixture was stirred for one hour. An aqueous solution of 0.5 N hydrochloric acid was added dropwise to the reaction mixture, and then water was added thereto. The mixture was stirred for 30 minutes. The resulting solid was collected by filtration, and washed with water and then with n-hexane. The solid was dissolved in ethyl acetate, and washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give crude 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester. The obtained crude product was recrystallized (ethyl acetate/hexane) to give 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester (68.9 g, 79%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[CH2:25]([CH2:27][NH2:28])O>CS(C)=O>[N+:20]([C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:28]3[CH2:27][CH2:25][O:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1)([O-:22])=[O:21]
Reactant: NCCO
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NC(=O)C(Cl)(Cl)Cl
Solvent: CS(C)=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C2(c3ccccc3)OCCN12
Temperature: 100 °C
Yield: 56.6 %

Procedure:
To a solution of 7.75 g of 2-trichloroacetamido-5-nitrobenzophenone in 50 ml. of dimethylsulfoxide was added 1.47 g of monoethanolamine, and the mixture was heated at 100°C for 2 hours. After cooling, the reaction mixture was poured into 500 ml. of water and the resulting precipitate was collected by filtration, washed successively with water and ether to give 3.52 g of 9-nitro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one, having a melting point of 275°-276°C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][C@H:13]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][C@H:13]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:11]
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](N)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
In a 100 mL round-bottomed flask, (S)-ethyl 1-((S)-2-(tert-butoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (220 mg, 507 μmol, Eq: 1.00) was combined with DCM (10 mL) to give a colorless solution. TFA (5 mL, 64.9 mmol, Eq: 128) was added and the reaction was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with DCM (2×10 mL), the combined organic layers dried over Na2SO4, and then concentrated in vacuo to give (S)-ethyl 1-((S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (140 mg), m/z=334 (M+H).
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:24].C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:24])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCCCN(CCCC)CCCOc1ccc(C(N)=O)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
6.5 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.02 mol) is dissolved in 60 mL of n-hexane. 2.50 g of ammonium hydroxide (0.02 mol, 1 eq) and 2.76 g of potassium carbonate (0.02 mol, 1 eq) are added. The reaction mixture is heated to 50° C. and stirred for 3 hours. After the reaction the solid inorganic salt is filtered, washed with 2×5 mL of n-hexane and the filtrate is concentrated. The residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 5.34 g of the title compound (VIa) (87%) as a yellowish solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:28]3[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Cn1ccnc1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3nccn3C)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 1-methylimidazole
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc3[nH]c(=O)c4ccccc4c23)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Compound 83 (100 mg, 0.43 mmol), 1-Boc-piperazine (161 mg, 0.87 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), X-Phos (21 mg, 0.04 mmol), and NaOtBu (167 mg, 1.73 mmol) were suspended in dioxane (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with EtOAc/H2O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 50 to 100% EtOAc in hexanes to provide 178 (70 mg, 42% yield) as a yellow solid. LC-MS (M+H=381, obsd.=381).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(C(C)(C)C)(C)C.[CH3:28]CCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[OH-].[Na+]>[CH3:28][O:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[CH2:16][CH2:15][CH:14]([C@H:12]3[CH2:13][C@H:11]3[CH2:10][CH2:9][OH:8])[CH2:19][CH2:18]2)=[N:25][CH:24]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1C[C@@H]1C1CCN(c2ccc(CO)cn2)CC1
Agent: [F-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCc1ccc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The (6-{4-[(1R,2S)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyridin-3-yl)methanol (2.471 ml, 0.494 mmol) was dissolved in THF (1.236 ml) and TBAF (0.741 ml, 0.741 mmol) added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with 1N NaOH (50 ml), extracted with EtOAc (3×30 ml), the organic fractions combined, washed with brine, dried over sodium sulfate, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel, Biotage 25 g, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 291 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][C@H:9]([C:31]([O:33][CH3:34])=[O:32])[CH2:10][O:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)C=CC=CC=1.[ClH:47]>CO.C(OCC)C>[ClH:47].[CH2:28]([NH:27][C:25]([NH:24][C:20]1[CH:19]=[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C@@H:9]([C:31]([O:33][CH3:34])=[O:32])[NH2:8])[CH:13]=2)[CH:23]=[CH:22][CH:21]=1)=[O:26])[CH2:29][CH3:30]
Reactant: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC)c2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](N)C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl N-triphenylmethyl-O-(3′-{[(propylamino)carbonyl]amino}-1,1′-biphenyl-3-yl)-L-serinate (Example 4) (291.2 mg, 0.48 mmol, 1 equiv) was dissolved in MeOH and treated with a 1 M solution of HCl in diethylether at rt. The solution was stirred for 2 h at rt and then the solvents were removed in vacuuo. The crude product was titurated with ether to give a yellow precipitate which was filtered off and dried in vacuo. Yield 195.0 mg, 99%. 1H NMR (DMSO, 200 MHz) δ 8.85 (brs, 2H); 7.82 (s, 1H); 7.55 (d, 2H); 7.49-7.22 (m, 3H); 7.05 (d, 2H); 4.85-4.55 (m, 1H); 4.49-4.29 (m, 2H); 3.80 (s, 3H); 2.92 (dd, 1H); 1.60-1.29 (m, 3H); 0.96 (t, 3H).
Reaction SMILES: N1(C(Cl)=O)CCOCC1.[N:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.C1(C)C=CC=CC=1>C(O)C>[N:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[O:35][C:36]1[CH:37]=[CH:38][C:39]([NH:40][C:19]([NH:18][C:16]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:17])=[S:20])=[CH:41][CH:42]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)N1CCOCC1
Agent: O=C(N=C=S)N1CCOCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4CCOCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
4-Morpholinecarbonyl isothiocyanate was prepared using commercially available 4-morpholinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Morpholinecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 62%).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11]>ClC1C=CC=CC=1>[C:13]1([S:10]([N:9]([CH3:8])[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3])(=[O:12])=[O:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CNS(=O)(=O)c1ccccc1
Solvent: Clc1ccccc1
Product: CN(S(=O)(=O)N=C=O)S(=O)(=O)c1ccccc1
Temperature: 120 °C
Yield: 58.7 %

Procedure:
44 g (0.31 mole) of chlorosulfonyl-isocyanate are added to a solution of 50 g (0.29 mole) of benzenesulfonic acid methylamide in 150 ml of chlorobenzene, and the whole is heated at 120°C for 4 hours with agitation. The distillation yields 47 g (58 %) of phenylsulfonyl-methylaminosulfonylisocyanate having a boiling point of 125° -128°C/ 0.03 torr.