Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:10]=3[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[Cl:32][C:30]1[CH:29]=[CH:28][C:10]2[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:7][CH2:6]3)[C:9]=2[CH:31]=1
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(N)CC2)c2cc(Cl)ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(NC(=O)c3ccccc3)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
5-(4-Aminopiperidin-1-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (50 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (31 μL, 0.22 mmol), a solution of benzoyl chloride (10 μL, 0.11 mmol) in dichloromethane (0.2 mL) was added dropwise, and stirred at ambient temperature for 30 minutes. To the solution was added silica gel and the mixture was concentrated. Column chromatography eluting with a gradient of 50-100% ethyl acetate in hexanes provided N-(1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-yl)benzamide (35 mg, 57% yield). ESI m/z measured 551.2224 [M+H]+. calculated 551.2214.
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][Si](C(C)(C)C)(C)C)=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=2)[N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:4]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:3]1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C1COCC1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O.C(Cl)Cl.CCCCCC.C1COCC1>[O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:23]([CH3:26])([CH3:24])[CH3:25])[CH:10]=2)[NH:6][C@@H:5]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:4]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O[Si](C)(C)C(C)(C)C)c(C(C)(C)C)c2)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C[C@@H]2N[C@@H](c3ccccc3)[C@@H](c3ccccc3)OC2=O)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a 250 mL 3-necked flask equipped with a nitrogen inlet and a magnetic stirrer were added 4.51 g of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzyl)-4-morpholinecarboxylate and 50 mL of anhydrous THF. The solution was cooled in an ice water bath, treated with 7.51 mL of 1M nBu4NF/THF (Aldrich), and then allowed to warm to RT with stirring under nitrogen. After 1.5 h, tlc (SiO2, 85:15 hexane:EtOAc) indicated no remaining starting material and a single new component at Rf =0.52. The solution was diluted with 125 mL of EtOAc, washed with water (4×100 mL), dried over MgSO4, and concentrated to give a thick, clear oil. Mass spectral analysis (APCI) indicated the desired intermediate with m/e=538 (M+H+Na)+. The oil was dissolved in 50 mL of CH2Cl2 and the solution treated with 15 mL of TFA. After stirring for 40 min, tlc (SiO2, 65:35 hexane:EtOAc) indicated a single new component at Rf =0.36. The solution was neutralized by addition of saturated aqueous NaHCO3. The mixture was transferred to a separatory funnel and the layers separated. The CH2Cl2 solution was washed with additional saturated NaHCO3 (3×50 mL), dried over MgSO4 and concentrated in vacuo to give a clear foam. The crude product was purified by flash chromatography (SiO2, 7:3 hexane:EtOAc) to afford 2.66 g (89%) of (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-tert-butyl-4-hydroxybenzyl)morpholine as a white foam, m.p. 76-80° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:12][CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:5])[CH3:2].[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[N:12]([CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[CH3:18])[C:35](=[O:36])[CH2:34][C:29]1[NH:28][C:27]2[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=2[S:31](=[O:32])(=[O:33])[N:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1NCCC(C)(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1N(CCC(C)(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of cis-2-(3,3-dimethylbutylamino)-cyclohexanecarboxylic acid ethyl ester (60.0 mg, 0.243 mmol) in N,N-dimethylformamide (5.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 162.0 mg, 0.486 mmol) and a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.49 mL, 0.49 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with dichloromethane and the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration. The filtrate was concentrated and dried in vacuo to afford the crude product, cis-2-{(3,3-dimethylbutyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclohexanecarboxylic acid ethyl ester, as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C25H38N4O7S2 570.22, found 571.4 [M+H+].
Reaction SMILES: [CH3:1][C@H:2]([C@@:10]([OH:25])([C:17]1[CH:18]=[CH:19][C:20]([F:24])=[CH:21][C:22]=1[F:23])[CH2:11][N:12]1[N:16]=[CH:15][N:14]=[CH:13]1)[C:3]1[N:8]=[CH:7][N:6]=[CH:5][C:4]=1[F:9].[C@@:26]12([CH2:36][S:37]([OH:40])(=[O:39])=[O:38])[C:33]([CH3:35])([CH3:34])[CH:30]([CH2:31][CH2:32]1)[CH2:29][C:27]2=[O:28]>CO>[CH3:1][C@H:2]([C@@:10]([OH:25])([C:17]1[CH:18]=[CH:19][C:20]([F:24])=[CH:21][C:22]=1[F:23])[CH2:11][N:12]1[N:16]=[CH:15][N:14]=[CH:13]1)[C:3]1[N:8]=[CH:7][N:6]=[CH:5][C:4]=1[F:9].[C@@:26]12([CH2:36][S:37]([O-:40])(=[O:38])=[O:39])[C:33]([CH3:35])([CH3:34])[CH:30]([CH2:31][CH2:32]1)[CH2:29][C:27]2=[O:28]
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Agent: C[C@@H](c1ncncc1F)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CO
Product: CC1(C)C2CC[C@]1(CS(=O)(=O)[O-])C(=O)C2
Temperature: 52.5 °C
Reaction time: 2 h

Procedure:
A mixture of racemic Voriconazole (5 g, 14.3 mmol) and (1R)-(−)-10-camphorsulfonic acid (3.33 g, 14.3 mmol) in methanol (50 ml) was heated until solution at 50-55° C. The solution was cooled down to 22-24° C., stirred for 2 hours and filtered. A white crystalline solid was isolated.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:15]([F:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:9]=1.[C:28]([O:32][C:33](=[O:42])[NH:34][C@@H:35]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:36][NH2:37])([CH3:31])([CH3:30])[CH3:29]>O1CCOCC1>[C:28]([O:32][C:33](=[O:42])[NH:34][C@@H:35]([CH2:38][CH:39]([CH3:40])[CH3:41])[CH2:36][NH:37][C:8]1[C:15]([F:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:9]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: N#Cc1cc(F)c(Cl)nc1Nc1ccc2ncccc2c1
Reactant: CC(C)C[C@@H](CN)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)C[C@@H](CNc1nc(Nc2ccc3ncccc3c2)c(C#N)cc1F)NC(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 52 %

Procedure:
Potassium carbonate (139 mg) and 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (60 mg) were added to a tube containing a 1,4-dioxane (2 ml) solution containing (S)-tert-butyl(1-amino-4-methylpentan-2-yl)carbamate (76 mg) and the tube was sealed, followed by stirring with heating at 140° C. for 13.5 hours. The reaction solution was adjusted to room temperature and an insoluble precipitate was removed. Subsequently, the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1), and a white solid of (S)-tert-butyl(1-((5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-yl)amino)-4-methylpentan-2-yl)carbamate (50 mg) was thus obtained.
Reaction SMILES: [F:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:37]([F:41])([F:40])([F:39])[F:38]>C(OCC)C>[F:38][B-:37]([F:41])([F:40])[F:39].[F:1][CH2:2][S+:3]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:18]([CH3:20])[CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: CC(C)c1ccccc1
Reactant: Cc1ccc(S(=O)CF)cc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CF)c2ccccc2C(C)C)cc1

Procedure:
1-((Fluoromethyl)sulfinyl)-4-methylbenzene (738 mg, 4.29 mmol) of example 5 was dissolved in dry diethyl ether (15 mL) under an argon atmosphere. Cumene (0.66 mL, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −50° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.72 mL, 1 eq) was added slowly maintaining the same temperature. The mixture was stirred, at the same temperature, until the reaction was complete. HBF4 in diethyl ether solution (54%, 1.18 mL, 2 eq) was added. The resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration and washed with diethyl ether at 0° C. The desired product was obtained as a slightly yellow oily solid (2.22 g) after heating at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C@@H:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]=1)[C:6]#[CH:7].[CH3:23][C:24]1[N:28]=[C:27]([C:29]2[CH:30]=[C:31](I)[CH:32]=[CH:33][CH:34]=2)[O:26][N:25]=1>CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C@@H:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]=1)[C:6]#[C:7][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:27]2[O:26][N:25]=[C:24]([CH3:23])[N:28]=2)[CH:30]=1
Reactant: Cc1noc(-c2cccc(I)c2)n1
Reactant: C#C[C@@H](CC(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](C#Cc1cccc(-c2nc(C)no2)c1)c1ccc(OC)c(OC2CCCC2)c1
Yield: 31.7 %

Procedure:
A solution of (R)-methyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylpropionate (150 mg, 0.5 mmol) and 3-(3-methyl[1,2,4]oxadiazol-5-yl) iodobenzene (144 mg, 0.5 mmol) in Et3N (4 ml) was treated with tetrakis(triphenylphosphine)palladium(0) (10 mg) and copper(I)iodide (10 mg). The reaction was heated to 55° for 30 min, and then the solvent was thoroughly evaporated. The residue was purified by flash chromatography (silica gel CH2Cl2 :hexane:Et2O/10:10:1) and gave the titled compound as an oil (73 mg, 17%) 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1 H), 8.02 (m, 1 H), 7.60 (m, 1 H), 7.60 (t, 1 H), 6.95 (m, 2 H), 6.86 (d, 1 H), 4.80 (m, 1 H), 4.33 (t, 1 H), 3.84 (s, 3 H), 3.72 (s, 3 H), 2.92 (d of d, 1 H), 2.82 (d of d, 1 H), 2.48 (s, 3 H), 1.78-2.02 (m, 6 H), 1.62 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[N:7]=[C:6]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1.C([O-])=O.[NH4+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[N:7]=[C:6]2[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1
Reactant: COc1cc2nc(C)nc(Oc3ccc([N+](=O)[O-])cc3)c2cc1OC
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc2nc(C)nc(Oc3ccc(N)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 3 h
Yield: 1257.6 %

Procedure:
A mixture of 6,7-dimethoxy-2-methyl-4-(4-nitro-phenoxy)-quinazoline (0.081 g, 0.236 mmole), Pt/S (0.008 g, 15 mol %), ammonium formate (0.098 g, 1.56 mmol) and EtOH (3 mL) was heated with stirring at 70° C. for 3 hours. The reaction mixture was then filtered while hot and washed with hot EtOH. The crude product of 4-(6,7-dimethoxy-2-methyl-quinazolin-4-yloxy)-phenylamine (0.924 g) was obtained as a yellow solid, which was used in the next reaction without further purification. LC/MS: m/z 312 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28]Cl>>[CH3:25][O:26][CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1
Reactant: COCCCl
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Product: COCCOc1ccc(CCc2ccc3cc(C(C)NC(C)=O)oc3c2)cc1
Yield: 25 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (32.3 mg, 0.100 mmol) obtained in Example 165 and 2-chloroethyl methyl ether (0.0189 mL, 0.200 mmol) and in the same manner as in Example 158, the title compound was obtained (9.4 mg, yield 25%) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S(O[CH2:57][C@H:58]2[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:57][C@H:58]5[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]5)=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@H]5COC(C)(C)O5)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution of 115 mg (0.177 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.5 ml of N,N-dimethylformamide, 111 mg (0.388 mmol) of (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate and 73.5 mg (0.532 mmol) of potassium carbonate were added, and the mixture was stirred at 90° C. for 4 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=80/20-59/41 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 113.3 mg of the title compound as a white solid (yield: 84%).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:24]=O)=[C:19]2[C:23]=1[O:22][CH:21]=[CH:20]2.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[Cl:14][C:15]1[C:23]2[O:22][CH:21]=[CH:20][C:19]=2[C:18](/[CH:24]=[CH:3]/[C:1]#[N:2])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)c2occc12
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#C/C=C/c1ccc(Cl)c2occc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl cyanomethylphosphonate (7.34 g) in dry tetrahydrofuran (20 ml) was added to a suspension of sodium hydride (60% oil dispersion; 1.65 g) in THF (40 ml) over 5 mins with ice cooling. After 15 min, a solution of 7-chloro-benzofuran-4-carbaldehyde in THF (20 ml) was added and after 5 mins the solution was warmed up and stirred at room temperature for 2 h. Brine (40 ml) and ethyl acetate (40 ml) were added, the phases separated and the aqueous extracted with ethyl acetate (2×20 ml). The extracts were dried (MgSO4) and evaporated and the residue crystallised from ethanol to give off-white fluffy needles (2.95 g) of (E)-3-(7-Chloro-benzofuran-4-yl)-acrylonitrile.
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]([CH2:38][S:39][C:40]5[N:41]([CH3:45])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>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]([CH2:38][S:39]([C:40]5[N:41]([CH3:45])[CH:42]=[CH:43][N:44]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4nccn4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4nccn4C)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methylimidazol-2-yl)sulfanyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (116 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, the mixture was stirred for 1 hour at −10° C. to −25° C. To the mixture was added an aqueous solution of sodium thiosulfate, and 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=1:8), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methylimidazol-2-yl)sulfinyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (122 mg) (Compound 359) as yellow amorphous.
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@H:9]4[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13][C@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[S:3](=[O:24])[CH2:2]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]1[N:11]2[C:12]3[C:8]([C@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[S:3](=[O:24])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCS3=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1CCN2c3c(cccc31)[C@H]1CNCC[C@H]12
Yield: 35.7 %

Procedure:
The title compound (28 mg, 17%) was prepared by treatment of tert-butyl(6bS,10aR)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3-oxide (110 mg) with excess TFA in CH2Cl2 at 0 C. followed by treatment with 1 N aq. NaOH. 1H NMR (300 MHz, CDCl3) 1.79-1.99 (m, 1H), 2.10 (d, 1H, J=12.2 Hz), 2.39-2.57 (m, 1H), 2.72-3.01 (m, 3H), 3.01-3.22 (m, 2H), 3.22-3.51 (m, 3H), 3.61-3.72 (m, 1H), 6.69-6.89 (m, 1H), 7.17 (d, 1H, J=7.0 Hz), 7.42 (d, 1H, J=9.6 Hz) ppm; CI MS m/z=249 [C13H16N2OS+H]+.
Reaction SMILES: CI.[CH3:3][N:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:20][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([N:4]([CH3:3])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CN(c1ccccc1)c1ccc(C(=O)O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(N(C)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Methyl iodide (227 mg, 0.1 mL, 1.68 mmol) was added drop wise to a suspension of 4-(Methyl-phenyl-amino)-benzoic acid (120 mg, 0.56 mmol) and K2CO3 in DMF (5 mL). The resulting mixture was heated at 80° C. with stirring overnight. The mixture was filtered, cold water was then added, and the product was extracted with EtOAc. The organic layer was washed with saturated brine solution and dried over Na2SO4. The organic layer was then concentrated under reduced pressure to get the residue The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 5% EtOAc in Hexane as eluent) to afford 85 mg (75% yield) of 4-(Methyl-phenyl-amino)-benzoic acid methyl ester. 1H-NMR (CDCl3): δ 7.8 (d, 2H), 7.4 (T, 2H), 7.2 (m, 2H), 6.8 (d, 2H), 3.8 (s, 3H), 3.2 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: OCCCCCCBr
Product: O=C(CCCc1ccccc1)OCCCCCCBr
Yield: 72 %

Procedure:
From 6-bromo-1-hexanol and 4-phenylbutyric acid. Working up by means of distillation. Yield: 72%. Boiling point: 158° C. (0.01 mbar)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][CH2:12][S:13]([NH2:16])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].O>N1C=CC=CC=1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][CH:10]([CH2:11][CH2:12][S:13](=[O:15])(=[O:14])[NH2:16])[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: NS(=O)(=O)CCC(O)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(CCS(N)(=O)=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of hydroxyl-sulfonamide 5 (77 g, 0.30 mol) in pyridine (730 mL, 9.5 vol) was cooled to <10° C. in a 2 L round bottom flask. Tosyl chloride (56.6 g, 0.30 mol) is added to the solution over 5 minutes maintaining the internal temperature below 10° C. The reaction was allowed to warm to room temperature with stirring overnight. The completed reaction was poured into water (10 vol, 770 mL) to give an orange solution which was extracted with iPrOAc/MTBE (1:1, 2×1.5L). The combined organics were washed with brine (2×500 mL), aqueous HCL (2M, 2×500 mL) then brine (1×500 mL). The organic portion was dried (Na2SO4), filtered and evaporated to give sulfonate 6 as an orange oil (78 g).