Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].BrCCCC[C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:16]([NH:18][C:19](=[O:20])[C:14]=12)=[O:17]>CN(C)C=O>[N:1]1([CH2:23][CH2:13][CH2:14][CH2:15][N:18]2[C:19](=[O:20])[C:14]3[C:15](=[CH:21][CH:22]=[CH:23][CH:13]=3)[C:16]2=[O:17])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1cncn1
Reaction time: 1.5 h
Yield: 172.7 %

Procedure:
A mixture of about 9.0 g of 1H-1,2,4-triazole, about 6.24 g of approximately 50% sodium hydride in oil and about 130 ml of dimethylformamide was stirred for about 1.5 hours, then about 33 g of bromobutylphthalimide was added and this mixture was heated on a steam bath for about 6 hours, then concentrated to a solid residue. Water and methylene chloride were added, the organic layer was separated, washed with water, dried and concentrated to a residue. This residue was recrystallized from ethanol, giving about 27.3 g of 2-[4-(1H-1,2,4-triazol-1-yl)butyl]-1H-isoindol-1,3(2H)-dione.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([N:5]2[CH2:6][CH:2]([OH:1])[CH2:3][C@H:4]2[C:7]([OH:9])=[O:8])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C(O)[C@@H]1CC(O)CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC(O)C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To a solution of 100 g (763 mmol) of 4-hydroxy-L-proline in 750 ml of water was added 169.9 g (1602 mmol) of sodium carbonate at 0° C. along with 174.5 g (916 mmol) of 4-toluenesulfonyl chloride (added in 3 portions over a period of 1 hour). The slurry was then warmed to room temperature and allowed to stir for 48 hours. The reaction was acidified with concentrated hydrogen chloride solution to pH 2 and the product was isolated via filtration. The filter cake was washed with pH 2 buffer and dried in a vacuum oven at 60° C. for 16 hours to obtain 215.3 g of the product as a white crystalline solid in 99% yield. M.P.=149°-151° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)=[S:4].[N-:13]=[N+:14]=[N-:15].[Na+]>O1CCCC1.O>[N:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)=[S:4])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C(=S)CBr)ccc1O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=S)CN=[N+]=[N-])ccc1O
Reaction time: 5 h

Procedure:
To a solution of the product of Step A (150.5 g, 0.576 mole) in tetrahydrofuran (1 liter) cooled to 20° C., add dropwise sodium azide (37.4 g, 0.576 mole) in water (450 ml) and stir for five hours. Partially evaporate the solvent and extract the concentrated reaction mixture with chloroform. Dry the organic phase and evaporate in vacuo to obtain 2-azido-4'-hydroxy-3'-methylthioacetophenone, mp. 124°-129° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=O)=[C:8]([O:15][CH2:16][CH3:17])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH3:51])[C:29]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[NH:28]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH3:51])[C:29]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)([CH3:30])[NH:28][C:10]([C:9]3[CH:13]=[CH:14][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=3[O:15][CH2:16][CH3:17])=[N:26]2)=[CH:21][CH:20]=1
Reactant: CCOc1cc(S(=O)(=O)CC)ccc1C(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(S(=O)(=O)CC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-ethanesulfonyl-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 4-ethanesulfonyl-2-ethoxy-benzoyl chloride (prepared from ethyl 2-ethoxy-4-fluoro-benzoate and sodium ethanethiolate) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([Cl:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[C:12]([C:13](=[O:14])[C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[CH:4]=2)=[CH:16][CH:17]=[C:18]([CH3:20])[N:19]=1
Reactant: Clc1cccc(Br)c1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccc(Cl)c2)c(Cl)n1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
Magnesium (4.8 g, 200 mmol) was added to a tetrahydrofuran (400 ml) solution of 3-bromochlorobenzene (38 g, 200 mmol), and the mixture was stirred at room temperature. Since spontaneous exothermic reaction occurred, the stirring was continued until the exothermicity was ceased. The reaction solution was cooled to -40° C., mixed with 2-chloro-6-methylnicotinic acid (9.2 g, 53 mmol) and then stirred overnight at room-temperature. The reaction solution was mixed with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (chloroform) to give 2-chloro-3-(3-chlorobenzoyl)-6-methylpyridine (6.25 g, 44%) as an oily material.
Reaction SMILES: [Br:1][C:2]1[C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.CCOC(C)=O>CC(N(C)C)=O>[Br:1][C:2]1[C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:35][C:32]3[CH:33]=[CH:34][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(c1cccnc1Br)S(=O)(=O)c1ccc(F)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CN(c1cccnc1Br)S(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 130 °C

Procedure:
To a solution of N-(2-bromo-pyridin-3-yl)-4-fluoro-N-methyl-benzenesulfonamide (0.1 g, 0.28 mmol) from Step B in dimethylacetamide (2 ml) was added K2CO3 (0.08 g, 1.0 mmol) and 4-trifluoromethoxyphenol (0.051 g, 0.28 mmol). The mixture was microwaved/heated at 130° C. (PMAX 130 on CEM Reactor) for 15 minutes. The reaction mixture was diluted EtOAc and washed with saturated NaCl and water. The organic phase was dried over sodiumsulfate and concentrated. The crude was purified through chromatography (20-50% EtOAc in hexanes) MS 502.6 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([OH:19])=O)=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH:43]([O:45][CH2:46][CH2:47][O:48][NH2:49])=[CH2:44].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH:43]([O:45][CH2:46][CH2:47][O:48][NH:49][C:17]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:20])=[CH:14][C:13](=[O:15])[N:12]([CH3:16])[CH:11]=1)=[O:19])=[CH2:44]
Reactant: C=COCCON
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cn(C)c(=O)cc1Nc1ccc(Br)cc1F
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture or 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.120 g, 0.352 mmol), EDCl (0.10 g, 0.53 mmol), and HOBt (0.071 g, 0.53 mmol) in DMF (5 mL) was stirred for 3 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (0.071 mL, 0.70 mmol) was added followed by Et3N (0.098 mL, 0.70 mmol). After 2 hours, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHC3 solution and brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (3% MeOH in methylene chloride) gave 0.078 g (52%) clean desired product.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=4)=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[C:26](O)(=[O:30])[C@H:27]([CH3:29])[OH:28].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:30])[C@@H:27]([OH:28])[CH3:29])=[CH:22][CH:23]=4)=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Reactant: C[C@H](O)C(=O)O
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)C(=O)NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Reaction time: 0.25 h

Procedure:
1-{4-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]phenyl}methanamine (19 mg, 0.055 mmol), L-lactic acid (9.9 mg, 0.11 mmol, 2 equiv), N,N-diisopropylethylamine (48 μL, 0.27 mmol, 5 equiv) and (1H-benzotriazol-1-yloxy) (tripyrrolidin-1-yl) phosphonium tetrafluoroborate (43 mg, 0.082 mmol, 1.5 equiv) were combined in dichloromethane (1.5 mL) and stirred for 15 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (95:5 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.33 (1H, t, J=6.9 Hz), 8.30 (1H, d, J=8.5 Hz), 7.51 (1H, d, J=8.7 Hz), 7.36-7.32 (4H, m), 4.72 (2H, d, J=7.2 Hz), 4.41-4.33 (2H, m), 4.08-4.03 (1H, m), 1.46-1.38 (1H, m), 1.27 (3H, d, J=6.6 Hz), 0.60-0.55 (2H, m), 0.53-0.50 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 419.1700 [(M+H)+; calculated for C21H22F3N4O2: 419.1689].
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8](SC)[N:7]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21](O)C.O[O:25][S:26]([O-:28])=O.[K+]>O>[C:1]([C:5]1[N:9]=[C:8]([S:26]([CH3:21])(=[O:28])=[O:25])[N:7]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1nc(C(C)(C)C)nn1-c1c(Cl)cc(Cl)cc1Cl
Reactant: O=S([O-])OO
Reactant: CCO
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1nc(S(C)(=O)=O)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.5 g (0.01 mol) of 3-(tert-butyl)-5-methylthio-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole was added to 120 ml of 85% ethanol, and 24.6 g (0.04 mol) of Oxone (trade mark) was further added thereto. The mixture was stirred at room temperature for 4 hours. Then, water was added to such an extent that Oxone (as described above) remained in a small amount, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 3.0 g (yield: 78.9 g) of the desired compound as white powder. Melting point: 179°-180° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:27])[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[C:35]1(=[O:39])[O:38][CH2:37][CH2:36]1>C1COCC1>[Cl:19][C:18]1[CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:37][CH2:36][C:35]([OH:39])=[O:38])=[CH:22][CH:21]=2)[CH:15]=[C:14]([Cl:27])[C:13]=1[CH2:12][CH:9]1[CH2:10][CH2:11][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:28]
Reactant: O=C1CCO1
Reactant: O=C1C(Cc2c(Cl)cc(-c3ccc(O)cc3)cc2Cl)CCN1C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)CCOc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 11.3 %

Procedure:
Treat a solution of 1-cyclohexyl-3-(3,5-dichloro-4′-hydroxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one (55) (0.20 g, 0.47 mmol) in THF (3 mL) with a 1 molar solution of potassium tert-butoxide in THF (0.50 mL, 0.49 mmol) and stir for 5 minutes at room temperature. Add dropwise a solution of beta-propiolactone (0.038 g, 0.527 mmol) in THF (3 mL) and stir the reaction at room temperature for 16 hours under N2. Quench the reaction with 1 N HCl, extract with ethyl acetate and water, dry the organic layer (Na2SO4) and purify by normal phase chromatography (30 to 100% gradient of ethyl acetate in hexanes) to afford 26 mg (11%) of the title compound: LC-MS (ES+) m/z=exact mass calcd for C26H29Cl2NO4 489, found 490 and 492 (M+1 and M+3, 100%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>C1COCC1.C([O-])(O)=O.[Na+].CCOC(C)=O.O>[CH:17]1[C:18]2[CH:6]([CH2:5][O:4][C:2]([CH:20]([NH2:19])[CH2:21][CH2:22][CH2:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][CH:25]=3)=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CCCC(N)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
9-Fluorenylmethyl chloroformate (6.9 g) was added to biphasic mixture of tert-butyl 4-(4-aminobutyl)benzoate (5.7 g) in THF (100 mL) and saturated aqueous NaHCO3 (50 mL). The resulting mixture was stirred at r.t. for 1 h and then diluted with EtOAc and H2O. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography to give 7.4 g of tert-butyl 4-(4-(9-fluorenylmethoxycarbonyl)-aminobutyl)benzoate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[N:14]1[CH:19]=[CH:18][C:17]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: OB(O)c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cn(-c2ccncc2)c2ccccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a vial containing methyl 1H-indole-3-carboxylate (402 mg, 2.297 mmol), pyridin-4-ylboronic acid (847 mg, 6.89 mmol), copper (II) acetate (542 mg, 2.99 mmol), 4 {acute over (Å)} molecular sieves (4 g) and 1,10-phenanthroline (828 mg, 4.59 mmol) were added DCM (9 ml) and triethylamine (0.320 ml, 2.297 mmol). The mixture was stirred at RT for 4 days then filtered through a pad of Celite (washed with MeOH). Evaporation and purification by HPLC (after dilution with DMF and filtration) afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[CH3:21][C:22]1[CH:23]=[C:24]([NH:29][NH2:30])[CH:25]=[CH:26][C:27]=1[Cl:28].O>C(O)(=O)C>[Cl:28][C:27]1[CH:26]=[CH:25][C:24]([N:29]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][C:13]([C:14]([F:17])([F:16])[F:15])=[N:30]2)=[CH:23][C:22]=1[CH3:21]
Reactant: Cc1cc(NN)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1Cl
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]-4,4,4-trifluorobutane-1,3-dione (620 mg) and (3-methyl-4-chlorophenyl)hydrazine hydrochloride (425 mg) in acetic acid (2 ml) was refluxed for 1 hour. After cooling, the solvent was poured into water (50 ml) and stirred for 30 minutes. The resulting precipitates were collected by filtration and washed with water and dried in vacuo. The residue was recrystallized from ethanol to afford 1-(4-chloro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (569 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:6][O:7][C:8](=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:3].[Br:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][OH:64]>C(#N)C>[Br-:43].[C:26]([O:25][CH:5]([CH2:6][O:7][C:8](=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4][N+:2]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][OH:64])([CH3:3])[CH3:1])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: OCCCCCCCCCCCCCCCCCCCCBr
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CN(C)C)OC(=O)CCCCCCCCCCCCCCC
Solvent: CC#N
Product: CCCCCCCCCCCCCCCC(=O)OCC(C[N+](C)(C)CCCCCCCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCC
Product: [Br-]

Procedure:
Synthesis was performed as described in example 19 step b using 17.89 g Hexadecanoic acid 1-dimethylaminomethyl-2-hexadecanoyloxy-ethyl ester, 11.33 g 20-Bromo-icosan-1-ol and 500 ml acetonitrile. The crude product was recrystallized from chloroform/methanol 3:1 and purity of the product was judged by thin layer chromatography and 1H-NMR.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].O.[BrH:24].N([O-])=O.[Na+]>O1CCCC1>[Br:24][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c2c(Br)cccc2c1S(=O)(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
7-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (26 mg, 0.080 mmol, 1.0 equiv) was dissolved in 2 mL of a 1:1 solution of tetrahydrofuran:water to which 0.2 mL of concentrated aqueous HBr was added and the mixture was cooled to 0° C. NaNO2 (28 mg, 0.40 mmol, 5.0 equiv) was added in one portion, followed by CuBr (57 mg, 0.40 mmol, 5.0 equiv) 25 minutes later. The reaction was warmed to ambient temperature and stirred for 72 hours. The reaction mixture was partitioned between dichloromethane and water and extracted three times with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 388.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]2[C@:9]3([OH:29])[C@@H:14]([OH:15])[CH2:13][C@@H:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@:10]3([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[O:11][C:7]=2[CH:6]=1.[CH3:32][NH:33][CH3:34]>>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C@:10]23[C@H:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:13][C@H:14]([OH:15])[C@@:9]2([OH:29])[C:8]2[CH:30]=[CH:31][C:5]([O:4][CH2:3][CH2:2][N:33]([CH3:34])[CH3:32])=[CH:6][C:7]=2[O:11]3)=[CH:27][CH:26]=1
Reactant: CNC
Reactant: O[C@H]1C[C@@H](c2ccccc2)[C@]2(c3ccc(Cl)cc3)Oc3cc(OCCCl)ccc3[C@]12O
Product: CN(C)CCOc1ccc2c(c1)O[C@@]1(c3ccc(Cl)cc3)[C@H](c3ccccc3)C[C@H](O)[C@@]21O

Procedure:
100 mg (0.22 mmol) of (1S*,3S*,3aR*,8bS*)-6-(2-chloroethoxy)-3a-(4-chlorophenyl)-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-1,8b-(1H)-diol (Example 48A) are heated in 10 ml of 33% strength ethanolic dimethylamine solution in a closed apparatus at 70° C. under argon overnight. Cooling is followed by concentration. Column chromatography on silica gel 60 (mobile phase: dichloromethane/methanol/triethylamine 95:5:1) results in 89 mg (87% of theory) of the product as racemic mixture.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[N:21]=[C:22]2[N:27]([C:28](=[O:38])[C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:25][O:24][C:23]2([CH3:40])[CH3:39])=[O:19])(=O)=O.[CH3:41][S-:42].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]([CH2:16][NH:17][C:18]([C:20]2[N:21]=[C:22]3[N:27]([C:28](=[O:38])[C:29]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25][O:24][C:23]3([CH3:39])[CH3:40])=[O:19])=[C:9]([C:8]#[C:7][CH2:6][S:42][CH3:41])[CH:14]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCOS(C)(=O)=O)c(OCc1ccccc1)c2=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCC#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of intermediate 183, 3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynyl methanesulfonate (0.160 g, 0.28 mmol) in N,N-dimethylformamide (3 ml) was treated at 0° C. with sodium thiomethoxide (0.026 g, 0.37 mmol) and the resulting mixture stirred for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.114 g (78% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 2.28 (3H, s, SCH3), 3.45 (2H, s, SCH2), 4.05 (4H, m, 2×CH2), 4.69 (2H, d, J=6.1 Hz, NCH2), 5.31 (2H, s, OCH2), 6.98 (1H, m, aromatic), 7.15 (1H, dd, J=3 Hz and J=9.1 Hz, aromatic), 7.32–7.38 (4H, m, aromatics), 7.50–7.53 (2H, m, aromatics), 7.80 (1H, broad t, NH). HRMS (ESI+) calculated for C28H29FN3O4S [M+H+]: 522.1863. Found: 522.1844.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[C:16]1([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)(=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1)C1CCNCC1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(C(=O)c3ccccc3)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and phenyl(piperidin-4-yl)methanone. MS (+ESI) m/z 381 (MH+).