Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:19]4[CH:20]=[C:21]([C:24](OC)=[O:25])[CH:22]=[CH:23][C:18]=4[O:17][CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.[H-].C([Al+]C(C)C)(C)C.[OH-].[Na+].C(=O)([O-])O.[Na+]>CCCCCC.CO.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:19]4[CH:20]=[C:21]([CH2:24][OH:25])[CH:22]=[CH:23][C:18]=4[O:17][CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)N1CCC(c3cccnc3)C1)CCO2
Agent: CC(C)[Al+]C(C)C
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: O=C(N1CCC(c2cccnc2)C1)N1CCOc2ccc(CO)cc21
Temperature: -78 °C
Yield: 56.8 %

Procedure:
0.4 g of methyl 4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate and 10 ml of dichloromethane are placed in a 100 ml round-bottomed flask under a nitrogen atmosphere. The temperature of the reaction medium is lowered to −78° C. and then 5.44 ml of a molar solution of diisopropylaluminum hydride in hexane are added. The reaction mixture is left stirring at −78° C. for eighteen hours. The reaction mixture is hydrolyzed with methanol, then an aqueous sodium hydroxide solution and subsequently with a saturated aqueous sodium hydrogencarbonate solution. The aqueous phase is extracted three times with dichloromethane. The organic phases are combined, washed with water and with a saturated aqueous sodium chloride solution and dried over sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol 90/10 mixture. 0.21 g of {4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}methanol is obtained.
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC(F)(F)F.C([O:21][CH:22]([CH2:42][CH2:43][CH2:44][CH2:45][C:46](F)(F)F)[CH2:23][CH2:24][CH2:25][N:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[S:27]([CH3:30])(=[O:29])=[O:28])(=O)C>>[OH:21][C@H:22]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:23]#[C:24][CH2:25][N:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[S:27]([CH3:30])(=[O:28])=[O:29]
Reactant: CCOC(=O)CCCCCCN(CCCC(CCCCC(F)(F)F)OC(C)=O)S(C)(=O)=O
Agent: CC(=O)OC(CCCCl)CCCCC(F)(F)F
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1, except that, in Step A, the 1-chloro-4-acetoxy-9,9,9-trifluorononane (Example E). The product of Step A is thus ethyl 7-[N-(4-acetoxy-9,9,9-trifluorononyl)methanesulfonamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxy-9,9,9-trifluorononyl)methanesulfonamido]heptanoic acid (B).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:6][C:5]=1[CH2:20][C:21]([OH:23])=[O:22])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:29][CH2:30]O>>[CH2:29]([O:22][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:30]
Reactant: CCO
Reactant: O=C(O)Cc1cc(Nc2cccc([N+](=O)[O-])c2)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(Nc2cccc([N+](=O)[O-])c2)ccc1[N+](=O)[O-]

Procedure:
A solution of [2-nitro-5-(3-nitro-phenylamino)-phenyl]-acetic acid (0.49 g, 1.5 mmol) in EtOH (20 ml) is refluxed in the presence of 0.2 ml concentrated H2SO4 for 3 hours before it is concentrated. To the residue is added saturated NaHCO3. The mixture is extracted with ethyl acetate (30 ml×3). The organic layers are combined and dried with Na2SO4 to give [2-nitro-5-(3-nitro-phenylamino)-phenyl]-acetic acid ethyl ester: LC-MS: 346.0 (MH+).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:61]([NH2:63])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])[CH2:46][C:47](=[O:49])[OH:48])=[O:43])[CH2:38][CH2:39][S:40][CH3:41])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])[CH3:3].CCOCC>FC(F)(F)C(O)=O.C(S)(S)C>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:61]([NH2:63])=[O:62])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:51])[CH2:46][C:47](=[O:48])[OH:49])=[O:43])[CH2:38][CH2:39][S:40][CH3:41])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])[CH3:3]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: CC(S)S
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: 4 °C
Yield: 76.1 %

Procedure:
1.00 g of Boc-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (m.p. 197°-200° C. Anal. Calcd. (%) for C48H61N9O12S: C, 58.35; H, 6.22; N, 12.75. Found (%): C, 58.35; H, 6.43; N, 12.61) was dissolved in 5 ml of trifluoroacetic acid containing 0.2 ml of ethanedithiol and reacted at room temperature for 30 minutes. Then 100 ml of anhydrous ether was added to the reaction mixture, and the resulting precipitate was filtered and dried. This deprotected heptapeptide was dissolved in 20 ml of DMF containing 0.14 ml of triethylamine, and 0.40 g of glutaric anhydride was added under cooling with ice. After 17-hour stirring at 4° C., the reaction mixture was distilled in vacuo to remove the solvent, and 1N citric acid was added to the residue to form a precipitate. It was washed with water and recrystallized from 20 ml of methanol, giving 0.77 g of Glt-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ; yield 76.1%, m.p. 167°-170° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([C@H:27]2[CH2:31][CH2:30][N:29]([C@H:32]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=4)[C:33]3=[O:47])[CH2:28]2)[CH:23]=[C:24]([Cl:26])[CH:25]=1>C(#N)C>[Cl:26][C:24]1[CH:23]=[C:22]([C@H:27]2[CH2:31][CH2:30][N:29]([C@H:32]3[CH2:36][CH2:35][N:34]([C:37]4[CH:38]=[CH:39][C:40]([S:43]([NH:1][C:2]5[S:3][CH:4]=[CH:5][N:6]=5)(=[O:44])=[O:45])=[CH:41][CH:42]=4)[C:33]3=[O:47])[CH2:28]2)[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nccs1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
Synthesized according to General Procedure 12, Method B: To a stirred solution of 2-aminothiazole (88.8 mg, 0.89 mmol) in acetonitrile (1 mL) at 0° C. was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (152 mg, 0.89 mmol) dropwise and the reaction mixture was stirred at 0° C. for 15 min. To this was slowly added a suspension of 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]benzene-1-sulfonyl chloride (100 mg, 0.17 mmol) in acetonitrile (0.5 mL) and the reaction mixture was stirred at 0° C. for 15 min, the cooling bath was removed and the reaction mixture was stirred at RT for 30 min. The reaction mixture was then poured into water, the pH was adjusted to ˜7 with 1M HCl, and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. Purification by silica gel chromatography (0-10% MeOH in EtOAc) afforded the desired product as a solid (27 mg, 28%). 1H-NMR (400 MHz, DMSO-d6) δ 7.84-7.77 (m, 4H), 7.43-7.37 (m, 3H), 7.24 (d, J=4.6 Hz, 1H), 6.81 (d, J=4.6 Hz, 1H), 3.83-3.72 (m, 2H), 3.58 (t, J=8.8 Hz, 1H), 3.07-2.96 (m, 3H), 2.87 (td, J=8.6, 4.3 Hz, 1H), 2.34-2.20 (m, 2H), 2.11-2.02 (m, 1H) and 1.74 (dt, J=19.9, 6.9 Hz, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=537.3; tR=1.21 min.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[CH:12][C:3]=1[NH:4][CH:5]([CH3:11])[C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[CH:12][C:3]=1[NH:4][CH:5]([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C)Nc1ccc(F)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Ethyl 2-(2,3,4-trifluoroanilino)propionate (2.47 g) was dissolved in ethanol (40 ml) and an aqueous solution (3 mol/l; 10 ml) of sodium hydroxide was slowly added thereto at 0° C. After stirring at room temperature for 3 hours, the solvent was evaporated. After adding water, the residue was washed with chloroform. Next, hydrochloric acid (6 mol/l) was slowly added to the aqueous layer until pH value reached 1. Then the aqueous layer was extracted with IPE. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated to give the title compound (2.19 g) as colorless crystals. Various spectral data of this product was identical with those obtained in Example 23.
Reaction SMILES: C([S-])C.[Na+].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]3)=[C:18]([CH3:28])[CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1>CN(C=O)C>[CH3:28][C:18]1[CH:17]=[C:16]([S:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)(=[O:15])=[O:14])[CH:21]=[CH:20][C:19]=1[CH:22]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]1
Reactant: COc1ccc(S(=O)(=O)c2ccc(C3CCN(C)C3)c(C)c2)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)c2ccc(O)cc2)ccc1C1CCN(C)C1
Temperature: 100 °C

Procedure:
Sodium ethanethiolate (94 mg, 1.111 mmol) was added to a solution of 3-[4-(4-methoxy-benzenesulfonyl)-2-methyl-phenyl]-1-methyl-pyrrolidine (128 mg, 0.3705 mol) in DMF (2 mL) and the reaction mixture was heated at 100° C. for 4 hours. The solvent was evaporated under reduced pressure and the residue was purified via flash chromatography (DCM/MeOH/NH4OH) to give 4-[3-methyl-4-(1-methyl-pyrrolidin-3-yl)-benzenesulfonyl]-phenol as a white foam. The free amine was transformed in the corresponding hydrochloride (white foam) by addition of a small excess of HCl in 1,4-dioxane: MP=186.0-187.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[CH:12][CH3:13]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC=COc1ccccc1[N+](=O)[O-]
Yield: 91.9 %

Procedure:
2-Nitrophenol (142.0 g, 1.02 mole), allyl bromide (120.9 g, 1.00 mole), anhydrous potassium carbonate (140.0 g, 1.02 mole) and dry acetone (500 cc) were refluxed for 21 hours, and filtered to remove the potassium bromide. The residue was washed with acetone and the solvent was removed by rotary evaporation. The residue was partitioned between 200 cc of dichloromethane and water. The dichloromethane layer was washed with 200 cc of 10% potassium hydroxide, separated and the solvent was removed by rotary evaporation. The crude product was fractionally distilled at 124° C. at 2.0 mm. Hg to yield 164.7 g of product (91.9%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][CH:17](O)[CH:18]([CH3:21])[CH2:19][CH3:20])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:21][CH:18]([C:17]1[NH:7][C:8]2[C:9]([CH:16]=1)=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:19][CH3:20]
Reactant: CCC(C)C(O)Cc1cc(OC)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)c1cc2cc(OC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of tert-butyl[2-(2-hydroxy-3-methylpentyl)-4-methoxyphenyl]carbamate (2.65 g) in dichloromethane (25 mL) was added trifluoroacetic acid (5 mL) under ice-cooling. This mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Under an argon atmosphere, the residue was dissolved in N,N-dimethylformamide (30 mL), and then 2-bromomesitylene (1.50 mL), tetrakis(triphenylphosphine) palladium(0) (472 mg), and potassium carbonate (2.25 g) were added thereto. The mixture was stirred overnight at 150° C. The reaction mixture was cooled to room temperature, and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.46 g). 1H-NMR (CDCl3) δ ppm: 0.91 (3H, t, J=7.4 Hz), 1.32 (3H, d, J=7.0 Hz), 1.55-1.80 (2H, m), 2.75-2.90 (1H, m), 3.84 (3H, s), 6.15-6.20 (1H, m), 6.77 (1H, dd, J=2.4, 8.8 Hz), 7.02 (1H, d, J=2.4 Hz), 7.19 (1H, d, J=8.8 Hz), 7.77 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH3:1][C:2]1[C:7]([O:8][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(O)c(C)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3C)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
2,6-Dimethylpyridin-3-ol (165 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-(N,N-dimethylamino)pyridine (164 mg) were dissolved in 1,2-dichlorobenzene (4.5 ml) to prepare a solution which was then stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (116 mg, yield 83%).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9](=O)[CH2:10][C:4]2=[N:3][N:2]=1.CO>O1CCCC1>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][CH2:9][CH2:10][C:4]2=[N:3][N:2]=1
Reactant: O=C1Cc2nncn2-c2ccccc2N1
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCc1nncn1-2
Temperature: 25 °C

Procedure:
A mixture of 7.0 g of 5,6-dihydro-4H-[1,2,4]-triazolo-[4,3-a][1,5]benzodiazepin-5-one in 25 ml of tetrahydrofuran is added 9 ml of 10M boranedimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours, cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum and to the residue is added 100 ml of 2N sodium hydroxide. The mixture is refluxed for 5 hours, chilled and extracted with dichloromethane. The extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed under vacuum to give a solid. The solid is purified by chromatography on silica gel to give the desired product.
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.C1C=CC=CC=1>[CH2:21]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[C:2]([F:12])([F:1])[C:3]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCO
Product: FC(F)(c1ccccc1)C(F)(F)c1ccccc1CNCc1ccccc1

Procedure:
A mixture of 3.9 g. (0.0138 mole) of 2-(α,α,β,β -tetrafluorophenethyl)benzylamine, 1.77 g. (0.014 mole) of benzyl chloride, 2.5 g. of anhydrous potassium carbonate, and 25 ml. of benzene is stirred and heated to refluxing for about 40 hours. After filtration, the solvent is evaporated under reduced pressure, leaving the product as the residual oil. Purification is effected by column chromatography on 250 g. of silica, the product being eluted with 1% methanol in chloroform. The fractions that show one spot of rf 0.7 on a fluorescent silica thin layer plate developed with 5% methanol in chloroform are combined. Evaporation of the solvent under reduced pressure leaves the product as the residual oil. The base is converted to the hydrochloride salt by treating an ethanolic solution with a slight excess of 8N hydrogen chloride in ethanol. Dilution with absolute ether precipitates the hydrochloride as white crystals, m.p. 188°-189.5°C. Recrystallization from acetone yields a purified sample, m.p. 188.5°-190°C.
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][C:9]=2[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[Cl:27][CH2:14][C:12]1[CH:11]=[CH:10][C:9]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2CCCCCC2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a stirred solution of 78.7E (0.185 g, 0.6 mmol) in DCM (6 mL) and DMF (0.04 mL) at 0° C. was added thionyl chloride (0.08 mL, 1 mmol). The reaction was stirred at room temperature for one hour and then concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 78.7F as a colorless oil (0.165 g, 84% yield).
Reaction SMILES: [C:1]1([C:7]([CH:9]=[N+]=[N-])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][C:14](=[O:39])[C@:15]1([OH:38])[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@:29]([F:35])([C@@H:30]([OH:34])[CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:36])[CH:25]=[CH:26]2)[CH2:21][CH2:20]3)[CH2:17][C@H:16]1[OH:37]>CCOCC.CCCCC.CO>[Cl:12][CH2:13][C:14](=[O:39])[C@:15]1([OH:38])[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@:29]([F:35])([C@@H:30]([OH:34])[CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:36])[CH:25]=[CH:26]2)[CH2:21][CH2:20]3)[CH2:17][C@H:16]1[O:37][CH2:9][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:8]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: C=C(C=[N+]=[N-])c1ccccc1
Solvent: CCOCC
Solvent: CCCCC
Solvent: CO
Product: C=C(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl)c1ccccc1
Yield: 47.6 %

Procedure:
A solution of 2-phenyl-3-diazo-1-propene (prepared from 28.5 g of N-(2-phenyl-2-propenyl)ethyl carbamate, prepared as described in Example 4) in 700 ml of ether and 50 ml of pentane is diluted with 150 ml of methanol at 0°C and 10 g of 21-chloro-9-fluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions. After nitrogen evolution ceases the solvents are removed in vacuo and the residue is recrystallized from methanol to give 6.1 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[(2-phenyl-2-propenyl)oxy]-pregna-1,4-diene-3,20-dione, melting point 212°-214°C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.[S:10](Cl)(Cl)=O.C(O)C.[CH:17]1([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CCOCC.C(OCC)(=O)C.O>[CH:24]1([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1.[CH3:1][C:2]1[N:3]=[C:4]([C:7](=[S:10])[OH:9])[S:5][CH:6]=1
Reactant: Cc1csc(C(=O)O)n1
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1csc(C(O)=S)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 10 g. (0.07 moles) of 4-methyl-2-carboxythiazole and 50 ml. of thionyl chloride was refluxed for 22 hours and stirred for 72 hours at room temperature. The reaction mixture was concentrated under reduced pressure to a yellow oil which was flushed 2 times with methylene chloride. This acid chloride was slurried in 10 ml. of benzene. Not all went in solution and the insoluble material was removed by filtration. The benzene filtrate was added dropwise to a stirred, cooled and filtered solution of 15.4 g. (0.14 mole) of hydrated sodium sulfhydrate in 158 ml. of ethanol and 17.5 ml. of water at such a rate as to keep the temperature of the mixture at 10°-15°. After the addition was completed, the reaction mixture was stirred for 40 minutes at 5°-10° C. Most of the ethanol was removed under reduced pressure and the residue was dissolved in 90 ml. of water. The pH of the solution was lowered to 2.8 by addition of 6N hydrochloric acid and was maintained there while the mixture was extracted with 5 × 100 ml. of ethyl acetate. The extracts were combined, washed with ice water, dried over magnesium sulfate, filtered and evaporated to dryness to give a reddish solid. This was weighed, redissolved in 50 ml. of hot ethyl acetate and one equivalent of dicyclohexylamine was added. After a small amount of ether was added, crystals precipitated. After cooling for 1 hour they were removed by filtration, washed with ether and dried under high vacuum to give 10.81 g. (45.5%) of a yellow solid. NMR spectrum was consistent with the desired material.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(OC([N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:40]1[NH:39][CH:43]=[CH:42][CH:41]=1)(=[O:14])=[O:13])(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1
Yield: 29.9 %

Procedure:
2-Methylsulfonyl-N-[3-(1H-pyrrol-2-yl)-1H-indazol-5-yl]benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 365 mg of 1-(tert-butyloxycarbonyl)pyrrole-2-boronic acid, 20 ml of dimethylformamide, 1.87 ml of saturated aqueous sodium hydrogencarbonate solution and 24.5 mg of tetrakis(triphenylphosphine)palladium[0]. 108 mg of 2-methylsulfonyl-N-[3-(1H-pyrrol-2-yl)-1H-indazol-5-yl]benzenesulfonamide are thus obtained in the form of a pale green solid melting at 255° C. (analysis C18H16N4O4S2 % calculated: C, 51.91; H, 3.87; N, 13.45; O, 15.37; S, 15.40. % found C, 51.63; H, 3.87; N, 13.27; S, 15.21).