Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:22]([Si:26]([CH3:46])([CH3:45])[O:27][CH2:28][CH2:29][N:30]([CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C:31](=[O:34])[CH2:32]Cl)([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[C:41]([Si:38]([CH3:40])([CH3:39])[O:37][CH2:36][CH2:35][N:30]([CH2:29][CH2:28][O:27][Si:26]([CH3:45])([CH3:46])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:31]([CH2:32][O:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)=[O:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCC(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
(R)-tert-Butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (1.0 g, 3.741 mmol) was dissolved dry N,N-dimethylformamide (10 mL) and cooled in an ice bath. To this was added portionwise a 60% dispersion of sodium hydride in mineral oil (344 mg, 8.604 mmol). The mixture was then warmed to 10° C. for 0.5 hours, then cooled in an ice bath and N,N-bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-chloro-acetamide (2.13 g, 4.67 mmol) added slowly in dry N,N-dimethylformamide (5 mL). The reaction mixture was warmed to ambient temperature and stirred overnight. Analysis of the reaction mixture by 1H NMR indicated 75% conversion to product. The reaction mixture was cooled in an ice bath and a 60% dispersion of sodium hydride in mineral oil (68 mg, 0.748 mmol) added. After a few minutes N,N-bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-chloro-acetamide (0.46 g, 0.426 mmol) was added. The reaction mixture was warmed to ambient temperature over 1 hour. The reaction mixture was then poured into water (50 mL) and extracted with diethyl ether (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL). The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo to give (R)-[4-({bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-carbamoyl}-methoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid (2.2 g, 45.9%) which was used in step 14-E without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[CH3:32][O-:33].[Na+].O>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[C:5]([C:16]#[N:17])=[C:6]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[C:7]([C:8]#[N:9])=[C:2]([O:33][CH3:32])[N:3]=3)[N:21]=2)=[CH:26][CH:27]=1
Reactant: C[O-]
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(N2CCCCC2)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100.0 mg (0.21 mmol) of the compound from Example 4A are initially charged in 2 ml of dry methanol. 12.2 mg (0.23 mmol) of sodium methoxide are added to this solution, and the mixture is stirred at +65° C. for 20 h. After cooling to RT the reaction mixture is stirred into 2 ml of water and stirred at RT for 1 h. The precipitate that is formed is filtered off with suction and washed with 1 ml of cold water. Purification is carried out by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH3:1][C:2]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][OH:20])[O:16][C:15]3=[O:21])[CH:11]=2)[N:6]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:4][C:2]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][S:40]([CH3:39])(=[O:42])=[O:41])[O:16][C:15]3=[O:21])[CH:11]=2)[N:6]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])([CH3:1])[CH3:3]
Reactant: CC(C)(C)C1Cc2cc(N3C[C@H](CO)OC3=O)ccc2N1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C1Cc2cc(N3C[C@H](COS(C)(=O)=O)OC3=O)ccc2N1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
The alcohol prepared in Step 5 (11.3 g, 26.6 mmol) is dissolved in CH2Cl2 (125 ml) with triethylamine (11.0 ml, 79 mmol) and cooled to 0°. Methanesulfonylchloride (2.4 ml, 31 mmol) is added and the reaction stirred for 2 hours. Extra CH2Cl2 (100 ml) is added and the solution washed with water (100 ml) and brine (50 ml) then dried (MgSO4). Evaporation gave a gum which is chromatographed over silica gel (500 g) eluting with 25-60% ethyl acetate-hexane. The product is obtained as a white foam (10.95 g, 82%): HRMS (FAB): Calcd for m+Na=525.1672; Found: 525.1671. Anal: Calcd. for C25H30N2O7S: C, 59.74; H, 6.02; N, 5.57. Found: C, 59.44; H, 6.07; N, 5.49.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]#[N:9].C([O-])([O-])=O.[K+].[K+].[CH2:16]([O:18][C:19](=[O:22])[CH2:20][SH:21])[CH3:17]>CCO.C1COCC1>[CH2:16]([O:18][C:19]([C:20]1[S:21][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]=1[NH2:9])=[O:22])[CH3:17]
Reactant: CCOC(=O)CS
Reactant: N#CC1=C(Cl)CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2c(c1N)CCCC2
Temperature: 90 °C
Yield: 101.4 %

Procedure:
A 250 mL flask was charged with 2-chloro-cyclohex-1-enecarbonitrile (3.0 g, 21 mmol) in a 6:1 mixture of EtOH/THF (42 mL), K2CO3 (2.9 g, 21 mmol), and mercapto-acetic acid ethyl ester (3.5 mL, 32 mmol), after which it was fitted with a reflux condenser under N2 atmosphere and heated to 90° C. for 24 h. The mixture was filtered through a pad of diatomaceous earth, such as celite®, rinsing thoroughly with MeOH (400 mL). After concentration, the title compound was purified by FCC (60% ethyl acetate (EtOAc)/hexanes) to give an amber-colored oil (4.8 g). MS: 226.1. 1H NMR (400 MHz, CDCl3) δ ppm 5.35 (s, 2H), 2.71-2.64 (m, 2H), 2.36-2.26 (m, 2H), 1.87-1.77 (m, 4H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][C@H:18]2[C:19](=[O:32])[N:20]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.O>[C:28]([O:27][C:25](=[O:26])[NH:20][C@@H:21]1[CH2:22][CH2:23][C@H:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C:13]2=[O:33])[C@H:18]([CH2:19][OH:32])[CH2:24]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
To a solution of (1R,2S,5R)-tert-butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (4.55 g, 9.94 mmol) in THF (50 mL) and water (50 mL) was added NaBH4, and the mixture was stirred for 5 h at rt. After quenching the reaction with sat. NaHCO3, the product was extracted with EtOAc (2×). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give an oily residue, which crystallized upon tritulation with 4:6 EtOAc and hexane to provide pure ((1R,3R,4S)-4-((S)-3-(benzyloxycarbonyl)amino-2-oxopyrrolidin-1-yl)-3-(hydroxymethyl)cyclohexyl)carbamic acid tert-butyl ester (2.61 g).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:9]#[N:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:21].[OH-].[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH3:11])[C:9]([NH2:10])=[O:21])=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C#N)(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(N)=O)(c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
) A mixture of 0.020 mol of p-nitro-α-phenylhydratroponitrile and 28 ml of concentrated sulfuric acid solution (90%) is heated in a water-bath for 3.5 hours. The reaction mixture is poured onto crushed ice, neutralized with a sodium hydroxide solution and the product is extracted with chloroform. The organic layer is washed with water, dried and evaporated in vacuo and the residue is crystallized from ether, yielding 2.4 grams of p-nitro-α-phenylhydratropamide. (interm. 7)
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.CC(C)=O.Cl.[CH2:24]([N+:28]([O-:30])=[O:29])/[CH:25]=N\O>O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[C:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:1]=[CH:25][C:24]=1[N+:28]([O-:30])=[O:29]
Reactant: Cc1cc(C)c(N)c(C(=O)c2ccccc2Cl)c1
Reactant: O=[N+]([O-])C/C=N\O
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)c2ncc([N+](=O)[O-])c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-amino-2'-chloro-3,5-dimethylbenzophenone (1 g), acetone (50 ml), 20 % hydrochloric acid (20 ml) and methazonic acid (4.5 g, wet) was stirred for 2 hrs. at room temperature and refluxed for 4 hrs. The mixture was diluted with water, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by a column chromatography on silica gel to give 4-(2-chlorophenyl)-6,8-dimethyl-3-nitroquinoline as crystals, which was recrystallized from a mixture of methanol and chloroform. m.p. 130°-131° C. Yield 1.95 g (54.2 %).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[C:16](Cl)(Cl)(Cl)Cl>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[N:11][C:3]=1[O:2][CH3:1]
Reactant: COc1ncccc1C(=O)O
Reactant: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A mixture of 2-methoxy-nicotinic acid (5.00 g, 32.6 mmol), thionyl chloride (50 mL) and carbon tetrachloride (50 mL) was head at reflux for 2 h. The reaction mixture was allowed to cool and volatiles were removed on a rotary evaporator. The residue was co-evaporated three times with carbon tetrachloride to remove residual oxalyl chloride. Methanol (50 mL) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated and chloroform (150 mL) was added. The solution was washed with saturated aqueous sodium hydrogen carbonate (2×150 mL) and brine (150 mL), dried (magnesium sulfate), filtered, and evaporated to give 2-methoxy-nicotinic acid methyl ester (4.42 g, 81%) as a clear yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(C)(C)C.[Li]C(C)(C)C.CCCCC.CON(C)[C:29]([CH:31]1[CH2:33][CH2:32]1)=[O:30]>CCOCC>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=1[C:29]([CH:31]1[CH2:33][CH2:32]1)=[O:30]
Reactant: CON(C)C(=O)C1CC1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: Cc1ccc(N)c(C(=O)C2CC2)c1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
To a stirred solution of p-tolyl-carbamic acid tert-butyl ester (1.0 g, 4.8 mmol) in Et2O (10 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (6.5 mL, 11.1 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopropanecarboxylic acid methoxy-methyl-amide (0.92 g, 6.3 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (15 mL) and TFA (15 mL) and stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 0.80 g crude (2-amino-5-methyl-phenyl)-cyclopropyl-methanone as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[N:3]=1.CO.[Br-:24].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCCl>[Br:24][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[NH2:11])[N:4]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[N:3]=[C:2]2[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc(N)cc32)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N)cc32)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 147.7 %

Procedure:
3-Methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (301 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (80 ml) and methanol (40 ml) at room temperature. The mixture was heated to 80° C. and then the tetrabutylammonium tribromide (1.0 eq, 482 mg) was added. Stirring was continued for 10 minutes, and then the mixture was partitioned between diethyl ether and saturated aqueous sodium sulfite solution. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 hexanes/ethyl acetate) to give 5-bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (280 mg, 73.7%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:40][C:41](OC2C=CC=CC=2)=[O:42])[C:27](=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH:22][C:41]([NH:40][C:26]2[CH:25]=[C:24]([Cl:23])[CH:39]=[CH:38][C:27]=2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[O:42])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)cc1NC(=O)OCc1ccccc1
Yield: 62 %

Procedure:
960 mg (3.00 mmol) of 3-benzyloxycarbonylamino-4-methylbenzenesulfonamide and 1.14 g (3.00 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 8 to obtain 1.14 g (yield 62% of benzyl 2-{[(3-benzyloxycarbonylamino-4-methylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 2.30 (3H, s), 5.17 (2H, s), 5.36 (2H, s), 7.20 (1H, dd), 7.33-7.48 (1H, m), 7.63 (1H, d), 7.97 (1H, d), 8.11 (1H, s), 8.25 (1H, s), 9.27 (1H, s), 10.30 (1H, s), 12.20 (1H, br).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[I:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([I:14])=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccn2cc(C3CC3)nc12
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccn2c(I)c(C3CC3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
[step 2] 8-Chloro-2-cyclopropylimidazo[1,2-a]pyridine (2.23 g, 11.6 mmol) obtained in step 1 was dissolved in DMF (23 mL), N-iodosuccinimide (2.36 g, 12.7 mmol) was added, and the mixture was stirred at room temperature for 2 hr. To the mixture was added water (100 mL), and the precipitated crystals were collected by suction filtration to give 8-chloro-2-cyclopropyl-3-iodoimidazo[1,2-a]pyridine (3.46 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CON(C)C(=O)c1ccnc(N)c1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccnc(NS(C)(=O)=O)c1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
2-Amino-N-methoxy-N-methyl-isonicotinamide (575 mg, 3.16 mmol) was dissolved in pyridine (4 mL), followed by the addition of methanesulfonyl chloride (0.73 mL, 9.48 mmol). The reaction was subsequently warmed to 40° C. and stirred 5 h. The resultant mixture was quenched with 10% HCl, diluted with EtOAc, and the organic layer washed with 10% HCl and saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to produce the desired sulfonamide.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[O:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=2)=[CH:6][CH:5]=1.CC(C)([O-])C.[Na+].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][N:29]=1.C(OCC)(=O)C>O1CCCC1>[N:38]1([CH2:37][CH2:36][CH2:35][CH2:34][C:31]2[CH:32]=[N:33][C:28]([O:18][CH2:17][C:15]3[N:16]=[C:12]([CH:11]=[CH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=4)[O:13][CH:14]=3)=[N:29][CH:30]=2)[CH:42]=[CH:41][N:40]=[N:39]1
Reactant: OCc1coc(C=Cc2ccc(OC(F)(F)F)cc2)n1
Reactant: Clc1ncc(CCCCn2ccnn2)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(C=Cc2nc(COc3ncc(CCCCn4ccnn4)cn3)co2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.097 g, 0.34 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (4 ml) followed by addition of sodium tert-butoxide (NaOtBu) (0.040 g, 0.41 mmol). After stirring for 15 min at r.t. 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine (0.090 g, 0.38 mmol) is added slowly and stirred for further 1.5 h at r.t. Ethyl acetate (20 ml) is added; the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate) 5-(4-[1,2,3]triazol-1-yl-butyl)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyrimidine is obtained as a colorless solid. Yield 0.104 g (63%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:16]1[C:20]2[CH:21]=[C:22]([C:25](O)=[O:26])[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:12][C:25]([C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][S:16][C:20]=2[CH:21]=1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: NCc1cccc(Oc2ccccc2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1cccc(Oc2ccccc2)c1)c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
To a solution of 3-phenoxybenzylamine described in Preparation Example 4 (33 mg, 0.167 mmol) and benzothiazole-6-carboxylic acid (30 mg, 0.167 mmol) in tetrahydrofuran (1 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (89 mg, 0.20 mmol) and triethylamine (28 μl, 0.20 mmol), and the solution was stirred at room temperature for 17 hours. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (37 mg, 62%) was obtained as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].Cl.[CH2:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][C:8]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:9]
Reactant: c1ccc(Cc2cccnc2)cc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCCl)c1ccc(Cc2cccnc2)cc1
Yield: 86.6 %

Procedure:
In 15 ml of methylene chloride was suspended 8.1 g of anhydrous aluminum chloride, and 3.0 ml of 3-chloropropionyl chloride was added to the suspension with ice-cooling, after which 5.0 g of 3-benzylpyridine hydrochloride was added in small portions to the resulting mixture over 30 minutes. The resulting mixture was subjected to reaction at room temperature for one hour, and then the reaction mixture was added to 30 ml of iced water. The crystals thus precipitated were collected by filtration, and suspended in a mixture of 50 ml of ethyl acetate and 30 ml of water, after which the resulting suspension was neutralized with sodium hydrogen-carbonate with ice-cooling. Insolubles were removed by filtration, and the organic layer of the filtrate was separated, washed with 10 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 5.5 g (yield 86.6%) of pale yellow, oily 3-[p-(3-chloropropionyl)benzyl]pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30].CCN(CC)CC>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(CC(=O)OCc2ccccc2)ccc1N
Reactant: O=C=Nc1ccccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)OCc2ccccc2)ccc1NC(=O)Nc1ccccc1F
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a stirred solution of benzyl 4-amino-3-methoxyphenylacetate (1.36 g, 5 mmol) in THF (20 mL) was added 2-fluorophenyl isocyanate (561 ul, 5 mmol) and a catalytic amount of Et3N. The resulting mixture was stirred for 3 hr. The mixture was quenched by the addition of H2O (10 mL) and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with CHCl3 as eluent to give 2.06 g (q.y.) benzyl 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetate as a green oil. 1H-NMR (CDCl)3 δ3.63 (2H, s), 3.82 (3H, s), 5.14 (2H, s), 6.79-7.37 (12H, m), 8.01 (1H, d, J=7.8 Hz), 8.09-8.14 (1H, m).
Reaction SMILES: Br.CS(O[C@H:7]1[C:26]2[C@:21]([CH3:28])([CH2:22][CH2:23][C:24](=[O:27])[CH:25]=2)[C@@H:20]2[C@H:9]([C@H:10]3[C@:17]([CH3:29])([CH2:18][CH2:19]2)[C@@:13]([OH:30])([C:14](=[O:16])[CH3:15])[C:12](=[CH2:31])[CH2:11]3)[C@H:8]1OS(C)(=O)=O)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>C(O)(=O)C.CN(C)C=O>[N:37]([C:7]1[C:26]2[C@:21]([CH3:28])([CH2:22][CH2:23][C:24](=[O:27])[CH:25]=2)[C@@H:20]2[C@H:9]([C@H:10]3[C@:17]([CH3:29])([CH2:18][CH2:19]2)[C@@:13]([OH:30])([C:14](=[O:16])[CH3:15])[C:12](=[CH2:31])[CH2:11]3)[CH:8]=1)=[N+:38]=[N-:39]
Reactant: C=C1C[C@H]2[C@@H]3[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C1C[C@H]2[C@@H]3C=C(N=[N+]=[N-])C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(C)=O

Procedure:
In a manner similar to that described in Example 26, treat 6β,7β-dimethanesulfonyloxy-16β-methyl-16α,17α-oxido-4-pregnene-3,20-dione with hydrogen bromide in acetic acid; treat the resulting 6β,7β-dimethanesulfonyloxy-16-methylene-17α-hydroxy-4-pregnene-3,20-dione with sodium azide in dimethylformamide to obtain 6-azido-16-methylene-17α-hydroxy-4,6-pregnadiene-3,20-dione.