Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][O:5][CH2:6][CH:7]=1.CN1CCOCC1.[N+:15]([C:18]1[CH:27]=[CH:26][C:21]([O:22][C:23](Cl)=[O:24])=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(Cl)Cl>[N+:15]([C:18]1[CH:27]=[CH:26][C:21]([O:22][C:23]([O:1][CH2:2][C:3]2[CH2:4][O:5][CH2:6][CH:7]=2)=[O:24])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCC1=CCOC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(OCC1=CCOC1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To 65 mg (0.65 mmol) of the compound from Example 336D in methylene chloride was added 0.079 mL of 4-methylmorpholine and 144 mg (0.715 mmol) of p-nitrophenoxycarbonylchloride. The mixture was stirred for 2 hours, diluted with solvent, washed with saturated brine, and the solvent removed. The residue was chromatographed on a silica gel column, eluting with 20% and 30% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.115 g of the title product.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNCCC(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 69.1 %

Procedure:
2.132 g (10.1 mmol) 3,3-diphenylpropylamine (Aldrich, Milwaukee, Wis.) was added to a mixture of 0.853 g (5.11 mmol) ethyl bromoacetate (Aldrich) and 2.7 g (19.57 mmol) potassium carbonate in 14 ml acetonitrile at rom temperature. The mixture was stirred under argon for 18 hours. The reaction mixture was filtered, the solvent evaporated and the residue chromatographed on a silica gel column with 40% ethyl acetate in hexanes to give 1.05 g (yield 69%) N-[(3,3-diphenyl)propyl]glycine ethyl ester (Compound A22) as an oil. NMR spectra of the product showed: 1H NMR (CDCl3, 300 MHz) 7.40–7.10 (m, 10 H), 4.14 (q, 2 H), 4.03 (t, 1 H), 3.33 (s, 2 H), 2.56 (t, 2 H), 2.24 (dt, 2 H), 1.22 (t, 3 H); 13C NMR (CDCl3, 75 MHz) 172.44, 144.66, 128.43, 127.75, 126.15, 60.63, 50.93, 48.80, 47.92, 35.85, 14.17, 0.019 g of A28 was also isolated from the silica gel column.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.[CH:23](O)=[O:24]>Cl(O)(=O)(=O)=O>[CH:23]([O:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1)=[O:24]
Reactant: O=CO
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Agent: [O-][Cl+3]([O-])([O-])O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](OC=O)C[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 20 h

Procedure:
The starting 11β-formyloxy-androst-4-ene-3,17-dione was prepared from 11β-hydroxy-androst-4-ene-3,17-dione by dissolving the latter in excess formic acid in the presence of a catalytic amount of perchloric acid and, after 20 hours at room temperature, pouring the reaction mixture on ice, extracting with methylene chloride and evaporating. There was obtained a product melting at 139°-139.5° (crystallized from ethyl acetate), [α]D25 = 188° (dioxane).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16]C)[C:12](=[O:18])[CH2:11][CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1>O>[CH2:1]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[C:12](=[O:18])[CH2:11][CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2c(cc1OC)C(=O)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCc1cc2c(cc1O)C(=O)CC2

Procedure:
5.6 g (22.7 mmol) of 5-hexyl-6-methoxyindan-1-one, 9.4 g of aluminium chloride and 125 ml of toluene are refluxed for 15 minutes. The mixture is poured into water and extracted with ether. The organic phase is dried (Na2SO4) and the solvents are evaporated off. The residue is purified by flash chromatography (4.5 g; 85%).
Reaction SMILES: CS(C)=O.O=C1CCC(=O)N1OC(=O)CCC(NC[CH:20]1[O:24][C:23]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]([N:32](CC)[C:33](=O)[C:34](F)(F)F)[CH3:31])=[CH:28][C:22]=2[O:21]1)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[CH3:34][CH2:33][NH:32][CH:30]([CH2:29][C:27]1[CH:26]=[CH:25][C:23]2[O:24][CH2:20][O:21][C:22]=2[CH:28]=1)[CH3:31]
Reactant: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCNC(C)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 500 mg of bovine serum albumin (BSA) in 6.7 mL of 50 mM potassium phosphate (pH 7.5) was cooled in an ice-bath. To the solution was added 8.5 mL of DMSO dropwise, and the reaction mixture was maintained below room temperature. To the protein solution was added a solution of 12 mg (0.022 mmol) of 2L in 1.5 mL of anhydrous DMF dropwise. The reaction mixture was allowed to stir at room temperature 48 hours. The resulting conjugate was placed in a dialysis tube (10,000 MW cut-off) and was dialyzed in 1 L of 70% DMSO in 50 mM potassium phosphate (pH 7.5, 3 changes, at least 3 hours each), 1 L of 50% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 30% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 10% DMSO in 50 mM potassium phosphate (at least 3 hours) at room temperature. The trifluoroacetamido group of the conjugate was deprotected by dialysis of the resulting conjugate against 10% ammonium hydroxide for 3 days (1 L each for approximately 24 hours each), followed by 6 changes with 50 mM potassium phosphate (pH 7.5) at 4° C. (1 L each). The protein concentration was determined to be 7.12 mg/mL using BioRad Coomassie blue protein assay (Bradford, M., Anal. Biochem. 72:248, 1976). A total of 45 mL of the conjugate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1ccc(Cl)c2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2ccc(Cl)c3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a solution of 64 mg (0.33 mmol) of 4-chloro-1H-indole-7-carboxylic acid and 91 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (25 g silica gel; heptane/EtOAc 7:3) to yield 104 mg (72%) product as a light yellow foam. MS (ISP) 479.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])=[CH:19][CH:18]=[C:17]([F:28])[C:13]=1[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:23])=[O:24])=[CH:19][CH:18]=[C:17]([F:28])[C:13]=1[C:14]([NH:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)=[O:15]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1Cl
Reactant: Nc1cnc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1Cl
Reaction time: 24 h
Yield: 25.5 %

Procedure:
1H-Pyrrolo[2,3-b]pyridin-5-amine (20 mg, 0.150 mmol) in N,N-dimethylformamide (1.5 mL) was sequentially treated with 2-chloro-6-fluoro-3-(propylsulfonamido)benzoic acid (48.9 mg, 0.165 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.7 mg, 0.165 mmol), and 1-hydroxybenzotriazole (22.3 mg, 0.165 mmol) at ambient temperature. After 24 hours, the reaction mixture was diluted with ethyl acetate and washed with water (4×), sodium bicarbonate (2×), and brine (1×), dried over sodium sulfate and concentrated. The crude product was triturated with dichloromethane to provide 2-chloro-6-fluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (61.7 mg, 0.0382 mmol, 25.4% yield) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.40-8.35 (d, 2H), 7.73-7.67 (q, 1H), 7.45-7.42 (d, 1H), 7.31-7.25 (t, 1H), 6.53-6.50 (d, 1H), 3.15-3.08 (t, 2H), 1.93-1.82 (m, 2H), 1.08-1.02 (t, 3H); MS (APCI-neg) m/z=409.1 (M-H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][N:15]=[N+]=[N-])[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][NH2:15])[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=NCCOc1cc(F)cc2c1OCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: NCCOc1cc(F)cc2c1OCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
A solution of 2-(6-fluorochroman-8-yloxy)ethylazide (4.12 g, 0.017 mol) and triphenylphosphine (6.83 g, 0.026 mol) in tetrahydrofliran (80 ml) and water (1.5 ml) was allowed to stir for 18 hours at room temperature. The solvent was removed under vacuum. Chromatography (ethyl acetate) removed triphenylphosphine and triphenylphosphine oxide and (40% methanol-methylene chloride plus ammonium hydroxide) afforded 3.45 g (94%) of product as a white solid: mp 68-70° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[S:6]1(=[O:24])=[O:23].[CH3:25][NH2:26].Cl>>[ClH:1].[F:22][C:17]1[CH:16]=[C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:26][CH3:25])[S:6]2(=[O:24])=[O:23])[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)c(F)c1
Reactant: CN
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccc(F)c(F)c2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 3-(3-chloropropyl)-1-(3,4-difluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (71 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(3,4-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methyl propan-1-amine hydrochloride (53 mg):
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14](=[O:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH3:21])C.[OH-].[Na+]>C(O)C>[C:15]1([C:14]([C:10]2[CH:9]=[C:8]([CH3:21])[C:7]([O:6][CH2:5][C:4]([OH:22])=[O:3])=[C:12]([CH3:13])[CH:11]=2)=[O:20])[S:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)COc1c(C)cc(C(=O)c2cccs2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)c2cccs2)cc(C)c1OCC(=O)O
Reaction time: 3 h

Procedure:
11 g of the ester obtained according to (C) were dissolved in 150 ml of aqueous ethanol (50/50) containing 2.7 g of sodium hydroxide; the solution was kept for 3 hours at 95° C., the ethanol evaporated under reduced pressure and the aqueous phase acidified. 9.4 g of the acid precipitated - m.pt.=115° C.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl.N([O-])=O.[Na+].[I-:17].[K+].S(=O)(=O)(O)O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([I:17])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1c(Cl)cccc1I
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
The title compound was prepared according to the method described in Collection Czechoslov. Chem. Commn., vol. 40, p. 719 (1975). To an ice-cold mixture of 2-amino-6-chlorobenzoic acid (10.0 g, 58.3 mmol) and conc. hydrochloric acid (50 mL), was added dropwise a solution of sodium nitrite (4.42 g, 64.1 mmol) in water (10 mL). Furthermore, a solution of potassium iodide (14.5 g, 87.5 mmol) and conc. sulfuric acid (4 mL) in water (30 mL) was added thereto at the same temperature, and the mixture was heated to 100° C. and stirred for 2 hours. The reaction mixture was allowed to cool to room temperature, poured into an aqueous sodium thiosulfate solution, and organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous sulfuric acid, and the solvent was evaporated under reduced pressure. The resulting crude crystals were collected by filtration, washed with hexane/diethylether, and air dried to give the title compound (12.1 g, 73% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 7 h
Yield: 97.7 %

Procedure:
6.8 g (29 mmol) of 4-bromo-N-methyl-2-nitroaniline was dissolved in 20 mL of pyridine. After the addition of 5.0 g (35 mmol) of benzoyl chloride, the mixture was stirred at 90° C. for 7 hours in an argon atmosphere. After completion of the reaction, 200 mL of ethyl acetate was added to the reaction solution. The organic phase was washed with a 10% hydrochloric acid aqueous solution, a 10% potassium carbonate aqueous solution, and a saturated sodium chloride solution, and dried over magnesium sulfate. After filtering the organic phase, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 9.5 g of 4′-bromo-N-methyl-2′-nitrobenzanilide as a green-white solid (yield: 96%).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C=O)C.[Br:15][C:16]1[C:17](=[O:42])[N:18]([CH2:33][C:34]2[CH:39]=[N:38][C:37]([CH2:40]O)=[CH:36][N:35]=2)[C:19]([CH3:32])=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]>ClCCl>[Br:15][C:16]1[C:17](=[O:42])[N:18]([CH2:33][C:34]2[CH:39]=[N:38][C:37]([CH2:40][Cl:3])=[CH:36][N:35]=2)[C:19]([CH3:32])=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CO)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CCl)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
Cyanurylchloride (0.42 g, .0023 mol) was added to DMF (0.52 mL) and stirred at room temperature for 15 min. Then added dichloromethane (15 mL) followed by the addition of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one 1.0 g, 0.0022 mol) and reaction mixture was stirred at room temperature under argon atmosphere. After 1 h, an additional 1.0 mL of DMF was added and the reaction was allowed to proceed for another hour, when a clear solution was obtained. The solution was diluted with dichloromethane (20 mL) and washed with water, dried (Na2SO4), and concentrated to dryness under reduced pressure. The residue was triturated with EtOAc, filtered, washed with EtOAc and dried to afford 0.79 g (77%) of the title compound as a pale yellow powder: 1H NMR (CD3OD/400 MHz) δ 8.66 (s, 2H), 7.73 (m, 1H), 7.05 (m, 2H), 6.56 (s, 1H), 5.52 (s, 2H), 5.33 (s, 2H), 4.74 (s, 2H), and 2.57 (s, 3H); ES-HRMS m/z 470.0051 (M+H C19H16N3O2BrClF2 requires 470.0077).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([C@H:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:18])[CH2:14][S:13]1.[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>>[C:20]([O:19][C@@H:17]([C@H:15]1[CH2:14][S:13][C:12](=[N:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[N:16]1[CH2:24][CH:25]([CH3:27])[CH3:26])[CH3:18])([CH3:22])([CH3:21])[CH3:23]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H]([C@@H](C)OC(C)(C)C)CS1
Reactant: CC(C)CBr
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H]([C@@H](C)OC(C)(C)C)N1CC(C)C
Yield: 56 %

Procedure:
(1R,2R)-1-(Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride (Method B8a; 1.5 g, 5.5 mmol) was reacted with 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to that described in Method C1a to afford 4(S)-(1(R)-tert-butoxyethyl)-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (1.2 g, 67%). The (4S)-2-(2-methyl-4-nitrophenylimino)-4-(1(R)-tert-butoxyethyl)-1,3-thiazolidine was reacted with isobutyl bromide in a manner analogous to Method D2a to yield (4S)-4-(1(R)-tert-butoxyethyl)-3-isobutyl-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (0.26 g, 56%): TLC (25% EtOAc/hex) Rf0.67.
Reaction SMILES: [CH3:1][N:2]([C:21](=O)[CH3:22])[NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[S:5]>C(O)CCC>[CH3:1][N+:2]1[N:3]=[C:4]([S-:5])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=2)[C:21]=1[CH3:22]
Reactant: CCOC(=O)CN(C)c1ccc(NC(=S)NN(C)C(C)=O)cc1
Solvent: CCCCO
Product: CCOC(=O)CN(C)c1ccc(-n2c([S-])n[n+](C)c2C)cc1

Procedure:
A solution of 2.03 g (6.06 mmol) of 1-methyl-1-acetyl-4- {4-(N-methyl-N-carboethoxymethylamino)phenyl}-3-thiosemicarbazide in 50 ml of butanol was heated at reflux until tlc showed no starting material (Rf 0.3,EtOAc,5 hr ). Solvent was distilled and the residue crystallized with ethyl acetate. The solid (1.2 g ) was recrystallized from 25 ml of water to give 0.978 g (3.05 mmol,50%), mp 211°. Anal. C15H20N4O2S (320): Calcd.: C,56.23; H,6.29; N,17.49; S,10.01. Found: C,56.30; H,6.20;N,17.93; S,9.61. MS(FD) 320. 1H NMR (DMSO-d6):δ 7.08,d,2H,ArH; 6.71,d,2H,ArH; 4.23,s,2H, CH3—N; 4.08,q,2h,CH2—O; 3.68,s,3H,CH3—N+; 3.29,s,3H,CH3—N; 2.23,s,3H,CH3—C═; 1.16,t,3H,CH3—C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]=[CH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>[Pd].CO>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([F:19])([F:20])[F:21])[CH2:16][CH2:17]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C=C[C@H]2CC[C@H](C(F)(F)F)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C(F)(F)F)CC2)CC1
Reaction time: 2 h

Procedure:
A mixture of 0.1 mol of 1-(trans-4-propylcyclohexyl)-2-(trans-4-trifluoromethylcyclohexyl)ethene, 200 ml of methanol and 5 g of palladium/activated charcoal (15%) is hydrogenated for 2 hours under a pressure of 2 bar and at a temperature of 50° C. Customary work-up gives the product as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH3:14].Cl[CH2:20][C:21]1[S:25][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[S:25][C:24]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[N:23][C:22]=2[CH3:36])=[CH:8][C:7]=1[CH2:13][CH3:14]
Reactant: CCO[C@@H](Cc1ccc(O)cc1CC)C(=O)OC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CC)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], (2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester (example 23 g]) was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2002), WO 0292590 A1] in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{2-ethyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid methyl ester as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](NCC(OC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC([O:30][CH2:31][CH:32](C)[CH3:33])=O.[BH4-].[Na+]>O1CCCC1C([O-])=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11](/[CH:33]=[CH:32]/[CH2:31][OH:30])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)COC(=O)Cl
Reactant: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Agent: O=C([O-])C1CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-n2ccc(/C=C/CO)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.5 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-[E-2-(carboxy)ethenyl]-1H-pyrazole-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carboxyamide (1.0 g, 1.93 mmol) in 20 mL of tetrahydrofuran at-20° C. was added triethylamine (0.27 mL, 1.93 mmol) and iso-butyl chloroformate (0.25 mL, 1.93 mmol). This mixture was stirred for 30 min and then there was added sodium borohydride (0.22 g, 5.78 mmol) in a minimal amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 h and then was quenched with 10% aq HCl. After diluting with ethyl acetate, the organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 0.5 g (52%) of the title compound as a white powder. LRMS (ES+): 504.9 (M+H)+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11](=[O:17])[CH2:10]2.O>CS(C)=O>[O:17]1[CH2:2][C:11]21[CH:12]1[CH2:15][CH2:16][N:9]([CH2:14][CH2:13]1)[CH2:10]2
Reactant: C[S+](C)(C)=O
Reactant: O=C1CN2CCC1CC2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C1CN2CCC1C1(CO1)C2
Temperature: 67.5 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A mixture of trimethylsulfoxonium iodide (16.10 g, 73.2, mmol) and a dispersion of sodium hydride (60% in oil, 3.00 g, 75.0 mmol) in anhydrous dimethyl sulfoxide was stirred at room temperature under nitrogen for 30 minutes. Quinuclidin-3-one (7.05 g, 56.3 mmol) was then added as a solid portionwise, and the resulting mixture was stirred at 65-70° C. under nitrogen for 1 hour. The reaction mixture was cooled, water was added (200 mL), and the resulting solution was extracted with chloroform (3×200 mL). The chloroform extracts were combined, and back-extracted with water (4×200 mL). The chloroform layer was then dried (MgSO4), filtered, and evaporated under reduced pressure to afford spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (6.51 g, 46.8 mmol, 83%) as a clear, colorless liquid. To a stirred solution of spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (5.3 g, 38.1 mmol) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added dropwise a solution of borane in tetrahydrofuran (1.0 M, 38.1 mL, 38.1 mmol), and resulting solution was stirred at 0° C. under nitrogen for 30 minutes. Brine (100 mL) was added cautiously to the reaction solution, and the resulting aqueous mixture was extracted with ethyl acetate (2×100 mL). The organic extracts were combined, dried (MgSO4), filtered, and evaporated under reduced pressure to afford the title compound (4.3 g, 28.1 mmol, 74%) as a white solid: electrospray MS 152 ([M-H]+, 15).