Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:14]=[C:13](Cl)[C:12]2[C:7](=[CH:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=1.O>C1COCC1>[Cl:4][C:5]1[CH:14]=[C:13]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cccnc1-c1ccc2c(Cl)cc(Cl)nc2c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)nc2cc(-c3ncccc3C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add sodium methoxide (4M, 1.1 mmol) to a solution of 2,4-dichloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinoline (1.0 mmol) in THF (10 mL). Stir at room temperature for 1 hour, add water (15 mL) and extract with ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate. Purify the mixture of 2-chloro-4-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]quinoline and 4-chloro-2-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]quinoline by flash chromatography (elute with 1:2 hexane:ether) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].[CH:15](OCC)=[O:16]>>[CH:15]([CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:10]#[N:11])=[O:16]
Reactant: CCOC=O
Reactant: COc1cccc(CC#N)c1
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(C(C#N)C=O)c1

Procedure:
In a manner similar to Example 7, m-methoxyphenylacetonitrile is treated with sodium methoxide and ethyl formate to afford α-formyl-(3-methoxyphenyl)acetonitrile. Hydrogenation of this product yields 3-amino-2-(3-methoxyphenyl)-2-propenal which is condensed with dimethyl malonate to afford the product of the Example.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[NH2:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([NH2:21])=[CH:18][CH:19]=2)[NH:14][N:13]=1>>[NH2:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12]([NH:11][C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])=[N:13][NH:14]2)=[CH:19][CH:18]=1
Reactant: CN1CCC(C(=O)Cl)CC1
Reactant: Nc1ccc2c(N)n[nH]c2c1
Product: CN1CCC(C(=O)Nc2n[nH]c3cc(N)ccc23)CC1

Procedure:
1-Methylpiperidine-4-carbonyl chloride (1 mmol), prepared from its corresponding carboxylic acid using general procedure E, was reacted with 3,6-diaminoindazole (1 mmol) (see Example 69) employing general procedure E to yield 1-methylpiperidine-4-carboxylic acid (6-amino-1H-indazol-3-yl)-amide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=1)[NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)#[N:20]
Reactant: N#Cc1cccc(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc(C#N)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 3-aminobenzonitrile (57 mg, 0.486 mmol) similar to Example 11 and isolated as a pale white solid (107 mg, 76%). 1H NMR (DMSO-d6): 10.14 (s, 1H), 8.78-8.75 (m, 1H), 8.56 (s, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.04-7.96 (m, 2H), 7.60-7.47 (m, 3H), 6.75 (s, 1H) 2.47 (s, 3H).
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[C:7]2[CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:6]2=[N:5]1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][C:11]1([CH3:13])[C:6]2=[N:5][N:4]([CH2:3][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:8]=[C:7]2[CH2:9][CH2:10]1
Reactant: CC1(C)CCc2cn(CCl)nc21
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCc2cn(CC(C#N)(C#N)CCC(F)(F)F)nc21
Yield: 33.2 %

Procedure:
0.58 g of 2-(chloromethyl)-6,6-dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole hydrochloride and 0.43 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 8 ml of N,N-dimethylformamide. 0.73 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.27 g of [(6,6-dimethyl-5,6-dihydro-cyclopenta[c]pyrazole-2(4H)-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (5), hereinafter) shown by below formula.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][CH:35]1[CH2:37][CH2:36]1.O>CN(C)C=O>[CH:35]1([CH2:34][N:5]2[CH2:6][CH2:7][N:2]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[N:9]=3)[CH2:3][CH2:4]2)[CH2:37][CH2:36]1
Reactant: ClCC1CC1
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-n2nc(N3CCN(CC4CC4)CC3)c3ccccc32)cc1
Yield: 51.6 %

Procedure:
A stirred mixture of 5.0 g of 3-(1-piperazinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazole hydrochloride, 2.2 g of potassium carbonate, and 1.4 g of chloromethylcyclopropane in 50 ml of dimethylformamide was heated at 85°-90° for 20 hours. The reaction mixture was poured into water and the aqueous suspension extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was flash chromatographed on silica gel utilizing ethyl acetate as the eluent. Concentration of the appropriate fractions gave 2.7 g (48%) of 3-[4-(cyclopropyl)methyl-1-piperazinyl]-1-[4-(trifluoromethyl)phenyl]-1H-indazole, mp 98°-100°.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:10])=[CH:12]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=S(c1ccccc1)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(c1ccccc1)c1cn(Cc2ccccc2)c2ccccc12

Procedure:
This compound was prepared in the same manner as described in Example 7 using sodium hydride (0.036 g, 50% in mineral oil; 0.90 mmol), dimethylformamide (5 ml), 3-phenylsulfinylindole (0.200 g, 0.82 mmol) and benzyl bromide (0.11 ml, 0.154 g, 0.90 mmol). Crystallization of the crude product from dichloromethane-hexane gave the title compound. M.P.-148°-149° (dichloromethane-hexane).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([C@@H:22]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)(C)(C)C>C1COCC1>[CH3:27][N:24]1[CH2:25][CH2:26][C@@H:22]([C:19]2[CH:18]=[CH:17][C:16]([S:13]([C:10]3[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=3)(=[O:15])=[O:14])=[CH:21][CH:20]=2)[CH2:23]1
Reactant: CN1CC[C@@H](c2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2)C1
Solvent: C1CCOC1
Product: CN1CC[C@@H](c2ccc(S(=O)(=O)c3ccc(O)cc3)cc2)C1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A solution of n-tetrabutylammoniumfluoride (1.0 M in THF, 0.593 mL, 0.59 mmol), was added to a solution of (S)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-benzenesulfonyl]-phenyl}-1-methyl-pyrrolidine (242 mg, 0.561 mmol) in THF (2 mL) at 0-5° C. under argon atmosphere. The reaction mixture was stirred at 0-5° C. for 1 hour and then concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM/MeOH/NH4OH) to give 122 mg of 4-[4-((S)-1-methyl-pyrrolidin-3-yl)-benzenesulfonyl]-phenol. The amine (119 mg) was dissolved in isopropanol (2 mL) and was treated with HCl (4 M in 1,4-dioxane, 0.12 mL, 0.487 mL) under nitrogen atmosphere. The mixture was stirred for one hour and the white solid formed was collected by filtration, washed with isopropanol and dried under reduced pressure to give 63 mg of 4-[4-((S)-1-methyl-pyrrolidin-3-yl)-benzenesulfonyl]-phenol hydrochloride, MP=197-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:27][S-:28].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][S:28][CH3:27])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: C[S-]
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1c(C)n(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
1.14 g of isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and 0.21 g of sodium methanethiolate in 5 ml of dimethylformamide are stirred at room temperature for 16 hours. The reaction mixture is poured into 100 ml of water and the aqueous mixture is extracted with 50 ml of ethyl acetate. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using diethyl ether/n-hexane (7:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-methylthiomethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.83 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 3.67 ppm (d, 1H), 3.62 ppm (d, 1H), 3.50 ppm (s, 3H), 2.43 ppm (s, 3H), 2.17 ppm (s, 3H), 1.36 ppm (2xd, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11](=O)[CH3:12])=[C:9]2[C:4]([N:5]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[CH2:6][CH2:7][CH2:8]2)=[N:3]1.Cl.[O:24]([NH2:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:25][O:24][N:26]=[C:11]([C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][N:5]2[C:14]1[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])[CH3:12]
Reactant: CON
Reactant: CC(=O)c1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=C(C)c1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2
Temperature: 75 °C
Yield: 45.7 %

Procedure:
A mixture of 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-yl]ethanone (20 mg, 0.067 mmol), methoxylamine hydrochloride (12 mg, 0.148 mmol), and pulverized potassium carbonate (39 mg, 0.26 mmol) in 2 mL of 95% ethanol was heated at 75° C. under an atmosphere of nitrogen for 1 hr. The solvent was evaporated, the residue was treated with 50 ml of ethyl acetate, washed with brine, dried over magnesium sulfate, and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with acetone/hexane (4:96) affording 10 mg (47% yield) of 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazol[3,4-b]pyridine-3-yl]ethanone O-methyl-oxime (6-4) as a brown oil: ms (M+H)+=327.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[S:8]Cl.[C:11]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[OH:25])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[C:16]([OH:25])=[C:17]([S:8][C:2]2[C:3]([CH3:7])=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:10])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: Cc1cccc(C)c1SCl
Product: Cc1cccc(C)c1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Yield: 49.5 %

Procedure:
Under N2, 2.225 g m-xylene-2-sulfenyl chloride (12.9 mmol) were dissolved in 25 mL hexanes. Under air, a 100 mL 3-necked round-bottom flask was charged with stirbar and 2.64 g 2,4-di-tert-butylphenol (12.8 mmol), then reflux condenser with vacuum adapter and addition funnel were attached. The phenol was dried in vacuo for 20 minutes, then placed under N2 and immersed in an oil bath set at 100° C. The solution of m-xylene-2-sulfenyl chloride was then added via addition funnel and the reaction mixture refluxed overnight. Solvent had evaporated by morning, probably through a leaky joint. The resulting brown solid was ground up in mortar and pestle and recrystallized from ethanol, yielding 2.170 g cream-colored solid which melted at 101-102° C. A second, somewhat darker crop of 0.434 g was recovered from the mother liquor. Combined yield: 59% (based on 2,4-di-tert-butylphenol). 1H NMR (CDCl3), δ (ppm): 7.07-7.13 (m), 4H, Ar—H; 6.82 (d, J=2.4 Hz), 1H, Ar—H; 6.28 (s), 1H, OH; 2.41 (s), 6H, CH3; 1.38 (s), 9H, t-Bu; 1.13 (s), 9H, t-Bu.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16])\[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16])\[CH2:7][Br:18])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1SC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1SC
Yield: 37.7 %

Procedure:
To a stirred mixture of (E)-3-(2-methylsulfanyl-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.004 mol) in carbon tetrachloride (15 mL) under a nitrogen atmosphere was added N-bromosuccinimide (1.00 g, 0.006 mol) and benzoyl peroxide (0.13 g, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2-methylsulfanyl-phenoxy)-but-2-enoic acid ethyl ester (0.50 g, 38%) as a yellow oil: LR-ES-MS m/z calculated for C13H15BrO3S [M]+ 330, observed 333.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[S:4][C:3]=1[C:14]([NH2:16])=[O:15].C[Si]([N:21]=[C:22]=[O:23])(C)C>>[NH2:21][C:22]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[S:4][C:3]=1[C:14]([NH2:16])=[O:15])=[O:23]
Reactant: C[Si](C)(C)N=C=O
Reactant: NC(=O)c1sc(-c2ccccc2Cl)cc1N
Product: NC(=O)Nc1cc(-c2ccccc2Cl)sc1C(N)=O

Procedure:
Prepared by the method of Example 1 from 3-amino-5-(2-chlorophenyl)-2-thiophenecarboxamide and trimethylsilylisocynate.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:10]2[C@@:6]([CH3:15])([C@@H:7]([C@H:11]([CH3:14])C=O)[CH2:8][CH2:9]2)[CH2:5][CH2:4][CH2:3]1.O.O.P([O-])(O)(O)=O.[Na+].ClC1C=CC=C([C:31]([O:33]O)=[O:32])C=1>C(Cl)Cl>[CH:31]([O:33][C@H:11]([C@@H:7]1[C@:6]2([CH3:15])[C@H:10]([C@@H:2]([OH:1])[CH2:3][CH2:4][CH2:5]2)[CH2:9][CH2:8]1)[CH3:14])=[O:32]
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H](OC=O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
Under a nitrogen atmosphere, a solution of (S)-2-{(3R,3aR,7S,7aR)-octahydro-7-hydroxy-3a-methyl-1H-indene-3-yl}propanal (Compound 15: 1.85 g, 8.797 mmol) in methylene chloride (30 ml) was cooled in an ice bath, and sodium dihydrogen phosphate dihydrate (6.86 g, 43.99 mmol) was added thereto. Meta-chloroperbenzoic acid (3.50 g, 13.2 mmol, calculated as 65%) was added thereto over 10 minutes. The reaction solution was stirred in the ice bath for 30 minutes, and at 17° C. to 21° C. for 12.5 hours. The reaction mixture was transferred to a separatory funnel such that insoluble matters were not included therein (the reaction vessel was washed with ethyl acetate), and water (40 ml) and ethyl acetate were added thereto. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium thiosulfate solution (45 ml), saturated aqueous sodium hydrogen carbonate solution (25 ml) and with saturated brine (50 ml), and dried over sodium sulfate, followed by evaporation under reduced pressure. The crude product (2.41 g) was purified by flash column chromatography to obtain (S)-1-{(3S,3aS,7S,7aR)-octahydro-7-hydroxy-3a-methyl-1H-indene-3-yl}ethyl formate (1.80 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:11]=1[CH2:12][CH2:13][C:14](OC)=[O:15])=[O:9])(=[O:3])[CH3:2].[NH3:23]>CO>[CH3:2][C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:11]=1[CH2:12][CH2:13][C:14]([NH2:23])=[O:15])=[O:9])=[O:3]
Reactant: N
Reactant: COC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Solvent: CO
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(N)=O

Procedure:
8.15 g (0.025 mol) of methyl 2-(4-acetamidobutyryl)-5-chlorohydrocinnamate are stirred at room temperature for 30 hours in 200 ml of a solution of ammonia in methanol. After concentration of the solution the residue is extracted with methylene chloride/water, dried with magnesium sulfate, the solvent is distilled in a vacuum. The residue is chromatographed on silica gel with chloroform-methanol (9:1). Recrystallization from methanol/ether yields 2-(4-acetamidobutyryl)-5-chlorohydrocinnamide as white crystals with melting point 149°-151°.
Reaction SMILES: CO[C:3](=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.NCC[S:75]([OH:78])(=[O:77])=[O:76]>CN(C)C=O>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][CH2:3][S:75]([OH:78])(=[O:77])=[O:76])=[O:37]
Reactant: NCCS(=O)(=O)O
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCS(=O)(=O)O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 59 %

Procedure:
To a solution of 0.127 g (0.26 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 1.5 mL N,N-dimethylformamide were added 0.10 g (0.26 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.13 mL (0.79 mmol) N,N-diisopropylethylamine. To the yellow solution 0.036 g (0.29 mmol) taurine (commercially available, CAS RN 107-35-7) was added and the reaction mixture stirred at room temperature for 4.5 hours. The solution was filtered using a syringe micro filter and purified on a preparative HPLC system (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 0.092 g (59%) of the title compound as a brown solid. MS (ESI): m/z=591.086 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[NH:6][CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].CI.[CH:25](OC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[N:6]([CH3:25])[CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)Nc1nnnn1-2
Reactant: CC(C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1c2nnnn2-c2ccc(Cl)cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.4 g of 7-chloro-4,5-dihydro-5-phenyltetrazolo[1,5-a]quinazoline in 20 ml of dimethylformamide was added 0.07 g of 50% sodium hydride. After the mixture was stirred at room temperature for 1 hour, 0.4 g of methyl iodide was added thereto. The resulting mixture was stirred at room temperature for 2 hours and then poured into ice-water. The mixture was stirred with a small quantity of isopropyl ether, and the resulting precipitate was collected by filtration, washed successively with water and isopropyl ether, and dried to give 0.26 g of 7-chloro-4,5-dihydro-4-methyl-5-phenyltetrazolo[1,5-a]quinazoline as pale yellow crystals. Recrystallization from ethanol gave colorless scales, m.p. 282°-283° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([S:14]([NH2:17])(=[O:16])=[O:15])([C:10]([OH:13])([CH3:12])[CH3:11])[CH3:9])=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:22][O:23][C:24](OC)(OC)OC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:9])[C:10]([CH3:11])([CH3:12])[O:13][C:22]([O:23][CH3:24])=[N:17][S:14]2(=[O:15])=[O:16])=[CH:6][CH:7]=1
Reactant: COC(OC)(OC)OC
Reactant: CC(C)(O)C(C)(c1ccc(Br)cc1)S(N)(=O)=O
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(C)(c2ccc(Br)cc2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2.01 g of 2-(4-bromophenyl)-3-hydroxy-3-methylbutane-2-sulfonamide in 15 ml of tetramethoxymethane was admixed with 3 ml of acetic acid and stirred at 100° C. for 1.5 hours. After the removal of the solvent under reduced pressure, the crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined, concentrated by rotary evaporation and dried under high vacuum. This gave the product (0.21 g) with a molecular weight of 362.2 g/mol (C13H16BrNO4S).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C1([O:23][C:24](=O)[NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:24]([NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:23])[CH2:5][CH2:4]1
Reactant: O=C(NCCCc1ccccc1)Oc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)NCCCc2ccccc2)CC1

Procedure:
4-Dimethylamino-4-phenyl-cyclohexylamine (more polar diastereomer) (218 mg, 1.0 mmole) was added to a solution of (3-phenylpropyl)carbamic acid phenyl ester (255 mg, 1.0 mmole) in dioxane and refluxed for 12 h. Working up was performed by removing the dioxane by distillation and combining the residue with water. The batch was adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and evaporated. The more polar product was obtained as a colorless oil in a yield of 379 mg (100%).