Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[C:20]([O:24][C:25]([CH2:27][C@@H:28]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:29](N1[C@H](C(C)C)COC1=O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[CH2:1]([O:8][C:29](=[O:30])[C@H:28]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a stirred solution of dry benzyl alcohol (0.55 ml, 5.33 mmol) in anhydrous tetrahydrofuran (18 ml) under a nitrogen atmosphere at 0° C. was added a hexane solution of n-butyllithium (2.58 ml, 4.00 mmol). To this solution was added the product from Example 97 in anhydrous tetrahydrofuran (10 ml). After stirring 1 h at 0° C. the reaction was quenched by adding excess saturated aqueous ammonium chloride. The volatiles were removed by rotary evaporation and the resulting aqueous residue extracted two times with ether. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo provided an oil which was purified by chromatography on SiO2 (15% ether acetate/hexanes) to provide the desired product (0.89 g, 94%) as a colorless oil. Mass spectrum: (M)+ =354.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1(C)C=CC=CC=1.[ClH:28]>O>[ClH:28].[ClH:28].[C:2]1([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
10.00 kg (52.84 mol) 1-benzylpiperidone (K) were taken and 9.21 kg (105.68 mol) morpholine (L) as well as 50.0 L toluene were added. Then the reaction mixture obtained was heated to reflux temperature using the water separator (110° C.) and stirred until no more water separated off. Then the mixture was hydrogenated at 4 bar and an internal temperature of 60° C. in the presence of 0.50 kg Raney nickel catalyst in 6 L ethanol. The catalyst was separated off and washed with 20 L ethanol. Then the solvent was distilled off completely in vacuo. Then 80.0 L ethanol were added and at 50° C. 16.05 kg (132.10 mol) hydrochloric acid (30%) were metered in. The resulting suspension was cooled to 20° C. and stirred for 30 minutes at 20° C. The product was centrifuged off and dried.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[CH2:6][CH2:5]1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29])([O-:21])=[O:20]>C(Cl)Cl>[O:10]=[S:7]1(=[O:11])[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N+:19]([O-:21])=[O:20])(=[O:29])=[O:30])[CH2:5][CH2:6]1
Reactant: NCCN1CCS(=O)(=O)CC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
A mixture of 4-(2-aminoethyl)thiomorpholine 1,1-dioxide (2.00 g, 11.2 mmol) and triethylamine (1.42 g, 14.0 mmol) in DCM (100 mL) was cooled in an ice bath and treated slowly with 2-nitrobenzene-1-sulfonyl chloride (2.49 g, 11.2 mmol). The mixture was removed from the ice bath and stirred at rt for 18 h. The resulting mixture was washed with water (2×50 mL) and the combined aqueous washes were extracted with DCM (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a yellow solid. Purification by silica gel chromatography (linear gradient 100% DCM to 100:1 DCM:MeOH) gave the title compound as a pale yellow solid (3.47 g, 85% yield). LCMS: m/z 364 (M+H+), retention time 0.98 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.71 (t, J=5.49 Hz, 2H) 2.96 (br. s., 4H) 3.05 (br. s., 4H) 3.20 (q, J=5.49 Hz, 2H) 5.93 (br. s., 1H) 7.73-7.84 (m, 2H) 7.84-7.93 (m, 1H) 8.11-8.23 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[S:9][CH:10]=1)=O)C.[BH4-].[Li+].CO.O>C(OCC)C>[OH:3][CH2:4][C:6]1[N:7]=[C:8]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[S:9][CH:10]=1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CO)cs2)CC1

Procedure:
A mixture of 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Example 1, Step A) (3.4 g, 10 mmol), lithium borohydride (0.33 g, 15 mmol) and methanol (607 μL, 15 mmol) in diethyl ether (40 mL) was heated at reflux for 16 h. The reaction mixture was cooled, treated with water (5 mL) and extracted with diethyl ether and dichloromethane. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure and purified by silica gel chromatography using 50-100% ethyl acetate in hexanes as eluant to give 1.72 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH2:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.N=C=N.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:26][CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[NH:16][CH:17]=[CH:18]3)=[O:10])[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: Nc1nc(C(=O)O)cc(-c2ccco2)n1
Reactant: NCc1ccc2[nH]ccc2c1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(C(=O)NCc2ccc3[nH]ccc3c2)cc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
A mixture consisting of 2-amino-6-(2-furyl)pyrimidine-4-carboxylic acid (206 mg, 1.0 mmol), indole-5-methanamine (146 mg, 1.0 mmol), polymer supported carbodiimide (Argonaut Technologies, loading 1.38 mmol/g, 1.10 g, 1.5 mmol) and 1-hydroxybenzotriazole hydrate (203 mg, 1.5 mmol) in DMF (5 mL) was stirred at room temperature for 24 hr. The mixture was filtered through a pad of Celite, washing through with EtOAc. The filtrate was washed successively with H2O (10 mL), 2-M Na2CO3 (2×10 mL) and H2O (10 mL), dried (MgSO4) and concentrated in vacuo. The resulting oil was dissolved in MeOH (1.0 mL), added dropwise with stirring to H2O (2 mL) and the resulting precipitate filtered to give the title compound (198 mg, 59%) as a cream solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH2:12][C:13]3[C:17]=2[N:16]=[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=32)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][CH3:26]>>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH:12]([CH2:23][CH2:24][CH2:25][CH3:26])[C:13]3[C:17]=2[N:16]=[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=32)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=CC(OCc2ccccc2)=C2N=C3CCCCC3=C2C1
Reactant: CCCCBr
Product: CCCCC1C=CC(OCc2ccccc2)=C2N=C3CCCCC3=C21
Yield: 88.2 %

Procedure:
Using the procedure of Example 9, the alkylation of 5.0 g. of 1,2,3,4-tetrahydro-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole from Example 56 was reacted with 1-bromobutane (2.68 g) to give 5.3 g (88.2%) of 1,2,3,4-tetrahydro-6-phenylmethoxy-9-butyl-9H-dibenzo[b,d]pyrrole as a yellow oil after chromatographic purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22]>>[O:22]=[C:18]1[CH2:19][CH2:20][CH2:21][N:17]1[CH2:16][CH2:15][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: O=C1CCCN1CCCl
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: N#Cc1ccnc(-c2cn(CCN3CCCC3=O)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 1-(2-chloroethyl)-2-pyrrolidinone according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C15H15N5O, 282. Found, 282.
Reaction SMILES: C([N:3](C([O-])=O)[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O=[S:25](Cl)Cl>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:4]=[N:3][S:25][C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: CCN(N=C(Cc1ccccc1)c1ccc(OC)cc1)C(=O)[O-]
Product: COc1ccc(-c2nnsc2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
The acylhydrazine 12 (23.4 g, 75.0 mmol) was added to SOCl2 (200 ml) at 0° C. The reaction was warmed to 60° C. and complete (by TLC) after 3 hours. SOCl2 was removed under reduced pressure. The solid residue was dissolved in EtOAc, washed once with 10% aqueous NaOH and brine. The organic layer was dried over MgSO4, and the solvent was removed under reduced pressure. The crude solid was recrystallized from Et2O to afford 10 (13.0 g, 64.6%), m.p. 81.5°-82.5° C.
Reaction SMILES: ClCCl.[NH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[N:10]1[S:11][N:12]=[C:13]2[CH:18]=[C:17]([C:19](OC)=[O:20])[CH:16]=[CH:15][C:14]=12>C1(C)C=CC=CC=1>[N:10]1[S:11][N:12]=[C:13]2[CH:18]=[C:17]([C:19]([N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:20])[CH:16]=[CH:15][C:14]=12
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc2nsnc2c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(c1ccc2nsnc2c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Trimethylaluninum (2M in toluene; 3.0 mL, 6.0 mmol) was diluted into 30 mL dichloromethane to which piperidine (0.55 g, 6.5 mmol) and methyl benzo-2,1,3-thiadiazole-5-carboxylate (1.16 g, 6.00 mmol) were added. The reaction was stirred at room temperature for 2 hours and concentrated to one-half the volume by rotary evaporation. Dry toluene (25 mL) was added and the reaction solution was heated to 80° C. for 1 hour. Additional piperidine (about 0.2 g) was added and the temperature was increased to 100° C. for 1 hour. The solution was allowed to cool to room temperature and stirred overnight, at which time it was quenched with 10% citric acid and hydrochloric acid. The solution was diluted with ethyl acetate and sequentially washed with 10% citric acid, saturated sodium hydrogen phosphate and saturated sodium chloride, and subsequently dried over anhydrous sodium sulfate. The solution was concentrated onto silica and product was eluted with hexane/ethyl acetate (3:1). Purification by distillation in a kugelrohr at 180° C. and 0.5 mmHg yielded 1-(benzo-2,1,3-thiadiazole-5-ylcarbonyl)piperidine, 1 (1.29 g, 87%) as a pale yellow oil. IR: 2920, 2855, 1633, 1478, 1439, 1280, 1223, 1001, 816, and 748 cm−1. 1H NMR (500 MHz): δ8.06 (1H, d, J=9.1 Hz); 8.02 (1H, s); 7.63 (1H, t, J=9.0 and 1.5 Hz); 3.77 (2H, br s); 3.40 (2H, br s); 1.72 (4H, br s); and 1.57 ppm (2H, br s).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7](O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(Cl)C[Cl:19].C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:32][C@@H:33]([CH2:45][CH3:46])[CH:34]([C:36]1[O:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1)[OH:35].CN1CCOCC1>ClCCl>[ClH:19].[O:37]1[C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=[C:36]1[CH:34]([OH:35])[C@@H:33]([NH:32][C:7](=[O:8])[C@@H:2]([NH2:1])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:45][CH3:46]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: ClCCCl
Reactant: CC[C@H](N)C(O)c1nc2ccccc2o1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)[C@@H](N)CC(C)C)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
Boc-Leu-OH (350 mg, 1.40 mmol) was combined with EDC (500 mg, 2.6 mmol), HOBt (250 mg, 1.6 mmol), and (2S)-2-amino-1-benzoxazol-2-yl-butan-1-ol hydrochloride (300 mg, 1.24 mmol). Dichloromethane (10 mL) was added and then 4-methylmorpholine (1 mL). The reaction mixture was stirred at ambient temperature for 2 h. After dilution with ethyl acetate (150 mL), the solution was washed with 1N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in 4N HCl/dioxane solution and stirred for 2 h. Evaporation to dryness gave (S)-2-amino-4-methyl-pentanoic acid(S)-[1-(benzoxazol-2-yl-hydroxy-methyl)-propyl]-amide hydrochloride (450 mg) as brownish oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:5]1.[H-].[Na+].O>CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[CH:7]=[C:8]3[CH2:9][O:10][CH2:2][CH2:3][N:4]3[N:5]=2)=[CH:12][CH:13]=1
Reactant: OCc1cc(-c2ccc(F)cc2)nn1CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2cc3n(n2)CCOC3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 100 ml round-bottom flask, 780 mg (3.00 mmol) of [1-(2-chloroethyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]methanol are dissolved in 20 ml of N,N-dimethylformamide. Under argon and at 0° C., 120 mg of sodium hydride (3.00 mmol) are then added as a 60% suspension in oil. The mixture is then stirred at 25° C. for 18 h. The reaction mixture is then carefully poured into water and extracted repeatedly with ethyl acetate. The combined organic phases are then dried over Na2SO4 and concentrated. Purification is carried out by silica gel chromatography (cyclohexane/ethyl acetate). This gives 480 mg (49%) of the desired product; log P(HCOOH): 2.01; 1H-NMR (MeCN-d3): δ=7.81-7.77 (m, 2H), 7.15-7.11 (m, 2H), 6.36 (s, 1H), 4.81 (s, 2H), 4.14-4.12 (m, 2H), 4.10-4.08 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36]>ClCCl.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:35](=[O:36])[CH2:34][C:30]2[S:29][CH:33]=[CH:32][CH:31]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(Cl)Cc1cccs1
Reactant: COC(=O)c1cc(Br)ccc1NCc1ccc(OC)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1N(Cc1ccc(OC)cc1)C(=O)Cc1cccs1
Reaction time: 8 h

Procedure:
To a solution of methyl 5-bromo-2-[(4-methoxybenzyl)amino]benzoate (2.0 g, 5.7 mmol) in dichloromethane (0.50 M, 11 mL) at room temp were added triethylamine (1.6 mL, 11 mmol) and 2-thiophenylacetyl chloride (1.1 g, 6.9 mmol), followed by addition of DMAP (35 mg, 5.0 mol %). The reaction was left stirring overnight. Additional portions of 2-thiophenylacetyl chloride were added until the complete consumption of starting material was observed. The crude reaction mixture was poured in neutral water (100 mL). The product was extracted with dichloromethane (3×50 mL). The combined organic extractions were dried over magnesium sulfate, filtered, and concentrated in vacuo to furnish methyl 5-bromo-2-[(4-methoxybenzyl)(thiophen-2-ylacetyl)amino]benzoate as an orange oil. Used without further purification. LCMS (M+1)=473.7.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1N.N(OCCCCC)=O.[I:21]I>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[I:21]
Reactant: II
Reactant: Cc1cc(C(F)(F)F)ccc1N
Agent: CCCCCON=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(F)(F)F)ccc1I

Procedure:
To a solution of 2-methyl-4-trifluoromethyl aniline (Step A) (2.2 g, 12.6 mmol) in chloroform (20 ml) at room temperature were added n-pentyl nitrite (2.2 g, 18.9 mmol) and iodine (6.38 g, 25.1 mmol). The mixture was heated to reflux for 1 h. The mixture was diluted with methylene chloride (50 ml). The solution was washed with saturated aqueous sodium thiosulfate, brine and dried over sodium sulfate. The title compound was obtained after flash column using hexane as the eluant.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.S(Cl)(Cl)=O.[CH3:13][N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][NH:17][CH2:18]2.[OH-].[Na+]>COCCOC.C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:17]1[CH2:18][CH:19]2[N:14]([CH3:13])[CH:15]([CH2:21][CH2:20]2)[CH2:16]1)=[O:8]
Reactant: CN1C2CCC1CNC2
Reactant: O=C(O)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O=S(Cl)Cl
Product: CN1C2CCC1CN(C(=O)c1ccco1)C2

Procedure:
A mixture of 2-furoic acid (1.33 g, 11.9 mmol) and thionyl chloride (20 ml) was stirred at reflux for 2 hours. The mixture was evaporated and co-evaporated with toluene, 8-methyl-3,8-diaza-bicyclo[3.2.1]octane (1.5 g, 11.9 mmol) and 1,2-dimethoxyethane (40 ml) was added and was stirred at room temperature for 15 hours. Aqueous sodium hydroxide (50 ml, 1M) was added and the mixture was extracted twice with dichloromethane (2×40 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as a solid. Mp. 106° C. Yield 1.41 g (54%).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>O1CCCC1.CO>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([OH:8])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(Cl)cc1
Yield: 93.4 %

Procedure:
15.2 g (0.07 mole) of phenyl-(4-chlorophenyl)-ketone are dissolved in 30 ml of tetrahydrofuran and 10 ml of methanol. 1.32 g (0.035 mole) of sodium borohydride are gradually added, with stirring, and the exothermic reaction is maintained between 25° and 30° C. by cooling. After one hour ketone can no longer be detected by thin layer chromatography. The mixture is then extracted with water and chloroform, the chloroform is dried with sodium sulfate and removed in a rotary evaporator. The crude yield is 16.2 g (oil). Of this 15.5 g are distilled at 220° C. and 30 mbar in a bulb tube oven. 14.3 g of an oil are obtained which is more than 95% pure according to gas chromatography and solidifies into crystals on cooling. 13.3 g are recrystallised from a mixture of 25 ml of n-hexane and 5 ml of cyclohexane. The yield is 12.2 g; m.p. 58°-60° C.
Reaction SMILES: [N:1]1([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl>C(O)C>[NH2:13][C:12]1[C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1cccnc1N1CCNCC1
Agent: Cl
Solvent: CCO
Product: Nc1cccnc1N1CCNCC1

Procedure:
2-(1-piperazinyl)-3-nitropyridine (24.50 g), ethanol (445 ml) and hydrochloric acid (1.2 N, 44 ml) are combined and hydrogenated overnight at 40 psi, refilling when necessary. The mixture is filtered through celite, washed with ethanol, chloroform, ethanol and water. The organic solvents are removed with heat and reduced pressure. The remaining material is partitioned between methylene chloride (3×250 ml) and sodium bicarbonate. The organic layers are combined, dried over potassium carbonate, filtered and concentrated under reduced pressure to give an oil which slowly solidified upon standing to give 3-amino-2-(1-piperazinyl)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([S@:10]([CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[O:11])=[N:9][C:5]=2[CH:4]=1.[C:25](=[O:37])([O:34][CH2:35][CH3:36])[O:26][CH2:27][CH2:28][N:29]([C:31](Cl)=[O:32])[CH3:30].C(N(CC)CC)C.C(=O)(OCCN(C(N1C2C=C(OC)C=CC=2N=C1[S@](CC1C(C)=C(OC)C(C)=CN=1)=O)=O)C)OCC>O1CCCC1.CN(C)C1C=CN=CC=1>[C:25](=[O:37])([O:26][CH2:27][CH2:28][N:29]([C:31]([N:7]1[C:6]2[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]=[C:8]1[S@:10]([CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=1)=[O:11])=[O:32])[CH3:30])[O:34][CH2:35][CH3:36]
Reactant: CCOC(=O)OCCN(C)C(=O)Cl
Reactant: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: CCOC(=O)OCCN(C)C(=O)n1c([S@@](=O)Cc2ncc(C)c(OC)c2C)nc2ccc(OC)cc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OCCN(C)C(=O)n1c([S@@](=O)Cc2ncc(C)c(OC)c2C)nc2cc(OC)ccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (1.34 g) synthesized by a method described in Synthetic Example 1 of JP-A 10-504290 in tetrahydrofuran (10 mL) were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.9 mL) obtained in Reference Synthetic Example 34, triethylamine (1.08 mL) and 4-dimethylaminopyridine (0.010 g), and stirred at 60° C. for 6 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give a mixture of 3:2 of title compound and ethyl 2-[[[(S)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as pale yellow amorphous solid (0.92 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)=[N:10][N:11]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:12]=2[C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 33.6 %

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, Step 3) (2.11 g, 5.5 mmol) and ethyl bromoacetate (1.09 g, 6.5 mmol) were stirred vigorously in 15 mL dry DMF with finely powdered potassium carbonate (1.38 g, 10 mmol) under nitrogen at 25° C. for 3 hours. The mixture was diluted with ethyl acetate and filtered to remove solids. The organic filtrate was washed with two portions of water followed by brine, dried over MgSO4 and concentrated in vacuo. The desired isomer was isolated by chromatography on silica gel, using 10% ethyl acetate/90% heptane as the eluant, to give ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate as a white solid (0.87 g, 34%). Elemental analysis for C21H18N2F4SO4Calc'd: C, 53.62, H, 3.86, N, 5.96, S, 6.82. Found: C, 53.69, H, 3.97, N, 5.87, S, 7.05.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[CH3:6][C@@H:7]1[CH2:9][O:8]1>O>[OH:8][C@H:7]([CH3:9])[CH2:6][NH:1][C@H:2]([CH3:5])[CH2:3][OH:4]
Reactant: C[C@@H]1CO1
Reactant: C[C@@H](N)CO
Solvent: O
Product: C[C@H](CO)NC[C@@H](C)O
Temperature: 0 °C

Procedure:
To a mixture of (R)-2-aminopropan-1-ol (15 g, 200 mmol) in 200 mL water stirred at 0° C. was added (R)-2-methyloxirane (13 g, 220 mmol) dropwise using a syringe pump over 3 h. The mixture was stirred at 0° C.—RT over 4 h. The mixture was concentrated in vacuo with to remove water. The mixture was vacuum distilled to remove the unreacted alaninol at first (60° C. fraction), then collected the 110-115° C. fraction to give the (R)-2-((R)-2-hydroxypropylamino)propan-1-ol as a sticky pale yellow oil.