Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([NH2:25])(=[O:24])[CH:22]=[CH2:23].[Cl-].[Al+3].[Cl-].[Cl-].Cl.C(NC(=O)C=C)CCCCCCCCCCCCCCC>CC(C)=O>[C:1]([NH:25][C:21](=[O:24])[CH:22]=[CH2:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CC(N)=O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: C=CC(=O)NCCCCCCCCCCCCCCCC
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)=O
Product: C=CC(=O)NC(=O)CCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 250 ml capacity conical flask 15.1 g stearoyl chloride (0.05 M), 3.5 g acrylamide (0.05 M) and 50 ml acetone were placed to obtain a clear solution. The solution was stirred with a magnetic needle at room temperature. 6.5. g anhydrous aluminium chloride (0.05 M) was added and the reaction mixture was stirred at room temperature. After 5 to 10 minutes of stirring vigorous evolution of hydrogen chloride took place which ceased after about 5 minutes. The product was isolated following the procedure described for synthesis of N-cetylacrylamide.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][OH:28]>CC#N>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:30]([NH:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][CH2:27][OH:28])=[C:20]([F:19])[CH:21]=2)=[O:31])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1ccc(CCO)c(F)c1)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(CCO)c(F)c2)n(-c2cccc(Cl)c2)n1
Reaction time: 16 h
Yield: 92.3 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (synthesis described for example A141) (102 mg, 0.387 mmol, 1.0 eq) in MeCN (9 mL) was added TEA (0.214 mL, 1.55 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(2-hydroxyethyl)phenylcarbamate (108 mg, 0.395 mmol, 1.02 eq) and the mixture was stirred for 16 h at reflux. The reaction mixture was concentrated under vacuum and the residue purified by CC using EtOAc/hexane (2:1) as eluent to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(2-hydroxyethyl)phenyl)urea (159 mg; 92%, white solid).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22]([C:25]#[N:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[NH:28][C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30].CC1C=CC(S(O[CH2:46][C@@H:47]2[O:49][CH2:48]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[C:25]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH2:46][C@H:47]1[CH2:48][O:49]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:28][C:29]([NH:31][CH:32]2[CH2:33][CH2:34]2)=[O:30])=[C:7]([CH3:6])[C:12]=1[CH3:13])#[N:26]
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(O)c(C#N)cc23)c1C
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)c1C
Temperature: 50 °C
Yield: 49.6 %

Procedure:
Dimethylformamide (4 ml) was added to N-(2,3-dimethyl-4-(6-cyano-7-hydroxy-quinolin-4-yloxy)-phenyl)-N′-cyclopropylurea (476 mg), and then (2R)-(−)-glycidyl p-toluenesulfonate (365 mg) and potassium carbonate (340 mg) were further added and the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate to obtain the title compound (270 mg) as light yellow crystals.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH3:66])[CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH3:66])[CH:60]1[CH2:65][CH2:64][N:63]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:62][CH2:61]1
Reactant: CN(c1ccccc1Br)C1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccccc1Br)C1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.1 g, 0.00039 mol) in DMF (2 mL), was added DIPEA (0.2025 g, 0.00156 mol), HOBt (0.053 g, 0.00039 mol) and EDCI.HCl (0.0901 g, 0.00047 mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-methyl-piperidin-4-yl-amine hydrochloride (0.119 g, 0.00039 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water, and the resulting precipitate was isolated by filtration. Purification by preparative TLC using 30% ethyl acetate in hexane afforded 0.072 g (36%) of biphenyl-4-carboxylic acid (2-{4-[(2-bromo-phenyl)-methyl-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 506.1 (M+1)+, 97.07%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 8.0 (d, 2H), 7.8 (d, 2H), 7.75 (m, 4H), 7.6-7.25 (m, 6H), 7.0 (t, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.9 (m, 1H), 3.05 (m, 1H), 2.7 (m, 1H), 2.6 (s, 3H), 1.8-1.5 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[CH3:8][NH:9][C:10]([NH:12][NH2:13])=[S:11].C(O)(=O)C>CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:9]([CH3:8])[C:10](=[S:11])[NH:12][N:13]=1
Reactant: CNC(=S)NN
Reactant: O=C1CCCCO1
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(CCCCO)n[nH]c1=S
Temperature: 120 °C

Procedure:
Tetrahydro-2H-pyran-2-one (2 ml), N-methylhydrazinecarbothioamide (3.4 g) and acetic acid (0.3 ml) were suspended in methanol (10 ml). The reaction was heated in microwave oven at 120° C. for 20′ followed by further 10′ at 110° C. Acetic acid was added (0.3 ml) and reaction was heated in a microwave oven at 140° C. for 20′, further acetic acid (0.3 ml) was added and the reaction was in a microwave oven at 140° C. for 20′. The solvent was removed under reduced pressure, DCM was added to the crude and solid filtered-off. Solvent was removed under reduced pressure to give a crude product that was purified by flash chromatography on silica gel (DCM/MeOH from 0 to 10%) to give the title compound as a white solid (1 g).
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([CH3:27])[C:14]([C:20]1[CH:25]=[N:24][CH:23]=[C:22]([CH3:26])[N:21]=1)([OH:19])[C:15]([F:18])([F:17])[F:16]>CCCCCCC>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C@@H:13]([CH3:27])[C@:14]([C:20]1[CH:25]=[N:24][CH:23]=[C:22]([CH3:26])[N:21]=1)([OH:19])[C:15]([F:18])([F:16])[F:17]
Reactant: Cc1cncc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)n1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1cncc([C@](O)([C@H](C)c2ccc(Cl)cc2Cl)C(F)(F)F)n1

Procedure:
These compounds were obtained by preparative HPLC (Column: Chiralpack AD; solvent: 1% isopropanol in heptane) from racemic 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-(6-methyl-pyrazin-2-yl)-butan-2-ol (Example 39).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].CCN(C(C)C)C(C)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C1COCC1>[Cl:13][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26]([CH:23]2[CH2:25][CH2:24]2)=[O:27])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(CN)ccc1Cl
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(CNC(=O)C2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of methyl 5-(aminomethyl)-2-chlorobenzoate (15.0 g, 75 mmol) in dry THF (150 mL) was added DIPEA (15 mL) under nitrogen atmosphere. Cyclopropanecarbonyl chloride was added to the reaction mixture at 10° C. and (11.81 g, 113 mmol). The reaction mixture was stirred at RT for 5-6 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with dilute HCl, followed with sodium bicarbonate solution and concentrated to afford 10.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.59 (m, 1H), 3.86 (s, 3H), 4.29 (d, J=6.0 Hz, 2H), 7.43 (d, J=6.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 8.64 (br s, 1H); MS (m/z): 268.16 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-fluorophenyl)piperazine (2.0 g, 11.1 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.46 g, 11.7 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound P, 2.62 g (78%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:18]=O.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7](/[C:8](=[CH:18]/[C:17]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:15]([Cl:14])[CH:16]=2)/[C:9]([O:11][CH3:12])=[O:10])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CC(=O)c1ccc(Br)s1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)/C(=C\c1ccc(Cl)c(Cl)c1)C(=O)c1ccc(Br)s1
Temperature: 110 °C
Yield: 91.5 %

Procedure:
To a 250 mL round bottom flask was added a solution of methyl 3-(5-bromo-2-thienyl)-3-oxopropanoate (25.11 g, 95.44 mmol), 3,4-dichloro-benzaldehyde (21.71 g, 124.1 mmol) and piperidine (0.944 mL, 9.54 mmol) in anhydrous benzene (682 mL). Acetic acid (3.80 mL, 66.8 mmol) was added and the reaction mixture was fitted with a Dean-Stark trap. The oil bath was heated to 110° C. and the reaction stirred at reflux for 18 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and purified by silica gel chromatography to afford the product as a yellow oil (36.7 g, 91.6%). LCMS: (AA) ES+: 421. 1H NMR (400 MHz, d6-DMSO) δ 7.83 (s, 1H), 7.53-7.45 (m, 1H), 7.34 (t, J=10.0 Hz, 1H), 7.24 (dd, J=8.4, 2.7 Hz, 2H), 7.03 (d, J=4.1 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH3:26])[C:10](=[NH:14])[O:11]CC.[O:27]1CCC[CH2:28]1>>[CH3:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]=1[CH:9]1[O:8][C:28](=[O:27])[NH:11][C:10]1=[O:14]
Reactant: CCOC(=N)C(O)c1c(OC)ccc2ccccc12
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2ccccc2c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 12, except that 2.3 rather than 2.0 equivalents of triethylamine were used, ethyl 1-hydroxy-1-(2-methoxy-1-naphthyl)methanecarboximidate (16.5 g., 0.063 mole) in 500 ml. of tetrahydrofuran was converted to crude product. Recrystallization from ethyl acetate/toluene gave purified 5-(2-methoxy-1-naphthyl)oxazolidine-2,4-dione in two crops [7.7 g.; m.p. 199°-201° C.; ir (KBr) 1820, 1740 cm-1 ].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:22]([C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=O)=[CH:10][C:9]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[C:22]([C:24]3[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=3)[C:11]2=[CH:10][C:9]=1[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1
Reactant: Cn1ccnc1C(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCC(=O)C(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1c(C(=O)C(C)(C)C)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 150 °C

Procedure:
A mixture of 0.094 g (0.18 mmol) of the product of Step B and 0.027 g (0.18 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 2 mL DMF was placed in a 10 mL reaction tube of a CEM Corporation Discover 300 Watt microwave reactor. The reaction vessel was sealed, placed in the microwave reactor and heated at 150° C. for 5 min. After the reaction vessel had cooled again to room temperature, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with aq. NaHCO3, brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–75% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 504.2 (M+1), 506.0 (M+3); Rt=3.39 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[CH:10]([CH2:14]OS(C)(=O)=O)[CH:9]1/[CH:20]=[CH:21]/[CH:22]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].OCC1CCCC1=O.C(N(C(C)C)CC)(C)C>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[C:10](=[CH2:14])[CH:9]1/[CH:20]=[CH:21]/[CH:22]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(/C=C/C1C(OC2CCCCO2)CC(=O)C1COS(C)(=O)=O)OC1CCCCO1
Agent: O=C1CCCC1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: C=C1C(=O)CC(OC2CCCCO2)C1/C=C/C(CCCCC)OC1CCCCO1
Yield: 100.9 %

Procedure:
In a similar way to Example 24, (1), 293 mg of crude 4(RS)-(tetrahydropyran-2-yloxy)-3(RS)-[3-(tetrahydropyran-2-yloxy)-trans-1-octenyl]-2(SR)-(methanesulfonyloxymethyl)cyclopentanone was prepared from 243 mg of 4(RS)-(tetrahydropyran-2-yloxy)-3(RS)-]3-(tetrahydropyran-2-yloxy)trans-1-octenyl]-2(SR)-(hydroxymethyl)cyclopentanone. The crude product was reacted with diisopropylethylamine in ether in a similar way to Example 24, (2) to give 239 mg of crude 4(RS)-(tetrahydropyran-2-yloxy)-3(RS)-[3-(tetrahydropyran-2-yloxy)trans-1-octenyl]-2-methylidenecyclopentanone.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]([C:11]2[CH:15]=[CH:14][O:13][N:12]=2)[C:9]([C:16]2[C:21]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=3)(=[O:25])=[O:24])=[CH:20][C:19]([Cl:37])=[CH:18][N:17]=2)=[N:8][N:7]=1)=O)C.[BH4-].[Li+].CO.Cl>C1COCC1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([NH:22][C:21]2[C:16]([C:9]3[N:10]([C:11]4[CH:15]=[CH:14][O:13][N:12]=4)[C:6]([CH2:4][OH:3])=[N:7][N:8]=3)=[N:17][CH:18]=[C:19]([Cl:37])[CH:20]=2)(=[O:25])=[O:24])=[CH:27][C:28]=1[C:33]([F:36])([F:35])[F:34]
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1-c1ccon1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(Nc1cc(Cl)cnc1-c1nnc(CO)n1-c1ccon1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-4-isoxazol-3-yl-4H-[1,2,4]triazole-3-carboxylic acid ethyl ester (28 mg, 0.05 mmol), 0.14 ml (0.28 mmol) of lithium borohydride (2.0M) and 0.020 ml of methanol in 1.5 ml of THF was stirred at room temperature for 2 hours. The mixture was mixed with diluted HCl (1.0M), extracted with ethyl acetate, and the extracts were combined and washed with brine and dried. After concentration the residue was purified by prep TLC to afford title compound as a white solid. MS (ES) [M+H]+ expected 535.0, found 535.0
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[C@H:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:11]1)(=O)=O.O>CN(C=O)C>[N:1]([C@@H:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:11]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CCN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])CCN1C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 97.7 %

Procedure:
NaN3 (15.8 g, 243 mmol) was added to a solution of (2R,4S)-1-tert-butyl 2-methyl 4-(methylsulfonyloxy)piperidine-1,2-dicarboxylate (26.7 g, 81 mmol) in dry DMF (100 mL). The mixture was heated at 60° C. for 18 hours. Water (300 mL) was added to the reaction mixture and extracted with ethyl acetate/heptane (2:1) (2×200 mL). The combined organic layer was washed by brine and dried over MgSO4, filtered and concentrated under reduced pressure to give a colorless oil 22.5 g (98%). LC-MS: 285.0 (t=2.5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:14]#[N:15])[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([CH2:14][NH2:15])[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C#N)CC12CCCCC2
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1(CN)CC12CCCCC2
Reaction time: 70 h
Yield: 69.2 %

Procedure:
To a solution of 1-cyano-spiro[2.5]octane-1-carboxylic acid ethyl ester (7.1 g, 34.2 mmol) in 95 mL ethanol (EtOH) was added triethylamine (5.0 mL) and Raney nickel (4.0 g). The mixture was hydrogenated in a Parr shaker at 48 psi for 70 hours, filtered, and concentrated. Flash chromatography of the residue (5→10→15% MeOH/methylene chloride (CH2Cl2)) provided 5.0 g (69%) of 1-aminomethyl-spiro[2.5]octane-1-carboxylic acid ethyl ester as a colorless oil. 1H NMR δ 4.15 (q, J=7.1 Hz, 2H), 3.23 (d, J=13.9 Hz, 1H), 2.65 (d, J=13.9 Hz, 1H), 1.41–1.57 (m, 10H), 1.24 (m, 4H), 0.53 (d, J=4.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:40]1([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:43]3[CH2:42][CH2:41][N:40]([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-acetamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C37H46N5O4Cl2 [(M+H)+] 694.2922, observed 694.2918.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1)[CH2:3][OH:4]>C(OCC)C>[CH3:1][C:2]([CH3:21])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1)[CH:3]=[O:4]
Reactant: CC(C)(CO)COCc1cccc(Oc2ccccc2)n1
Solvent: CCOCC
Product: CC(C)(C=O)COCc1cccc(Oc2ccccc2)n1

Procedure:
2,2-Dimethyl-3-(6-phenoxypyridin-2-yl)methoxypropan-1-ol was reacted according to the procedure set out in Example 6. The crude product was subject to column chromatography on silica gel using petroleum ether (boiling range 40°-60° C.) containing 20% by volume diethylether as eluent, to give 2,2-dimethyl-3-(6-phenoxypyridin-2-yl)methoxypropan-1-al.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C(Cl)(=O)C(Cl)=O.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](=[O:29])[C:26](Cl)=[O:27])=[CH:17]1.[C:30]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CCOCC>[C:30]([CH:38]1[CH2:43][CH2:42][N:41]([C:26](=[O:27])[C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:16][CH:17]=2)=[O:29])[CH2:40][CH2:39]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C(C(=O)N1CCC(C(=O)c2ccccc2)CC1)c1c[nH]c2ccccc12

Procedure:
A sample of an indole of the formula ##STR7## in a solvent such as anhydrous ether is allowed to react with oxalyl chloride at a temperature of from -15 to 15° C. for from a couple of minutes to 1 hour to produce a mixture of a corresponding 3 -indoleglyoxyloyl chloride in the solvent which is then added to a cooled solution of 4-benzoylpiperidine in a suitable organic solvent such as chloroform optionally containing an acid scavenger such as potassium carbonate and allowing the mixture to react at a temperature of from 15° to 40° C. for a few minutes to 12 hours to produce a 4-benzoyl-1(indol-3-ylglyoxyloyl)piperidine of the formula ##STR8##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=O)=[CH:4][CH:3]=1.C(C(C(C(O)=O)O)O)(O)=O.[CH3:23][C@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.[BH3-]C#N.[Na+].[OH-].[Na+]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:25]2[CH2:26][CH2:27][CH2:28][C@@H:24]2[CH3:23])=[CH:4][CH:3]=1
Reactant: O=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: C[C@H]1CCCN1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.12 h

Procedure:
A solution of the product from Example 34E, (1S,2S)-2-(4-bromophenyl)cyclopropanecarbaldehyde (5.7 g, 25.3 mmol) in DCM (20 ml) and MeOH (300 mL) was treated with (S)-2-methylpyrrolidine tartrate (8.94 g, 38.0 mmol) at ambient temperature, and the mixture was stirred for 5-10 minutes. Then, the mixture was cooled to 0° C., and a solution of NaCNBH3 (2.51 g, 38.0 mmol) in MeOH (50 mL) was added dropwise. After addition, the reaction mixture was raised to room temperature and stirred overnight. The reaction mixture was treated with NaOH (1N) till basic, extracted with DCM thrice (500 mL×3), dried and concentrated under reduced pressure. The crude product was loaded onto a silica gel column and eluted with 1% to 3% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title product. 1H NMR (300 MHz, CDCl3): δ 0.87-0.92(m, 1H), 0.97-1.02 (m, 1H), 1.16 (d, J=6 Hz, 2H), 1.22 (m, 1H), 1.39-1.49(m, 1H), 1.73-1.81(m, 3H), 2.0 (m, 2H), 2.36 (q, J=6 Hz, 1H), 2.45 (m, 1H), 3.13 (dd, J=12 Hz, J=6 Hz, 1H), 3.25 (m, 1H), 7.00 (d, J=6 Hz, 2H), 7.37 (d, J=6 Hz, 2H). MS (DCl—NH3) m/z 294 (M+H)+.