Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.N#N.[C:20]([NH:23][C@H:24]([C:40]([OH:42])=O)[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])(=[O:22])[CH3:21].C(N=C=NCCCN(C)C)C.[C:54]([O:58][C:59](=[O:83])[CH:60]([CH2:81][NH2:82])[CH2:61][C:62]1([C:67](=[O:80])[NH:68][C@H:69]2[CH2:74][CH2:73][C@@H:72]([C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:71][CH2:70]2)[CH2:66][CH2:65][CH2:64][CH2:63]1)([CH3:57])([CH3:56])[CH3:55]>ClCCl>[C:54]([O:58][C:59](=[O:83])[CH:60]([CH:81]([C:40](=[O:42])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[NH:23][C:20](=[O:22])[CH3:21])[NH2:82])[CH2:61][C:62]1([C:67](=[O:80])[NH:68][C@H:69]2[CH2:70][CH2:71][C@@H:72]([C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:73][CH2:74]2)[CH2:66][CH2:65][CH2:64][CH2:63]1)([CH3:56])([CH3:55])[CH3:57]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1
Reactant: CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)OC(C)(C)C)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1-Hydroxybenztriazole (207 mg, 1.53 mmole) and N-methylmorpholine (235 mg, 2.36 mmole) were added to a stirred solution of N2 -acetyl-N6 -benzyloxycarbonyl-L-lysine (456 mg, 1.41 mmole) in dry dichloromethane at 0° C., followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (361 mg). The solution was stirred at 0° C. for 20 minutes and 3-{1-[(cis-4-ethoxycarbonylcyclohexyl)-carbamoyl]cyclopentyl}-2-(aminomethyl)propanoic acid t-butyl ester (500 mg, 1.18 mmole) in dichloromethane (10 ml) was added in one portion and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. The solution was concentrated under vacuum to a volume of 10 ml and partitioned between ethyl acetate and water. The organic phase was washed with water (2×50 ml), 2M hydrochloric acid (50 ml, 2×25 ml), sodium bicarbonate solution (2×25 ml) and brine and then dried (MgSO4) and the solvent evaporated. The residue was chromatographed on silica eluting with ethyl acetate to give the title compound (610 g, 71%). Found: C,63.34; H,8.61; N,7.45. C39H60N4O9 (0.25H2O) requires C,63.48; H,8.33; N,7.59%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[O:13][C:12]([C:14]2[C:18]([C:19](Cl)=[O:20])=[CH:17][N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:15]=2)=[CH:11][CH:10]=1)([O-:8])=[O:7]>O1CCOCC1>[N+:6]([C:9]1[O:13][C:12]([C:14]2[C:18]([C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:20])=[CH:17][N:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:15]=2)=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: O=C(c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1)N1CCCC1
Temperature: 25 °C
Yield: 99 %

Procedure:
Add 1.06 ml. of pyrrolidine in 2 ml of dioxane dropwise to 1.0 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride in 43 ml of dioxane at 35° C under stirring. Stir the resulting solution for an hour at room temperature and then concentrate it. Wash the resulting precipitate with water to obtain a 99% yield of 1-[3-(5-nitro-2-furyl)-1-phenyl-4-pyrazolylcarbonyl]pyrrolidine [m.p. 236.5° to 237.5° C].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([F:24])[C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[C:34]([CH2:36][C:37](O)=[O:38])#[N:35].CCN=C=NCCCN(C)C>C(Cl)Cl>[C:34]([CH2:36][C:37]([NH:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([F:24])[C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[O:16])[CH2:13][CH2:14]1)=[O:38])#[N:35]
Reactant: N#CCC(=O)O
Reactant: CN1CCN(C(=O)C2CCN(c3c(N)cncc3F)CC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)CC#N)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of [1-(3-amino-5-fluoro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanone hydrochloride 17b (300 mg, 0.8383 mmol) and DIPEA (541.8 mg, 730.2 μL, 4.192 mmol) in DCM (8 mL) was added cyanoacetic acid 7 (106.9 mg, 1.257 mmol). The reaction mixture was cooled on an ice bath and EDCI (241.0 mg, 1.257 mmol) was then added. The mixture was stirred at room temperature overnight, then heated under reflux for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL), washed with water (2×10 ml), then saturated sodium hydrogen carbonate solution (10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford the desired product 8a as an orange foam (292 mg, 90%). MS (ES+) 389.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:29]1[CH:36]=[CH:35][C:32](C=O)=[CH:31][CH:30]=1>C(O)C>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:29]1[CH:36]=[CH:35][C:32]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:31][CH:30]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccc(C2CNCCN2CCO)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(C3CNCCN3CCO)cc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A one liter three necked flask fitted with a dropping funnel, mechanical stirrer, and condenser is charged with 34.35 g of 4-nitrophenylacetic acid. Piperidine (16.2 g) is added dropwise over a period of 30 minutes. At the end of the addition period, 44.46 g of 4-[N-(2-hydroxyethyl)piperazinyl]benzaldehyde is added. The mixture is heated at 100° C. for three hours, and at 130° C. for three hours. After cooling, the resultant semi-solid mass is ground up in ethanol in a blender, then filtered, washed with water, and vacuum dried. The crude solid is recrystallized from chlorobenzene: m.p. 221°-224° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:17][CH2:18]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncn2)CC1
Temperature: 120 °C
Yield: 105.6 %

Procedure:
4,6-Dichloropyrimidine (284 mg, 1.9 mmol), N-Boc-4-aminomethyl piperidine (409 mg, 1.9 mmol) and potassium carbonate (317 mg, 2.3 mmol) were dissolved in acetonitrile (5 mL) and the solution was heated for 30 minutes at 120° C. using microwave irradiation. The reaction mixture was partitioned between water and dichloromethane and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and evaporated to give tert-butyl 4-((6-chloropyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate (656 mg, 100%) as a yellow oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:32])([F:31])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21]1)[OH:13].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([O:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:21]2)[C:11]([F:10])([F:32])[F:31])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OC(c1ccccc1-n1ccc(-c2ccccc2)n1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OC(c2ccccc2-n2ccc(-c3ccccc3)n2)C(F)(F)F)n1
Temperature: 42.5 °C
Reaction time: 6 h
Yield: 112.2 %

Procedure:
2-Amino-4,6-dichloro pyrimidine (0.041 g, 0.25 mmol), 2,2,2-trifluoro-1-[2-(3-phenyl-pyrazol-1-yl)-phenyl]-ethanol (0.070 g, 0.22 mmol), and NaH (0.012 g, 0.31 mmol) were added to anhydrous THF (7 ml) under nitrogen atmosphere. The reaction was stirred at 40-45° C. for 6 h, and then cooled to room temperature, and quenched with water (0.04 ml). The reaction mixture was concentrated to give crude 4-chloro-6-{2,2,2-trifluoro-1-[2-(3-phenyl-pyrazol-1-yl)-phenyl]-ethoxy]-pyrimidin-2-ylamine (0.110 g, >90% pure by LCMS), which was directly used in the following step.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH:20]1C=CC=C[CH:21]=1>ClC(Cl)C>[Cl:15][C:14]1[C:6]([Cl:5])=[C:7]2[C:11]([CH2:20][CH2:21][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C1CCc2ccc(Cl)c(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Thionyl chloride (5.73 mL, ˜79 mmol) and 2,3-dichloro-benzoic acid (commercially available from Aldrich) (10.0 g, 52.4 mmol) in benzene was heated to reflux until no more gas evolution was observed. After cooling to rt the mixture was concentrated. The concentrate was diluted with dichloroethane and added to AlCl3 (7.0 g, ˜53 mmol) in dichloroethane at 10-20° C. Ethylene was bubbled through the mixture for 4 h. The mixture was stirred overnight and quenched with 4 N HCl. The resulting layers were separated and the aqueous layer was extracted with Et2O (3×250 mL). The combined organic extracts were washed with H2O (3×150 mL), saturated NaHCO3 (3×150 mL), brine (1×150 mL), dried over MgSO4 and concentrated. The concentrate was added to a slurry of AlCl3 (9.0 g) and NaCl (2.4 g) at 130° C. The resulting mixture was stirred at 180° C. for 2 hours after which it was cooled to room temperature and quenched with ice followed by concentrated HCl. The mixture was extracted with CH2Cl2 (3×500 mL) and the combined organic extracts were concentrated and purified by column chromatography using 20% EtOAc:hexane eluant to give 6.8 g (80%) of 6,7-dichloro-1-indanone. Use of 6,7-dichloro-indan-1-one in Method NINETEEN produced 4-(4,5-dichloro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 153).
Reaction SMILES: N1C(C)=CC=CC=1C.[F:9][C:10]([F:23])([F:22])[S:11]([O:14]S(C(F)(F)F)(=O)=O)(=[O:13])=[O:12].[Cl:24][C:25]1[CH:33]=[C:29]([C:30]([OH:32])=[O:31])[C:28](O)=[C:27]([N+:35]([O-:37])=[O:36])[CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([N+:35]([O-:37])=[O:36])[C:28]([O:14][S:11]([C:10]([F:23])([F:22])[F:9])(=[O:13])=[O:12])=[C:29]([CH:33]=1)[C:30]([OH:32])=[O:31]
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Yield: 95.2 %

Procedure:
2,6-Lutidine (1.83 ml, 15.7 mmol) and trifluoro-methanesulfonic anhydride (3.67 g, 13 mmol) were added dropwise in turn to a solution of methyl ester of 5-chloro-3-nitrosalicylic acid (2.32 g, 10.0 mmol) in methylene chloride (25 ml) with stirring under ice cooling and the mixture was stirred under ice cooling for 0.5 hrs. Methylene chloride (20 ml) and ice water (30 ml) were added to the reaction mixture and the aqueous layer was separated and extracted with methylene chloride. The organic layers were combined, washed with water and dried. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=10) to give methyl ester of 5-chloro-2-trifluoromethanesulfonyloxy-3-nitrobenzoic acid (3.33 g, 91%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[S:5][C:6]=1[CH3:7].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[CH:22]=1>C(OCC)(=O)C>[CH3:26][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:4]3[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=3)=[CH:9][CH:10]=2)[O:25][N:24]=1
Reactant: Cc1cc(CCCCCBr)on1
Reactant: Cc1nc(-c2ccc(O)cc2)sc1C
Solvent: CCOC(C)=O
Product: Cc1cc(CCCCCOc2ccc(-c3nc(C)c(C)s3)cc2)on1

Procedure:
3-Methyl-5-{5-[4(4,5-dimethyl-2-thiazolyl)phenoxy]pentyl}isoxazole [II; R1 and R2 =H, Het=(4,5-dimethyl-2-thiazolyl)] was prepared from 2.0 g 4-(4,5-dimethyl-2-thiazolyl)phenol and 2.3 g 5-(5-bromopentyl)-3-methylisoxazole according to the procedure of Example 1: yield 2.5 g, m.p. 96°-97° C. (yellow to orange crystals from ethyl acetate).
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1)[NH2:4].[CH3:17][C:18](=O)[CH2:19][CH2:20][C:21](=O)[CH3:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:22][C:21]1[N:4]([NH:3][C:5]2[N:6]=[N:7][C:8]([N:11]3[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)=[CH:9][CH:10]=2)[C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: NNc1ccc(N2CCSCC2)nn1
Reactant: CC(=O)CCC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Nc1ccc(N2CCSCC2)nn1
Yield: 50 %

Procedure:
3-Hydrazino-6-(4-thiomorpholinyl)-pyridazine di-hydrochloride and 2,5-hexanedione are reacted in acetic acid in the presence of sodium acetate according to the procedure of example 2. The product is recovered by evaporating the acetic acid and slurring the residue in aqueous sodium bicarbonate. The solid obtained after filtration is purified by chromatography through silicagel using a chloroform-methanol mixture 97.5:2.5 mixture as the eluent. Yield 50%. M.p. 203° C. (from ethyl acetate). Elemental analysis, I.R. and N.M.R. data are in agreement with the assigned structure.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]1[CH:42]=[C:43]([CH:52]2[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]2)[CH:44]=[CH:45][C:46]=1[O:47][C:48]([F:51])([F:50])[F:49]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:55]1[CH2:54][CH2:53][CH:52]([C:43]2[CH:44]=[CH:45][C:46]([O:47][C:48]([F:49])([F:51])[F:50])=[C:41]([F:40])[CH:42]=2)[CH2:57][CH2:56]1
Reactant: O=C1CCC(c2ccc(OC(F)(F)F)c(F)c2)CC1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1cc(C2CCC(=CCC3OCCCO3)CC2)ccc1OC(F)(F)F
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (9.1 g, 20 mmols), followed by adding tetrahydrofuran (100 ml), suspending, stirring under ice cooling till the liquid temperature reached 10° C. The resulting reaction mixture was added potassium t-butoxide (2.2 g, 20 mmols) followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(3-fluoro-4-trifluoromethoxyphenyl)cyclohexanone (5.5 g, 20 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure, and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(3-fluoro-4-trifluoromethoxyphenyl)cyclohexane.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH3:15][N:16]([CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH3:17]>O1CCCC1.[Fe](Cl)(Cl)Cl>[CH3:17][N:16]([CH2:18][CH:19]1[C:20]([OH:25])([C:7]2[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1)[CH3:15]
Reactant: CN(C)CC1CCCCC1=O
Reactant: COc1cccc(Br)c1
Agent: Cl[Fe](Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
To 230 mL of anhydrous tetrahydrofuran (THF) cooled to −60° C. was added 9.36 g of n-butyl lithium (0.123 mol, 10 M solution in hexanes). The resulting yellow solution was stirred for 10 min and then 23.06 g of neat 3-bromoanisole (0.34 mol) was added dropwise with stirring. The resulting white suspension was stirred for 15 min. To the white suspension was then added dropwise, over a 4 hour period, a solution of 19.14 g of (±) 2-((dimethylamino)methyl)cyclohexanone (0.123 mol) and 400 mg of iron (III) chloride (2.5 mmol, 2 mol percent) in 190 mL of anhydrous THF at −60° C. The resulting reaction mixture was quenched with water, the organic phase was separated, the aqueous phase was extracted twice with diethyl ether and the diethyl ether extracts were combined. The combined ether extracts were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to provide 37.77 g (0.084 mol, 68% yield) of the above-titled mixture in a ratio of 91.9:8.1 as determined using HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-])=[C:4]([CH3:10])[C:3]=1[CH3:11].C(OC(=O)C)(=[O:14])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH2:10][OH:14])[C:3]=1[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Solvent: Cc1ccccc1
Product: Cc1cnc(CO)c(C)c1Cl
Temperature: 50 °C

Procedure:
At 90-95° C., a solution of 4-chloro-2,3,5-trimethylpyridine-N-oxide (60.0 g, 350 mmol) in toluene (920 mL), which was kept at about 60° C., was added over 7 h to acetic anhydride (232 mL). Under vacuum at about 60° C., the reaction mixture was concentrated until 820 mL had been distilled off. Toluene (840 mL) was added and, again, solvents were distilled off (940 mL). Then, toluene (180 mL) and 40% aqueous NaOH (80 mL) were added before the reaction mixture was heated at 50° C. for about 15 h. After addition of saturated aqueous sodium bicarbonate (120 mL), the phases were separated and the aqueous layer was extracted once more with toluene (80 mL). Finally, the combined organic phase was washed with saturated aqueous sodium bicarbonate (120 mL) and evaporated to dryness to give 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine as a brownish oil which solidified upon standing; yield 61.8 g (quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:14]1[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:13]1=[O:21])[CH2:6][CH2:5]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1CCc2cc(Br)ccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=C1CCc2cc(Br)ccc21
Temperature: 110 °C
Yield: 11.2 %

Procedure:
A reaction mixture of 0.422 g 5-bromoindanone, 1.3 g oxindole and 0.9 ml piperidine in 3 ml of dimethylforamide was heated in a sealed tube at 110° C. overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The black residue was chromatographed on a silica gel column, eluting with ethyl acetate and hexane to give 73.0 mg of 3-(5-bromoindan-1-ylidene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[CH3:11][NH2:12]>>[CH3:11][NH:12][CH2:7][CH:6]([OH:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C2CO2)cc1
Reactant: CN
Product: CNCC(O)c1ccc(C)cc1
Yield: 71.2 %

Procedure:
4-Methyl styrene oxide(1.0 g, 8.0 mmol) and 3 ml of methylamine in methanolic solution(28%) were charged into a flask. The flask was sealed and put in a refrigerator for 5–7 days. The solution was concentrated and the residue crystallized from ether, the title compound was obtained as white needle crystals, mp. 90.5–93.2° C., yield 71.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]=[C:19]([CH3:30])[CH:18]=2)[C@H:14]([C:31]([NH:33][C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[O:32])[CH2:13]1)(=[O:11])=[O:10].[C:39]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:42])([CH3:41])[CH3:40]>>[C:37]([C:34]1([NH:33][C:31]([C@@H:14]2[CH2:13][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([N:46]4[CH2:47][CH2:48][N:43]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:44][CH2:45]4)=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]=[C:19]([CH3:30])[CH:18]=2)=[O:32])[CH2:36][CH2:35]1)#[N:38]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(CCc2ccccc2)n1
Reactant: CC(C)(C)N1CCNCC1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C(C)(C)C)CC4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(CCc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 392, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-phenethyl-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (example 484c) was reacted with 1-tert-butylpiperazine (CAS Reg. No. 38216-72-7) to give the title compound as colorless oil. MS (ESI): m/z=678.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:16]=2)[CH:4]=1.[OH-].[Li+].[ClH:27]>C1COCC1.O>[ClH:27].[F:23][C:2]([F:1])([F:24])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]([OH:20])=[O:19])[CH:16]=2)[CH:4]=1
Reactant: CCOC(=O)Cn1cc(-c2cc(C(F)(F)F)cc3[nH]ncc23)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1cc(-c2cc(C(F)(F)F)cc3[nH]ncc23)cn1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a mixture of ethyl 2-(4-(6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)acetate (0.14 g, 0.414 mmol) and THF—H2O (5:1, 4 mL) was added lithium hydroxide (0.621 mL, 1.242 mmol) at room temperature. The reaction mixture was stirred for 1 hour, then acidified with concentrated HCl, and concentrated in vacuo to give an HCl salt of the title compound as a light brown solid (0.12 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H), 7.58 (s, 1H), 7.76 (s, 1H), 8.22 (s, 1H), 8.54 (s, 1H), 8.59 (s, 1H), 13.70 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C13H9F3N4O2, 311.1. found 311.15.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=[O:12].[BH4-].[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][OH:12]
Reactant: Cn1c(C=O)nc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(CO)nc2ccccc21

Procedure:
To 432 mg of 1-methyl-1H-benzoimidazole-2-carbaldehyde (2.7 mmol, 1 eq) dissolved in a mixture of THF (10 mL) and methanol (10 mL) was added 340 mg of sodium borohydride (9.0 mmol, 3.33 eq) in several portions. After 12 h the reaction mixture was quenched with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (1-methyl-1H-benzoimidazol-2-yl)-methanol in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.8 (s, 3 H) 4.7 (d, J=5.6 Hz, 2 H) 5.6 (t, J=5.7 Hz, 1 H) 7.2 (m, 1 H) 7.2 (m, 1 H) 7.5 (m, 1 H) 7.6 (m, 1 H).