Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][N:25]1[C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:28]3[CH2:27][CH2:26][N:25]([C:30]4[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=4)[CH:24]([CH3:23])[CH2:29]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(-c4ccccc4)n3)CC2C)c1

Procedure:
54 mg (65%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (53 mg, 0.179 mmol), 2-methyl-1-m-tolylpiperazine (32 mg, 0.179 mmol), DIPEA (0.033 mL, 0.187 mmol) and NaBH(OAc)3 (108 mg, 0.510 mmol).
Reaction SMILES: [CH2:1]([C:3]1([CH3:17])[C:11](=O)[C:10]2[C:5](=[C:6]([CH3:15])[CH:7]=[C:8]([CH3:14])[C:9]=2[CH3:13])[C:4]1=O)[CH3:2].C1C=CC=CC=1>Cl.C(O)C>[CH2:1]([C:3]1([CH3:17])[CH2:11][C:10]2[C:5](=[C:6]([CH3:15])[CH:7]=[C:8]([CH3:14])[C:9]=2[CH3:13])[CH2:4]1)[CH3:2]
Reactant: CCC1(C)C(=O)c2c(C)cc(C)c(C)c2C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: CCC1(C)Cc2c(C)cc(C)c(C)c2C1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a mixture of 60 g of 7% Zn/Hg in 200 ml of 20% hydrochloric acid and 70 ml of ethanol was added 27.92 g of the 2-ethyl-2,4,5,7-tetramethylindan-1,3-dione with stirring. After refluxing for 6 hours, the reaction mixture was added 100 ml of benzene and refluxed for 3 hour. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 17.77 g of the title compound as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: NCCCn1ccnc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(3-aminopropyl)imidazole 2.1 g, 16.8 mmol), diisopropylethylamine (3.5 mL, 20.0 mmol) and 4-N,N-dimethylaminopyridine (200 mg, 1.7 mmol) in methylene chloride (15 mL) at 0° C. was added dropwise 4-chlorobenzoylchloride (2.1 mL, 16.8 mmol). The reaction was then allowed to warm to room temperature. After 5 hours, the reaction was diluted with methylene chloride, washed with 1N sodium hydroxide, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide a white solid. This material was washed with diethyl ether to provide N-(3-imidazol-1-yl-propyl)-4-chlorobenzamide. To a slurry of the above amide (1.58 g, 6.0 mmol.) in tetrahydrofuran (30 mL) was slowly added lithium aluminum hydride (456 mg, 12.0 mmol) upon which the reaction became exothermic. The mixture was heated to 80° C., stirred for 1 hr, cooled to 0° C. and quenched by addition of water (0.5 mL), 15% sodium hydroxide (0.5 mL) and an additional 1.5 mL of water. The reaction was diluted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide compound 20.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.Cl.NC1C=CC(C(O)=O)=CC=1>O1CCCC1>[C:1]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(C(=O)O)cc1
Yield: 78.8 %

Procedure:
0.66 g (7.3 mmoles) of acryloyl chloride was added to a solution of 2 g (14.3 mmoles) of p-aminobenzoic acid in 40 mL tetrahydrofuran (THF). A white precipitate consisting of p-aminobenzoic acid hydrochloride formed. The suspension was filtered and the filtrate was dried by vacuum evaporation to yield 1.1 g p-acrylamidobenzoic acid (reaction shown in FIG. 16a).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[Na].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OC)=O)=[CH:25][CH:24]=1>C(O)C>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(C)cc1
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(Cc2nc3c(nnn3C(C)CCCc3ccccc3)c(=O)[nH]2)cc1
Yield: 57.9 %

Procedure:
1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide are dissolved in a solution of 439 mg of sodium (19 mmol) in 38 ml of ethanol. 2.22 g (14.6 mmol) of methyl 4-methylphenylacetate are added, and the mixture is then refluxed overnight. The solvent is removed under reduced pressure, the residue is taken up with CH2Cl2, the organic phase is extracted twice with 1N HCl and dried over Na2SO4 and the solvent is removed under reduced pressure. Two chromatographic purifications (cyclohexane/ethyl acetate=3:1) give 853 mg (57%) of a solid.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][CH3:5].[N+:8]([CH3:11])([O-:10])=[O:9]>>[CH3:5][NH:4][C:3]([S:2][CH3:1])=[CH:11][N+:8]([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: CN=C(SC)SC
Product: CNC(=C[N+](=O)[O-])SC

Procedure:
A process according to claim 1 wherein methylcarbonimidodithioic acid dimethyl ester is reacted with nitromethane in the presence of a secondary catalyst containing a rare earth exchanged faujasite to form 1-methylamino-1-methylthio-2-nitroethene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24]CC)=[O:23].BrC1N=C(N)C=CC=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:46]=[C:45]([NH2:47])[NH:44][N:43]=2)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:47][C:45]3[NH:44][N:43]=[C:42]([C:39]4[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=4)[CH:46]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: Nc1cc(-c2ccc(Cl)cc2)n[nH]1
Agent: Nc1cccc(Br)n1
Product: O=C(Nc1cc(-c2ccc(Cl)cc2)n[nH]1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1

Procedure:
Prepared according to the method of Example 39, substituting 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid in Step A with 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid and 6-bromopyridin-2-amine with 3-(4-chlorophenyl)-1H-pyrazol-5-amine. MS (apci) m/z=524.1 (M+H).
Reaction SMILES: O=[C:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][CH:5]([CH2:10][CH2:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:25]([OH:27])=[O:26].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>O1CCCC1>[S:29]=[C:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][CH:5]([CH2:10][CH2:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:25]([OH:27])=[O:26]
Reactant: CCC1CC(CCc2ccc(C(=O)OCC(C)C)cc2)CN(C(=O)O)C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: CCC1CC(CCc2ccc(C(=O)OCC(C)C)cc2)CN(C(=O)O)C1=S
Temperature: 60 °C

Procedure:
A mixture of 3.75 g (10 mmol) of 4-(2-[2-oxo-3-ethylcarboxypiperidin-5-yl]ethyl)benzoic acid, 2,2-dimethylethyl ester and 2.44 g (5.5 mmol) of phosphorus pentasulfide in 70 mL of tetrahydrofuran is heated at 60° C. until complete conversion is obtained. The mixture is evaporated to a residue which is purified by chromatography on silica gel, providing 4-(2-[2-thioxo-3-ethylcarboxypiperidin-5-yl]ethyl)benzoic acid, 2,2-dimethylethyl ester.
Reaction SMILES: C(O[N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[N:17]12[CH2:18][CH2:19][CH:20]([CH2:21][CH2:22]1)[CH:15]([N:12]1[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1)[CH2:16]2
Reactant: c1ccc(CON2CCN(C3CN4CCC3CC4)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: C1CN(C2CN3CCC2CC3)CCN1
Yield: 98 %

Procedure:
A solution of 1-benzyloxy-4-(3-quinuclidinyl)piperazine (728 mg, 2.21 mmol) in methanol (5 ml). was hydrogenated at an atmospheric pressure in the presence of 10% palladium on carbon (73 mg) at room temperature for 15 h. The mixture was then filtered through a pad of celite. The filtrate was concentrated to afford a white solid (423 mg, 98% yield).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:26]=[C:25]([CH2:27][OH:28])[O:24][N:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:26]=[C:25]([CH2:27][O:28][C:6](=[O:7])[NH2:5])[O:24][N:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Solvent: C1CCOC1
Product: NC(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
1.04 ml of chlorosulfonyl isocyanate (12 mmol) was slowly added to [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (2.813 g, 10 mmol) in THF (50 ml, 0.2 M) in a 250 ml-flask at −78° C. The consumption of all the starting materials was confirmed by liquid chromatography, and then water was added to the reaction mixture. After 1 hour, the THF was distilled off under reduced pressure, and the resulting solid after addition of 100 ml of water to the mixture was filtered off. The filtered solid was each washed with 100 ml of water and a solution of ethyl acetate/hexane (1/2) and then dried to obtain 3.4 g of a crude product (95.9% pure). The crude compound was recrystallized from an ethyl acetate/hexane/methylene chloride (1/4/1) solution containing 1% MeOH to obtain 2.743 g of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester of 99% purity.
Reaction SMILES: [C:1]([NH:4][C@@:5]1(O)[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1Cl)(=[O:3])[CH3:2].[CH3:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]2[C:35]([CH3:41])=[CH:36][C:37]([CH3:40])([CH3:39])[NH:38][C:32]2=[CH:31][CH:30]=1>CC(C)=O>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:38]1[C:32]2[C:33](=[CH:34][C:29]([O:28][CH2:27][CH3:26])=[CH:30][CH:31]=2)[C:35]([CH3:41])=[CH:36][C:37]1([CH3:39])[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@]1(O)C(Cl)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Solvent: CC(C)=O
Product: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2C1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O
Reaction time: 0.5 h
Yield: 63 %

Procedure:
2-Acetamido-3,4,6-tri-O-acetyl-D-glucopyranosyl chloride (18.3 g) and ethoxyquin (22.1 g) were vigorously stirred together at 80° for 3 hours. Acetone (50 ml) was added to the hot reaction mixture and stirring was continued for 0.5 hours. After cooling, the solid ethoxyquin-hydrochloride was filtered, washed with acetone and the combined filtrates were evaporated under reduced pressure. The crude product was purified by column chromatography on silica (ethylacetate-benzene 1:4). 16.5 g of 1-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranosyl)-6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline were obtained. Analytical grade sample was obtained by recrystallisation from ether or isopropanol. m.p. 186°-187°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:34][N:35]1[C:39]([C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[OH:49])=[CH:38][CH:37]=[N:36]1.[N:50]1([CH2:56][CH2:57]O)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C1COCC1>[CH3:34][N:35]1[C:39]([C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[O:49][CH2:57][CH2:56][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=[N:36]1
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A mixture of triphenylphosphine (7.5 g, 1.8 eq), and diisopropylazodicarboxylate (5.66 mL, 1.8 eq) in 50 mL THF was stirred at 0° C. for 10 minutes, then 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol (3.5 g, 15.9 mmole), and 2-morpholin-4-yl-ethanol (3.66 mL, 1.8 eq) was added into the mixture at 0° C. Reaction mixture was stirred at room temp for another 1 hour. The mixture was purified by HPLC to give title compound as a yellow gummy solid (9.436 g, 89%). Exact mass calculated for C16H20N4O5 332.2, found 333.3 (MH+).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](O)(=[O:16])[CH2:11]CCCC>C(O)(=O)C>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:16])[CH3:11]
Reactant: CCCCCCCCO
Reactant: CCCCCC(=O)O
Solvent: CC(=O)O
Product: CCCCCCCCOC(C)=O

Procedure:
To a 5 mL reaction vial equipped with stir bar was added approximately 200 μL of 3-butyl-1-(butyl-4-sulfonyl)imidazolium trifluoromethanesulfonate (1.9 M). Added next via syringe was 1-octanol (60 μL, 0.38 mmol) followed by hexanoic acid (48 μl, 0.38 mmol). The resulting monophase was allowed to stir at room temperature for a period of 7 days at which time the oil was washed with toluene (5×2 mL). Shorter reaction times using higher reaction temperatures also afforded excellent conversion of acid to ester. Reaction of 1-octanol and acetic acid resulted in 89% conversion to n-octyl acetate at 40° C. for a period of 72 h whereas 83% conversion was observed at 40° C. for 48 h. The collected organic washes were concentrated in vacuo to afford 76 mg of n-octyl hexanoate. GC analysis of the crude product revealed only trace amounts of starting material in the organic washes. Purification of the crude colorless oil by bulb-to-bulb distillation afforded the desired compound in 72 mg (0.31 mmol, 82% yield) as a clear and colorless oil (bp 130° C./3 mm Hg (air bath temp)). 1H NMR (300 MHz, CDCl3), δ 4.04, J=6.6, 2H), 2.27 (t, J=7.4, 2H), 1.63-1.58 (m, 4H), 1.30-1.25 (m, 14H), 0.87-0.80 (m, 6H). 13C NMR (75.5 MHz, CDCl3); δ 174.10, 64.47, 34.42, 31.84, 31.39, 29.26, 28.72, 26.00, 24.78, 22.70, 22.38, 14.13, 13.96. IR (thin film) 2956, 2929, 2858, 1739, 1466, 1173 cm−1. GC ((HP-1 methyl siloxane; f=1.0 mL/min) 100° C. (2 min), 10° C./min, 275° C. (10 min)) 11.05 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[N:15][CH:16]=1.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH:18][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH:14]=[N:15][CH:16]=1
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccccc21
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCc1cncc(-c2cc3ccccc3n2C)c1

Procedure:
C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 200b) and ethanesulfonyl chloride are processed according to the method described in Example 186f to give N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 1.37 (t, J=7.3 Hz, 3H), 3.13 (q, J=7.4 Hz, 2H), 3.82 (s, 3H), 4.43 (s, 2H), 6.70 (s, 1H), 7.01-7.18 (m, 1H), 7.20-7.36 (m, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 8.10 (t, J=2.1 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 330.1288 [(M+H)+ Calcd for C17H20N3O2S: 330.1276].
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CO>C1COCC1>[CH2:1]([NH:8][S:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([CH2:15][OH:16])[CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)NCc2ccccc2)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(NCc1ccccc1)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To solution of 3-Benzylsulfamoyl-benzoic acid (395 mg, 1.36 mmol) in THF (10 ml) was added BH3.THF (1M, 5.4 ml, 5.4 mmol) dropwise. After addition, the reaction mixture was allowed to stir for 3 d at room temperature. Methanol was added to the reaction, and the mixture concentrated in vacuo (5×). This compound was used in the next step without further purification.
Reaction SMILES: ClC1C=C(NC2C3C(=CC(OCCOC)=C(N)C=3)N=CN=2)C=CC=1F.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([N+:37]([O-])=O)[CH:35]=2)[N:30]=[CH:29][N:28]=1.[Cl:42][C:43]1[CH:51]=[CH:50][C:46]2[O:47][CH2:48][O:49][C:45]=2[C:44]=1[NH2:52]>>[Cl:42][C:43]1[CH:51]=[CH:50][C:46]2[O:47][CH2:48][O:49][C:45]=2[C:44]=1[NH:52][C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([NH2:37])[CH:35]=2)[N:30]=[CH:29][N:28]=1
Reactant: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1c(Cl)ccc2c1OCO2
Agent: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncnc(Nc3c(Cl)ccc4c3OCO4)c2cc1N

Procedure:
Starting material: N4-(5-chlorobenzo[d][1,3]dioxol-4-yl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting material were 4-chloro-7-methoxy-6-nitroquinazoline and 5-chlorobenzo[d][1,3]dioxolan-4-amine; other starting materials were prepared as example 1.
Reaction SMILES: Cl.Cl.[N:3]1[N:4]=[C:5]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([O:22][CH2:23][C:24]4([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.CN(C=O)C.Br[CH2:37][C:38]([NH2:40])=[O:39]>C1COCC1.ClCCl.C([O-])(O)=O.[Na+].O>[N:3]1[N:4]=[C:5]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([O:22][CH2:23][C:24]4([F:30])[CH2:29][CH2:28][N:27]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:26][CH2:25]4)[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: FC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCNCC1
Reactant: NC(=O)CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)CN1CCC(F)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a suspension of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinoline dihydrochloride (0.050 g, 0.111 mmol) and TEA (0.0619 mL, 0.444 mmol) in 0.4 mL THF, 0.3 mL dichloromethane, and 0.2 mL DMF was added 2-bromoacetamide (0.0184 g, 0.133 mmol). The reaction mixture was heated in a 40° C. reaction block and stirred 1 hour. The reaction mixture was cooled to ambient temperature, several drops of saturated NaHCO3 were added, and the milky mixture was heated back to 40° C. and stirred another 3 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and the resulting solids were collected by vacuum filtration through a 0.2 micron nylon filter disc, rinsed with water, air dried, then washed successively with ethyl acetate, dichloromethane, and ether, air dried, and dried in vacuo to give the title compound (0.014 g, 0.0322 mmol, 29.0% yield) as a white powder. MS APCI (+) m/z 435 (M+1) detected.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14].CO[NH2:22].Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:22][C:10]1[C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=[C:8]([Cl:7])[CH:9]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CON
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)cc(C(=O)O)c1[N+](=O)[O-]
Yield: 100.5 %

Procedure:
Under nitrogen, to a solution of t-BuOK (156.8 g) and Cu(OAc)2 (3.6 g) in DMF (1.2 L) was added a solution of 5-chloro-2-nitrobenzoic acid (40.0 g) and MeONH2HCl (33.2 g) in DMF (300 mL) at 0° C. After 3 h the reaction was quenched by addition of H2O (2.5 L) and acidified with 10% HCl solution to pH=1.The mixture was extracted with EA (2 L×2) and the combined organic layers were then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo to afford the crude product as a yellow solid (43.2 g, yield 100%). 1H NMR (300 MHz, CDCl3): δ ppm 6.88 (s, 1H, J=2.4 Hz), 6.91 (d, 1H, J=2.4 Hz), 8.08 (br s, 2H); LC-MS: m/e=217 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:22]([F:24])[F:23])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:24][CH:22]([F:23])[N:7]1[C:6]([CH2:4][OH:3])=[CH:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:20])([F:19])[F:21])=[CH:15][CH:16]=2)=[N:8]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)nn1C(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1C(F)F

Procedure:
In analogy to the procedure described for example 1 a], 2-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [2-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[NH2:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:10][C:11]1[C:16]([O:17][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Br:1])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: BrCc1ccccc1Br
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1ncccc1OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
A mixture of 2-bromobenzyl bromide (50 g, 0.20 mol) and 2-amino-3-hydroxypyridine (20.0 g, 0.18 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to obtain the product (35.4 g, 63%), m.p. 99°-100° C.
Reaction SMILES: C1(C[N:8]2[CH2:12][C@H:11]3[CH2:13][C@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:10]3[O:9]2)C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:12][C@@H:11]1[C@H:10]([OH:9])[CH2:15][C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H]2CN(Cc3ccccc3)O[C@@H]2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1C[C@H](CN)[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of (±)-1,1-dimethylethyl (3aR,5S,6aR)-2-(phenylmethyl)hexahydro-2H-cyclopenta[d]isoxazole-5-carboxylate (13.0 g, 42.9 mmole) in EtOH (100 mL) in a Parr flask was added Pd(OH)2 (˜400 mg). The reaction contents were shaken under 50 psi of H2 overnight at RT. The reaction contents were filtered through Celite® (MeOH) and concentrated to give the title compound (7.87, 99%) as a white solid: LC-MS (ES) m/e 216 (M+H)+.