Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([C@H:23]([CH2:25][CH3:26])[CH3:24])[NH2:22].C([BH3-])#N.[Na+]>C(OCC)(=O)C.CCCCCC>[CH3:18][O:19][C:20](=[O:27])[C@H:21]([C@H:23]([CH2:25][CH3:26])[CH3:24])[NH:22][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC[C@H](C)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OC

Procedure:
The starting material can be obtained, for example, analogously to Example 1b): The reaction of 2.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 9.6 g of molecular sieve 5 A, 1.76 g of (L)-isoleucine methyl ester hydrochloride and 680 mg of sodium cyanoborohydride yields N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-isoleucine methyl ester after flash chromatography (ethyl acetate/hexane 1:3). 1H-NMR (DMSO): 1.21 ppm (d, 3H), 3.63 ppm (s, 3H), 3.75 (dd, 1H), 4.56 ppm (d, 2H), 4.58 ppm (d, 2H), 5.31 ppm (t, 1H), 7.4-8 ppm aromatics.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=c1c(Br)coc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(-c2ccc(F)cc2)coc2ccccc12
Yield: 22.5 %

Procedure:
Prepared according to general procedure using 3-bromochromone (338 mg, 1.5 mmol), 4-fluorophenylboronic acid (231 mg, 1.65 mmol), K2CO3 (622 mg, 4.5 mmol), PdCl2(PPh3)2 (45 mg, 0.045 mmol), THF (3 mL) and water (1.5 mL). Purified by flash column chromatography (SiO2, 10% EtOAc/Hex) to afford afford 37 (81 mg, 23%) as a white solid. Analytical data for isoflavone 37: 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J=9 Hz, 1H), 8.04 (s, 1H), 7.72 (app t, J=9 Hz, 1H), 7.58-7.56 (m, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.47 (app t, J=8 Hz, 1H), 7.16 (app t, J=9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 176.5, 164.0, 162.0, 156.5, 153.2, 134.0, 131.0, 128.0, 126.7, 125.6, 124.8, 118.3, 115.8; LCMS: Mass calculated for C15H9FO2, [M+H]+, 241. Found 241.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C>[O:29]([C:27]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([NH:15][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:28]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)COc1ccccc1
Reaction time: 2 h

Procedure:
0.029 mL of 2-phenoxyacetyl chloride was added to 2.5 mL of methylene chloride solution containing 40 mg of tert-butyl 2-amino-4-phenoxybenzoate and 0.039 mL of triethylamine at room temperature and stirred at the same temperature for 2 hours. 0.25 g of aminomethylated polystyrene was added to the reaction mixture and after stirred at the same temperature overnight, 5 mL of 10% citric acid aqueous solution was added. The organic layer was separated and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate: acetic acid=20:5:1] to obtain tert-butyl 4-phenoxy-2-(2-phenoxyacetamido)benzoate.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([CH3:14])[CH:6]=1)([CH3:3])[CH3:2].[C:15](OC(N(C)C)N(C)C)(C)(C)C>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:15]=[CH:14]2)([CH3:3])[CH3:2]
Reactant: Cc1cc(OC(C)C)ccc1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CC(C)Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 4-isopropoxy-2-methyl-1-nitrobenzene (3.55 g,0.018 mol) and tert-butoxybis(dimethylamino)methane (9 mL) was refluxed for 4 hours and the volatile was removed. The dark brown residue was dissolved in THF (150 mL) and hydrogenated with catalytic amount of 10% Pd on Carbon with H2 in a balloon. After stirring at room temperature overnight, the catalyst was filtered off and the filtrate was concentrated to afford 3.07 g 5-isopropoxyindole (96%). MS(EI): (M+1) 176.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.Br[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)=[CH:28][CH:27]=1)[C:22]([O:24][CH3:25])=[O:23]>C1C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[CH:21]([O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc(Oc2ccccc2)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 41.4 %

Procedure:
To a mixture of 4.66 g of p-phenoxyphenol, 1.19 g of sodium methoxide, 10 ml of benzene and 40 ml of methanol is added 8.27 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate in 10 ml of benzene. The mixture is refluxed for 22 hours and the solvent removed under reduced pressure. The residue is chromatographed over silica gel with dichloromethane as eluent giving a viscous oil which is again chromatographed over silica gel with dichloromethane as eluent. There is obtained 4.3 g of viscous oil which is crystallized from methylcyclohexane-methanol to give 3.6 g of white crystals, mp 78°-80° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)=[CH:12][N:11]=2)[CH2:5]1.[BH4-].[Na+]>CO.O>[OH:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([N:6]3[CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[N:11][CH:12]=2)[CH2:17][CH2:18]1
Reactant: COCC1CN(c2ccc(C3CCC(=O)CC3)cn2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC1CN(c2ccc([C@H]3CC[C@H](O)CC3)cn2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.4 g of (RS)-5-methoxymethyl-3-[5-(4-oxo-cyclohexyl)-pyridin-2-yl]-oxazolidin-2-one in 25 ml of methanol and 2.5 ml of water was treated with 0.2 g of sodium borohydride and stirred at room temperature for 16 h. Then, the mixture was concentrated and the residue was taken up in methylene chloride and washed with water. The aqueous phase was extracted with methylene chloride and the organic phases were combined, dried with magnesium sulfate and concentrated. The residue (0.4 g) was recrystallized from ethyl acetate and there was obtained 0.2 g of (RS)-3-[5-(trans-4-hydroxy-cyclohexyl)-pyridin-2-yl]-5-methoxymethyl-oxazolidin-2-one. M.p.: 142°-143°.
Reaction SMILES: [NH2-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12].O>C1(C)C=CC=CC=1>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[NH:13][C:11](=[O:12])[CH2:10][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: O=C1CCCN1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)CN1CCCC1=O
Reaction time: 2 h
Yield: 91.2 %

Procedure:
In 300 ml of toluene was suspended 9.0 g of sodium amide in a nitrogen stream, and 21.3 g of 2-pyrrolidinone was slowly added thereto dropwise. After stirring the mixture at 60° to 70° C. for 2 hours, 19.7 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added thereto, followed by allowing to react at 60° to 70° C. for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70° to 85° C., and the mixture was allowed to cool with stirring. The precipitated crystals in the aqueous layer were recovered by filtration and dried under reduced pressure to obtain 22.4 g (91%) of the titled compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([O-:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].[C:13](#[N:17])[C:14]([CH3:16])=[CH2:15].[H-].[Na+].C(O)(=O)C>C(O)C>[CH2:10]([O:9][P:8]([CH2:15][CH:14]([C:13]#[N:17])[CH3:16])([CH:4]([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[O:12])[CH3:11]
Reactant: CCOC(OCC)P([O-])OCC
Reactant: C=C(C)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(CC(C)C#N)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 23.5 g of ethyl (diethoxymethyl)phosphonite and 6.7 g of methacrylonitrile in 30 ml of ethanol is added dropwise to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl-2-cyanopropyl(diethoxymethyl)phosphinate, b.p. 116° C./0.01 mbar, 31P=+40.4 and +40.3 ppm (CDCl3).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:26])[C:13]([NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH3:15])[CH3:14])=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:5])C.[OH-].[K+].Cl>CCO.O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([NH:16][C:13]([CH3:14])([CH3:15])[C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:8]=2)=[O:26])=[O:25])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1sc(NC(=O)C(C)(C)NC(=O)c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccc(F)cc2)c(C(=O)O)s1
Reaction time: 15 h

Procedure:
To a solution of Ethyl-2-(2-(4-fluorobenzamido)-2-methylpropanamido)-4-(4-fluorophenyl)thiazole-5-carboxylate (4.3 g, 9 mmol) in EtOH (25 mL) was added KOH (1 eq) in water (25 mL). The reaction was stirred at 65 C for 15 hours followed by stirring at room temperature over 3 days. It was then acidified with 1 N HCl and the resulting precipitates were collected by filtration and dried to afford the title compound. 1H NMR (400 MHz, DMSO-d6) ppm 1.53 (s, 6H) 7.20 (t, J=8.97 Hz, 2H) 7.32 (t, J=8.84 Hz, 2H) 7.70 (dd, J=8.72, 5.68 Hz, 2H) 8.03 (dd, J=8.72, 5.56 Hz, 2H) 8.64 (s, 1H) 12.43 (s, 1H) 12.94 (br. s., 1H). MS m/z 446 (M+H), 444 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:16][O:15][CH2:14]1)[C:5]([O:7]C)=[O:6].[OH-].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:14][O:15][CH2:16]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2COC2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OC2COC2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude methyl 3-fluoro-4-(oxetan-3-yloxy)benzoate from Step 1, MeOH (1 mL), and KOH (4.0 mL of 3.0 M, 12 mmol) were combined and the mixture was allowed to stir for 3 h at rt. The mixture was extracted with EtOAc and the organic layer was discarded. The aqueous layer was then treated with 1N HCl and the pH was adjusted to pH 3. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were dried over sodium sulfate and the solvent was removed. The crude acid was used without further purification. ESI-MS m/z calc. 212.1. found 213.0 (M+1)+; Retention time: 1.65 minutes (4 min run).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C(Nc1ccc2oc3c(c2c1)CCCCCC3)c1ccncc1
Yield: 44.1 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.20 g, 0.92 mmol), isonicotinoyl chloride hydrochloride (0.20 g, 1.1 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (12 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)isonicotinamide (0.13 g). MS (ESI) m/z 321 ([M+H]+); MS (ESI) m/z 319 ([M−H]−).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[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][CH3:16].[NH2:39][CH2:40][CH2:41][C:42]([NH:44][C@H:45]([C:49]([OH:51])=[O:50])[C@@H:46]([CH3:48])[OH:47])=[O:43]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][CH2:40][CH2:41][C:42]([NH:44][C@H:45]([C:49]([OH:51])=[O:50])[C@@H:46]([CH3:48])[OH:47])=[O:43])=[O:23])(=[O:17])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: C[C@@H](O)[C@H](NC(=O)CCN)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@H](C(=O)O)[C@@H](C)O
Yield: 48 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (150 mg) prepared by the method described in Preparation A-2 (5) and N-β-alanyl-L-threonine (110 mg), N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-threonine (95 mg) was obtained as powder according to similar manner to that of Preparation B-1.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:20](Br)#[C:21][CH3:22].O>CC(C)=O>[CH2:22]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:2]([Cl:1])=[N:3]1)[C:21]#[CH:20]
Reactant: CC#CBr
Reactant: O=[N+]([O-])c1ccc2c(Cl)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C#CCn1nc(Cl)c2ccc([N+](=O)[O-])cc21

Procedure:
Compounds III-A, III-B and III-D were prepared by a modification of the procedure of Zaugg, Swett and Stone (5). In a stirred solution of sodium ethylate prepared from 0.23 g (0.01 mol) of sodium metal and 50 ml of absolute ethanol was dissolved 0.01 mole of the appropriate nitro- or chloroindazole. To such solution was added 2.38 g (0.02 mol) of propynyl bromide, and the reaction mixture was stirred for twenty-four hours at room temperature during which time sodium bromide precipitated. The reaction mixture was poured into 100 ml of water and the oily layer was extracted with ether. The ether layer was separated, washed with water, 10% potassium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give the desired N-(2-propynyl) indazoles. To prepare compound III-C, a mixture of 10 g (0.043 mol) of 3-chloro-6-nitroindazole, 6.9 g (0.043 mol) of anhydrous potassium carbonate and 0.10 g (0.086 mol) of propynyl bromide was placed in 100 ml of acetone. The reaction mixture was refluxed for twenty-four hours, and then poured into 100 ml of water. The oily layer was extracted with ether, and the ether layer was separated, washed with water, 10% sodium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give N-(2-propynyl)-3-chloro-6-nitroindazole.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[O:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[C:12]([O:19][CH3:20])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a stirred solution of benzylamine (3.94 mL, 36 mmol) and 4,3-dimethoxybenzaldehyde (5.0 g, 30 mmol) in chloroform (120 mL), was added sodium triacetoxyborohydride (9.53 g, 45 mmol). The mixture was stirred at rt for 18 hrs prior to addition of saturated NaHCO3. The organic phase was separated and the aqueous phase extracted with chloroform. The combined extracts were washed with brine, dried over MgSO4 and evaporated to afford the crude product. Purification by flash column chromatography afforded the title compound as a pale yellow oil (5.47 g, 71%). 1H NMR (270 MHz, CDCl3) δ 3.74 (2H, s), 3.80 (2H, s), 3.86 (3H, s), 3.88 (3H, s), 6.80-6.89 (3H, m), 7.22-7.34 (5H, m); HRMS (ESI+) calcd. for C16H20NO2 (M++H) 258.1489, found 258.1478; LC/MS (ES+) tr=0.79 min, m/z 258.2 (M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][S:8][N:9]=2.Br[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[N:14]([CH3:16])[CH3:15]>>[N:9]1[S:8][N:7]=[C:6]2[CH:10]=[C:2]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[N:14]([CH3:16])[CH3:15])[CH:3]=[CH:4][C:5]=12
Reactant: Brc1ccc2nsnc2c1
Reactant: CN(C)c1ccccc1Br
Product: CN(C)c1ccccc1-c1ccc2nsnc2c1

Procedure:
Starting from 5-bromo-benzo[1,2,5]thiadiazole and 2-bromo-N,N-dimethylaniline. Orange resin. MS(ES+): 256 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:25])[N:3]=1.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>>[CH3:25][C:4]1[N:3]=[C:2]([NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=1
Reactant: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)nc(Cl)n1
Reactant: NCC(F)(F)F
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)nc(NCC(F)(F)F)n1
Temperature: 100 °C
Yield: 12 %

Procedure:
A mixture of 2-chloro-6-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (50 mg, 0.13 mmol, Step-1 of Example 536, single enantiomer) and 2,2,2-trifluoroethanamine (3.5 mL) is heated at 100° C. for 4 days in a sealed tube. After cooled to room temperature, the mixture is concentrated and then purified by preparative LC-MS to give 7 mg (12% yield) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].I[CH3:18]>O1CCCC1.C(OCC)(=O)C>[CH3:18][O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.42 h
Yield: 98.2 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-hydroxypiperidine-1-carboxylate (Preparation 128, 1.6 g, 7.95 mmol) in anhydrous tetrahydrofuran (35 ml) was added sodium hydride (60% dispersion in oil, 0.32 g, 7.95 mmol) in portions. The resulting mixture was stirred for 25 min then iodomethane (2.27 g, 16 mmol) was added dropwise and the reaction mixture was stirred for 17 h. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with brine (5% solution, 150 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography on silica gel (70 g) eluting with dichloromethane:methanol (100:1 and then 50:1) to give a yellow oil (1.68 g). The trace of iodine was removed by dissolving the product in ethyl acetate (50 ml) and washing with aqueous sodium metabisulphite (5% solution, 2×35 ml), water (35 ml) and aqueous sodium hydrogen carbonate (5% solution, 35 ml). The organic extracts were dried (MgSO4) and concentrated in vacuo to give the desired product as a colourless oil (1.62 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:22][N+:23]([CH3:25])=[CH2:24].[Cl-].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH3:22][N:23]([CH2:25][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[C:2]=1[CH3:1])[CH3:24]
Reactant: C=[N+](C)C
Reactant: COC(=O)c1ccc(Cn2c(C)cc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2c(C)c(CN(C)C)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
Methyl 4-((2-methyl-1H-indol-1-yl)methyl)benzoate 3 (0.500 g, 1.90 mmol) and dimethylformiminium chloride (0.200 g, 2.15 mmol) were heated to reflux in a solution of DCM (5 mL) and DMF (2 mL) for 20 h. The reaction was then cooled to RT and DCM (50 mL) was added along with sat. NaHCO3 (20 mL). The organic fraction was isolated and the aqueous solution was further extracted with DCM (2×20 mL). The combined organic fractions were washed with H2O (20 mL), brine (20 mL), dried with Na2SO4 and concentrated in vacuo. The desired product was purified via automated column chromatography method 2 (0.221 g, 37%). 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J=8.1 Hz, 2H), 7.69 (m, 1H), 7.14 (m, 3H), 7.02 (d, J=8.0 Hz, 2H), 5.38 (s, 2H), 3.90 (s, 3H), 3.62 (s, 2H), 2.35 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].O=S(Cl)Cl.[CH2:20](N(CC)CC)C>>[CH3:20][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To 3,5-Dinitro-benzoic acid (Aldrich, 21.2 g, 100 mmol) was added SOCl2. The mixture was refluxed overnight. The excess SOCl2 was removed under reduced pressure. The residue was dissolved in 100 mL of MeOH, cooled in ice bath, and triethylamine (Aldrich, 21 mL, 150 mmol) was added slowly added. After the mixture was stirred at ambient temperature for 3 h, solvent was removed under reduced pressure. The residue was diluted with EtOAc and 1N HCl. The mixture was extracted 3× with EtOAc (100 mL). The organic layers were washed twice with a brine solution (100 mL), dried over Na2SO4. Removal of the solvent gave 22.0 g (97%) of product, which was pure enough for the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (t, J=2.1 Hz, 1H), 8.92 (d, J=2.1 Hz, 2H), 3.99 (s, 3H).