Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.[F:31]C1C=C(C(=O)CC2C=CN=CC=2)C=CC=1OCC1C=CC2C(=CC=CC=2)N=1>>[F:31][C:29]1[CH:30]=[C:13]([C:4]2[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)=[CH:6][N:2]([CH3:1])[N:3]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)c(F)c2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-[3-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.2 Hz, 2H), 8.21 (d, J=8.3 Hz, 1H), 8.05 (d, J=8.7 Hz, 1 H), 7.83 (d, J=7.9 Hz, 2H), 7.72 (m, 2H), 7.55 (m, 2H), 7.16 (m, 2 H), 7.07 (m, 1H), 6.99 (m, 2H), 5.45 (s, 2 H), 3.95 (s, 3H); MS: (M+H m/z=411.0).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13](N)=[NH:14]>O>[CH3:12][O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:14][CH:13]=[N:1]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: N=CN
Solvent: O
Product: COc1ccc2c(O)ncnc2c1
Temperature: 125 °C
Yield: 76.4 %

Procedure:
To a solution of 2-amino-4-methoxy benzoic acid (8.6 g, 51.4 mmol) in 2-dimethoxy ethane (100 ml) was added formamidine (10.71 g, 103 mmol). The reaction mass was heated to 125° C. 18 h. The reaction mass was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (6.92 g, 74.8%) as pale yellow solid. 1H NMR (400 MHz, DMSO): δ ppm 12.10 (br, s, 1H), 8.06 (s, 1H), 8.03-8.01 (d, J=8 Hz, 1H), 7.11-7.09 (m, 2H), 3.89 (s, 3H);
Reaction SMILES: [C:1]([C:3]1[C:4](=N)[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)=[CH:10][CH:9]=[C:8]1[N:22]([CH3:25])[CH:23]=[CH:24][C:7]=21)#[N:2].[OH-:27].[Na+]>CO>[C:1]([C:3]1[C:4](=[O:27])[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)=[CH:10][CH:9]=[C:8]1[N:22]([CH3:25])[CH:23]=[CH:24][C:7]=21)#[N:2]
Reactant: Cn1ccc2c3oc(=N)c(C#N)c(-c4cccc([N+](=O)[O-])c4)c3ccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: Cn1ccc2c3oc(=O)c(C#N)c(-c4cccc([N+](=O)[O-])c4)c3ccc21

Procedure:
A solution of 3-cyano-2-imino-7-methyl-4-(3-nitro-phenyl)-2H-pyrrolo[2,3-h]chromene (31 mg, 0.087 mmol) 10% HCl (3 mL) and methanol (5 mL) was stirred at room temperature for 7 h. The reaction mixture was neutralized with 10% NaOH. The yellow precipitate was collected by vacuum filtration, washed with water, and dried in vacuo (24 mg, 77%). 1H NMR (acetone-d6): 8.58-8.52 (m, 2H), 8.11 (dt, J=7.2, 0.9 Hz, 1H), 8.03 (dt, J=7.8, 0.9 Hz, 1H), 7.53 (d, J=3.3 Hz, 1H), 7.49 (dd, J=0.6, 8.7 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 6.94 (dd, J=0.9, 3.3 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20]>COCCOC>[CH3:16][O:17][CH2:18][CH2:19][NH:20][C:2]1[C:3]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COCCN
Reactant: O=C(c1cccnc1)c1nccnc1Cl
Solvent: COCCOC
Product: COCCNc1nccnc1C(=O)c1cccnc1
Temperature: 120 °C

Procedure:
A microwave tube is charged with (3-chloro-pyrazin-2-yl)-pyridin-3-yl-methanone (85 mg, 0.39 mmol), DME (2 ml) and 2-methoxyethylamine (0.95 g, 4.26 mmol) and the tube is sealed with a microwave cap. The mixture is heated at 120° C. for 15 hours, then the solvent is removed in vacuo. [3-(2-Methoxy-ethylamino)-pyrazin-2-yl]-pyridin-3-yl-methanone is obtained by flash chromatography (SiO2, toluene/EtOAc, 2:1)
Reaction SMILES: O=[C:2]([CH3:14])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[CH3:14][CH:2]([NH2:21])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: CC(=O)CCn1cnc2ccccc21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)CCn1cnc2ccccc21

Procedure:
A mixture of 7.0 grams of 1-(3-oxobutyl)-1H-benzimidazole, 28.7 grams of ammonium acetate and 1.6 grams of sodium cyanoborohydride in 100 ml. of methanol was stirred at room temperature for about 24 hours. The mixture was then acidified with about 40 ml. of concentrated hydrochloric acid and the solvent was evaporated. The residue was dissolved in 150 ml. of water and the aqueous solution was extracted first with ether and then it was made alkaline (pH greater than 10) with solid potassium hydroxide. The alkaline solution was extracted with several portions of methylene chloride and the organic extracts were combined, washed with water and dried over magnesium sulfate and the methylene chloride was evaporated. The residue was chromatographed on a silica gel column packed in acetonitrile and eluted with acetonitrile and acetonitrile containing increasing percentages of methanol. The fractions containing the desired product, as determined by thin-layer chromatography, were combined and the solvent evaporated to give α-methyl-1H-benzimidazole-1-propanamine as an oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3C(=CC=CC=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[C@H]2[C@H](O)C[N:36]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])C2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@H:11]2[C@H:12]([OH:20])[CH2:13][N:36]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:19]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)n1
Product: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting benzyl(trans)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.38, 5.17, 4.48, 4.38, 4.28, 4.12, 3.91; 3.42, 2.86–2.78, 2.58, 1.32–1.24; HRMS (FAB) calcd for C20H25BrN4O3+H 449.1189, found 449.1175.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COCCOc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COCCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 86.9 %

Procedure:
Using general procedure A, 4-(2-methoxy-ethoxy)-phenylamine (Ishidate; Maruyoma, Chem. Abstr., 1952, 8810) (1.15 g, 6.84 mmol) and 1-Boc-4-piperidone (1.36 g, 6.83 mmol) afforded 4-[4-(2-methoxy-ethoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (2.08 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[NH:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)NCC(=O)c1ccccc1
Yield: 85 %

Procedure:
The title compound (0.63 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (0.50 g) and 2-amino-1-phenylethanone (0.35 g) according to the method of description 54.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>CN(C)C(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(C#N)cc2)CC1
Yield: 88.3 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (9.19 g, 30.8 mmol) and 4-cyanobenzeneboronic acid (5.18 g, 35.2 mmol) in N,N-dimethylacetamide (90 mL) and water (35 mL), purge with nitrogen for 0.5 hr. and then add tetrakis(triphenylphosphine)palladium(0) (0.170 g, 0.15 mmol). Heat for 3 hr. at 110° C., allow to cool about 1.5 hr. to room temperature, filter and then dry the solid in an oven overnight to give 3′-(4-cyanophenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester as a white solid (9.94 g, 88%). MS (ES): m/z=366 [M+H]+. Add 4 M HCl in 1,4-dioxane (10 mL) to 3′-(4-cyanophenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (3.29 g, 9.0 mmol). Add more 4 M HCl in 1,4-dioxane (10 mL) to the reaction mixture and heat at 40° C. for 3 hr. Filter off the solid and wash with a mixture of 1,4-dioxane/isohexane to give the dihydrochloride salt as a yellow solid (4.2 g). MS (ES): m/z=266 [M+H]+. Dissolve the dihydrochloride in water (20 mL), add 2 N sodium hydroxide (10 mL), extract with DCM and concentrate the DCM extract to give the title preparation as a yellow solid (1.8 g). MS (ES): m/z=266 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1.[OH:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH3:27][O:26][C:23]1[C:22]([O:28][CH3:29])=[CH:21][C:20]2[C:3]3[C:4]([CH:7]4[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]4)=[N:5][NH:6][C:2]=3[N:1]=[C:35]([C:34]3[CH:37]=[CH:38][C:31]([OH:30])=[CH:32][CH:33]=3)[C:25]=2[CH:24]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccc(-c2c(C3CCN(C(=O)OC(C)(C)C)CC3)n[nH]c2N)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(-c3ccc(O)cc3)nc3[nH]nc(C4CCNCC4)c3c2cc1OC
Yield: 61 %

Procedure:
A solution of 1,1-dimethylethyl 4-{5-amino-4-[3,4-bis(methyloxy)phenyl]-1H-pyrazol-3-yl}piperidine-1-carboxylate (0.39 g, 0.97 mmol) and 4-hydroxybenzaldehyde (0.12 g, 0.97 mmol) was heated to 72° C. in trifluoroacetic acid (5 mL) for 18 h. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase HPLC (CH3CN/H2O with 0.1% TFA) to give 4-[7,8-bis(methyloxy)-1-piperidin-4-yl-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetate (0.24 g, 61%). 53 mg (0.12 mmol) 4-[7,8-bis(methyloxy)-1-piperidin-4-yl-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetate was dissolved in ethanol (10 mL) and it was treated with polymer bound Hunig's base (Argonaut Technologies Inc. PS-DIEA, 3.44 mmol/g) for 30 minutes to adjust the pH to 7. The resin was filtered off and the filtrate was concentrated to dryness. The residue was treated with hydrogen chloride (4M in 1,4-dioxane, 3.0 mL). The precipitating solid was collected by filtration to result in 4-[7,8-bis(methyloxy)-1-piperidin-4-yl-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol hydrochloride (42 mg, 89%). 1H-NMR (400 MHz, d6-DMSO): 9.18 (s, 1H), 8.78 (s, 1H), 7.48 (d, 2H), 7.44 (d, 2H), 6.88 (d, 2H), 4.00, 3.68 (2 s, 2×3H), 3.34 (m, 2H), 3.16 (m, 2H), 2.22 (m, 2H), 2.02 (m, 2H), 1.22 (m, 1H), MS (EI) for C23H24N4O3: 405.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[SH:12])([O-:3])=[O:2].[CH3:13][O:14][C:15](=[O:23])[CH:16]=[CH:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19](=[O:20])[CH2:18][CH:17]([S:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:16][C:15]([O:14][CH3:13])=[O:23]
Reactant: COC(=O)C=CCC(=O)OC
Reactant: COc1ccc([N+](=O)[O-])c(S)c1
Product: COC(=O)CC(CC(=O)OC)Sc1cc(OC)ccc1[N+](=O)[O-]

Procedure:
The starting material can be obtained by reaction of 2-nitro-5-methoxyphenol with N,N-dimethyl-thiocarbamoyl chloride in DMF in the presence of NaH to give 1-dimethylamino-thiocarbonyloxy-2-nitro-5-methoxyphenol (m.p. 125°), rearrangement, by heating for half an hour at 210°, to give 1-dimethylaminocarbonylmercapto-2-nitro-5-methoxyphenol (m.p. 101°), saponification with aqueous-ethanolic sodium hydroxide solution at 20° to give 2-nitro-5-methoxy-thiophenol (m.p. 87°), addition reaction with glutaconic acid dimethyl ester to give 3-(2-nitro-5-methoxy-phenylmercapto)-glutaric acid dimethyl ester (m.p. 91°), saponification to give the free acid (m.p. 165°-166°), cyclization to give 5-methoxy-8-nitro-thiochroman-4-one-2-acetic acid (m.p. 182°-183°), conversion into the amide (m.p. 228°-230°), and the nitrile (m.p. 164°-165°), ether cleavage to yield 5-hydroxy-8-nitro-thiochroman-4-on-2-acetonitrile (m.p. 187°-188°), hydrogenation on 5% Pd-C in methanol at 20° and normal pressure to give 5-hydroxy-8-amino-thiochroman- 4-one-2-acetonitrile (hydrochloride, m.p. 240° with decomposition), acetylation with ketene in dichloromethane/methanol to give 5-hydroxy-8-acetamidothiochroman-4-one-2-acetonitrile (m.p. 142°), reaction to give the aldehyde (m.p. 142°-144°) and condensation with 2-phenyl-2-thiazolin-5-one to give 2-phenyl-4-[2-(5-hydroxy-8-acetamidothiochroman-4-on-2-yl)-ethylidene]-2-thiazolin-5-one (m.p. 222°-224°), condensation with acetonedicarboxylic acid monomethyl ester-monoamide to give a mixture of stereoisomeric 4-thiobenzamido-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12-trihydroxy-7-acetamido-1,11-dioxo-6-thianaphthacene-2-carboxamides (m.p. 238°-240° with decomposition), epimerization with pyridine at 40° to give a mixture (m.p. 228°-230° with decomposition) of 4-de-dimethylamino-4-thiobenzamido-7-acetamido-12a-de- hydroxy-6-thiatetracycline and its 5a-epimer, hydroxylation of the mixture and separation of the isomers via the imino ethers.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[CH:13]=[N:12]2)[CH:5]=1>CO.O>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:14]2[CH:13]=[N:12][N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])[CH:15]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(Cn2cc(-c3ccc(C#N)cc3)cn2)c1
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)O)c3)c2)cc1
Yield: 82.4 %

Procedure:
Add LiOH monohydrate (0.03 g, 0.8 mmol) to a suspension of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoic acid methyl ester (0.2 g, 0.6 mmol) in 5 mL of a 4:1 MeOH-water mixture and stir the reaction at room temperature overnight. Concentrate the reaction to remove most of the MeOH, dilute with additional H2O and neutralize by the addition of 1 N aqueous HCl. Isolate the resulting solid by filtration and dry to afford 0.15 g, 71% yield of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C.[ClH:25].O1CCOCC1>>[ClH:25].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C#Cc2cccs2)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1cccc(C#Cc2cccs2)c1

Procedure:
Deprotection of tert-butyl 2-(3-(thiophen-2-ylethynyl)phenoxy)ethylcarbamate with HCl-dioxane following the method used in Example 13 gave 2-(3-(thiophen-2-ylethynyl)phenoxy)ethanamine hydrochloride as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (br s, 3H), 7.66 (dd, J=5.2, 1.2 Hz, 1H), 7.40 (dd, J−3.6, 1.2 Hz, 1H), 7.14 (dd, J=7.6, 1.2 Hz, 1H), 7.10-7.12 (m, 2H), 7.03 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 4.19 (t, J=5.2 Hz, 2H), 3.17 (t, J=5.2, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].Br.[CH3:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>CN(C=O)C>[CH3:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH2:6][CH2:7][C@H:8]1[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCC[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Reactant: C[C@@H]1CCCN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CC[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the mesylate from Example 28G (methanesulfonic acid, 2-[(1R,2S)-2-(4′-cyano-biphenyl-4-yl)-cyclopropyl]-ethyl ester) and potassium carbonate in DMF was added (R)-2-methylpyrrolidine hydrobromide [CAS 117607-13-3]. The mixture was stirred at 50° C. overnight. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel eluted with 7.5/20/70 MeOH/EtOAc/CH2Cl2 to provide the title compound. 1H NMR (300 MHz, CDCl3, free base): δ 0.88-1.0 (m, 2H), 1.18 (d, J=6 Hz, 3H), 1.4-2.4 (m, 11H), 2.9 (m, 1H), 3.15-3.23 (m, 1H), 7.15 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.66 (q, J=9 Hz, 4H). MS (DCl—NH3) m/z 331.2 (M+H)+. Anal. Calc. for C23H26N2C4H6O6 1.25H2O (L-tartaric acid salt): C, 64.46; H, 6.91; N, 5.57. Found: C, 64.46; H, 6.91; N, 5.57.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH2:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][C:15]([Br:20])=[CH:14][N:13]=1.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[Br:20][C:15]1[CH:16]=[C:17]([C:18]#[N:19])[C:12]([NH:11][C:22](=[O:23])[O:24][CH3:25])=[N:13][CH:14]=1
Reactant: N#Cc1cc(Br)cnc1N
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Nc1ncc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
Lithium bis(trimethylsilyl)amide in THF (1.0 N, 22 mL, 22 mmol) was added to a stirred solution of 2-amino-5-bromopyridine-3-carbonitrile (2.0 g, 10 mmol) in THF (30 mL) at −78° C. and the mixture was stirred at this temperature for 30 minutes. Methyl chloroformate (1.06 g, 11.1 mmol) was added and the mixture was warmed to room temperature and stirred for 2 hours. It was cooled in ice bath and quenched with saturated aqueous ammonium chloride (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic fractions were washed with brine (2×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by LC (elution with 10% ethyl acetate in petroleum ether) to afford the carbamate (1.43 g, 63%). 1H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 7.45 (br s, 1H), 8.05 (s, 1H), 8.65 (s, 1H). LCMS (M−1, 254.0).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[Br:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(Br)ccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(Br)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-bromobenzoxazole (87 mg, 0.25 mmol) and 1,2,4-benzenetricarboxylic anhydride (54 mg, 0.28 mmol) the title compound was obtained (77 mg, 59%). 1H NMR (DMSO) δ 8.41(dd, 1H), 8.37(t, 1H), 8.30(s, 1H), 8.09–8.05(m, 3H), 7.74(d, 1H), 7,57(dd, 1H), 7.48(dd, 1H), 7.03(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS 518.0 m/z (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1>C(O)(=O)C>[C:24]([C:23]1[CH:27]=[C:19]([N:18]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[CH:7]=[C:6]2[C:5]2[CH:16]=[CH:17][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:20]=[CH:21][C:22]=1[OH:28])([OH:26])=[O:25]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: Cc1ccc(C(=O)CC2CCCCC2=O)cc1
Solvent: CC(=O)O
Product: Cc1ccc(-c2cc3c(n2-c2ccc(O)c(C(=O)O)c2)CCCC3)cc1

Procedure:
A mixture of 23 g. (0.1 mole) of 2-(p-methylphenacyl)cyclohexanone, 15.3 g. (0.1 mole) of 5-aminosalicylic acid and 100 ml. of glacial acetic acid was heated under reflux for 45 minutes, cooled and filtered. The collected solid was recrystallized from acetonitrile to provide 23.0 g. (66%) of yellow crystals, m.p. 212.5°-214.5°.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([O:8][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ncccc1Br
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccnc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
3-bromo-2-hydroxypyridine (1.74 g, 10 mmol) was added to a suspension of NaH (440 mg of 60% dispersion in mineral oil, 11 mmol) in DMF (10 mL), and the resultant mixture was stirred at rt for 30 min. Benzyl bromide (1.3 mL, 11 mmol) was then added, and the reaction was stirred at rt overnight. It was then quenched by the addition of water, and the product extracted with ethyl acetate (2×50 mL). The extracts were combined, washed with 1N HCl solution, then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography using hexanes to 100% ethyl acetate in hexanes as eluent to give the title compound as a colorless thick oil, (1.37 g, 52% yield). MS m/z 264, 266(MH+); 1H NMR (500 MHz, CDCl3) δ ppm 5.17 (s, 2 H) 6.05 (t, J=7.02 Hz, 1 H) 7.27–7.88 (m, 6 H) 7.70 (dd, J=7.17, 1.98 Hz, 1 H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([NH2:16])[C:8]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[N:7][C:6]=1[CH3:22])[CH3:2].C(O)(=O)C.[N:28]([O-])=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]2[N:16]=[N:28][N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]2=[N:7][C:6]=1[CH3:22])=[O:23])[CH3:2]
Reactant: CCCCNc1c(N)c(NCC(C)C)nc(C)c1C(=O)OCC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCNc1c(C(=O)OCC)c(C)nc2c1nnn2CC(C)C
Reaction time: 10 h

Procedure:
33 g. of the oil obtained in part d, 5-amino-4-butylamino-6-(2-methylpropyl)amino-2-methylnicotinic acid ethyl ester (about 0.1 mol.), are dissolved in 100 ml. of acetic acid 20 ml. of water. A solution of 0.75 g. of sodium nitrite in 20 ml. of water is added dropwise at about 10° with stirring. Stirring is continued for 10 hours. After this time, the mixture is evaporated. The resulting oil is mixed with 100 ml. of water and extracted three times with 50 ml. portions of ether. The ether phase is dried over sodium sulfate, filtered and evaporated. The residue, 7-butylamino-5-methyl-3-(2-methylpropyl) [1,2,3]triazolo[4,5-b]pyridine-6-carboxylic acid ethyl ester, is recrystallized from benzene, yield 27 g. (81%), m.p. 34°-36°.