Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3C(=O)[O:9]2)=[CH:4][CH:3]=1>[OH-].[Na+]>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:11][C:12]=1[CH:8]([C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1)[OH:9]
Reactant: O=C1OC(c2ccc(F)cc2)c2ncccc21
Agent: [Na+]
Agent: [OH-]
Product: OC(c1ccccc1)c1ccccn1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
A suspension of 7-(4-fluorophenyl)-5-oxo-5,7-dihydrofuro[3,4-b]pyridine (2.93 g, 12.79 mmol) in 64 ml of 0.2N NaOH is heated to 75° C. with stirring for 24 hours. The mixture is then filtered and the filtrate evaporated to produce crude 2-pyridyl phenyl carbinol, which is not further purified, but rather, dissolved in 70 mL of pyridine and treated with chromium (VI) oxide pyridine complex (10.0 g, 38.78 mmol). A black mixture results which is stirred at 23° C. for 24 hours, then treated with saturated aqueous NaHCO3 (50 ml) and extracted with CHCl3 (3×75 mL). Acidification of the basic aqueous layer to pH 2 with concentrated HCl generates a precipitate which is filtered and dried to produce crude 2-(4-fluorobenzoyl)pyridine-3-carboxylic acid. Treatment of the latter with diazomethane in ether, followed by silica gel chromotography of the resulting solid (using hexane-EtOAc (3:1) as the eluent) produces 3 -carbomethoxy-2-(4-fluorobenzoyl)pyridine. M.P. 95°-96.5° C.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:19]1[C:28]2[C:23](=[CH:24][N:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[N:25][CH:24]=3)[N:19]=2)=[O:30])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1C[C@H]1c1ccccc1)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
To a stirring mixture of trans-2-phenylcyclopropylamine hydrochloride (75.3 mg, 0.431) in anhydrous DMF (1.0 mL) was added triethylamine (60.0 μL, 0.431 mmol). After 5 minutes, 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol), 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol) were added sequentially. The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (79.2 mg, 95%): m.p. 123-124 ° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=O)[S:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:29]\[C:26]1[S:27][CH:28]=[C:24]([CH3:23])[CH:25]=1)/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: Cc1csc(C=O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1cc(C)cs1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A stirred solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (5.01 g, 15.1 mmol) and 4-methylthiophene-2-carbaldehyde (95a) (2.50 g, 19.8 mmol) in dry dichloromethane (100 mL) was cooled to 0° C. and treated dropwise with DBU (2.76 g, 18.1 mmol). The mixture was warmed to ambient temperature and stirred overnight. The solution was concentrated, taken up in ethyl acetate (150 mL) and washed with 5% hydrochloric acid (2×100 mL). The organic extract was washed with saturated aqueous sodium bicarbonate (2×150 mL), water (200 mL), dried (magnesium sulfate), filtered and evaporated. The residue was purified by crystallization from 4:1 (v/v) ethyl acetate/hexanes to afford the title compound (3.38 g, 67%) as the sole product. 1H NMR (300 MHz, d6-DMSO) δ2.20 (s, 3H), 3.70, (s, 3H), 5.12 (s, 2H), 7.20-7.52 (m, 7H), 7.69 (s, 1H), 8.82 (s, 1H). MS APCI, m/z=354 (M+Na). LC/MS: 2.43 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:25](=[O:26])[CH2:24][Cl:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Yield: 78 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 16.1 mmol) and DIPEA (3.1 ml, 18.0 mmol) were dissolved in DCM (32 ml) and cooled in ice bath. To the above stirred mixture was added a solution of chloroacetyl chloride (1.33 ml, 16.7 mmol) at 0° C. Three hours later, the mixture was washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography using EA/PE (4/1) as eluent to afford the title compound (3.3 g, yield 78.0%).
Reaction SMILES: C([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([NH2:23])=[O:22])[S:19][CH:20]=2)=[N:6]1)(C)(C)C>FC(F)(F)C(O)=O.O>[CH3:15][O:14][C:9]1[C:8]2[C:7]([C:16]3[CH:17]=[C:18]([C:21]([NH2:23])=[O:22])[S:19][CH:20]=3)=[N:6][NH:5][C:13]=2[CH:12]=[CH:11][N:10]=1
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1nccc2[nH]nc(-c3csc(C(N)=O)c3)c12
Temperature: 25 °C
Yield: 54.7 %

Procedure:
4-(1-tert-Butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (150 mg) obtained in Step C of Example 129 was dissolved in a mixed solvent of trifluoroacetic acid (20 mL)/water (2 mL), and the mixture was heated with reflux for 24 hr. The reaction mixture was allowed to be cooled to room temperature, and concentrated under reduced pressure. The residue was extracted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate to ethyl acetate) to give the title compound (68.1 mg).
Reaction SMILES: Br.C([O:4][C:5](=[O:29])[CH2:6][C:7]1[N:8]([CH2:13][C:14]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]3[C:15]=2[NH:16][C:17](=[O:28])[C:18](=[O:27])[NH:19]3)[CH:9]([NH2:12])[S:10][CH:11]=1)C.[ClH:30]>[OH-].[Na+]>[ClH:30].[O:27]=[C:18]1[C:17](=[O:28])[NH:16][C:15]2[C:20](=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:14]=2[CH2:13][N:8]2[C:7]([CH2:6][C:5]([OH:29])=[O:4])=[CH:11][S:10][CH:9]2[NH2:12])[NH:19]1
Reactant: CCOC(=O)CC1=CSC(N)N1Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Agent: Br
Agent: Cl
Agent: [Na+]
Product: NC1SC=C(CC(=O)O)N1Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
80 mg (0.2 mmol) of [N-(2,3-dioxo-7-nitro-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-2-amino-4-thiazolyl]-acetic acid ethyl ester hydrobromide are stirred in 2 ml of 2N sodium hydroxide solution at room temperature for 16 hours. The mixture is acidified with 3N HCl, and the resulting solid is filtered off and washed with a small amount of water and 2×20 ml of diethyl ether. After drying, the title compound is obtained in the form of a yellow solid.
Reaction SMILES: [N:1]([C@H:4]([C@H:50]([O:66][C:67](=[O:74])[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)/[CH:51]=[CH:52]/[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:5][O:6][C@H:7]1[O:39][C@H:38]([CH2:40][O:41][CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])[C@H:28]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C@H:18]([O:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:8]1[O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+:2]=[N-:3]>FC(F)(F)C(O)=O>[C:67]([O:66][C@H:50](/[CH:51]=[CH:52]/[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C@@H:4]([N:1]=[N+:2]=[N-:3])[CH2:5][O:6][C@H:7]1[O:39][C@H:38]([CH2:40][O:41][CH2:42][C:43]([OH:45])=[O:44])[C@H:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])[C@H:18]([O:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:8]1[O:9][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:74])[C:68]1[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](OC(=O)c1ccccc1)[C@H](CO[C@H]1O[C@H](COCC(=O)OC(C)(C)C)[C@H](OCC(=O)OC(C)(C)C)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)N=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCC/C=C/[C@@H](OC(=O)c1ccccc1)[C@H](CO[C@H]1O[C@H](COCC(=O)O)[C@H](OCC(=O)O)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)N=[N+]=[N-]
Temperature: 22 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
A solution of (2S,3R,4E)-2-Azido-3-benzoyloxy-1-(2,3-di-O-benzoyl-4,6-di-O-tert-butyloxycarbonylmethyl-α-D-galactopyranosyloxy)-4-octadecene described in Example 1-F (0.145 g, 0.14 mmol) in aqueous trifluoroacetic acid (90%, 3 mL) was stirred at 22° C. during 5 minutes. The solvents were evaporated under vacuum and the residue was co-evaporated with toluene (3×5 mL) and then dissolved in a mixture of dioxane/water (1:1, 10 mL). This mixture was stirred at 22° C. for 30 minutes. The solvents were evaporated under vacuum and the residue was co-evaporated again with toluene (4×10 mL). The residue was purified by silica gel plates (chloroform/methanol/water 75:25:2). The residue upon solvent evaporation was redissolved in methylene chloride/methanol (1:1, 40 mL) and treated at 0° C. (ice bath) with Dowex 50W X8 (H+) resin for 40 minutes to give the title compound (0.076 g, 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:35].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:35])[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Fc1ccc(CNc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc(F)cc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
5,6-bis(Benzyloxy)-N-[(4-fluorophenyl)methyl]pyridazin-3-amine (Intermediate 45; 0.7 g, 1.68 mmol) was dissolved in N,N-dimethylformamide (8 ml) and the solution was cooled to 0° C. before sodium hydride (60% by weight in paraffin; 0.101 g, 2.53 mmol, 1.5 equiv.) was added under nitrogen atmosphere. The reaction mixture was allowed to warm at room temperature for approximately 30 minutes and iodomethane (1.189 g, 8.43 mmol, 5 equiv.) was added. The reaction was allowed to stir at room temperature for one hour before being poured into water (100 ml) and the organic materials were extracted into ethyl acetate (50 ml×2). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude compound was purified by column chromatography (silica gel, eluting with 0-50% ethyl acetate in hexane) to yield 5,6-bis(benzyloxy)-N-(4-fluorobenzyl)-N-methylpyridazin-3-amine (0.51 g, 64% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[C:4]([CH3:13])[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH2:65]([SH:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:65]([S:72][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[C:4]([CH3:13])[CH:3]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: Cc1cc(Br)cc2nccc(Cl)c12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(SCc2ccccc2)cc2nccc(Cl)c12
Temperature: 60 °C
Yield: 62 %

Procedure:
To a vial charged with 7-bromo-4-chloro-5-methylquinoline (0.048 g, 0.187 mmol) was added Xantphos (0.022 g, 0.037 mmol), Pd2(dba)3 (0.017 g, 0.019 mmol), dioxane (0.748 ml), DIEA (0.065 ml, 0.374 mmol) and benzyl mercaptan. The mixture was purged with argon and heated to 60° C. overnight. The mixture was directly loaded onto a 25 HP silicycle column and purified by ramping EtOAc in heptane (0 to 50%, 10% DCM throughout) to provide product as a light yellow solid (35 mg, 62%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.97 (s, 3H) 4.31 (s, 2H) 7.22-7.26 (m, 1H) 7.27-7.31 (m, 1H) 7.31-7.39 (m, 3H) 7.44 (d, J=6.94 Hz, 2H) 7.82 (d, J=1.96 Hz, 1H) 8.61 (d, J=4.70 Hz, 1H). m/z (ESI) 300.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][NH2:13])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[C:16]1[C:17]([NH2:23])=[N:18][CH:19]=[C:20]([Br:22])[N:21]=1.C(N(CC)CC)C>CC#N>[Br:22][C:20]1[N:21]=[C:16]([NH:13][CH2:12][C:11]2[C:2]([F:1])=[C:3]3[C:8](=[CH:9][C:10]=2[F:14])[N:7]=[CH:6][CH:5]=[CH:4]3)[C:17]([NH2:23])=[N:18][CH:19]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1c(F)cc2ncccc2c1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ncc(Br)nc1NCc1c(F)cc2ncccc2c1F
Temperature: 180 °C
Yield: 43.2 %

Procedure:
A mixture of (5,7-difluoroquinolin-6-yl)methanamine (2.7 g, 13.9 mmol), 3,5-dibromopyrazin-2-amine (2.4 mg, 9.49 mmol) and triethyl amine (4.8 g, 47.5 mmol) in CH3CN (6 mL) was heated under microwave irradiation at 180° C. for 40 min. The reaction mixture was concentrated in vacuo and purified by column chromatography (hexane:EtOAc) to provide 6-bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (1.50 g, 43%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.00 (d, 1H), 8.52 (d, 1H), 7.73 (d, 1H), 7.64 (m, 1H), 7.21 (s, 1H), 7.00 (s, 1H), 6.21 (s, 2H), 4.69 (d, 2H). LCMS (method B): [MH]+=367.9, tR=2.36 min
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29](O)[C:30]#[N:31])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O=S(Cl)[Cl:35]>C(Cl)(Cl)Cl.CN(C=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29]([Cl:35])[C:30]#[N:31])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(-c2ccc3cc(C(O)C#N)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3cc(C(Cl)C#N)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
To a solution of 2-[6-(3-[1-adamantyl]-4-methoxyphenyl)-2-naphthyl]-2-hydroxy-acetonitrile, (0.314 mg, 0.74 mmol) in anhydrous chloroform (10 mL) were added SOCl2 (0.17 mL, 2.23 mmol) and DMF (3 drops). The reaction mixture was heated under reflux for 40 minutes before it was allowed to cool down, washed with water, saturated NaHCO3, brine to give 2-[6-(3-[1-adamantyl]-4-methoxyphenyl)-2-naphthyl]-2-chloro-acetonitrile that was used without further purification.
Reaction SMILES: CC(C)CC(C1C=C2C(=CC=1)NC(C(O)=O)=C2)=O.CN(C=O)C.[CH2:24]([O:26][C:27]([C:29]1[NH:30][C:31]2[C:36]([C:37]=1Br)=[CH:35][C:34]([C:39](=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:33][CH:32]=2)=[O:28])[CH3:25].C([O-])=O.[NH4+]>[Pd].O>[CH2:24]([O:26][C:27]([C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][C:34]([C:39](=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:33][CH:32]=2)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1[nH]c2ccc(C(=O)CC(C)C)cc2c1Br
Agent: [Pd]
Agent: CC(C)CC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Agent: O=C[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(C(=O)CC(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
Synthesis of 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid. DMF (5 mL) and water (0.625 mL) are added to the mixture of 3-Bromo-5-(3-methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester (408 mg, 1.1 mmol), ammonium formate (110 mg, 1.7 mmol), and 10% Pd/C (200 mg). The mixture is slightly shaken at room temperature for 70 minutes and then filtered through celite. The solvent is evaporated under vacuum to give 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester as light yellow liquid as crude product with the purity of 90%; EI-MS m/z 274.1 (M++H). The crude ethyl ester is dissolved in dioxane (10 mL), then a solution of LiOH.H2O (195 mg, 4.6 mmol) in water (5 mL) is added to the flask. The mixture is stirred at room temperature for 2 days. Dioxane is stripped under vacuum. 10 mL water is added and extracted with CH2Cl2. The aqueous phase is then acidified with 6N HCl and extracted with CH2Cl2. The CH2Cl2 phase is then washed with saturated brine and dried over anhydrous Na2SO4. Solvent is removed under vacuum to give 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid (250 mg, 88% for two steps) as white solid. EIMS m/z 246.1 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=1)=[O:9]
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1cccc(NC(=O)c2cc(Br)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method B; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in THE (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and 3-methoxybenzenamine (80 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1). The crude product was added to a silica gel column and was eluted with DCM:hexane (2:1). The crude product was then added to a preparative HPLC column and was eluted with 0.05% trifluoroacetic acid, water/acetonitrile to yield the title compound. 110 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][C:9]2[S:10][C:11]([CH3:16])=[CH:12][C:13]=2[C:14]#[N:15])[CH:7]=1.[Sn](Cl)Cl>C(O)C.Cl.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:14]([NH2:15])[C:13]3[CH:12]=[C:11]([CH3:16])[S:10][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: Cc1cc(C#N)c(Nc2cc(Cl)ccc2[N+](=O)[O-])s1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1cc2c(s1)Nc1cc(Cl)ccc1N=C2N
Yield: 180.7 %

Procedure:
Suspend 2-(5-chloro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile (0.58 g, 1.98 mmol) in ethanol (20 ml), add anhydrous tin(II)chloride(1.5 g, 6.66 mmol) in concentrated hydrochloric acid (6 ml) and heat the mixture under reflux for 75 minutes. Dilute the mixture with water and allow to cool. Collect the precipitate by filtration and dry under high vacuum to give 6-chloro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride as a yellow solid (0.537 g, 90%): Mass Spectrum (FIA) 300/302 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][C:22]=1[C:27](O)=[O:28]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:27]([C:22]3[NH:23][C:24]([CH3:26])=[CH:25][C:21]=3[CH3:20])=[O:28])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(C(=O)O)[nH]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cc1cc(C)c(C(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)[nH]1
Yield: 58 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 3,5-dimethylpyrrole-2-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as crystals, melting 140°-141° C., in a 58% yield.
Reaction SMILES: [C:1]([CH:6]1[CH2:11][C:10](O)([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]1=[O:17])(=[O:5])[CH2:2][CH2:3][CH3:4].B(F)(F)F>C1C=CC=CC=1>[C:1]([C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][C:7]=1[OH:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C1CC(O)(C(=O)OC)C=CC1=O
Agent: FB(F)F
Solvent: c1ccccc1
Product: CCCC(=O)c1cc(C(=O)OC)ccc1O
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 5-butyryl-1-hydroxy-4-oxocyclohex-2-ene-1-carboxylate in benzene was added BF3.O (Et)2 (1.3 mL, 10 mmol). The mixture was stirred for 0.25 h and then quenched with saturated sodium bicarbonate followed by extraction with dichloromethane. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford methyl 3-butyryl-4-hydroxybenzoate which was used without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([Cl:8])[NH:4][C:3]=1[C:9]([O:11]CC)=[O:10].C(O)C.O.Cl>O>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([Cl:8])[NH:4][C:3]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1[nH]c(Cl)c(C)c1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)[nH]c(C(=O)O)c1Cl
Yield: 104.1 %

Procedure:
A solution of 1.1 gm (4.95 mmol) of ethyl 3,5-dichloro-4-methyl-1H-pyrrole-2-carboxylate (Intermediate 194) and 1.7 g (9.9 mmol) of Ba(OH)2 in 50 ml 1:1 EtOH—H2O was heated at 85° C. for 9 h. The mixture was diluted with water, acidified with 20 ml 1N HCl and extracted 3 times with ether. The ether was washed with water, dried (MgSO4) and concentrated to give 1.0 g of product as a solid. MS (ES) (M−H−): 194 for C6H5Cl2NO2; NMR (d6-DMSO): 1.9 (s, 3H), 12.7 (s, 1H), 12.8 (s, 1H).
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C1OC1CO.S(=O)(=O)(O)O.[OH-].[Na+]>CS(C)=O.OCC(CO)O>[C:8]([OH:10])(=[O:9])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: OCC1CO1
Agent: [Na+]
Solvent: OCC(O)CO
Solvent: CS(C)=O
Product: O=C(O)C=Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
17.4 g of p-hydroxy cinnamic acid and 40.0 g of glycidol were dissolved in 20 ml of DMSO, and catalytic amount of sulfuric acid was added. The solution was heated to 90° C. and then heating and agitation was carried out for 3 hours, neutralized by adding sodium hydroxide and then adduct of cinnamic acid and glycerin was obtained.