Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([C:11]2([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:33][C@@H:34]([CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)[C:35](O)=[O:36])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([CH2:7][O:8][C:9]([C:11]2([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH2:12][CH2:13][N:14]([C:35](=[O:36])[C@@H:34]([NH2:33])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[CH2:15][CH2:16]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(CC2(C(=O)OCC3CCCCC3)CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CC2(C(=O)OCC3CCCCC3)CCN(C(=O)[C@@H](N)Cc3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-cyano-benzyl)-piperidine-4-carboxylic acid cyclohexylmethyl ester (0.377 mmol; 0.128 g) in DMF (2 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (0.377 mmol; 0.102 g), N,N-diisopropyl-N-ethylamine (0.755 mmol; 0.134 mL) and HBTU (0.491 mmol; 0.186 g), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The residue was dissolved in a 4 M HCl solution in 1,4-dioxane (3 mL) and the resulting solution was stirred overnight at room temperature. The solution was then evaporated, and the residue was triturated with diethyl ether and dried under vacuum to yield 1-[2-(S)-amino-3-thiophen-2-yl-propionyl]-4-(4-cyano-benzyl)-piperidine-4-carboxylic acid cyclohexylmethyl ester as a hydrochloride salt.
Reaction SMILES: CO[CH:3]([O:6]C)[CH2:4][NH2:5].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18](Cl)=[O:19]>O1CCOCC1>[OH:6][CH2:3][CH2:4][NH:5][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1)=[O:19]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COC(CN)OC
Solvent: C1COCCO1
Product: O=C(NCCO)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 3.15 g (30 mmol) 2,2-dimethoxy-ethylamine and 40 mL dioxane is added 1.91 g (10 mmol) naphthalene-2-carbonyl chloride. After stirring overnight the solution is pored into 200 mL of ice water. Filtration yields the product in almost quantitative yield as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:16][O:17][CH2:18][CH3:19])[CH2:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[NH2:20][C:21](=[N:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[S:22][CH3:23].C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[N:16][O:17][CH2:18][CH3:19])[CH2:12][C:13](=[O:15])[NH:20][C:21](=[N:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[S:22][CH3:23])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: CSC(N)=NC(=O)OC(C)(C)C
Reactant: C=CCOc1ccc(C(CC(=O)O)=NOCC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOc1ccc(C(CC(=O)NC(=NC(=O)OC(C)(C)C)SC)=NOCC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.1 %

Procedure:
A mixture of 3-(4-(Allyloxy)phenyl)-3-(ethoxyimino)propanoic acid from Step C (850 mg), tert-butyl amino(methylthio)methylenecarbamate (675 mg), Py.Bop (2.01 g), and triethylamine (0.68 mL) in dichloromethane (1.8 mL) was stirred at room temperature for 12 h. The crude reaction mixture was purified directly by Boitage flash chromatography eluting with 15-30% ethyl acetate/85-70% hexanes to give the title compound as a white solid (1.14 g). HPLC retention time: 2.37 min (method A). MS (ESI) (M+Na)+ 436.25.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([O:29][CH3:30])[CH:22]=[C:23](O)[CH:24]=2)[CH2:19]1)[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([O:29][CH3:30])[CH:22]=[C:23]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH:24]=2)[CH2:19]1)[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCN1CCc2cc(O)cc(OC)c2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CCc2cc(OS(=O)(=O)C(F)(F)F)cc(OC)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
Triflic anhydride (0.54 mL, 3.2 mmol) was added dropwise over 15 minutes to a suspension of 2-ethyl-8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol (328 mg, 1.6 mmol) in pyridine (0.52 mL, 6.4 mmol) and DCM (15 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was diluted with DCM (60 mL), washed with water (100 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The resultant solid was purified by flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in pentane) to afford the title compound as a yellow solid (341 mg, 63%). 1H NMR (CDCl3, 300 MHz): 6.76 (d, J=2.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 4.30-4.10 (m, 2H), 3.87 (s, 3H), 3.50-3.37 (m, 2H), 3.36-3.10 (s, 4H), 1.51 (t, J=7.2 Hz, 3H). LCMS (Method B): RT=2.39 min, M+H+=340.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[C:24]1([NH:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([NH:30][CH2:31][CH2:32][NH:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCNc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccccc1NCCNc1ccccc1

Procedure:
A mixture of 1-fluoro-2-nitrobenzene(15.5 g, 110 mmol) and potassium carbonate (15.2 g, 110 mmol) was stirred and a mixture of N-methylpyrrolidone (20 ml) and N-phenylethylenediamine (15.0 g, 110 mmol) was added over 1 h at room temperature. The mixture was stirred for 1 h. Water (200 ml) was added crystals were filtered off and triturated with petroleum ether. Yield 14.7 g, 52%. M.p. 64-66° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>C(O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[O:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[N:1]=2)=[CH:16][CH:15]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
2-Amino-4-(trifluoromethyl)phenol (250 mg, 1.41 mmol) and 1-bromo-4-isothio-cyanatobenzene (302 mg, 1.41 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight. The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 85:15 hexanes/ethyl acetate to provide the title compound (315 mg, 62%). LC-MS m/z 357.1 (MH+), retention time 4.20 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:29]([CH3:30])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 103 %

Procedure:
A mixture of the compound (1.0 g) obtained in Example 263, dimethylamine hydrochloride (485 mg), triethylamine (0.8 ml) and dimethylformamide (10 ml) was heated at 80° C. for 5.5 h. The reaction mixture was distilled under reduced pressure and water and 2 N HCl were added to the residue; after extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 1.1 g of the titled compound quantitatively.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O[C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:35])[C:23]3[C:24](=[C:26]([CH2:33][CH3:34])[N:27]([CH2:29][CH2:30][O:31][CH3:32])[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:36]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)(=[O:38])=[O:37])=[CH:16][N:15]=1)C.[CH3:46][CH:47]([CH3:50])[CH2:48][OH:49]>>[CH2:48]([O:49][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:35])[C:23]3[C:24](=[C:26]([CH2:33][CH3:34])[N:27]([CH2:29][CH2:30][O:31][CH3:32])[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:36]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)(=[O:37])=[O:38])=[CH:16][N:15]=1)[CH:47]([CH3:50])[CH3:46]
Reactant: CC(C)CO
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(C)CC4)cnc3OCC(C)C)[nH]c(=O)c2nn1CCOC

Procedure:
Potassium bis(trimethylsilyl)amide (306 mg, 1.54 mmol) was added to a solution of the title compound of example 2 (155 mg, 0.31 mmol) in 2-methyl-n-propanol (10 ml) and the reaction stirred under reflux for 24 hours. The cooled mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (100:0 to 95:5) to afford the title compound, 88 mg, as a solid.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH:31][CH:2]2[CH2:11][CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:5]=[CH:4][C:3]2=3)[CH:26]=[CH:27][CH:28]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3NCCc2cccc(Cl)c2)nc1
Yield: 91.6 %

Procedure:
Using a method similar to Example 1, using 6-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (Intermediate 2, 846 mg, 3.00 mmol), 2-(3-chlorophenyl)ethylamine (560 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (1.16 g) as a white solid. Mass spectrum (ion spray): m/z=422 (M+1); 1HNMR (CDCl3): 8.58 (s, 1H), 8.15 (d, 1H), 7.33 (d, 1H), 7.24-7.17 (m, 3H), 7.11 (d, 1H), 6.94 (d, 1H), 6.90 (d, 1H), 6.85 (s, 1H), 5.87 (br. s, 2H), 3.79 (t, 1H), 3.06-2.91 (m, 2H), 2.83-2.67 (m, 4H), 1.97-1.79 (m, 3H), 1.73 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O>[CH2:22]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of 45.8 g (0.20 mole) 2-hydroxy-4-(benzyloxy)benzaldehyde in 250 mL of dimethylformamide was added dropwise over 1 hour to a slurry of 10.6 g (0.26 mole) of 60% sodium hydride/mineral oil dispersion in 100 mL of dimethylformamide. The mixture was stirred under nitrogen for 1 hour at room temperature, and then 28 mL (0.33 mole) of allyl bromide in 30 mL of dimethylformamide was added. The reaction was heated at 60° C. for 4 hours under nitrogen. The solvent was then removed in vacuum and replaced with 500 mL of ethyl acetate. This solution was washed with 500 mL portions of 2 N aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum to give 53.6 g (100%) of the title compounds as a pale yellow solid. 1H-NMR (d6-DMSO): singlet 10.2 δ (1H); doublet of doublets 7.65 δ (1H); multiplet 7.40 δ (5H); doublet 6.80 δ (1H); doublet of doublets 6.75 δ (1H); multiplet 6.05 δ (1H); doublet of doublets 5.45 δ (1H); doublet of doublets 5.30 δ (1H); singlet 5.20 δ (2H); multiplet 4.70 δ (2H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[OH:17].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc2cc(OC3CCCCO3)ccc2c1
Reaction time: 2 h

Procedure:
To a solution of 2 drops of 6N hydrochloric acid in 17 g. of dihydropyran is added 14.4 g. of β-naphthol under ice cooling. The resulting solution is stirred at 5° to 10° for 2 hours and then 5 g. of anhydrous sodium carbonate is added. After stirring at room temperature for 15 minutes, the resulting solids are filtered off and the filtrate is concentrated under reduced pressure to yield crude 2-tetrahydropyranyloxynaphthalene, suitable for use in the next step (2).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][C:10]#[CH:11])=[C:4]([OH:12])[N:3]=1.OS(O)(=O)=O>>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([CH3:11])[O:12][C:4]=2[N:3]=1
Reactant: C#CCc1c(O)nc(C)nc1O
Agent: O=S(=O)(O)O
Product: Cc1nc2oc(C)cc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
To a 50 mL flask was added 3 (1.64 g, 10 mmol) and 15 mL H2SO4 (conc.). The solution was stirred overnight and poured in to 100 mL distilled water and extracted by 3×30 mL CHCl3. The organic layer was pooled and concentrated to afford 1.36 (83%) of 4 as a yellow powder: TLC Rf0.35 (CHCl3/MeOH 6:1); mp>300° C.; 1H NMR (DMSO-d6) δ 2.42 (s, 3 H), 2.44 (s, 3 H), 6.63 (s, 1 H), 12.50 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[S:19](Cl)(=[O:21])=[O:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:21])=[O:20])=[C:4]([NH:9][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:20])=[O:21])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1ccc(Br)cc1N
Product: O=S(=O)(Nc1ccc(Br)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1

Procedure:
N,N′-(4-bromo-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (255 mg) was prepared as in Example 31 using 4-bromobenzene-1,2-diamine and benzothiophene-2-sulfonyl chloride as requisite starting materials.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1.[CH3:20]I.O>CN1C(=O)CCC1>[CH3:20][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=2)=[N:12]1
Reactant: CI
Reactant: CSc1nccc(-c2n[nH]c3ccccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1nccc(-c2nn(C)c3ccccc23)n1
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 99 mg, 2.47 mmol) was added to a stirring solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indazole (520 mg, 2.15 mmol) in NMP at 0° C. The mixture was stirred for 15 min and then methyliodide (0.14 mL, 2.25 mmol) was added and the resulting mixture was stirred for 2 h. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc, 9/1) to give 415 mg of 1-methyl-3-(2-methylsulfanylpyrimidin-4-yl)-1H-indazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[N:10]=[N:11][C:12]([Cl:16])=[C:13](Cl)[N:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[N:10]=[N:11][C:12]([Cl:16])=[C:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: Clc1nnc(Cl)c(Cl)n1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1nnc(Cl)c(Nc2ccccc2)n1

Procedure:
To a solution of Aniline (205 mg, 2.2 mmol) and 3,5,6-trichloro-1,2,4-triazine (2.7 mmol) in CH2Cl2, is added triethylamine (3 mmol). The reaction mixture is stirred at room temperature until formation of the desired product. Solvent is removed under reduced pressure. The residue can be purified by silica gel flash chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([C:14]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20])=[O:15])=[CH:6]2.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([C:14]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([OH:21])=[O:20])=[O:15])=[CH:6]2
Reactant: COC(=O)c1ccccc1NC(=O)C1=Cc2cc(OC)c(OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CC(C(=O)Nc1ccccc1C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a stirred solution of methyl 2-(5,6-dimethoxy-1H-indene-2-carboxamido)benzoate (120 mg, 0.34 mmol) in THF (6 mL) and MeOH (3 mL) was added 2 N NaOH solution (0.85 mL) dropwise. The resulting mixture was stirred at room temperature for 2 h, then quenched with 1N HCl solution and extracted with DCM. The organic extracts were washed with a saturated aqueous NaCl solution and dried over sodium sulfate. The solvent was then removed under reduced pressure to give 2-(5,6-dimethoxy-1H-indene-2-carboxamido)benzoic acid (100 mg, 87%). 1H-NMR (400 MHz, DMSO-d6) δ 3.72 (br s, 2H), 3.79 (s, 3H), 3.81 (s, 3H), 7.15 (m, 1H), 7.24 (s, 1H), 7.26 (s, 1H), 7.55-7.66 (m, 2H), 8.04 (dd, J=8.0, 1.6 Hz, 1H), 8.70 (dd, J=8.4, 1.2 Hz, 1H), 11.91 (s, 1H); LC-MS (ES-API); rt 9.23 min; m/z calculated for C19H17NO5 [M−H]− 338.1, found 338.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[O-:12][C:13]#[N:14].[K+].[OH-].[Na+]>O.C(O)(=O)C>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][C:13](=[O:12])[NH:1]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(C(=O)O)c(N)c1
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(=O)[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a suspension of 2-amino-4-methylbenzoic acid (58.9 g, 390 mmol) in water (1.5 L) and glacial acetic acid (50 ml) was added dropwise a solution of potassium cyanate (80.5 g, 993 mmol) in water (300 ml). After completion of the addition and stirring at room temperature for half an hour, sodium hydroxide pellets (500 g) were added at such a rate that the temperature was kept below 50° C. (with ice cooling). During the addition the mixture became a clear solution for a short period, and upon continuation of the sodium hydroxide addition a cream precipitate started forming. The suspension was cooled to 0-5° C. and the precipitate was collected by filtration and washed twice with water (150 ml). The solid was poured in water (1 L) and was acidified with concentrated aqueous HCl (30%, 150 ml). The solid was collected by filtration and washed with water (150 ml) to yield 7-methylquinazoline-2,4(1H,3H)-dione (57.0 g, 83%) after drying at 45° C. under vacuum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:24](Cl)(=[O:26])=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:29]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:24](=[O:26])(=[O:25])[NH2:29])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(OCc2ccccc2)c1-c1ccccc1
Reaction time: 2.5 h

Procedure:
3-Benzyloxy-5-chlorosulfonyl-4-phenylbenzoic acid (1.0 g) is in portions added to conc. ammonium hydroxide (10 ml), while stirring at 10°-12° C. After additional stirring at room temperature for 18-20 hours, the mixture is left in a refrigerator for 2-3 hours. The separated ammonium salt is collected by filtration and washed with a small amount of icecold water. After drying, the salt is dissolved in 1 N sodium hydroxide (10 ml) and the 3-benzyloxy-4-phenyl-5-sulfamylbenzoic acid is precipitated by the dropwise addition of the solution to 1 N hydrochloric acid (12 ml). The acid is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, it is obtained with a melting point of 199°-200° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:27]([NH2:29])=[O:28])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)[CH:8]=3.[Cl:30][C:31]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][C:32]=1[CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:30][C:31]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]([C:27]([NH2:29])=[O:28])[C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[C:9]([C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[CH:8]=4)[CH:41]=[CH:40][C:32]=1[CH2:33][N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(-c3ccc(N4CCOCC4)nc3)ccc12
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(CN3CCOCC3)c(Cl)c2)cc2c1[nH]c1cc(-c3ccc(N4CCOCC4)nc3)ccc12
Temperature: 105 °C

Procedure:
To the reaction mixture above (482A) was added 4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine 477B (0.098 g, 0.289 mmol) and additional PdCl2(dppf)-CH2Cl2 adduct (0.020 g, 0.024 mmol). The mixture was heated in microwave at 105° C. for 1 hr. The mixture was filtered and then purified using preparative HPLC to give titled product. MS (ESI) m/z 582.21 (M+H)+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3([C:24]#N)[CH2:23][CH2:22]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C([OH:29])(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3([CH:24]=[O:29])[CH2:23][CH2:22]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)O
Reactant: N#CC1(c2ccc3ncccc3c2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=CC1(c2ccc3ncccc3c2)CC1
Temperature: -2.5 °C
Reaction time: 3 h

Procedure:
Diisobutylaluminum hydride (1M in THF, 96 mL, 96 mmol) was added to a solution of 1-quinolin-6-ylcyclopropanecarbonitrile (12.4 g, 63.9 mmol) in toluene (120 mL) at −78° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to −5 to 0° C., and stirred at that temperature for 3 h. The reaction mixture was cooled to −60° C. Isopropyl alcohol (10 mL) was carefully added dropwise. After stirring for 30 min, the reaction mixture was warmed to −5 to 0° C. The reaction mixture was diluted with ethyl acetate, quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered through a pad of silica gel eluting with 40% ethyl acetate in hexanes. The filtrate was concentrated to yield the desired product. (12 g, 95.1%).