Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[NH2:14][CH:15]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.[Cl-].[Na+].O>[Si:26]([O:25][CH2:24][C@H:15]([NH:14][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[C@@H:16]([OH:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)OCC(N)C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1cc2cc(Cl)ncc2[nH]1)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 520 mg, 2.65 mmol) and 2-amino-3-(tert-butyldimethylsilanyloxy)-1-phenylpropan-1-ol (Preparation 99, 780 mg, 2.77 mmol) in DMF (15 mL) was added HOBt (411 mg, 2.68 mmol), DIPEA (0.96 mL, 5.51 mmol) and EDCI (589 mg, 3.07 mmol). After stirring at rt for 12 h the mixture was added to diluted brine (150 mL, water/brine: 1/1). Extraction with ethyl acetate (4×50 mL), washing of the combined extracts with diluted hydrochloric acid (1M, 50 ml), diluted aqueous sodium hydroxide solution (1M, 50 ml) and brine (50 mL) followed by drying (MgSO4) gave after concentration a residue which was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate: 50/50). The title compound was obtained as colourless oil. δH (CD3OD): 0.00, 0.01 (6H, 2s), 0.84 (9H, s), 3.60 (1H, dd), 3.84 (1H, dd), 4.33 (1H, ddd), 4.98 (1H, d), 7.05 (1H, s), 7.12-7.37 (5H, 3m), 7.60 (1H, s), 8.49 (1H, s); m/z (ES+)=460.36 [M+H]+; RT=4.16 min.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.COC1C=CC(C[N:30]2[C@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@@H:32]([C@H:38]([O:40][C:41]([O:43][CH2:44][CH:45]=[CH2:46])=[O:42])[CH3:39])[C:31]2=[O:47])=CC=1>O.C(#N)C>[CH2:44]([O:43][C:41]([O:40][C@@H:38]([C@@H:32]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[NH:30][C:31]1=[O:47])[CH3:39])=[O:42])[CH:45]=[CH2:46]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(Cc2ccc(OC)cc2)[C@@H]1OC(C)=O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 10°, a solution of 5.37 g of cerium(IV) ammonium nitrate in 15 ml of water is added to a solution of 900 mg (1.18 mmol) of (3R,4R)-1-(p-methoxybenzyl)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-acetoxy-2-azetidinone in 30 ml of acetonitrile, and the whole is stirred for two hours at room temperature. After extraction with ethyl acetate, washing with saturated NaHCO3 solution, drying of the organic phase over sodium sulphate and concentration by evaporation under reduced pressure, the crude title compound, which is purified by chromatography over silica gel using toluene/ethyl acetate (4:1 and 1:1), is obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH:25][CH2:26][C:27]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39](Br)[CH:40]=1)(=[O:34])=[O:33])([CH2:29][OH:30])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39]([C:14]#[C:13][C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:7][C:8]=23)[CH:40]=1)(=[O:34])=[O:33])([CH2:29][OH:30])[CH3:28]
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (81 mg, 0.25 mmol) (Example B.4) according to general procedure II. Obtained as a yellow solid (81 mg, 57%). MS (ISP) 572.3 [(M+H)+]; mp 190-191° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4](Cl)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[C:22]1([C:28]2[NH:32][C:31]([SH:33])=[N:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>CO>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([S:33][C:31]2[NH:32][C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:29][N:30]=2)[C:3]([O:2][CH3:1])=[O:21])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Sc1ncc(-c2ccccc2)[nH]1
Reactant: COC(=O)C(Cl)Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Sc1ncc(-c2ccccc2)[nH]1

Procedure:
The solution of 0.3 g (0.001 mol) of methyl3-[4-(Benzyloxy)phenyl]-2-chloropropionate in methanol (2 ml) was added dropwise to the solution of 0.18 g (0.001 mol) 5-phenyl-1H-imidazol-2-thiol and 0.04 g (0.001 mol) of NaOH in methanol (3 ml). The solution then was heated at reflux for 5 h. The crude product obtained after removing the solvent was used without purification in the next step of the synthesis.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH3:17])[O:9][CH2:8][CH2:7][O:6]1.[O:18]=[C:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][NH:20]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:5]1([O:9][CH2:8][CH2:7][O:6]1)[CH2:4][CH2:3][CH2:2][N:26]1[CH2:25][CH2:24][C:23]2([N:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:21][NH:20][C:19]2=[O:18])[CH2:28][CH2:27]1
Reactant: Cc1cc(F)ccc1C1(CCCCl)OCCO1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1C1(CCCN2CCC3(CC2)C(=O)NCN3c2ccccc2)OCCO1
Temperature: 0 °C

Procedure:
A mixture of 3 g of 4-chloro-1-(2-methyl-4-fluorophenyl)-1,1-ethylenedioxybutane, 2.3 g. of 4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane, 1.4 g of anhydrous potassium carbonate, 0.05 g of potassium iodide and 30 ml of dimethylformamide was refluxed for 3 hour. The resulting mixture was poured into ice water. The precipitated crystals were collected by filtration and washed with water to give 8-[4-(2-methyl-4-fluorophenyl)-4,4-ethylenedioxybutyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane as crude crystals (5 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=2)=[CH:3][N:2]=1.[OH-].[Na+].O.Cl>CO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][CH:17]=2)=[CH:3][N:2]=1
Reactant: CCOC(=O)c1ccc(-c2ccnnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccnnc2)cc1
Yield: 98.9 %

Procedure:
Ethyl 4-(4-pyridazinyl)benzoate (580 mg) was dissolved in methanol (12.5 ml) and 1.0M NaOH (12.7 ml) and heated at 60° C. for 4 hours. The resulting mixture was reduced to low volume then water (25 ml) added, the solution neutralised to pH 7 with 1.0M HCl, the resulting precipitate filtered and dried over P2O5 to give 4-(4-pyridazinyl)benzoic acid as a light brown solid (503 mg); mp>330° C.; 1H NMR (300 MHz, DMSO-d6) δ=8.05 (m,5H), 9.32 (d,1H), 9.67 (s,1H) ppm; MS: m/z 201 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([CH3:17])=[N:7]2.Br[C:20]1C(F)=CC=C2C=1NC(=O)C(C)=N2.C(N)(CC)(C)C>CS(C)=O>[Br:1][C:2]1[C:3]([F:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH2:14][CH3:20])([CH3:15])[CH3:16])[C:8]([CH3:17])=[N:7]2
Reactant: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Agent: CCC(C)(C)N
Solvent: CS(C)=O
Product: CCC(C)(C)Nc1nc2c(Br)c(F)ccc2nc1C
Yield: 81 %

Procedure:
This compound (580 mg, 1.78 mmol, 81% yield) as an orange amorphous solid was prepared according to the procedure described for Intermediate 605a, using 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (607 mg, 2.20 mmol) and tert-amylamine (Aldrich Chemical Company) (1.29 mL, 11.02 mmol) in DMSO (5.0 mL) as the starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (1H, dd, J=9.0, 5.7 Hz), 7.15 (1H, t, J=8.7 Hz), 4.74 (1H, br. s.), 2.54 (3H, s), 2.09 (2H, q, J=7.4 Hz), 1.58 (6H, s), 0.88 (3H, t, J=7.5 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −103.39 (1F, s). m/z (ESI, +ve ion) 326.0/328.0.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][C@@H:27]([CH:32]([CH3:34])[CH3:33])[CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].Cl>COCCO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: CC(C)[C@H](N)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: CC(C)C(CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 130 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
A mixture of 1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmole), (R)-3-amino-4-methylpentanoic acid hydrochloride (52 mg, 0.31 mmole) (Chem-Impex International Inc., Wood Dale Ill.), and sodium methoxide (25 mg, 0.46 mmole) in 2-methoxyethanol was stirred at 130° C. for two hours before it was cooled to room temperature and acidified with 1 N HCl. The mixture was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of 1% acetic acid, ethyl acetate and hexanes to give the title compound as a yellow solid (9 mg): MS: (+) m/z 420.06 (M+1), (−) m/z 418.02 (M−1).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:12]1([C:11]2[C:6]([CH:4]3[CH2:5][N:2]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:3]3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Clc1ccc2ccccc2n1
Reactant: c1cnc(N2CCCCC2)c(C2CNC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2nc(N3CC(c4nccnc4N4CCCCC4)C3)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 2-azetidin-3-yl-3-piperidin-1-yl-pyrazine hydrochloride (127 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs2CO3 (325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to give 2-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-quinoline (58 mg, 0.17 mmol yield 17%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[NH:32]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]1>>[O:38]=[S:35]1(=[O:39])[CH2:36][CH2:37][N:32]([C:3]([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:21])([F:22])[F:23])[N:12]=[CH:11]3)=[CH:8][CH:9]=2)=[O:2])[CH2:33][CH2:34]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Reactant: O=S1(=O)CCNCC1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1)N1CCS(=O)(=O)CC1
Yield: 77.3 %

Procedure:
As described for Example 32, 4-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid methyl ester (100 mg, 0.23 mmol) was converted, using thiomorpholine 1,1-dioxide (125.4 mg, 0.9 mmol) instead of cyclopropanemethylamine, to the title compound (95 mg, 77%) which was obtained as a white solid. MS: m/e=534.8 [M+H]+.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[OH-:19].[Na+].Cl>O>[N+:14]([C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:4])=[O:19])=[CH:6][NH:7]2)=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: O=C(c1c[nH]c2cc([N+](=O)[O-])ccc12)C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C

Procedure:
3.7 g 2,2,2-trifluoro-1-(6-nitro-1H-indol-3-yl)-ethanone are combined with 20 ml of a 40% sodium hydroxide solution solution and refluxed for 4 hours. After cooling to 0° C. the mixture is diluted with a little water and adjusted to pH 1 by the careful addition of concentrated hydrochloric acid. The precipitated solid is suction filtered and dissolved in dichloromethane/methanol 10:1. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is extracted from diethyl ether.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2C=CC(=O)NN=2)=CC=1.ClC1C=C(C2C=CC(=O)NN=2)C=CC=1Cl.COC1C=C(C2C=CC(=O)NN=2)C=CC=1OC.OC1C=C(C2C=CC(=O)NN=2)C=CC=1O.CC1C=CC(C2C=CC(=O)NN=2)=CC=1.O(C1C=CC(C2C=CC(=O)NN=2)=CC=1)C1C=CC=CC=1.CC1C(C2C=CC=CC=2)=NNC(=O)C=1.C1(C2C(C3C=CC=CC=3)=NNC(=O)C=2)C=CC=CC=1.CC1C(=O)NN=C(C2C=CC=CC=2)C=1.CN1C(=O)C=CC(C2C=CC=CC=2)=N1.C1(N2C(=O)C=CC(C3C=CC=CC=3)=N2)C=CC=CC=1.C(N1C(=O)C=CC(C2C=CC=CC=2)=N1)C1C=CC=CC=1>>[C:5]1([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=c1ccc(-c2ccc(F)cc2)n[nH]1
Agent: COc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Agent: Cc1cc(-c2ccccc2)n[nH]c1=O
Agent: Cc1cc(=O)[nH]nc1-c1ccccc1
Product: O=c1ccc(-c2ccccc2)n[nH]1

Procedure:
The following compounds are prepared according to the procedure set forth in Example 1: 6-(4-fluorophenyl)-3(2H)-pyridazinone; 6-(4-chlorophenyl)-3(2H)-pyridazinone; 6-(3,4-dichlorophenyl)-3(2H)-pyridazinone; 6-(3,4-dimethoxyphenyl)-3(2H)-pyridazinone; 6-(3,4-dihydroxyphenyl)-3(2H)-pyridazinone; 6-(4-methylphenyl)-3(2H)-pyridazinone; 6-(4-phenoxyphenyl)-3(2H)-pyridazinone; 5-methyl-6-phenyl-3(2H)-pyridazinone; 5,6-diphenyl-3(2H)-pyridazinone; 4-methyl-6-phenyl-3(2H)-pyridazinone; 2-methyl-6-phenyl-3(2H)-pyridazinone; 2,6-diphenyl-3(2H)-pyridazinone; and 2-benzyl-6-phenyl-3(2H)-pyridazinone.
Reaction SMILES: [C:1](OC1C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2C(C)(C)CC=1)(=[O:3])[CH3:2].[CH3:30][C:31]1([CH3:53])[C:40]2[CH:39]=[CH:38][C:37]([C:41]#[C:42][C:43]3[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=3)=[CH:36][C:35]=2[C:34](=[O:52])[CH2:33][CH2:32]1>>[C:1]([O:52][C:34]1[C:35]2[CH:36]=[C:37]([C:41]#[C:42][C:43]3[CH:44]=[CH:45][C:46]([C:47]([OH:49])=[O:48])=[CH:50][CH:51]=3)[CH:38]=[CH:39][C:40]=2[C:31]([CH3:53])([CH3:30])[CH2:32][CH:33]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OC(C)=O)cc1
Product: CC(=O)OC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105), 100.0 mg (0.31 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoic acid (Compound 8) was converted into the title compound (white solid) using 0.08 ml (0.94 mmol) of acetic anhydride and 30 mg (0.16 mmol) of p-toluenesulfonic acid.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1.Cl.[OH-].[Na+]>O1CCOCC1>[NH:8]1[CH:7]=[C:6]([C:9]2[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)[CH:5]=[CH:4][C:3]1=[O:2]
Reactant: COc1ccc(-c2c(-c3ccccc3)nn3ccncc23)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccncc23)c[nH]1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A mixture of 3-(6-methoxy-3-pyridinyl)-2-phenylpyrazolo[1,5-a]pyrazine (2.36 g) and concd. HCl (7.8 mL) in 1,4-dioxane (48 mL) was stirred at 100° C. for 1 h. After cooling to room temperature, to the reaction mixture was added 5N sodium hydroxide solution and adjusted to pH 8, extracted with EtOAc, washed with brine, dried over sodium sulfate, evaporated in vacuo. The resulting solid was collected by filtration and washed with ether to give 3-(2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (1.95 g) as a solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[C:15]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][O:17][CH2:16]1>C(Cl)Cl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:19]([CH2:18][O:17][CH2:16][C:15]([OH:22])=[O:21])=[O:20]
Reactant: CC(C)(S)CN
Reactant: O=C1COCC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(S)CNC(=O)COCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To an ice-cooled suspension of 1-amino-2-methylpropane-2-thiol hydrochloride (4.21 g, 29.72 mmol) in methylene chloride (50 mL) was added triethylamine (4.56 mL, 32.72 mmol), followed by diglycolic anhydride (3.43 g, 29.55 mmol). After stirring at room temperature for 30 minutes, the reaction was concentrated in vacuo and cold 2 N HCl (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (5×30 mL). The combined extracts were washed with brine (30 mL) and dried over anhydrous sodium sulfate. Volatiles were evaporated and the residue was triturated with ether/hexane to afford 5.50 g (84%) of the title compound as a white solid. mp 81-82° C.; 1H NMR (CDCl3, 300 MHz): δ1.38 (s, 6H), 1.59 (s, 1H), 3.41 (d, 2H, J=6.4 Hz), 4.20 (s, 2H), 4.24 (s, 2H), 7.48 (br s, 1H), 8.80 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ29.83, 44.91, 51.90, 68.39, 70.77, 170.40, 172.84; LCMS (m/e): 239 (M+H2O), 222 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([OH:16])[C:7]1=2)[CH3:2].[C:25]([O:29][C:30](=[O:36])[NH:31][CH2:32][CH2:33][CH2:34]Br)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([O:16][CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:36])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCCCNC(=O)OC(C)(C)C)c21
Yield: 59.6 %

Procedure:
A solution of [1,4-dihydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (100 mg, 0.303 mmol) in DMF (10 mL) was treated with (3-bromo-propyl)-carbamic acid tert-butyl ester (100 mg, 0.454 mmol) and potassium carbonate (209 mg, 1.52 mmol) at 50° C. for 5 h. The reaction was concentrated to dryness. The residue was diluted with MeOH/H2O and the mixture was adjusted pH to 3. The solution was purified by preparative HPLC to afford the title compound as a white solid (88 mg, 60%). MS calcd for (C23H30BN3O8+H)+: 488.2. MS found: (M+H)+=488.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]([F:17])([F:16])[F:15])([O-])=O.Cl[Sn]Cl.O>CO.Cl>[F:15][C:14]([F:16])([F:17])[C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:12])([F:13])[F:11])=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a solution of 2-nitro-1,4-bis(trifluoromethyl)benzene (3.3 g, 12.7 mmol) in methanol (15 mL) was added a solution of SnCl2.H2O (8.57 g, 38.1 mmol) in conc. HCl (15 mL) at room temperature, and the mixture was heated to 50° C. and stirred for 4 hours. Methanol was removed, and the aqueous solution was basified with conc. NaOH solution until pH 10. The suspension was diluted with EtOAc (100 mL), and the mixture was stirred at room temperature for 30 minutes and filtered. The solid was discarded, and the filtrate was washed with brine (50 mL), dried over sodium sulfate, and filtered. The solution was concentrated to give 2,5-bis(trifluoromethyl)benzenamine as a yellow oil (2.5 g). MS (ESI): m/z 230 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(OC)=[O:2].[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[OH:2][CH2:1][C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: COC(=O)c1nccc2c1[nH]c1ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1nccc2c1[nH]c1ccccc12
Reaction time: 2 h
Yield: 21.4 %

Procedure:
In 50 ml of dry tetrahydrofuran were dissolved 160 mg of 1-carbomethoxy-9H-pyrido[3,4-b]indole. The solution was cooled with ice, 2 ml of diisobutyl-aluminum hydride were added and the reaction mixture allowed to stand for 2 hours. Unreacted reagent was then decomposed with a small amount of water and the mixture extracted with chloroform. The chloroform was removed by distillation and the residue recrystallized from methanol to yield 30 mg of 1-hydroxymethyl-9H-pyrido[3,4-b]indole as pale-yellow needles melting at 228°-230° C. The IR spectrum shows the absorption peak at 1680 cm-1 has disappeared, with an intense absorption being observed at 1630 cm-1. Mol. wt. (based on mass spectrum) 198.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH2:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:20][C@H:18]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=3[N:10]=2)[CH3:19])[N:25]=[CH:24][N:23]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1Cc1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1Cc1ccccc1
Temperature: 90 °C
Yield: 35.6 %

Procedure:
A mixture of (S)-1-(1-benzyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (320 mg, 1.19 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (184 mg, 1.19 mmol) and DIPEA (1.06 mL, 5.95 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial overnight. The resultant mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-10% [2M NH3 in MeOH] in DCM) to afford 394 as a white solid (164 mg, 36%). LCMS (Method K): RT 3.58 min [M+H]+ 388.1 1H NMR (DMSO-d6, 400 MHz): δ 7.94 (1H, s), 7.69 (1H, d, J=7.9 Hz), 7.61 (1H, dd, J=8.9, 4.5 Hz), 7.13-7.28 (5H, m), 6.95-7.05 (3H, m), 5.65 (1H, qn, J=7.9 Hz), 5.46 (2H, q, J=9.91, 5.5 Hz), 3.12 (1H, d, J=5.5 Hz), 1.49 (3H, d, J=6.77 Hz)