Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[OH:12].[CH2:13]=[O:14].CO>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH2:13][OH:14])=[C:7]2[OH:12]
Reactant: Oc1ccnc2c(Cl)cccc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cnc2c(Cl)cccc2c1O

Procedure:
8-Chloro-4-hydroxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide to give the novel compound 8-chloro-4-hydroxy-3-hydroxymethylquinoline, m.p. >300° (from methanol).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]2[C:7]=1[C:8](=[O:32])[C:9]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C(C)C)=[CH:22][C:21]=1[O:30][CH3:31])=[CH:10][NH:11]2.O>ClCCl>[F:5][C:6]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]2[C:7]=1[C:8](=[O:32])[C:9]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[O:30][CH3:31])=[CH:10][NH:11]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC(C)C)cc3OC)c[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(O)cc3OC)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Aluminum chloride (108 mg, 0.81 mmol) was added to a dichloromethane solution (5 ml) of 5-fluoro-3-(4-isopropoxy-2-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (120 mg, 0.31 mmol). The mixture was stirred at room temperature for 1 hour. Water and dichloromethane were added to the reaction mixture, and separated. The organic layer was then washed with water. The washed organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 100 mg of powdery white 5-fluoro-3-(4-hydroxy-2-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([CH2:17][CH2:18][CH3:19])[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:17][CH2:18][CH3:19])=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[NH:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCCC(C(=O)c1ccc(Cl)cc1)C(=O)c1cccs1
Solvent: CCO
Solvent: O
Product: CCCc1c(-c2ccc(Cl)cc2)n[nH]c1-c1cccs1
Yield: 94.1 %

Procedure:
1-(4-Chlorophenyl)-2-propyl-3-(2-thienyl)-1,3-propanedione (1.4 g, 4.6 mM) was dissolved in ethanol (50 ml), and hydrazine hydrate (343 mg, 6.9 mM) was added thereto. This mixture was heated under reflux for 3 hours. After the mixture was allowed to cool, the solvent was distilled off under reduced pressure. The resulting precipitate was filtered while being washed with a solvent mixture composed of hexane and ether to obtain 1.3 g (4.3 mM) of 3-(4-chlorophenyl)-4-propyl-5-(2-thienyl)-1H-pyrazole, m.p. 129-132° C., in a 94% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: COC(=O)COc1ccc(N)cc1
Product: COC(=O)COc1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1
Yield: 86 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (60 mg, 0.306 mmol) was condensed with methyl 4-aminophenoxyacetate, and the resultant was purified by silica gel chromatography (0.5% methanol-chloroform) to obtain methyl 4-[(4,5-diisopropylfuran-2-carbonyl)amino]phenyloxyacetate (94 mg, 86%) as colorless needles.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:19][O:20][C:21]([CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1)=[O:22]>>[CH3:19][O:20][C:21]([CH:23]1[CH2:28][N:27]([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:26][CH2:25][NH:24]1)=[O:22]
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: COC(=O)C1CNCCN1
Product: COC(=O)C1CN(c2c(C=O)c3ccccc3n2-c2ccccc2)CCN1
Yield: 9 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with piperazine-2-carboxylic acid methyl ester as described in Example 1 to afford 4-(3-formyl-1-phenyl-1H-indole-2-yl)-piperazine-2-carboxylic acid methyl ester (9% yield) as a yellow solid. LC/MS: MS 364 (M+H); RT 2.54 min; NMR (CDCl3): 10.29 (1H, s), 8.26 (1H, d), 7.07-7.65 (m, buried), 6.98 (1H, d), 3.60-4.10 (4H, m), 2.60-3.55 (6H, m).
Reaction SMILES: [O:1]1[CH2:3][C:2]21[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]2=1.[NH2:18][NH2:19]>>[NH:18]([CH2:3][C:2]1([OH:1])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[NH2:19]
Reactant: c1ccc2c(c1)CCc1ccccc1C21CO1
Reactant: NN
Product: NNCC1(O)c2ccccc2CCc2ccccc21

Procedure:
A mixture of 10.0 g. of 10,11-dihydro-spiro[dibenzo[a,d] cycloheptene-5,2'-oxirane] and 100 ml. of anhydrous hydrazine is refluxed for 3 hours, the resulting mixture evaporated in vacuo to dryness, the residue dissolved in methanol and again evaporated in vacuo to dryness. The residue is crystallized from diethyl ether to obtain 5-hydrazinomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5-ol, m.p. 95°-105° C. (decomp.). It was observed that this product decomposed slowly at room temperature to form dibenzo[a,d]cyclohepten-5-one and thus must be stored at reduced temperatures if to be preserved in relatively pure form for any substantial period of time.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:20]1[Se:24][C:23]([C:25]([NH2:27])=[O:26])=[C:22]([OH:28])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+].Cl>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:22]1[CH:21]=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[Se:24][C:23]=1[C:25]([NH2:27])=[O:26]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(O)c(C(N)=O)[se]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a solution of 4-chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol) in DMF (5 mL) was added sequentially 5-tert-butyl-3-hydroxyselenophene-2-carboxamide (220 mg, 0.89 mmol), powdered NaOH (147 mg, 3.568 mmol) and catalytic amount of KI at rt and the mixture was stirred at rt for 3 h. The mixture was poured into ice cooled water, neutralized with dil. HCl and stirred for 15 min. The precipitated solid was filtered, washed with water and dried. The crude product was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as an yellow color solid (245 mg, 63%), mp 220-224° C. 1H NMR (400 MHz, CDCl3): δ 15.16 (1H, br s, exchangeable with D2O), 13.63 (1H, br s, exchangeable with D2O), 8.17 (1H, s), 7.51 (1H, s), 7.21 (1H, s), 6.87 (1H, s), 4.05 (6H, s), 1.38 (9H, s); 13C NMR (100 MHz, CDCl3): δ 175.5, 172.0, 164.8, 156.6. 155.1, 150.7, 145.9, 139.9, 118.7, 113.1, 112.7, 108.4, 103.3, 56.5, 56.3, 37.1, 32.2; LC-MS (positive ion mode): m/z 434, 436 (M+H)+.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:22])[CH3:21]>C1COCC1>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH3:8])[CH2:21][O:22]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(F)cc2F)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(2,4-difluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)[N:5]=[C:4]([N:20]2[C:25]([CH3:27])([CH3:26])[CH2:24][CH2:23][CH2:22][C:21]2([CH3:29])[CH3:28])[N:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[O:33]1[CH2:34][CH2:35][N:30]([C:2]2[N:7]=[C:6]([O:8][CH:9]3[CH2:10][C:11]([CH3:19])([CH3:18])[N:12]([OH:17])[C:13]([CH3:15])([CH3:16])[CH2:14]3)[N:5]=[C:4]([N:20]3[C:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][CH2:24][C:25]3([CH3:27])[CH3:26])[N:3]=2)[CH2:31][CH2:32]1
Reactant: CC1(C)CC(Oc2nc(Cl)nc(N3C(C)(C)CCCC3(C)C)n2)CC(C)(C)N1O
Reactant: C1COCCN1
Solvent: O
Product: CC1(C)CC(Oc2nc(N3CCOCC3)nc(N3C(C)(C)CCCC3(C)C)n2)CC(C)(C)N1O

Procedure:
5 g of 2-chloro-4-(1-hydroxyl-2,2,6,6-tetramethylpiperidin-4-oxy)-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 36) are stirred under reflux with 50 ml of morpholine for 3 hours. After cooling to 20°, 200 ml of water are added and the precipitate is filtered off. After recrystallization from petroleum ether, the above product is obtained as reddish crystals which melt at 153°-157°.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](N1CCCC1)=[CH:6]2.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[N+:24]=[N-:25])=[CH:20][CH:19]=1>>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[C:4]1[N:25]=[N:24][N:23]([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:27][CH:26]=3)[C:5]=1[CH2:6]2
Reactant: CN1C2C=C(N3CCCC3)CC1CCC2
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Product: COc1ccc(Cn2nnc3c2CC2CCCC3N2C)cc1
Temperature: 50 °C
Yield: 57.6 %

Procedure:
A mixture of 9-methyl-3-(pyrrolidin-1-yl)-9-azabicyclo[3.3.1]non-3-ene (1.2 g, 5.9 mmol) and 4-methoxybenzylazide (0.96 g, 5.9 mmol) was heated at 50° C. for 2 days. The crude mixture was purified by prep HPLC to afford the product (1.0 g, 3.4 mmol, 57% yield) as yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.I[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]3)=[C:9]([OH:8])[CH:14]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: ICC1CCCCC1
Product: O=C1CN(c2ccc(CC3CCCCC3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and iodomethylcyclohexane analogous to Example 57, steps B, C and D: (M−1)−=323. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (d, J=11.37 Hz, 2 H) 1.09-1.19 (m, 2 H) 1.14 (d, J=9.60 Hz, 1 H) 1.44 (dd, J=14.78, 3.66 Hz, 1 H) 1.62 (d, J=10.86 Hz, 5 H) 2.34 (d, J=7.07 Hz, 2 H) 4.00 (s, 2 H) 6.54 (dd, J=7.96, 1.89 Hz, 1 H) 6.61 (d, J=1.77 Hz, 1 H) 7.25 (d, J=8.08 Hz, 1 H) 8.85 (s, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([N:40]2[C:45](=[O:46])N(CC3C(F)=CC(F)=CC=3F)[C:43]3[N:57]=[CH:58][CH:59]=[CH:60][C:42]=3[S:41]2(=[O:62])=[O:61])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:5]1[C:43]2[N:57]=[CH:58][CH:59]=[CH:60][C:42]=2[S:41](=[O:62])(=[O:61])[N:40]([C:34]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=2)[C:45]1=[O:46]
Reactant: NCc1c(F)cccc1Cl
Reactant: COc1ccc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ncccc3S2(=O)=O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ncccc3S2(=O)=O)cc1OC

Procedure:
The title compound (48 mg, 0.10 mmol) was prepared in two steps from (IntC1) (82 mg, 0.25 mmol) and 2-chloro-6-fluorobenzyl amine (0.1 mL, 0.75 mmol); followed by 1,1′-carbonyldiimidazole (191 mg, 1.18 mmol) and triethylamine (0.08 mL, 0.59 mmol) using the methods of (93).
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:15][CH2:14]1>>[F:25][C:22]([F:23])([F:24])[C:21]([NH:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:13]([C:2]2[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:14][CH2:15]1)=[O:26]
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Reactant: CC(C)n1ncc([N+](=O)[O-])c1Cl
Product: CC(C)n1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 52 %

Procedure:
Reaction of 5-chloro-1-isopropyl-4-nitro-1H-pyrazole and (R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide gave (R)-2,2,2-trifluoro-N-(1-(1-isopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide as a pale yellow gum (90 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 6.39 (s, 1H), 4.83-4.70 (m, 1H), 4.24-4.17 (m, 1H), 3.45-3.32 (m, 1H), 3.28-3.12 (m, 3H), 2.23-2.02 (m, 2H), 2.00-1.80 (m, 4H), 1.54-1.44 (m, 6H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])[C:9](=[O:22])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[F:21])[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[F:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[N:10]1[CH:11]([CH3:12])[C:5]2[C:6](=[N:7][C:2]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:3][CH:4]=2)[N:8]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])[C:9]1=[O:22]
Reactant: Nc1ccccc1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Cl)ncc3C2C)c(F)c1
Solvent: CO
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4ccccc4)ncc3C2C)c(F)c1
Temperature: 110 °C

Procedure:
(±)-3-[7-Chloro-3-(2-fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (1.03 g; 2.42 mmol) (from Example 9a supra) was combined with aniline (1.00 mL; 10.97 mmol) (Aldrich) and heated at 110° C. for 1 hour. At this point, the reaction mixture was a solid mass. Methanol (75 mL) was added and the mixture was heated at 110° C. for 20 minutes with vigorous stirring (solid remained insoluble). Upon cooling, the solid was collected, washed with methanol and then ether and dried under high vacuum to give (±)-3-[3-(2-fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile. (Yield 1.00 g; 85.6%). A portion of this material was recrystallized from dichloromethane-ether-petroleum ether for characterization and testing. (Yield 0.22 g).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:7]1([CH3:23])[CH:12]=[CH:11][C:10]([S:13]([CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[CH2:2]([C:16]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:23])=[CH:8][CH:9]=2)(=[O:14])=[O:15])[S:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCI
Reactant: Cc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Product: C#CCCCC1(S(=O)(=O)c2ccc(C)cc2)SC(=O)NC1=O

Procedure:
In the manner of Example 100 above, 5-iodo-1-pentyne is reacted with 5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione to give the title compound, mp 226° C., THEORY: C, 53.4, H, 4.48, N, 4.15. FOUND: C, 53.3, H, 4.58, N, 4.13.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[NH:25][NH2:26].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:29]([O:28][C:24]([N:25]([C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1)[NH2:26])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Ic1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(N)c1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
The product of Example 38A (420 mg, 1.0 mmol) was coupled with tert-butyl carbazate (Aldrich, 158 mg, 1.2 mmol) under the catalysis of Cul (Strem Chemicals, 9.5 mg, 0.05 mmol) with Cs2CO3 (Strem Chemicals, 489 mg, 1.4 mmol) in DMF (anhydrous, Aldrich, 5 mL) at 80° C. overnight. The mixture was diluted with EtOAc (50 mL) and washed with water (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.20) as an oil (190 mg, yield, 45%). 1H NMR (MeOH-d4, 300 MHz) δ 1.46 (s, 9H), 1.76–2.16 (m, 3H), 2.20–2.39 (m, 1H), 2.41–2.54 (m, 1H), 3.16–3.47 (m, 5H), 3.66–3.86 (m, 1H), 4.70–4.84 (m, 1H), 6.77–6.93 (m, 2H), 6.94–7.04 (m, 4H), 7.25–7.48 (m, 2H) ppm. MS (DCl/NH3) m/z 426 (M+H)+.
Reaction SMILES: C(O)C.[CH3:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:36])[C:12]=2[C:14]2[N:15]=[C:16]([O:34]C)[C:17]3[CH2:23][N:22]([C:24]4[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:25]=4[CH3:33])[CH2:21][CH2:20][C:18]=3[N:19]=2)[NH:7][N:6]=1.Cl>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:36])[C:12]=2[C:14]2[N:15]=[C:16]([OH:34])[C:17]3[CH2:23][N:22]([C:24]4[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:25]=4[CH3:33])[CH2:21][CH2:20][C:18]=3[N:19]=2)[NH:7][N:6]=1
Reactant: COc1nc(-c2c(C)ccc3[nH]nc(C)c23)nc2c1CN(c1cc(C(C)C)ccc1C)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)ccc4[nH]nc(C)c34)nc(O)c2C1
Temperature: 85 °C

Procedure:
Ethanol (12 mL) was added to 2-(3,5-dimethyl-1H-indazol-4-yl)-6-(5-isopropyl-2-methylphenyl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.07 g, 3.47 mmol), followed by 12 N aqueous hydrochloric acid (12 mL). The mixture was then heated at 85° C. for 18 h. The mixture was cooled to room temperature, diluted with dichloromethane and slowly neutralized with saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layers were extracted with dichloromethane. The organic layers were combined. The combined organics were dried and concentrated. The residue was purified by FCC (0-100% EtOAc/heptane) to provide 2-(3,5-dimethyl-1H-indazol-4-yl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol. MS (ESI+) m/z 428.3 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:26][N:27]([CH3:41])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:38][C:37]([NH2:39])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32]>>[CH3:26][N:27]([CH3:41])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:38][C:37]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NCCN(C)C
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NCCN(C)C

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.15) according to general procedure II.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]
Reactant: Fc1ccc(OCCBr)c(F)c1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1F

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-2,4-difluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1 H), 7.76 (d, J=8.7 Hz, 1 H), 7.50 (d, J=8.7 Hz, 1 H), 7.26-7.15 (m, 1 H), 7.10-7.00 (m, 1 H), 6.92-6.88 (m, 1 H), 4.67 (t, J=5.0 Hz, 2 H), 4.30 (t, J=5.0 Hz, 2 H), 3.30 (s, 3 H); MS (ES) m/z 347 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]2([C:21]([OH:23])=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
The mixture of ethyl 1-[2-(4-benzyl-1-piperazinyl)ethyl]cyclopentanecarboxylate (300 mg, 0.871 mmol) and KOH (85%, 0.36 g, 3.49 mmol) in methanol (5.0 ml) and water (1.2 ml) was stirred at 95° C. overnight. To the mixture was added 2 N HCl until the pH became 5. After the solvent was removed in vacuo, the residue was extracted with dichloromethane (30 ml). The extract was washed with brine, dried over NASO4, filtered and concentrated in vacuo to provide a yellow oil (276 mg/100%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:7][C:8](=[O:31])[N:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[O:29][CH3:30])/[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:10])[CH2:4][CH2:5][CH3:6].C(O)(=O)C>O1CCCC1>[CH2:3]([NH:7][C:8](=[O:31])[N:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[CH:19][C:20](/[CH:23]=[C:24](\[O:29][CH3:30])/[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:10])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2)c1
Temperature: 68 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2.7 mL (2.7 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 0.7 g (1.8 mmol) of methyl (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate in 12 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 2 hours. The reaction medium is acidified with 2.8 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is recrystallized from hot ethyl acetate. 530 mg (77%) of (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylic acid are obtained in the form of a white solid with a melting point of 146° C.