Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[N:19][CH:18]=[CH:17]2>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH:20]=[N:19][CH:18]=[CH:17]3)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc3cnccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
In pyridine (30 ml) was dissolved 6-aminoisoquinoline (3.348 g, Synthesis, 733 (1975), and 4-toluenesulfonyl chloride (5.13 g) was added thereto, followed by stirring at room temperature overnight. Water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was recrystallized from ethanol, to give the title compound (5.958 g, 85%) as pale yellow crystals.
Reaction SMILES: C12(C3C=C[C:14]([O:15]CC(O)=O)=[CH:13]C=3)CC3CC(CC(C3)C1)C2.N[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.C[N:34](C=O)C>CN(C)C1C=CN=CC=1>[S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:13][C:14]([NH2:34])=[O:15])=[CH:24][CH:25]=1)(=[O:31])(=[O:30])[NH2:32]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Product: NC(=O)Cc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To a solution of the (4-adamantan-1-yl-phenoxy)-acetic acid (143 mg, 0.5 mmol) and 4-amino-benzenesulfonamide (103 mg, 0.6 mmol) in DMF (5.0 mL) were added benzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (390 mg, 0.75 mmol), and 4-dimethylaminopyridine (DMAP) (92 mg, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (CH2Cl2:MeOH=40:1) gave 2-(4-Adamantan-1-yl-phenoxy)-N-(4-sulfamoyl-phenylacetamide as a white solid (78.9 mg, 35.8% yield).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[N:13]=[N:12][C:11]=1[C:26]([NH:28][CH:29]1[CH2:31][CH2:30]1)=[O:27])C1C=CC=CC=1.CO>CN(C=O)C.[C].[Pd]>[CH:29]1([NH:28][C:26]([C:11]2[N:12]=[N:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[C:10]=2[CH2:9][OH:8])=[O:27])[CH2:30][CH2:31]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 76 %

Procedure:
To a solution of 5-[(benzyloxy)methyl]-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (4.29 g) obtained in Example 94 in DMF (60 ml)-methanol (180 ml) was added palladium-carbon (1.0 g). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 days, and the insoluble material was filtered off. The solvent was evaporated, and the residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (2.56 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([O:7]C1C=CC([N+]([O-])=O)=CC=1)=O.[C:20]1(=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[CH2:21]1.[F-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([CH:21]1[C:20](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:29])=[O:7]
Reactant: O=C1CC(=O)c2ccccc21
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cccc(Cl)c1
Agent: [F-]
Agent: [K+]
Product: O=C(c1cccc(Cl)c1)C1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 160.4 %

Procedure:
A 25-mL 3-neck round bottom flask was charged with 4-nitrophenyl 3-chlorobenzoate (0.64 g, 2.3 mmol), indane-1,3-dione (0.39 g, 2.7mmol) and (methyl sulfoxide)-d6 (5.0 g). The mixture was heated to 80° C. and potassium fluoride (0.60 g, 10 mmol) was added in a single portion. After stirring at 80° C. for 7 hours, the mixture was cooled, partitioned between diethyl ether-ethyl acetate (1:1, 100 mL) and 1N hydrochloric acid (25 mL). The organic layer was washed with additional portions of 1N hydrochloric acid (3×10 mL), then with brine (10 mL), dried over magnesium sulfate, filtered, and evaporated to leave a brown solid (1.05 g).
Reaction SMILES: BrC1C=CC2C(C3C=CC(O)=CC=3)=NOC=2C=1.BrC/C=C/CBr.[Br:24][C:25]1[CH:45]=[CH:44][C:28]2[C:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39]/[CH:40]=[CH:41]/[CH2:42]Br)=[CH:34][CH:33]=3)=[N:30][O:31][C:27]=2[CH:26]=1.[CH2:46]([NH:49][CH3:50])[CH:47]=[CH2:48]>>[CH2:46]([N:49]([CH2:42]/[CH:41]=[CH:40]/[CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]2[C:28]3[CH:44]=[CH:45][C:25]([Br:24])=[CH:26][C:27]=3[O:31][N:30]=2)=[CH:33][CH:34]=1)[CH3:50])[CH:47]=[CH2:48]
Reactant: C=CCNC
Reactant: BrC/C=C/COc1ccc(-c2noc3cc(Br)ccc23)cc1
Agent: BrC/C=C/CBr
Agent: Oc1ccc(-c2noc3cc(Br)ccc23)cc1
Product: C=CCN(C)C/C=C/COc1ccc(-c2noc3cc(Br)ccc23)cc1

Procedure:
Analogously to Example 14d, from 4-(6-bromo-benzo[d]isoxazol-3-yl)-phenol and (E)-1,4-dibromo-2-butene via (E)-6-bromo-3-[4-(4-bromo-but-2-enyloxy)-phenyl]-benzo[d]isoxazole and by reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[4-(6-bromo-benzo[d]isoxazol-3-yl)-phenoxy]-but-2-enyl]-methyl-amine which is converted into the fumarate, MS: m/e 413 (M+H+, 1 Br).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[N:10][C:4]=2[CH:3]=1.C([O:19][C:20]1[C:23](=[O:24])[C:22](=O)[C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:27]1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]([C:22]3[C:23](=[O:24])[C:20](=[O:19])[C:21]=3[N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:28]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:27]3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1O2
Reactant: CCOC(=O)C1CN(c2c(OCC)c(=O)c2=O)CCN1c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1CN(c2c(N3Cc4ccccc4Oc4ccc(Cl)cc43)c(=O)c2=O)CCN1c1ccccc1
Yield: 43.8 %

Procedure:
A mixture of 8-chloro-dibenz[b,f][1,4]oxazepine (1.02 g) and the product of Example 3 (0.26 g) and diphenyl ether (3 mL) was heated to reflux for 1.75 hours. The mixture was rapidly filtered thourough a small column of silica gel and the filtrate was concentrated. The residue was purified by chromatography on silica gel to obtain the title compound (0.173 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]([C@@H:12]1[CH2:17][O:16][CH2:15][CH2:14][NH:13]1)[CH3:11].CCN(C(C)C)C(C)C>CC#N>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][C@H:12]2[CH2:10][CH3:11])[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC[C@@H]1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Temperature: 150 °C
Yield: 86.6 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (240 mg, 1.46 mmol) in CH3CN (8 mL) were added (3R)-3-ethylmorpholine (244 mg, 1.61 mmol) and Hunig's base (1.02 mL, 5.85 mmol), and the reaction mixture was heated in a microwave at 150° C. for a total of 3 hours, checking the progression of the reaction at regular intervals. The mixture was evaporated under vacuum, and the resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×) and CH2Cl2 (2×). The organics were washed with water and brine, dried (MgSO4), filtered and evaporated. The resulting material was triturated with Et2O and dried in vacuo to afford the title compound (307 mg). LC-MS (ES) m/z=243, 245 [M+H]+.
Reaction SMILES: [BH4-].[Na+].C([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:16]=1)=O.[CH2:17]([OH:19])C>>[OH:19][CH2:17][CH:12]1[CH2:11][C:10]([CH3:14])([CH3:15])[C:9]2[CH:16]=[CH:5][CH:6]=[CH:7][C:8]=2[S:13]1
Reactant: CCO
Reactant: CC1(C)CCSc2ccc(C=O)cc21
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)CC(CO)Sc2ccccc21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Sodium borohydride (NaBH4) (0.36 g, 9.7 mmol) is added at 0° C. to a solution of the previous 6-formyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran (2.00 g, 9.7 mmol) in 20 ml of ethanol. The agitation was continued at this temperature for 30 minutes. After evaporation of the ethanol, it is taken up again in 100 ml of ethyl ether and acidified by an aqueous 3N solution of HCl to pH 1. The mixture is extracted with ether, dried over MgSO4 filtered and the solvents evaporated. The crude product is purified by flash chromatography on silica (eluent petroleum ether:ethyl ether:100:10). 1.85 g of 6-(hydroxymethyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyrane is obtained (gross yield=92%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[CH:12]([C:15]1[N:19]=[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:17][N:16]=1)([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[OH-].[NH4+]>C(O)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:23]3[CH2:22][CH2:21][CH:20]([C:18]4[O:17][N:16]=[C:15]([CH:12]([CH3:14])[CH3:13])[N:19]=4)[CH2:25][CH2:24]3)[C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncnc2c(Br)csc12
Reactant: CC(C)c1noc(C2CCNCC2)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1noc(C2CCN(c3ncnc4c(Br)csc34)CC2)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 61.1 %

Procedure:
7-bromo-4-chlorothieno[3,2-d]pyrimidine (100 mg) was added to isopropyl alcohol (3 mL), and 4-(3-isopropyl-[1,2,4]-oxadiazol-5-yl)piperidine (100 mg) and diisopropylethylamine (200 μL) were further added thereto. The reaction mixture was stirred at 100° C. for 12 hours. Then, the reaction mixture was mixed with saturated ammonium hydroxide solution and extracted twice with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a foamy residue. The residue was crystallized in the presence of diethyl ether to obtain the title compound (100 mg) as a whitish solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(Oc2ccccc2C(C)(C)C)n1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A solution of 2-chloro-6-methoxy-3-nitropyridine (5.20 g, 27.6 mmol) in DMF (50 mL) was treated with 2-tert-butylphenol (4.9 mL, 31.7 mmol) and cesium carbonate (27.0 g, 82.8 mmol). The mixture was heated at 80° C. for 18 h. The reaction was allowed to cool to rt, the mixture was poured into water (500 mL) with stirring. The brown precipitate formed was filtered and washed with water, and recrystallized twice from ethanol to afford 2a as brown crystals (6.66 g, 80%). [M+H]+=303.2.
Reaction SMILES: ClC(C[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[O:13][CH3:14])C=O.[NH2:15]C(N)=S>C(O)C>[F:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH3:14])=[C:6]([NH2:15])[CH:11]=1
Reactant: COc1ccc(F)cc1CC(Cl)C=O
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(F)cc1N

Procedure:
A mixture of 2-chloro-3-(5-fluoro-2-methoxy-phenyl)-propionaldehyde (crude from above) and thiourea (29.2 g, 0.384 mol) in ethanol (400 mL) was heated to reflux for 15 hours. The solvent was removed and the residue was diluted with dichloromethane (300 mL), sodium hydroxide (10% aqueous solution, 150 mL) and water (200 mL). The aqueous phase was extracted twice with dichloromethane (150 mL). The combined organic layer was washed with water, a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude product was recrystallized from a mixture of ethyl acetate and hexanes to give the pure product (6.5 g, 0.027 mol, 6.2% from 5-fluoro-2-methoxy-phenylamine). ESI-MS m/z calc. 238.1. found 239.2 (M+1)+ 1H NMR (CDCl3): δ 6.90-6.81 (m, 2H), 6.79-6.76 (m, 2H), 4.75 (br, 2H), 3.91 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:27]1([CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][C:38]([OH:43])=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:43][C:38]2[CH:37]=[C:36]3[C:41]([CH2:42][CH:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][O:35]3)=[CH:40][CH:39]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)C2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)C3)nc1

Procedure:
5-Nitro-2-(3-phenylchroman-7-yloxy)pyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 200 mg of 3-phenylchroman-7-ol. 1H NMR (400 MHz, d6-DMSO) δ: δ: 9.05 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.34-7.38 (m, 4H), 7.27-7.30 (m, 1H), 7.22 (m, 2H), 6.70-6.74 (m, 2H), 4.31 (dd, 1H, J 10.4, 3.5 Hz), 4.12 (t, 1H, 10.4 Hz), 3.24 (m, 1H), 3.01-3.11 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH3:14]O>S(=O)(=O)(O)O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: CO
Reactant: O=C(O)Cc1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1n[nH]c2ccccc12

Procedure:
A solution of 1H-indazole-3-acetic acid (1.0 g) prepared according to J. Am. Chem. Soc., 79, 5245 (1957), in methanol (30 ml) containing five drops of concentrated sulfuric acid was refluxed for 8 hours. The reaction mixture was then concentrated to a low volume and diluted with ethyl acetate (20 ml). The organic layer was washed with water (2×10 ml) and then with sodium bicarbonate solution (10 ml, 10%). The ethyl acetate layer was collected and then dried to obtain the title compound (yield: 0.8g; m.p. 146° C.).
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[C:19]([CH2:22][CH2:23][C:24](=[O:40])[C:25]2[S:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)[CH:18]=[CH:17][C:3]=1[O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Na+]>>[Cl:1][C:2]1[C:20]([Cl:21])=[C:19]([CH2:22][CH2:23][C:24](=[O:40])[C:25]2[S:26][C:27]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=3)=[CH:28][CH:29]=2)[CH:18]=[CH:17][C:3]=1[O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(CCc1ccc(OC(C(=O)O)c2ccccc2)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-phenylacetic acid is prepared from ethyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl) phenoxy)-2-phenylacetate according to general procedure F using 20 equivalents of 2N sodium hydroxide solution.
Reaction SMILES: [CH2:1]([C:3]([OH:33])([CH2:31][CH3:32])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25](OC)=[O:26])[C:18](=[CH:23][CH:24]=2)[C:19](OC)=[O:20])=[CH:11][CH:10]=1)[CH3:8])[CH3:2].[BH4-].[Li+]>>[OH:26][CH2:25][C:17]1[CH:16]=[C:15]([CH:24]=[CH:23][C:18]=1[CH2:19][OH:20])[CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([OH:33])[CH2:31][CH3:32])=[CH:30][CH:29]=1
Reactant: CCC(O)(CC)CCCC(C)c1ccc(OCc2ccc(C(=O)OC)c(C(=O)OC)c2)cc1
Agent: [BH4-]
Agent: [Li+]
Product: CCC(O)(CC)CCCC(C)c1ccc(OCc2ccc(CO)c(CO)c2)cc1

Procedure:
In a manner similar to Example 53(e), by reacting 607 mg (1.33 mmol) of dimethyl 4-[4-(5-ethyl-5-hydroxy-1-methylheptyl)phenoxymethyl]phthalate (prepared in a manner similar to Examples 64(a-d)) with 116 mg (5.32 mmol) of lithium borohydride, a colourless oil is obtained (m=421 mg; Y=79%).
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[C@H:20]([CH3:21])[CH2:19][N:18]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=2)[C@@H:17]([CH3:34])[CH2:16]1)C1C=CC=CC=1>ClC(Cl)C>[CH3:34][C@H:17]1[CH2:16][NH:15][C@H:20]([CH3:21])[CH2:19][N:18]1[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1Cc1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1
Reaction time: 48 h
Yield: 80.8 %

Procedure:
A 0.92 ml portion of 1-chloroethyl chloroformate was added to 20 ml of dichloroethane solution containing 0.31 g of (2S,5R)-4-(4-benzyl-2,5-dimethylpiperazin-1-yl)-2-trifluoromethylbenzonitrile, and the mixture was stirred for 2 days with heating under reflux. The reaction mixture was concentrated, mixed with 20 ml of methanol and then stirred for 1 day with heating under reflux. The reaction mixture was concentrated and the residue was subjected to a silica gel column chromatography and purified with chloroform-methanol (9:1, v/v) to obtain 0.19 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:20]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:21])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: O=C(c1ccc(-c2ccc(Cl)cc2)cc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-chlorobiphenyl (1.0 g), cyclohexanecarbonyl chloride (0.788 mL) and nitromethane (10.6 mL) was added aluminum chloride (0.848 g) at 0° C. The reaction mixture was stirred at 0° C. for 3 hr, and water was added at 0° C. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.792 g).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].O.[NH2:34][NH2:35].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:35][N:34]=1
Reactant: Cc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(C(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methylphenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (568 mg, 1.3 mmol) produced in Synthesis Example 36 in DMF (5.5 mL) was added hydrazine monohydrate (purity of 80%, 207 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methylbenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (519 mg, yield 92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:27][C@H:15]4[C:16]=3[N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:18]=2)=[O:10])[CH2:2]1.[C:28](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:28][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:27][C@H:15]4[C:16]=3[N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:18]=2)=[O:10])[CH2:2]1
Reactant: O=C(NCC1CNCCO1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCOC(CNC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)C1
Temperature: 23 °C
Reaction time: 18 h
Yield: 106.2 %

Procedure:
To a mixture of (1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (morpholin-2-ylmethyl)-amide (40 mg, 0.097 mmol) and potassium carbonate (26.9 mg, 0.195 mmol) in DMF (0.5 mL) was added iodomethane (6.06 μL, 0.097 mmol). The reaction was stirred at 23° C. for 18 h. The mixture was filtered then purified by HPLC to provide the title compound (TFA salt, 40 mg) as a hygroscopic white solid. LCMS m/z=389.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.37-0.41 (m, 1H), 1.14-1.20 (m, 1H), 2.11-2.21 (m, 1H), 2.25-2.32 (m, 1H), 2.74-3.47 (m, 11H), 3.61-3.69 (m, 1H), 3.77-3.83 (m, 1H), 3.94-4.05 (m, 1H), 7.30-7.35 (m, 1H), 7.59-7.64 (m, 1H), 7.74-7.80 (m, 1H), 8.15-8.21 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1Br.C(N(CC)CC)C.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:30]#[C:29][C:26]1[CH:25]=[CH:24][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:28][CH:27]=1
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Reactant: COC(=O)c1ccncc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccncc1C#Cc1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-isonicotinic acid methyl ester (648 mg, 3.00 mmol) in DMF (6 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (210 mg, 0.30 mmol), copper(I) iodide (17.1 mg, 0.090 mmol), triethylamine (1.25 ml, 9.00 mmol) and 1-tert-butyl-4-ethynyl-benzene (570 mg, 3.60 mmol). The resulting dark brown solution is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 3 hours. The reaction mixture is allowed to cool to room temperature and reduced in volume under vacuum. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-tert-butyl-phenylethynyl)-isonicotinic acid methyl ester as brown oil; HPLC/MS 2.28 min (A), [M+H] 294.