Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4](CS([O-])(=O)=O)=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:5][CH:6]=1
Reactant: O=S(=O)([O-])Cc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(=O)c1ccc(Nc2ccc(-c3ccccc3)cc2)cc1
Temperature: 110 °C
Yield: 96.7 %

Procedure:
Following general procedure A, a mixture of 4-biphenylmethanesulfonate (124 mg, 0.5 mmol), 4′-aminoacetophenone (81 mg, 0.6 mmol), K2CO3 (97 mg, 0.7 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and t-BuOH (6 mL) was heated to 110° C. for 16 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 15-50% EtOAc/hexanes) to provide the title compound as a white solid (139 mg, 97%), mp 136-139° C. 1H NMR (300 MHz, CDCl3) δ: 7.90 (d, J=9.0 Hz, 2H), 7.59 (m 4H), 7.45 (t, J=7.0 Hz, 2H), 7.35 (t, J=7.0 Hz, 1H), 7.25 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 6.35 (s 1H), 2.55 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 196.8, 148.4, 140.7, 140.2, 136.2, 130.9, 129.3, 129.1, 128.4, 127.3, 127.0, 120.9, 114.9, 26.5 ppm. IR (neat, cm−1): 3324, 1656, 1586, 1524, 1487, 1339, 1278, 1178, 827, 763.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29]C)=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:26][O:25][C:24]1[C:3](=[O:2])[C:4]([CH3:31])=[C:5]([CH2:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:8]=2)[C:22](=[O:29])[C:23]=1[O:27][CH3:28]
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.7 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-phenylbenzoic acid (76 mg, 1.1800 mmol) was dissolved in a mixed solvent of acetonitrile (3 ml) and water (1 ml), then CAN (247 mg, 0.4507 mmol) was added thereto at room temperature and the mixture was stirred for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (54 mg, 0.1377 mmol, 77%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C(OCC)(=O)C>CC1C=CC=CC=1C>[CH3:1][C:2]1([CH3:21])[O:7][C:6](=[S:31])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC1(C)OC(=S)Nc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 25 °C
Yield: 19.8 %

Procedure:
A mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile (1 g, 3.6 mmol) and Lawesson's reagent (1.8 g, 4.3 mmol) in o-xylene (30 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, poured into ethyl acetate (50 mL) and washed with 1 N HCl (2×20 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified via flash chromatography (silica gel, 20% ethyl acetate/hexane) to give 3-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile (0.21 g, 20%) as a white solid: mp 236-237° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 8.24 (s, 1H), 8.05 (d, 1H, J=8.07 Hz), 7.82 (d, 1H, J=7.68 Hz), 7.74-7.64 (m, 3H), 7.14 (d, 1H, J=8.78 Hz), 1.71 (s, 6H); MS (APCI) m/z 295 ([M+H]+, 100%); Anal. Calcd. For C17H14N2OS: C, 69.36; H, 4.79; N, 9.52. Found: C, 68.35; H, 4.91; N, 9.07
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=2)[C:6](=[S:25])[NH:5][C:4](=[O:26])[CH:3]=1.P(=O)(O)(O)O.[N:32]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CS(C)=O.C1COCC1.O.CO>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH2:8][N:7]1[C:2]([NH2:1])=[C:3]([NH2:32])[C:4](=[O:26])[NH:5][C:6]1=[S:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(Cn2c(N)cc(=O)[nH]c2=S)cc1OCc1ccccc1
Reactant: O=N[O-]
Agent: O=P(O)(O)O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1OCc1ccccc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 105.6 %

Procedure:
6-amino-1-(3-benzyloxy-4-methoxy-benzyl)-2-thiouracil (36.94 g, 100 mmole) was dissolved in DMSO (74 ml), diluted with THF (185 ml) and treated with 85% phosphoric acid (7.46 ml). At 55-60° C., 4M sodium nitrite (30 ml, 120 mmole) was added slowly. After 30 minutes, methanol (10 ml) was added, the reaction was cooled to 30° C., and a suspension of 85% sodium dithionite (40.96 g, 200 mmole) in water (80 ml) was added slowly. After the addition of water (200 ml) the solvent was removed in vacuo and the suspension diluted with water to 1 l. The solid was collected at 0-5° C. to give crude 1-(3-benzyloxy-4-methoxy-benzyl)-5,6-diamino-2-thiouracil (40.58 g).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:24])[C:10](S(O)(=O)=O)=[CH:11][C:12]=3[N+]([O-])=O)[C:7](=[O:25])[C:6]=2[C:5]([N+]([O-])=O)=[CH:4][C:3]=1S(O)(=O)=O.S(=O)(=O)(O)O.S(=O)(=O)(O)[O-].[Na+]>>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:24])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c([N+](=O)[O-])cc(S(=O)(=O)O)c(O)c2C(=O)c2c([N+](=O)[O-])cc(S(=O)(=O)O)c(O)c21
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: O=C1c2cccc(O)c2C(=O)c2cccc(O)c21

Procedure:
140 Parts of 1,5-dihydroxy-4,8-dinitro-anthraquinone-2,6-disulphonic acid in the form of 270 parts of an aqueous paste, containing sulphuric acid and sodium bisulphate and obtained by sulphonation and nitration of 81 parts of 1,5-dihydroxy-anthraquinone, are entered with stirring at 40° into 700 parts of water. 60 Parts of hydrazine hydrate are then added dropwise over the course of 90 minutes. The pH of the reaction mass immediately rises from 1,7 to 4 and then to 6.5. This value is kept by the dropwise addition of 45 parts of 30% aqueous hydrochloric acid. The temperature of the reaction mass is then raised to 80°. 10 Parts of hydrazine hydrate are then added dropwise over the course of 10 minutes. The pH is kept at 5.8 to 6 by the addition of 20 parts of 30% aqueous hydrochloric acid. The mass is stirred at 80° for 10 minutes. 58 Parts of 30% aqueous sodium hydroxide solution are subsequently added dropwise over the course of 5 minutes, whereby the pH is adjusted to 8. The precipitate is suction filtered, washed with 2000 parts of aqueous 10% sodium sulphate solution and 5000 parts of aqueous 5% sodium sulphate solution, and dried at 120°. 129 Parts of 1,5-dihydroxy-4,8-diamino-anthraquinone-2,6-disulphonic acid, containing 80% of free disulphonic acid, are obtained.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH:19]1([C:25](OC)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.C(O)(=O)C.O>[CH:19]1([C:25](=[O:26])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)C1CCCCC1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a stirred solution of dimethyl methylphosphonate (11.73 g, 0.095 mol) in 150 ml of anhydrous THF at -78° C. was added dropwise a solution of n-butyl lithium in hexane (1.67N, 56.7 ml, 0.095 mol) under argon atmosphere, and the mixture was stirred for 30 minutes. To this reaction mixture was added dropwise a solution of methyl cyclohexanecarboxylate (5.6 g, 0.0394 mol) in 10 ml of anhydrous THF. After being stirred for 30 minutes, the reaction mixture was allowed to warm to 0° C., diluted with 5.5 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue, and the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 2-cyclohexyl-2-oxo-ethylphosphonate (8.62 g, 0.037 mol, yield 93.4%, b.p. 114°-115° C./0.25 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [CH3:1][C:2]1([CH3:53])[CH2:11][CH:10]([O:12][Si](C(C)C)(C(C)C)C(C)C)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:47][C:46](=[O:48])[O:45][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:49][CH2:50][CH3:51])[N:25]=[C:24]3[CH3:52])[CH:8]=2)[O:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:12][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:47][C:46](=[O:48])[O:45][N:44]=5)=[CH:35][CH:36]=4)=[C:26]([CH2:49][CH2:50][CH3:51])[N:25]=[C:24]3[CH3:52])[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:53])[CH2:11]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 3-{2,2-dimethyl-4-[(triisopropylsilyl)oxy]-3,4-dihydro-2H-chromen-6-yl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (4.0 g) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 8.2 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with 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 to give the title compound (3.0 g, 95%) as a solid.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[Cl:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:28]=[CH:27][CH:26]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)NCCCCc1cccnc1
Yield: 77.7 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3- chlorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (6.4 g) and 3-pyridinebutanamine (2.7 g) in tetrahydrofuran (75 mL) was stirred for 40 minutes at 40° C. and was worked up in the usual manner. The crude amide was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to yield 5.1 g of (E)-5,5-bis(3-chlorophenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 100°-102° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:15]O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:5]=[C:4]([CH2:15][Br:37])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(Br)cc(-c2ccccc2Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1-c1cc(Br)cc(CBr)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
177 mg (0.60 mmol) of the compound from Example 115A and 187 mg (0.71 mmol) of triphenyl-phosphine were dissolved in 4 ml of THF, and 237 mg (0.71 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically [Method 19]. This gave, in a purity of 79%, 129 mg (60% of theory) of the target compound, which were immediately reacted further.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: Cc1nc(-c2ccccc2)cc2cc[nH]c(=O)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)cc2c1C(=O)NCC2
Yield: 91.6 %

Procedure:
8-methyl-6-phenyl-2H-[2,7]naphtyridine-1-on (500 mg, 2.116 mmol) was suspended in anhydrou ethanol, added with 5% Pd/C (400 mg) and then stirred at room temperature under the hydrogen atmosphere for about 72 hours. The mixture was filtered and then concentrated under reduced pressure. A silica gel column chromatography (2% MeOH/MC) was performed on the resulting residue and obtained 462 mg (92%) of 8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]naphtyridine-1-on in white solid.
Reaction SMILES: [CH:1]1[N:2]=[C:3]([NH2:44])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][CH2:25][C@H:26]4[O:30][C@@H:29]([N:31]5[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H:28]([OH:40])[C@@H:27]4[OH:41])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:42])[C@H:11]3[OH:43])[C:5]=2[N:6]=1.[C:45]([O-:50])(=[O:49])[CH:46]([CH3:48])[OH:47]>>[C:45]([O-:50])(=[O:49])[CH:46]([CH3:48])[OH:47].[CH:33]1[CH:32]=[N+:31]([C@@H:29]2[O:30][C@H:26]([CH2:25][O:24][P:21]([O:20][P:17]([O:16][CH2:15][C@H:13]3[O:14][C@@H:10]([N:7]4[C:5]5[N:6]=[CH:1][N:2]=[C:3]([NH2:44])[C:4]=5[N:9]=[CH:8]4)[C@H:11]([OH:43])[C@@H:12]3[OH:42])([OH:19])=[O:18])([OH:23])=[O:22])[C@@H:27]([OH:41])[C@H:28]2[OH:40])[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH:34]=1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: CC(O)C(=O)[O-]
Product: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1

Procedure:
In the case of this determination, ADP is reacted with phosphoenol pyruvate (PEP) in the presence of pyruvate kinase (PK) to give pyruvate which, in turn, is reacted with NADH in the presence of lactate dehydrogenase (LDH) to give lactate and NAD+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]Cl.[Na].[OH:10][CH2:11][C:12]1([CH3:20])[O:16][C:15]([CH3:19])([C:17]#[N:18])[CH2:14][CH2:13]1>CN(C)C=O>[CH3:19][C:15]1([C:17]#[N:18])[CH2:14][CH2:13][C:12]([CH3:20])([CH2:11][O:10][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:16]1
Reactant: ClCc1ccccn1
Reactant: CC1(C#N)CCC(C)(CO)O1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC1(C#N)CCC(C)(COCc2ccccn2)O1

Procedure:
Freshly liberated 2-picolinyl chloride was secured by extracting a mixture of 1.48 g potassium carbonate and 1.64 g 2-picolinyl chloride in 10 ml water with methylene chloride. The extract was dried (MgSO4) and concentrated (rotary evaporator). To the residue was added 10 ml dry dimethylformamide and the remaining methylene chloride was removed by further evaporation. The resulting solution was then added to a mixture of 10 mmol of the sodium salt of tetrahydro-5-(hydroxymethyl)-2,5-dimethyl-2-furancarbonitrile as a mixture of cis-trans isomers in 10 ml dry dimethylformamide prepared as described in Embodiment 10 above. The reaction progress and workup also followed the procedure for Embodiment 10 with the exception that crude product was secured from both pentane and ether extraction of the ice-quenched mixture. The crude product, which consisted of both cis- and trans-isomers, was purified and isomerically separated by preparative hplc using a silica gel column and ethyl acetate:pentane (60:40) as eluent. The cis (Z)-isomer amounted to 0.69 g, bp not determined.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:9]1(=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)CCCCC=C1CCCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCCCCCC=C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
To a stired solution of 6-cyclohexylidene-hexanoic acid methyl ester (1.28 g, 6.10 mmol) in toluene (60 mL) was added DIBAL-H (15.3 mL, 1 M solution in hexane, 15.3 mmol) dropwise at 0° C. under N2. After stirring at 0° C. for 30 min, the reaction was quenched by MeOH (5 mL). Saturated aqueous sodium potassium tartrate (40 mL) was added to the reaction mixture. After string for 1 h, the organic layer was separated and the aqueous phase was extracted with ether. The combined organic layers were washed with water and brine and dried. Evaporation of the solvent gave 6-cyclohexylidene-hexan-1-ol (1.12 g, 100%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.05 (1H, m), 3.62 (2H, t, J=6.6 Hz), 2.05 (6H, m), 1.42–1.64 (8H, m), 1.34 (2H, m); 13C NMR (75 MHz, CDCl3) δ 139.78, 121.25, 63.22, 37.43, 32.96, 30.22, 28.96, 28.11, 27.23, 25.58.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:20](=O)[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13]2)=[C:4]([F:22])[CH:3]=1.P(Cl)(Cl)([Cl:25])=O>C(Cl)(Cl)Cl>[Cl:25][C:20]1[N:12]([C:5]2[CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=2[F:22])[N:13]=[C:14]2[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Oc1cc(-n2[nH]c3c(c2=O)CCCC3)c(F)cc1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Yield: 28.4 %

Procedure:
A mixture of 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one (1 g) and phosphorus oxychloride (0.7 g) was heated under reflux heating for 6 hours. After cooling, the reaction mixture was dissolved in chloroform, washed with a 5% sodium hydroxide solution and water, dried and concentrated. The residue was purified by silica gel column chromatography to give 0.3 g of 3-chloro-2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (Compound No. 2). nD26 1.5530.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>>[C:15]([CH2:14][CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[N:7]=2)[CH:9]=[N:10]1)[CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)#[N:16]
Reactant: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Cl)n2)cn1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Temperature: 25 °C

Procedure:
A mixture of 3-[4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (from example 308 step 3, 140 mg, 0.00044 mol), p-aminobenzoic acid (90.6 mg, 0.000661 mol), and p-toluenesulfonic acid (64 mg, 0.00037 mol) in dry 1,4-dioxane (3 mL, 0.04 mol) was refluxed overnight, cooled to room temperature. The desired product crashed out and was collected by filtration (180 mg, 97.64%). LCMS (M+H) 419.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:5][C:4]=1[CH3:14].CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:17])=[O:13])=[CH:5][C:4]=1[CH3:14]
Reactant: COc1ccc(CCCCO)cc1C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COc1ccc(CCCC(=O)O)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1.7 grams (0.009 mole) of 4-(4-methoxy-3-methylphenyl)butan-1-ol in 50 mL of acetone was cooled to 0° C.-4° C., and about 15 to 20 mL (excess) of Jones Reagent was added dropwise. Upon completion of addition, the reaction mixture was stirred at 0° C. for two hours, then it was allowed to warm to ambient temperature, where it stirred for an additional three hours. After this time, the reaction mixture was diluted with isopropanol and filtered. The filter cake was washed with acetone, and the combined filtrate and wash were concentrated under reduced pressure to a residue. The residue was partitioned with methylene chloride and water and the separated organic layer was washed with water. The organic layer was then dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dried under vacuum, yielding 1.1 grams of subject compound. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain an additional amount of subject compound.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([OH:20])=O)=[CH:7]1)=[O:2].[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1>CN(C)C=O>[CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([NH:21][C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[O:20])=[CH:7]1)=[O:2]
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(CCOC=O)c2n1
Reaction time: 1 h

Procedure:
1(2-formyloxyethyl)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.3 g) and N,N'-carbonyldiimidazole (0.8 g) in dimethylformamide (25 ml) were heated at 80° for 5 hours. 5-Amino-1H-tetrazole (0.45 g) was added and the mixture was stirred at 80° for 1 hour. The solid was collected and dried, m.p. 268.5°-269° (d), (40%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-])=O.[H][H]>[Pd].CCO>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14]
Reactant: CC1CCCCN1c1ccncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CCCCN1c1ccncc1N
Yield: 35.6 %

Procedure:
2-Methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl (650 mg, 2.94 mmol) and 10% palladium on carbon (156 mg, 0.15 mmol) in EtOH were stirred under 1 atmosphere of hydrogen gas for 16 hours. Filtration followed by removal of volatiles under reduced pressure gave the title compound (200 mg, 36%) which was used in the next step without further purification.