Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:35](=[O:36])[N:4]2[C:5]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:6]([C:9]3[C:12](=[O:13])[C:11](=[O:14])[C:10]=3[O:15][CH:16]([CH3:18])[CH3:17])[CH2:7][S:8][C@H:3]12.[NH2:37][C:38]1[S:39][CH:40]=[C:41](/[C:43](=[N:53]/[O:54][CH3:55])/[C:44](N2C(=S)N(C)N=N2)=[O:45])[N:42]=1>>[NH2:37][C:38]1[S:39][CH:40]=[C:41](/[C:43](=[N:53]/[O:54][CH3:55])/[C:44]([NH:1][CH:2]2[C:35](=[O:36])[N:4]3[C:5]([C:19]([O:21][CH:22]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:6]([C:9]4[C:12](=[O:13])[C:11](=[O:14])[C:10]=4[O:15][CH:16]([CH3:17])[CH3:18])[CH2:7][S:8][C@H:3]23)=[O:45])[N:42]=1
Reactant: CC(C)Oc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Reactant: CO/N=C(\C(=O)n1nnn(C)c1=S)c1csc(N)n1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OC(C)C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Yield: 95.3 %

Procedure:
Acylation of diphenylmethyl 7-amino-3-[3,4-dioxo-2-(2-propoxy)-1-cyclobutenyl]-3-cephem-4-carboxylate (287 mg, 0.569 mmol) with 1-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl]-4-methyltetrazole-5-thione (204 mg, 0.683 mmol), according to Example 13, afforded the title compound (373 mg, 93% yield) as a bright yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[CH3:2][CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[CH:9][CH:10]=1)[CH3:3]
Reactant: CC(C)Oc1ccc(CN)cc1
Reactant: O=C(O)c1ccncc1F
Product: CC(C)Oc1ccc(CNc2cnccc2C(=O)O)cc1
Yield: 28 %

Procedure:
The title compound was prepared in 28% yield from 1-(4-isopropoxyphenyl)-methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.80 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 7.21 (d, 2H, J=8.0 Hz), 4.49 (s, 2H), 2.82-2.89 (m, 1H), 1.19 (d, 6H, J=4.5 Hz). [M+H] calc'd for C16H18N2O3, 287; found 287.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.B(Br)(Br)Br.ClCCl.CO.C([O-])(O)=O.[Na+]>ClCCl>[CH2:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc2c(ccn2CCc2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCN2CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
To a solution of 5-methoxy-1-phenethylindole (95 mg, 0.38 mmol) in 1.9 mL of dry dichloromethane was added boron tribromide-dichloromethane solution (4 M, 0.47 mL, 1.9 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at room temperature for 30 min, methanol (1 mL) was added with additional stirring at room temperature for 5 min. After the reaction mixture was neutralized by saturated NaHCO3 aqueous solution, the solution was extracted with ethyl acetate. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to obtain the title compound (25.3 mg, 28%).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.I.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](SC)=[NH:20].O>CN(C=O)C>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:19]([C:15]3[S:14][CH:18]=[CH:17][CH:16]=3)=[NH:20])=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)CNCCO2
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CN(C)C=O
Solvent: O
Product: N=C(Nc1ccc2c(c1)CNCCO2)c1cccs1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylamine (3.67 g, 18 mmol) in DMF (60 ml) was added 2-thiophenecarboximidothioic acid, methyl ester, hydroiodide (5.52 g, 19 mmol). The mixture was heated to 50° C. for 24 h. The mixture was poured into water (50 ml), then basic water (150 ml) and was allowed to stir for 1 h. The solids were collected by filtration. The solid was dissolved in hot ethyl acetate, filtered, and diluted with hexane. The solids were collected by filtration (3.13 g, 64%), MS m/Z 274 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([Br:12])[C:3]=1C=O.[OH:13]O>[OH-].[Na+]>[Br:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([OH:1])[C:3]=1[OH:13]
Reactant: COc1ccc(Br)c(C=O)c1O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Br)c(O)c1O
Reaction time: 2 h
Yield: 64.2 %

Procedure:
Aldehyde 12 (23 g) was suspended in 2% sodium hydroxide (300 mL) and a solution of 30% hydrogen peroxide (15.8 g, 1.4 eq.) was added. After 2 hours, another portion of 30% hydrogen peroxide (1.4 eq.) was added and the solution stirred overnight. The reaction mixture was acidified, extracted with dichloromethane, washed with sodium thiosulfate and the solvent removed in vacuo to afford a tan solid. The solid was recrystallized from methanol to afford colorless crystals (14 g, 64%): m.p. 122.3-124.3° C., lit20 m.p. 124-126° C.; EIMS m/z 220 (M+, 81Br), 218 (M+, 79Br), 205, 203, 177, 175, 95; 1HNMR δ 6.99 (1H, d, J=9.0 Hz, H5), 6.42 (1H, d, J=9.0 Hz, H4), 5.56 (1H, s, OH), 5.51 (1H, s, OH), 3.88 (3H, s, OCH3); 13C—NMR (75.5 MHZ) δ 146.59, 140.95, 133.47, 122.21, 104.35, 101.55, 56.31; Anal. Calcd. For C7H7O3Br: C, 38.39; H, 3.22. Found: C, 38.47; H, 3.36.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=2)[CH:20]=1)[CH2:16][CH3:17])=O)(C)(C)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[CH2:16]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[N:26]=2)[CH:22]=[CH:23][CH:24]=1)[CH2:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH3:17]
Reactant: CCN(CCC1CCCN1C(=O)OC(C)(C)C)Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CCN(CC[C@@H]1CCCN1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 107 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 447. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.62 (s, 1H), 8.37 (d, 1H), 8.34 (m, 1H), 7.93 (d, 1H), 7.72 (t, 1H), 7.66 (d, 1H), 7.11 (d, 2H), 6.67 (d, 2H), 4.52 (m, 2H), 3.95 (m, 2H), 3.58 (m, 2H), 3.27 (m, 4H), 2.93 (t, 2H), 2.24 (m, 4H), 1.99 (m, 2H), 1.70 (m, 1H), 1.40 (t, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6](=[O:13])[C@@H:5]([NH:14]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]>C(OCC)(=O)C>[NH2:14][C@H:5]1[CH2:4][C@@H:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[C@@H:2]([CH3:1])[N:7]([CH2:8][C:9]([F:10])([F:11])[F:12])[C:6]1=[O:13]
Reactant: Cc1ccccc1[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(F)(F)F)[C@@H]1C
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@@H]1C[C@H](N)C(=O)N(CC(F)(F)F)[C@@H]1C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [(3S,5S,6R)-6-methyl-5-(2-methylphenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate (152 mg, 0.37 mmol) in ethyl acetate (10 mL), pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The reaction mixture was allowed to sit for 30 min at 0° C. The mixture was then concentrated to dryness to afford the title compound as a hydrochloride salt. MS: m/z=301.3 (M+1).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:26]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: N#Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(C#N)c(F)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 56 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.20 g, Example 33), 4-bromo-2-fluorobenzonitrile (0.16 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) in ethanol (3 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a gum (0.14 g)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[C:4]([CH3:10])[N:3]=1.[Br:11]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([Br:11])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cnc(C#N)c(N)n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)c(C#N)nc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred solution of 8.5 grams (0.063 mole) of 2-amino-3-cyano-6-methylpyrazine [prepared by the method of Taylor and Kobayashi; JOC, 41, 1299 (1976)]in 125 mL of N,N-dimethylformamide is cooled in an ice bath, and a solution of 11.2 grams (0.063 mole) of N-bromosuccinimide in 125 mL of N,N-dimethylformamide is added dropwise during a 30 minute period, while maintaining the reaction mixture temperature at about 15°-25° C. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours. After this time, the reaction mixture is poured into 1 liter of aqueous 3N sodium hydroxide. The mixture is then diluted to a volume of about 1700 mL with distilled water. A solid precipitate is collected by filtration and dried under reduced pressure, yielding 2-amino-3-cyano-5-bromo-6-methylpyrazine.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]([C@@H:16]1[CH2:20][C@@H:19]([OH:21])[CH2:18][N:17]1[S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)(=[O:24])=[O:23])=[O:15].[CH3:35][C:36]([Si:39](Cl)([CH3:41])[CH3:40])([CH3:38])[CH3:37]>C(#N)C>[CH3:12][O:13][C:14]([C@@H:16]1[CH2:20][C@@H:19]([O:21][Si:39]([C:36]([CH3:38])([CH3:37])[CH3:35])([CH3:41])[CH3:40])[CH2:18][N:17]1[S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)(=[O:24])=[O:23])=[O:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
29 ml (194 mmol, 1.6 eq) DBU were added to a suspension of 41.4 g (121.4 mmol) (2S,4R)-4-Hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester in 150 ml acetonitrile at 0° C. To the resulting solution 29.25 g (194 mmol, 1.6 eq) TBDMSCl were added in portions and the reaction was stirred at RT overnight. After concentrating the crude oil was purified by column chromatography with EtOAc/hexane 1:2 on silica gel to give 49.2 g (90%) (2S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.O>O1CCCC1>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])[CH2:8][CH2:9]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: COC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc([C@H]2CC[C@H](CCCC=O)CC2)cc1

Procedure:
A solution of 2.95 g of p-[trans-4-(4-methoxy-3-butenyl)cyclohexyl]benzonitrile in 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1 ) was heated to reflux for 15 minutes. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated, whereby 2.6 g (93%) of 4-[trans-4-(p-cyanophenyl)cyclohexyl]butyraldehyde were obtained as a slightly yellowish oil; Rf-value (toluene/ethyl acetate vol. 95:5) 0.23.
Reaction SMILES: [ClH:1].[C:2]1([O:12][CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[C:11]2[CH2:10][CH2:9][CH2:8]C[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18]1([O:28]C2CCN(CC3C=CC=CC=3)C2)C2CCCCC=2C=CC=1>>[ClH:1].[CH3:18][O:28][C:3]1[C:2]([O:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:8][CH2:9][CH2:10]2
Reactant: c1ccc(CN2CCC(Oc3cccc4c3CCCC4)C2)cc1
Reactant: c1cc2c(c(OC3CCNC3)c1)CCCC2
Agent: Cl
Product: COc1ccc2c(c1O[C@H]1CCNC1)CCC2

Procedure:
3-[(5,6,7,8-Tetrahydro-1-naphthalenyl)oxy]-pyrrolidine hydrochloride m.p. 207° C., starting from 3-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]-1-(phenylmethyl)-pyrrolidine
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.[NH4+].[Cl-]>C(Cl)Cl>[CH2:5]([C@@H:2]1[CH2:3][O:4][C:17](=[O:19])[NH:1]1)[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)C[C@@H](N)CO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H]1COC(=O)N1
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 264.9 %

Procedure:
To a cooled (4° C.) solution of (R)-2-amino-4-methylpentan-1-ol (2.98 g, 25.4 mmol) and triethylamine (7.6 mL, 54 mmol, 2.1 equiv) in CH2Cl2 (80 mL) was added dropwise a solution of triphosgene (2.52 g, 8.49 mmol, 0.334 equiv) in 10 ml of CH2Cl2 over 30 min. The reaction mixture was stirred at 4° C. for 15 min, warmed up to room temperature and stirred for an additional 1 h. The mixture was treated with saturated NH4Cl (25 mL), followed by CH2Cl2 (50 mL) and the resulting mixture was stirred for 20 min. The layers were separated and the organic layer was washed with water. The combined aqueous layers were extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give (R)-4-isobutyloxazolidin-2-one (3.22 g) in 88% yield. The crude product was used for the next reaction without purification. 1H NMR (400 MHz, CD3OD) δ 4.53-4.47 (m, 1H), 4.00-3.92 (m, 2H), 1.67 (ddq, J=13, 8.0, 6.5 Hz, 1H), 1.56-1.48 (m, 1H), 1.40-1.32 (m, 1H), 0.95 (d, J=6.1 Hz, 3H), 0.93 (d, J=6.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:20][CH2:21][N:22]([CH2:33][CH2:34]Cl)[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>O>[CH3:9][C:3]1[CH:4]=[C:5]([CH3:8])[N:6]=[CH:7][C:2]=1[N:1]1[CH2:34][CH2:33][N:22]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:21][CH2:20]1
Reactant: Cc1cc(C)c(N)cn1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCN(c3cnc(C)cc3C)CC2)cc1
Yield: 15.7 %

Procedure:
To 5-amino-2,4-dimethylpyridine (883 mg) were added N,N-diisopropylethylamine (2.1 mL) and N,N-bis(2-chloroethyl)-p-toluenesulfonamide (2.08 g), and the mixture was stirred with heating under reflux. After completion of the reaction, water was added to the reaction mixture, the mixture was extracted with chloroform, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 1-(4,6-dimethylpyridin-3-yl)-4-(toluene-4-sulfonyl)piperazine (380 mg). The obtained 1-(4,6-dimethylpyridin-3-yl)-4-(toluene-4-sulfonyl)piperazine (380 mg) was dissolved in acetic acid (2 mL), 40% hydrobromic acid (2 mL) was added, and the mixture was stirred at 100° C. After completion of the reaction, the reaction mixture was neutralized with aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (131 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[S:10][C:3]=12
Reactant: Brc1ncccn1
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Product: Clc1ccnc2cc(-c3ncccn3)sc12
Yield: 40.4 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.218 g, 0.66 mmole) with 2-bromopyrimidine (0.104 g, 0.66 mmole) using tereakis(triphenylphosphine) palladium(0) (31 mg) as catalyst in a manner as previously described for example 39b to give a white solid (0.066 g, 40%). 1H NMR (300 MHz, CDCl3) δ8.76 (2H, d, J=4.90 Hz), 8.57 (1H, d, J=5.1 Hz), 8.41 (1H, s), 7.26 (1H, d, J=5.1 Hz), 7.20 (1H, m); ESIMS (MH+): 248.00.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC(c1cccnc1)c1c[nH]c2ccc(F)cc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2[nH]cc(Cc3cccnc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A suspension of (5-fluoro-1H-indole-3-yl)-pyridin-3-yl-methanol (5.00 g, 21 mmol) in methylene chloride is treated with triethylsilane (3.70 ml, 23 mmol) and trifluoroacetic acid (TFA), stirred at room temperature overnight, and concentrated in vacuo. The resultant residue is basified with 2.5 N NaOH and saturated NaHCO3, and extracted with methylene chloride. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. This residue is purified by column chromatography (50%EtOAc/CH2Cl2) to give the title compound as a pale orange solid 3.24 g (68%) mp 109-112° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[C:12](=[O:32])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:14]3[C:19]([C:20]=2O)=[CH:18][CH:17]=[CH:16][N:15]=3)=O)=[CH:4][CH:3]=1.O.[NH2:34][NH2:35].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:11]3[C:12](=[O:32])[N:13]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:20]=3[NH:35][N:34]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C(Cc1ccc(F)cc1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc(F)cc3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(4-fluorophenylacetyl)-4-hydroxy-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (604 mg, 1.4 mmol) produced in Synthesis Example 34 in DMF (5.5 mL) was added hydrazine monohydrate (purity of 80%, 220 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-(4-fluorobenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (536 mg, yield 90%).
Reaction SMILES: CO.[C:3]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([O:26][C:27]([NH:29][S:30]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])=[O:31])=[O:28])[CH2:23][CH2:24][CH3:25].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:22]([O:26][C:27]([N:29]([CH3:3])[S:30]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:31])=[O:32])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCOC(=O)NS(=O)(=O)NCC(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOC(=O)N(C)S(=O)(=O)NCC(=O)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methanol (8.5 mmol) and triphenylphosphine (2.6 g, 8.5 mol) in dry THF is added a solution of ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate from the previous step (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF dropwise at 0° C. under N2 atmosphere. The mixture is stirred at 0° C. for 2 h, warmed to RT and is stirred overnight. After the solvent is removed in vacuo, the residue is purified by column chromatography to afford ethyl 2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]2.[H-].[Na+].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>O1CCCC1>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:29])=[CH:26][CH:25]=1
Reactant: CCOC(=O)C=CC=Cc1cc2cc(OC)ccc2[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1cc2cc(OC)ccc2n1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 63.1 %

Procedure:
A solution of ethyl 5-(5-methoxyindol-2-yl)-2,4-pentadienoate (0.8 g, 2.9 mmol) in 20 ml of tetrahydrofuran (THF) was added dropwise to a suspension of sodium hydride (0.024 g of a 60% reagent) at 0° C. (ice bath). After addition, the mixture was stirred in the ice bath for 1 hour and a solution of p-chlorobenzoyl chloride (0.54 g) in 10 ml of THF was added; the resulting mixture was filtered to remove the precipitate and the filtrate was washed with brine, dried (magnesium sulfate) and concentrated on rotary evaporator to give a yellow oil. Crystallization of this oily substance from acetone-ether afforded 0.75 g of ethyl 5-(1-p-chlorobenzoyl-5-methoxyindol-2-yl)-2,4-pentadienoate as yellow powders, m.p., 121°-125° C. MS(EI): 40 g(M+), 336 (M+ --CO2Et).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[O:15])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH3:2].[F:17][C:18]([Si](C)(C)C)([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([OH:15])([C:18]([F:20])([F:19])[F:17])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)(CC(C)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h

Procedure:
4.4 g of 2-oxo-4-phenylvaleric acid ethyl ester is dissolved in 40 ml of tetrahydrofuran and mixed at −78° C. with 3.6 ml of trifluoromethyl-trimethylsilane and 2 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran. After 24 hours at −78° C., another 20 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran is added. It is stirred for 1.5 hours at 0° C., ethyl acetate and saturated common salt solution are added, the organic phase is separated, and it is washed with saturated common salt solution and water. Then, it is dried (Na2SO4) and concentrated by evaporation and distilled on a bulb tube. 4.4 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester, boiling point 95-100° C./0.04 hPa, is obtained.