Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C[O-].[Na+].[CH3:17][S-:18].[Na+].O>CO>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[S:18][CH3:17])[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: C[S-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 57.5 °C

Procedure:
0.75 mol of 4-fluoro-3-nitrobenzoic acid was charged in 2 l of methanol, and 0.75 mol of sodium methoxide was added dropwise. 0.83 mol of sodium thiomethoxide was then added and the reaction mixture was heated at from 55 to 60° C. for 5 hours. After cooling, 1 l of water was added, the precipitate was filtered off with suction and washed with 100 ml of methylene chloride. The residue was then taken up in 500 ml of 2 N hydrochloric acid and the precipitate formed was filtered off with suction and washed with water. The residue was then taken up in tetrahydrofuran and dried over sodium sulfate and the solvent was distilled off.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]2)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C>C1COCC1>[CH3:4][S:1]([O:20][CH:17]1[CH2:18][CH2:19][N:15]([C:12]2[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=2)[CH2:16]1)(=[O:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
40 ml (0.516 mol) of mesyl chloride were added dropwise at 5° C. to 83.3 g (0.4 mol) of N-(4-nitrophenyl)-3-hydroxypyrrolidine dissolved in 625 ml of anhydrous THF and 72.7 ml (0.6 mol) of triethylamine. The mixture was allowed to return to room temperature and was then poured into ice to form a precipitate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23](N)([NH2:26])(=[O:25])=[O:24]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH:22][S:23]([NH2:26])(=[O:25])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 95 °C

Procedure:
To a solution of 1,4-dibenzyl-2-aminomethyl-piperazine (2.5 g, 8.46 mmol) in dioxane (50 mL), was added sulfamide (1.63 g, 16.9 mmol) and the resulting mixture was stirred at 95° C. under N2 atmosphere for several hours (monitored by TLC). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel using acetonitrile/water with gradient as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CN=C1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1c2cc(Br)ccc2CC12CCC(O)CC2
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](OC1CCC2(CC1)Cc1ccc(Br)cc1C2=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.4 %

Procedure:
To a 4 mL vial was placed 6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (41 mg, 0.139 mmol) and it was azeotroped with toluene twice (1 mL/each). The solid was dissolved in DMF (1.5 mL). To this solution was added TBDPS-Cl (40 μL, 0.154 mmol) followed by imidazole (24 mg, 0.353 mmol). The reaction was allowed to stir overnight (˜14 hours) at room temperature. The reaction was quenched with H2O (1 mL) and diluted with diethyl ether (1 mL). The phases were separated and the aqueous phase was back extracted twice with diethyl ether (2 mL/each). The combined organic phases were washed with H2O, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 6′-bromo-4-(tert-butyldiphenylsilyloxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (58 mg, 0.109 mmol, 78% yield). M+H=did not ionized. 1H NMR=(CDCl3, 400 MHz) δ 7.83 (d, J=1.6 Hz 1H), 7.69-7.66 (m, 5H), 7.45-7.32 (m, 7H), 3.73 (m, 1H), 2.98 (s, 2H), 1.93-1.89 (m, 2H), 1.62-1.47 (m, 4H), 1.37 (m, 2H), 1.08 (s, 9H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:13]=3[N:12]=2)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][CH:48]([CH:58]1[CH2:60][CH2:59]1)[CH2:49][C:50]([NH:52][C:53]1[NH:54][CH:55]=[CH:56][N:57]=1)=[O:51]>>[CH:58]1([CH:48]([NH:47][C:20]([C:18]2[CH:17]=[CH:16][C:14]3[NH:15][C:11]([C:3]4[N:2]=[CH:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[N:12][C:13]=3[CH:19]=2)=[O:21])[CH2:49][C:50](=[O:51])[NH:52][C:53]2[NH:54][CH:55]=[CH:56][N:57]=2)[CH2:60][CH2:59]1
Reactant: NC(CC(=O)Nc1ncc[nH]1)C1CC1
Reactant: O=C(O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(CC(NC(=O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1)C1CC1)Nc1ncc[nH]1
Yield: 4.3 %

Procedure:
289 mg (1 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid (289 mg, 1 mmol) was reacted with 380 mg (1 mmol) of HBTU and 3-amino-3-cyclopropyl-N-(1H-imidazol-2-yl)-propionamide (230 mg, 1 mmol) as described in general procedure A. A solid precipitated from the solution and was collected by filtration, washed with H2O and Et2O, to give 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1-cyclopropyl-2-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide (20 mg, 4%). LCMS: 466 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 9.20 (s, 1H), 8.56 (s, 1H), 8.09-7.34 (m, 9H), 6.39 (s, 2H), 3.71 (t, 1H), 2.44 (m, 2H), 0.81 (m, 1H), 0.10 (m, 4H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH2:20](O)[CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=1
Reactant: O=C(O)CCCCCOc1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cl
Product: O=C(CCCCCOc1ccc([N+](=O)[O-])cc1)OCCO
Yield: 78.3 %

Procedure:
To a mixture of 6-(4-nitrophenoxy)hexanoic acid 53 (50 g, 197.62 mmol) and ethylene glycol (200 ml) was passed dry HCl gas for one hr. During HCl gas bubbling the temp. rose to 60° C. The crude reaction mass was poured onto ice (1 Kg), extracted into ethyl acetate, washed with water (2×250 ml), dried over sodium sulphate and distilled to get crude 54, which was purified by column chromatography on silica gel using benzene as eluant to get pure 54 (46 g, 78.3%) as a light yellow syrup.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.C(N)C.CN(C(ON1N=[N:32][C:27]2[CH:28]=CC=N[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:32][CH:27]([CH3:28])[CH3:26])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (250 mg, 1.03 mmol), ethanamine (0.2 mL 2.2 mmol) and HATU (456 mg, 1.2 mmol) in 20 mL of dry THF was stirred for 4 hours at room temperature. The reaction mixture was evaporated to dryness, the residue was suspended in 20 mL of 0.5 N HCl, product extracted with ethyl acetate (3×50 mL), organics combined dried with sodium sulfate, filtered and concentrated. Residue purified by column chromatography (silica gel, 200-300 mesh, eluting with ethyl acetate/petroleum ether 2:1) to give 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (180 mg, 43%). LCMS: (M+H)+=269/271; 1H NMR (300 MHz, CD3OD): δ 12.95 (s, 1H), 8.50 (s, 1H), 8.43 (s, 1H), 7.77-7.72 (m, 1H), 3.42-3.36 (m, 2H), 1.25-1.12 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]([C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[OH-].[Na+].C(Cl)Cl>[C:15]([C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[S:30]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:32])=[O:31])(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: NCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
24.16 g (0.12 mole) of 11-aminoundecanoic acid in 250 ml of normal caustic soda are added to 37.9 g (0.12 mole) of 2-benzoyl-4-chlorobenzenesulphonyl chloride in 250 ml of methylene chloride, at 0° C. and with stirring.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26]Cl)[C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[Na]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[C:24]=2[Cl:25])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(Cn2ccnc2)c1Cl

Procedure:
In a manner similar to that described in Paragraph A above, N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.30 g, 0.64 mmol) reacted with sodium imidazole (0.17 g, 1.9 mmol) in DMF (10 mL) to afford N-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide. Purification by HPLC on a C18 Dynamax column with acetonitrile in water gradient with 0.1% trifluoroacetic acid afforded two products: The earlier eluting material afforded N-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, trifluoroacetic acid salt as a cream-colored solid; NMR (DMSO-d6/TFA) 11.1 (s, 1), 10.8 (s, 1), 9.2 (s, 1), 8.3 (d, 1), 8.1 (s, 1), 7.9 (d, 1), 7.7 (m, 5), 7.4 (d, 2), 5.4 (s, 2) ppm. The later eluting material afforded N-(4-chlorophenyl)-2-[((3-chloro-4-(hydroxymethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a white solid; NMR (DMSO-d6/TFA) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 5.4 (br, 1), 4.4 (s, 2) ppm.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]#[N+:9][O-:10])([O-:4])=[O:3].[CH2:14]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)[C:15]#[CH:16].[OH-].[Na+]>C1(C)C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:8]2[CH:16]=[C:15]([CH2:14][N:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[O:10][N:9]=2)[CH:11]=[CH:12][CH:13]=1)([O-:4])=[O:3]
Reactant: C#CCN1CCc2ccccc2C1
Reactant: O=[N+]([O-])c1cccc(C#[N+][O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-c2cc(CN3CCc4ccccc4C3)on2)c1
Yield: 68 %

Procedure:
A solution of 80 (0.2 g, 1.0 mmol) and 81 (0.2 g, 1.17 mmol) in toluene (5 mL) was heated at reflux for 4 hours. The reaction was cooled and mixed with 0.5 N NaOH (5 mL), then extracted with ethyl acetate (2×10 mL). The organic material was combined, dried (K2CO3) then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution, hexane to 3:1 hexane/ethyl acetate) to give 82 (228 mg, 68%) as a yellow oil.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26](O)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CC(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (13.9 mg, 49.6%), MS (ISP) m/z=401.5[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and isobutyric acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH2:22]([O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O)[CH:23]([CH3:25])[CH3:24].[O-]CC.[Na+]>C(O)C>[CH2:22]([O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1/[CH:29]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)c1OCC(C)C
Yield: 44.2 %

Procedure:
The title compound was prepared by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 2-isobutoxy-3-methoxybenzaldehyde (400 mg, 1.922 mmol) in presence of sodium ethoxide (175 mg, 2.578 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to give 285 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=3.6 Hz, 6H), 1.72 (br s, 1H), 3.58 (br s, 2H), 3.77 (s, 3H), 6.91-7.00 (m, 4H), 7.53-7.58 (m, 3H), 7.78-7.84 (m, 2H), 8.00 (br s, 1H), 8.12 (d, J=15.3 Hz, 1H); ESI-MS (m/z) 501.24 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cn2cnnn2)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(Cn2cnnn2)cc1C(=O)O
Reaction time: 4 h

Procedure:
Combine methyl 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoate (0.45 g, 1.73 mmol) and methanol/tetrahydrofuran (1/1, 10 mL). Add a 1 M aqueous solution of lithium hydroxide (5.8 mL, 5.8 mmol). After 4 hours, partition the reaction mixture between water and ethyl acetate. Acidify the aqueous with a 10% aqueous citric acid solution, extract four times with ethyl acetate, combine the ethyl acetate layers, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoic acid: Rf=0.60 (silica gel, 1/1 methanol/dichloromethane).
Reaction SMILES: [NH3:1].N.N.N.N.N.[OH2:7].O.O.O.[OH:11][Mo:12](O)(=O)=O.[OH:16][Mo](O)(=O)=O.[OH:21][Mo](O)(=O)=O.[O:26]=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O>O>[NH3:1].[NH3:1].[NH3:1].[NH3:1].[NH3:1].[NH3:1].[OH2:11].[OH2:16].[OH2:21].[OH2:26].[OH2:7].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12]
Reactant: O=[Mo](=O)(O)O
Reactant: O=[Mo](=O)=O
Agent: N
Solvent: O
Product: [Mo]

Procedure:
A first aqueous solution of ammonium heptamolybdate was prepared by dissolving 83.3 g of (NH4)6Mo7O24.4H2O in 380 ml H2O at ambient temperature; a second aqueous solution of nitrates by mixing at the ambient temperature the following three solutions:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]C(=O)N(C)C)=[CH:4][C:3]=1[CH3:15].C[O-].[Na+].Cl>CO.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([SH:9])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(SC(=O)N(C)C)cc(C)c1Br
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(S)cc(C)c1Br
Temperature: 25 °C

Procedure:
Dimethyl-thiocarbamic acid S-(4-bromo-3,5-dimethyl-phenyl)ester (5.78 g, 20.14 mmol) was diluted with methanol (50 mL) and to this was added sodium methoxide (4.75 mL of 4.25M in methanol, 20.14 mmol). The reaction was heated to reflux under nitrogen and monitored by TLC. After complete conversion, 20 h., the reaction was allowed to cool to room temperature. The reaction was neutralized with 1N HCl (7.5 mL) and diluted with ethyl acetate (150 mL). The two phases were separated and the organic layer was washed with water (75 mL), then brine (75 mL). The organic layer was then dried over anhydrous sodium sulfate, then concentrated and loaded onto silica gel column. The title compound was purified using flash column chromatography, yielding 4.0 g, or 92%.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.[C:17]([NH:24][C@@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(Cl)CCl>C(Cl)Cl>[C:17]([NH:24][C@@H:25]([C:29]([N:1]1[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6]1)=[O:30])[CH:26]([CH3:27])[CH3:28])([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18]
Reactant: C1=CNCCC1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CCC1
Temperature: 25 °C

Procedure:
1.245 g of tetrahydropyridine in 50 ml of CH2Cl2 are treated with 1.5 mmol per mmol of tetrahydropyridine of HOBT, 2.17 g of N-BOC-(R)-valin and 1.5 mmol per mmol of tetrahydropyridine of EDC and the mixture obtained is stirred at RT. From the mixture obtained solvent is evaporated, the evaporation residue obtained is mixed with EE and the mixture obtained is extracted with 0.1N HCl and saturated aqueous NaHCO3 solution. The organic phase obtained is dried and solvent is evaporated. N—(N-BOC-(R)-valyl-1,2,5,6-tetrahydropyridine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:32](=[C:33]([F:35])[CH:34]=1)[CH2:31][C:30](=O)[CH2:29][CH2:28]2>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:30]3[CH2:29][CH2:28][C:27]4[C:32](=[C:33]([F:35])[CH:34]=[C:25]([F:24])[CH:26]=4)[CH2:31]3)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]2)=[CH:8][CH:9]=1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(-c2ccc(C(=O)OC)cc2)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(-c2ccc(C(=O)OC)cc2)cn1

Procedure:
4-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-benzoic acid methyl ester was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: MS m/z 483.2 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1>CN(C=O)C.C1COCC1>[Cl:10][C:11]1[N:16]=[C:15]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: OC1CCOCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Clc1ncc(Cl)c(OC2CCOCC2)n1
Temperature: 25 °C

Procedure:
To a solution of tetrahydro-4-pyranol (0.36 g, 3.54 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion, 0.17 g, 4.25 mmol). The resulting mixture was added to a solution of 2,4,5-trichloropyrimidine (650 mg, 3.5 mmol) in THF at 0° C. The combined mixture was then allowed to warm to room temperature. To the reaction was then added water and the product was extracted with a 1:1 EtOAc-Heptane mixture. The extract was then dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-30% EtOAc in heptane) to give 2,5-dichloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrimidine. 1H-NMR (CDCl3): δ 8.33 (s, 1H), 5.42 (m, 1H), 4.09-3.90 (m, 2H), 3.65 (m, 2H), 2.19-1.99 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>CN(C=O)C>[CH2:18]([NH:22][C:23]([O:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CN(C)C=O
Product: CCCCNC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C

Procedure:
The title compound was prepared in DMF using 3,5-di-tert-butyl-4-hydroxybenzaldehyde and n-butyl isocyanate according to the procedure described in Example H. The title compound was isolated in 87.5% yield as a buff solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example A1) (1.62 g, 5.0 mmol) and morpholine (2.18 mL, 25.0 mmol) in DMSO (10 mL) at 23° C. according to the general procedure B. Obtained as a yellow solid (1.83 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: OB(O)C1=CCCCC1
Product: Nc1ccc(CCO)cc1C1=CCCCC1

Procedure:
The title compound was prepared by Suzuki coupling of 2-(4-amino-phenyl)-ethanol (prepared in the previous step) and 1-cyclohexen-1-yl-boronic acid according to the procedure of Example 44, step (b). Mass spectrum (ESI, m/z): Calcd. for C14H19NO, 218.1 (M+H), found 218.1.
Reaction SMILES: [CH3:1][S:2][C:3](=[C:6]([C:10]#[N:11])[C:7]([NH2:9])=[O:8])SC.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[NH:21][NH2:22].O>CO>[NH2:11][C:10]1[N:21]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([Cl:19])=[CH:16][C:15]=2[Cl:20])[N:22]=[C:3]([S:2][CH3:1])[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: O
Solvent: CO
Product: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Yield: 81.5 %

Procedure:
A mixture of bis(methythio)methylenecyanoacetamide (7.800 g, 50 mmol) and 2,4,6-trichlorophenylhydrazine (10.575 g, 50 mmol) in 250 ml of methanol was heated at reflux for 2.5 hours. The mixture was cooled and water was added. Precipitate formed and filtered to give 14.323 g (81.5% yield) of the title compound as a white solid. 1H NMR(CDCl3): 2.6 (s,3H), 5.5(brs, 2H), 7.5(s,2H) ppm. Recrystallization of a small portion of the solid from chloroform gave white crystals; m. p. 198-199° C. Anal. Calc. for C11H9Cl3N4OS: C, 37.57; H, 2.58; N, 15.93; Found: C, 37.54; H, 2.51; N, 15.73.