Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl.O.[CH3:16]O>>[F:1][C:2]([F:12])([F:13])[CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:16])=[O:10])[CH2:7][CH2:8]1
Reactant: O=C(O)C1CCC(C(F)(F)F)CC1
Reactant: CO
Agent: Cl
Solvent: O
Product: COC(=O)C1CCC(C(F)(F)F)CC1
Temperature: 25 °C

Procedure:
In 25 ml of methanol, 1.0 g of 4-trifluoromethylcyclohexanecarboxylic acid was dissolved. Thereto 50 mg of concentrated hydrochloric acid was added and the mixture was heated under reflux for 10 hours. After the reaction mixture was cooled to room temperature, water was added thereto and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.83 g of methyl 4-trifluoromethylcyclohexanecarboxylate (cis/trans ratio 7/1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][CH:12]([CH:14]=[N:15]O)[CH2:11]3)[N:7]([CH3:17])[C:6]=2[CH:18]=1.P(Cl)(Cl)(Cl)=O>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][CH:12]([C:14]#[N:15])[CH2:11]3)[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cn1c(C2CC(C=NO)C2)nc2ccc(Br)cc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cn1c(C2CC(C#N)C2)nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
To a stirred solution of 1-(3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutyl)-N-hydroxymethanimine (100 mg) in CH3CN (10 ml) was added phosphorous oxychloride (1 ml), and the mixture was stirred at room temperature for 16 h. The mixture was then concentrated in vacuo and poured into saturated NaHCO3 solution. The mixture was extracted with DCM, and the organic layer was washed with brine, dried over Na2SO4 and purified by column chromatography (MeOH/DCM) to afford the title compound (50 mg) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]#[N:12])[C:5]=1[Cl:13])#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[SH:24]>>[F:22][C:21]1[C:16]2[N:2]=[C:1]([CH2:3][C:4]3[C:5]([Cl:13])=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=3)[S:24][C:17]=2[CH:18]=[CH:19][C:20]=1[F:23]
Reactant: N#CCc1cccc(CC#N)c1Cl
Reactant: Nc1c(S)ccc(F)c1F
Agent: Cl
Product: N#CCc1cccc(Cc2nc3c(F)c(F)ccc3s2)c1Cl
Yield: 20 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-2-chlorobenzene (870 mg, 4.4 mmol) and 2-amino-3,4-difluorothiophenol hydrochloride (956 mg, 4.8 mmol) and the resultant product was recrystallized from ethyl acetate-hexane to give 3-[(4,5-difluorobenzothiazol-2-yl)methyl]-2-chlorophenylacetonitrile (295 mg, 20%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@@H:10]1[C@H:17]2[C@@H:13]([O:14]C(C)(C)[O:16]2)[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[NH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:11]1>C(O)(=O)C.O>[CH:30]1([NH:29][C:25]2[N:24]=[CH:23][N:22]=[C:21]3[C:26]=2[N:27]=[CH:28][N:20]3[CH:12]2[C@H:13]([OH:14])[C@H:17]([OH:16])[C@@H:10]([CH2:9][S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[O:11]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@@H](CSc1ccccc1F)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Solvent: O
Solvent: CC(=O)O
Product: O[C@@H]1[C@@H](CSc2ccccc2F)OC(n2cnc3c(NC4CCCC4)ncnc32)[C@@H]1O

Procedure:
(9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylamine, a compound of formula (4) (50 mg) was dissolved in a mixture of acetic acid (8 mL) and water (2 mL) and heated at 90 C for 16 hours. Solvents were removed under reduced pressure, and the residue was purified by preparative TLC [methanol-dichloromethane (1:9)] to afford (4S,5S,3R)-2-[6-(cyclopentylamino)purin-9-yl]-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol, a compound of Formula I.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([O:18][C:19](=[O:28])[NH:20][C@H:21]1[CH2:25][C@@H:24]([CH2:26]Br)[CH:23]=[CH:22]1)([CH3:17])([CH3:16])[CH3:15].CCOC(C)=O>CN(C=O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:26][C@H:24]1[CH2:25][C@@H:21]([NH:20][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:28])[CH:22]=[CH:23]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CBr)C1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)OCC
Temperature: 60 °C
Reaction time: 19 h
Yield: 58.3 %

Procedure:
Diethyl malonate (1.29 mL, 8.5 mmol) was added to a mixture of NaH (60%, 0.34 g; 8.5 mmol) in DMF (10 mL). After stirring at room temperature for 15 min a solution of cis-(4-bromomethyl-cyclopent-2-enyl)-carbamic acid tert-butyl ester (1.95 g, 7.1 mmol) in DMF (12 mL) was added, and the reaction mixture was stirred at 60° C. for 19 h. EtOAc was added and the organic phase was extracted with water and brine, dried and concentrated under reduced pressure to give 2.44 g of the crude product. Purification by flash chromatography (CH2Cl2/EtOAc: 1/0→68/32) afforded of 2-(cis-4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl)-malonic acid diethyl ester (1.47 g, 58%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:11]1([C:9]2[N:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]3=[CH:7][N:8]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NCc1ccccn1)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc2c(-c3ncc4ccccn34)cccc2c1
Temperature: 90 °C
Yield: 72.3 %

Procedure:
To a solution of naphthalene-1-carboxylic acid (pyridin-2-ylmethyl)-amide (2.80 g, 10.7 mmol) in toluene (100 mL) was added POCl3 (9 mL). The mixture was heated to 90° C. for 12 h. After this time the mixture was allowed to cool and poured slowly into 10% aqueous potassium carbonate (500 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield 3-naphthalen-1-yl-imidazo[1,5-a]pyridine (1.89 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.C[Al](C)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C@H:28]2[O:32][C:31](=[O:33])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH:13][C:31](=[O:33])[CH2:30][CH2:29][C@H:28]([OH:32])[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1cnc(Oc2ccc(Cl)cc2)cn1
Reactant: COc1cccc([C@@H]2CCC(=O)O2)c1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc([C@@H](O)CCC(=O)Nc2cnc(Oc3ccc(Cl)cc3)cn2)c1
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a stirred solution of 5-(4-chlorophenoxy)pyrazin-2-amine (149 mg, 0.67 mmol) in dry CH2Cl2 (1.5 mL) at room temperature, under argon, is added trimethylaluminum (0.335 mL of a 2.0 N solution in toluene, 0.67 mmol) dropwise. The resulting mixture is stirred for 15 min, then (S)-dihydro-5-(3-methoxyphenyl)furan-2(3H)-one (107 mg, 0.555 mmol) in CH2Cl2 (1.5 mL) is added slowly and stirring is continued at ambient temperature for 3 days. The reaction is quenched carefully with 10% aqueous citric acid (0.5 mL) at 0° C. The mixture is then partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (10 mL). The aqueous layer is extracted further with CH2Cl2 (3×10 mL). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is then purified on silica gel (0-75% ethyl acetate in hexane) to give (S)—N-[5-(4-chlorophenoxy)pyrazin-2-yl]-4-hydroxy-4-(3-methoxyphenyl)butanamide (230 mg, 100%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OC/C=C\COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC/C=C\COCc1ccccc1
Yield: 102.2 %

Procedure:
To a solution of (Z)-4-benzyloxy-2-buten-1-ol (2.0 g, 11.2 mmol) in methylene chloride (40 ml) were added carbon tetrabromide (4.46 g, 13.4 mmol) and triphenylphosphine (3.51 g, 13.4 mmol) at 0° C. under stirring in a nitrogen gas stream. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from hexane/ethyl acetate (4/1) eluate fractions, the title compound (2.76 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:31][CH3:32])=[C:12]([CH:30]=2)[CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]2)[CH:5]=[C:4]([CH3:33])[N:3]=1.[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40]([N:14]([CH2:13][C:12]1[CH:30]=[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=2)[CH:9]=[CH:10][C:11]=1[O:31][CH3:32])[CH:15]1[CH2:16][CH2:17][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][CH2:20]1)=[O:41]
Reactant: COc1ccc(-c2cc(C)nc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2cc(C)nc(C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 92 (268 mg, 0.59 mmol) is treated with acid chloride 8 (205 mg, 0.77 mmol) using Method D to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([NH:29][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2cc(N)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cc(NS(C)(=O)=O)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To a solution of 2-(4-tert-butylbenzoylamino)-5-amino-N-(4-methoxyphenyl)benzamide (150 mg, 0.36 mmol) in methylene chloride (5 mL) cooled to 0° C. was added pyridine (32 μl, 0.40 mmol) followed by-,methanesulfonyl chloride. (31 μl, 0.40 mmol). After 5 min, the reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with methylene chloride and washed twice with water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 30% ethyl acetate/70% methylene chloride) to give 130 mg (73%) of the title compound.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:9].[O:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[O:13]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=2)[CH:8]=[O:9])=[CH:14]1
Reactant: O=Cc1ccnc(Br)c1
Reactant: OB(O)c1ccoc1
Agent: OBO
Product: O=Cc1ccnc(-c2ccoc2)c1

Procedure:
2-(furan-3-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and furan-3-ylboronic acid (67 mg, 93.2 mg theoretical, 61.2%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22]I>C1COCC1.CCCCCC>[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][N:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[C:10](=[O:12])[CH3:11]
Reactant: ClCCCCI
Reactant: CC(=O)Nc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)N(CCCCCl)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9 g (54.1 mmol) of N-(4-cyanophenyl)acetamide are dissolved in 100 ml of THF. The mixture is cooled to 0° C. before the dropwise addition of 51 ml of a 1.6 N solution in hexane of nBuLi (1.5 eq.). The solution is left for one hour to return to ambient temperature and is then cooled to 0° C. before the dropwise addition of 9.9 ml of 1-chloro-4-iodobutane (81 mmol). The reaction mixture is stirred at ambient temperature for 18 h and then hydrolysed with a saturated aqueous solution of ammonium chloride (100 ml) and extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated. Purification by chromatography on silica (eluant: petroleum ether/ethyl acetate: 1/1) yields a yellow oil containing the expected product.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][NH:12][S:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=O)(=[O:15])=[O:14].N>>[CH3:11][NH:12][S:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:18]([C:19]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:17]=1)(=[O:14])=[O:15]
Reactant: CNS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: CNS(=O)(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and the product of Example 57A. 1H NMR (300 MHz, CD3OD) δ 2.60 (s, 3 H), 7.65 (ddd, J=8.1, 5.0, 0.8 Hz, 1 H), 7.87 (t, J=8.1 Hz, 1 H), 8.15 (ddd, J=8.0, 1.9, 1.0 Hz, 1 H), 8.48 (ddd, J=7.8, 1.7, 1.0 Hz, 1 H), 8.58 (dt, J=8.1, 1.9 Hz, 1 H), 8.67 (t, J=1.5 Hz, 1 H), 8.75 (dd, J=4.7, 1.7 Hz, 1 H), 9.31 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 317 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:21][C:14]3=[N:15][C:16]([OH:20])=[CH:17][C:18](=[O:19])[N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:21][C:14]3=[N:15][C:16]([OH:20])=[C:17]([N+:22]([O-:24])=[O:23])[C:18](=[O:19])[N:13]3[N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)cc(O)nc3s2)cc1
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(O)nc3s2)cc1
Temperature: 80 °C

Procedure:
10.0 g of 2-(4-tert-butylphenyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in 100 ml of acetic acid, and 15 ml of fuming nitric acid was added dropwise to the suspension while maintaining the temperature at 80° C. After completion of the reaction, the mixture was cooled and the precipitate was separated by filtration to obtain 7.1 g of 2-(4-tert-butylphenyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as pale yellow prisms having a melting point of 245° to 246° C. (decomposition).
Reaction SMILES: [N+]([C:4]1[C:5](=O)[N:6](C)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.N.[CH3:16][N:17]1[CH2:22]C[C:20](=O)[C:19](C)([CH3:24])[CH2:18]1>CO>[N+:10]([C:8]1[CH:7]=[N:6][C:5]2[C:19]([CH3:24])([CH3:20])[CH2:18][N:17]([CH3:22])[CH2:16][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: CN1CCC(=O)C(C)(C)C1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: CN1Cc2cc([N+](=O)[O-])cnc2C(C)(C)C1
Temperature: 70 °C

Procedure:
3,5-Dinitro-1-methylpyridin-2-one [prepared by the method of E. Matsumura, M. Ariga and Y. Tohda. Bull. Chem. Soc. Japan, 1979, 52, 2413-2419] (2 g; 10 mmol) was suspended in MeOH (50 ml) and treated with 0.88 aq, ammonia (10 ml; 157 mmol). 1,3,3-Trimethylpiperidin-4-one (1.7 g; 12 mmol) was added and the mixture heated at 70° C. for 5 h. The mixture was cooled to room temperature then evaporated to dryness in vacuo. The residue was digested with dichloromethane (2×50 ml) and the hot solution decanted from the red gum. The extracts were combined, evaporated to dryness in vacuo and the residue purified by chromatography on SiO2, with 50% ethyl acetate: 60-80° C. petroleum to give the title compound as a yellow oil, which solidified on standing (1.05 g; 48%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17]>CN(C)C=O.CCOC(C)=O>[CH2:16]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:17]
Reactant: CCI
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (226 mg, 2.0 mmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (0.33 g, 2.4 mmol) and iodoethane (0.37 g, 2.4 mmol). The resulting mixture was stirred at rt overnight. TLC showed the reaction was complete. The mixture was diluted with EtOAc (40 mL), then washed with water (2×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. The crude material was purified by chromatography on silica gel, eluting with Hex:EtOAc=70:30 to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=1.55 (t, J=7.3 Hz, 3H), 4.22 (q, J=7.3 Hz, 2H), 8.07 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C@H:24]([CH2:26]OS(C3C(C)=CC=CC=3)(=O)=O)[CH2:23][C:22]=2[CH:38]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C@H:24]([CH2:26][N:10]3[CH2:9][CH2:8][C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=4)([OH:13])[CH2:12][CH2:11]3)[CH2:23][C:22]=2[CH:38]=1
Reactant: COc1ccc2c(c1)C[C@@H](COS(=O)(=O)c1ccccc1C)O2
Reactant: OC1(Cc2ccc(Cl)cc2)CCNCC1
Product: COc1ccc2c(c1)C[C@@H](CN1CCC(O)(Cc3ccc(Cl)cc3)CC1)O2

Procedure:
The title compound, MS: m/e=387.9 (M+H+), was prepared from 4-(4-chloro-benzyl)-piperidin-4-ol and (S)-toluenesulfonic acid 5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl ester.
Reaction SMILES: [CH:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[ClH:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)C>[ClH:22].[C:23]([N:11]1[CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]1=2)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CNc1ccncc1O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N1Cc2ccccc2Oc2cnccc21

Procedure:
A solution of 5,6-dihydropyrido[3,4-b][1,4]benzoxazepine (2.8 g) in acetic anhydride (15 ml) was stirred for one hr at ambient temperature. The reaction mixture was poured over ice, basified with sodium carbonate solution and extracted with ether. The organic extract was washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography (silica, ethyl acetate) to give 3 g (88%) of producet, mp 130°-133° C. The product was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride in ethanol. Recrystallization from ethanol-ether gave the analytical sample, mp 225°-227° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6]C(=O)C)=[C:4]([F:12])[CH:3]=1.Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CCO
Product: Nc1ccc(Cl)cc1F

Procedure:
A mixture of 119 parts of 4'-chloro-2'-fluoroacetanilide in 475 parts of ethanol and 200 parts of 37% hydrochloric acid was refluxed for 17 hours and the solvent removed under a reduced pressure of 300 mm.Hg to yield the moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:14][CH:15]=1.CC(C)=O>O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)c1cccc(Nc2cc(Cl)ncn2)c1

Procedure:
A stirred mixture of 4,6-dichloropyrimidine (18.6 g, 125 mmol), 3-aminobenzotrifluoride (16.5 mL, 133 mmol), acetone (60 mL) and H2O (90 mL) is kept at reflux for 3 h. Acetone is removed in vacuo, the remaining aqueous layer is basified with conc. aqueous ammonia solution and extracted with ethyl acetate. The organic extract is dried over Na2SO4 and evaporated. The residue is suspended in a small amount of acetone, filtered and the filter cake dried in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21](SC)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:30])[F:29])[CH:4]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21]([N:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:29])[F:30])[CH:4]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(Cn2ncc3cc(C=C4SC(SC)=NC4=O)ccc32)c(C(F)(F)F)c1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCNCC5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-piperazin-1-yl-thiazol-4-one was prepared from 5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperazine following General Procedure C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:9]([N:6]2[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:8][CH2:7]2)=[O:10])=[CH:14][CH:15]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)OCc2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(F)cc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of (4-fluoro-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2C) (0.10 g, 0.38 mmol), 2-chloro-5-fluoro-pyrimidine (0.05 g, 0.38 mmol) and triethylamine (0.11 mL, 0.75 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-fluoro-benzyl ester. M.S. (M+1): 363.31
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[C:10]([S:17](Cl)(=[O:19])=[O:18])[C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)=[O:7].[CH3:21][NH2:22].CO>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[C:10]([S:17]([NH:22][CH3:21])(=[O:19])=[O:18])[C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)=[O:7]
Reactant: O=C(CCCCCl)c1cc2c(c(S(=O)(=O)Cl)c1)OCC2
Reactant: CN
Solvent: CO
Product: CNS(=O)(=O)c1cc(C(=O)CCCCCl)cc2c1OCC2

Procedure:
Using 5-(5-chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonyl chloride (5.06 g) obtained in Reference Example 69 and a 40% mehtylamine-methanol solution (2.6 g) according to the same method as that of Reference Example 66, the title compound was obtained as colorless crystals (4.82 g) having a melting point of 120 to 121° C.