Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[NH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[C:29]([F:32])([F:31])[F:30])=[O:21])[CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:28][C:26]1[CH:25]=[CH:24][C:23]([C:29]([F:32])([F:30])[F:31])=[C:22]([C:20]([N:17]2[CH2:18][CH2:19][C@@H:15]([NH:14][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:3]=3)[CH2:16]2)=[O:21])[CH:27]=1
Reactant: Clc1ccnc(-c2ccccc2)n1
Reactant: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](N)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](Nc3ccnc(-c4ccccc4)n3)C2)c1
Reaction time: 23 h
Yield: 45.4 %

Procedure:
A solution of 30 mg (0.16 mmol) 4-chloro-2-phenyl-pyrimidine (CAS: 14790-42-2), 42.8 mg (0.16 mmol) ((R)-3-Amino-pyrrolidin-1-yl)-(5-methyl-2-trifluoromethyl-phenyl)-methanone (intermediate 13), 54.3 mg (0.39 mmol) K2CO3 and 6.5 mg (0.039 mmol) KI in 1 mL N,N-dimethylacetamide was heated in a 60° C. for 2 h, and at 100° C. for 23 h. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed twice with water. The organic layer was dried with Na2SO4 and filtered. The mixture was concentrated and purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 31 mg (46%) of the titled compound as a light yellow solid. MS(m/e): 427.2 (M+H+).
Reaction SMILES: S(Cl)(C)(=O)=O.Cl.[CH3:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][CH:18]=1)\[C:11](O)=[O:12].C(N(CC)C(C)C)(C)C.[NH2:48][C@@H:49]1[C:68](=[O:69])[N:51]2[C:52]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[C:53]([CH:56]3[CH2:60][CH2:59][CH2:58][O:57]3)[CH2:54][S:55][C@H:50]12.N1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH3:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[S:17][CH:18]=1)\[C:11]([NH:48][C@@H:49]1[C:68](=[O:69])[N:51]2[C:52]([C:61]([O:63][C:64]([CH3:65])([CH3:67])[CH3:66])=[O:62])=[C:53]([CH:56]3[CH2:60][CH2:59][CH2:58][O:57]3)[CH2:54][S:55][C@H:50]12)=[O:12]
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)C1=C(C2CCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(C3CCCO3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Mesyl chloride (14 μl, 1.8 mmol) was added to 2-(Z)-methoxyimino-2-(2-tritylaminothiazol-4-yl) acetic acid hydrochloride (0.744 g, 1.65 mmol) and N,N-diisopropylethylamine (576 μl, 3.3 mmol) in DMF (5 ml) at -40° C. The reaction mixture was stirred 0.5 h at -30±10° C. then t-butyl (6R,7R)-7-amino-3-(tetrahydrofuran-2-yl)ceph-3-em-4-carboxylate, more mobile diastereoisomer (0.431 g, 1.3 mmol) in DMF (5 ml) followed by pyridine (147 μl, 1.8 mmol) were added. Stirred 1 h without further cooling then diluted with ethyl acetate, washed twice with water and with brine, dried, concentrated and flash chromatographed on silica gel eluting with 30,35 and 40% ethyl acetate in hexane to give the title compound as a foam (0.83 g, 84%); νmax (CH2Cl2) 3396, 3277, 1782, 1732, 1683, 1526, 1248, 1156 and 1051 cm-1 ; δH [(CD3)2SO, 250 MHz] 1.47 (9H, s), 1.55-1.75 (1H, m), 1.8-2.0 (2H, m), 2.05-2.2 (1H, m), 3.44 and 3.50 (2H, ABq, J18.3 Hz), 3.65-3.95 (2H, m), 3.81 (3H, s), 4.6-4.7 (1H, m), 5.14 (1H, d, J4.8 Hz), 5.66 (1H, dd, J4.8, 7.9 Hz), 6.70 (1H, s), 7.2-7.4 (15H, m), 8.88 (1H, s) and 9.54 (1H, d, J7.9 Hz). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (774)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:21]([O:23][CH3:24])=[O:22])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.[C:30]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:21]([O:23][CH3:24])=[O:22])[CH3:30])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a solution of methyl 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate (32 g, 65 mmol) and Cs2CO3 (42.4 g, 130 mmol) in DMF (500 mL) was added CH3I (12 mL, 195 mmol). The reaction mixture was stirred at room temperature overnight. Then it was concentrated to remove the DMF, and water was added into the mixture. The resulting precipitate was filtrated, washed by water, and dried to give methyl 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate (31 g, 94%) 1H NMR (CDCl3, 400 MHz): δ8.07-7.08 (m, 6H, ArH), 6.81 (s, 1H, ═CH), 4.22 (t, J=5.2 Hz, 2H, CH2), 3.94 (s, 3H, OCH3), 3.40 (s, 3H, NCH3), 3.01 (t, J=5.2 Hz, 2H, CH2)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[S:12]([NH:16][C:17](=[NH:22])[CH2:18][CH2:19][S:20][CH3:21])(=[O:15])(=[O:14])[NH2:13]>C(Cl)(Cl)Cl.CO>[S:12]([NH:16][C:17](=[NH:22])[CH2:18][CH2:19][S:20]([CH3:21])=[O:9])(=[O:14])(=[O:15])[NH2:13]
Reactant: CSCCC(=N)NS(N)(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CS(=O)CCC(=N)NS(N)(=O)=O
Reaction time: 2 h

Procedure:
A solution of commercial 80% pure m-chloroperbenzoic acid (5.4 g, 25 mmol) in chloroform (40 ml) was added dropwise to a solution of N-sulfamyl-3-(methylthio)propionamidine (4.94 g, 25 mmol) in methanol (50 ml) at room temperature. After stirring for two hours, the product was collected by filtration, analytically pure, to give 4.44 g, mp 141°-144°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:20]([O:30][CH3:31])[CH:19]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(Oc3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Yield: 73 %

Procedure:
The title compound was prepared in analogous manners as described in example 9) from 4-chlorophenol and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 73% yield as a pale-brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:19][CH2:18]2)=[O:16])[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH2:10][CH2:9]2)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:19][CH2:18]2)=[O:16])[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH2:10][CH2:9]2
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cc3c(c([N+](=O)[O-])c2)NC(=O)CC3)CC1
Agent: [Pd]
Solvent: CCO
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(N)c3c(c2)CCC(=O)N3)CC1
Yield: 98.8 %

Procedure:
0.5 g of 5% palladium-carbon was suspended in 0 ml of ethanol. Thereto was added 5 g of 8-nitro-6-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinylcarbonyl}-3,4-dihydrocarbostyril. The mixture was subjected to catalytic reduction at 30°-40° C. at normal pressure in a water bath. After the completion of hydrogen absorption, the reaction mixture was filtered to remove the catalyst. The catalyst was washed with ethanol. The filtrate and the washings were mixed. The mixture was subjected to distillation to remove the solvent to obtain 4.6 g of 8-amino-6-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinylcarbonyl}-3,4-dihydrocarbostyril as a white amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCNCC2)cc1
Yield: 17.8 %

Procedure:
Following General Procedure C, tert-butyl 4-[4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl]piperazine-1-carboxylate (160 mg, 0.33 mmol) was reacted with TFA (4 mL) to afford the desired product (23 mg, 22%) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.72 (s, 2H), 7.76 (d, J=5.4 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.37 (d, J=9.1 Hz, 1H), 7.20-7.03 (m, 4H), 5.95 (d, J=5.4 Hz, 1H), 3.68 (s, 3H), 3.52-3.41 (m, 4H), 3.31 (s, 4H).
Reaction SMILES: B.[C:2]([N:10]1[CH2:29][CH2:28][N:13]2[CH2:14][C@@H:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[C:21]([C@@H:12]2[CH2:11]1)=[CH:20][CH:19]=[CH:18][CH:17]=3)(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[ClH:30]>O1CCCC1>[ClH:30].[ClH:30].[CH2:2]([N:10]1[CH2:29][CH2:28][N:13]2[CH2:14][C@@H:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[C:21]([C@@H:12]2[CH2:11]1)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)N1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3C[C@@H](c4ccccc4)c4ccccc4[C@@H]3C2)cc1

Procedure:
To a stirred solution of 1.0 M borane in tetrahydrofuran (70 ml) maintained under nitrogen at 0° was added cis-1,3,4,6,7,11b-hexahydro-2-benzoyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline (6.8 g, 0.0184 m) and the mixture heated to reflux for 3 hours, then cooled in an ice bath and carefully treated with 10% HCl (50 ml). This mixture was heated to reflux for 1 hour, then cooled, and tetrahydrofuran removed on an aspirator. The residue was basified to pH 11 with 10% NaOH and extracted with chloroform (3×100 ml). The extracts were dried over MgSO4 and evaporated to a yellow oil, 7.8 g. This crude product was purified by chromatography on a Prep 500 HPLC on silica gel eluting with 1:1 ether:cyclohexane (1% diethylamine). The pure fractions were combined and evaporated to an oil which was dissolved in methanol (50 ml) and isopropanol (25 ml) and acidified with HCl gas. The white solid which crystallized was collected by filtration and vacuum dried at 80° for 24 hours to give 3.9 g of cis-1,3,4,6,7,11b-hexahydro-2-benzyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, m.p. 203°-204°.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C(N(CC)CC)C.Cl[C:26]([O:28][CH3:29])=[O:27].O>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: Cc1nccn2c(C3CCNCC3)nc(Br)c12
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)N1CCC(c2nc(Br)c3c(C)nccn23)CC1
Yield: 85.4 %

Procedure:
1-Bromo-8-methyl-3-(piperidin-4-yl)imidazo[1,5-a]pyrazine (0.169 mmol, 50 mg) was dissolved in dichloromethane (1 ml) and triethylamine (0.337 mmol, 47 μl) and methyl chloroformate (0.186 mmol, 14.40 μl) were added at 0° C. After stirring at room temperature for one hour water and dichloromethane were added. The organic layer was separated, dried (sodium sulfate) and concentrated in vacuo to give methyl 4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (51 mg).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([O:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2cccc(Cl)c2nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,8-dichloroquinoline-3-carbaldehyde (1 eq) in DMF (0.25 M) was added phenol (1.5 eq) and K2CO3 (2.0 eq) at rt and the mixture was stirred for 3 h at rt. The mixture was diluted with water, extracted with EtOAc (2 times) and the combined organic layers were washed with water (2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on a Redi-Sep™ column using 0 to 40% gradient of EtOAc in hexane to provide 8-chloro-2-phenoxyquinoline-3-carbaldehyde.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=[C:8]([S:17][CH3:18])[N:7]=1)=[CH2:5])C.Cl>C(O)C>[C:4]([C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=[C:8]([S:17][CH3:18])[N:7]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1nc(SC)ncc1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1C(C)=O
Temperature: 50 °C

Procedure:
A solution of Example 1A (2.0 g, 7.45 mmol) in a solvent mixture of ethanol (24.84 ml) and 10% HCl solution (4.53 ml, 14.91 mmol) was heated to 50° C. for 18 hours. The reaction mixture was cooled, and the majority of the ethanol removed by rotary evaporation. The residue was partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound, which was used in the subsequent step without further purification. MS ESI(+) m/z 241 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C1COCC1.CO.O.O[Li].O>O>[CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of methyl 4-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (65 mg, 0.12 mmol) in mixed solvents (THF/MeOH/H2O; 2:2:1; 5 mL) was added LiOH H2O (15 mg, 0.36 mmol) at 0° C. The reaction mixture was allowed to room temperature over 30 min. and stirring was continued for 1 h. The reaction mixture was concentrated to give crude product, which was diluted with water and extracted with MTBE. The aqueous layer was neutralized with 0.5N HCl and extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound (55 mg, 87%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.28 (dd, J=8.0, 1.6 Hz, 1H), 8.14 (s, 1H), 7.77 (dd, J=13.6, 8.4 Hz, 1H), 7.63 (s, 0.5H), 7.51 (s, 0.5H), 7.23-7.13 (m, 3.5H), 6.95 (d, J=9.2 Hz, 0.5H), 4.79 (s, 1H), 4.48 (s, 1H), 3.77 (s, 1.5H), 3.68 (s, 1.5H), 3.58-3.01 (m, 6H), 2.88-2.80 (m, 2H), 1.60-1.40 (m, 2H), 1.39-1.20 (m, 4H), 1.19-1.00 (m, 2H), 0.99-0.90 (m, 3H), 0.85-0.75 (m, 3H); MS(ESI+) m/z 517.4 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[C:6]=1[N+:20]([O-:22])=[O:21].[OH-].[Li+]>CO>[CH3:18][C:15]1([CH3:19])[O:14][C@H:13]([CH2:12][O:11][C:7]2[C:6]([N+:20]([O-:22])=[O:21])=[C:5]([CH2:4][C:3]([OH:23])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH2:17][O:16]1
Reactant: COC(=O)Cc1cccc(OC[C@@H]2COC(C)(C)O2)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC[C@@H](COc2cccc(CC(=O)O)c2[N+](=O)[O-])O1
Yield: 100.4 %

Procedure:
To a solution of 2-diazo-1-[3-(2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-2-nitrophenyl]ethanone (0.9 g, 2.8 mmol) in 30 mL of methanol at room temperature was added dropwise a solution of silver benzoate (84 mg, 13%) in 4.2 mL of triethylamine. The solution turned greenish and then brown, black precipitate formed. After stirring for 1.5 h, it was filtered through celite and the filtrate was concentrated. The residue was then purified on a silica gel column with 20% ethyl acetate in hexane to afford 0.75 g of [3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-nitrophenyl] acetic acid methyl ester. The above ester (0.52 g, 1.6 mmol) was then hydrolyzed by stirring with lithium hydroxide (0.27 g) in 5 mL of methanol at room temperature to give 0.5 g of [3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-nitrophenyl] acetic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:19]([O-])=[O:20].[Na+].O>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 98.3 %

Procedure:
A solution of 0.60 g of 1-(2-chloroethyl)-3-(β-D-glucopyranosyl)urea in 15 ml of 99% formic acid was admixed with 282 mg of sodium nitrite under ice-cooling and stirring. The mixture was stirred for 1 hour under ice-cooling to effect the nitrosation. The reaction mixture, after addition of 15 ml of cold water thereto, was ice-cooled for 30 minutes and then treated with 5 ml of Amberlite IR-120 (H+ form) for the removal of sodium cation. The reaction mixture so treated was concentrated to dryness below 30° C by distilling off the solvent under a reduced pressure. The residue was taken up into a small volume of n-propanol and the solution was admixed with a volume of petroleum ether to give precipitate. The precipitate which deposited was collected by filtration and then dried in a desiccator under vacuum, affording 0.65 g of the titled compound as an amorphous solid of pale yellow color. Yield 92%. mp. 85° C (decomposition). [α]D6 -14° (c 0.5, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12](Cl)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:11]([CH:12]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: c1nc[nH]n1
Reactant: FC(F)(F)c1cccc(C(Cl)c2ccc3ncccc3c2Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1cccc(C(c2ccc3ncccc3c2Cl)n2cncn2)c1
Yield: 16.5 %

Procedure:
A mixture of intermediate 6 (8.4 g), 1,2,4-triazole (4.89 g) and potassium carbonate (9.78 g) in acetonitrile (300 ml) was stirred and refluxed for 12 hours. The solvent was evaporated and the residue was partitioned between CH2Cl2 and water. The separated organic layer was dried over MgSO4, filtered and the filtrate evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 98.5/1.5/0.1). The pure fractions were collected and the solvent evaporated. The residue was crystallized from diisopropyl ether/petrol ether, yielding 1.51 g (32%) (±)-5-chloro-6-[1H-1,2,4-triazol-1-yl[3-(trifluoromethyl)phenyl]-methyl]quinoline (intermediate 7; mp. 144.5° C.). In a similar manner, there were prepared: (±)-8-methyl-6-[1H-1,2,4-triazol-1-yl[3-(trifluoromethyl)phenyl]methyl]quinoline (intermediate 8; mp. 108.9° C.) and (±)-8-fluoro-6-[1H-1,2,4-triazol-1-yl[3-(trifluoromethyl) phenyl]methyl]quinoline (intermediate 9; mp. 146.6° C.).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]([F:17])([F:16])[C:9]([C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=[O:10]>CS(C)=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:9]([C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([OH:10])[C:8]([F:17])([F:16])[F:7]
Reactant: O=C(c1nccs1)C(F)(F)F
Reactant: Brc1nccs1
Solvent: CS(C)=O
Product: OC(c1nccs1)(c1nccs1)C(F)(F)F

Procedure:
From 2-bromothiazole and 2-trifluoroacetylthiazole. M.p. 113°-115° C. 13C Nmr (d6 -DMSO) 77.3 (q, J 30Hz), 122.8, 123.0 (q, J 286 Hz), 142.7 and 166.1 ppm. Found: C, 36.25; H, 1.7; N, 10.5. C8H5F3N2OS2 requires C, 36.1; H, 1.9; N, 10.5%.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1N=C[N:16](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>CCOC(C)=O>[C:1]12([C:11]([NH2:16])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
A solution of adamantane-1-carboxylic acid (2.00 g, 11.10 mmol) in EtOAc (20 mL) was treated with CDI (2.00 g, 12.33 mmol), stirred at RT for 20 minutes, treated with NH4OH (˜14M, 5 mL, ˜70 mmol) and stirred at RT for 20 minutes. The mixture was concentrated to dryness, treated with satd. NaHCO3 and the solids collected via filtration and dried to afford adamantane-1-carboxamide (1.74 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.91 (s, 1H), 6.65 (s, 1H), 1.92 (m, 3H), 1.74-1.71 (m, 6H), 1.68-1.57 (m, 6H); MS (ESI) m/z: 180.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:2]3[N:18]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: N#Cc1ccc(-c2cccn3nc(Cl)nc23)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3nc4c(-c5ccc(C#N)cc5)cccn4n3)cc2)CC1

Procedure:
4-{4-[8-(4-Cyano-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-cyano-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.164 g, 0.644 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.214 g, 0.773 mmol) in a manner analogous to Example 311a and 311b to give product (0.181 g, 57%). MP=96-100° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.70 (s, 1H), 8.85 (d, 1H), 8.40 (d, 2H), 8.00 (m, 3H), 7.62 (d, 2H), 7.15 (m, 3H), 4.05 (m, 2H), 2.80 (br m, 2H), 2.60 (m, 1H), 1.75 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H). MS=495 (MH)+.