Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:16]([CH3:26])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:32][OH:33].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[N:32][OH:33])[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:16]([CH3:26])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)CC(C)C
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(CC(C)C)=NO
Temperature: 70 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of 1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-3-methyl-butan-1-one (i.e. the product of Step 2, 228 mg) in methanol (14.3 mL) was added hydroxylamine hydrochloride (38 mg) and a catalytic amount of concentrated hydrochloric acid. The mixture was stirred at 70° C. for 4 h and concentrated in vacuum. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue on silica gel obtained the title compound (94 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[CH:23][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:26]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH3:21])=[CH:18][CH:19]=1)=[CH:7]3
Reactant: C1CNCCN1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCNCC4)cc3)cc12

Procedure:
8-Methyl-2-(4-(1-(piperazin-1-yl)ethyl)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and piperazine (commercially available) following the procedures described for Example 182. 1H NMR (Methanol-d4) TFA Salt: δ 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (d, 1H), 7.51 (s, 1H), 7.46 (d, 1H), 7.26 (m, 4H), 3.62 (m, 1H), 3.25 (t, 2H), 3.12 (t, 2H), 2.80 (m, 4H), 2.69 (m, 4H), 2.56 (s, 3H), 1.42 (d, 3H). LRMS [M+H]=426.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29]/[C:30](=[N:33]/[H])/[NH:31]O)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:8]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=3)[O:10][N:33]=2)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Reactant: O=C(O)c1cc(Cl)ccn1
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3cc(Cl)ccn3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 10.9 %

Procedure:
4-Chloro-2-pyridinecarboxylic acid (40 mg, 0.25 mmol) and CDl (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The reaction mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid (13 mg, 11%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:47]1[CH2:50][CH:49]([N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:47]4[CH2:50][CH:49]([N:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)[CH2:48]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C1CCN(C2CNC2)C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CC(N3CCCC3)C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 1-azetidin-3-ylpyrrolidine (VWR) to give the title product. LC-MS (ES+) 773 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:12][NH2:13])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][O:15][C:16]([NH:18][C:19](=NC(OC)=O)SC)=[O:17]>CO>[CH3:14][O:15][C:16]([NH:18][C:19]1[NH:11][CH2:10][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][N:13]=1)=[O:17]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: COc1cccc(C(CN)CN)c1
Solvent: CO
Product: COC(=O)NC1=NCC(c2cccc(OC)c2)CN1
Yield: 68.7 %

Procedure:
A solution of 2.61 g (14.5 m. mole) of 2-(3-methoxyphenyl)-1,3-propanediamine in 200 ml of methanol is combined with a solution of 3.0 g (14.55 m. mole) of 1,3-bis(methoxycarbonyl)-S-methylisothiourea in 200 ml of methanol and allowed to stand at room temperature over night. The crystalline product which separates is collected, washed with methanol and dried at 78° under vacuum to give 2.62 g of 2-methoxycarbonylamino-5-(3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine, mp 218°-221°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]2[C:18]([CH3:19])([CH3:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)=[CH:3][C:2]=1[NH:1][C:40]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:41]
Reactant: O=C(Cl)C1CCCCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(N)c1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(NC(=O)C3CCCCC3)c1)N2
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a solution of methyl 2-(3-amino-4-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (200 mg, 0.58 mmol) in 8 mL of dichloromethane, was added N,N-diisopropylethylamine (150 mg, 1.16 mmol) under nitrogen atmosphere. Then a solution of cyclohexanecarbonyl chloride (127 mg, 0.87 mmol) was added via syringe with an ice bath. The mixture was stirred for 1.5 h. The mixture was purified by column chromatography to afford 250 mg of methyl 2-(4-chloro-3-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a crude product. (Yield: 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH2:13]O.[Br:15]P(Br)Br>ClCCl>[Br:15][CH2:13][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Cl:1]
Reactant: COc1cc(Cl)c(CO)cc1[N+](=O)[O-]
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1cc(Cl)c(CBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.5 %

Procedure:
To a solution of (2-chloro-4-methoxy-5-nitrophenyl)methanol (5.0 g, 23 mmol) in dichloromethane (50 mL) at 0° C., tribromophosphine (3.08 g, 11.5 mmol) was added in portions and the resulting mixture was stirred at RT for 2 h. The mixture was poured into ice-water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product (3.5 g, 54.2% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][C:17]2=[O:30])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[CH2:1]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]2=[O:30])[CH:11]=1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(NCc1ccccc1)c1ccnc(-n2ccc(OCc3ccccc3)cc2=O)c1
Agent: [Pd]
Solvent: CO
Product: O=C(NCc1ccccc1)c1ccnc(-n2ccc(O)cc2=O)c1
Yield: 49.4 %

Procedure:
A solution of N-benzyl-2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)isonicotinamide (0.88 g, 2.14 mmol) and 20 weight % palladium on activated carbon (0.10 g) in methanol (50 mL) was stirred in atmospheric pressure of hydrogen for 2 hours. The resulting solution was filtered and concentrated in vacuo. The residue was recrystallized from methanol (10 mL) to give 4-hydroxy-2-oxo-2H-[1,2′]bipyridinyl-4′-carboxylic acid benzylamide as a colorless solid (0.34 g, 50%): mp 102-105° C. (methanol); 1H NMR (300 MHz, CD3OD) δ 8.66 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 7.81-7.78 (m, 2H), 7.36-7.24 (m, 5H), 6.20-6.17 (m, 1H), 5.86 (s, 1H) 4.57 (s, 2H); 13C NMR (75 MHz, CD3OD) δ 167.6, 164.0, 162.9, 150.8, 147.9, 142.4, 136.5, 135.9, 126.6, 125.7, 125.4, 119.5, 117.9, 100.9, 96.8, 41.8; MS (ES+) m/z 322.3 (M+1).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:27][NH:26][CH2:25]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2].[C:29]1([CH:35]2[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:18])([F:19])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:25][N:26]([CH:38]3[CH2:37][CH2:36][CH:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:40][CH2:39]3)[CH2:27]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(c2ccccc2)CC1
Product: CC(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(c4ccccc4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid isopropylamide and 4-phenyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15](=[O:30])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(=O)=O.[CH3:31][NH:32][CH:33]1[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH2:34]1.C(N(CC)CC)C>ClCCl>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:15](=[O:30])/[CH:14]=[CH:13]/[C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:32]([CH3:31])[CH:33]4[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH2:34]4)=[CH:8][CH:9]=3)=[CH:22][CH:21]=2)=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)OCc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Reactant: CNC1CCC(C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCC(N(C)Cc2ccc(/C=C/C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A reaction mixture of 100 mg (0.226 mmol) of 4-[(E)-2-(4′-chlorobiphenyl-4-ylcarbamoyl)vinyl]benzyl methanesulfonate, 37.34 mg (0.29 mmol) of methyl-(4-methylcyclohexyl)amine, and 0.1 mL of triethylamine in 10 mL of dichloromethane is stirred for 18 hours at ambient temperature. Then the reaction mixture is extracted between water and dichloromethane, the organic phase is separated off, dried, and evaporated down. The residue is purified by column chromatography on silica gel (eluant: dichloromethane/methanol/ammonia (90:10:1)). Yield: 52 mg (49% of theory); C30H33ClN2O (M=473.05); melting point: 227° C.-258° C.; calc.: molecular ion peak (M+H)+: 473/475 (Cl); found: molecular ion peak (M+H)+: 473/475 (Cl); Rf value: 0.48 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:11]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCCNC1
Yield: 48 %

Procedure:
Prepared according to Example 53, using tert-butyl (3R)-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)-1-piperidinecarboxylate (Ex. 52) and (2.5:1) DCM:TFA. Purification by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 80%) provided 2-(2-methyl-3-((3R)-3-piperidinylamino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (115 mg, 48%) as the free base after washing with saturated aq. NaHCO3, extracting with 10% MeOH/DCM, drying over Na2SO4, and concentrating under reduced pressure. 1H NMR (DMSO-d6) δ: 7.90-7.95 (m, 1H), 7.62-7.70 (m, 1H), 7.30-7.42 (m, 1H), 7.09 (s, 1H), 5.83 (s, 1H), 4.06 (br. s., 1H), 3.61-3.69 (m, 2H), 3.21-3.31 (m, 1H), 2.89-3.09 (m, 5H), 2.66 (s, 3H), 2.15-2.33 (m, 2H), 2.10 (m, 2H), 1.77-1.89 (m, 2H), 1.55-1.70 (m, 1H). m/z (ESI, +ve) 377.2 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCN1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a mixture of 0.286 g (2 mmole) of 3-piperidin-1-yl-propan-1-ol, and 2 mL of pyridine was added 0.001 g of 4-dimethylaminopyridine and 0.381 g (2 mmole) of p-toluenesulphonyl chloride. The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was taken up in 20 mL of dichloromethane and washed once with 10 mL of saturated sodium bicarbonate, twice with 10 mL of water, and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.384 g of toluene-4-sulfonic acid 3-piperidin-1-yl-propyl ester as a pink solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.CCOCC.[OH-].[Na+]>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH:11]=[CH:10][N:9]=2)[CH:14]=[O:15])[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(CO)ccn2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(C=O)ccn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
A solution of (2-(4-methylthiazol-2-ylamino)pyridin-4-yl)methanol (0.210 g, 0.949 mmol) in THF (5 mL) was added to a solution of Dess-Martin periodinane (0.604 g, 1.42 mmol) in THF (5 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 minutes, then diluted with ether and 1N NaOH (40 mL). The reaction mixture was stirred for 30 minutes, then extracted with ether, washed with water, brine, dried and concentrated to afford 2-(4-methylthiazol-2-ylamino)isonicotinaldehyde (0.197 g, 94.7% yield) as a yellow wax/powder. The crude product was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[C:3](=[O:29])[N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21]C(=O)OC(C)(C)C)=[N:19][CH:20]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:30][CH:31]([F:40])[O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>CN(C=O)C>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([CH2:14][N:4]2[C:5](=[O:13])[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([O:32][CH:31]([F:30])[F:40])=[CH:34][CH:35]=3)[C:3]2=[O:29])=[CH:16][CH:17]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cn1
Solvent: CN(C)C=O
Product: Nc1ccc(CN2C(=O)C(Nc3ccc(OC(F)F)cc3)=C(c3ccccc3)C2=O)cn1
Temperature: 150 °C
Yield: 53.9 %

Procedure:
A mixture of tert-butyl {5-[(3-chloro-2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)methyl]pyridin-2-yl}carbamate ( 0.70 g, 1.7 mmol) and 4-(difluoromethoxy)-aniline (0.54 g, 3.4 mmol) in DMF (4 mL) was heated in a microwave reactor at 150° C. for eight min. The solvent was evaporated and the residue was purified on a column (Isolute® SI, 10 g/70 mL), using CH2Cl2 and then CH3OH/CH2Cl2 (1:99, 2:98 and then 5:95) as eluant, to give 0.4 g (54%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.99 (bs, 1H), 7.67-7.62 (m, 2H), 7.14-7.04 (m, 3H), 6.91 (d, J=8 Hz, 2H), 6.78 (d, J=8 Hz, 1H), 6.72 (d, J=9 Hz, 2H), 6.63 (d, J=9 Hz, 2H), 6.33 (t, J=74 Hz, 1H), 4.60 (s, 2H).
Reaction SMILES: CS[C:3](=[O:12])[C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5].C(=O)([O-])[O-:14].[Na+].[Na+].Cl>O>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4](=[O:5])[C:3]([OH:12])=[O:14])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: CSC(=O)C(=O)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(C(=O)C(=O)O)cs1
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To 10.1 g of 2-(2-aminothiazol-4-yl)thioglyoxylic S-acid methyl ester and 80 ml of water was added 10.6 g of sodium carbonate with ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hour. Subsequently, the thus obtained reaction mixture was adjusted to pH 2.5 with 6 N hydrochloric acid at the same temperature. The deposited crystals were collected by filtration, washed with water, and then dried to obtain 6.2 g (67.8% yield) of 2-(2-aminothiazol-4-yl)glyoxylic acid having a melting point of above 200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:12])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(Cl)cc12
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(=O)Nc2ccccc2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 86 %

Procedure:
To 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 0.98 mmol) in 5 mL of dry tetrahydrofuran is added oxalyl chloride (0.10 mL, 1.18 mmol) followed by dimethylformamide (0.02 mL). The solution is stirred at room temperature for 1.75 hours, then aniline (0.54 mL, 5.88 mmol) is added. The solution is stirred at room temperature overnight then partitioned between ethyl acetate and 1N HCl . The organic layer is washed with saturated aqueous NaHCO3, followed by brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography eluting with 3:1 hexane:ethyl acetate to provide 5-chloro-3-(1-methylethoxy)-N-phenyl-2-benzofurancarboxamide, 86% yield; mp=147°-149° C.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)(O)[C:26]=2[CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([Br:48])(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)([Br:48])[C:26]=2[CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(=O)Br
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(O)(c1ccc(Cl)cc1)c1ccccc1-2
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(Br)(c1ccc(Cl)cc1)c1ccccc1-2
Reaction time: 1 h

Procedure:
2-Docosyloxy-9-(4-chlorophenyl)-9-fluorenol (200 mg, 0.33 mmol) prepared in the above-mentioned 1-2 was dissolved in chloroform (2 ml), acetyl bromide (48 μl, 0.65 mmol) was added dropwise and the mixture was stirred for 1 hour. After completion of the reaction, the solvent was evaporated, and the residue was precipitated with acetonitrile (2 ml) to give 2-docosyloxy-9-(4-chlorophenyl)-9-bromofluorene (209 mg, 0.31 mmol, 95%.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].[CH2:6]([NH:8][C:9](=[O:21])[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:7].C([O-])(=O)C.[Na+].[BH4-].[Na+]>O.C(O)(=O)C>[CH2:6]([NH:8][C:9](=[O:21])[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:18][CH:19]=1)[CH3:7]
Reactant: CCC(C)=O
Reactant: CCNC(=O)OCCOc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCNC(=O)OCCOc1ccc(NC(C)CC)cc1

Procedure:
To a mixture of 2-butanone (5 ml), 2-(4-aminophenoxy)ethyl N-ethylcarbamate (1.00 g) and sodium acetate (2.50 g) in a solution of 5 ml of acetic acid and 10 ml of water, cooled to -5°, is added sodium borohydride (4.00 g) in portions. After addition is complete, the reaction mixture is adjusted to alkaline pH and is extracted with ether. The combined organic extracts are concentrated and the crude product is purified by column chromatography to give 2-[4-(1-methylpropylamino)phenoxy]ethyl N-ethylcarbamate (compound 35, Table B).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:19][CH:18]=[CH:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:1]([C@@H:14]1[CH2:19][C@@H:18]2[C@@H:17]([O:28]2)[CH2:16][O:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Reaction time: 20 h
Yield: 50.1 %

Procedure:
To a solution of (2S)-2-benzhydryl-3,6-dihydro-2H-pyran 27a (0.15 g, 0.6 mmol) in CH2Cl2 (20 ml) was added mCPBA (0.3 g, 70%, 1.2 mmol) in a portionwise manner at 0° C. The mixture was brought to room temperature and the reaction mixture was stirred for 20 h under N2. Na2SO3 (20 ml 1.0 M solution) was added to the reaction mixture at 0° C. to quench the reaction. The aqueous phase was extracted with CH2Cl2 (20 ml×2). The combined organic phase was washed in turn with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4. Evaporation of the solvent gave light brown solid residue. The crude products were purified by flash chromatography on silica gel (hexane/ethyl ether=9:1) to give 0.08 g (1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (50.3%, [α]D=(−) 60, c=1, MeOH) and 0.065 g 28b (1R,4S,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane (41%, [α]D=(−)76, c=1, MeOH).