Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1.O[CH2:27][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:33]([O:32][C:31]([NH:30][C@@H:28]([CH3:29])[CH2:27][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1)=[O:37])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8 %

Procedure:
Diisopropyl azodicarboxylate (1.9 M solution in toluene, 9.52 mL) was added to a mixture of methyl 5-hydroxypyridine-2-carboxylate (5.00 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (8.58 g), triphenylphosphine (12.9 g), and THF (50 mL) at 0° C. dropwise. The mixture was stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give methyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylate (810 mg) as a mixture with impurities. A mixture of methyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylate (810 mg, a mixture with impurities), THF (8 mL), methanol (8 mL), and 1 M sodium hydroxide (8 mL) was stirred at room temperature for 4 hr. The mixture was neutralized with 1 M hydrochloric acid at 0° C., and brine was added. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylic acid (765 mg) as a mixture with impurities. A mixture of 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylic acid (765 mg, a mixture with impurities), 4-aminobenzene-1,3-diol hydrochloride (417 mg), HATU (982 mg), N,N-diisopropylethylamine (0.902 ml), and DMF (7 mL) was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (442 mg) as a pale yellow oil.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O[BH-](O[C:37](=O)[CH3:38])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:11]1[C:9]2=[C:10]3[C:5](=[CH:6][CH:7]=[CH:8]2)[CH2:4][CH2:3][CH2:2][N:1]3[C:37]=1[CH2:38][N:11]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2cccc3c2n1CCC3)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 49 %

Procedure:
To a solution of the above crude aldehyde (180 mg, 0.97 mmol) and 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione (372 mg, 1.06 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (410 mg, 1.93 mmol). The reaction mixture was stirred at room temperature for 3 days. Then the solvent was removed under reduced pressure to afford a yellow oil. Purification by flash column chromatography on silica gel using 2% CH3OH/CH2Cl2 afforded the product as a yellow oil (135 mg, 27%). 1H NMR (CDCl3) δ 1.42-1.47 (m, 2H), 1.56-1.63 (m, 2H), 1.93-1.96 (m, 2H), 2.06-2.07 (m, 2H), 2.22 (t, 2H, J=6.0 Hz), 2.60-2.67 (m, 3H), 2.70 (m, 1H), 2.95 (t, 2H, J=6.0 Hz), 3.56 (t, 2H, J=6.0 Hz), 4.01 (t, 1H, J=6.0 Hz), 4.16 (ABq, 2H, J=42.0, 15.0 Hz), 4.29-4.35 (m, 1H), 4.51 (br s, 1H), 4.58-4.66 (m, 1H), 6.94 (d, 1H, J=7.2 Hz), 7.01-7.06 (m, 1H), 7.09 (t, 1H, J=8.1 Hz), 7.29 (d, 1H, J=7.5 Hz), 7.47 (d, 1H, J=8.1 Hz), 7.68-7.70 (m, 2H), 7.78-7.81 (m, 2H), 8.41 (d, 1H, J=3.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]=[CH:23]N(C)C)=[CH:17][C:16]=1[N:28]([CH3:32])[C:29](=[O:31])[CH3:30].C(OCC)(=O)C>C(O)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[N:28]([CH3:32])[C:29](=[O:31])[CH3:30]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1Cl
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1Cl
Yield: 78.7 %

Procedure:
A mixture of 0.083 g (0.43 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.12 g (0.43 mmol) of N-[2-chloro-5-(3-dimethylamino-acryloyl)-phenyl]-N-methyl-acetamide in 12 ml of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 139 mg of N-{2-chloro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 79%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:3]=1.FC(F)(F)C(O)=O.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[N:21]1.C(N(CC)CC)C.O>CN(C)C=O>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[S:6][N:5]=[C:4]([N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)[N:3]=3)[CH2:34][CH2:33]2)=[O:31])=[N:21]1
Reactant: Clc1nc(N2CCOCC2)ns1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(N3CCOCC3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a solution of 4-(5-chloro-1,2,4-thiadiazol-3-yl)morpholine (114 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of methanol, ethyl acetate and tetrahydrofuran to give 89.4 mg (38.7%) of the desired product.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[C:13]3[CH2:14][O:15][C:16](=[O:17])[C:12]=3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CN(C)C=O.[Rh]>[C:1]1([C@H:7]([N:9]2[C@H:13]3[CH2:14][O:15][C:16](=[O:17])[C@H:12]3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](c1ccccc1)n1c2c([nH]c1=O)C(=O)OC2
Agent: [Rh]
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Reaction time: 10 h

Procedure:
A solution of 8.98 g (36.8 mmol) of 1-[(R)-(1-phenylethyl)]-1H-furo[3,4-d]imidazol-2,4(3H,6H)-dione in 90 ml of dimethylformamide was placed in a 250-ml autoclave and 0.90 g of Rh/Al2O3 (5 percent) is added. Then the autoclave was flushed twice successively with hydrogen, and filled to 40 bars. The mixture was stirred for 10 hours. Then the catalyst was filtered off. The solvent was evaporated at 13.3 mbar and the residue was crystallized with 10 ml of ethyl acetate. (3aS,6aR)-1[(R)-(1-phenylethyl)]-dihydro-1H-furo[3,4-d]imidazol-2,4(3H,3aH)-dione was obtained as a white crystalline product in a yield of 4.89 g=54 percent. Concerning the product: Melting point: 153°-154° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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.Br[CH2:35][CH2:36][Cl:37]>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:35][CH2:36][Cl:37])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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: ClCCBr
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: O=C(O)/C(=N\OCCCl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
The starting material was prepared by reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)-hydroxyimino)acetate with 1-bromo-2-chloroethane followed by hydrolysis of the ester to give 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-(2-chloroethoxy)imino]acetic acid; n.m.r. in solvent C: 3.75(t, 2H); 4.36(t, 2H); 6.64(s, 1H); 7.35(s, 15H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[C:10](=O)[C:11](=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([O:30][C:31](=[O:36])/[CH:32]=[C:33](\[NH2:35])/[CH3:34])[CH3:29].Cl>CCO>[C:1]1([CH:7]2[CH2:9][CH:8]2[C:10]2[NH:35][C:33]([CH3:34])=[C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:36])[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)C1CC1c1ccccc1
Reactant: CCOC(=O)/C=C(/C)N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C2CC2c2ccccc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A solution of ethyl 3-(2-phenyl-1-cyclopropyl)-2-(m-nitrophenylmethylen)-3-oxo-propanoate (5 g) and ethyl-3-aminocrotonate (1.6 g) in EtOH (50 ml) is heated to the reflux temperature for 4 hours, then it is cooled at 0° C., acidified with concentrated aqueous HCl (0.2 ml) and stirred at 0° C. for 30 minutes. After neutralization with a few drops of a saturated Na2HPO4 water solution, the mixture is evaporated and the residue is dissolved in AcOEt (60 ml), washed with water (3×10 ml), dried on Na2SO4 and purified on silica gel (200 g, eluent: diisopropylether/Et ether/Et2O 80/20) to give 4.0 g of 2-(2-phenyl-1-cyclopropyl)-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24])[CH:7]=[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]2=[O:30].C(O)(=O)C.ClC(Cl)C>C(O)C.[Pd]>[NH2:19][C:17]1[CH:18]=[C:13]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=3)[C:5](=[O:30])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:7]2)[C:14]([F:24])=[C:15]([F:23])[C:16]=1[F:22]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)c(F)c2F)c2cc(F)c(F)cc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(N)c(F)c(F)c2F)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
Ethyl 6,7-difluoro-1,4-dihydro-4-oxo-1-(2,3,4-trifluoro-5-nitrophenyl)quinoline-3-carboxylate (280 mg) was dissolved in 10 ml of ethanol, 5 ml of acetic acid, and 5 ml of dichloroethane, to which was added 30 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred overnight at room temperature. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Ethanol was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 200 mg of the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][CH:3]=[N:2]1.[F:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH2:29][C@@H:28]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=4)[CH2:27][NH:26]3)=[O:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[N:1]1([CH2:6][C:7]([N:26]2[CH2:27][C@H:28]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=3)[CH2:29][C@H:25]2[C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:39][CH:38]=3)=[CH:17][CH:18]=2)=[O:24])=[O:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1cccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Reactant: O=C(O)Cn1cncn1
Product: Cc1cccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)N(C(=O)Cn3cncn3)C2)c1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(3-methylbenzyl)pyrrolidine-2-carboxamide, gave Compound 171, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methylbenzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.55 (d, 2H), 7.23-7.15 (m, 3H), 7.08-6.91 (m, 8H), 5.23 (q, 2H), 4.53-4.48 (m, 1H), 3.83-3.76 (m, 1H), 2.73-2.61 (m, 4H), 2.29 (s, 3H), 2.00-1.89 (m, 2H). MS (EI) for C29H28FN5O3. found 514.2 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[O:26][CH3:27]>CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>[F:35][C:34]([F:36])([F:37])[C:32]1[CH:33]=[C:28]([CH:4]([NH:5][CH2:6][C:7]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:20]=[CH:19][C:18]=2[O:26][CH3:27])[CH2:3][OH:2])[CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: COC(=O)C(NCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of methyl[3,5-bis(trifluoromethyl)phenyl]({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)acetate (13.2 mg, 0.0217 mmol) was dissolved in Et2O (1.5 mL) and cooled to 0° C. LAH (108.5 μL of a 1 M solution in LAH, 0.1085 mmol) was added dropwise by syringe. The reaction was warmed to room temperature and stirred at room temperature for 1 hour. The reaction was then quenched by addition of H2O (100 μL) followed by 1 N NaOH (100 μL), followed by H2O (300 μL). The gelatinous precipitate was washed several times with CH2Cl2. The organic washes were filtered through a plug of silica gel with 2% MeOH/CH2Cl2 and the filtrate was concentrated. Purification of the residue by PTLC with 25% EtOAc/hexanes afforded 2-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol. Rf=0.27 (25% EtOAc/hexanes). LCMS=580.4 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.79 (s, 1H), 7.75 (s, 2H), 7.63-7.68 (m, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.23 (m, 1H), 6.94 (m, 1H), 6.89 (m, 1H), 3.43-3.76 (m, 9H), 2.86 (m, 1H), 1.90 (bs, 1H), 1.20 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:20])[C@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](OCC(O)C(C1C=CC=CC=1Cl)O)[C:22]1C=CC=C[CH:23]=1>>[CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[O:12][C:22]([CH3:23])([CH3:21])[O:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H](COCc1ccccc1)[C@@H](O)c1ccccc1Cl
Reactant: OC(COCc1ccccc1)C(O)c1ccccc1Cl
Product: CC1(C)O[C@@H](COCc2ccccc2)[C@@H](c2ccccc2Cl)O1
Yield: 85 %

Procedure:
The substantially same method as described in Example 371 was conducted, except that (1S,2R)-3-(benzyloxy)-1-(2-chlorophenyl)propane-1,2-diol (Preparation example 375) was used instead of that (±)-3-(benzyloxy)-1-(2-chlorophenyl)propane-1,2-diol (Preparation example 370), to obtain the title compound (0.84 g, 85%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>>[Br:26][C:14]1[C:13]2[CH:12]=[C:11]([O:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)[CH:19]=[CH:18][C:17]=2[N:16]2[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]=12
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: O=C1CCC(=O)N1Br
Product: CC(C)N1CCC(Oc2ccc3c(c2)c(Br)c2n3[C@H](C)CNC2=O)CC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 82, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8) and N-bromosuccinimide, to give the desired product as a light yellow oil (69%).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2CC(C(O)=O)C2)C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCN(CC)CC.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>C1COCC1>[CH3:53][S:54]([O:13][CH2:12][CH:10]1[CH2:11][N:8]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)(=[O:56])=[O:55]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A solution of 1-(diphenylmethyl)-3-(hydroxymethyl) azetidine (1 g, 3.9 mmol) [prepared by reduction of 1-(diphenylmethyl)azetidine-3-carboxylic acid (CAS No.: 36476-87-6) using LiAlH4 in refluxing THF] and Et3N (0.71 mL, 5.1 mmol) in THF (30 mL) was treated with methanesulfonyl chloride (0.36 mL, 4.7 mmol) and stirred for 2 h at room temperature. The precipitate was removed by filtration and washed with THF. The liquors were evaporated and the residue partitioned between water and DCM. The DCM layer was separated and the aqueous re-extracted. The combined organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was triturated with isohexane, the solid then isolated by filtration and dried to give the title compound as an orange solid (1.1 g, 84%). m/z (ES+) 332 (M+H)+.
Reaction SMILES: [CH:1]1[N:10]2[C:4]([CH2:5][CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:9]=32)=[N:3][CH:2]=1.[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=1)=[O:19]>>[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[CH2:7][CH2:6][CH2:5][C:4]4[N:10]([CH:1]=[CH:2][N:3]=4)[C:9]=3[CH:11]=2)[N:27]=1)=[O:19]
Reactant: Nc1ccc2c(c1)-n1ccnc1CCC2
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)-n2ccnc2CCC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 5,6-dihydro-4H-3,10b-diaza-benzo[e]azulen-9-ylamine and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide were converted to 3-[5-chloro-2-(5,6-dihydro-4H-3,10b-diaza-benzo[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide. HCl salt: 1H NMR (300 MHz, CD3OD) δ 8.25 (s, 1H), 8.08 (d, 1H), 7.85 (s, 1H), 7.81 (d, 1H), 7.68 (d, 1H), 7.65 (s, 2H), 7.51 (d, 1H), 3.07 (t, 2H), 2.91 (s, 3H), 2.80 (t, 2H), 2.50 (pent, 2H); MS (m/e) 466 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:22]([N:25](CC2C=CC(OC)=CC=2OC)[C:26]2[S:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[O:20][CH3:21])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:22]([NH:25][C:26]2[S:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][C:11]=1[O:20][CH3:21])#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Cc3ccc(C(F)(F)F)cc3OC)c(C#N)c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)ccc1Cc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-Cyano-N-(2,4-dimethoxybenzyl)-4-[2-methoxy-4-(trifluoromethyl)benzyl]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 30, 33.8 mg, 0.056 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0° C. Trifluoroacetic acid (22 μL, 0.28 mmol) was added and the reaction stirred for 3 hours warming slowly to room temperature. The solvent was removed in vacuo and the residue re-dissolved in methanol (˜5 mL). Once again the solvent was removed in vacuo. The material was suspended in methanol (5 mL) and filtered through Celite™. The reaction mixture was concentrated in vacuo and purified by the B-HPLC method to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(Cc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(Cc2ccccc2)c1
Yield: 94.6 %

Procedure:
A mixture of ethyl 1-benzyl-1H-pyrazole-4-carboxylate (53.0 g, 0.23 mol) and LiOH (19.4 g, 0.46 mol) in THF (100 mL) and H2O (100 mL) was stirred at refluxed for 6 h. Then, THF was removed, the residue was acidify by 6 N HCl, precipitation was formed, filtered and dried to give the desired compound as a white solid (44.0 g, 92.8%). 1H NMR (DMSO-d6) δ 12.36 (s, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.38-7.27 (m, 5H), 5.37 (s, 2H). MS (ESI) m/e [M+1]+ 202.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C@H:20]([C:34]1[NH:38][C:37]2[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:36]=2[N:35]=1)[CH2:21][CH2:22][NH:23]C(OCC1C=CC=CC=1)=O.C[Si](I)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C@H:20]([C:34]1[NH:38][C:37]2[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:36]=2[N:35]=1)[CH2:21][CH2:22][NH2:23]
Reactant: O=C(NCC[C@H](Nc1ncnc2cc(C(=O)N3CC=CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)OCc1ccccc1
Agent: C[Si](C)(C)I
Product: NCC[C@H](Nc1ncnc2cc(C(=O)N3CC=CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 15c from 6-chloro-4-[(1S)-3-(benzyloxycarbonyl-amino)-1-(5-chloro-1H-benzimidazol-2-yl)-propyl-amino]-7-(2,5-dihydropyrrol-1-yl-carbonyl)-quinazoline and trimethylsilyl iodide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(#N)C.CN(C)C1C=CN=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:27])[F:28])=[CH:22][CH:21]=2)(=[O:25])=[O:24])=[N:3][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Br)cn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(Nc1ccc(Br)cn1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To 2-Amino-5-bromopyridine (15, 1.50 g, 8.67 mmol) in acetonitrile (20.0 mL) were added pyridine (6.0 mL, 0.074 mol), 4-dimethylaminopyridine (0.10 g, 0.82 mmol) and 4-trifluoromethyl-benzenesulfonyl chloride (48, 2.14 g, 8.75 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated, poured into water, acidified with 1N HCl to pH=2, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was washed with ethyl acetate to give a white solid as desired compound (49, 2.80 g, 84.8%). MS (ESI) [M+H+]+=381.0, 383.0.