Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:23]=1.O>CN(C)C=O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[N:23]=2)=[CH:33][CH:32]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: ClCc1cccc(-c2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2cccc(-c3ccc(Cl)cc3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 2-Chloromethyl-6-(4-chloro-phenyl)-pyridine [ZA 6706809] were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water and n-heptane. The residue was dried at 40° C. to give 143 mg (78%) of the title compound as white powder.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[OH:13].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[O:13][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1
Reactant: Cc1nc2ccccc2c(Br)c1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3c(C)nc4ccccc4c3Br)c2cc1OC
Temperature: 140 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
4-Bromo-3-hydroxy-2-methyl-quinoline (35 mg), 4-chloro-6,7-dimethoxyquinoline (110 mg), and 4-dimethylaminopyridine (89 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (20 mg, yield 32%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:5].[N:13](OCCC(C)C)=O.C(O)(=O)C>C1C=CC=CC=1>[N+:5](=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3]([O:2][CH3:1])=[O:12])=[N-:13]
Reactant: CC(C)CCON=O
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)CCC(=[N+]=[N-])C(=O)OC

Procedure:
A solution of L-glutamic acid dimethyl ester (2.6 g, 14.8 mmol), isoamyl nitrite (2.13 mL, 15.9 mmol) and acetic acid (0.22 mL) in benzene (150 mL) is heated to reflux for one hour. The solution is washed with IN aqueous sulfuric acid, water, saturated sodium hydrogen carbonate solution, water and brine (50 mL each). The solvent is removed in vacuo to yield dimethyl 2-diazopentane-1,5-dioate which can be further purified by column chromatography.
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=O)[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:23]([OH:29])=[N:24][CH:25]=[CH:26][C:27]=1[OH:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:29][C:23]1[C:22]([NH:21][C:18]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:10]=2[N:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:17]=[CH:16]3)=[O:20])=[C:27]([OH:28])[CH:26]=[CH:25][N:24]=1
Reactant: Nc1c(O)ccnc1O
Reactant: O=C(O)c1cccc2ccc(Oc3ccccc3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1c(O)ccnc1O)c1cccc2ccc(Oc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-phenoxyquinoline-8-carboxylic acid (178c 217 mg, 0.818 mmol), 3-aminopyridine-2,4-diol (155 mg, 1.227 mmol), HATU (622 mg, 1.636 mmol), and DIPEA (438 μl, 2.454 mmol) in DMF (1636 μl) was stirred at RT for 1 h. Purification by silica gel (100% DCM to 5% MeOH/DCM) provided N-(2,4-dihydroxypyridin-3-yl)-2-phenoxyquinoline-8-carboxamide (179c) as a yellow solid. MS (ESI, pos. ion) m/z: 374.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:19]1[CH:18]=[CH:17][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccc2ccccc2c1
Temperature: 50 °C
Yield: 49 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 1.21 g, 5.44 mmol), 2-naphthaleneboronic acid (Lancaster; 1.00 g, 5.8 mmol), copper(II) acetate (990 mg, 5.45 mmol) and triethylamine (1.9 mL, 13.6 mmol) in 1,2-dichloroethane (30 mL) was heated in an oil bath at 50° C. for 1.5 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 15-30% ethyl acetate/hexanes, to give N-benzyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (929 mg, 49%) as a yellow oil that solidified on standing.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.Cl.Cl.[CH2:19]([NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1)[CH3:20].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH2:19]([NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:33][CH2:34]2)=[C:25]([CH3:35])[CH:24]=1)[CH3:20]
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(C)c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (7.20 mg, 0.033 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (13.40 mg, 0.042 mmol) and (cyanomethyl)trimethylphosphonium iodide (13.02 mg, 0.054 mmol) in Propiononitrile (Volume: 0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.029 mL, 0.167 mmol) at 23° C. The reaction was stirred at 95° C. for 18 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×1 mL) and dried in vacuo to provide N-ethyl-3-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.004 g, 0.01 mmol, 27.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3 H) 2.26 (s, 3 H) 2.53-2.65 (m, 4 H) 2.84-2.99 (m, 4 H) 3.20-3.27 (m, 2 H) 3.65 (s, 2 H) 6.71-6.76 (m, 1 H) 7.02 (d, J=8.34 Hz, 1 H) 7.07 (dd, J=3.54, 1.26 Hz, 1 H) 7.57-7.60 (m, 1 H) 7.60-7.66 (m, 2 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.22 (t, J=5.56 Hz, 1 H) 8.36 (d, J=1.52 Hz, 1 H) 11.58 (s, 1 H). ESI-MS: m/z 445.4 (M+H)+. mp=254.8-258.5° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.C([Li])CCC.O=C1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCCC1.CCCCCC>[C:4]1([CH:3]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3([CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[O:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(c1ccccc1)c1ccccc1Br
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(C2OC3(CCOCC3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 11.1 g. of 2-bromobenzhydryl methyl ether in 23 ml. of tetrahydrofuran and 7 ml. of hexane is cooled to -50°C. and 22 ml. of butyllithium is introduced while maintaining the temperature below -50°C. The solution is stirred for 2 hours at -60° to -70°C. To the suspension is then added a solution of 5 g. of 4-oxo-tetrahydropyran in 5 ml. of tetrahydrofuran over a span of a few minutes. The mixture is stirred at -60°C. for 3 hours and at ambient temperature overnight. Ice-water is added, the organic layer is separated, the aqueous layer is extracted with methylene chloride and the combined organic solutions are dried over sodium sulfate. The solvent is removed under reduced pressure and subjected to column chromatography over alumina. Elution with benzene removes benzhydryl methyl ether, and the column is then eluted with diethyl ether. The solid obtained is heated at reflux in 60 ml. of glacial acetic acid, and then the solvent is removed under reduced pressure to leave a crystalline solid. This solid is recrystallized from hexane to give 1,2',3,3',5',6'-hexahydro-3-phenylspiro[isobenzofuran-1,4'-pyran] as colorless crystals, m.p. 132° - 134°C.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:8][Si:9]([CH3:24])([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]1[CH2:17][O:16]1>C(O)C>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[CH2:17][CH:15]([OH:16])[CH2:14][O:13][CH2:12][CH2:11][CH2:10][Si:9]([CH3:8])([CH3:24])[CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: CC(C)N(CC(O)COCCC[Si](C)(C)CC[Si](C)(C)C)C(C)C
Temperature: 60 °C

Procedure:
Diisopropylamine (3.68 g, 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 60° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 60° C. for an additional 8 hours. Ethanol and diisopropylamine were stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:10][C:11]1[N:12]=[CH:13][C:14]([C:15]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:16])=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1ccc(Br)nc1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Br)nc1)c1c[nH]c2ncccc12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
To a solution of 1H-Pyrrolo[2,3-b]pyridine (1, 1.2 g, 0.010 mol) in dichloromethane (50 mL) was added 6-bromo-nicotinoyl chloride (86, 2.6 g, 0.012 mol) at −10° C. After the solution turned clear, aluminum trichloride (10.2 g, 0.0765 mol) was added in one portion with vigorous stirring. The reaction mixture was stirred at −10° C. for 30 minutes, then was allowed to warm to room temperature and stirred at room temperature overnight. The reaction was quenched with ice water and neutralized with sodium bicarbonate. The solution was extracted with dichloromethane, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a white solid (87, 0.35 g, 11%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:38])=[C:11]([CH2:13][O:14][C:15]3[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]4[C:25]([CH:26]=[O:27])=[CH:24][N:23]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:22]=4)=[CH:17][C:16]=3[O:36][CH3:37])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:40][C:41]([O:43][CH3:44])=[O:42].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:26]([C:25]1[C:21]([O:20][CH2:19][C:18]2[CH:34]=[CH:35][C:15]([O:14][CH2:13][C:11]3[N:12]=[C:8]([C:4]4[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=4)[O:1][CH2:40][C:41]([O:43][CH3:44])=[O:42])[O:9][C:10]=3[CH3:38])=[C:16]([O:36][CH3:37])[CH:17]=2)=[N:22][N:23]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=1)=[O:27]
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(O)c2)oc1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A mixture of 3-[(4-{[2-(3-hydroxyphenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), methyl bromoacetate (0.37 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl (3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenoxy)acetate as colorless crystals (0.38 g, yield 41%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-109° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[C:11]([CH3:17])([CH3:16])[S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.CCN(CC)CC.[CH2:42]([NH2:45])[CH:43]=[CH2:44].Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:15])[NH:45][CH2:42][CH:43]=[CH2:44])[C:11]([CH3:17])([CH3:16])[S:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)N1CSC(C)(C)[C@H]1C(=O)O
Agent: Cl
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCNC(=O)[C@H]1N(C(=O)OC(C)(C)C)CSC1(C)C
Temperature: 2 °C

Procedure:
(4R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester (which can be prepared according to the methods of Ikunaka, M. et al., Tetrahedron Asymm. 2002, 13, 1201; Mimoto, T. et al., J. Med. Chem. 1999, 42, 1789; and Mimoto, T. et al., European Patent Application 0574135A1 (1993), 250 g; 0.957 mol) was added to an argon-purged 5-L flask and was dissolved in EtOAc (1.25 L). The solution was cooled to 2° C. and (PhO)2POCl (208 mL; 1.00 mol) was then added in one portion. NEt3 (280 mL; 2.01 mol) was added dropwise via addition funnel and the resulting suspension was then stirred at 0° C. Seven minutes later, allylamine (75.4 mL; 1.00 mol) was added dropwise. The ice bath was removed and the suspension was allowed to warm to room temperature. One-half hour later, 1 N HCl (750 mL; 0.750 mol) was added. The mixture was transferred to a 4-L separatory funnel using EtOAc (50 mL) for rinsing. The layers were separated. The organic fraction was washed with 7.2% aqueous Na2CO3 (2×1.25 L), and was then transferred to a 3-L distillation flask and was diluted with EtOAc (400 mL). The solution was dried azeotropically and concentrated to a volume of 800 mL by distillation of EtOAc at one atmosphere. After cooling to 25° C., the resulting clear yellowish EtOAc solution of (4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester was carried on directly into the next step. An aliquot was removed and concentrated to give (4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester as a white crystalline solid: mp=94–98° C., 1H NMR (300 MHz, CDCl3) δ 6.12 (br s, 1H), 5.88 (app ddt, J=10.2, 17.1, 5.6 Hz, 1H), 5.28 (app dq, J=17.1, 1.5 Hz, 1H), 5.18 (app dd, J=1.2, 10.2 Hz, 1H), 4.68 (s, 2H), 4.14 (br s, 1H), 3.95 (br t, J=5.4 Hz, 2H), 1.62 (s, 3H), 1.49 (s, 9H), 1.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.0, 154.0, 134.4, 116.9, 82.0, 73.3, 54.0, 48.7, 42.0, 30.6, 28.6, 24.6; MS (CI) m/z 301.1599 (301.1586 calcd for C14H25N2O3S, M+H+); elemental analysis calcd for C14H24N2O3S: C, 55.97; H, 8.05; N, 9.32; found: C, 56.11; H, 8.01; N, 9.11.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN([CH2:41][C:42]3C=CC=[CH:44][C:43]=3Cl)C=2N=1)(C)(C)C.C1(N)CCCCC1>>[C:1]([C:5]1[N:6]=[C:7]([NH:22][CH:27]2[CH2:26][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: NC1CCCCC1
Product: CC(C)(C)c1nc(NC2CCCCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and cyclohexane-amine and isolated as light-yellow solid (3.8 mg, 20%). MS (m/e): 399.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](O)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:45]([NH:47][NH2:48])=[O:46]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15]([NH:48][NH:47][CH:45]=[O:46])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C(=O)O)c2ccccc2)CC1
Reactant: NNC=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NNC=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.4 %

Procedure:
A mixture of 4-(1-phenyl-1-carboxy-methylene)piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 3.31 mmol), EDCI (0.888 g, 4.63 mmol) and HOBt (0.626 g, 4.63 mmol) in DMF (4 mL) was stirred for 30 min at room temperature and then formic hydrazide (3.97 g, 66.2 mmol) was added. Stirring was continued for 1 h and then the mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed (H2O ×3, brine), dried (Na2SO4) and evaporated to give the title compound (1.48 g, 97%) as a colorless oil:
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH:6]=[CH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(O)CCCC(CC=Cc1cccc(C(=O)O)c1)C(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(O)CCCC(CCCc1cccc(C(=O)O)c1)C(C)=O

Procedure:
3-(4-Acetyl-8-hydroxy-1-tridecenyl)benzoic acid (7.2 g., 0.02 mole) in ethanol (75 ml.) is hydrogenated over 1.5 g. of a 5% Pd on charcoal catalyst at 1 atmosphere pressure and room temperature. When the theoretical amount (0.02 mole) of hydrogen has been absorbed, the catalyst is filtered off, the solvent evaporated, and the residue chromatographed on silica gel with 4% methanol in chloroform as the eluant. The title compound is obtained as a colorless, viscous oil.
Reaction SMILES: [H-].[Na+].[Si]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2)(C(C)(C)C)(C)C.CS(O[CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=O)=O.O>CN(C=O)C>[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[N:15]=[CH:14]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(O)ccc32)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To a solution of NaH (60% in mineral oil) (43.5 mg, 1.81 mmol) in DMF at 0° C. was added 5-((tert-butyldimethylsilyl)oxy)-1H-indazole (300 mg, 1.21 mmol), and the mixture was stirred at 0° C. for 15 min. Tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (243 mg, 1.21 mmol) was then added to the mixture at 0° C. After addition, the mixture was stirred at 85° C. for 12 h. The mixture was poured into water, and the product extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by TLC (Pet.Ether:EtOAc=2:1) to give tert-butyl 4-(5-hydroxy-1H-indazol-1-yl)piperidine-1-carboxylate (250 mg, yield 65%) as a colorless oil. LCMS (m/z): 318.2 [M+H]+
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@H:13]([NH:26][C:27](=[O:36])[C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1.O.NN>C(O)C>[NH2:3][CH2:12][C@H:13]([NH:26][C:27](=[O:36])[C@H:28]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:29])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:18][CH:19]=1
Reactant: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)[C@@H](C)c2ccccc2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC[C@H](C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 60 °C
Yield: 51.3 %

Procedure:
A mixture of (S)-N-((R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methyl-butoxy)-phenyl)-ethyl)-2-phenyl-propionamide (320 mg, 0.66 mmol) and ethanol (20 mL) was treated dropwise with hydrazine monohydrate (0.32 mL, 6.6 mmol), and the resulting reaction was maintained at 60° C. overnight. The mixture was allowed to cool to room temperature and the solids were removed by filtration. The filtrate was concentrated to dryness, and triturated with ethyl acetate (15 mL), and the mixture was filtered. The collected solids were air dried, then dissolved in diethyl ether (5 mL). The resulting solution was treated with concentrated HCl (0.05 mL), and the precipitate was collected by filtration to afford (2S)-N-((1R)-2-amino-1-[4-((S)-2-methylbutoxy)phenyl]-ethyl)-2-phenylpropionamide (120 mg, 52% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 7.21-7.31 (m, 5H), 7.09 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.12 (dd, J=8.8, 5.8 Hz, 1H), 3.81 (dd, J=9.3, 6.1 Hz, 1H), 3.70-3.77 (m, 2H), 3.23-3.30 (m, 2H), 1.81 (s, 1H), 1.57 (ddd, J=13.4, 7.6, 5.8 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.24-1.33 (m, 1H), 1.02 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 355.1 [(M+H)+, calcd for C22H31N2O2 355.5].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=2[NH:19][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1.[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1[CH3:38].FC(F)(F)C1C=C(C=CC=1)N>CO>[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH:35][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([S:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:11]([NH:19][C:20]3[C:21]4[CH:29]=[CH:28][CH:27]=[N:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH:12]=2)=[CH:33][C:32]=1[CH3:38]
Reactant: Cc1cc(N)ccc1F
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3ncccc23)cc1
Agent: Nc1cccc(C(F)(F)F)c1
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(F)c(C)c3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product from Example 260B was reacted with 4-fluoro-3-methylaniline according to the procedure from Example 260C substituting 4-fluoro-3-methylaniline for 3-(trifluoromethyl)aniline to provide the title compound as an off white solid after trituration of the reaction product from methanol (44 mg, 52%).