Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:45])([F:44])[F:33])=[CH:37][CH:38]=3)=[CH:6][CH:7]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Cl)cc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 598.2 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH2:31][C:32](O)=[O:33].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.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH2:31][C:32]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:33]
Reactant: Cc1ccc(F)c(CC(=O)O)c1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)c(CC(=O)N2CCc3cc(-c4nn(C)c5ncnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (2-fluoro-5-methylphenyl)acetic acid (34.7 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, off-white solid formed. The solid was filtered to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H), 3.28 (t, J=8.46 Hz, 2H), 3.89 (s, 2H), 3.93 (s, 3H), 4.29 (t, J=8.46 Hz, 2H), 7.07 (s, 1H), 7.09-7.16 (m, 2H), 7.43 (d, J=8.34 Hz, 1H), 7.52 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CO>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCOc2ccc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCOc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a stirred solution of methyl 4-butyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (412 mg) in methanol (5 mL) was added 1 M potassium hydroxide (17 mL). The mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with chloroform (4×50 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 384 mg of the title compound: ESI MS m/z 236 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[NH:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].C(OP(Cl)(OCC)=O)C.[N+:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])#[C-:36]>C1COCC1>[CH2:41]([O:40][C:38]([C:37]1[N:35]=[CH:36][N:11]2[C:10]=1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=1)=[O:39])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2ccccc2C1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1CN(C(=O)OC(C)(C)C)Cc1ccccc1-2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (10.0 g, 38.16 mmol) in dry THF (300 mL) at 0° C., was added potassium tert-butoxide (6.4 g, 56.76 mmol) under nitrogen atmosphere and the reaction mixture was stirred at this temperature for 30 min followed by dropwise addition of diethylchlorophosphate (11 mL, 76.3.3 mmol). The reaction mixture was stirred at 0° C. for 40 min. This solution was transferred via cannula to a suspension of potassium tert-butoxide (12.86 g, 114.56 mmol) and ethyl isocyanoacetate (11.66 mL, 102.65 mmol) in dry THF (150 mL), kept in a separate flask at 0° C. under nitrogen atmosphere. When the addition was complete, the reaction mixture was allowed to come to r.t. and stirred for 45 min. during which the reaction was complete as confirmed by TLC. Reaction mixture was cooled to 0° C. and quenched with 10% acetic acid solution and stirred for 20 min. The crude compound was extracted with ethylacetate. The organic layer was washed with water, separated, dried over Na2SO4 and concentrated in vacuo to afford the crude compound which was purified by column chromatography (neutral alumina using neutral alumina, 3:7 EtOAc:Pet.Ether) to afford a viscous gel which was further purified by crystallisation from diethyl ether and hexane to afford 4H,6H-2,5,10b-triaza-benzo[e]azulene-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester a white solid (4.4 g, 33%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[Li+].[Cl-].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][Zn+])=[CH:26][CH:25]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C.O.C1COCC1.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 20 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a nitrogen-degassed mixture of 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (3.27 g, 10.0 mmol), lithium bromide (2.58 g, 30.0 mmol), (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) dichloride (0.136 g, 0.2 mmol), 1-methyl-2-pyrrolidinone (30 mL) and THF (30 mL) was added a solution of 4-fluoro-benzylzinc chloride in THF (0.5 M, 40 mL, 20 mmol) and resulting mixture was stirred at 20° C. for 3 h. The mixture was poured into water (150 mL) and 5% aqueous citric acid (30 mL) and the resulting mixture extracted with Et2O (3×70 mL). The organic phase was washed with water (100 mL), brine (3×100 mL), dried (MgSO4) and evaporated in vacuo to give an oil. Chromatography (SiO2, eluted with petrol-EtOAc 0-30%) gave the title compound (3.5 g, 99%) as an oil. MS: [M+H]+=357.
Reaction SMILES: Cl/[C:2](=[N:15]\[OH:16])/[C:3]1[CH:8]=[CH:7][C:6]([P:9]([CH3:14])(=[O:13])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.[C:17]([C:19]1[C:20]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[N:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>C1COCC1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][O:31][C:20]2[C:19]([C:17]3[O:16][N:15]=[C:2]([C:3]4[CH:8]=[CH:7][C:6]([P:9]([CH3:14])(=[O:13])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=4)[CH:18]=3)=[CH:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:21]=2)=[CH:38][CH:37]=1
Reactant: C#Cc1cnc(-c2ccccn2)nc1OCc1ccc(OC)cc1
Reactant: CCOP(C)(=O)c1ccc(/C(Cl)=N/O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3OCc3ccc(OC)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.3 %

Procedure:
A mixture of compound 38-e (750 mg, 2.8 mmol), compound 37-j (820 mg, 2.6 mmol) and triethylamine (780 mg, 7.8 mmol) in THF (20 mL) was stirred at room temperature for 12 h. The resulting mixture was concentrated under reduce pressure, purified by column chromatography on silica gel (DCM:MeOH=30:1) to give compound 38-f (780 mg). LC-MS 543 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24](O)=[O:25].Cl.[CH3:28][O:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH2:32][CH2:33][NH:34][CH2:35]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[N:6]=[C:5]2[C:24]([N:34]1[CH2:33][CH2:32][C:31]2[C:36](=[CH:37][CH:38]=[CH:39][C:30]=2[O:29][CH3:28])[CH2:35]1)=[O:25]
Reactant: COc1cccc2c1CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1cccc2c1CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccc(F)cc13)C2
Yield: 41.1 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 104 (41.1% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.88 and 3.03 (2t, 2H), 3.55 and 4.02 (2t, 2H), 3.72-3.3.77 (m, 6H), 3.86 and 3.92 (2s, 6H), 4.48 and 4.92 (2s, 2H), 6.63-7.27 (m, 3H), 7.62-7.85 (m, 3H), 7.98-8.07 (m, 1H), 8.23-8.26 (m, 1H); MS (ESI) m/z 504 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([NH:17][NH2:18])=O)[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl.[C:22](=N)([NH2:24])[CH3:23].[OH-].[Na+].CCOC(C)=O>C1COCC1>[CH3:23][C:22]1[NH:18][N:17]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=3)[N:14]=2)[N:24]=1
Reactant: CC(=N)N
Reactant: NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
To a solution of 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide (9.7 g, 33.7 mmol) and acetimidamide hydrochloride (4.8 g, 50.5 mmol) in dry THF (300 mL), NaOH (2.0 g, 50.5 mmol) was added at RT. The mixture was refluxed overnight. The solution was cooled, concentrated and ethane-1,2-diol (100 mL) was added. The resulting mixture was heated at 180° C. for 3 h, cooled to RT, diluted with H2O (800 mL), and extracted with EtOAc (3×400 mL). The combined organic layers were washed with H2O (300 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude solid product, which was treated with EtOAc (150 mL). The resulting suspension was stirred at RT for 15 min, and then filtered to afford 4.8 g of the pure desired compound. The remaining filtrate was concentrated and purified by silica gel column chromatography (Petroleum ether:EtOAc=1:1) to afford 1.4 g of another batch of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid-overall 6.2 g, yield 59%. MS (ES+) C12H8F3N5O2 requires: 311. found: 312 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH3:1][C:2]1[N:7]2[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N)n1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2c(C)cccc2n1
Yield: 100 %

Procedure:
A solution of 6-methyl-2-pyridinamine (10 g, 93 mmol) [Aldrich, A75706] and ethyl bromopyruvate (15 mL, 110 mmol) in ethanol (93 mL) was heated at 90° C. for 4 h. The reaction mixture was concentrated, diluted with dichloromethane (250 mL), and washed with 10% aqueous potassium carbonate (200 mL). The aqueous layer was separated and extracted with additional dichloromethane (100 mL). The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude solid. The solid was treated with diethyl ether (300 mL) and, after several minutes, the diethyl ether was decanted to give the desired product (19 g, quantitative) as a solid after drying under reduced pressure. This material was used without further purification. LCMS for C11H13N2O2 (M+H)+: m/z=205.1.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:14]1([C:20]([NH:33][C@@H:34]([CH2:37][C:38]2[N:42]([C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:41]=[N:40][CH:39]=2)[CH2:35][OH:36])([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)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[Si:6]([O:36][CH2:35][C@@H:34]([NH:33][C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:37][C:38]1[N:42]([C:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:41]=[N:40][CH:39]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H](Cc1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](Cc1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 101.4 %

Procedure:
Imidazole (12.269 g, 0.180 mol) and tert-butyldimethylsilyl chloride (TBDMSCl) (20.37 g, 0.135 mol) were added to a solution of the compound (XXI) (56.390 g, 0.0901 mol) in dry DMF (560 ml) under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into water, extracted with Et2O, washed with water and a saturated NaCl aqueous solution, then dried over Na2SO4, and concentrated to obtain a light-yellow foamy material (67.602 g). This crude product was purified by silica gel column chromatography (hexane/acetone=5/1) to obtain the objective compound (XX) (58.770 g; yield: 88.1%) as a white foamy material.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH3:14]>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH2:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: N
Solvent: C1CCOC1
Product: Cc1ccc2nc(Cl)nc(N)c2c1

Procedure:
A mixture of 2,4-dichloro-6-methylquinazoline (500 mg, 2.348 mmol) and a solution of ammonia in tetrahydrofuran (20 mL, 3.0 M) was stirred in an ice-bath for 2 hours. The resulting mixture was concentrated in vauco to afford 454 mg of the crude product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][CH2:25][CH2:26][CH:27]2[S:31][C:30](=[O:32])[NH:29][C:28]2=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:14][CH:15]=1>[C].[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][CH2:25][CH2:26][CH:27]2[S:31][C:30](=[O:32])[NH:29][C:28]2=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:14][CH:15]=1
Reactant: COc1cc(CCCC2SC(=O)NC2=O)ccc1OCc1coc(/C=C/c2ccccc2)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(CCCC2SC(=O)NC2=O)ccc1OCc1coc(CCc2ccccc2)n1
Yield: 53.8 %

Procedure:
A mixture of 5-[3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2,4-thiazolidinedione (0.37 g), palladium-carbon (5%, 0.74 g) and tetrahydrofuran (20 ml) was subjected to catalytic hydrogenation at 1 atm and room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give crystals. The crystals were recrystallized from ethyl acetate-hexane to give 5-[3-[3-methoxy-4-(2-phenethyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-thiazolidinedione (0.20 g, 54%). Colorless prisms, mp: 126-127° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[C:21](Cl)=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[C:21]([C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3cccc(Cl)c32)cc1
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3cccc(-c4cccnc4)c32)cc1
Temperature: 25 °C

Procedure:
A mixture of intermediate 25 (30 mg, 0.06 mmol), 3-pyridine boronic acid (74 mg, 0.60 mmol), Pd(OAc)2 (13 mg, 0.06 mmol), S-Phos (49 mg, 0.12 mmol) and K3PO4 (100 mg) in 4 mL 99:1 v:v toluene/H2O was heated at 150° C. for 40 min in a microwave reactor. After cooling to rt, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (10-100% EtOAC/hexanes) to afford the title compound as a racemic mixture. 1H NMR (500 MHz, (CD3)2CO): δ 8.62 (s, 1H), 8.58 (d, 1H), 8.42 (s, 1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.40 (m, 2H), 7.20 (d, 2H), 7.16 (d, 1H), 7.14 (m, 1H), 7.02 (d, 2H), 5.20 (d, 1H), 4.85 (d, 1H), 1.23 (s, 9H). LC-MS: m/z 539.2 (M+H)+. The racemic mixture was separated by HPLC using a chiralcel OD-H column and 20% EtOH/hexanes as the mobile phase. The fastest eluting isomer (E1) has a retention time of 12.0 min, the slower eluting isomer (E2) has a retention time of 20 min.
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH2:29][O:30]C(=O)C)=[O:28])[CH:21]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CO>[C:1]([C:3]1[CH:35]=[CH:34][C:6]([CH2:7][O:8][NH:9][C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:28])[CH2:29][OH:30])[CH:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)OCC(=O)Nc1cc(CNc2ccccc2C(=O)NOCc2ccc(C#N)cc2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(CONC(=O)c2ccccc2NCc2ccnc(NC(=O)CO)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetic acid (4-{[2-(4-cyano-benzyloxycarbamoyl)phenylamino]-methyl}-pyridin-2-ylcarbamoyl)-methyl ester (Example 537, 52 mg) was suspended in methanol (2 ml) and 2M aqueous sodium hydroxide (1 ml) was added. The reaction mixture was stirred at room temperature for 10 minutes. The pH of the mixture was adjusted to 7 by addition of 2M hydrochloric acid. The resulting precipitate was isolated by filtration and dried in vacuo, affording the title compound. 13C-NMR (DMSO-d6) δ 171.2, 167.5, 151.7, 151.3, 148.6, 148.1, 141.9, 132.8, 132.3, 129.3, 128.1, 118.8, 118.1, 114.9, 113.0, 111.6, 111.0, 110.9, 76.1, 61.6, 45.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1>O.[Zn]>[SH:4][CH2:3][CH2:2][NH:1][C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: NCCS
Reactant: O=C1CCC(=O)O1
Agent: [Zn]
Solvent: O
Product: O=C(O)CCC(=O)NCCS
Temperature: 100 °C
Yield: 84.7 %

Procedure:
A mixture of 5 g of cysteamine and 6 g of succinic anhydride is stirred under an inert atmosphere at a temperature of about 100° C. The transformation of the starting products is practically total one-half hour after the beginning of the reaction. The mixture is dissolved in 50 cm3 of water to which are added, with stirring, 5 g of sulfonic acid resin and 3 g of zinc powder to transform the disulfide present in the mixture. The resin is removed by filtration and the filtrate is concentrated under reduced pressure. After drying, 9 g of N-(2-mercapto ethyl) succinamic acid are obtained whose characteristics are identical to those of the acid obtained following the procedure of section (a), above.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)=O>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][C@H:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)OC(=O)N1CCC(C(C)Oc2cnc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1
Agent: O=C=O
Solvent: CO
Product: CC(C)OC(=O)N1CCC([C@H](C)Oc2cnc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1

Procedure:
The racemic 1-methylethyl 4-[1-({5-[4-(methylsulfonyl)phenyl]-2-pyrazinyl}oxy)ethyl]-1-piperidinecarboxylate (prepared as in Example 162) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 85% CO2: 15% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers, which were further purified by chromatography on an ISCO silica gel column using 0 to 50% EtOAc/hexanes. The title compound was isolated as a white foam with Tr of 13.37 min (first eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1.[OH-].[K+].O>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1COCC1>[CH2:17]([O:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1c(F)cc(F)cc1Br
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(F)c(OCc2ccccc2)c(Br)c1
Temperature: 64 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
2-Bromo-4,6-difluoro-phenol (10 g, 48 mmol), Bu4NBr (0.24 g, 0.72 mol) and BnBr (8.22 g, 48 mmol) was mixed in THF (100 mL). 50% KOH (13.46 g, 240 mmol) was added to the mixture, heated to 64° C. and stirred for 2 h. Water was added to the mixture, the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product 2-(benzyloxy)-1-bromo-3,5-difluorobenzene (13.7 g, 96%), which was used immediately without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6](N)=[CH:5][CH:4]=[N:3]1.[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][N:12]=1)[CH3:9]>>[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([NH:17][C:1]2[N:3]=[CH:4][C:5]3[CH2:5][CH2:6][NH:2][CH2:1][C:6]=3[N:2]=2)[CH:14]=[CH:13][N:12]=1)[CH3:9]
Reactant: Cn1nccc1N
Reactant: CCOc1cc(N)ccn1
Product: CCOc1cc(Nc2ncc3c(n2)CNCC3)ccn1

Procedure:
N-(2-ethoxypyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (186) was prepared in accord with the procedures described in steps 1 to 4 of example 25 except in step 1, 1-methyl-1H-pyrazol-5-amine was replaced with 2-ethoxypyridin-4-amine.