Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:31]3[CH:32]=[CH:33][C:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])=[CH:29][CH:30]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:22])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 105 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see intermediate 100) (39.0 g, 106 mmol), {4-[(ethyloxy)carbonyl]phenyl}boronic acid (22.5 g, 116 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.83 g, 1.584 mmol) were mixed in DME (430 mL) and the mixture treated with a 2M Na2CO3 aqueous solution (210 mL, 420 mmol). The resulting mixture was degassed under house vacuo with several quenches with nitrogen, stirred at 105° C. under nitrogen for approximately 6 h and then cooled to room temperature and partitioned between AcOEt and water. The two layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed brine then were filtered through a 70 g silica cartridge, washing the cartridge with AcOEt. The combined filtrate and washings were concentrated in vacuovacuo. The residue was triturated with Et2O then filtered off to give ethyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (35.2 g, 80.56 mmol, 76%) as a grey solid. The mother liquors were concentrated in vacuo and the residue obtained triturated with Et2O. The solid formed was filtered off to give ethyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (5.96 g, 13.64 mmol, 13%) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1([C:5]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH3:15])[N:6]=2)[CH2:4][CH2:3]1.[Cl:16]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:16][C:9]1[C:5]([C:2]2([Cl:1])[CH2:4][CH2:3]2)=[N:6][N:7]([CH3:15])[C:8]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(C2(Cl)CC2)nn1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cl)c(C2(Cl)CC2)nn1C
Temperature: 80 °C

Procedure:
500 mg (2.19 mmol) of ethyl 3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate are dissolved in 10 ml of N,N-dimethylformamide p.a., and 438 mg (3.28 mmol)) of N-chlorosuccinimide are added. The reaction mixture is heated at 80° C. for 15. The cooled reaction solution is diluted with water and extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. The crude product is filtered through silica gel and eluted with ethyl acetate. This gives 517 mg (80%) of ethyl 4-chloro-3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate in a purity of 89%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([OH:26])=O)[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2].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.[CH2:61]([NH2:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:68][CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[O:26])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2]
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)O)OC[C@H]2C)n1
Reactant: NCc1ccccc1
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
Solvent: CCOC(C)=O
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)OC[C@H]2C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinecarboxylic acid (302 mg, 0.81 mmol), HATU (340 mg, 0.89 mmol), and Hünig's base (0.21 mL, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 10 minutes. Benzylamine (0.100 mL, 0.92 mmol) was then added and stirring continued at room temperature for 17 hours. LC-MS indicated about 50% conversion so another portion each of Hünig's base (0.21 mL, 1.20 mmol) and HATU (340 mg, 0.89 mmol) were added. After about 10 minutes more benzylamine (0.100 mL, 0.92 mmol) was added, and the mixture was stirred for an additional 1.5 hours, then diluted with EtOAc (25 mL) and washed successively with water, saturated aqueous NaHCO3, and brine (25 mL each). The organic phase was then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g SiO2, 15-50% EtOAc in hexanes gradient) to give the title compound (302 mg) as a yellow oil. LC-MS (ES) m/z=461 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:27])[CH2:16][C:15]2[NH:14][CH:13]=[C:12]([CH2:17][CH2:18][C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=O)[C:11]=2[C:10](=O)[CH2:9]1>C1COCC1.[OH-].[Na+].O>[CH3:27][C:8]1([CH3:7])[CH2:16][C:15]2[NH:14][CH:13]=[C:12]([CH2:17][CH2:18][CH2:19][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11]=2[CH2:10][CH2:9]1
Reactant: CCN(CC)C(=O)CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCCc1c[nH]c2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
LAH (0.57 g, 15.1 mmol) was added dropwise to a suspension of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-N,N-diethylpropionamide (1.1 g, 3.8 mmol) in THF (80 mL). The mixture was refluxed overnight. The reaction was cooled and ice was added until no more gas was generated. A few drops of 15% NaOH in water was then added. The mixture was stirred at room temperature for 30 minutes and then filtered to remove insolubles. The filtrate was concentrated to give 0.9 g of [3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-diethyl-amine as a light yellow oil.
Reaction SMILES: COC1C=CC(C[N:8]2[C:13](=[O:14])[C:12]([NH:15][CH2:16][C:17]3[S:18][C:19]([CH3:22])=[N:20][N:21]=3)=[CH:11][C:10]([O:23][CH2:24][C@H:25]3[CH2:27][C@@H:26]3[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=3)=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C@H:26]2[CH2:27][C@@H:25]2[CH2:24][O:23][C:10]2[CH:11]=[C:12]([NH:15][CH2:16][C:17]3[S:18][C:19]([CH3:22])=[N:20][N:21]=3)[C:13](=[O:14])[NH:8][N:9]=2)=[N:29][CH:30]=1
Reactant: COc1ccc(Cn2nc(OC[C@H]3C[C@@H]3c3ccc(OC)cn3)cc(NCc3nnc(C)s3)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C)s3)c(=O)[nH]n2)nc1
Temperature: 60 °C

Procedure:
2-(4-methoxybenzyl)-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-4-(((5-methyl-1,3,4-thiadiazol-2-yl)methyl)amino)pyridazin-3(2H)-one (50 mg, 0.096 mmol) was dissolved in TFA (2 ml) and heated at 60° C. for 24 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The crude was purified by Prep-HPLC to afford title product. LRMS m/z (M+H) 401.1 found, 401.1 required. 1H NMR (400 MHz, MeOD) δ 8.06 (d, 1H), 7.30 (dd, 1H), 7.17 (d, 1H), 5.94 (s, 1H), 4.81 (s, 2H), 4.15 (dd, 1H), 4.04 (dd, 1H), 3.85 (s, 3H), 2.75 (s, 3H), 2.11 (m, 1H), 1.72 (m, 1H), 1.21 (m, 1H), 1.07 (m, 1H).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([C:27]([N:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH:30]2[CH2:42][O:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:28])=[CH:24][CH:23]=1>CO>[ClH:15].[ClH:1].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH:30]2[CH2:42][O:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:28])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccc3Cl)s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(c1ccc(-c2ccccc2Cl)s1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 40 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(5-(2-chlorophenyl)thiophene-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (75.9 mg, 0.121 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 23.8 mg (40%) of the desired product as a white solid. LC-MS: RT=5.27 min, [M+H]+=414.1.
Reaction SMILES: [C:1]([C:4]1[CH2:5][CH2:6][C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]>[Pd]>[C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(=O)CC1
Agent: [Pd]
Product: CC(=O)c1ccc(=O)[nH]c1C

Procedure:
Kato et al. [J. Heterocyclic Chem. 18, 603-606 (1981)] show, inter alia, the dehydrogenation of 5-acetyl-3,4-dihydro-6-methyl-2(1H)-pyridinone by heating it with palladium black to produce 5-acetyl-6-methyl-2(1H)-pyridinone, which in turn is reacted with phosphorus oxychloride (phosphoryl chloride) to produce a mixture of 6-chloro-3-ethynyl-2-methylpyridine and 6-chloro-3-(1-chlorovinyl)-2-methylpyridine.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[C:15]([NH2:31])=[N:16][CH:17]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:24]=2)[CH:19]=1.C(N(CC)CC)C>CC(N(C)C)=O>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[C:15]([NH2:31])=[N:16][CH:17]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:26][CH2:27][N:28]([CH:2]([CH3:4])[CH3:3])[CH2:29][CH2:30]3)[CH:24]=2)[CH:19]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2o1
Reactant: CC(C)I
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2-Iodopropane (0.029 ml) was added in one portion to 3-(1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.100 g) and triethylamine (0.05 8 ml) in DMA (3 ml) and the resulting solution was stirred for 30 minutes. A further portion of 2-iodopropane (0.029 ml) was added, the temperature was increased to 50° C. and the reaction mixture was stirred for a further 90 minutes. A third portion of 2-iodopropane (0.029 ml) was added, and then triethylamine (0.058 ml) was added and the reaction heated at 50° C. for a further hour. The reaction mixture was then evaporated to dryness and redissolved in DMSO (3.6 ml) and the crude product was purified by preparative X bridge HPLC (C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length using decreasingly polar mixtures of water containing 1% ammonia and MeCN as eluents). There was thus obtained 3-(1,3-benzoxazol-2-yl)-5-[1-(1-isopropyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.065 g); Mass Spectrum: M+H+ 403.17; RT 2.49 min; NMR Spectrum: (DMSOd6) 8.53 (1H, d), 8.44 (1H, d), 8.32 (1H, s), 7.90 (1H, s), 7.82-7.86 (1H, m), 7.77-7.81 (1H, m), 7.62 (2H, s), 7.41-7.49 (2H, m), 4.05-4.16 (1H, m), 2.91 (2H, d), 2.77 (1H, quintet), 2.29 (2H, t), 2.02-2.11 (2H, m), 1.94 (2H, qd), 1.01 (6H, d).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][C:10]1([O:24][CH2:25][CH3:26])[CH2:13][C@@H:12]([C:14](OCC)=[O:15])[C@@H:11]1[C:19](OCC)=[O:20])[CH3:8].[Cl-].[NH4+].S(=O)(=O)(O)O>C1COCC1.CCOCC>[CH2:25]([O:24][C:10]1([O:9][CH2:7][CH3:8])[CH2:13][C@@H:12]([CH2:14][OH:15])[C@@H:11]1[CH2:19][OH:20])[CH3:26]
Reactant: CCOC(=O)[C@@H]1CC(OCC)(OCC)[C@H]1C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC1(OCC)C[C@@H](CO)[C@@H]1CO
Yield: 70.1 %

Procedure:
To a suspension of lithium aluminum hydride (2.38 g, 0.0627 mol) in dry THF (50 ml) was added slowly (trans)-3,3-diethoxy-1,2-cyclobutanedicarboxylic acid, diethyl ester (11.29 g, 0.0392 mol) in THF (25 ml) so that a gentle reflux was maintained. The reaction was heated at 55° for 4 hours and then diluted with ether (100 ml) and poured into saturated aqueous ammonium chloride (100 ml). The pH was lowered to 4 with 3M sulfuric acid. The suspension was extracted with ether (4×100 ml) and then chloroform (3×100 ml). The ether extracts were combined, dried over sodium sulfate, filtered and concentrated to give 5.613 g of desired product. The chloroform extracts were combined, dried over sodium sulfate, filtered and concentrated to give 112 mg of additional desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[NH2:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[CH3:38][N:37]1[C:33]([NH:32][C:19](=[O:21])[CH:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=3)=[CH:17][CH:16]=2)[CH3:22])=[CH:34][C:35]([CH3:39])=[N:36]1
Reactant: CCOc1ccc(C#Cc2ccc(C(C)C(=O)O)cc2)cc1
Reactant: Cc1cc(N)n(C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(C#Cc2ccc(C(C)C(=O)Nc3cc(C)nn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 30 mg (0.11 mmol) 2-[4-(4-ethoxy-phenylethynyl)-phenyl]-propionic acid in (XI.2) 3 mL THF are added 55 μL (0.32 mmol) DIPEA, followed by 30 mg (0.11 mmol) chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate. The mixture is stirred at rt for 30 min. After that time, 12 mg (0.11 mmol) 5-amino-1,3-dimethylpyrazole are added and stirring is continued for 12 h. The solvent is removed and the residue is taken up in 1 mL DMF. 50 μL DIPEA are added, followed by 30 mg TBTU (0.11 mmol) and 12 mg (0.11 mmol) 5-amino-1,3-dimethylpyrazole. Stirring is continued for 12 h. The solvent is removed and the residue is purified by RP-HPLC (narrow gradients, water/ACN+0.1% TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:23])=[CH:4][CH:3]=1.[Sn](Cl)Cl>CO.Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[N:10]=2)=[CH:14][CH:15]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(Cl)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: Nc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1

Procedure:
5-(4-Chlorophenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide obtained in Example 55 is suspended in methanol and ice-cooled. To the suspension was added a solution of tin(II) chloride 6 hydrate in 6 M hydrochloric acid and the mixture is reacted and treated in the same manner as in Example 48 to give 2-(4-aminophenyl)-5-(4-chlorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH:7]=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)([O-:3])=[O:2].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])[CH3:21]>C(O)C>[CH2:20]([O:22][C:23]([C:24]1[CH:7]([C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:26][C:25]=1[NH2:27])=[O:28])[CH3:21]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(c2ccccc2)=CC1c1cccc([N+](=O)[O-])c1
Yield: 71 %

Procedure:
Upon boiling a solution of 25.3 g of 3-nitrobenzylideneacetophenone and 13.0 g of amidinoacetic acid ethyl ester in 250 ml of ethanol for 2 hours, 2-amino-6-phenyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 171°-172°C (ethanol) is obtained. Yield: 71 percent of theory.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:30]=[C:29]([O:31][CH2:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[CH:28]=[CH:27][CH:26]=2)[N:4]=1)[CH3:2].[ClH:43]>C(OCC)(=O)C>[ClH:43].[ClH:43].[NH2:35][CH2:34][CH2:33][CH2:32][O:31][C:29]1[N:30]=[C:25]([CH2:24][N:5]2[C:6]3[C:11](=[C:10]([NH:12][C:13]([C:15]4[N:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]5=[N:17][CH:16]=4)=[O:14])[CH:9]=[CH:8][CH:7]=3)[C:3]([CH2:1][CH3:2])=[N:4]2)[CH:26]=[CH:27][CH:28]=1
Reactant: CCc1nn(Cc2cccc(OCCCNC(=O)OC(C)(C)C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2cccc(OCCCN)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-(6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yloxy)propylcarbamate (17.2 mg, 0.0302 mmol) in ethyl acetate was added hydrogen chloride (1 mL; 4M in dioxane). The mixture was stirred for 30 minutes. The solvent was removed under reduced pressure to give N-(1-((6-(3-aminopropoxy)pyridin-2-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (11.6 mg). MS (APCI), positive scan, m/z=470.1 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[O:29]>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:29]
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(F)cc1F
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccc(F)cc2F)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:28]2[CH:32]=[C:31]([C:33]3[C:34]4[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=4[N:36]=[CH:37][N:38]=3)[CH:30]=[N:29]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].C(N)CN>FC(F)(F)C(O)=O.C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:28]2[CH:32]=[C:31]([C:33]3[C:34]4[CH:41]=[CH:40][NH:39][C:35]=4[N:36]=[CH:37][N:38]=3)[CH:30]=[N:29]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)Nc6ccc(F)cc6C(F)(F)F)CC5)C4)c3)ncnc21
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)Nc3ccc(F)cc3C(F)(F)F)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide (210 mg, 0.3 mmol) was dissolved in a 50 M solution of trifluoroacetic acid in methylene chloride (20 mL). After being stirred at room temperature for one hour, the solvents were removed under reduced pressure. The residue was dissolved in methanol (20 mL) and ethylenediamine (1.0 g, 17 mmol). After being stirred at room temperature for one hour, the mixture was purified by HPLC (method B) to give 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide as a white powder. LC-MS: 568.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (s, 1H), 8.76 (s, 1H), 8.63 (s, 1H), 8.36 (s, 1H), 8.18 (s, 1H), 7.55 (d, J=3.6 Hz, 1H), 7.50 (m, 1H), 7.43 (m, 1H), 7.34 (m, 1H), 7.01 (d, J=3.6 Hz, 1H), 3.79 (m, 2H), 3.67 (d, J=8 Hz, 2H), 3.51 (m, 4H), 2.92 (m, 2H), 2.38 (m, 1H), 1.62 (m, 2H), 1.09 (m, 2H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.BrBr.[CH3:27][C:28]1[CH:29]=[C:30]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[O:31][CH2:32][C:33]([O:35]CC)=[O:34]>C(Cl)Cl>[CH3:27][C:28]1[CH:29]=[C:30]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[O:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)COc1cc(C)cc(C)c1
Agent: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)cc(OCC(=O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Referring to FIG. 42, a mixture of PPh3 (0.8 g, 3.0 mmol) and imidazole (0.3 g, 4.5 mmol) in DCM (20 mL) was stirred for 30 min at 0° C. Then a solution of Br2 (0.7 g, 4.5 mmol) in DCM (5 mL) was added. The mixture was kept at 0° C. for 10 min and compound 1 (0.3 g, 1.5 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min (monitored by TLC and UPLC analysis). The mixture was washed with diluted HCl solution (20 mL×2), saturated aqueous NaHSO3 (20 mL) and brine (20 mL), respectively. The organic layer was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1 to 30:1) to afford the title compound 2 (0.2 g, 40% yield); 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J=8.4 Hz, 2H), 7.10 (d. J=8.4 Hz, 2H), 4.51 (s, 2H), 2.86-2.81 (m, 2H), 2.68-2.65 (m, 2H), 2.07-2.06 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc3ccccc3n2)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Quinoline-2-carboxylic acid. LC-MS (basic): tR=0.96 min; [M+H]+=503.3.