Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Oc1ccc(F)cc1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccc(F)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.F[C:17]1[C:22]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:21][CH:20]=[CH:19][N:18]=1>CS(C)=O.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([O:15][C:17]3[C:22]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(NC2CCC(O)CC2)nc1
Reactant: Fc1ncccc1C1CCOCC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC2CCC(Oc3ncccc3C3CCOCC3)CC2)nc1
Yield: 60 %

Procedure:
4-(5-methyl-pyridin-2-ylamino)-cyclohexanol (50 mg) was added to a solution of 2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine, as prepared in preparation 1a, (50 mg) in DMSO (15 mL) and the reaction mixture was stirred until TLC analysis confirmed the absence of starting materials. Then the mixture was diluted with water (10 mL), and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography (EtOAc:Petrol ether=1:1) to provide (5-methyl-pyridin-2-yl)-{4-[3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-amine (0.03 g, yield 60%) as a solid. [M+1] 368. IC50 (uM): 0.057.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[OH:6])([O-])=O.CC(C)=O.[NH4+].[Cl-]>[Zn].O>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[OH:6]
Reactant: O=[N+]([O-])CC(O)c1ccc(-c2ccccn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: NCC(O)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
To a solution of consisting of 2-nitro-1-(4-pyridin-2-yl-phenyl)-ethanol (275 mg, 1.1 mmol) and acetone (5 mL) were added NH4Cl (900 mg, 16.9 mmol), Zn dust (1.10 g, 16.9 mmol), and water (1 mL). The reaction mixture was stirred for 2 h at rt and then filtered. The filtrate was washed with saturated NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (45 mg, 19%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([O:8][CH2:20][CH:19]=[CH2:18])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1cccc(OC(C)=O)c1
Temperature: 80 °C
Yield: 56.9 %

Procedure:
Resorcinol monoacetate (10.0 g, 65.7 mmoles) in anhydrous DMF (100 mL) was treated with K2CO3 (18.2 g, 131 mmoles) and allyl bromide (6.83 mL, 78.9 mmoles). The mixture was heated at 80° C. overnight, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 8% to 10% ethyl acetate:hexanes) to provide the title compound as a colorless oil (7.19 g, 57%). MS (DCI) m/z 193 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[OH-].[K+].[CH3:23]I>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:23])[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc(-c2nc3cccc(C(N)=O)c3[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(-c2nc3c(C(N)=O)cccc3n2C)cc1

Procedure:
2-(4'-Methoxyphenyl)benzimidazole-4-carboxamide (NU1076 from Example 5) (105.3 mg, 0.394 mmol) and powdered potassium hydroxide (22 mg, 0.394 mmol) were suspended in acetone (4 ml) and stirred until all the solids had dissolved. Methyl iodide (24.6 μl1, 0.394 mnol) was added and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure and the white solid residue purified by column chromatography with dichloromethane/methanol 95:5 to give fine white crystals of the title compound. (33.2 mg, 30%)
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].Br[NH:11][C:12](=[O:14])[CH3:13].O.C[CH2:17][O:18]CC>>[CH3:1][O:2][CH2:3][CH:4]1[O:18][CH:17]2[N:11]([C:12](=[O:14])[CH2:13]2)[CH:5]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOCC
Reactant: COC/C=C/C(=O)OC
Reactant: CC(=O)NBr
Solvent: O
Product: COCC1OC2CC(=O)N2C1C(=O)OC
Reaction time: 168 h

Procedure:
Methyl 4-methoxy-trans-crotonate (6.5 g, 50 m.mole) and N-bromoacetamide (7.6 g, 55 m.mole) were dissolved together in peroxide-free dioxane (30 ml) and water (12 ml) was added. The solution was kept at room temperature in the dark for 7 days. The resulting clear, colourless solution was diluted with ether (150 ml) and washed three times with water (50 ml portions). The solution was dried (MgSO4) and the solvent removed under reduced pressure to yield a colourless oil (9.47 g) which was chromatographed on silica-gel (elution with ethyl acetate/petroleum ether) to give the erythro bromohydrin (e2) as a colourless oil (3.46 g, 30.5%).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]3[C:11]=2[CH2:12][CH2:13][C:14](=[O:22])[NH:15]3)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(C1C(=O)C([Cl:33])=C(Cl)C(=O)C=1C#N)#N.O1CCOCC1.Cl>CC(C)=O>[OH2:20].[ClH:33].[N:1]1[C:2]([C:10]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14](=[O:22])[NH:15]3)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COc1ccc(-c2cn3ccccc3n2)c2c1NC(=O)CC2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2cn3ccccc3n2)c2ccc(=O)[nH]c12
Product: O
Yield: 49.7 %

Procedure:
5-(Imidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril (1.4 g) and DDQ (3.5 g) were added to dioxane (30 ml) and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted by the addition of chloroform and 0.5 N sodium hydroxide. The chloroform layer was washed with 0.5 N sodium hydroxide and then with water twice. After drying, chloroform was evaporated. The residue was isolated and purified through a silica gel column. The crude crystals thus obtained were dissolved in acetone and hydrochloric acid was added to the resulting solution. Crystals which precipitated were collected by filtration and recrystallized from water to give 410 mg of 5-(imidazo[1,2-a]-pyridine-2-yl)-8-methoxycarbostyril monohydrochloride monohydrate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CCCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-one and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: Fc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(F)c1

Procedure:
Using 2,4-difluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part P was converted into the title compound of EXAMPLE 163. 1H NMR(CDCl3) δ: 7.30-7.20 (m, 1H), 6.80-6.70 (m, 2H), 6.27 (d, 1H, J=2.2 Hz), 6.15 (d, 1H, J=2.2 Hz), 4.20 (broad s, 2H), 3.59 (ABq, 2H, JAB=15.2 Hz), 3.53-3.40 (m, 2H), 3.29-3.21 (m, 1H), 3.20-3.10 (m, 1H), 3.02-2.77 (m, 5H), 2.52 (dd, 1H, J=12.8, 9.2 Hz), 1.82-1.70 (m, 2H). LRMS (ES)+: 388.4 (M+H)+.
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].CI.[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][NH:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:12][CH:11]=1>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][N:19]([CH3:1])[C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:25][CH:26]=1
Reactant: O=C([O-])O
Reactant: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.9 %

Procedure:
1.18 g of sodium bicarbonate and 0.876 ml of methyl iodide were added, whilst ice-cooling, to a solution of 3.3 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methoxycarbonylpyrrolidine [prepared as described in step (9) above] dissolved in 30 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography over silica gel (eluted with a 1:2 by volume mixture of ethyl acetate and benzene), to afford 968 mg of the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C@H:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:9])=[CH:6][C:5]=1[F:26])([O-])=O.CO>C(O)C.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C@H:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:9])=[CH:6][C:5]=1[F:26]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])c(F)c1)C(=O)OCC
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(F)c1)C(=O)OCC
Reaction time: 1.5 h

Procedure:
A solution of diethyl N-(4-nitro-3-fluorobenzoyl)-(L)-glutamate (5.3 g, 14 mmoles) in 95% ethanol (150 mL) was mixed with 10% palladium on carbon (0.4 g) and placed on a Parr apparatus. The mixture was shaken under hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered, spin evaporated, and dried to give a cream solid; yield, 4.7 g (98%); mp 92°-97° C.; 1H-NMR (CDCl3) δ 1.22 and 1.29 (2t overlapped, 6H), 1.6 (br s, 2H), 2.1-2.5 (m, 4H), 4.10 and 4.22 (2q overlapped, 4H), 4.74 (m, 1H), 6.75 (t, 1H), 6.84 (d, 1H), 7.4-7.5 (m, 2H); uv (MeOH) 281 nm max (12000), 236 min (1480), 210 sh (10600); mass spec (CI) m/e 341 (100%), 138 (64).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:31])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:29]#[N:30])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].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>[CH2:15]([O:17][C:18]([C:20]1([NH:31][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:29]#[N:30])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccc(C#N)cc2C1
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (377 mg, 1.94 mmol), 2-amino-5-cyano-indan-2-carboxylic acid ethyl ester (670 mg, 2.91 mmol), HATU (1.11 g, 2.91 mmol) in anhydrous DMF (15 mL) is added DIPEA (480 μL, 2.91 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-70% EtOAc in heptane) to give a pure product (110) as a white semisolid (680 mg, 86%).
Reaction SMILES: C(N1[CH2:13][CH2:12][C:11](=O)[CH2:10]C1)C1C=CC=CC=1.[F:15][C:16]([F:48])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]([CH3:36])[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)=[O:21].C1(CBr)CC1>>[F:48][C:16]([F:15])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:28]([CH3:36])[N:27]([CH2:10][CH:11]3[CH2:13][CH2:12]3)[C:26]2=[O:37])[CH2:38][CH2:39]1)=[O:21]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Agent: BrCC1CC1
Product: CC1N(CC2CC2)C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1

Procedure:
The title compound, MS: m/e=540.3 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 1-benzyl-piperidin-4-one and cyclopropyl methyl bromide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH2:26])[CH2:10][C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH:26][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[CH2:10][C:9]1=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)C[C@H]2CC[C@H](n3cnc4c(N)ncnc43)[C@@H]1C2
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ncnc3c2ncn3[C@H]2CC[C@@H]3CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C3)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A 100 ml two-necked round-bottomed flask was loaded with 4.96 g of Boc-A lactams [sic] 15e (13.3 mmol) and 60 ml of dry CH2Cl2. 5.35 ml of dry pyridine (66.5 mmol) were then added, followed by 1.59 g of DMAP (1.3 mmol). After cooling to 0° C., 5.4 ml of 4-methoxybenzoyl chloride (39.9 mmol) were added dropwise and the mixture was stirred at 0° C. for 15 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 22 h. The reaction mixture was then again cooled to 0° C. and 35 ml of MeOH were added dropwise. After 30 min at 0° C., 80 ml of a saturated solution of NH3 in MeOH were added dropwise. A white precipitate was formed, which dissolved after complete addition of the solution. After 30 min, the ice bath was removed and the reaction was stirred at room temperature for a further 2 h. The solvent was then removed under reduced pressure and the resulting residue was dissolved in 200 ml of CH2Cl2. The solution was washed successively with 150 ml of saturated NaHCO3 solution and aqueous citric acid solution (20%, 2×100 ml), washed [sic] over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by means of chromatography (5.2×18 cm silica gel; eluent: EtOAc/MeOH 40:3) to afford 5.93 g of 15f (88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C1C=CC=CC=1)[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.N.[CH:21]1[CH:22]=[CH:23][C:24]2N(O)N=N[C:25]=2[CH:26]=1.CC[N:33]=C=NCCCN(C)C.Cl>ClCCl>[NH:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:10]([NH2:33])=[O:12])[C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:26]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(N)=O)c1ccccc1
Yield: 15.1 %

Procedure:
In a dichloromethane solution containing 4.3 g of N-(tert-butoxycarbonyl)phenylglycine, 5 ml of ammonia water, 1.5 g of HOBt and 23 g of EDC hydrochloride were added under ice cooling and the resultant mixture was stirred overnight at room temperature. The reaction mixture was treated similarly to that in Example 144 (Process 2) to give 0.42 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[CH2:7][CH:8]([NH:12][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:33]=2[C:34]([NH:36][CH2:37][C:38]#[CH:39])=[O:35])[C:28]([Cl:45])=[CH:27][N:26]=1>>[Cl:45][C:28]1[C:29]([NH:31][C:32]2[C:33]([C:34](=[O:35])[NH:36][CH2:37][C:38]#[CH:39])=[CH:40][CH:41]=[CH:42][C:43]=2[F:44])=[N:30][C:25]([NH:1][C:2]2[CH:23]=[CH:22][C:5]3[C:6]([CH3:20])([CH3:21])[CH2:7][CH:8]([NH:12][C:13]([N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[O:14])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:26][CH:27]=1
Reactant: CC1(C)CC(NC(=O)N2CCCC2)C(=O)Nc2cc(N)ccc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)N2CCCC2)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from Pyrrolidine-1-carboxylic acid (8-amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-amide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (47 mg, 35%), HPLC purity 96%, LCMS 550 (M-propargyl amide), 1H-NMR (DMSO-d6, 400 MHz) δ 9.48 (s, 1H), 9.39 (s, 1H), 9.16 (s, 1H), 8.92 (t, 1H), 8.18 (s, 1H), 7.58-7.48 (m, 2H), 7.40-7.32 (m, 1H), 7.23-7.20 (d, 1H), 7.08-7.02 (m, 2H), 5.95 (m, 1H), 4.18-4.12 (m, 1H), 3.99 (d, 2H), 3.56 (m, 1H), 3.20 (m, 4H), 2.15-2.10 (m, 1H), 2.00-1.92 (m, 1H), 1.79 (m, 4H), 1.32 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14](C)(C)C)(C)(C)C.[C]=O.[CH3:20][OH:21]>>[C:1]1([CH2:7][C:20]([O:13][CH3:14])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CO
Agent: [C]=O
Product: COC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
Toluene (1.38 g), methanol (32 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 67 mg methyl phenylacetate was obtained by column chromatography, in a yield of 89%. 1HNMR (400 MHz, CDCl3) δ 3.60 (s, 2H), 3.65 (s, 3H), 7.22-7.32 (m, 5H); 13CNMR (100 MHz, CDCl3) δ 41.2, 52.0, 127.1, 128.6, 129.3, 134.1, 172.0; HRMS (ESI) calcd. for C9H10NaO2 [M+Na]: 173.0568. found: 173.0573. The methyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 58 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 95%.
Reaction SMILES: [OH-:1].[K+:2].[CH2:3]([OH:5])C.[SH2:6].C(=S)=S>O>[C:3](=[S:6])([O-:5])[O-:1].[C:3](=[S:6])([O-:5])[O-:1].[C:3](=[S:6])([O-:5])[O-:1].[C:3](=[S:6])([O-:5])[O-:1].[K+:2].[K+:2].[K+:2].[K+:2].[K+:2].[K+:2].[K+:2].[K+:2]
Reactant: S
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Solvent: O
Solvent: S=C=S
Product: [O-]C([O-])=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Twenty grams (0.36 moles) of reagent grade potassium hydroxide was added to 200 grams (255 cc) of absolute ethyl alcohol, with the mixture being refluxed until all of the KOH had dissolved (approximately 1 hour), after which the water formed was removed by a conventional water-alcohol azeotropic distillation. After adding a sufficient amount of absolute alcohol to bring the alcoholic solution back up to about 250 cc and cooling the solution back to room temperature, 5.7 grams (0.18 moles) of finely divided sulfur was added, with stirring, after which 6.1 grams (0.18 moles) of hydrogen sulfide was dissolved therein. At the conclusion of this addition, the temperature of the exothermically heated solution was adjusted to about 130° F. and 13.6 grams (0.19 moles) of carbon disulfide were added, dropwise, thereto over a period of about 30 minutes. The mixture was then heated, under reflux, with stirring, for between about 20 minutes and about 1 hour, after which time a yellow-orange precipitate of potassium tetrathiocarbonate formed. The precipitate was vacuum filtered, under an inert atmosphere, and washed 3 times with about 50 cc of pentane. The washed material was dried, under vacuum, for about 8 hours at 60° C., to produce free-flowing salt particles.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[CH3:33][C:34]1[CH:50]=[CH:49][C:37]([C:38]([NH:40][C:41]2[C:42]([C:46](O)=O)=[N:43][NH:44][CH:45]=2)=[O:39])=[CH:36][CH:35]=1.[CH3:51][C:52]1[CH:53]=[C:54]([NH2:60])[C:55]([NH2:59])=[CH:56][C:57]=1[CH3:58]>>[CH3:51][C:52]1[C:57]([CH3:58])=[CH:56][C:55]2[NH:59][C:46]([C:42]3[C:41]([NH:40][C:38](=[O:39])[C:37]4[CH:49]=[CH:50][C:34]([CH3:33])=[CH:35][CH:36]=4)=[CH:45][NH:44][N:43]=3)=[N:60][C:54]=2[CH:53]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: Cc1ccc(C(=O)Nc2c[nH]nc2C(=O)O)cc1
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: Cc1ccc(C(=O)Nc2c[nH]nc2-c2nc3cc(C)c(C)cc3[nH]2)cc1

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide, however using 4-(4-methyl-benzoylamino)-1H-pyrazole-3-carboxylic acid and 4,5-dimethylbenzene-1,2-diamine to give N-[3-(5,6-dimethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-4-methyl-benzamide (32 mg) as a white solid. (LC/MS: Rt 3.42, [M+H]+ 346.26).