Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[H][H].[ClH:36]>CO>[NH2:1][C@H:2]([C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[ClH:36]
Reactant: [H][H]
Reactant: CCOC(=O)CNC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)CNC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1

Procedure:
19.78 g (43 mmoles) of Z-Tyr(But)-Gly-OEt are dissolved in 200 ml of methanol. A Pd-on-charcoal catalyst is added to this solution and hydrogen is passed through the solution while stirring and adding approx. 2N methanolic HCL at pH 4.5 (autotitrator), until no further methanolic HCl is taken up. The catalyst is then filtered off and the filtrate is concentrated. The residue is stirred with ether and suction-drained. Yield 14.87 g (93.7%), melting point 140°-142°, [α]D22 =+30.9° (c=1, methanol).
Reaction SMILES: Br[CH2:2][Br:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH:8](=[O:15])[C:9]1[CH:14]=C[CH:12]=[CH:11][CH:10]=1.BrCl.Cl>>[Br:3][C:2]1[CH:14]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:15]
Reactant: O=Cc1ccccc1
Reactant: BrCBr
Agent: Cl
Agent: ClBr
Agent: [Al+3]
Product: O=Cc1cccc(Br)c1
Yield: 85 %

Procedure:
Charge 0.8 molar proportion of dibromomethane and 1.3 molar proportions of anhydrous aluminum chloride to a suitable reaction vessel. Add one molar proportion of benzaldehyde to the resultant slurry with agitation over a period of one hour at 40°-50° C. After completing the addition of the benzaldehyde, add one molar proportion of bromine chloride over a period of 4-5 hours while continuing agitation and maintaining the pot temperature at 50°-70° C. Continue agitation for an additional hour at 60°-70° C. Transfer the reaction mass to a flask containing dilute hydrochloric acid, separate the organic, and recover the solvent by distillation. The process results in the formation of 3-bromobenzaldehyde which is isolated in an 85% yield (99+% purity) by vacuum distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[NH:6][C:7]1[S:8][C:9]([CH3:14])=[CH:10][C:11]=1[C:12]#[N:13])([O-])=O.[ClH:19]>C(OCC)(=O)C.C(O)(C)C.[Pd]>[ClH:19].[NH2:13][C:12]1[C:11]2[CH:10]=[C:9]([CH3:14])[S:8][C:7]=2[NH:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:1]=1
Reactant: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N
Temperature: 81 °C
Reaction time: 15 h

Procedure:
2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile (100 g) is taken in ethyl acetate (1000 ml). 5% Pd/C (15 g) is added and hydrogenated at 50° C. for 15 hours. Ethyl acetate is distilled off to get the solid. The solid is taken in isopropyl alcohol (500 ml), concentrated hydrochloric acid (102 ml) is added at room temperature and the mixture is heated up to 80-82° C. for 12 hours under stirring. The solution is cooled to precipitate the solid, filtered and dried under vacuum at 55-60° C. to give the title compound (80 g).
Reaction SMILES: FC1C=CC=CC=1NN[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(NNc1ccccc1F)c1ccccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred mixture, under nitrogen, of 3.0 g of 2-fluorobenzoic acid, 2-(2-fluorophenyl)hydrazide, 3.0 g of triphenylphosphine, and 25 ml of acetonitrile was added, dropwise, 1.6 g of carbon tetrachloride. The reaction mixture was stirred for 22 hours at ambient temperature and concentrated to an oil. Flash chromatography on silica gel, eluting with 25% ethyl acetate/hexane afforded α-chloro-2-fluorobenzaldehyde, (2-fluorophenyl)hydrazone as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[C:3]1[C:16]([NH2:18])=[O:17].[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[C:29](=[O:34])[N:28]([C:35]1[N:42]=[CH:41][CH:40]=[C:39](I)[C:36]=1[CH:37]=[O:38])[N:27]=[CH:26]2)([CH3:22])([CH3:21])[CH3:20].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[C:29](=[O:34])[N:28]([C:35]1[C:36]([CH:37]=[O:38])=[C:39]([C:5]3[CH:4]=[C:3]([C:16]([NH2:18])=[O:17])[N:2]([CH3:1])[CH:6]=3)[CH:40]=[CH:41][N:42]=1)[N:27]=[CH:26]2)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(I)c3C=O)ncc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(N)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc1C(N)=O
Reaction time: 32 h
Yield: 28.2 %

Procedure:
In a 100 mL round-bottomed flask, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxamide (61.0 mg, 244 μmol, Eq: 1.10), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-iodonicotinaldehyde (100 mg, 222 μmol, Eq: 1.00) and [1,1′-bis(Diphenylphosphino)ferrocene]dichloro palladium (II) (16.2 mg, 22.2 μmol, Eq: 0.1) were combined with dioxane (667 μl) to give a red solution. Potassium carbonate (61.3 mg, 443 μmol, Eq: 2) in water (66.7 μl) was added and the resultant suspension was heated to 70° C. and stirred for 32 h. The reaction was diluted with ethyl acetate (10 mL), washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 10% to 15% EtOAc in hexanes to give 4-[2-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-3-formyl-pyridin-4-yl]-1-methyl-1H-pyrrole-2-carboxylic acid amide (28 mgs, 28.2%) as an off white solid. 1H NMR (DMSO-d6) δ: 10.06 (s, 1H), 8.72 (d, J=5.3 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 7.91 (d, J=1.8 Hz, 1H), 7.79 (dd, J=13.3, 1.8 Hz, 1H), 7.73 (d, J=5.3 Hz, 1H), 7.69-7.76 (m, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.12 (br. s., 1H), 3.93 (s, 3H), 1.39 (s, 9H); MS m/e 448.5 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([NH:1][C@@H:2]2[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:6][CH2:7]2)=[O:38])[CH2:36][CH2:35]1
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Reactant: O=C(Cl)C1CC1
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)C5CC5)CC4)c[nH]c13)OCO2

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH2:13][OH:14]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH:13]=[O:14]
Reactant: OCc1n[nH]c2ccc(OC(F)(F)F)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1n[nH]c2ccc(OC(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A solution of [5-(trifluoromethoxy)-1H-indazol-3-yl]methanol (0.109 g, 0.470 mmol) in ethyl acetate (2 mL) was added with manganese dioxide (0.409 g, 4.70 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite, then the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the objective 5-(trifluoromethoxy)-1H-indazole-3-carbaldehyde (0.0710 g, 65%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:15][OH:16])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:17](I)[CH3:18]>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:15][O:16][CH2:17][CH3:18])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 35.5 %

Procedure:
Sodium hydride (60% purity, 4.6 g) was suspended in tetrahydrofuran (50 mL) and a solution (50 mL) of (R)-1-tert-butoxycarbonyl-2-hydroxymethylpyrrolidine (20 g) in tetrahydrofuran was added dropwise under ice-cooling. After the completion of the dropwise addition, the mixture was stirred with heating at 50° C. for 30 min and ice-cooled. Ethyl iodide (18.7 g) was added to the reaction mixture and the mixture was stirred overnight at room temperature. After the completion of the reaction, the solvent was concentrated and water was added to the obtained residue. The mixture was extracted with chloroform and dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography. The fraction eluted with hexane:ethyl acetate=3:1 was concentrated to give (R)-1-tert-butoxycarbonyl-2-ethoxymethylpyrrolidine (8.1 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:3].Br[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19]>>[CH2:21]([O:20][C:18]([C:17]1[C:6]2[NH:7][C:8]3[CH:9]=[C:10]([F:14])[CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4][CH:2]([CH3:1])[NH:3][CH:16]=1)=[O:19])[CH2:22][CH3:23]
Reactant: CCCOC(=O)C(=O)CBr
Reactant: CC(N)Cc1c[nH]c2cc(F)ccc12
Product: CCCOC(=O)C1=CNC(C)Cc2c1[nH]c1cc(F)ccc21

Procedure:
2-Methyl-8-fluoro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid n-propyl ester was prepared in a manner similar to that described in Example 1A by using α-methyl-6-fluorotryptamine and n-propyl 3-bromopyruvate; MS (ESI): 303 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:12]=[N:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][N:4]=1.C1(C2N=CN(C3CCNCC3)C=2C2C=CN=CN=2)C=CC=CC=1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]([CH:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:12]=[N:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CNc1nccc(-c2c(-c3ccccc3)ncn2C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: c1ccc(-c2ncn(C3CCNCC3)c2-c2ccncn2)cc1
Product: CNc1nccc(-c2c(-c3ccccc3)ncn2C2CCNCC2)n1

Procedure:
The title compound was prepared from tert-butyl 4-{5-[2-(methylamino)pyrimidin-4-yl]-4-phenyl-1H-imidazol-1-yl}piperidine-1-carboxylate (C25) according to the general procedure for the synthesis of 4-(4-phenyl-1-piperidin-4-yl-1H-imidazol-5-yl)pyrimidine (C23) in Example 11. In this case, after the organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure, the product was obtained as a white solid. Yield: 174 mg, 0.520 mmol, 100%. APCI m/z 335.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.09-2.20 (m, 2H), 2.37 (br d, J=12 Hz, 2H), 2.97 (s, 3H), 3.0-3.04 (m, 2H), 3.41-3.46 (m, 2H), 4.93 (tt, J=12, 4 Hz, 1H, assumed; partially obscured by water signal), 6.33 (d, J=5.1 Hz, 1H), 7.27-7.35 (m, 3H), 7.37-7.41 (m, 2H), 8.05 (s, 1H), 8.09 (d, J=5.1 Hz, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.[CH3:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.[CH2:36]([O:43][C:44]1[CH:55]=[CH:54][C:47]([C:48](N(OC)C)=[O:49])=[CH:46][CH:45]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(=O)C>C1COCC1>[CH2:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([C:48](=[O:49])[CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:54][CH:55]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CC(=O)O
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An oven-dried, 3-neck, 250 mL round bottom flask equipped with a magnetic stirbar, addition funnel, and internal thermometer was cooled to ambient temperature under a stream of dry nitrogen. The flask was charged with lithium diisopropylamide, 1.8M solution in THF/heptane/ethylbenzene (22.07 mL, 39.7 mmol), diluted with THF (30 mL), and the solution was chilled to 0° C. To this stirred, 0° C. solution was added dropwise via syringe a solution of 4-methylpyridine (3.87 mL, 39.7 mmol) in THF (25 mL). After the addition was complete the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was then further chilled to −78° C. To this stirred, −78° C. solution was added dropwise via the addition funnel a solution of 4-(benzyloxy)-N-methoxy-N-methylbenzamide (4.9 g, 18.06 mmol) in THF (30 mL). The resulting reaction mixture was stirred at −78° C. for 2 hours. At this point the reaction was quenched with 4.5 equivalents of acetic acid (4.7 mL) added dropwise to the −78° C. reaction mixture. The reaction was then allowed to slowly warm to ambient temperature overnight. Desired product had precipitated from the reaction mixture. Saturated aqueous sodium bicarbonate was added to the reaction mixture. The two layers were filtered to collect the white, insoluble product (3.765 g, 68.7%), then the layers were separated. The aqueous layer was extracted with EtOAc. The combined EtOAc extracts were diluted with CHCl3 to better solubilize the product, then dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow solid. This solid was rinsed with Et2O repeatedly to remove 4-methylpyridine. The pale yellow solid weighed 1.456 g (26.7%, 95% overall). 1H NMR (300 MHz, CDCl3) δ 9.55 (dd, J=4.5, 1.5, 2H), 8.00-7.94 (m, 2H), 7.45-7.31 (m, 5H), 7.19 (d, J=5.9, 2H), 7.05-6.99 (m, 2H), 5.14 (s, 2H), 4.22 (s, 2H). MS (DCI—NH3) m/z=304 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][C:19](=[O:29])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N+:26]([O-])=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.O1CCCC1.[H][H].N>[Ni].CO>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([N:6]2[C:5]3[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH2:15][CH2:14]1)=[O:29]
Reactant: [H][H]
Reactant: O=C(NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 16 parts of N{2-[4-(5-chloro-2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-nitrobenzamide in 90 parts of tetrahydrofuran and 40 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, there is added a solution of methanol, previously saturated with gaseous ammonia. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in acidified water and the whole is washed twice with trichloromethane. The aqueous phase is separated and alkalized with a diluted sodium hydroxide solution. The product is extracted twice with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of ethanol and a small amount of water, yielding 2 parts of 2-amino-N-{2-[4-(5-chloro-2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl} benzamide; mp. 226.8° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([C:13](OC)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>CCOCC>[CH3:1][O:2][CH2:3][CH2:4][C:5]1([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COCCC1(C(=O)OC)CCCCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COCCC1(CO)CCCCCCC1
Temperature: 0 °C

Procedure:
A solution of EXAMPLE 46B (6.5 g) in ether (50 mL) was added dropwise to a suspension of LiAlH4 (1.2 g) in ether (60 mL). Once the addition was finished, the mixture was refluxed for 90 minutes, cooled to 0° C. and 2N aqueous NaOH (50 mL) was added slowly. The mixture was then extracted with ethyl acetate (300 mL) and the organic layer was washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent provided the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][C@@H:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15].FC1C=CC(N[C@H](CC)C(O)=O)=C([N+]([O-])=O)C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][C@@H:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: CC[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: CC[C@@H](Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Product: CC[C@H](Nc1cc(Br)ccc1[N+](=O)[O-])C(=O)O

Procedure:
4-Bromo-2-fluoronitrobenzene was treated with (S)-2-aminobutyric acid according to the procedure for the preparation of (R)-2-(4-fluoro-2-nitrophenylamino)-butyric acid (see Example 1) to yield (2S)-2-[(5-bromo-2-nitrophenyl)amino]butanoic acid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C:26]1([CH2:32][C:33]([OH:35])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C[O-].[Na+].Cl>CN(C=O)C.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C:26]2([CH2:32][C:33]([OH:35])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC1(CC(=O)O)CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nc(C(=O)NC2(CC(=O)O)CCCCC2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 20000 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.3 μmol) and (1-amino-cyclohexyl)-acetic acid (245 mg, 1.56 mmol) (Matrix Scientific, Columbia S.C.) in 3 mL of DMF was added NaOMe solid (67 mg, 1.25 mmol). The resultant mixture was heated in a 150° C. oil bath for 7 h. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, dried and the purified by silica gel chromatography, eluting with 10-70% EtOAc/hexanes to provide the title compound 27 mg (0.06 mmol) in 19% yield. LC-MS ESI−: 443.95 (M−1)−.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13]([CH2:15]I)[CH:12]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:10]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:8][C:9]1[N:10]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[CH:12]=[C:13]([CH2:15][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: Sc1ccncc1
Reactant: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1COCCN1c1cc(CSc2ccncc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 64.5 %

Procedure:
4-Mercaptopyridine (0.752 g, 6.77 mmol) was added to 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.596 g, 4.51 mmol) in acetonitrile (100 mL) at RT under air. DBU (0.3 mL, 2.01 mmol) was then added and the resulting solution was stirred at RT for 2 minutes. The solvent was removed and DCM was added. The reaction mixture was washed sequentially with water, the organic layer dried (MgSO4), filtered and evaporated. The crude product was chromatographed on silica, eluting with 0-2% methanol in DCM. Impure fractions were further chromatographed on silica, eluting with 0-4.5% methanol in DCM and combined with the initial pure fractions to give the desired material as a yellow gum (0.980 g).
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:32][N:33]([CH2:34][C:35]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([C:18]2[N:19]3[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)=[C:16]([C:11]3[CH:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=4)[CH:17]=2)[CH2:27]1)=[O:36])[CH3:38]
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(C3CCCNC3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCCC(c2cc(-c3ccc4cn(-c5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
A mixture of 5-(2-phenyl-2H-indazol-6-yl)-7-piperidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (120 mg, 0.27 mmol), N,N-dimethylglycine (31 mg, 0.30 mmol), EDCl (62 mg, 0.32 mmol), HOBt (44 mg, 0.32 mmol), and N,N-diisopropylethylamine (187 μL, 1.08 mmol) in DMF (2 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 19 mg (16%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.10 (d, 2 H), 7.94 (d, 1 H), 7.85 (d, 1 H), 7.69 (s, 1 H), 7.53-7.63 (m, 2 H), 7.39-7.48 (m, 1 H), 722 (s, 1 H), 6.67-6.73 (m, 1 H), 3.98-4.57 (m, 2 H), 2.84-3.38 (m, 5 H), 2.58-2.81 (m, 1 H), 2.08-2.29 (m, 6 H), 1.68-1.91 (m, 2 H), 1.39-1.66 (m, 1 H); ES-MS m/z 495.15 [M+H]+, HPLC RT (min) 2.27.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:5]=[C:4]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH:31]([N:34]([CH3:36])[CH3:35])[CH2:30]4)=[O:28])=[CH:23][CH:22]=3)[CH:18]=[N:19][CH:20]=2)[CH:3]=1.[CH2:37]([OH:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:44][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:5]=[C:4]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH:31]([N:34]([CH3:36])[CH3:35])[CH2:30]4)=[O:28])=[CH:23][CH:22]=3)[CH:18]=[N:19][CH:20]=2)[CH:3]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: OCc1ccccc1
Reactant: Cc1cccc(-c2nc(Cl)cc(-c3cncc(-c4ccc(C(=O)N5CCC(N(C)C)C5)cc4)c3)n2)n1
Product: Cc1cccc(-c2nc(OCc3ccccc3)cc(-c3cncc(-c4ccc(C(=O)N5CCC(N(C)C)C5)cc4)c3)n2)n1

Procedure:
This compound is prepared from (4-{5-[6-chloro-2-(6-methyl-pyridin-2-yl)-pyrimidin-4-yl]-pyridin-3-yl}-phenyl)-(3-dimethylamino-pyrrolidin-1-yl)-methanone (Ex. 16) and benzyl alcohol analogously to Example 8; [M+H]+=571.