Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](Cl)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][NH:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:18]([CH2:19][CH2:20][OH:21])[CH3:17])=[CH:4][CH:3]=1
Reactant: CNCCO
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCO)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 72.4 %

Procedure:
A solution of 4,4′-dichlorobenzhydryl chloride (5.20 g, 19.1 mmol) and 2-(methylamino)ethanol (9.0 g, 0.106 mol) in acetonitrile (100 ml) was treated with powdered anhydrous potassium carbonate (10 g) and the resulting mixture was heated under reflux for 4 h. The cooled mixture was filtered and the filtrate was concentrated in vacuo. The residual oil was diluted with ethyl acetate, washed with water and brine and then dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by chromatography on silica gel (elution toluene-ethyl acetate 9:1) gave 4.29 g (79%) of the title material as a white solid: mp 49-50° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH3:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=2)=[CH:22][CH:21]=1>CN(C)C(=O)C>[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[N:27]=2)=[CH:22][CH:21]=1
Reactant: CN(C)CCOCCCN
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(=O)Nc3ccccc3N)cc2)n1
Solvent: CC(=O)N(C)C
Product: CN(C)CCOCCCNc1nccc(-c2ccc(C(=O)Nc3ccccc3N)cc2)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of dimethylaminoethoxypropylamine (2.02 mg, 12.5 μmol) in N,N-dimethylacetamide (125 μl), was added a solution of N-(2-aminophenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]benzamide (Method 62, 2.2 mg, 5 mop in N,N-dimethylacetamide (100 μl). The reaction mixture was heated to 50° C. and agitated for a period of 16 hours, before being evaporated to dryness to give the title compound; Mass Spectrum: M+H+ 435.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][O:8][CH3:9])[C@H:4]([OH:6])[CH3:5].C(N(CC)CC)C.[Br:17][C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1>C(#N)C>[Br:17][C:18]1[C:19]([NH:2][C@H:3]([CH2:7][O:8][CH3:9])[C@H:4]([OH:6])[CH3:5])=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1
Reactant: COC[C@@H](N)[C@@H](C)O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC[C@@H](Nc1nc(Cl)ncc1Br)[C@@H](C)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
311 mg (2.6 mmol) of (2R,3R)-3-amino-4-methoxy-butan-2-ol hydrochloride (production according to A. I. Meyers, D. Hoyer, Tet. Lett. 1985, 26, 4687) in 2 ml of acetonitrile is mixed with 0.28 ml of triethylamine and shaken. It is filtered, and the filter cakes are washed with 2 ml of acetonitrile. The filtrate is added in drops to a solution of 455 mg (2.0 mmol) of 5-bromo-2,4dichloro-pyrimidine in 26 ml of acetonitrile at −30° C. By removal of the cooling bath, it is slowly heated to room temperature while being stirred. After 16 hours, the solvent is drawn off in a rotary evaporator, and the remaining residue is purified by chromatography (hexane/ethyl acetate: 4:1-1:1). 509 mg (1.6 mmol, corresponding to 80% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH3:18])[NH:16][CH:17]=1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH3:18])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:17]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(-c2c(-c3ccccc3)noc2C)c[nH]1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)c(C)n1
Yield: 9 %

Procedure:
As described for Example 57, 5-methyl-4-(2-methyl-1H-imidazol-4-yl)-3-phenyl-isoxazole (70 mg, 0.3 mmol) using 4-fluorobenzotrifluoride instead of 4-fluoroacetophenone was converted to the title compound (10 mg, 9%) which was obtained as a light yellow solid. MS: m/e=384.1 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15]3=[C:16]([CH2:22][C:23](=[O:24])[N:14]3[CH2:13]1)[CH:17]=[CH:18][CH:19]=2)=[O:11])(=O)C.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15]3=[C:16]([CH2:22][C:23](=[O:24])[N:14]3[CH2:13]1)[CH:17]=[CH:18][CH:19]=2)=[O:11]
Reactant: CC(=O)OCCCCCC(=O)C1Cc2cccc3c2N(C1)C(=O)C3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: O=C(CCCCCO)C1Cc2cccc3c2N(C1)C(=O)C3
Reaction time: 5 h
Yield: 93.5 %

Procedure:
5-(6-Acetyloxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (10.0 g, 30.6 mmol) is suspended in anhydrous ethanol (150 ml), mixed with catalyst amounts of 4-methylbenzenesulfonic acid monohydrate and stirred for five hours at boiling temperature. The solvent volume is concentrated by evaporation to one third, and the product is obtained in the form of light yellow needles (8.22 g, 93.5%) by crystallization at −20° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1.Cl>CO>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:5]([OH:7])=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[N:23]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)cc2O)cc1
Reaction time: 22 h
Yield: 52.7 %

Procedure:
A mixture of 5 g (27.2 mmol) of ethyl trifluoroacetoacetate, 4.76 g (27.2 mmol) of 4-methoxyphenylhydrazine hydrochloride, and 0.5 ml of conc. HCl in 60 ml of methanol was refluxed with stirring for 22 hours. After removing methanol in vacuo, toluene was added and the resulting mixture was refluxed for 20 hours and cooled. The mixture was diluted with aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from methylene chloride/hexane and ethyl acetate/hexane to afford 3.7 g (53%) of 1-(4-methoxyphenyl)-3-trifluoromethyl-5-hydroxypyrazole as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([NH:34][C:6]1[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=[C:2]([Cl:1])[N:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
2,4-Dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (0.500 g, 1.89 mmol) was dissolved in THF (10 mL) then was added DIPEA (1.65 mL, 9.47 mmol), followed by benzylamine (0.406 g, 3.79 mmol). Then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to remove THF. To this residue, water (10 mL) was added and the aqueous solution was extracted with CH2Cl2 (25×3 mL). The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 11% EtOAc/hexanes) to afford N-benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.400 g, 63.1%). LCMS Condition B-47: retention time 2.70 min, [M+1]=335.0.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.[F:29][C:30]1[CH:35]=[C:34](O)[CH:33]=[CH:32][C:31]=1[C:37](=[O:39])[CH3:38]>>[F:29][C:30]1[CH:35]=[C:34]([O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)[CH:33]=[CH:32][C:31]=1[C:37](=[O:39])[CH3:38]
Reactant: CC(=O)c1ccc(O)cc1F
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1F

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of (2-fluoro-4-hydroxyphenyl)ethanone are treated as described in Example 56.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=3)=[O:12])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:22]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cc1
Yield: 53.9 %

Procedure:
Using 4-methanesulfonylaminobenzoic acid (800 mg) and (4-chlorophenyl)(piperidin-4-yl)methanone hydrochloride (967 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (843 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2].C(N(C(C)C)CC)(C)C.[ClH:41].[N:42]1([C:47](N)=[NH:48])C=CC=N1>CN(C)C=O>[ClH:41].[ClH:41].[CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:47](=[NH:42])[NH2:48])[CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2]
Reactant: N=C(N)n1cccn1
Reactant: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CNCC3)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CN(C(=N)N)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.2 %

Procedure:
To a solution of 3-[4-[4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester (70 mg) in dimethylformamide (1 ml) were added diisopropylethylamine (0.032 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (27 mg), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and to the obtained residue was added diethyl ether and the supernatant was removed. This procedure was repeated twice and hydrogen chloride-ethanol solution was added to the obtained residue and insoluble material was removed. The solution was concentrated and dried under reduced pressure to give the title compound (50 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:18]=1[O:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:18]=3[O:19][C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2N)C1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1C
Temperature: 70 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (1.17 g), (S)-tert-butyl 3-(2-amino-5-fluorophenoxy)piperidine-1-carboxylate (Intermediate 1.1 g) was dissolved in dioxane (10 ml) and p-toluenesulfonic acid (61 mg) was added. The reaction was heated at 70° C. for 1.5 h. The solution was poured into sat. NaHCO3 (50 ml) and extracted with chloroform. The organic phases were passed through a phase separator and concentrated in vaco. The sample was purified by chromatography (silica gel; solvent: isohexan:EtOAc 3:1→2:1) to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)[O:17][C:10]=23)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S:31]1[C:35]2[CH2:36][CH2:37][CH2:38][CH2:39][C:34]=2[CH:33]=[C:32]1[C:40](Cl)=[O:41]>>[CH3:1][C:2]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)[O:17][C:10]=23)=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:40]([C:32]1[S:31][C:35]2[CH2:36][CH2:37][CH2:38][CH2:39][C:34]=2[CH:33]=1)=[O:41]
Reactant: O=C(Cl)c1cc2c(s1)CCCC2
Reactant: Cc1c(N)cccc1-c1ccnc2cc(-c3ccc(C(=O)N4CCCC4)cc3)oc12
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1ccnc2cc(-c3ccc(C(=O)N4CCCC4)cc3)oc12

Procedure:
The compound was synthesized according to the procedure M using 2-methyl-3-{2-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furo[3,2-b]pyridin-7-yl}aniline (40.00 mg, 0.10 mmol) and 4,5,6,7-tetrahydro-1-benzothiophene-2-carbonyl chloride (22.22 mg, 0.11 mmol). The title compound was obtained as a white solid (8.00 mg, 14%). HPLC (method F): 82%, RT=4.365. MS: m/z=562 [M+H]+, RT=4.33 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[CH:12]=[CH:11][NH:10][C:8]=2[N:9]=1.[CH3:13]I>C1COCC1.O>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[CH:12]=[CH:11][N:10]([CH3:13])[C:8]=2[N:9]=1
Reactant: CI
Reactant: Clc1ncc2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2cnc(Cl)nc21
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of NaH (106.6 mg, 2.67 mmol) in THF (5 mL) was added 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.54 mmol) at 0° C. and stirred for 30 minutes at the same temperature. CH3I (1.5 g, 10.2 mmol) was added at 0° C. and the combined mixture stirred for 3 h at 15° C. After TLC showed the reaction was complete, the mixture was diluted with water 20 mL) and extracted with ethyl acetate EA (2×20 mL) and the combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (254 mg, 47.4%) as colorless oil which was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]1([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(N(CCCC)CCCC)CCC>[NH2:1][C:2]1[N:6]=[C:5]2[N:7]=[C:15]([OH:16])[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:20]([OH:21])[N:4]2[N:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Nc1n[nH]c(N)n1
Solvent: CCCCN(CCCC)CCCC
Product: Nc1nc2nc(O)c(-c3ccccc3)c(O)n2n1
Temperature: 25 °C

Procedure:
A solution of 9.0 g 3,5-diamino-1,2,4-triazole and 22.4 mL diethyl phenylmalonate in N,N-dibutylbutan-1-amine was heated under microwave irradiation to 180° C. for 8 h. The reaction mixture formed two layers after cooling to room temperature. The top layer was removed and the solvent of the lower layer was evaporated. The residue was treated with water and acidified with 5N HCl. The precipitated product was collected by filtration and dried. The crude product was used without further purification.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([SiH:11]([CH3:13])[CH3:12])[C:7](Br)=[N:8][CH:9]=1)[CH:2]=[CH2:3].C([Li])CCC.CN([CH:22]=[O:23])C>C1COCC1>[CH2:1]([C:4]1[CH:5]=[C:6]([SiH:11]([CH3:13])[CH3:12])[C:7]([CH:22]=[O:23])=[N:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: CN(C)C=O
Reactant: C=CCc1cnc(Br)c([SiH](C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCc1cnc(C=O)c([SiH](C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To a solution of 5-allyldimethylsilyl-2-bromopyridine (7 Scheme 27, 14.5 g, 56 mmol) in dry THF (400 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 22.5 mL, 56 mmol) over a period of 20 min. After stirring 30 min at this temperature, anhydrous DMF (6.5 mL, 84 mmol) was added over a period of 5 min, and the reaction mixture was stirred for 30 min then warmed to room temperature. Saturated NCl (10 mL) was added to the reaction mixture. The layers were separated, and the organic layer was dried (Na2SO4), concentrated. The crude product was purified by column chromatography (1:7 ethyl acetate/hexanes) to afford an oil (4.2 g, 36%); 1H NMR (300 MHz, CDCl3) δ 0.26 (s, 6 H), 1.71 (d, J=8.40 Hz, 2 H), 4.74 (m, 1 H), 4.79 (s, 1 H), 5.62 (m, 1 H), 7.80 (d, J=7.80 Hz, 1 H), 7.89 (m, 1 H), 8.75 (d, J=0.90 Hz, 1 h), 9.97 (s, 1 H); 13C NMR (75 MHz, CDCl3) 3.65 (2C), 23.1, 114.7, 120.7, 133.3, 139.9, 142.7, 153.0, 154.5, 193.8. HRMS (EI) calcd for C11H15NOSi 205.0923, found 205.0927.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](O)=[CH:10][C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7]=1[CH3:17])=[O:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:20])=[CH:10][C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7]=1[CH3:17])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCn1c(C)c(C(=O)OCC)c(O)cc1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1c(C)c(C(=O)OCC)c(Cl)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-hydroxy-2-methyl-6-oxo-1-propyl-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (2.00 g, 8.36 mmol) and phosphoryl chloride (4.67 mL, 50.2 mmol), triethylamine (1.16 mL, 8.36 mmol) and methylene chloride (2 mL) were added and the mixture was stirred at r.t. overnight. It was concentrated in vacuo, poured into ice and carefully neutralised with sat.aq. K2CO3 solution. It was extracted with ethyl acetate (3×300 mL), the combined organic solution was washed with brine (20 mL), dried (MgSO4) and evaporated. The title compound was purified by flash chromatography, yield 0.6 g, 30%. LC-MS (m/z) 258.5 (MH+); tR=1.21 (method C).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH:11]([NH:13]CC1C=CC=CC=1)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:4][CH:5]([CH:11]([NH2:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(NC(C)=O)C(C)NCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)C(C)N
Yield: 100 %

Procedure:
Five grams of ethyl 2-acetamido-3-benzylaminobutyrate were dispersed in 20 ml of ethanol together with 0.5 of 5% palladium-on-carbon and shaken under 40 psi of hydrogen until hydrogen uptake had ceased. The mixture was filtered through Celite and evaporated to give a 100% yield of ethyl 2-acetamido-3-aminobutyrate.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5](B3OC(C)(C)C(C)(C)O3)=[CH:6][CH:7]=[CH:8]2)=[N:3]1.Cl[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.CN(C=O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:27][C:26]1[C:21]([C:5]2[C:4]3[C:9](=[CH:10][N:2]([CH3:1])[N:3]=3)[CH:8]=[CH:7][CH:6]=2)=[N:22][CH:23]=[C:24]([Cl:28])[CH:25]=1
Reactant: Cn1cc2cccc(B3OC(C)(C)C(C)(C)O3)c2n1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc2cccc(-c3ncc(Cl)cc3Cl)c2n1
Temperature: 65 °C

Procedure:
A mixture of 2-methyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (0.040 g, 0.15 mmol), 2,3,5-trichloropyridine (0.274 g, 1.50 mmol), (Ph3P)4Pd(0) (0.019 g, 0.017 mmol), 2 mL of DMF, and 2 mL of a 2 M K3PO4 solution was stirred at 65° C. for. 16 h then allowed to cool. Water (10 mL) was added, and the mixture was extracted with three 5 mL portions of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a brown solid. Column chromatography (0→50% EtOAc/hexanes) afforded of 7-(3,5-dichloro-pyridin-2-yl)-2-methyl-2H-indazole (7:R=Me; R′=H; Ar=3,5-dichloro-pyridin-2-yl; 0.042 g; 93%).
Reaction SMILES: Br[C:2]1[C:3]([C:16]#[N:17])=[N:4][N:5]([CH2:13][CH2:14][CH3:15])[C:6]=1[CH2:7][C:8]([C:11]#[N:12])([CH3:10])[CH3:9].Cl.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:17][C:16]1[C:3]2=[N:4][N:5]([CH2:13][CH2:14][CH3:15])[C:6]([CH2:7][C:8]([CH3:9])([CH3:10])[C:11]#[N:12])=[C:2]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1
Reactant: CCCn1nc(C#N)c(Br)c1CC(C)(C)C#N
Reactant: Nc1ccccc1B(O)O
Agent: Cl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C#N
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A modification of the method described in Example 1283 was used to couple 4-bromo-5-(2-cyano-2-methylpropyl)-1-propyl-1H-pyrazole-3-carbonitrile (1.48 g, 5.00 mmol) with 2-aminophenylboronic acid hydrochloride (1.73 g, 10.0 mmol). The reaction was completed in one hour. The coupling product was purified by IFC (silica cartridge, eluting with 40% to 60% ethyl acetate in hexane). The reaction with hydrogen chloride was heated at reflux for a total of about seven hours. 3-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanenitrile (840 mg) was obtained as a white solid, mp 248-250° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13](=[O:24])[N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:34])[NH:1][CH2:2][C:3]([N:5]([CH2:12][C:13](=[O:24])[N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:4])[CH:29]=[CH:30][CH:31]=1
Reactant: NCC(=O)N(CC(=O)N1CCc2ccccc2C1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCc3ccccc3C2)c2ccccc2)c1
Yield: 36.5 %

Procedure:
The procedure is analogous to that described in Example 106, but 2.0 g of 2-amino-N-[2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethyl]-N-phenylacetamide and 0.8 g of 3-methylphenyl isocyanate are used as the starting material. The crude product is purified by chromatography on 70 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride/methanol (98-2 by volume)], collecting 20 cm3 fractions. Fractions 12 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from ethyl acetate, 1.0 g of 2-[3-(3-methylphenyl)ureido]-N-[2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethyl]-N-phenylacetamide melting at 135° C is obtained.
Reaction SMILES: [OH-].[Na+].C([O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:14]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:13]=1)(=O)C1C=CC=CC=1.CO.Cl>O1CCCC1>[CH2:29]([O:28][C:14]1[CH:13]=[C:12]([OH:11])[CH:27]=[CH:26][C:15]=1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (6.39 mL) was added to a mixture of benzyl 4-benzoyloxy-2-benzyloxy-benzoate (2.80 g), methanol (10 mL) and tetra hydrofuran (10 mL), and the mixture was stirred at room temperature for 5 hrs. 2 mol/L hydrochloric acid (6.39 mL) was added to the reaction mixture at room temperature, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure liquid silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to afford benzyl 2-benzyloxy-4-hydroxybenzoate (0.86 g).