Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 7.7 %

Procedure:
A mixture of hydroxylammonium chloride (2.02 g), sodium hydrogen carbonate (3.24 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.87 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.076 g, 8%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]1[C:38]([CH2:43]Br)=[CH:39][CH:40]=[CH:41][CH:42]=1>C(Cl)Cl>[Cl:22][C:21]1[C:16]2[C:15](=[O:23])[N:14]3[CH2:24][CH2:25][C@H:13]3[C:12]3[N:11]([CH:10]=[N:9][C:8]=3[C:5]3[N:4]=[C:3]([CH2:2][N:1]4[CH2:43][C:38]5[C:37](=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36]4)[O:7][N:6]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Reactant: BrCc1ccccc1CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CN4Cc5ccccc5C4)n3)c2[C@@H]2CCN12
Yield: 33.8 %

Procedure:
3.56 g (10 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 15 ml of methylene chloride, 8.6 ml (50 mmol) of N-ethyldiisopropylamine and 2.64 g (10 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 20 hours. The reaction solution was washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on 500 g of silica gel while eluting with methylene chloride/methanol 19/1. There were obtained 1.55 g (33%) of (S)-8-chloro-12,12a-dihydro-1-(5-isoindolin-2-ylmethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 218°-222°.
Reaction SMILES: ClCCC[O:5][P:6]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1.[CH2:12](O)[CH2:13][OH:14].C(Br)C>ClCCCl>[OH:14][CH2:13][CH2:12][P:6]1(=[O:5])[CH2:10][CH2:9][C:8]([CH3:11])=[CH:7]1
Reactant: CC1=CCP(OCCCCl)C1
Reactant: OCCO
Solvent: ClCCCl
Solvent: CCBr
Product: CC1=CP(=O)(CCO)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 14.7 g. (0.076 mole) of 1-(chloropropoxy)-3-methyl-3-phospholene in 50 ml. of 1,2-dichloroethane was added, with stirring, over a period of 5 minutes, a total of 14.14 g. (0.23 mole) of ethylene glycol. The resulting solution was cloudy. Ethyl bromide (1.66 g.) was added and the mixture was heated under reflux for 1 hour. At the end of this time the solvent and other volatile materials were removed by evaporation and the residue was distilled under reduced pressure. There was thus obtained 1.3 g. (10.6% theoretical yield) of a mixture of the 2- and 3-isomers of 1-(2-hydroxyethyl)-3-methylphospholene-1-oxide in the form of a liquid having a boiling point of 125° - 150° C at 0.2 mm. of mercury. A glassy residue remained in the distillation flask and was believed to be 1,1'-ethylenebis-(3-methylphospholene-1-oxide).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.BrN1[C:32](=[O:33])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH2:18][O:33][CH3:32])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COCc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2OC)o1
Temperature: 70 °C
Reaction time: 4 h
Yield: 1.2 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.95 g, 5.56 mmol) in carbon tetrachloride (20 ml) was added N-bromo succinimide (990 mg, 5.56 mmol) and 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) and the reaction mixture was stirred for 4 h at 70° C. Further 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) was added and stirring was continued for another 14 h at 70° C. N-Bromo succinimide (378 mg, 2.12 mmol) was added and the mixture stirred for another 4 h at 90° C. After the reaction mixture was cooled to 0° C. the suspension was filtered off and was washed with dichloromethane (30 mL) and aqueous sodium hydrogencarbonate (1 N).It was extracted with dichloromethane and dried over sodium sulfate resulting in crude material (1.66 g). A part of this light brown solid (200 mg) was dissolved in tetrahydropyran (2 mL), sodium methoxide (30% in methanol, 0.43 ml, 2.32 mmol) was added and the resulting mixture was stirred for 1 h at ambient temperature. It was diluted with ethyl acetate (20 mL) and washed aqueous ammonium chloride (saturated). The aqueous layers were extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (25 mg, 14%) as a white solid. MS: m/e=382.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:33]([CH2:38][CH3:39])[C:34](=[O:37])[CH2:35]Cl)[CH3:32].O>CC(C)=O>[CH2:31]([N:33]([CH2:38][CH3:39])[C:34]([CH2:35][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH3:13])=[O:37])[CH3:32]
Reactant: CCN(CC)C(=O)CCl
Reactant: C[C@H](Cc1c[nH]c2c(O)cccc12)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N3C(=O)c4ccccc4C3=O)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A residue 10.27 g containing (R)-7-hydroxy-3-(2-phthalimidopropyl)indole was dissolved in 200 ml of acetone, and 8.00 g of potassium carbonate was added thereto. After addition of N,N-diethylchloroacetamide 15.5 ml, the solution was heated to reflux in an oil bath of 80° C. For 3 hours. After cooling down 200 ml of water was added, and a deposited crystal was collected by filtration and washed with water, whereby 9.56 g of the title compound was obtained in the form of a pale yellowish white substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.N1C=C[CH:21]=[CH:20][CH:19]=1.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:20]([C:21]1[N:12]([C@@H:13]([CH3:16])[CH2:14][OH:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:19]
Reactant: c1ccncc1
Reactant: C[C@@H](CO)Nc1c(N)cnc2ccccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1nc2cnc3ccccc3c2n1[C@@H](C)CO
Temperature: 90 °C
Reaction time: 20 h
Yield: 609.3 %

Procedure:
A suspension of (2S)-2-[(3-aminoquinolin-4-yl)amino]propan-1-ol (0.98 g, 4.49 mmol) in 50 mL of toluene was treated with triethyl orthopropioate (1.1 mL, 5.39 mmol) and pyridine HCl (52 mg, 0.45 mmol), and heated to 90° C. under an atmosphere of N2. After ˜20 hours, the reaction was allowed to cool back to ambient temperature and the solvent was removed under reduced pressure to give an orange solid. Chromatography (AFC, SiO2, 20-40% CMA/CHCl3) gave (2S)-2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol (0.70 g) as a white solid.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:18][C:19]([NH2:21])=[S:20])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br.[C:32]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=O)[CH2:42]Br)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]>C(O)C.C(OCC)(=O)C>[O:1]([C:8]1[C:9]([NH:18][C:19]2[S:20][CH:42]=[C:41]([CH:38]3[CH2:39][CH2:40][N:35]([C:32](=[O:34])[CH3:33])[CH2:36][CH2:37]3)[N:21]=2)=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(C(F)(F)F)cc1Oc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)CBr)CC1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2csc(Nc3ncc(C(F)(F)F)cc3Oc3ccccc3)n2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
1-(3-phenoxy-5-(trifluoromethyl)pyridin-2-yl)thiourea (0.076 g, 0.243 mmol) was suspended in ethanol (3 mL) and diisopropylethylamine (0.127 mL, 0.728 mmol) was added, followed by 1-(1-acetylpiperidin-4-yl)-2-bromoethanone hydrobromide (0.120 g, 0.364 mmol). The mixture was heated to 60° C. and agitated for 3 hours, then diluted with ethyl acetate, washed with sodium bicarbonate, brine, dried and evaporated. The crude product was purified on silica gel (30% ethyl acetate/hexanes) to afford 1-(4-(2-(3-phenoxy-5-(trifluoromethyl)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone (0.065 g, 57.9% yield) as white solid. 1H NMR (d6-DMSO) δ 1.45-1.61 (m, 2H), 1.93-2.04 (m, 2H), 2.51-3.18 (m, 3H), 3.90 (d, 1H), 4.44 (d, 1H), 6.97 (s, 1H), 7.20-7.50 (m, 6H), 8.59 (s, 1H).
Reaction SMILES: [OH-].[Na+].[NH:3]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:4]([C:17]([O:19]C)=[O:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[NH:3]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:4]([C:17]([OH:19])=[O:18])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide (1 N, 15 ml, 15 mmoles) was added to an ice-cold solution of Z-Tyr(But)-OMe (3.85 g, 10 mmoles) in methanol (20 ml) and the mixture was stirred at 0° to 50° C. for one hr. After completion of the reaction, the solution was acidified with 10% aqueous citric acid, diluted with water (100 ml) and extracted with ethyl acetate. The organic layer was washed several times with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gives Z-Tyr(But)-OH in quantitative yield, which was used as such in the next step. The latter acid and 1-hydroxybenzotriazole (1.62 g, 12 mmoles) were dissolved in dry, distilled dimethylformamide (30 ml), the solution was cooled to 0° C. and dicyclohexylcarbodiimide (2.48 g, 12 mmoles) was added. The mixture was stirred 1 hr at 0° C. and 1 hr at room temperature and a solution of H-Phe-OMe.HCl (2.58 g, 12 mmoles) in dimethylformamide (35 ml) containing N-ethylmorpholine (1.6 ml, 13 mmoles) was added at 0° C. The mixture was stirred at room temperature overnight. After filtering, the filtrate was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous citric acid, water, saturated NaHCO3 solution and water, dried over sodium sulfate and evaporated. The residue was crystallized twice from methanol-isopropyl ether giving 4.3 g of the title compound: mp 106°-107° C., [α]D -36.40 (1% in dimethylformamide), nmr (CDCl3)δ 1.25(s), 3.60(s) and 5.10(s), and Anal. Calc'd. for C31H36N2O6 : C, 69.91%; H, 6.81%; N, 5.26% and Found: C, 69.63%; H, 6.85%; N, 5.41%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:35]=[N+:36]=[N-:37].[Na+]>CCOC(C)=O>[N:35]([CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCOS(C)(=O)=O)c2cccc(Cl)c2)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN=[N+]=[N-])c2cccc(Cl)c2)C1
Temperature: 80 °C
Yield: 99.1 %

Procedure:
(R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (15 g, 34 mmol) was dissolved into anhydrous DMF (150 mL), solid NaN3 (6.7 g, 102 mmol, 3 eq) was added and the reaction mixture was heated to 80° C. for overnight. The reaction mixture was cooled to rt and then was added with EtOAc (500 mL), the organic phase was washed with water (3×100 mL) and brine (2×80 mL), dried over Na2SO4 and concentrated in vacuo to provide crude (R)-tert-butyl 3-((R)-(2-azidoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (13.3 g), which was used for next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].C([O:15][C:16]([CH:18]1[CH2:20][CH2:19]1)=O)C.C(O)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:15])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C(=O)C1CC1)c1ccc(Cl)cc1
Reaction time: 0.17 h

Procedure:
2-(4-Chlorophenyl)acetonitrile (5.74 g) is dissolved in 120 mL of THF at 0° C. After adding 60% NaH (4.2 g, 2.7 eq), the reaction mixture is stirred for 10 minutes. Ethylcyclopropane carboxylate is added and the mixture is stirred overnight. The reaction is stopped by adding acetic acid (5 mL) and water. The aqueous layer is extracted with ethyl acetate (50 mL×3). The collected organic layer is washed with brine and dehydrated with MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield 7.74 g of the target compound. 1H NMR (CDCl3, 300 MHz): δ 7.42 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 4.79 (s, 1H), 2.10 (m, 1H) 1.16 (m, 2H), 1.03 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:16]=1[CH2:17]N1CCNCC1.C(N(C(C)C)CC)(C)C>CC(O)CC>[Cl:14][C:15]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Fc1cccc(Cl)c1CN1CCNCC1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(N2CCN(Cc3c(F)cccc3Cl)CC2)nc[nH]1
Temperature: 80 °C
Reaction time: 40 h
Yield: 17.1 %

Procedure:
A mixture of 6-chloro-3H-pyrimidin-4-one (Intermediate 4; 100 mg, 0.77 mmol), 1-(2-chloro-6-fluorobenzyl)piperazine (Oakwood; 87 mg, 0.38 mmol), and diisopropylethylamine (200 μL, 1.1 mmol) in 2-butanol (5 mL) was heated in a sealed scintillation vial on a hot plate at about 80° C. for 8 hours and then allowed to cool to room temperature and stand at room temperature for 40 hours. The mixture was filtered. The solid was washed with 2-butanol and air-dried to give 6-[4-(2-chloro-6-fluorobenzyl)-piperazin-1-yl]-3H-pyrimidin-4-one (21 mg, 17%) as a white solid, mp 255-256° C. (dec). 1H NMR (d6-DMSO) δ 2.41-2.44 (m, 4H), 3.42-3.45 (m, 4H), 5.24 (s, 1H), 7.19-7.24 (m, 1H), 7.40-7.43 (m, 1H), 7.51-7.56 (m, 1H), 7.87 (s, 1H), 11.61 (br s, 1H). LRMS ES+M+H 323. HRMS Calcd. for C15H17ClFN4O (M+H), 323.1070. Found, 323.1069.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=O)[CH2:3][CH2:2]1.[Br-].[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[C:13]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[C:15]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:7])[CH2:10][CH2:11]2)[CH:14]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C1CCNCC1
Reactant: C1COCCN1
Agent: [Br-]
Product: O=C(C1CCN(c2cccc(-c3ccccc3)c2)CC1)N1CCOCC1

Procedure:
The title compound was prepared from commercially available ethyl isonipecotate, m-biphenyl bromide as the aryl halide, and morpholine as the secondary amine utilizing general procedures A and B described above. 1H NMR (300 MHz, CDCl3) δ 7.59-7.30 (m, 6H), 7.14 (t, J=2.0 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.94 (dd, J=2.0, 7.6 Hz, 1H), 3.85 (m, 1H), 3.80 (m, 1H), 3.63-3.55 (m, 8H), 2.80 (dt, J=2.6, 12.2 Hz, 2H), 2.60 (tt, J=2.8, 11.4 Hz, 1H), 2.07 (dd, J=3.8, 12.8 Hz, 1H), 2.01 (dd, J=4.0, 12.0 Hz, 1H), 1.85 (m, 1H), 1.81 (m, 1H). ESI MS: 351.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.[OH:24]OS([O-])=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:24])[CH:5]=[N:4][C:3]=1[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20]
Reactant: C[C@H](Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine (Preparation 232, 130 mg, 0.37 mmol) in acetone (1 mL) was added an aqueous solution of Oxone® (1 mL, 287 mg, 0.44 mmol) dropwise with stirring at 0° C. for 15 minutes. The reaction mixture was diluted with water and extracted with DCM (3×5 mL). The mixture was filtered through a phase separation cartridge, the organic phase was washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product that was purified by silica gel column chromatography eluting with 0-30% EtOAc in heptane to give the title compound (62 mg, 69%) as colourless oil.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.Br[C:20]1[C:21]([O:36][CH2:37][C:38]2[N:39]([CH2:43][CH3:44])[N:40]=[CH:41][N:42]=2)=[N:22][N:23]2[C:28]=1[CH:27]=[N:26][N:25]=[C:24]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35]>>[CH2:43]([N:39]1[C:38]([CH2:37][O:36][C:21]2[C:20]([C:6]3[O:7][CH:8]=[CH:9][CH:10]=3)=[C:28]3[N:23]([C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[N:25][N:26]=[CH:27]3)[N:22]=2)=[N:42][CH:41]=[N:40]1)[CH3:44]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccco1
Yield: 59 %

Procedure:
This was prepared in 59% yield using a similar procedure to that described in Example 53 except using 2-(tributylstannyl)furan instead of 2-(tributylstannyl)pyridine and 3-bromo-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazine instead of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-pyrazolo[1,5-d][1,2,4]triazine. Data for title compound: mp=182-183° C. (CH2Cl2-EtOAc); 1H NMR (360 MHz, CDCl3) δ 1.39 (3H, t, J=7.3 Hz), 4.17 (2H, q, J=7.3 Hz), 5.59 (2H, s), 6.51 (1H, m), 6.70 (1H, m), 7.28 (1H, m), 7.39 (1H, dt, J=7.6 and 0.9 Hz), 7.56 (1H, m), 7.65 (1H, m), 7.81 (1H, m), 7.90 (1H, s), 9.69 (1H, s); MS (ES+) m/e 406 [MH]+; Anal. Found C, 58.57; H, 4.08; N, 23.87%. C20H16FN7O2.0.3H2O requires C, 58.48; H, 4.07; N, 23.87%.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([C:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH2:19][CH2:20][NH:21]4)([CH3:16])[CH2:11][C:12]([O:14]C)=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].O.[Li+].[OH-].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([C:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)([CH3:16])[CH2:11][C:12]([OH:14])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)CC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2c1CCN2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c2[nH]ccc2c1C(C)(CC(=O)O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(±)-Methyl 3-(5-cyano-1H-benzo[d]imidazol-2-yl)-3-(5-methoxy-7-methylindolin-4-yl)butanoate (Example 156-K) (25 mg, 0.062 mmol) was dissolved in THF (0.371 mL), water (0.124 mL) and MeOH (0.124 mL). LiOH (13 mg, 0.304 mmol) was then added and the reaction was stirred for 18 hours at room temperature. At this point, NaOH (1 mL, 2.000 mmol), MeOH (1 mL) and THF (3 mL) were added and the reaction was stirred for further 4 hours. The reaction was then concentrated and diluted with EtOAc and water. The layers were separated, the aqueous layer was adjusted to pH=1 and directly purified using RP-HPLC (HC-A) to isolate the title compound. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 11.01 (br. s., 1H) 8.11 (br. s., 1H) 7.68 (q, J=7.66 Hz, 2H) 7.22 (br. s., 1H) 6.74 (s, 1H) 5.95 (br. s., 1H) 3.55 (d, J=15.16 Hz, 1H) 3.43 (s, 1H) 3.39 (s, 3H) 2.44 (s, 3H) 1.99-2.15 (m, 3H). HRMS calcd. for C22H20N4O3 (M+H)+ 389.1614. found 389.1609.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 79.2 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 5-hydroxy-2-methylindole (74 mg, 0.5 mol) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (137 mg, 79%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]([CH3:12])[C:9]([Cl:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.CO.[CH3:18][C:19]#N.O.CC#N>O>[CH2:7]([N:8]([CH:12]1[CH2:19][CH2:18]1)[C:9]([Cl:11])=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#N
Reactant: CN(CC1CCCCC1)C(=O)Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(Cl)N(Cc1ccccc1)C1CC1

Procedure:
The title compound is prepared analogously as described for cyclohexylmethyl-methylcarbamoyl chloride. TLC, Rf (CH2Cl2/MeOH 95:5)=0.9. MS (LC-MS): [M+H]+=210.2. tR (HPLC, Waters Symmetry C18 column, 20-100% CH3CN/H2O/5 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.67 min.