Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27]Cl)[CH2:22][CH2:21]3)[C:5]=2[CH:4]=1.[OH:29][C:30]1[CH:44]=[CH:43][C:33]([O:34][CH2:35][C@@H:36]([OH:42])[CH2:37][NH:38][CH:39]([CH3:41])[CH3:40])=[CH:32][CH:31]=1>CS(C)=O.O.[OH-].[Na+]>[CH3:41][CH:39]([NH:38][CH2:37][C@H:36]([OH:42])[CH2:35][O:34][C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][N:6]3[C:5]4[CH:4]=[C:3]([Cl:2])[CH:16]=[CH:15][C:14]=4[S:13][C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:25][CH2:24]2)=[CH:44][CH:43]=1)[CH3:40]
Reactant: CC(C)NC[C@H](O)COc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)NC[C@H](O)COc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of the chloride of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (9.4 g) in 75 ml dimethylsulfoxide was added (S)-1-(4-hydroxyphenoxy)-3-(1-methylethyl)amino-2-propanol (6.0 g) followed by 6.25 ml 4N sodium hydroxide solution. The mixture was stirred under argon at 55° for 2 hours then was cooled and diluted with 500 ml water and 35 ml 1N sodium hydroxide, and extracted with dichloromethane (3×). The extracts were backwashed with water (2×), dried over potassium carbonate and the solvent was removed in vacuo to give 12.8 g of crude (S)-1-(1-methylethylamino)-3-[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]piperazin-1-yl]ethoxy]phenoxy]-2-propanol as an oil.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[CH:6]=1)=[O:4].[CH3:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:2]([CH3:15])[C:3]([C:5]3[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[CH:6]=3)=[O:4])[CH2:24][CH2:23]2)=[CH:28][CH:29]=1
Reactant: COc1c(C)cc(C(=O)C(C)Br)cc1C
Reactant: Cc1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1c(C)cc(C(=O)C(C)N2CCC(Cc3ccc(C)cc3)CC2)cc1C

Procedure:
5.9 g (0.022 mol) of 2-bromo-4'-methoxy-3',5'-dimethylpropiophenone are dissolved in 30 ml of ethanol, 4.2 g (0.022 mol) of 4-(4-methylbenzyl)-piperidine and then 2.12 g (0.02 mol) of sodium carbonate are added and the mixture is heated under reflux for 2 hours. It is left to cool, the inorganic precipitate is filtered off and the filtrate is evaporated. The residual oil is purified by chromatography on silica using acetone as the eluant. This gives 8 g of a product, which is used as such.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[C:11]1(=[O:21])[O:15][CH2:14][CH:13]2[CH2:16][CH2:17][CH:18]3[CH2:20][CH:19]3[CH:12]12>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:14][CH:13]2[CH2:16][CH2:17][CH:18]3[CH:19]([CH2:20]3)[CH:12]2[C:11]([OH:21])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C1OCC2CCC3CC3C12
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C1C(CSc2ccc(F)cc2)CCC2CC21
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (165 mg, 4.05 mmol) in dry dimethylformamide (10 mL) under an atmosphere of dry nitrogen was added 4-fluorothiophenol (430 μL, 4.05 mmol) dropwise and the reaction was stirred for 15 min. A solution of (3αR/S,5αS/R,6αR/S,6βR/S)-octahydro-1H-cyclopropa[3,4]benzo[1,2-c]furan-1-one (202 mg, 1.35 mmol) in dry dimethylformamide (2 mL) was added to the reaction mixture and was heated to 110° C. for 4.5 h. The reaction mixture was cooled to room temperature and quenched with aqueous 10% HCl, the product extracted with ethyl acetate, and dried on anhydrous sodium sulfate. The solvent was removed in vacuo and the product was purified by flash chromatography over silica gel (ethyl acetate/hexanes, 2/8+0.5% AcOH) to afford the desired product (1R/S,2R/S,3R/S,6S/R)-3-{[(4-fluorophenyl)-sulfanyl]methyl}bicyclo[4.1.0]heptane-2-carboxylic acid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][CH2:14][C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]3[CH:10]=[CH:9][C:8]([C:24]#[N:25])=[CH:7][C:6]=3[C:5]=2[CH2:4]1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:28]>>[N+:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][C:27](=[O:28])[NH:2][CH:3]2[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[C:8]([C:24]#[N:25])[CH:7]=4)[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[C:13]=3[CH2:14][CH2:15]2)=[CH:35][CH:34]=1)([O-:38])=[O:37]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(N)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Yield: 33 %

Procedure:
Prepare the title compound by essentially following the procedures as described in Example 162, using 6-amino-9-(3-fluoro-benzyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile hydrochloride (Preparation 51) and 4-nitrophenyl chloroformate. Purify by silica gel chromatography (50% (4% (2M NH3/MeOH)/CH2Cl2)/hexanes) to give the title compound in 33% yield as a white solid. MS (ES): m/z 346 (M-p-nitrophenolate); HPLC (Method B): Rt=2.23 min (86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23]Cl)=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:30]#[N:31].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23][C:30]#[N:31])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CCl)nc2[nH]1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CC#N)nc2[nH]1
Yield: 52.1 %

Procedure:
A solution of 2-[5-(benzyloxy)-2-isopropoxyphenyl]-5-(chloromethyl)-3H-imidazo[4,5-b]pyridine (0.11 g) and potassium cyanide (30 mg) in N,N-dimethylformamide (5 ml) was stirred at 60° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC, and saturated aqueous sodium hydrogencarbonate solution was added to the obtained fraction to neutralize the mixture. The mixture was extracted with dichloromethane, and the extract was concentrated to give the title compound (56 mg, yield 52%) as colorless crystals. purity 90%. M+H: 399.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1>N1C=CC=CC=1>[NH:2]([C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1)[NH2:3]
Reactant: Clc1ncc(-c2ccccc2)nn1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2ccccc2)nn1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
Hydrazine hydrate (1.50 mL, 0.0308 mol) was added to suspension of 3-chloro-6-phenyl-1,2,4-triazine (2.20 g, 0.0115 mol) in pyridine (12.0 mL) at 0° C. and stirred at 0° C. until a precipitate formed. The mixture was then heated at 65° C. for 30 min. The solvent was evaporated under reduced pressure. The residue was triturated with water, filtered, and washed with water. The crystalline formed was collected and dried under high vacuum to give the desired product (2.0 g, 93%). Analytical LCMS: (M+H)+=188.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)[CH:7]=1)[CH3:2].IC.[CH3:26][Si](C)(C)N[Si](C)(C)C.[Na]>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([B:14]2[O:15][C:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[O:18]2)[CH:7]=1)[CH3:26])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.100 g, 0.31 mmol) and iodomethane (0.04 mL, 0.63 mmol) in THF (5 mL) at −78° C. was added sodium hexamethyldisilazane (1M in THF; 0.63 mL, 0.63 mmol). The reaction was warmed to room temperature and stirred under N2 for 1 hour, and then quenched with H2O and partitioned between EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1C=CC=CC=1>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:31](=[O:33])[CH3:32]
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(C)=O)c1ccccc1-c1ccccc1
Yield: 76.8 %

Procedure:
Analogously to Example 47, 16.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 7.3 g of ethyldiisopropylamine in 70 ml of benzene are reacted with 4.4 g of acetyl chloride to obtain, as reaction product, 14.0 g (76.2% of theory) of ethyl 4-[N-(biphenyl-2-yl)acetamido]butyrate as a viscous non-distillable oil. The saponification of this ester and recrystallization of the crude product obtained from isopropyl alcohol yields 10.1 g (79.0% of theory) of 4-[N-(biphenyl-2-yl)acetamido]butyric acid, MP 124° to 125°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](O)[CH2:9][CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)O)=[CH:4][CH:3]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][CH2:10][C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:29]2[C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:31])([F:21])[F:30])=[N:28][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O[C@H](CC[C@@H](O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccc(C(F)(F)F)nc1
Product: FC(F)(F)c1ccc(N2[C@H](c3ccc(Br)cc3)CC[C@H]2c2ccc(Br)cc2)cn1
Yield: 10 %

Procedure:
The product from Example 69A (1.0 g, 2.5 mmol) was subjected to the procedure described in Example 182A, substituting 6-(trifluoromethyl)pyridin-3-amine for Example 144C, to give the title compound (0.13 g, 10%).
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>ClCCl.CO>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]1=[O:30]
Reactant: C[C@@](CCn1ccc(CCc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@@](CCn1ccc(CCc2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A solution of hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(2-phenylethyl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (14 mg, 0.029 mmol) in 5:1 dichloromethane-methanol (1.2 mL) at 0° C. After 2 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with 1:1 pentane-dichloromethane, filtered, washed with pentane, and dried under reduced pressure to provide a light pink solid (8 mg, 70%). MS (APCI) m/z 393.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (s, 3 H) 2.00-2.14 (m, 1 H) 2.24-2.36 (m, 1 H) 2.63-2.74 (m, 2 H) 2.78-2.88 (m, 2 H) 3.06 (s, 3 H) 3.58-3.73 (m, 1 H) 3.94-4.08 (m, 1 H) 6.16-6.26 (m, 2 H) 7.11-7.32 (m, 5 H) 7.55 (d, J=7.41 Hz, 1 H) 11.14 (br s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].ClC1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CSc1ccc(NC(C)=O)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
The product from Example 39c (1.00 g, 5.0 mmol) and t-BuSNa (1.88 g, 15.1 mmol) in anhydrous DMF (10 mL) was heated at 160° C. for 4 hours under N2 flow, and then cooled to room temperature. To the reaction mixture was added 1-chloro-4-methyl-2-nitrobenzene (2.36 mL, 17.6 mmol) at room temperature and then the mixture was heated at 80° C. for 4 hours under N2 flow. The mixture was diluted with H2O and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by silica gel column chromatography eluting with 2:1 EtOAc/hexane to give the title compound as yellow crystals (1.04 g, 65%).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][C:20](=[O:22])[C:19]([C:23](=O)[CH2:24][CH3:25])=[C:18]([OH:27])[CH2:17]2)=[CH:12][CH:11]=1)=[O:8].[CH2:28]([O:30][NH2:31])[CH3:29]>O>[CH2:28]([O:30][N:31]=[C:23]([C:19]1[C:20](=[O:22])[CH2:21][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7]([O:6][CH3:5])=[O:8])=[CH:11][CH:12]=2)[CH2:17][C:18]=1[OH:27])[CH2:24][CH3:25])[CH3:29]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NC(=O)OC)cc2)CC1=O
Reactant: CCON
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NC(=O)OC)cc2)CC1=O
Temperature: 40 °C
Reaction time: 15 h
Yield: 58.7 %

Procedure:
Into 30 ml of chloroform was dissolved 1.8 g of 5-[4-(methoxycarbonylamino)phenyl]-2-propionyl-3-hydroxy-2-cyclohexen-1-one and to the solution was added 0.5 g of ethoxyamine. The mixture was agitated for 15 hours at 40° C. and the chloroform containing produced water and a surplus amount of ethoxyamine was distilled off from it under a reduced pressure. And then, the ethyl ether was added in the residue and the crystal sedimented was collected with a filtering step and 1.2 g of desired compound was obtained. It was in the form of colorless crystals having a melting point of 160°-161° C.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:3])[CH3:2].[CH2:24]1[O:26][CH2:25]1>C(O)C>[CH:1]([N:4]([CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:24][CH2:25][OH:26])([CH3:2])[CH3:3]
Reactant: C1CO1
Reactant: COc1ccc(C2=C(CC(C)NC(C)C)C(=O)NCCC2)cc1
Solvent: CCO
Product: COc1ccc(C2=C(CC(C)N(CCO)C(C)C)C(=O)NCCC2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
The mixture of 6.3 g of 3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 20 ml of ethylene oxide and 25 ml of absolute ethanol is stirred in a sealed vessel at room temperature for 5 days. The resulting solution is evaporated, the residue crystallized from petroleum ether and recrystallized from ethyl acetate-hexane, to yield the 3-[2-(N-isopropyl-N-hydroxyethylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 109°-111°.
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: C[O-]
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CI)c2OC1C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1=Cc2cc(C)cc(COC)c2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
The ethyl 8-(iodomethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605e, Step 2 (0.2 g, 0.47 mmole) was dissolved in methanol (5 mL) and then the solution was cooled to 0° C. (ice bath). Sodium methoxide (0.32 mL, 1.41 mmole) was added dropwise to above solution, which was stirred for 2 hours at 0° C. The solution was warmed to room temperature and stirred for an additional 2 hours. The reaction was condensed in vacuo to give a yellow oil (0.15 g, 98%). No further purification was performed: GCMS m/z 330.00 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[N:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[N:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=1
Reactant: CCOC(=O)c1cnn(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ncc(C(=O)O)n2)CC1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Ethyl 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-2H-1,2,3-triazole-4-carboxylate (0.35 g, 0.82 mmol) (i.e. the product of Example 32, Step B) was dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (2 mL). A 1 N aqueous solution of sodium hydroxide (1.6 mL, 1.6 mmol) was added to the reaction mixture and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in water. The aqueous layer was washed with diethyl ether and the aqueous layer was acidified with concentrated hydrochloric acid to pH 1, and extracted with dichloromethane and then chloroform. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 0.27 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH:42]([NH2:45])([CH3:44])[CH3:43]>C(Cl)Cl>[CH:42]([NH:45][C:5]1[N:4]=[C:3]([O:2][CH3:1])[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=1)([CH3:44])[CH3:43]
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Reactant: CC(C)N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(NC(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A solution of Example C2 (0.13 g, 0.309 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.09 g, 0.37 mmol), stirred at RT overnight, treated with isopropyl amine (0.5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with DCM (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain N-isopropyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (63 mg, 47%). MS (ESI) m/z: 432.2 (M+H+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH:10][C:11](=[O:36])[CH2:12][N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:24]=[CH:25][CH2:26][CH2:27][OH:28])[CH:20]=2)[N:15]=[C:14]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:6]([NH:10][C:11]([CH2:12][N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:24]=[CH:25][CH2:26][CH2:27][O:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:20]=2)[N:15]=[C:14]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[O:36])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(C=CCCO)cc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(C=CCCOS(C)(=O)=O)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
Methanesulfonyl chloride (114 μL, 1.46 mmol) was added to a stirred solution of N-tert-butyl-2-[2-(3-chlorophenyl)-6-(4-hydroxybut-1-enyl)-4-oxo-4H-quinazolin-3-yl]acetamide (536 mg, 1.22 mmol) and triethylamine (510 μL, 3.66 mmol) in dry dichloromethane (12 mL) at 0° C. The cooling bath was removed after 2 h, and the mixture was stirred for an additional 3 h at room temperature. The reaction mixture was diluted with ethyl acetate (40 mL), and washed with 1 N HCl (aq.) (25 mL), sat. NaHCO3 (aq.) (25 mL) and brine (25 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford methanesulfonic acid 4-[3-(tert-butylcarbamoylmethyl)-2-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]but-3-enyl ester (528 mg, 1.02 mmol, 84%) as a yellow foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH2:22])[C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:32]1([CH2:38][S:39](Cl)(=[O:41])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C@H:11]([NH:22][S:39]([CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:41])=[O:40])[C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(C[C@H](NS(=O)(=O)Cc2ccccc2)c2csc(-c3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 8, (330 mg, 0.80 mmol) in CH2Cl2 (6 mL) at 0° C. is added diisopropylethylamine (0.30 mL, 1.6 mmol) followed by phenylmethanesulfonyl chloride (167 mg, 0.88 mmol). The reaction mixture is stirred at room temperature for 14 hours. The mixture is diluted with CH2Cl2 and washed with sat. NaHCO3 followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is purified over silica to afford 210 mg of the desired product as a white solid.
Reaction SMILES: [OH:1][C@H:2]([CH3:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1.CN(C=O)C>C(Cl)Cl>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][C@H:2]([OH:1])[CH3:13])[CH:8]=3)=[O:11])[CH3:31])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: Cc1nc(C(=O)O)cn1C[C@@H](C)O
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C[C@@H](C)O
Yield: 76.8 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from (R)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid (1.059 mmol, 195 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-benzonitrile (0.882 mmol, 230 mg) using DMF (2 ml) as the solvent. DCM was added and evaporated. The residue was purified by flash chromatography. The product was further purified by dissolving it in MeOH/DCM and washing twice with 1 M NaHCO3. The separated organic phase was dried, purified and evaporated. 289 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.02-1.10 (m, 6H), 2.34 (s, 3H), 3.70-3.91 (m, 3H), 4.22-4.48 (m, 3H), 4.92 (d, 1H), 6.95 (d, 1H), 7.47 (s, 1H), 7.83 (d, 1H), 7.97-8.00 (m, 2H), 8.04 (d, 1H), 8.09-8.13 (m, 1H).