Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[O:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:13][CH2:14][CH2:15][O:9][CH2:10][CH2:11]2)=[N:6][CH:7]=1
Reactant: C1CNCCOC1
Reactant: Clc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Brc1ccc(N2CCCOCC2)nc1
Yield: 92.7 %

Procedure:
The solution of 5-bromo-2-chloropyridine (1.5 g, 7.8 mmol), 1,4-oxazepane (1.29 g, 9.36 mmol) and K2CO3 in 15 mL of NMP was stirred at 120° C. overnight. The mixture was added to 150 mL of water, washed with EA, dried over Na2SO4, and the volatiles were removed in vacuo to give 1.86 g of 4-(5-bromopyridin-2-yl)-1,4-oxazepane. MS(m/z)=259 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]([N:18]([CH3:20])[CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[CH:21]1([CH2:27][S:28](Cl)(=[O:30])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([CH2:27][S:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH3:20])[CH3:19])[CH:13]=3)[CH2:8][CH2:7]2)(=[O:30])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C)c1cccc(N2CCN(CCCCN)CC2)c1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Product: CN(C)c1cccc(N2CCN(CCCCNS(=O)(=O)CC3CCCCC3)CC2)c1

Procedure:
Reaction of {3-[4-(4-amino-butyl)-piperazin-1-yl]-phenyl}-dimethyl-amine and cyclohexyl-methanesulfonyl chloride as described in Preparation 8 gave desired compound, C-Cyclohexyl-N-{4-[4-(3-dimethylamino-phenyl)-piperazin-1-yl]-butyl}-methanesulfonamide.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[CH:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1>O1CCCC1>[C:7]([CH:9]=[CH:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CC(CC=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CC=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium tert-butoxide, 1M in tetrahydrofuran (3694 μl, 3.69 mmol) at 0° C. was added dropwise by syringe a solution of diethyl cyanomethylphosphonate (570 μl, 3.52 mmol) in 5 ml tetrahydrofuran. The reaction mixture was warmed to room temperature and then cooled to 0° C. again. This solution was treated with tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (701 mg, 3.52 mmol) in 2 ml tetrahydrofuran dropwise by syringe and then allowed to warm to room temperature. After stirring overnight the gelatinous mixture was quenched with water (20 ml) and extracted with ethyl acetate (2×20 ml); the organic layers were washed with brine (20 ml), dried with magnesium sulfate, filtered and concentrated. The liquid residue was flash chromatographed to give the title compound as a 1:1 mixture of E/Z isomers.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([CH:34]=O)=[CH:28]3)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:34][C:29]1[NH:30][C:31]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:24][CH2:23][CH2:22][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:33][CH:32]=2)(=[O:5])=[O:4]
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCCC4)ccc3[nH]1)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:25])[N:6]2[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOCCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOCCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
6-Amino-9-benzyl-2-(3-ethoxypropoxy)purine (354 mg, 1.08 mmol) and bromine (1.0 ml) were dissolved in methylene chloride (50 ml). The solution was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (289 mg, yield 66%).
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C(Cl)(Cl)Cl>[I:41][CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CO)CN1C(=O)COc2ccccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H](CI)CN1C(=O)COc2ccccc21
Yield: 80 %

Procedure:
The compound (S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM26-23) (2.52 g, 11.4 mmol), triphenylphosphine (6.12 g, 23.3 mmol), imidazole (1.98 g, 29.1 mmol) and iodine (8.88 g, 35.0 mmol) in CHCl3 (30 mL) were reacted according to GP4 to give the title compound (108LM27-24) (3.02 g, 80%). 1H NMR (CDCl3) δ 7.07-7.00 (m, 4H), 4.65-4.55 (m, 2H), 3.94 (dd, J=1.7 Hz, J=6.7 Hz, CH2), 3.23-3.14 (m, 2H), 2.18-2.07 (m, 1H), 1.05 (d, J=6.1 Hz, CH3).
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:15][CH:14]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CS(C)=O.C1(C)C=CC=CC=1>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH3:3])=[CH:14][CH:15]=1)=[O:27])[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1CCCN1CCCOc1ccc(C(=O)Cc2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C(=O)c1ccc(OCCCN2CCC[C@H]2C)cc1)c1ccccn1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A mixture of sodium hydride (0.092 g, 3.8 mmoL) in 10 mL of DMSO was stirred under N2 as the product from step 3 (1.0 g, 3.8 mmol) in 5.0 mL of DMSO was added dropwise. After the reaction was stirred for 30 min, a solution of ethyl bromoacetate (0.64 g, 8.83 mmol) in 6.0 mL of toluene was added dropwise, and the reaction was stirred at rt for 1 h. The reaction was then quenched with NH4Cl solution and the solvent was evaporated. The residue was extracted with CH2Cl2 (3×20 mL), combined, washed with saturated NaHCO3, saturated NaCl then dried over Na2SO4. The crude product was purified by flash chromatography using 10% MeOH in CH2Cl2 to give the product (0.65 g, 52%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(I)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
To a solution of 4-iodophenol (30 mmol) in CH2Cl2 (100 mL) was added N-methyl-N-phenylcarbamoyl chloride (27 mmol) and diisopropylethylamine (60 mmol) at room temperature. The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL) and washed with aqueous citric acid (5%), aqueous Na2CO3 and brine. The organic phase was dried (MgSO4) and evaporated to give the crude product which was purified by FC (Quad flash 40 EtOAc-Heptane) to give 6.55 g (69%) of the title compound as light brown crystals.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:35]=O>C1COCC1>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[CH:35]=[CH:10]/[CH2:9][CH2:8][OH:7])[CH:37]=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(/C=C/CCO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
n-Butyllithium (1.55M in hexane, 194 ml) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (60.3 g) in dry THF (375 ml) cooled to 0° under nitrogen. The resulting blood-red solution was stirred at 0° for 15 min and then a solution of 3-methoxy-4-(phenylmethoxy)benzaldehyde (36.3 g) in dry THF (50 ml) was added dropwise over 15 min. The mixture was stirred at 0° for 30 min, allowed to warm up to room temperature, stirred for a further 2 h and then the reaction quenched by the addition of 2N hydrochloric acid (100 ml). The THF was removed in vacuo at 40°, the aqueous residue extracted with ethyl acetate (350 ml) and the organic layer washed with 2N HCl (200 ml). The aqueous phase was extracted with further ethyl acetate (150 ml), the organic layers combined, washed with 8% sodium bicarbonate solution (200 ml) and dried. Concentration afforded a product which was purified by FCC eluting with System B (1:2) yielding the title compound as a cream powder (14.5 g) m.p. 57°-61°
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([N:11](S(C)(=O)=O)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[Cl:20].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[Cl:20]
Reactant: COC(=O)c1c(Cl)cc(N(S(C)(=O)=O)S(C)(=O)=O)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1c(Cl)cc(NS(C)(=O)=O)cc1Cl

Procedure:
The mixture of 100 mg of 2,6-dichloro-4-[bis(methanesulfonyl)amino] benzoic acid methylester, 3 ml of an aqueous solution of 1N sodium hydroxide and 10 ml of ethanol was stirred. After the solvent was removed, the obtained substance was treated by an ordinary method using ethyl acetate as an extractant to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:26]2[O:27][CH:28]([C:31](O)=[O:32])[CH2:29][O:30][C:25]=2[CH:24]=1>>[OH:22][C:23]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:26]2[O:27][CH:28]([C:31]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:32])[CH2:29][O:30][C:25]=2[CH:24]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)(C)c1cc2c(cc1O)OCC(C(=O)O)O2
Product: CC(C)(C)c1cc2c(cc1O)OCC(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Yield: 74 %

Procedure:
That compound is obtained in a yield of 74% starting from 1-[bis(4-fluorophenyl) methyl]piperazine and 6-hydroxy-7-tert-butyl-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(Cl)(Cl)[Cl:14].S(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: COc1ncc(Cl)cc1C(=O)O
Reactant: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ncc(Cl)cc1C(=O)Cl

Procedure:
To a suspension of 3.76 g. (0.02 mole) of 5-chloro-2-methoxynicotinic acid in 100 ml. of carbon tetrachloride, there were added 100 ml. of thionyl chloride in one portion and the resulting mixture was then refluxed on a steam bath for a period of 90 minutes. Upon completion of this step, the clear solution so obtained was cooled and then concentrated in vacuo at room temperature to afford a residual oil. The excess thionyl chloride present was next removed in the same manner as described in Preparation A for the production of 2-methoxynicotinoyl chloride, except that only 100 ml. of benzene was employed this time (i.e., during each purification step). The yield of pure 5-chloro-2-methoxynicotinoyl chloride, obtained as the residual product, was quantitative in this particular instance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCc1ccc(Cl)cc1

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 4-chlorobenzylamine to provide yellow solid 4-(4-chlorobenzylamino)-3-nitroquinoline, melting point of crude product 168°-173° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)(=[O:4])=[O:3].P(Br)(Br)[Br:18].O.[OH-].[Na+]>CCOCC>[Br:18][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=1[C:13]([F:16])([F:15])[F:14]
Reactant: BrP(Br)Br
Reactant: CS(=O)(=O)c1ccc(CO)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
To a suspension of (4-methanesulfonyl-2-trifluoromethyl-phenyl)-methanol (50.3 g, 0.20 mol) in dry Et2O (400 ml), cooled to 0° C., is added PBr3 (6.5 ml, 0.07 mol) dropwise over 10 min. A sticky, thick yellow suspension forms which upon agitation and warming to room temperature changes to a fine white suspension. The reaction mixture is cooled again to 0° C. and water (200 ml) is added slowly. The suspension is neutralised at 10° C. with 4N NaOH aq (30 ml). The product is collected by filtration to give a white solid which is dried at 50° C. under high vacuum.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]2.[NH3:20]>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([NH2:20])=[O:19])[NH:12]2
Reactant: N
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc2c(Br)cccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Oxalyl chloride (0.9 mL, 10 mmol) was added to a suspension of 4-bromo-1H-indole-2-carboxylic acid (2.1 g, 8.8 mmol) in DCM and the mixture was stirred for 2 h. The solution formed was added drop-wise to a stirring mixture of ammonia (37%, 50 mL) and ice (50 mL). The resulting mixture was allowed to stand for 3 days. The mixture was filtered and the filtrate extracted with EtOAc. The solid from the filtration was dissolved in EtOAc and the organic solutions were combined, dried (MgSO4) and then evaporated to afford the title compound as a brown solid (2.1 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][N:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)[CH3:2].[CH3:30]I.[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:28][N:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)[N:6]([C:7](=[O:16])[C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)[CH3:30])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)NC(=O)c1cc(C)cc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C

Procedure:
A solution of N-(3,5-dimethylbenzoyl)-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester (3,8 g) and methyliodide (1.8 ml) in dry N,N-dimethylformamide (40 ml) is cooled in an ice bath and sodium hydride (60% in oil, 390 mg) is added in portions. The mixture is allowed to warm to room temperature during 5 hours, then poured into water, extracted with ethyl acetate, the organic phase washed with water, and with brine, dried and evaporated. Flash chromatography of the residue on silica gel (hexane/ethyl acetate 3:1) gives pure N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester. NMR (CDCl3, 400 MHz) δ [ppm] 8.30 (d, broad, 1H), 7.75 (m, 2H), 7.41 (d, broad, 1H), 7.12 (d, broad, 1H), 6.97 (s, 0.5H), 6.93 (s, 0.5 H), 6.70 (s, 1H), 6.53 (d, broad, 1H), 6.36 (d, broad, 1H), 5.40 (m, 0.5H), 4.58 (m, 0.5H), 4.27 (m, 2H), 3.54 (m, 0.5H), 3.25 (m, 1H), 3.05 (m, 2H), 2.78 (s, 1.5H), 2.23 (s, 3H), 2.13 (s, 3H), 1.27 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[NH:16]1[CH2:21][CH2:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:30])[CH2:18][CH2:17]1>>[F:14][C:2]([F:1])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([N:16]1[CH2:21][CH2:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:30])[CH2:18][CH2:17]1)=[O:13]
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Reactant: O=C1Nc2ccccc2C12CCNCC2
Product: O=C(CCc1ccccc1C(F)(F)F)N1CCC2(CC1)C(=O)Nc1ccccc12

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 31 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and spiro[indoline-3,4′-piperidin]-2-one. LC-MS Method 3 tR=1.157, min, m/z=403; 1H NMR (CDCl3) 1.39 (m, 2H), 1.47 (m, 2H), 1.65 (m, 2H), 1.78 (m, 3H), 2.62 (m, 2H), 3.15 (m, 2H), 3.61 (m, 2H), 3.83 (m, 2H), 4.17 (m, 1H), 6.83 (d, 1H), 6.97 (m, 1H), 7.15 (m, 2H), 7.26 (m, 1H), 7.38 (m, 1H), 7.43 (m, 1H), 7.58 (d, 1H), 7.84 (s, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:9]([N+:20]([O-])=O)[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1.[Pd]>[NH2:20][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:19]=[CH:18][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(N2CCOCC2)cc1N
Yield: 3.9 %

Procedure:
127 g (0.412 mol) of tert-butyl 4-morpholin-4-yl-2-nitrobenzoate (WO 2007/06837 A1) were dissolved in 1000 ml of tetrahydrofuran, 12.7 g of palladium/carbon (5%, water-moist) were added, and the mixture was stirred over hydrogen at room temperature for 5 h. Conventional work-up gave 4.5 g (Y=100%) of tert-butyl 2-amino-4-morpholin-4-ylbenzoate.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH:1]1([NH:7][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
Cyclohexylamine (80 gm., 0.8 mole) is dissolved in 2.5 l. of benzene and treated dropwise with 70 gm. (0.4 mole) of p-chlorobenzoyl chloride in 250 ml. of benzene over 45 minutes with intermittent cooling to maintain reaction temperature between 22°-30°. After stirring an additional 15 minutes, the mixture is diluted with benzene and washed with water. A suspended solid is filtered and the filtrate concentrated to 1 l. to give a second crop; these are combined and recrystallized from methanol, 65.0 gm. (68.5%), m.p. 191°-193°.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([CH2:24][OH:25])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:2]1[N:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([CH2:24][OH:25])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CNC
Reactant: OCc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Agent: Cl
Product: CN(C)c1cc2c(cn1)-c1nc(-c3nc(CO)nn3CC(F)(F)F)cn1CCO2

Procedure:
(5-(9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol 387 was reacted with dimethylamine-HCl to give 394 (11 mg) as a colorless solid. LCMS: 410.1. 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 7.94 (s, 1H), 6.13 (s, 1H), 5.84 (q, J=8.9 Hz, 2H), 5.32 (t, J=6.1 Hz, 1H), 4.50 (m, 4H), 4.45 (d, J=6.0 Hz, 2H), 3.05 (s, 6H)
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].Cl[C:14]1[CH:15]=[C:16]2[N:23]([CH:24]([CH3:26])[CH3:25])[CH2:22][CH2:21][N:17]2[C:18](=[O:20])[N:19]=1>C1COCC1.CN(C=O)C>[CH:24]([N:23]1[C:16]2[N:17]([C:18](=[O:20])[N:19]=[C:14]([O:3][CH2:4][C:5]3[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=3)[C:8]#[N:9])[CH:15]=2)[CH2:21][CH2:22]1)([CH3:26])[CH3:25]
Reactant: CC(C)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)N1CCn2c1cc(OCc1cccc(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (17.97 mg, 0.449 mmol) in THF (4 mL), 3-(hydroxymethyl)benzonitrile (59.8 mg, 0.449 mmol) and 7-chloro-1-isopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (80 mg, 0.374 mmol) in DMF (2.00 mL).
Reaction SMILES: [C:1]1([CH:7]([CH2:12][CH3:13])[CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:20]1CCCC1>>[C:1]1([CH:7]2[CH2:12][CH2:13][CH:10]([OH:20])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: CCC(CC(C)=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OC1CCC(c2ccccc2)CC1
Yield: 74 %

Procedure:
4-Phenylhexanone (1.74 g; 10 mmoL) is mixed with 1M lithium aluminum hydride (LiAlH4) solution in tetrahydrofuran (THF) (10 mL; 10 mmoL). The reaction mixture is stirred and refluxed for 6 hrs. After the starting ketone is consumed as determined by thin-layer chromatography (TLC) and gas phase chromatography (GC), the reaction mixture is carefully quenched with water (40 mL) whereupon a precipitate forms. Then, hydrochloric acid (10 mL) is added to dissolve the precipitate, and the solution is twice extracted with diethyl ether (20 mL twice). The combined ether portions are dried with Na2SO4, and the solvent is evaporated to yield 4-phenylcyclohexanol (1.71 g; 74%). The purity and identity of the compound are established by TLC and GC using an authentic sample of the material obtained from Lancaster Company.