Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](O)=[O:4].S(Cl)(Cl)=O.C[N:13]([CH:15]=O)C.[CH2:17](Cl)Cl>>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([NH:13][CH2:15][CH3:17])=[O:4]
Reactant: ClCCl
Reactant: CN(C)C=O
Reactant: CCC(Br)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCNC(=O)C(Br)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen, to a solution of 2-bromobutanoic acid (2.0 g, 12.0 mmol) in DCM (50 mL) at 0° C. were sequentially added thionyl chloride (2.6 mL, 35.9 mmol) and 0.5 mL of DMF. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction mixture was concentrated in vacuo and then cooled to 0° C. Thirty (30) mL of 40% ethylamine water solution was added slowly. The reaction was allowed to warm to room temperature and was stirred for 2 h, followed by extraction with EtOAc. The combined organic extracts were dried (Na2SO4), and concentrated in vacuo to afford 2-bromo-N-ethylbutanamide.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([NH:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: CCOC(=O)C1=Cc2cccc(N)c2OCC1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1=Cc2cccc(NC(=O)CCCCl)c2OCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 9-amino-2,3-dihydro-1-benzoxepin-4-carboxylate (0.35 g), 4-chlorobutyryl chloride (0.202 ml) and pyridine (0.146 ml) in dichloromethane (3.5 ml) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (3:1) as an eluent to give colorless crystals of ethyl 9-(4-chlorobutyryl)amino-2,3-dihydro-1-benzoxepin-4-carboxylate (0.48 g).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:7]=2[S:8][CH:9]=1.Cl[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[O:20][N:19]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][O:14][C:11]3[CH:12]=[CH:13][C:6]4[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[CH:9][S:8][C:7]=4[CH:10]=3)[CH:22]=2)=[CH:28][CH:27]=1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Product: O=C(O)Cc1csc2cc(OCc3cc(-c4ccc(Cl)cc4)on3)ccc12

Procedure:
The title compound was prepared from compound 5C and commercially available 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole in the manner analogous to example 5F. MS m/z 414 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>CC#N.C(Cl)(Cl)Cl>[Br-:23].[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][O:26][CH2:25][CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)=[CH:33][CH:32]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: Clc1ccc(COCCBr)cc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3ccc(Cl)cc3)(CC1)CC2
Product: [Br-]
Temperature: 60 °C
Yield: 31.4 %

Procedure:
1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) was added to a solution of 1-{[(2-bromoethyl)oxy]methyl}-4-chlorobenzene (36 mg, 0.143 mmol) in 2:3 CH3CN/CHCl3 (3 mL), and the reaction was heated at 60° C. for 96 h. The reaction was concentrated, and the crude product washed with EtOAc (3×1 mL). The product was dried under high vacuum to give the title compound (17.4 mg, 32%). LC/MS ESI RT 2.09 min M+462
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C@@H:28]1([NH2:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[O:1]([CH2:8][CH2:9][CH2:10][C:11]([NH:38][C@@H:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCOc1ccccc1
Reactant: N[C@H]1CCCc2ccccc21
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCOc1ccccc1)N[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.4 %

Procedure:
4-Phenoxybutanoic acid (1.05 g, 5.8 mmol, Lancaster) and triethylamine (2.4 mL, 17.4 mmol) in anhydrous CH2Cl2 (25 mL) were treated with pivaloyl chloride (0.75 mL, 6.1 mmol) at 0° C. After stirring for 1 hour, the reaction mixture was treated with (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine (1.0 mL, 6.9 mmol) and the reaction mixture was allowed to warm to room temperature and stir for 16 hours. The reaction mixture was diluted with CH2Cl2, washed with 1N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 40% ethyl acetate/hexanes) to provide the title compound as a colorless oil (2.07 g).
Reaction SMILES: [NH2:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:9]1([C:15](Cl)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[OH:8][CH2:7][C:2]1([NH:1][C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC1(CO)CCCC1
Solvent: ClCCl
Product: OCC1(NC(c2ccccc2)(c2ccccc2)c2ccccc2)CCCC1

Procedure:
A mixture of 1-amino-1-cyclopentanemethanol (3.00 g; 26.05 mmol) and triphenylmethylchloride (7.26 g; 26.05 mmol) in 70 ml CH2Cl2 is heated overnight. The reaction mixture is cooled and flash chromatographed twice using 5:1; hexane:EtOAc to obtain 1-hydroxymethyl-1-triphenylmethylaminocyclopentane as a thick yellow oil which is used directly in the next step.
Reaction SMILES: C([Li])CCC.[C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])#[CH:7].[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[C:7]#[C:6][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](C#C[C@@H]1CCCN1C(=O)OC(C)(C)C)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (2.5M solution in hexanes. 11 mL) was added dropwise to a cooled solution of tert-butyl (S)-2-ethynylpyrrolidine-1-carboxylate (prepared according A Paul et al, Tetrahedron, 2006, 62, 8919, 4.49 g) in dry THF (230 ml) under an atmosphere of nitrogen while maintaining the temperature below −65° C. When the addition was completed, the mixture was stirred at −78° C. for 15 minutes then allowed to warm to 0° C. and stirred for 2.5 hours. Tributyl tin chloride (7.7 mL) was added dropwise over five minutes and the mixture was stirred at room temperature for 1.5 hours. The mixture was cooled to 0° C. and saturated sodium bicarbonate was added while maintaining the temperature below 15° C. The layers were separated and the aqueous layer was extracted with ethyl acetate, washed with saturated sodium bicarbonate, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of pentane and ethyl acetate with a gradient of 0-7.5% to give tert-butyl (S)-2-tributylstannanylethynylpyrrolidine-1-carboxylate (0.39 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([C:26](O)=[O:27])=[CH:23][CH:24]=4)[N:19]=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.[C:29]([O:33][C:34](=[O:41])[NH:35][CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38])([CH3:32])([CH3:31])[CH3:30].C(Cl)CCl.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[C:29]([O:33][C:34](=[O:41])[NH:35][CH2:36][C:37]([CH3:39])([NH:40][C:26]([C:22]1[CH:21]=[C:20]2[C:25]([C:16]([C:9]3[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)=[N:12][N:11]4[CH2:13][CH2:14][CH2:15][C:10]=34)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1)=[O:27])[CH3:38])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(C(=O)O)ccc24)CCC3)n1
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(C(=O)NC(C)(C)CNC(=O)OC(C)(C)C)ccc24)CCC3)n1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid (0.16 g, 0.43 mmol), (2-amino-2-methyl-propyl)-carbamic acid tert-butyl ester (0.09 g, 0.47 mmol), EDC (0.09 g, 0.47 mmol), 1-hydroxybenzotriazole (0.06 g, 0.47 mmol) in dichloromethane (8.6 mL) is added N,N-diisopropylethylamine (0.25 mL, 1.29 mmol). The mixture is stirred at room temperature for 18 hand concentrated in vacuo. The residue is taken up in ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on SiO2 (methanol/dichloromethane/2:98) to yield the title compound 0.21 g (91%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH3:33][C:34]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]2[C:35]=1[CH2:36][CH2:37][CH2:38][CH:39]2[NH2:45]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:45][CH:39]1[C:40]2[C:35](=[C:34]([CH3:33])[CH:43]=[C:42]([CH3:44])[CH:41]=2)[CH2:36][CH2:37][CH2:38]1)=[O:31]
Reactant: Cc1cc(C)c2c(c1)C(N)CCC2
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CCCc3c(C)cc(C)cc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 5,7-dimethyl-1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:20][CH3:21])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
A solution of 4-chloro-3-trifluoromethyl benzoic acid (10 g, 44.5 mmol) in ethanol (10 ml) was split equally between two microwave vials. Concentrated sulfuric acid (0.75 ml) was added to each vial (1.5 ml in total). The reactions were heated in the microwave at 120° C. for 30 minutes in total. The reaction mixtures were combined and concentrated in vacuo. The residue was partitioned between EtOAc (100 ml) and aq. sodium bicarbonate (100 ml), the organic phase was separated, washed with aq. sodium bicarbonate (100 ml) and water (2×100 ml) and then dried (phase separator) and the solvent removed in vacuo to give the title compound (4.126 g) as a colourless oil. δH (400 MHz, methanol-d4) consistent with previous example.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18](SC)[CH:19]=[C:20]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:29])[CH2:3][CH2:2]1.O[O:32][S:33]([O-:35])=O.[K+].O.[CH3:38]N(C)C=O>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([S:33]([CH3:38])(=[O:35])=[O:32])[CH:19]=[C:20]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:29])[CH2:2][CH2:3]1
Reactant: CSc1cc(NCC(C)(C)O)c2ncc(-c3ccc(C(=O)NC4CC4)c(C)c3)n2n1
Reactant: CN(C)C=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: Cc1cc(-c2cnc3c(NCC(C)(C)O)cc(S(C)(=O)=O)nn23)ccc1C(=O)NC1CC1
Temperature: 23 °C
Reaction time: 60 h
Yield: 39 %

Procedure:
To a solution of 38.7 mg (91 μmol) N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(methylsulfanyl)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to intermediate example 15 in 1.2 mL N,N-dimethylformamide were added 168 mg Oxone and the mixture was stirred at 23° C. for 2.5 days. Water was added and the mixture was extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 18.5 mg (39%) of the title compound.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[NH2:10][C:11]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]([CH3:28])[N:12]=1.O>FC(F)(F)C(O)=O>[CH2:21]([C:14]1[N:13]([CH3:28])[N:12]=[C:11]([N+:10]([O-:6])=[O:5])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O
Reactant: CCOC(=O)c1c(N)nn(C)c1Cc1ccccc1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c([N+](=O)[O-])nn(C)c1Cc1ccccc1
Temperature: 75 °C

Procedure:
A mixture of sodium perborate tetrahydrate (95%, 3.12 g, 19.3 mmol) and trifluoroacetic acid (10 mL) was heated to 75° C. To this was added a solution of ethyl 3-amino-5-benzyl-1-methyl-1H-pyrazole-4-carboxylate (prepared according to the method of Y. Xia et al., J. Med. Chem. 1997, 40, 4372-4377; 1.00 g, 3.86 mmol) in trifluoroacetic acid, and the mixture was allowed to react at 75° C. for 2.5 hours. The reaction was then cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo; purification via silica gel chromatography (Eluant: 30% EtOAc in heptane) provided C20 as a dark yellow oil. Yield: 333 mg, 1.15 mmol, 30%. LCMS m/z 290.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.32 (t, J=7.1 Hz, 3H), 3.74 (s, 3H), 4.33 (br s, 2H), 4.34 (q, J=7.1 Hz, 2H), 7.14-7.18 (m, 2H), 7.25-7.30 (m, 1H), 7.31-7.36 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.[Br:11]Br.[OH-].[Na+]>O>[Br:11][C:10]1[C:4]2[C:5](=[CH:6][N:7]=[C:2]([CH3:1])[CH:3]=2)[NH:8][N:9]=1
Reactant: BrBr
Reactant: Cc1cc2cn[nH]c2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(Br)n[nH]c2cn1

Procedure:
5-Methyl-1H-pyrazolo[3,4-c]pyridine (2 g, 15.02 mmol) and bromine (0.774 mL, 15.02 mmol) in water (71.5 mL) were stirred at RT for 1 h. The reaction mixture was neutralized with NaOH (20% in water), the precipitate was filtered, washed with water and dried under high vacuum. Yellow powder, MS (UPLC/MS): 212/214 [M+H]+, 210/212 [M−H]−; tR (HPLC conditions f): 0.74 min.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]Cl)[CH2:2][CH2:3][CH3:4].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][N:29]1[C:25](=[O:35])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Yield: 86.6 %

Procedure:
A solution of 4-butoxy-6-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.59 g, 4.5 mmol) and potassium phthalimide (1.26 g, 6.8 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-{(4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (1.81 g, 86.6%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[F:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH:25]2[CH2:28][NH:27][CH2:26]2)=[CH:22][CH:21]=1>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:27]2[CH2:28][CH:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:30][CH:29]=3)[CH2:26]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Fc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OC2CN(c3ccnc(Cl)n3)C2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To 2,4-dichloropyrimidine (200.0 mg, 1.342 mmol) in 2-propanol (7 mL) at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (0.702 mL, 4.03 mmol) followed by 3-(4-fluorophenoxy)azetidine hydrochloride (273 mg, 1.342 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min then at RT for 41 h and concentrated. Purification of the crude product was done using MPLC (25 g cartridge, 40 g column, 0 to 60% EtOAc-hexanes) to give 2-chloro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidine (314.2 mg).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:27]/[C:28](/[CH3:34])=[CH:29]\[C:30]([O:32][CH3:33])=[O:31].[F:35][C:36]([F:46])([F:45])[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O>C(O)C>[CH3:5][C:3]1[NH:27][C:28]([CH3:34])=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:40]([C:39]2[CH:42]=[CH:43][CH:44]=[C:37]([C:36]([F:35])([F:45])[F:46])[CH:38]=2)[C:2]=1[C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)=[O:6]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCOC/C=C/c1ccc(Cc2cccnc2)cc1
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOC/C=C/c2ccc(Cc3cccnc3)cc2)C1c1cccc(C(F)(F)F)c1
Yield: 72.8 %

Procedure:
In 5 ml of ethanol were dissolved 500 mg of 2-[(E)-3-[4-(3-pyridylmethyl)phenyl]allyloxy]ethyl acetoacetate, 0.20 g of methyl 3-aminocrotonate and 300 mg of 3-trifluoromethylbenzaldehyde, and the resulting solution was subjected to reaction under reflux for 15 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform:ethanol (100:1 by volume)] to obtain 660 mg (yield 72.8%) of pale yellow, powdery 3-[2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyloxy]ethyl] 5-methyl 2,6-dimethyl-4-(3-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: C(=O)=O.CC(C)=O.[Cl:8][C:9]1[CH:37]=[CH:36][C:12]2[N:13]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:14](=[O:26])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:11]=2[CH:10]=1.CC([O-])(C)C.[K+].[Br:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48]Br>C1COCC1>[Br:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48][CH:15]1[C:14](=[O:26])[N:13]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:12]2[CH:36]=[CH:37][C:9]([Cl:8])=[CH:10][C:11]=2[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:16]1
Reactant: BrCc1cccc(Br)c1
Reactant: COc1ccc(CN2C(=O)CN=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(Cc3cccc(Br)c3)N=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Yield: 84.5 %

Procedure:
To a stirred and cooled (dry ice/acetone bath) solution of (Z)-7-chloro-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (6.00 g, 14.2 mmol) in THF (80 mL) was slowly added 1 M KOtBu (21 mL, 21 mmol, 1.5 eq). The resulting deep red mixture was stirred over dry ice/acetone bath ˜10 min followed by the slow addition of a solution of 3-bromobenzyl bromide (5.10 g, 21.4 mmol, 1.5 eq) in THF (15 mL). After stirring another ˜45 min at −78° C., the reaction mixture was quenched with saturated brine and diluted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated (rotovap, then high vacuum). Chromatography over silica gel using 10-30% EtOAc/heptane gave 7.08 g (yield of 84%) of the title product. [Note: when using benzyl chlorides as alkylating agents, tetrabutyl ammonium iodide was added along with the alkylating agent at the low temperature]. 1H NMR (300 MHz, CDCl3) δ 3.57 (d, 2H), 3.70 (s, 3H), 3.73 (t, 1H), 3.83 (s, 3H), 4.59 (d, 1H), 5.62 (d, 1H), 6.61 (d, 2H), 6.8-6.9 (m, 4H), 7.2-7.45 (m, 8H), 7.63 (fine d, 1H).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH3:11][CH2:12][N:13]1[C:25]2[C:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.C(N1C2C=CC([CH:52]=[O:53])=CC=2C2C1=CC=C(C=O)C=2)CCCCCC>>[CH3:11][CH2:12][N:13]1[C:25]2[C:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][C:22]([CH:52]=[O:53])=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[C:17]([CH:4]=[O:5])[CH:18]=2
Reactant: CCCCCCCn1c2ccc(C=O)cc2c2cc(C=O)ccc21
Reactant: CN(C)C=O
Reactant: CCCCCCc1cccc2c3ccccc3n(CC)c12
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCc1cc(C=O)cc2c3cc(C=O)ccc3n(CC)c12

Procedure:
N-2-ethylhexyl-3,6-diformyl carbazole was prepared from DMF (97 ml, 1.25 mol), POCl3 (116.5 ml, 1.25 mol), and N-2-ethylhexylcarbazole (50 g, 0.18 mol) according to the procedure described for N-Heptyl-3,6-Diformylcarbazole. The product was obtained as 40 g of brownish liquid (66% yield). The product was used as is in the next step without any purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:21](=[S:23])=S.CI.[NH4+:26].[OH-]>C1COCC1>[C:21]([O:18][CH2:17][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])(=[S:23])[NH2:26]
Reactant: S=C=S
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccccc1
Reactant: [NH4+]
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)NC(COC(N)=S)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
In a 500 mL flask equipped with magnetic stirrer, N-(t-butyloxycarbonyl)-(DL)-phenylalaninol(0.051 mole, 13.6 g) was dissolved in 200 mL of THF and was added with NaH(0.061 mole, 1.47 g) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, followed by the addition of CS2 (0.061 mole, 4.66 g). After being stirred for 40 min. at 0° C., MeI(0.061 mole, 8.69 g) was added to the reaction mnixture. The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of 5N NH4OH (0.090 mole, 18.0 mL) for 6 hours. The resulting solution was quenched with water. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a solid. This was recrystalized in a solution mixture-of n-hexane and diethyl ether, to produce 14.7 g of O-thiocarbamoyl-N-(t-butyloxycarbonyl)-(DL)-phenylalaninol: Yield 80%.