Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C(C(O)=O)CSC1(C)C)(=[O:8])C1C=CC=CC=1.ON1C2C=CC=CC=2N=N1.[CH:29]1([N:35]=[C:36]=[N:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1>[C:36]([NH:35][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)([NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:8]
Reactant: CC1(C)SCC(C(=O)O)N1C(=O)c1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 48 g. (181 mmole) of 3-benzoyl-2,2-dimethyl-4-thiazolidinecarboxylic acid, prepared by the procedure described above in 1.5 l. of tetrahydrofuran were added 27.8 g. (181 mmole) of 1-hydroxybenzotriazole followed by 37.4 g. (181 mmole) of dicyclohexylcarbodiimide. The mixture was stirred for 30 minutes at room temperature. The reaction mixture developed into a thick slurry resulting from the precipitation of dicyclohexylurea. To the heavy slurry was added 63 g. (181 mmole) of benzyl D-4-benzyloxyphenylglycinate and the reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was filtered to remove the dicyclohexylurea, the filtrate evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with 5% hydrochloric acid, water, aqueous sodium bicarbonate, and finally with water. The washed solution was dried, treated with carbon, and evaporated to dryness under reduced pressure to yield 107 g. (99% yield) of N-[α-(benzyl D-4-benzyloxyphenylacetate]-3-benzoyl-2,2-dimethyl-4-thiazolidinecarboxamide.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:15])=[C:10]([C:12]([OH:14])=[O:13])[N:11]=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Na].[CH2:17](I)[CH3:18]>C(O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:15])=[C:10]([C:12]([O:14][CH2:17][CH3:18])=[O:13])[N:11]=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2nc(C(=O)O)c(C)nc21
Reactant: CCI
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1nc2cnn(CC)c2nc1C

Procedure:
12.1 g. of 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid (0.059 mol.) are added to a solution of 1.36 of sodium (0.059 mol.) in 250 ml. of absolute ethanol and is stirred for 30 minutes at room temperature. The alcohol is distilled off in vacuo and the sodium salt is dissolved in 350 ml. of dry dimethylformamide. Then, 14 g. of ethyl iodide (0.88 mol.) are added and the solution is heated in an autoclave at 120° for 10 hours. After the dimethylformamide has been removed in vacuo, the residual 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid ethyl ester is treated with water, dried at 50° and recrystallized from hexane, yield 9.4 g. (68%), m.p. 64°-65°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:34]=[CH:33][C:20]4[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].FC(F)(F)C(O)=O>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:34]=[CH:33][C:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1Cl
Product: Cl
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 96) (305 mg, 0.629 mmol) in dichloromethane (2 mL) at room temperature was treated with trifluoroacetic acid (1 ml, 12.98 mmol) and the mixture stirred for 1 hr. The reaction mixture was concentrated and the residue partitioned between 2M NaOH and ethyl acetate. The ethyl acetate extract was washed with brine, dried and concentrated to a colourless gum which slowly crystallized, to give the title compound free base (229 mgs).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:29][CH2:30]CCCCO.C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li].Cl>O.CCOCC.CS(C)=O>[C:10]1([C:9]([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)[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:29]#[CH:30])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCCCCCl
Agent: Cl
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: C#CCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred suspension of 68.1 g. (0.18 moles) of 1-chloro-6-triphenylmethoxyhexane, prepared from 1-chloro-6-hydroxyhexane and triphenylmethyl chloride in the manner of Example 277, in 60 ml. of dimethylsulfoxide is added a solution of 19.9 g. (0.216 moles) of lithium acetylideethylenediamine complex in 120 ml. of dimethylsulfoxide during 20 minutes. The temperature is maintained at 25°C. with an ice bath during the addition, after which the mixture is stirred at ambient temperature for 3.5 hours and then at 30°C. for 15 minutes. The mixture is diluted with 100 ml. of ether and treated dropwise with 150 ml. of water with ice bath cooling. The mixture is diluted with 400 ml. of water and 250 ml. of 2:1 ether-pet ether and acidified with 120 ml. of 4N hydrochloric acid in the ice bath. The phases are separated, and the aqueous phase is extracted with 3:1 ether-pet ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil affords the subject compound as white crystals, m.p. 43°-45°C. after recrystallization from pet-ether, ν max 3300 (acetylenic hydrogen), 2360 (triple bond), 1600, 1068, and 706 cm-1 (triphenylmethoxy group).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([OH:30])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.CO[CH:33]1[CH2:37][CH:36]=[C:35](OC)O1>C(O)(=O)C>[OH:30][C:9]1[C:10]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:2]([N:1]2[CH:33]=[CH:37][CH:36]=[CH:35]2)=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: Nc1cc(C(NC(=O)COc2ccccc2)c2ccccc2)c(O)c2ncccc12
Reactant: COC1=CCC(OC)O1
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)NC(c1ccccc1)c1cc(-n2cccc2)c2cccnc2c1O

Procedure:
N-[(5-amino-8-hydroxyquinolin-7-yl)(phenyl)methyl]-2-phenoxyacetamide (150 mg, 0.37 mmol), 2,5-dimethoxydihydrofuran (50 mg, 0.37 mmol) in acetic acid (1 ml) were heated at 65 C for 40 min. The reaction mixture was concentrated, dissolved in ethylacetate, washed with aq. Sodium bicarbonate and dried over sodium sulfate. The solvent was removed in vacuo to afford N-[[8-hydroxy-5-(1H-pyrrol-1-yl)quinolin-7-yl](phenyl)methyl]-2-phenoxyacetamide as a tan solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[C:6]([F:18])[CH:5]=1)[CH3:3].Cl[C:20]1[N:25]=[C:24]([N:26]2[C@@H:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][O:28][C:27]2=[O:34])[C:23]([F:35])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:35][C:23]1[C:24]([N:26]2[C@@H:30]([CH:31]([CH3:32])[CH3:33])[CH2:29][O:28][C:27]2=[O:34])=[N:25][C:20]([NH:1][C@H:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:11])=[C:6]([F:18])[CH:5]=2)[CH3:3])=[N:21][CH:22]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1nc(Cl)ncc1F
Reactant: C[C@H](N)c1ccc(C(=O)N2CCCCC2)c(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1nc(N[C@@H](C)c2ccc(C(=O)N3CCCCC3)c(F)c2)ncc1F
Temperature: 107.5 °C
Yield: 12.5 %

Procedure:
To (S)-(4-(1-aminoethyl)-2-fluorophenyl)(piperidin-1-yl)methanone (0.019 g, 0.076 mmol) was added (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (0.030 g, 0.114 mmol), NMP (0.5 ml) and Hunig's Base (0.033 ml, 0.190 mmol). The reaction was heated at 105-110° C. for 8 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 4.5 mg of (S)-3-(5-fluoro-2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one as TFA Salt. LCMS m/z 474.2 (M+H)+, Rt 0.91 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:12]1[N:16]=[C:15]([NH2:17])[S:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:9]([NH:17][C:15]2[S:14][CH:13]=[CH:12][N:16]=2)=[O:11])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1nccs1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1nccs1)c1nc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution (400 ml) of 14.1 g (73.0 mmol) of 3,6-dichloro-2-pyridinecarboxylic acid in chloroform were successively added 9.00 g (89.9 mmol) of aminothiazole, 12.1 g (89.7 mmol) of N-hydroxybenzotriazole hydrate and 19.0 g (99.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride followed by stirring at room temperature for 24 hours. After the reaction solution was concentrated, ethyl acetate was added to the residue followed by washing with 0.2N aqueous solution of hydrochloric acid, water and saturated aqueous solution of sodium hydrogen carbonate. After drying and concentrating, the resulting residue was crystallized from a mixed solvent of hexane and ethyl acetate (5:1) to give 12.8 g (yield: 64%) of 3,6-dichloro-N-(thiazole-2-yl)-2-pyridine carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:21])[C:13]([CH3:15])=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CI
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.4 %

Procedure:
In dry N,N-dimethylformamide (8 ml) was dissolved 400 mg (1.3 mmol) of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methyl-1H-imidazole (5a), followed by addition of 80 mg (2.0 mmol) of sodium hydride under ice-cooling. After 5 minutes, 245 mg (1.73 mmol) of methyl iodide was added. After 30 minutes, the reaction mixture was poured in ice-water and extracted with diethyl ether. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:2) and recrystallized from n-hexane to provide 313 mg (yield 75%) of 5-(3,5-dichlorophenylthio)-1,2-dimethyl-4-isopropyl-1H-imidazole (Compound I-1). mp 95 to 96° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.C(=O)(O)[O-].[Na+].[C:21]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[C:21]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:33])=[O:34])=[CH:28][CH:27]=1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)cc1

Procedure:
6.3 grams (0.03 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile are dissolved in 70 ml of acetone, and 30 ml water are added thereto. Sodium bicarbonate (2.6 g, 0.03 mol) is added with stirring, followed by a solution of 7 g (0.03 mol) of 4-carbethoxybenzenesulfonyl chloride in 30 ml acetone. The reaction mixture is stirred overnight, filtered and the filtrate diluted with 750 ml water. The dark, cream-colored solid which separates and which is recovered by filtration and drying constitutes 3-[4-(4-carbethoxyxbenzenesulfonamido)benzenesulfonyl]acrylonitrile: ##SPC31##
Reaction SMILES: C(C[CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#N.[OH-:22].[Na+].[CH2:24]([OH:27])[CH2:25]O>O>[C:24]([CH2:25][CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([OH:27])=[O:22]
Reactant: [OH-]
Reactant: N#CCCCCc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: OCCO
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCc1c(-c2cccnc2)[nH]c2ccccc12

Procedure:
3-(4-Cyanobutyl)-2-(3-pyridyl)-indole (540 mg) is heated at 185° for 0.5 hour with 450 mg of powdered NaOH and 5 ml of ethylene glycol; the reaction solution is diluted with 50 ml water, washed with ether, and adjusted to pH 6 with 2N HCl, to give 3-(4-carboxybutyl)-2-(3-pyridyl)indole.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH:13]1(/[CH:16]=[C:17](\[O:19][CH2:20][CH3:21])/[O:18][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)CC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCO/C(=C\C1CC1)O[Si](C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium in hexanes (1.6M, 26 ml) was added with stirring to a solution of diisopropylamine (6.2 ml) in tetrahydrofuran (8 ml) at below −25° C. under nitrogen. After 30 min, the mixture was cooled to −75° C. and ethyl cyclopropylacetate (4.5 g) added dropwise keeping the temperature below −65° C. The mixture was then maintained below −75° C. for 3 h before chlorotrimethylsilane (3.8 ml) was added below −65° C. The reaction was allowed to warm to ambient temperature and then evaporated to dryness. The residue was slurried with hexane and filtered. The filtrate was evaporated to an orange oil which was distilled in vacuo to give the title compound (4.0 g) as a clear mobile liquid, b.p 80-82° C., 3×10−2 bar.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reaction time: 0.5 h

Procedure:
N-methylpiperazine 3.6 mL, N,N-diisopropylethylamine 5.7 mL and tetrahydrofuran 31 mL were mixed and dropped into a solution of 4-chloro-3-nitrobenzenesulfonyl chloride 8.19 g in tetrahydrofuran 51 mL, under cooling with ice, followed by stirring for 30 minutes under cooling with ice. The stirring was then continued for 17 hours at room temperature. The solvent was distilled off and the residue was poured in water, of which pH was raised to 9 with saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate-tetrahydrofuran mixed solvent. The organic layer was washed with saturated brine, dried over magnesium sulfate, and from which the solvent was distilled off. Recrystallizing the crude product from ethyl acetate-hexane mixed solvent, 4.29 g of the title compound was obtained.
Reaction SMILES: Br[C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(CC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[NH3:26]>O.[Cu+2].C(CC(=O)C)(=O)C.CN1C(=O)CCC1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([NH2:26])[C:3]([NH2:12])=[N:4][CH:5]=1
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Reactant: N
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)CC(C)=O
Solvent: O
Product: Nc1cc(C(F)(F)F)cnc1N
Temperature: 110 °C

Procedure:
To an autoclave reactor, 3-bromo-5-trifluoromethyl-pyridine-2-ylamine (40 g), acetylacetone copper(II) (2.2 g), acetylacetone (6.6 g), cesium carbonate (59 g), and NMP (105 ml) were added, and then 28% of aqueous ammonia solution (25 mL) was added under ice-cooling. After the reactor was sealed, the mixture heated to 110° C., and stirred with heating for 12 hours. The mixture was ice-cooled to room temperature, then diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 15 g 5-trifluoromethyl-pyridine-2,3-diamine (Compound (1F)-22).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH:9](O)[CH:8]([CH2:11][CH2:12][CH3:13])[S:7][C:6]=2[C:14]=1[Cl:15].[B]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: CCCC1Sc2c(cc(OC)c(Cl)c2Cl)C1O
Agent: [B]
Solvent: CC(=O)O
Product: CCCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
To a mixture of 44 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxy-2-n-propylbenzo[b]thiophene in 275 ml of glacial acetic acid is added 65 ml of boron triluoride etherate and the mixture is warmed on a steam bath unitl it becomes clear. The solution is stired for 10 mins and then quenched with a mixture of 500 g of ice and 200 ml of a 10% sodium hydroxide solution. The mixture is neutralized with 50% sodium hydroxide solution and then extracted with two 300-ml portions of ethyl ether. The organic layers are combined, washed with 100 ml of a saturated sodium bicarbonate solution, 100 ml of water, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil. Chromatography of the oil on an alumina column using 9:1-hexane:ethyl ether as eluting solvent gives 31 g of 6,7-dichloro-5-methoxy-2-n-propylbenzo[b]thiophene as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1.[Cl:13]N1C(=O)CCC1=O.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.O.ClCCl>[NH2:1][C:2]1[C:3]([Cl:13])=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1
Reactant: CN1CCc2ncc(N)cc2C1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CN1CCc2nc(Cl)c(N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine D4 (900 mg, 5.52 mmol) was dissolved in acetic acid (50 ml) before being treated portionwise with N-chlorosuccinimide (1.11 g, 8.28 mmol) 20 min. The reaction mixture was stirred overnight at room temperature under argon. The reaction mixture was diluted with water (125 ml), basified to pH10 with solid K2CO3 and extracted with dichloromethane (×2). The combined organic extracts were washed with sodium bicarbonate, dried (MgSO4) and evaporation in vacuo gave a crude black solid. Flash chromatography using dichloromethane (10% MeOH) gave thetitle compound as a pale orange solid.
Reaction SMILES: Cl[N:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[CH2:3]1.[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[CH2:3][N:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(c1)CN(Cl)C=C2Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CN(c1ccc(OC(C)C)cc1)C=C2Cl
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 83.9 %

Procedure:
To a solution of 2,4-dichloro-7-methoxyisoquinolin (0.7 g, 3.07 mmol), 4-isopropoxyphenylboronic acid (0.60 g, 3.38 mmol) in 1,4-Dioxane (15 ml) and water (10 ml) was added K2CO3 (0.84 g, 6.14 mmol). The reaction mass was degasified for 20 min. Pd (Ph3P)4 (0.17 g, 0.15 mmol) was added to the above reaction mass and degasified again for 5 min at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 90° C. for 18 h. The reaction mass was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.85 g, 84%) as white solid. 1HNMR (400 MHz, CDCl3): δ ppm 8.25-8.22 (d, J=8 Hz, 1H), 8.13 (s, 1H), 8.07-8.05 (d, J=8 Hz, 1H), 7.48-7.47 (d, J=4 Hz, 1H), 7.34-7.32 (d, J=8 Hz, 1H), 7.07-7.05 (m, 2H), 4.77-4.71 (m, 1H), 4.15 (s, 3H), 1.32-1.31 (d, J=4 Hz, 6H); MS: MS m/z 328.20 (M++1).
Reaction SMILES: [Cl:1][C:2]([Cl:4])=[CH2:3].Cl[C:6]([CH3:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].Cl>[Fe](Cl)(Cl)Cl>[Cl:1][C:2]([Cl:4])=[CH:3][C:6]([CH2:7][CH3:8])([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(C)(Cl)CC
Reactant: C=C(Cl)Cl
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Product: CCCCC(C)(C=C(Cl)Cl)CC
Temperature: 30 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
1,235 g (12.7 moles) of 1,1-dichloroethene and 630 g (4.23 moles) of 3-chloro-3-methylheptane are taken at 20° C. 85 g of anhydrous iron(III) chloride are added in portions, while cooling. The mixture is then subsequently stirred at 30° C. for 2 hours. It is poured onto ice and dilute aqueous hydrochloric acid. The organic phase is separated off, dried and subjected to fractional distillation. 627 g (71% of theory) of 1,1-dichloro-3-ethyl-3-methyl-hept-1-ene are isolated at boiling point6.1 50°-60° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH:23]([CH3:25])[N:11]2[C:12]3[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=3[CH2:18][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:24][C@@H:23]([CH3:25])[N:11]2[C:12]3[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[C:15]([Br:26])=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1CN(C(=O)OC(C)(C)C)CC2Cc3ccc(C(F)(F)F)cc3N12
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(C(F)(F)F)cc3N21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (0.83 g; 2.4 mmol) was dissolved in dimethylformamide (7 mL) and N-bromosuccinimide (0.43 g, 2.5 mmol) was added in portions. The mixture was stirred for 1 h, added to ice water (500 mL) and extracted with diethylether (2×150 mL). Organic phases were pooled, washed with water, dried with MgSO4 and the solvent was removed in vacuo. Chromatography on silica gel (n-hexane/diethylether 4:1) yielded the title product as a colorless wax (0.99 g, 98%). ISP-MS: m/e=435.3, 437.3 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].[H-].[Na+].[CH2:18](Br)[CH:19]=C.[CH3:22]OCCOC>>[CH2:1]([C:2]1([CH3:22])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15])[CH:18]=[CH2:19]
Reactant: C=CCBr
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Product: C=CCC1(C)Cc2cc(OC)c(Cl)c(Cl)c2C1=O

Procedure:
2-Allyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone is prepared following substantially the same procedure described in Example 5, Step E, using the following substances: 2-methyl-5-methoxy-6,7-dichloro-1-indanone (14.7 g., 0.06 mole), sodium hydride (1.7 g., 0.072 mole), 1,2-dimethoxyethane (500 ml.) and allyl bromide (8 ml.). The above procedure gives 11.0 g. of 2-allyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone which after recrystallization from methyl cyclohexane melts at 58° C.