Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13]SC)[CH:7]=1)=[O:4].[CH:18]1C=C(Cl)C=C(C(OO)=O)C=1.[S:29]([O-:33])([O-])(=[O:31])=S.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][S:29]([CH3:18])(=[O:33])=[O:31])[CH:7]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CSCCc1cccc(NC(=O)C(F)(F)F)c1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)CCc1cccc(NC(=O)C(F)(F)F)c1
Yield: 89 %

Procedure:
A solution of 2,2,2-trifluoro-N-(3-(2-(methylthio)ethyl)phenyl)acetamide (4 g, 15 mmol) and m-CPBA (7.9 g, 45 mmol) in DCM (30 mL) was heated to reflux overnight. Aqueous solution of sodium thiosulfate (10 mL) was added. The solid was filtered from the mixture solution. The aqueous layer was extracted by ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give 2,2,2-trifluoro-N-(3-(2-(methylsulfonyl)ethyl)phenyl)acetamide (4 g, yield 89%). 1H NMR: 400 MHz CDCl3 δ 7.85 (s, 1H), 7.50-7.49 (m, 1H), 7.36-7.28 (m, 2H), 7.07-7.05 (m, 1H), 3.26-3.22 (m, 2H), 3.14-3.10 (m, 2H), 2.79 (s, 3H).
Reaction SMILES: [CH2:1]=O.CO.[F:5][C:6]([F:21])([F:20])[C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[CH2:10][NH:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].[C:22](=[O:25])([O-])[O-].[K+].[K+]>>[CH3:1][O:25][CH2:22][N:11]([CH2:10][C:9]1[CH:17]=[CH:18][CH:19]=[C:7]([C:6]([F:20])([F:5])[F:21])[CH:8]=1)[CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C=O
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CNCc1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CO
Product: COCN(Cc1cccc(C(F)(F)F)c1)C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Formaldehyde (4.08 g, 50.2 mmol) was dissolved in methanol (2.032 mL, 50.2 mmol). The reaction was cooled to 0° C. (ice bath) and N-(3-(trifluoromethyl)benzyl)-1-(trimethylsilyl)methanamine (Example 56A, 10.94 g, 41.9 mmol) was added dropwise via addition funnel over 30 minutes. Potassium carbonate (4.63 g, 33.5 mmol) was added, and the mixture was stirred at 0° C. for 2 hours. The reaction solution was decanted from the potassium carbonate. The solution was treated with more potassium carbonate and decanted again. The potassium carbonate solids were sequentially washed with ether and these washes were added to the reaction solution. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[C:5]1([C@H:11]2[CH2:16][CH2:15][C@H:14](N)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.[N+:25]([O-:28])(O)=[O:26]>>[N+:25]([C:8]1[CH:7]=[CH:6][C:5]([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:4][C:1](=[O:3])[CH3:2])[CH2:13][CH2:12]2)=[CH:10][CH:9]=1)([O-:28])=[O:26]
Reactant: N[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: CC(N)=O
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@H]1CC[C@H](c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice-cooled solution of 4.67 g. of trans 4-phenylcyclohexylamine acetamide (obtained as in Example 80) in 25 ml. of trifluoroacetic acid, 9 ml. of nitric acid is added. Following about 4 hours of standing in the cold, the mixture is poured onto ice. The precipitate is extracted with methylene chloride and the organic layer washed with aqueous sodium bicarbonate solution. The organic solution is evaporated to dryness and the residue chromatographed on a 500 ml. column of Florisil, with elution by 2 l. of 20% acetone in Skellysolve B. The higher melting solid fractions recovered are combined and recrystallized from a mixture of methylene chloride and ethyl acetate to give 3.09 g. (54% yield) of crystalline trans N-[4-(p-nitrophenyl)cyclohexyl]acetamide, having a melting point of 221° to 224° C.
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+].[C:12](O)(=O)[CH:13]=[CH2:14].S(=O)(=O)(O)[OH:18]>O.C(O)(C)C>[CH2:4]([CH2:3][CH2:2][C:1]([OH:18])=[S:9])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCS
Reactant: O=S(=O)(O)O
Reactant: C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCC(O)=S
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A charge of 1.00 mole of n-octylmercaptan in an isopropyl alcohol and water 1:1 blend was added to a vessel At room temperature, 1.16 mole of sodium hydroxide in an equal volume of water was added to the vessel, and an exotherm proceeded at 50 to 60° C. Over a 30-minute period, 1.05 mole of acrylic acid was added dropwise, the temperature was then raised to 85° C., and the mixture was allowed to reflux for 2 hours. After cooling to 55° C., 70% aqueous sulfuric acid (0.59 mole) was added, with stirring for 30 minutes, followed by pouring into a separatory device. The aqueous layer was drained off, and the organic layer was washed with an equal volume of water containing 2% sodium sulfate. After vacuum stripping at 60° C., the reaction product was analyzed to contain 0.04% octylmercaptan and a yield of 98.6% of 3-octylthiopropionic acid product.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.Cl>C(O)C>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 65.2 %

Procedure:
To a mixture of ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyrate (2.1 g) in ethanol (10 ml) was added a solution of sodium hydroxide (0.26 g) dissolved into water (10 ml). After heating on a hot water bath for 5 minutes, the mixture was cooled by adding ice-water and was made acidic by addition of hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The resultant residue was separated and purified by silica-gel column chromatography (eluting with ethanol:methylene chloride=3:100) to give the title compound (1.3 g, 65.2%) as colorless crystals, mp 79–81° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[C:16]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[SH:25])#[N:17]>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[C:16]#[N:17])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: N#Cc1c(S)cccc1Cl
Solvent: CCOCC
Product: N#Cc1c(Cl)cccc1SSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 86.3 %

Procedure:
30.7 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 500 ml of diethyl ether is reacted in a stirred apparatus with 17 g of 2-cyano-3-chlorothiophenol for 4 hours at 30° C. There is obtained 38 g (86% of theory) of (4-nitro-2-trichloromethylphenyl)-(2-cyano-3-chlorophenyl)-disulfide; m.p.: 137° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[N:4][C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc(F)c(-c2n[nH]c3ncccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(F)c(-c3n[nH]c4ncccc34)n2)CC1
Temperature: 140 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 3-(3,6-difluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.430 mmol) and 1-methylpiperazine (100 uL, 0.901 mmol) and DIPEA (75 uL, 0.434 mmol) in NMP (1 ml) was allowed to stir at 140° C. overnight. The reaction mixture was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (35 mg, 15% Yield).
Reaction SMILES: C(O)C=C.[Cl:5][CH2:6][C:7]([CH3:26])=[CH:8][CH2:9][CH2:10][C:11]([CH3:25])=[CH:12][CH2:13][CH2:14][C:15]([CH3:24])=[CH:16][CH:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20].[Mn]([O-])([O-])(=O)=O.[Ba+2]>C(Cl)Cl>[Cl:5][CH2:6][C:7]([CH3:26])=[CH:8][CH2:9][CH2:10][C:11]([CH3:25])=[CH:12][CH2:13][CH2:14][C:15]([CH3:24])=[CH:16][CH:17]=[C:18]([CH:21]([CH3:22])[CH3:23])[CH:19]=[O:20]
Reactant: CC(=CCCC(C)=CCCC(C)=CC=C(CO)C(C)C)CCl
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Solvent: C=CCO
Product: CC(=CCCC(C)=CCCC(C)=CC=C(C=O)C(C)C)CCl
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of the allylalcohol which is 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraen-1-ol (492 mg, 1.51 mmol) in methylene chloride (22 ml) is added powdered barium manganate (8.5 g) and the mixture is vigorously stirred under argon atmosphere. After 8 hours, disappearance of the starting compound is confirmed and the reaction mixture is filtered and washed. The filtrate and the washing liquid are combined and concentrated. The resulting residue is purified by silica gel column chromatography (n-nexane/ethyl acetate=15:1) to give the desired 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenal (468 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][CH:24]=O)[CH:20]=[CH:19][C:18]=3[N+:26]([O-:28])=[O:27])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(OCC)C.ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][CH2:24][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH:20]=[CH:19][C:18]=3[N+:26]([O-:28])=[O:27])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(Nc2cc(CC=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(CCc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.200 g (0.43 mmole) of 4-(3-chloro-phenyl)-2-[5(2,2-dimethoxy-ethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.9a) and 3 mL of 96% formic acid was stirred at room temperature for 1 hour. The solution was poured into water and the resulting precipitate was collected by filtration, washed with water and air-dried to give 0.135 g of 4-(3-chloro-phenyl)-2-[2-nitro-5-(2-oxo-ethyl)-phenylamino]-thiazole-5-carboxylic acid amide (VI.9b) as an orange solid. A mixture of 0.135 g of 4-(3-chloro-phenyl)-2-[2-nitro-5-(2-oxo-ethyl)-phenylamino]-thiazole-5-carboxylic acid amide (VI.9b), 0.10 mL of N-methylpiperazine, 0.10 mL of glacial acetic acid, 0.50 g of sodium triacetoxyborohydride and 10 mL of dichloromethane was stirred at room temperature for 16 hours. To the mixture was carefully added 1 mL of 1M hydrochloric acid and stirring was continued at room temperature for 30 minutes. The mixture was partitioned between 30 mL of dichloromethane and 30 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed once with 30 mL of water, then 30 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 15:85-20:80) to give an orange foam. Trituration with diethyl ether gave 0.100 g of 4-(3-chlorophenyl)-2-{5-[2-(4-methyl-piperazin-1-yl)-ethyl]-2-nitro-phenylamino}-thiazole-5-carboxylic acid amide (VI.9c) as an orange solid.
Reaction SMILES: [Na].[CH2:2]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[C:19](=[N:24]O)[CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[CH2:26])[CH2:7][C@@H:6]1[OH:27])[CH3:3]>C(O)CC.O>[NH2:24][C@@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[CH2:26])[C@H:11]2[C@H:20]1[C@:21]1([CH3:23])[C@@H:8]([CH2:9][CH2:10]2)[CH2:7][C@H:6]([OH:27])[C@@H:5]([O:4][CH2:2][CH3:3])[CH2:22]1
Reactant: C=C1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=NO)C[C@]12C
Agent: [Na]
Solvent: CCCO
Solvent: O
Product: C=C1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](N)C[C@]12C

Procedure:
Sodium (2.7 g) was added portionwise to a stirred and refluxing solution of 2β-ethoxy-3α-hydroxy-17-methylene-5α-androstan-11-one 11-oxime (1.7 g) in propanol (100 ml) under nitrogen. The cooled reaction mixture was diluted with water and the precipitated solid (1.43 g) was collected by filtration. A portion of this material (300 mg) was purified by partitioning between 2 N-hydrochloric acid and ether when the insoluble hydrochloride which precipitated was collected by filtration and again partitioned between ether and 2 N-sodium hydroxide solution. The organic layer was washed, dried (Na2SO4) and evaporated to give the title compound as a froth (180 mg), [α]D +1.6°.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH:4]=1.[Cl-].[CH3:19][NH:20][C:21]([N:23]1[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]1)=[O:22].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:19][NH:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]2[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]3[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=3)[CH:4]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: CNC(=O)N1CC[NH2+]CC1
Reactant: Cc1cnc(Nc2ncc(C#N)s2)cc1CCl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CNC(=O)N1CCN(Cc2cc(Nc3ncc(C#N)s3)ncc2C)CC1
Reaction time: 3.5 h

Procedure:
2-(4-Chloromethyl-5-methyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (9-9, 0.204 g, 0.771 mmol) and 4-methylcarbamoyl-piperazin-1-ium chloride (4-3, 0.277 g, 1.54 mmol) were dissolved in 2 mL DMSO. Diisopropylethyl amine (0.537 mL, 3.08 mmol) was added and the reaction was stirred for 3.5 hours. The reaction mixture was then directly loaded onto a reverse phase purification system to afford the titled compound, 9-10, as the TFA salt. 1H NMR (CD3OD) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 4.25 (s, 2H), 3.37 (bs, 4H), 3.24 (bs, 4H), 2.73 (s, 3H), 2.39 (s, 3H). MS [M+H]+=372.1. 4-(tert-Butyl-dimethyl-silanyloxymethyl)-2-chloro-3-methyl-pyridine (10-1)
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH:31][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cccc(Oc4ccccc4)c3)cc2s1

Procedure:
The title compound is prepared by following General Method A, using 3-phenoxy-benzoic acid (0.22 g, 1.04 mmol), and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.20 g, 0.80 mmol) to afford an off-white solid (0.19 g, 53%). LC/MS: Retention time=4.45 nm in; (m/z): calcd for C25H2(N4O2S (M+H)+: 447.6; found: 447.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>CN(C)C=O.O>[CH:13]1([CH2:12][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnn(CC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (5.05 g, 44.7 mmol) in N,N-dimethylformamide (250 mL) was added sodium hydride (2.7 g, 68 mmol, 60% mineral oil suspension) at 0° C. in portions and then followed by bromomethylcyclopropane (6.5 mL, 67 mmol) dropwise at same temperature. The mixture was stirred at room temperature for 4 h and diluted with water (300 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/50 to 1/20) to give the product as yellow oil (7.38 g, 98.9%).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][CH2:40][C:41]([OH:43])=[O:42]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][CH2:40][C:41]([OH:43])=[O:42])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCC(=O)O
Yield: 58.8 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (400 mg) prepared by the method described in Preparation 2 and glycine (300 mg), N-(3-hexadecanoyloxyoctadecanoyl)glycine (260 mg) was obtained as powders according to a similar manner to that of Example 6.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[C:19](=[O:22])([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[NH2:6][C@@H:5]([CH3:4])[C@@H:19]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:22][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2
Reactant: OCc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Solvent: CCCC#N
Product: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(CO)cc2)c1)c1ccccc1
Reaction time: 0.83 h
Yield: 92.1 %

Procedure:
(4-(5-iodo-1H-indazol-1-yl)phenyl)methanol (141b, 1.06 g, 3 mmol), (2R,3S-norephedrine (1.39 g, 9.2 mmol), CuI (206 mg, 1 mmol) and was stirred under argon atmosphere in butyronitrile (14 mL) at 125° C. Caesium carbonate (5.1 g, 15.7 mmol) was added and the mixture was vigorously stirred for 50 min, cooled, filtered and evaporated. Chromatography (SiO2, 040% MeOH in EtOAc) afforded (4-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)phenyl)methanol (516 mg, 45%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:7](=[O:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:5]2.[C-:28]#[N:29].[K+]>CN(P(N(C)C)(N(C)C)=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:15]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:28]#[N:29])=[CH:10][C:9]=2[C:11]([F:14])([F:12])[F:13])[CH2:5][N:6]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=1
Reactant: O=C1c2c(cc(Cl)cc2C(F)(F)F)CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: [C-]#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1cc2c(c(C(F)(F)F)c1)C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
A mixture of 5-chloro-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.123 g, 0.3 mmol), Pd(PPh3)4 (0.035 g, 0.03 mmol), KCN (0.057 g, 0.88 mmol), and KI (0.125 g, 0.75 mmol) in HMPA (3 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate afforded 1-Oxo-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-1H-isoindole-5-carbonitrile (0.112 g, 93%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.39 (s, 2H), 4.72 (s, 2H), 7.22 (d, 2H), 7.37 (d, 2H), 7.89 (s, 1H), 8.06 (s, 1H) GC-MS: m/z 400 (M)+, 379 (M−21)+.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:13][S:14]([C:9]1[S:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:12])=[CH:11][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccccc1-c1cccs1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1-c1ccc(S(=O)(=O)Cl)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To the cold (-5 to 0° C.) solution of 2-(2-tolyl)thiophene (0.87 g, 5 mmole) was added chlorosulfonic acid (0.33 ml, 5 mmole) over a 15 min. period with constant stirring. After 10 min., phosphorous oxychloride (2 ml) and phosphorous pentachloride were added. The reaction mixture was slowly allowed to attain ambient temperature and stirred for 3 hours. The mixture was then poured onto crushed ice (50 g) and was extracted with ethyl acetate (2×50 ml). The combined organic layers was dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica gel using 2% ethyl acetate in hexane to give 2-chlorosulfonyl-5-(2-tolyl)thiophene, (1.1 g, 72% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6](I)=[CH:5]2.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:5]2
Reactant: COc1ccc(CNc2nc3ccc(Br)cc3cc2I)cc1
Reactant: C1COCCN1
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2N2CCOCC2)cc1
Temperature: 125 °C

Procedure:
A mixture of 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine (710 mg, 1.5 mmol), morpholine (1.9 mL, 22.7 mmol), Cu(I)(14.4 mg, 0.08 mmol), cesium carbonate (986 mg, 3.0 mmol), 2-isobutyrylcyclohexanone (50.9 mg, 0.30 mmol) and DMF (10 mL) was heated to 125° C. in a microwave unit for 20 min. The mixture was concentrated in vacuo then partioned the crude product between EtOAc and water. The organic layer was washed with water and brine 3× each, dried over MgSO4 and concentrated in vacuo to give an orange colored oil. This material was purified by silica flash chromatography (0-5% MeOH/DCM) to give 6-bromo-N-(4-methoxybenzyl)-3-morpholinoquinolin-2-amine as a yellow colored oil.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].BrCC(OC)=O>CN(C=O)C>[C:6]1(=[O:11])[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH2:4][NH:5]1
Reactant: O=C1NCc2c(O)cccc21
Agent: COC(=O)CBr
Solvent: CN(C)C=O
Product: O=C1NCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 4-hydroxy 2,3-dihydro-1H-isoindol-1-one (27) (0.250 gm, 1.67 mmol) in DMF (5 ml) K2CO3 and was added, followed by addition of methyl bromoacetate, and the reaction mixture was stirred at room temperature for 2hr. Then the reaction mixture was then poured on ice and extracted with ethyl acetate (2×15 ml). After the standard workup, the residue was dissolved in methanol (3 ml), and treated with NaOH (5 ml, 1N) at 0° C. and then stirred for and additional hour. After the standard workup, the solid was recrystalized in methanol to give compound 29 (0.140 gm, 60%).