Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[CH2:21][N:22]1[CH:26]=[N:25][C:24]([NH2:27])=[N:23]1>>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([NH:27][C:24]2[N:25]=[CH:26][N:22]([CH2:21][C:20]3[CH:28]=[CH:29][CH:30]=[C:18]([C:17]([F:32])([F:16])[F:31])[CH:19]=3)[N:23]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Nc1ncn(Cc2cccc(C(F)(F)F)c2)n1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2ncn(Cc3cccc(C(F)(F)F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 1-(3-trifluoromethyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a light yellow solid (Yield=63%). MS ISP (m/e): 429.3 (100) [(M+H)+].
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([O-])(C)(C)C.[K+].F[C:13]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>CN(C)C=O>[CH3:1][C:2](=[N:4][O:5][C:13]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[CH3:3]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1F
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=NOc1cc(OCc2ccccc2)ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of 7.83 g (0.107 mol) of acetone oxime in 200 ml of dimethylformamide is stirred for 30 minutes in the presence of 12 g (0.11 mol) of 95% potassium t-butanolate. A solution of 20.3 g (0.089 mol) of 2-fluoro-4-(phenylmethoxy)benzonitrile in 100 ml of dimethylformamide is then added over 15 minutes. The mixture is stirred for 2 hours and then poured into ice-water. The crystalline product is filtered off and dissolved in dichloromethane, and the solution is then dried over sodium sulphate and concentrated under reduced pressure. 21.2 g of product are obtained.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][CH:4]=[CH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:14][C:15]([Cl:22])([Cl:21])[CH2:16][O:17][C:18](Cl)=[O:19]>O>[Cl:14][C:15]([Cl:22])([Cl:21])[CH2:16][O:17][C:18](=[O:19])[NH:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][CH:4]=[CH:3]1
Reactant: N[C@@H]1C=CC[C@H]1O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N[C@@H]1C=CC[C@H]1O)OCC(Cl)(Cl)Cl

Procedure:
A 10.18 (103 mM) quantity of crude (3R,4R)-3-amino-4-hydroxycyclopentene (prepared as in Preparation 19, step 4) is dissolved in 75 ml of water and the mixture treated with 10.6 g (100 mM) of sodium carbonate. The mixture is then cooled in an ice bath to <10° and treated dropwise while stirring vigorously, with 24 g (110 mM) of trichloroethylchloroformate over 30 minutes. After 3 hours the reaction is filtered and the collected solid product washed throughly with water. On drying there is obtained 22.43 g of (1R,5R)-2,2,2-trichloroethyl-5-hydroxy-2-cyclopentene-1-carbamate as crystalline solid, m.p. 82°-84°. Recrystallization of a small sample from isopropylether-Skellysolve B gives material with a m.p. 87°-87.5° [α]-92° (C=0.14, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][CH3:29])=[O:27]>O1CCOCC1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[O:28][CH3:29]
Reactant: Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Yield: 27.3 %

Procedure:
To a mixture of 5-(3-amino-4-chlorophenyl)-3-(2-furanyl)-1,2,4-oxadiazole (1.35 g) and 1.05 g of potassium carbonate in 30 ml of dioxane, 0.75 g of methyl chloroformate is added. The resulting mixture is heated at reflux for 16 hours, concentrated to dryness and the residue placed on an alumina column. The product is eluted with benzene to yield 0.45 g of the title compound, melting point 200°-201°C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCCCC)=O.[CH3:26][C:27]1([CH3:33])[NH:31][C:30](=[O:32])[CH2:29][NH:28]1>CN(C)C=O>[CH3:26][C:27]1([CH3:33])[NH:31][C:30](=[O:32])[CH2:29][N:28]1[C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CC1(C)NCC(=O)N1
Reactant: O=C(O)CN1CCCC1=O
Agent: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)CN1C(=O)CN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An ice cold solution of 2-oxo-1-pyrrolidineacetic acid (2.2 g) and triethylamine (2.15 ml) in dimethylformamide (10 ml) was treated dropwise while stirring with butyl chloroformate (1.95 ml). After stirring at 0° C. for 30 minutes, 2,2-dimethyl-4-imidazolidinone (1.75 g) was added at once, and stirring was continued at room temperature overnight. After evaporation under reduced pressure the residue was chromatographed on a silica gel column, eluting with dichloromethane/methanol 1:1. The selected fractions were collected and evaporated to give an oil which was washed twice with ethyl acetate. The residue was crystallized from ethyl acetate, to give the title compound as a white powder, m.p. 214°-217° C. (decomp.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnccn1
Solvent: c1ccccc1
Product: O=C(Cl)c1cnccn1
Yield: 74 %

Procedure:
Pyrazinecarboxylic acid (3.7 g, 30 mmol), benzene (25 mL) and thionyl chloride (15 mL) were added into a 100 mL round bottom flask. The reaction mixture was heated under reflux for two hours after which time benzene and excess thionyl chloride were removed by distillation. The dark red crude pyrazinoyl chloride was purified by sublimation under vacuum at a bath temperature of 50°-60° C. to give colorless crystals that weighed 3.2 g (74% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].Cl.O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[CH:20]1[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1 eq.) is dissolved in tetrahydrofuran and treated with 3.6 N HCl solution. The reaction is stirred at 40° C. for 5 h. Water is then added and the reaction mixture is cooled to room temperature. The reaction mixture is extracted with ethyl acetate (2×50 mL). The combined extracts are washed with 25 mL of aqueous saturated NaHCO3 and 2×50 mL of water. The organic layer is concentrated to a thick oil and 50 mL of heptane is added to the mixture to precipitate the desired compound which is filtered to give of 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH2:32][CH:33]([C:39](OCC)=[O:40])[C:34](OCC)=[O:35])[CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]1)[N:17]=2>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH2:32][CH:33]([CH2:39][OH:40])[CH2:34][OH:35])[CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]1)[N:17]=2
Reactant: CCOC(=O)C(Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(CO)Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 1 h

Procedure:
To a slurry of lithium aluminum hydride, 1.0 m solution in tetrahydrafuran (1.39 mL, 1.39 mmol) in 4 mL THF at 0° C. under nitrogen was added diethyl 2-((3-fluoro-4-(5-(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)malonate (0.240 g, 0.463 mmol) as a solution in 4 mL THF slowly dropwise via syringe, with 1 mL THF rinse. The slightly yellow reaction mixture was allowed to stir 1 h, then the bath was removed. After 4 h at ambient temperature, the reaction was judged complete. Water (0.05 mL) was added carefully dropwise under nitrogen, followed by 0.10 mL 5 N NaOH, followed by 0.15 mL water. After 1 h, the reaction mixture was filtered to remove a solid, rinsing with THF, and concentrated in vacuo. The material was adsorbed onto 2 g silica gel from DCM/MeOH and purify by silica gel chromatography, 12 g, 20-100% EA/hexanes to give 2-((3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)propane-1,3-diol as a light yellow solid. MS (ESI) m/z: calculated: 434.2; Observed: 435.1 (M++1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CN(C)[CH:21]=[O:22]>>[OH:22][CH2:21][CH2:11][CH2:12][CH2:4][CH2:5][CH2:13][CH2:18][CH2:17][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH3:3])=[C:5]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C=O
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: Cc1c(-c2cccnc2)n(CCCCCCCCO)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.9 g (0.06 mole) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0°-5° is added dropwise over 20 minutes a solution of 10.4 g of 3-methyl-2-(3-pyridyl)indole in 60 ml of dimethylformamide. The mixture is stirred for 0.5 hour at 0°-5° followed by the dropwise addition of 17.6 g (0.06 mole) of 1-tetrahydropyranyloxy-8-bromooctoane in 50 ml of dimethylformamide. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting mixture is kept at room temperature for 0.5 hour, washed with ether, basified with aqueous with 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness to give 1-(8-hydroxyoctyl)-2-(3-pyridyl)-3-methylindole.
Reaction SMILES: O=O.[CH3:3][C:4](C)([O-])C.[K+].[C:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])[CH3:10].ICC>N#N.O>[CH2:3]([CH:12]([C:13](=[O:15])[CH3:14])[C:9](=[O:11])[CH3:10])[CH3:4]
Reactant: CC(=O)CC(C)=O
Reactant: CC(C)(C)[O-]
Agent: N#N
Agent: O=O
Agent: [K+]
Solvent: CCI
Solvent: O
Product: CCC(C(C)=O)C(C)=O
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a three-neck flask in N2 atmosphere free of water and oxygen were successively added 0.066 mol potassium tert-butoxide and 150 mlTHF. Then to the resulting mixture was slowly added dropwise 0.06 mol acetylacetone with stirring while cooling the mixture with ice-bath. The reaction was allowed to continue at room temperature for 1 hour, then 0.07 mol iodoethane was added dropwise at room temperature. Next, the reaction was allowed to continue at room temperature for further 48 hours. After the reaction was finished, the solvent was removed by distillation. To the solid mixture was added saturated saline until the solid mixture was just completely dissolved. The solution was extracted with suitable amount of anhydrous ethyl ether for three times. The organic phase was combined and dried over anhydrous sodium sulfate. The solvent was removed to give 6.5 g product.
Reaction SMILES: [C-]#N.[K+].[F:4][C:5]([F:17])([F:16])[C:6](=[O:15])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[C:23](=O)(O)[O-:24].[Na+].CC(C[AlH]CC(C)C)C>O.C1COCC1.C1(C)C=CC=CC=1>[OH:15][C:6]([C:5]([F:16])([F:17])[F:4])([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:23]=[O:24]
Reactant: O=C([O-])O
Reactant: O=C(CCc1ccccc1)C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Agent: [C-]#N
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=CC(O)(CCc1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
200 mg (3.1 mmol) of potassium cyanide in 2 ml of water is added to 0.55 g (2.7 mmol) of 1,1,1-trifluoro-4-phenyl-butan-2-one (D. Yang; M-K. Wong; Z. Yan J. Org. Chem. (2000); 65; 4179-4184) in 4 ml of THF and 2 ml of water. It is cooled to 0° C., and 1 ml of a 25% sulfuric acid is added, allowed to heat to room temperature and stirred for 16 hours. Saturated sodium bicarbonate solution is added and extracted with ethyl acetate. After washing with saturated sodium chloride solution and drying on sodium sulfate, the crude cyanide, which is dissolved in 15 ml of diethyl ether and cooled to −70° C., is obtained quantitatively. 4.6 ml (5.5 mmol) of a 1.2 M DIBAL solution in toluene is added in drops over 10 minutes. It is allowed to heat for 2 hours to room temperature, quenched with 10% tartaric acid solution, and vigorous stirring is continued. After extraction with ethyl acetate, 5 g of silica gel and 10 ml of a 1 M sulfuric acid are added. It is stirred vigorously for 12 hours and filtered through Celite. The phases are separated, and it is extracted again with ethyl acetate. After chromatography on silica gel (hexane/ethyl acetate 30%), 300 mg of still contaminated 2-hydroxy-4-phenyl-2-(trifluoromethyl)-butanal is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28](=O)[CH:27]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:29])[CH2:27][C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc([N+](=O)[O-])c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 2,2-dimethyl-6-(3-nitro-phenyl)-[1,3]dioxin-4-one (Example J12) according to the general procedure K. Obtained as a yellow solid (113 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH:25]1([NH:28][C:29]([CH3:34])([CH3:33])[C:30]([NH2:32])=[O:31])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:28]([CH:25]4[CH2:27][CH2:26]4)[C:29]([CH3:34])([CH3:33])[C:30](=[O:31])[N:32]=3)[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: CC(C)(NC1CC1)C(N)=O
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: Cc1c(C2=NC(=O)C(C)(C)N2C2CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 11 was synthesized from 4a (248 mg, 0.66 mmol) and 5f (148 mg, 1.05 mmol) as a white solid (122 mg, 38%) in a manner similar to that described in Example 36. 1H NMR (600 MHz, CDCl3) δ 7.42 (d, 1H), 7.28-7.26 (m, 3H), 7.21 (d, 1H), 7.07 (d, 2H), 2.91-2.89 (m, 1H), 2.29 (s, 3H), 1.49 (s, 6H), 0.88-0.86 (m, 2H), 0.76-0.73 (m, 2H); ESMS m/z: 487.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH2:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][N:23](C)C.Cl.CN>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:23][CH3:22])[N:15]=[C:14]([NH:19][CH2:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CN(C)C
Agent: CN
Agent: Cl
Solvent: CCO
Product: CCNc1nc(NC)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Yield: 53 %

Procedure:
0.1 g (0.00031 mol) of 4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol and stirred with 0.6 ml (0.0043 mol) of trimethylamine and 0.1 g (0.0015 mol) of methylamine hydrochloride in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 150 ml of 1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.053 g (54%) of 4-amino-N-(2-ethylamino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: 261-263° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:47]([C@H:51]1[CH2:56][CH2:55][C@H:54](O)[CH2:53][CH2:52]1)[CH2:48][CH2:49][CH3:50].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[C:23]([O:22][C:21](=[O:27])[NH:20][C:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C@H:54]4[CH2:55][CH2:56][C@@H:51]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:52][CH2:53]4)[CH:3]=3)[CH:8]=2)[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Reactant: CCCC[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc(C4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
[5-(6-Hydroxynaphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester (Example 13, 498 mg, 0.00133 mol, Apex), PS-triphenylphosphine (3.00 mmol/g loading, 689 mg, 0.00207 mol, Aldrich) were slurried in Tetrahydrofuran (10 mL, Acros), then trans-4-butylcyclohexanol (0.255 g, 0.00163 mol, Synthon) and diisopropyl azodicarboxylate (0.315 mL, 0.00160 mol, Acros) was added. The reaction was stirred at room temperature. After 4 d, the mixture was diluted with ethyl acetate, filtered and concentrated and the crude product was taken up into methylene chloride and subjected to silica gel chromatography purification to give the title compound in 353 mg yield (52%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:34][CH3:35]>>[CH3:32][N:31]([CH3:33])[CH:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([F:17])=[CH:4][N:3]=3)=[C:20]([O:34][CH3:35])[CH:21]=2)[CH2:30][CH2:29]1
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1N
Reactant: Fc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1Nc1ncc(F)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1H-indole (INTERMEDIATE 3) and 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (INTERMEDIATE 28).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]3=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:3]>C1COCC1.C(O)C.[C].[Rh]>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: [Rh]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.1 %

Procedure:
A mixture of 5% rhodium-carbon (50% wet, 15 mg) and 9-[4-(1-methylethyl)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF (30 mL) and ethanol (30 ml) was stirred under a hydrogen atmosphere at room temperature for 7 hr. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (143 mg) as a gray white solid. The obtained solid was crystallized from THF and diisopropyl ether to give a white solid.
Reaction SMILES: IC[CH2:3][CH2:4][CH:5]([S:15][CH:16](CCCI)[CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])CCC(F)(F)C(F)(F)F.[CH3:30][NH2:31]>O1CCCC1>[CH3:30][NH:31][CH2:3][CH2:4][CH2:5][S:15][CH2:16][CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21]
Reactant: CN
Reactant: FC(F)(F)C(F)(F)CCC(CCCI)SC(CCCI)CCC(F)(F)C(F)(F)F
Solvent: C1CCOC1
Product: CNCCCSCCCC(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 133.5 %

Procedure:
In a solution of 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentylsulfide in 200 ml of absolute tetrahydrofuran, 45 g of methylamine is condensed at a bath temperature of -78° C., and it is stirred for 1.5 hours at room temperature and for 4 hours at 60° C. in the pressurized reactor. To open the reactor, it is allowed to cool overnight to room temperature and then to -78° C. Then, it is allowed to reach room temperature, excess methylamine is evaporated, diluted with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 15.7 g of N-methyl-[3-(4,4,5,5,5-pentafluoropentylthio)-propyl]-amine is obtained as an oil.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+:6].[Cl:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(OCC)=O>>[Cl:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2][O-:4].[K+:6]
Reactant: CCOC(=O)CCl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC=O
Product: CCOC(=O)C(Cl)=C[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a suspension of potassium tert-butoxide (5.2 g) in IPE (50 mL) were added ethyl 2-chloroacetate (5.6 g) and ethyl formate (3.4 g) under ice-cooling, and the mixture was stirred overnight at room temperature. The precipitate was collected by filtration, and dried to give the title compound (5.8 g). 1H NMR (300 MHz, DMSO-d6) δ 1.11 (3H, t, J=7.2 Hz), 3.92 (2H, q, J=7.2 Hz), 8.95 (1H, brs).