Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].NCC[CH2:9][CH2:10][CH2:11][CH2:12]N>O>[CH3:9][CH2:10][CH2:11][CH2:12][NH:4][C:3]([NH2:5])=[N:2][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: NCCCCCCN
Reactant: N=C(N)N
Agent: Cl
Solvent: O
Product: CCCCN=C(N)NCCCC
Temperature: 120 °C

Procedure:
A mixture of guanidine hydrochloride (200 parts) and hexamethylene diamine (292 parts) were heated to 120° C. for 4 hours under a nitrogen atmosphere The temperature was then raised to 150–170° C. for a further 5 hours. The mixture was cooled to 80° C. and water (400 parts) was added, maintaining the temperature at 80° C. until dissolution occurred. The mixture was then cooled to give a solution in water of polyhexamethyleneguanidine, referred to as Prepolymer 1, having a weight average molecular weight (Mw) of 1010 and a number average molecular weight (Mn) of 710, as determined by aqueous gel permeation chromatography.
Reaction SMILES: [CH2:1]1[CH2:12][O:11][C:3]([CH3:10])([CH2:4][CH2:5][CH2:6][C:7]([CH3:9])=[CH2:8])[O:2]1.C([OH:15])C.[OH-].[Na+].OO>CCCCCC>[CH2:12]1[CH2:1][O:2][C:3]([CH3:10])([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH2:8][OH:15])[O:11]1
Reactant: C=C(C)CCCC1(C)OCCO1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: CC(CO)CCCC1(C)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 6,6-ethylenedioxy-2-methyl-hept-1-ene (33.95 g) in hexane (132 ml) under a nitrogen atmosphere is added borane-methyl sulfide complex (7.05 ml) at 0° C. over a half hour period. The reaction is allowed to stir for 3 hours at room temperature and is treated with 95% ethanol (68 ml) and 3N sodium hydroxide (21.8 ml), cooled to 0° C., followed by the dropwise addition of 30% hydrogen peroxide (24.5 ml) to maintain a temperature of 25°-35° C. The reaction mixture is heated at reflux for one half hour, poured into ice water (500 ml) and partitioned between ether and water. The aqueous phase is extracted with ether and the combined extracts are washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give 6,6-ethylenedioxy-2-methyl-heptanol (33.35 g, 89%): nmr (CDCl3,δ), 0.93 (d, 3H, CH3CH<), 1.32 ##STR11## 3.45 (bd, 2H, CHCH2O), 3.93 (s, 5H, OCH2CH2O and CH3CH<).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][N:11]=[C:5]2[N:4]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]1=[O:17].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:24][CH:25]=3)[N:11]=[C:5]2[N:4]([CH2:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:3]1=[O:17]
Reactant: ClCc1ccc(-c2ccncc2)cc1
Reactant: Cn1c(=O)c2c[nH]nc2n(CC(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2cn(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.4 %

Procedure:
5-methyl-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (236 mg, 1.0 mmol), 4-(4-(chloromethyl)phenyl)pyridine (305 mg, 1.5 mmol) and potassium carbonate (414 mg, 3.0 mmol) are suspensed in 3 mL of DMF. The reaction mixture is stirred at room temperature overnight, and then diluted with 100 mL of water. The mixture is extracted with methylene chloride four times (40 mL×4). The combined organic phase is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated to dryness to give 510 mg of crude product, which is used in the next step without further purification. MS (ESI) m/z 404.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:19][CH2:20][C:21](O)=[O:22].N>O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20](=[O:19])[CH2:21][OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CO
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: N
Solvent: O
Product: O=C(CO)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 94.8 %

Procedure:
1.59 g of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine and 536 mg of hydroxyacetic acid were heated at 200° C. for 2 hours. The reaction mixture was cooled, and water was added. The mixture was alkalized with aqueous ammonia, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to afford 1.86 g of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][CH:11]=1)[C:3]([O:5]CC)=O.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:3](=[O:5])[CH:2]([OH:1])[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][CH:15]=1)([CH3:25])[CH3:24]
Reactant: CC(C)N
Reactant: CCOC(=O)C(O)CCc1ccc(-c2ccccc2Cl)cc1
Product: CC(C)NC(=O)C(O)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
Ethyl α-hydroxy-γ-(2'-chloro-4-biphenylyl)butyrate 0.1 mole is stirred with 20 ml. of isopropylamine at about 35°C with stirring overnight and the temperature is then raised to reflux for 28 hours. The reaction mixture is evaporated in vacuo and the residue distilled to obtain N-isopropyl α-hydroxy-γ-(2'-chloro-4-biphenylyl)butyramide.
Reaction SMILES: N1C=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.BrC1[CH:17]=[N:18]C=CC=1>>[N:18]1[CH:5]=[CH:4][CH:3]=[C:2]([C:7]2[CH:8]=[CH:9][C:10]([CH:11]=[O:12])=[CH:13][CH:14]=2)[CH:17]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Product: O=Cc1ccc(-c2cccnc2)cc1

Procedure:
This aldehyde was prepared using the procedure for 4-pyridin-2-yl-benzaldehyde in Example 126 from 3-bromopyridine and 4-formylboronic acid to give a white crystalline solid (94%): mp=53-55° C.; Rf=0.08 (30% EtOAc/hexanes); IR (KBr) 1700, 1605, 1219 cm−1; 1H NMR (CDCl3) δ 7.55-7.60 (m, 1H), 7.76-7.79 (m, 2H), 8.01-8.05 (m, 2H), 8.08-8.12 (m, 1H), 8.69-8.71 (m, 1H), 8.94-8.95 (m, 1H), 10.10 (s, 1H). LRMS 184 (M+H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=O)[CH3:23])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CSC.B.CO>C1COCC1>[CH2:22]([NH:21][CH2:20][CH:17]1[CH2:16][CH2:15][CH:14]([C:11]2[NH:12][CH:13]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:25])([F:26])[F:1])[CH:4]=3)[N:10]=2)[CH2:19][CH2:18]1)[CH3:23]
Reactant: CC(=O)NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: CCNCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (N-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-acetamide (207 mg, 0.57 mmol, from Example 2A) in THF, 3 equivalents of borane dimethylsulfide (2M in THF) was added, and the solution stirred overnight at room temperature. One volume of MeOH was added to the reaction mixture, and the mixture was concentrated under reduced pressure. 50 mL of 3N HCl was added, and the mixture was warmed for 5 minutes. After washing the solution with ether, the solution was made basic with NaOH and extracted with ethyl acetate. The solution was dried (Na2SO4), concentrated under reduced pressure, and purified using preparative plate chromatography to give Ethyl-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazole-2-yl]cyclohexylmethyl}-amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4][CH2:3]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][S:12]([O:9][CH2:8][CH:6]1[CH2:5][O:4][CH2:3][C:2]([CH3:10])([CH3:1])[O:7]1)(=[O:14])=[O:13]
Reactant: CC1(C)COCC(CO)O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COCC(COS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
TEA (0.52 mL, 3.74 mmol) and (6,6-dimethyl-1,4-dioxan-2-yl)methanol (390 mg, 2.67 mmol) were dissolved in DCM (10 mL). Methanesulfonyl chloride (0.249 mL, 3.20 mmol) was slowly added at 0° C. After the addition was completed the solution was warmed to ambient temperature and stirred for 1 hr. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 4:1 to 1:1) to give the product as a colorless oil (584 mg, 98%). 1H NMR (400 MHz, CDCl3) δ ppm 4.00-4.09 (3H, m), 3.74 (1H, dd, J=11.2, 2.8 Hz), 3.42 (1H, d, J=11.6 Hz), 3.16-3.23 (2H, m), 2.99 (3H, s), 1.27 (3H, s), 1.05 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH2:27])(=[O:26])[CH3:25].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:27][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(S(=O)(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 4-(4-bromo-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 9.92 mmol), acetamide (0.88 g, 14.9 mmol), Pd2(dba)3 (0.46 g, 0.49 mmol), Xantphos (0.56 g, 0.99 mmol) and cesium carbonate (9.7 g, 29.8 mmol) were suspended in dioxane (60 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and poured onto ice. Resulting yellow solids collected by filtration and dried. Crude product was purified by flash chromatography on silica gel to afford the title compound as a beige solid (3.12 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[S:41](Cl)(=[O:43])=[O:42]>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[S:41]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:24])(=[O:42])=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Product: COc1ccc(OC)c(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)c1

Procedure:
2,5-Dimethoxy-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2,5-dimethoxybenzenesulfonylchloride (57 mg, 0.239 mmol) according to general method 3 to give 60 mg of a purple solid. MS (posES-FIA) m/z=Found: 533.1; Calcd: 533.14; 1H-NMR δ 7.68-7.48 (m, 5H), 7.16-7.05 (m, 4H), 6.69 (dd, 1H), 6.42 (d, 1H), 4.03 (s, 3H), 3.69 (s, 3H), 3.26-3.10 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([OH:11])[CH:10]=1)[C:7](=O)[CH2:6][CH:5]2[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]2[CH2:7][CH2:6][CH:5]([CH3:13])[C:4]=2[CH:3]=1
Reactant: CC1CC(=O)c2c(O)cc(F)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CCc2c(O)cc(F)cc21
Temperature: 170 °C

Procedure:
5 g of 5-fluoro-2,3-dihydro-7-hydroxy-3-methyl-1H-inden-1-one was heated to 80° C. until all the solid was melted. After adding aluminium chloride (9.3 g) to this melt the reaction mixture was heated to 170° C. during 17 hours. After cooling water and ethyl acetate were added and the mixture was heated on a steam bath until everything was dissolved. The organic layer was separated and washed with water and brine. After removing the solvent the compound was purified by chromatography with the add of heptane/ethylacetate (9:1) resulting in 2.2 g of 6-fluoro-2,3-dihydro-1-methyl-1H-inden-4-ol as a semi-solid, M.S. (C.I.) (M/Z): 167 [M+H]+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([NH2:36])=O)[O:33][C:29]=2[C:28]([F:37])=[C:27]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]=1[CH3:44])#[N:24]>C1(C)C=CC=CC=1>[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34](=[S:10])[NH2:36])[O:33][C:29]=2[C:28]([F:37])=[C:27]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]=1[CH3:44])#[N:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(N)=O)nc2c1C#N
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(N)=S)nc2c1C#N
Temperature: 125 °C
Yield: 41.8 %

Procedure:
Lawesson's reagent (458 mg, 1.13 mmol) was added to a toluene solution of 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-196) (304 mg, 1.03 mmol), followed by heating under reflux in an oil bath at 125° C. for 10 minutes. After cooling to room temperature, the reaction liquid was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=20:1→10:1) to obtain the entitled compound (134 mg, 41.8%) as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[CH3:31][O:32][C:33]1[CH:56]=[CH:55][C:36]([CH2:37][N:38]2[CH2:44][C:43]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51]([OH:53])=O)[CH:47]=[N:48][C:42]=3[NH:41][C:40](=[O:54])[CH2:39]2)=[CH:35][CH:34]=1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:38]2[CH2:44][C:43]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51]([N:2]([CH3:1])[CH2:3][C:4]4[N:5]([CH3:13])[C:6]5[C:11]([CH:12]=4)=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:53])[CH:47]=[N:48][C:42]=3[NH:41][C:40](=[O:54])[CH2:39]2)=[CH:55][CH:56]=1
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)O)cc3C2)cc1
Reactant: CNCc1cc2ccccc2n1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)N(C)Cc4cc5ccccc5n4C)cc3C2)cc1
Yield: 83 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.20 g, 83%) was prepared as a tan powder: 1H NMR (300 MHz, DMSO-d6) δ 12.07 (br s, 1H), 11.23-11.21 (m, 1H), 8.78 (s, 1H), 8.27-8.20 (m, 1H), 7.64-6.99 (m, 10H), 6.42-6.18 (m, 1H), 5.06-4.86 (m, 2H), 4.32-4.20 (m, 4H), 3.77-3.68 (m, 8H), 3.12-3.00 (m, 3H); MS (ESI) m/e 510 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].CN(C1C=CC=CN=1)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g of 2-(4-cyanophenyl)ethanol are introduced into 50 ml of dimethylforamide. 2.54 g of imidazole, 5,63 g of tert-butyldimethylsilyl chloride and a spatula tip-ful of dimethylaminopyridine are added. The reaction medium is left for 2 hours at room temperature and is then added to an ice-water mixture. The mixture is extracted with ethyl acetate and the extracts dried over anhydrous sodium sulphate. The product is purified by chromatography on a column of silica gel, using a mixture of cyclohexane and ethyl acetate (10:1 v/v) as eluent, to give 1-cyano-4-(tert -butyldimethylsilyloxyethyl)benzene.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[S:25]>CN(C)C=O>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:24]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Br:16])=[S:25])=[C:7]([OH:14])[C:6]=1[S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4]
Reactant: S=C=Nc1ccccc1Br
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O
Yield: 71 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (50 mg, 0.2 mmol) and 2-bromophenylisothiocyanate (43 mg, 0.2 mmol) in 0.5 mL of N,N-dimethylformamide was stirred at room temperature for 3 hours. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v) to give the desired product (66 mg, 74%). EI-MS (m/z) 465.5 (M+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].Cl.[CH3:15][C:16]1([CH3:21])[CH2:20][CH2:19][NH:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:18]2[CH2:19][CH2:20][C:16]([CH3:21])([CH3:15])[CH2:17]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(F)c1F
Reactant: CC1(C)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC#CCOc1ncnc(N2CCC(C)(C)C2)c1F
Temperature: 70 °C
Reaction time: 5 h

Procedure:
0.36 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine, 0.25 g of 3,3-dimethylpyrrolidine hydrochloride and 0.62 g of potassium carbonate are added to 1 ml of acetonitrile, then the reaction mixture is stirred at 70° C. for 5 hours. Then saturated aqueous solution of ammonium chloride is added to the reaction mixture which is cooled to about room temperature, and extract with t-butyl methyl ether three times. The organic layers are joined, dried with anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 4-(2-butynyloxy)-5-fluoro-6-(3,3-dimethylpyrrolidine-1-yl)pyrimidine (referred as the present compound (8) hereinafter).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18][CH2:17]2.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([N:18]2[CH2:19][CH:20]3[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]3)[CH2:17]2)(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c2ccccc12
Reactant: C1CC2CCC1CNC2
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)c2ccccc12)N1CC2CCC(CC2)C1

Procedure:
The title compound was prepared by reacting 4-chloro-1-naphthalenesulfonyl chloride (0.27 g) with 3-azabicyclo[3.2.2]nonane (0.13 g) in the presence of DIEA using a procedure similar to that used in Example 5. Yield: 0.33 g, mp: 133.9°-137.3° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18]>>[Cl:8][C:7]1[C:2]([NH:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([F:9])([F:22])[F:21])(=[O:18])=[O:19])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: NS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: Clc1nccnc1Cl
Product: O=S(=O)(Nc1nccnc1Cl)c1ccccc1C(F)(F)F
Yield: 63 %

Procedure:
Following the general method as outlined for Intermediate 2, starting from 2,3-dichloropyrazine and 2-(trifluoromethyl)benzenesulfonamide, the title compound was isolated, after evaporation and recrystallization, as a yellowish solid in 63% yield (97% purity by HPLC).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:23][C:24]1[C:32]([I:33])=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=1)[N:6]2[CH2:12][CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:15][CH2:14][CH2:13][CH2:12][N:6]1[C:5]([CH2:23][C:24]2[C:32]([I:33])=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)=[N:4][C:3]2[C:7]1=[N:8][C:9]([F:11])=[N:10][C:2]=2[NH2:1]
Reactant: CC(C)(C)OC(=O)NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of 2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (3.3 g, 8 mmol) in DMF (50 mL) was added t-butyl (3-bromopropyl)carbamate (9.6 g, 40 mmol) and Cs2CO3 (5.26 g, 16 mmol). The resulting mixture was stirred at room temperature for 1 day. The reaction mixture was condensed and purified by flash chromatography to yield t-butyl (3-(6-amino-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)propyl)carbamate as white solid (3.1 g, 66%). The solution of t-butyl (3-(6-amino-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)propyl)carbamate (1.9 g, 3.3 mmol) in the mixture of TFA/CH2Cl2 (10 mL/2 mL) was stirred at room temperature for 2 hrs. The reaction mixture was condensed, purified by flash chromatography to yield 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine as yellow solid (1.4 g, 89%). 1H NMR (600 MHz, CDCl3/MeOH-d4): δ 7.28 (s, 1H), 6.70 (s, 1H), 5.98 (s, 2H), 4.21 (s, 2H), 4.13 (t, J=7.1 Hz, 2H), 2.67 (t, J=6.8 Hz, 2H), 1.89 (m, 2H); 13C NMR (150 MHz, CDCl3/MeOH-d4): δ 160.8, 159.4, 157.8, 153.7, 152.1, 150.4, 149.4, 132.4, 120.1, 117.2, 111.3, 103.4, 89.8, 41.7, 40.4, 39.3, 33.6; HRMS (ESI) m/z [M+H]+ calcd. for C16H17IFN6O2, 471.0436. found 471.0442.