Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCCC1C=NCCC2.Br[C@@H](CO)C(O)=[O:15].[CH:19]1([N:25]=[C:26]=[N:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].C([NH2+]CSC(C)(C)C)C1C=CC=CC=1>O1CCCC1>[C:26]([NH:25][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:15]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)[C@@H](Br)CO
Agent: C1=NCCCN2CCCCC12
Agent: CC(C)(C)SC[NH2+]Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 ml of a 2M solution of 1,5-diazabicyclo[5.4.0]-undec-5-ene (DBU) in tetrahydrofuran are added while stirring, at room temperature, to a solution of 845 mg (5 mmol) of 2-(S)-bromo-3-hydroxypropionic acid in 10 ml of absolute tetrahydrofuran and the resulting mixture is stirred for a further 2 hours at room temperature. The solvent is subsequently distilled off in vacuo and 25 ml of methylene chloride are added. To this solution containing the DBU salt of (R)-glycidic acid there are added 1.03 g (5 mmol) of dicyclohexyl carbodiimide and, after stirring for one hour, 1.3 g (5 mmol) of N-benzyl-N-tert.-butylthiomethylammonium chloride. After the addition of the last-mentioned reaction component, crystalline dicyclohexylurea is formed. After a reaction time of 3 hours at room temperature, the latter is filtered off with suction and the filtrate is diluted with methylene chloride and washed with phosphate buffer solution having a pH of 8. After concentration of the organic phase by evaporation, the residue is chromatographed over 50 g of silica gel. After a few first fractions have been removed with toluene, the title compound is eluted with a mixture of toluene/ethyl acetate (9:1) in the form of a colourless, viscous oil.
Reaction SMILES: CS(O[C@@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:17])=[CH:11][C:12]=2[F:16])[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Li+]>CN(C=O)C>[N:18]([C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:17])=[CH:11][C:12]=2[F:16])[CH2:7]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1CCc2c(F)cc(F)cc2C1
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCc2c(F)cc(F)cc2C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate (54.0 g), prepared as in Example 7, and lithium azide (15.8 g, 0.322 mol) in 400 mL of DMF was stirred under argon at 50° C. for 16 hours. The reaction was quenched with 200 mL of water and the mixture extracted with 1 L of pentane. The extract was washed with 50 mL of water and dried over magnesium sulfate. Evaporation under reduced pressure at 35° C. gave crude-(S)-2-azido-5,7-difluoro-1,2,3,4-tetrahydronaphthalene as a yellow oil residue (59.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH3:20])=[O:18])[CH:15]=3)[C:10]([S:26][CH3:27])=[CH:9]2)=[N:6][CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1B(O)O>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH3:20])=[O:18])[CH:15]=3)[C:10]([S:26][CH3:27])=[CH:9]2)=[N:6][CH:7]=1
Reactant: COC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Reactant: Cc1ccc(F)c(B(O)O)c1
Product: COC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1

Procedure:
Suzuki coupling of 304a) (0.5 g, 1.11 mmol) and (2-fluoro-5-methylphenyl)boronic acid (0.34 g, 2.22 mmol) under use of (Ataphos)2PdCl2 (79 mg, 0.11 mmol) as catalyst analogously to the protocol for example 261. White solid. Yield: 0.51 g (96% of theory)
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14](Cl)[CH:13]=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1.[Na].[CH3:22][OH:23]>>[CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([O:23][CH3:22])[CH:13]=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1
Reactant: CO
Reactant: CN(C)c1ccc(Nc2cc(Cl)ccc2[N+](=O)[O-])cc1
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc(N(C)C)cc2)c1

Procedure:
24.9 g of N,N-dimethyl-N′-(5-chloro-2-nitrophenyl)benzene-1,4-diamine was added to a solution that consists of 8 g of sodium in 200 ml of methanol, and the mixture was heated in an autoclave for 9 hours to 120° C. After cooling, crystalline product was suctioned out.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O)#[N:2].Cl.[OH:13][NH2:14]>C(O)C.N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[N:14][OH:13])#[N:2]
Reactant: NO
Reactant: N#Cc1cc(C=O)ccc1F
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#Cc1cc(C=NO)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.4 %

Procedure:
3-Cyano-4-fluorobenzaldehyde (5.00 g) and hydroxyamine hydrochloride (2.90 g, 1.25 Eq) were dissolved in ethanol (100 mL) and pyridine (100 mL). The mixture was stirred at RT under N2 for 45 minutes. The solvents were removed and the brown oil was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, and concentrated to give 3-cyano-4-fluorobenzaldehydeoxime (5.03 g). CI mass spectrum z (rel. intensity) 165 (M+H, 100).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18](B(O)O)=[CH:19][C:14]=2[O:13][CH2:12]1>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:2]3[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=3)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Nc1c(F)cc(Br)cc1F
Product: Nc1c(F)cc(-c2ccc3c(c2)OCO3)cc1F
Yield: 59.8 %

Procedure:
The title compound (143 mg) was prepared from 4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and benzo[d][1,3]dioxol-5-ylboronic acid (207 mg, 1.25 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.23-7.18 (m, 3H), 7.08 (dd, J 1.8, 8.2, 1H), 6.91 (d, J 8.1, 1H), 6.01 (s, 2H), 5.24 (s, 2H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([S:11](/[CH:14]=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=3[CH3:25])(=[O:13])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CO.[H][H]>C1COCC1>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([S:11]([CH2:14][CH2:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=3[CH3:25])(=[O:13])=[O:12])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Cc1cc(C(=O)O)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)OCCO2
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1CCS(=O)(=O)N1CCC2(CC1)OCCO2
Yield: 90.7 %

Procedure:
Pd(OH)2—C (20.0 g) was added to a solution of 4-[(E)-2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-vinyl]-3-methyl-benzoic acid (20.0 g, 54.43 mmol) in THF (600 ml)-methanol (200 ml), and the mixture was stirred at room temperature overnight in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was then concentrated under reduced pressure to give 4-[2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-ethyl]-3-methyl-benzoic acid as a white solid (18.23 g, 90.7%).
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:24][C:25]1[CH:31]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[CH:29]=[C:28]([O:41][CH2:42][CH2:43][CH2:44][N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])[C:26]=1[NH2:27])[CH2:21][CH2:22][CH3:23]>C(O)C>[CH2:20]([N:24]1[C:25]2[CH:31]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:37][CH3:38])[CH2:39][CH3:40])[CH:29]=[C:28]([O:41][CH2:42][CH2:43][CH2:44][N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])[C:26]=2[N:27]=[C:13]1[C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:9][C:8]2[CH:18]=[CH:19][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH:11]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CC(C)(C)c1ccc(Oc2cccc(C=O)c2)cc1
Reactant: CCCCNc1cc(OCCCN(CC)CC)cc(OCCCN(CC)CC)c1N
Solvent: CCO
Product: CCCCn1c(-c2cccc(Oc3ccc(C(C)(C)C)cc3)c2)nc2c(OCCCN(CC)CC)cc(OCCCN(CC)CC)cc21
Yield: 88.3 %

Procedure:
{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy]-propyl}diethyl-amine was formed employing 3(4-t-butyl-phenoxy)benzaldehyde (127 mg; 0.50 mmol) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized via General Procedures J1 and J2 and I) (1.6 mg; 0.25 mmol) in ethanol (1 mL) following General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 145 mg (76%) of {3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy]-propyl}diethyl-amine.
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:24][NH2:25]>>[OH:1][CH:2]([CH2:23][NH:25][CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: CN
Reactant: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccccc1

Procedure:
Reaction of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman with methylamine by an analogous method to that described in Example 2 gave 7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethyl-4-phenylchroman isolated as its hydrochloride salt, (57%), m.p. 182°-183°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7].[OH-].[Na+].[CH:16]1([CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH:30]3[O:32][CH2:31]3)=[CH:26][CH:25]=2)[CH2:18][CH2:17]1>C(O)C>[OH:32][CH:30]([CH2:29][O:28][C:27]1[CH:33]=[CH:34][C:24]([O:23][CH2:22][CH2:21][O:20][CH2:19][CH:16]2[CH2:18][CH2:17]2)=[CH:25][CH:26]=1)[CH2:31][NH:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7]
Reactant: NCCNC(=O)N1CCOCC1
Reactant: c1cc(OCC2CO2)ccc1OCCOCC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCNCC(O)COc1ccc(OCCOCC2CC2)cc1)N1CCOCC1

Procedure:
26.2 g of the hydrochloride of N-2-aminoethyl-4-morpholinecarboxamide and 5.0 g of NaOH were refluxed in 175 ml of ethanol for 1 h. Thereafter 22 g of 3-(4-(2-cyclopropylmethoxyethoxy)phenoxy)-1,2-epoxypropane in 100 ml of ethanol was added and the resulting mixture refluxed for 16 h, filtered, and evaporated. The residue was dissolved in 300 ml of ethyl acetate and washed three times with water. The organic phase was then extracted with 250 ml of water at pH 5 (HCl). The aqueous phase was then made alkaline and extracted with methylene chloride. The methylene chloride phase was dried over Na2SO4, filtered, and evaporated. The residue was treated with ether and recrystallized from ethyl acetate. Yield 8.0 g. Melting point 80°-81° C. (base). The structure was determined using NMR-analysis.
Reaction SMILES: [CH3:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[C:12](=[O:25])[C:13]2[C:21](=[CH:22][CH:23]=1)[C:20]1[C:15](=[CH:16][C:17]([OH:24])=[CH:18][CH:19]=1)[CH:14]=2.[OH-].[K+]>C(O)C>[OH:10][C:11]1[C:12](=[O:25])[C:13]2[C:21](=[CH:22][CH:23]=1)[C:20]1[C:15](=[CH:16][C:17]([O:24][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[CH:18][CH:19]=1)[CH:14]=2
Reactant: CCCCCCC(C)Br
Reactant: O=C1C(O)=CC=C2C1=Cc1cc(O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc2c(c1)C=C1C(=O)C(O)=CC=C12

Procedure:
According to a known method, optically active 2-octyl bromide and 2,7-dihydroxylfluorenone were reacted in ethanol in the presence of potassium hydroxide. The resultant reaction mixture was purified by a column chromatography and recrystallization to obtain optically active 2-hydroxy-7-(2-octyloxy)-fluorenone.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[C:12]([C:13]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1>>[Cl:6][C:7]1[C:12]([C:13]([C:15]2[NH:16][CH:17]=[C:18]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:19]=2)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=C(c1ccc[nH]1)c1cccnc1Cl
Reactant: O=S(=O)(O)Cl
Product: O=C(c1cc(S(=O)(=O)Cl)c[nH]1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Chlorosulfonic acid (6.6 mL, 100 mL) was added dropwise to (2-chloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone (from Example 2, 2.06 g, 10 mmol) at 0° C. After stirring at 0° C. for 24 hours, the reaction was poured slowly into ice water. The precipitate was collected by vacuum filtration, washed with water and dried to give 2.9 g (95%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonyl chloride as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1>C(OCC)(=O)C>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1cccc(N)n1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)n1
Yield: 51 %

Procedure:
4-Hydroxy-2-methyl-N-(6-methyl-2-pyridyl)-2H-naphtho[2,1-e]1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 10 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-6-methyl-pyridine. Yield: 51% of theory; m.p.221°-223° C (decomp.; from ethyl acetate).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]([NH2:29])[CH3:28])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)=[C:16]([Cl:15])[CH:17]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CC(N)c1cnc(OCC2CC2)c(Cl)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Product: CC(c1cnc(OCC2CC2)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 35 %

Procedure:
The title compound is prepared in 35% yield (263 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (561 mg, 2.02 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanamine (457 mg, 2.02 mmol, Amine-74, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22]>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:28]3[CH:29]=[C:24]([C:21](=[O:23])[CH3:22])[CH:25]=[CH:26][CH:27]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccc(C(C)=O)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-acetyl-phenylboronic acid to give 1-{3-[3-(5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 373(MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH2:31]([NH:33][S:34](Cl)(=[O:36])=[O:35])[CH3:32]>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([O:11][S:34](=[O:36])(=[O:35])[NH:33][CH2:31][CH3:32])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and nitrogen were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR; 6.86 g, 19.6 mmol), Et2O (100 mL), and NEt3 (3.25 mL, 23.4 mmol), respectively. The solution was cooled to 0° C. and treated rapidly with a solution of (ethyl amino)sulfonyl chloride (3.37 g, 23.4 mmol) in Et2O (10 mL). The reaction was stirred for 30 minutes and then filtered. The solids were washed with Et2O, and the filtrate was concentrated. The resulting residue was dried in a high vacuum oven at 40° C. overnight to yield the title compound. 1H NMR (CDCl3) δ 1.15 (s, 9 H), 1.23 (t, 3 H) 2.19 (s, 3 H), 2.35 (s, 3 H), 3.30 (m, 2 H), 4.75 (br t, 1 H), 7.16 (s, 1 H), 7.19 (s, 1 H), 7.32 (d, 2 H), 7.39 (d, 2 H).
Reaction SMILES: [CH:1]1([C:4]2[S:30][C:7]3[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:16]=4[F:29])[C:9](=[O:13])[NH:10][C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[O:42][CH3:43])=[O:34].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH:1]1([C:4]2[S:30][C:7]3[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:16]=4[F:29])[C:9](=[O:13])[N:10]([CH2:32][C:33]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=4[O:42][CH3:43])=[O:34])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(C4CC4)sc32)c(F)c1
Reactant: COc1cc(F)ccc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1C(=O)Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3C#N)cc2F)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a mixture of 4′-[(6-cyclopropyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.32 g), 2-bromo-1-(4-fluoro-2-methoxyphenyl)ethanone (0.25 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.046 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.3 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.C(N(C(C)C)C(C)C)C.[C:27]1([CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:35][CH2:34][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:3]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 104.1 %

Procedure:
A solution of 2,6-dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine (Preparation 1) (30.9 g, 0.11 mol) in isopropyl alcohol (600 ml) was treated with N-ethyl-N-isopropyl-2-propanamine (47.5 ml, 0.27 mol) and 2,2-diphenylethylamine (24.8 g, 0.13 mol) and the resulting mixture was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was azeotroped from ethyl acetate. The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:hexane (40:60 by volume) gradually changing to ethyl acetate:hexane (60:40 by volume) to afford the title compound as a foam (49.7 g).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[S:15][CH2:14][CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:10][CH:11]1[S:15][CH2:14][CH2:13][O:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@H]1OCCS1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
2(S)-(Benzoyloxymethyl)-1,3-oxathiolane (0.045 mmol, 10 mg, 1.0 equiv.), para-toluenesulfonic acid monohydrate (0.015 mmol, 3 mg, 0.3 equiv.) and toluene (1 mL) were heated to reflux and stirred while monitoring the racemization reaction by chiral HPLC. After 24 h, the reaction was allowed to cool to ambient temperature and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated by rotary evaporation to give 8 mg (80% yield) of (+/−)-2-(benzoyloxymethyl)-1,3-oxathiolane.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[OH:32][CH:33]1[CH2:37][C:36](=[O:38])[CH:35]=[CH:34]1>C(Cl)Cl>[C:1]([O:38][CH:36]1[CH2:37][C:33](=[O:32])[CH:34]=[CH:35]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C=CC(O)C1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1C=CC(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
A solution of trityl chloride (3.44 g, 12.3 mmol) in methylene chloride (20 mL) is treated sequentially with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.2 mL, 14.7 mmol, DBU) and 4-hydroxy-2-cyclopentenone (1.01 g, 10.0 mmol, in 5 mL of methylene chloride, prepared in example 1). The reaction is stirred for 3 days at room temperature and then poured onto ice (approximately 25 mL). The phases are separated and the organic phase is washed with water (25 mL). The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by column chromatography (silica gel, 10-20% ethyl acetate/hexane) to provide the title compound (1.26 g, 36 %) as a pale yellow oil; 1H NMR (CDCl3) δ 7.5 (m, 6 H), 7.3 (m, 9 H), 6.85 (dd, 1 H), 6.05 (d, 1 H), 4.8 (m, 1 H), 2.1 (m, 2 H); 13C NMR (CDCl3) δ 206.6, 162.9, 144.3, 135.2, 128.8, 128.4, 127.7, 88.2, 73.1, 43.4; IR (KBr) νmax 3061, 1719, 1491, 1449, 1352, 1181, 1107, 1053 cm-1.
Reaction SMILES: FC1C=C(F)C=CC=1CO[C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:8](=[O:20])[CH:7]=1.[I:26]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>CC#N>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:9]1[CH:10]=[CH:11][CH:6]=[C:7]([I:26])[C:8]1=[O:20]
Reactant: O=c1cc(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C(O)C(Cl)Cl
Solvent: CC#N
Product: O=c1c(I)cccn1Cc1cccc(F)c1
Temperature: 60 °C
Yield: 106 %

Procedure:
To a mixture of 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one (0.15 g, 0.43 mmol) and N-iodosuccinimide (0.10 g, 0.46 mmol) in CH3CN (3 mL) was added dichloroacetic acid (13 mg, 0.10 mmol), and the reaction mixture was heated to 60° C. for 4 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The organic solution was washed with a saturated solution of NaHCO3 and then brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 90:10 methylene chloride/hexanes to 99:1 methylene chloride/methanol) provided 4-(2,4-difluorobenzyloxy)-[(3-fluorobenzyl)-3-iodo-1H-pyridin-2-one as a white solid (0.15 g, 77%): mp 164-167° C.; 1H NMR (300 MHz, CDCl3) δ 7.65-7.55 (m, 1H), 7.35-7.26 (m, 2H), 7.15-6.80 (m, 5H), 6.05 (d, J=6 Hz, 1H), 5.22 (s, 2H), 5.16 (s, 2H) ES HRMS m/z 472.0033 (M+H C19H14F31NO2 requires 472.0018).