Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OO)(=[O:3])C.[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]=[CH:19][C:18]3[N:24]=[C:25]([CH2:32][O:33][CH2:34][CH3:35])[N:26]([CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[C:17]=3[C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)(=O)C>[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]2[N+:20]([O-:3])=[CH:19][C:18]3[N:24]=[C:25]([CH2:32][O:33][CH2:34][CH3:35])[N:26]([CH2:27][C:28]([CH3:29])([OH:30])[CH3:31])[C:17]=3[C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OO
Reactant: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)O
Solvent: CCOC(C)=O
Product: CCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.7 %

Procedure:
Peracetic acid (2.0 mL of 32% by weight in dilute acetic acid, 9.5 mmol) was added to a solution of (8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (2.5 g, 6.2 mmol) in ethyl acetate (400 mL), and the reaction was stirred for two days at ambient temperature. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed with aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from a mixture of ethyl acetate, hexanes, and 2-propanol and then purified by column chromatography on a HORIZON HPFC system (silica gel cartridge, eluting with dichloromethane:methanol ranging in ratios from 98:2 to 90:10) to provide 1.9 g of (8-benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a solid, mp 228-230° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].ClS([N:38]=[C:39]=[O:40])(=O)=O>CC#N>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([O:31][CH3:32])=[CH:25][CH:26]=[C:27]([C:39](=[O:40])[NH2:38])[C:28]=2[O:29][CH3:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)ccc(C(N)=O)c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (150 mg) was dissolved in MeCN (6 mL) under N2 and chlorosulfonyl isocyanate (45 μL) was added, and the mixture was stirred at room temperature for 2.5 h. The mixture was concentrated and 1N HCl (8 mL) was added. The mixture was stirred at room temperature overnight, extracted with AcOEt, dried (MgSO4), filtered and evaporated. The crude product was purified by preparative TLC (silica gel; eluent: AcOEt) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-carbamoylphenyl)-L-phenylalanine methyl ester (156 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[N:2]1.[H-].[Na+].[CH3:19]I>CN(C=O)C>[CH3:19][N:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2cn[nH]c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of tert-butyl 4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (700 mg, 3.14 mmol) in DMF (5 mL) was added NaH (251 mg, 6.28 mmol) at 0° C. and then MeI (669, 4.71 mmol). The mixture was then stirred at 25° C. for 4 hours after which the reaction was quenched by addition of water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to yield a residue which was used directly in the next step. 1H NMR (400 MHz, MeOD): δ 7.16 (s, 1H), 3.77 (s, 2H), 3.66 (s, 3H), 3.06 (t, J=6.0 Hz, 2H), 2.56 (t, J=6.0 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:26]1[NH:25][CH:24]=[C:23]2[C:22]=1[CH2:21][CH2:20][NH:19][C:18]2=[O:17])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (48 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:28])=[C:16]([C@:18]2([CH3:27])[CH2:23][S:22](=[O:25])(=[O:24])[CH2:21][C:20]([NH2:26])=[N:19]2)[CH:17]=1>>[NH2:26][C:20]1[CH2:21][S:22](=[O:24])(=[O:25])[CH2:23][C@:18]([C:16]2[CH:17]=[C:12]([NH:11][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:13]=[CH:14][C:15]=2[F:28])([CH3:27])[N:19]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)CC(N)=N1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)CS(=O)(=O)CC(N)=N1
Yield: 46 %

Procedure:
Prepared from 5-chloropicolinic acid (73.5 mg, 466 μmol, Eq: 1.1) and (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (115 mg, 424 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (80 mg, 195 μmol, 45.9% yield) as a light yellow solid. MS (ISP): m/z=411.4 [(M+H)+] and 413.2 [(M+2+H)+].
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([C:21]([CH:24]=O)=[N:22][N:23]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:26]1([CH2:24][C:21]2[N:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH2:14][CH2:13][CH:12]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:11][CH2:10]4)=[C:3]([C:1]#[N:2])[C:4]3=[N:23][N:22]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2c(C=O)nnc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2c(CN3CCOCC3)nnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of D9 (0.065 g, 0.196 mmol) in DCM (2.5 ml) were added morpholine (0.026 g, 0.294 mmol) and sodium triacetoxy-borohydride (0.062 mg, 0.294 mmol). The resulting mixture was stirred at r.t. for 1 day. The reaction mixture was washed with H2O, dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; DCM/MeOH up to 3% as eluent). The desired fractions were collected and concentrated in vacuo to yield final compound E11 (0.04 g, 51%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:14]([N+:19]([O-])=O)[C:10]=1[NH:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](O)C>C(O)=O.[Fe]>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH2:12][CH3:13])[CH:22]=[N:19][C:14]=2[CH:15]=[C:16]([Br:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Reactant: CCO
Agent: [Fe]
Solvent: O=CO
Product: CCn1cnc2cc(Br)cc(OCc3ccccc3)c21
Temperature: 90 °C

Procedure:
To a solution of 2-(benzyloxy)-4-bromo-N-ethyl-6-nitroaniline (230 mg, 0.66 mmol) in ethanol (10 mL) and formic acid (10 mL) was added iron (731 mg, 13.1 mmol) and the reaction mixture was heated at 90° C. at 2 h. The reaction mixture was concentrated, diluted with water and brought to pH ˜7 with sat′d NaHCO3 and then the aqueous layer was extracted with EtOAc (3×). Combined organic layer was then washed successively with water and brine and dried over anhydrous magnesium sulfate, filtered, evaporated, and dried to give the title compound which was used further without purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C16H16BrN2O: 331.0; found: 331.0.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1Br
Agent: O=S(=O)(O)O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Br
Temperature: -10 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a mixture of 2-bromo-1,3-dimethylbenzene (5.0 g, 27.03 mmol) in sulfuric acid (98%, 40 mL) at −10° C. was added dropwise a solution of nitric acid (68%, 2.74 g, 27.03 mmol) in sulfuric acid (98%, 10 mL). After the reaction was complete the mixture was stirred at −10° C. for 1 h. The reaction mixture was poured onto ice (200 g) the resulting solid filtered, washed with water, and dried in vacuo. The crude was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (100:1) as eluting solvent to afford 2.3 g (37%) of 2-bromo-1,3-dimethyl-4-nitrobenzene as yellow solid (298): 1H NMR (500 MHz, DMSO-d6): δ 7.79 (d, J=8.5, 1H), 7.43 (d, J=8.5, 1H), 2.47 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.Cl[C:9]1[N:14]=[C:13]2[NH:15][N:16]=[CH:17][C:12]2=[CH:11][N:10]=1.Cl>C(O)(C)C>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:9]2[N:14]=[C:13]3[NH:15][N:16]=[CH:17][C:12]3=[CH:11][N:10]=2)[CH:4]=[N:3]1
Reactant: Clc1ncc2cn[nH]c2n1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CC(C)O
Product: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Temperature: 140 °C

Procedure:
A suspension of 1-methyl-1H-pyrazol-4-amine (173 mg, 1.29 mmol), 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 1.29 mmol) and HCl (25 μL, 4M in dioxane) in isopropanol (2 mL) was heated in the microwave at 140° C. for 1 h. After cooling to rt, the mixture was filtered and the resulting solid washed with cold isopropanol and diethyl ether to give N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:19][CH2:20][CH3:21])([O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[CH3:18])=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:22][C:23]1[C:28](O)=[C:27]([Cl:30])[C:26]([Cl:31])=[C:25]([Cl:32])[C:24]=1[Cl:33].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([O:3][P:4]([O:19][CH2:20][CH3:21])([O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[CH3:18])=[CH:14]/[C:15]([O:17][C:28]2[C:27]([Cl:30])=[C:26]([Cl:31])[C:25]([Cl:32])=[C:24]([Cl:33])[C:23]=2[Cl:22])=[O:16])=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: CCOP(=O)(OCC)Oc1ccc(/C(C)=C/C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)Oc1ccc(/C(C)=C/C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)cc1
Yield: 72.2 %

Procedure:
A solution of 10b (2.0 g, 6.4 mmol), pentachlorophenol (1.9 g, 7.0 mmol), DCC (1.6 g, 7.7 mmol) and DMAP (0.08 g, 0.64 mmol) in 100 mL of EtOAc was stirred at room temperature for 24 h. The mixture was filtered through celite and the solvent removed in vacuo. The crude product was purified by silica gel chromatography eluting with 25% EtOac-hexanes to give 2.6 g (72%) of 11b1 as white solid. 1H NMR (CDCl3, 300 MHz) δ 1.26-1.32 (m, 6H), 2.54 (d, J=1.2 Hz, 3H), 4.12-4.21 (m, 4H), 6.34 (d, J=1.2 Hz, 1H), 7.2 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H). 11C NMR (CDCl3, 75.0 MHz) δ 16.0, 16.1, 18.4, 64.8, 64.8, 68.9, 113.4, 120.2, 120.3, 128.0, 128.1, 131.2, 131.9, 137.8, 141.9, 144.3, 152.1, 160.6, 161.9. HRMS (M+H) calc, 560.9362; found, 560.9197.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N:8]1[C:13]2[C:14]([C:17]([OH:19])=[O:18])=[CH:15][S:16][C:12]=2[CH:11]=[N:10][CH:9]=1>ClCCl.CO>[CH3:1][O:18][C:17]([C:14]1[C:13]2[N:8]=[CH:9][N:10]=[CH:11][C:12]=2[S:16][CH:15]=1)=[O:19]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1csc2cncnc12
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1csc2cncnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylsilyldiazomethane (2 M in hexane, 1 mL) was added to a suspension of thieno[3,2-d]pyrimidine-7-carboxylic acid (50 mg) in a mixture of dichloromethane and methanol (95/5, 1 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then evaporated under reduced pressure and the crude residue was purified by flash chromatography (DCM/MeOH, 97/3) to give 40 mg of thieno[3,2-d]pyrimidine-7-carboxylic acid methyl ester.
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[C:8]1([C:14]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:15]2[CH2:20][CH:19]([C:21](OC)=O)[CH2:18][N:17]=[CH:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:31]1([C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:15]2[CH2:20][CH:19]([C:21]3[O:7][N:6]=[C:3]([CH3:4])[N:5]=3)[CH2:18][N:17]=[CH:16]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Sodium hydride (60% dispersion in mineral oil 26 mg, 0.65 mmol) and acetamidoxime (48 mg, 0.65 mmol) were suspended in dry THF (4 ml) in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (250 mg, 0.65 mmol) was added dissolved in dry THF (3 ml) and reflux continued 18 hours. The solvents were evaporated in vacuo and the residue taken up in water (10 ml). The aqueous suspension was extracted exhaustively with chloroform and the organics dried over MgSO4. After evaporation the organic residue was chromatographed (silica, chloroform/methanol, 9:1) to yield 93 mg (rf=0.26, 35%) white crystals, mp 72°-74° C. identified by 300 MHz nmr and ms m/z=408. Calculated: C 76.44, H 5.9, N 13.7; found: C 76.27, H 6.06, N 13.59.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][N:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccnc(C(F)(F)F)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccnc(C(F)(F)F)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-2-trifluoromethyl-pyridine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.10 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].CC1(C)[O:21][C@H:20]([CH2:22][O:23][C:24]2[C:33]([CH3:34])=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[CH:26][C:25]=2[Cl:35])[CH2:19][O:18]1>>[Cl:35][C:25]1[CH:26]=[C:27]([C:28]2[N:30]=[C:12]([C:10]3[S:11][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([CH3:15])[CH:9]=3)[O:14][N:29]=2)[CH:32]=[C:33]([CH3:34])[C:24]=1[O:23][CH2:22][C@@H:20]([OH:21])[CH2:19][OH:18]
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H]1COC(C)(C)O1
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(OC[C@@H](O)CO)c(Cl)c3)no2)cc1C
Yield: 40.4 %

Procedure:
The title compound (22 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3-chloro-5-methyl-benzamidine (37 mg, 117 μmol) in analogy to Example 197; LC-MS: tR=0.54 min; [M+1]+=466.05.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]1(=[O:46])[N:28]([CH2:29][C:30]([N:32]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH3:33])=[O:31])[C:27](=[O:41])[C:26]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:25]12>CN(C=O)C>[C:27]1(=[O:41])[N:28]([CH2:29][C:30]([N:32]([C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:36][CH:35]=2)[CH3:33])=[O:31])[C:24](=[O:46])[C:25]2=[CH:45][CH:44]=[CH:43][CH:42]=[C:26]12
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-phthalimidomethylcarbonyl-N-methyl-amino)-aniline in DMF.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Br
Solvent: CC(=O)O
Product: O=C1CCCc2cc(O)ccc21
Temperature: 25 °C
Yield: 70.5 %

Procedure:
6-Methoxytetralone (50 g, 280 mmol) was suspended in glacial acetic acid (250 mL). Hydrobromic acid (47%; 500 mL) was added and the mixture was heated at reflux for 6 h, cooled to room temperature, and poured onto 500 g of crushed ice. After 1 h the precipitate was collected and recrystalized from ethanol to provide 32 g of 6-hydroxytetralone. Concentration of the mother liquor provided an additional 9 g of product, mp 149-152° C.; 1H NMR (CDCl3) δ7.80 (d, 1H), 6.78 (d, 1H), 6.68 (s, 1H), 2.90 (t, 2H), 2.55 (t, 2H), 2.05 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6](N)=[CH:7][CH:8]=2)[CH2:3]1.N([O-])=O.[Na+].[BrH:19]>OS(O)(=O)=O.O>[Br:19][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH3:13])([CH3:12])[CH2:11][N:2]([CH3:1])[CH2:3]2)=[CH:8][CH:7]=1
Reactant: CN1Cc2cc(N)ccc2C(C)(C)C1
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN1Cc2cc(Br)ccc2C(C)(C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of 2,4,4-trimethyl-1,2,3,4-tetrahydro-isoquinolin-7-ylamine (prepared essentially as described in PCT International Application Publication Numbers WO 00/009,486, WO 00/007,993 or WO 98/41507; 330 mg, 1.734 mmol) in 75% aqueous H2SO4, add NaNO2 (132 mg, 1.91 mmol) in 1 ml of water, dropwise. Stir the solution at 0° C. for 30 minutes. Add CuBr (298 mg, 2.08 mmol) and 48% HBr (2 ml). Stir the mixture at 0° C. for 15 minutes. Heat the mixture at 60° C. for 30 minutes. Cool to room temperature, adjust the pH to 9-10, and extract with EtOAc. Wash with brine, dry the solution (Na2SO4), and concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc:Hexanes-(1:1) to afford 7-bromo-2,4,4-trimethyl-1,2,3,4-tetrahydro-isoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH:27]([CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[K+]>CC(N(C)C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH:27]([CH2:31][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reactant: COc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OCC2CN(C(=O)OC(C)(C)C)CCO2)c1
Yield: 99.9 %

Procedure:
Following a procedure similar to that described in Example 40, 1.00 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 1.63 g of 4-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)morpholine and 0.490 g of potassium t-butoxide were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40, and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.87 g (yield 94.5%) of the title compound as a colorless oil.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].C([O-])([O-])=O.[K+].[K+].C([O:18][C:19](=[O:22])[CH2:20][SH:21])(C)(C)C>CC#N>[O:7]=[C:3]1[CH:2]([S:21][CH2:20][C:19]([OH:22])=[O:18])[CH2:6][CH2:5][O:4]1
Reactant: CC(C)(C)OC(=O)CS
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)CSC1CCOC1=O
Yield: 133.8 %

Procedure:
To a solution of 3-bromo-dihydro-furan-2-one (16 g, 97.6 mmol) in 300 mL of CH3CN was added K2CO3 (20 g, 146 mmol), followed by mercapto-acetic acid tert-butyl ester (14.5 g, 98 mmol). The reaction mixture was refluxed for 2 hrs and cooled. The mixture was filtered and the filtrate was concentrated. The residue was redissolved in 300 mL of EtOAc and the resulting solution was washed with 1N HCl (100 mL*2). The organic layer was dried over MaSO4, filtered and concentrated to afford the ter-butyl ester title compound (23 g). 16 g of the ester was dissolved in 250 ml of HCl-MeOH (4M) and stirred at 25° C. for 4 hrs. The reaction mixture was concentrated below 45° C. in vacuum. The residue was purified by column chromatography (EtOAc) to afford 7 g of the title compound.
Reaction SMILES: C([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[CH:8][C:7]=1[C:18]([F:21])([F:20])[F:19])(C)(C)C>Cl>[CH3:17][N:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([SH:5])=[C:7]([C:18]([F:21])([F:19])[F:20])[CH:8]=2)[CH:13]=[N:14]1
Reactant: Cn1cc(-c2ccc(SC(C)(C)C)c(C(F)(F)F)c2)cn1
Agent: Cl
Product: Cn1cc(-c2ccc(S)c(C(F)(F)F)c2)cn1
Temperature: 100 °C
Yield: 98.8 %

Procedure:
4-(4-tert-Butylsulfanyl-3-trifluoromethyl-phenyl)-1-methyl-1H-pyrazole (40.0 g, 127 mmol) was suspended in hydrochloric acid (25% w/w, 780 mL) and stirred at 100° C. under reflux. Part of the hydrochloric acid was distilled off (ca. 80 mL). After the reaction was complete as shown by HPLC, it was cooled to 85° C., water (240 mL) was added, and the mixture was cooled further to 20° C. The pH was adjusted to 4.0 by addition of a solution of sodium hydroxide (32% w/w, ca. 480 mL) in water (960 mL). The aqueous phase was extracted with 2-methyltetrahydrofuran (2×320 mL), the combined organic extracts were washed with a solution of sodium chloride (40.0 g) in water (400 mL) and concentrated in vacuo. The residue was redissolved in tetrahydrofuran (260 mL), concentrated in vacuo, dissolved again in tetrahydrofuran (110 mL) and filtered in order to remove inorganic salts. The precipitate was washed with tetrahydrofuran (30 mL) and the combined filtrate was concentrated in vacuo to obtain the title compound as light brown solid (32.4 g, 98.6%), that was used without further purification in the next step.