Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14]([NH2:16])=[N:13][CH:12]=[N:11][C:10]=3[NH:9][C:8]=2[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:38]([O:40][CH:41]([O:45][CH2:46][CH3:47])[C:42](O)=[O:43])[CH3:39].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>CN(C=O)C.C(OCC)(=O)C.ClCCl>[CH2:38]([O:40][CH:41]([O:45][CH2:46][CH3:47])[C:42]([NH:16][C:14]1[C:15]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([Si:17]([CH2:20][CH3:21])([CH2:22][CH3:23])[CH2:18][CH3:19])[NH:9][C:10]=2[N:11]=[CH:12][N:13]=1)=[O:43])[CH3:39]
Reactant: CCOC(OCC)C(=O)O
Reactant: CC[Si](CC)(CC)c1[nH]c2ncnc(N)c2c1-c1ccccc1
Agent: On1nnc2ccccc21
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(OCC)C(=O)Nc1ncnc2[nH]c([Si](CC)(CC)CC)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-phenyl-6-(triethylsilyl)-7-H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 5, Step C, 0.45 g, 1.38 mmol), EDC (0.34 g, 1.78 mmol) and HOBT (0.28 g, 2.07 mmol) in DMF (10.0 mL) was added 2,2-diethoxy acetic acid (0.25 g, 14.8 mmol) and the reaction mixture was stirred at rt for 16 h. Dichloromethane (50 mL) was added and the mixture was washed with brine, sat. NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The product was dissolved in 5 mL of THF and slowly added to a 11 mL of a 1 M solution of LiAlH4 in THF (11 mmol) (40 mL) at 0° C. under N2. The temperature of the reaction mixture was allowed to rise to room temperature for 1 hr after addition. The mixture was carefully poured into ice-water (50 mL). Ethyl acetate (50 mL) was added, and the organic layer was separated. The aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (CH2Cl2:MeOH=95:5) to give the title compound. 1H-NMR (400 MHz, DMSO-d6) δ 0.58 (q, 6H, 7.50 Hz), 0.79 (t, 9H, J=8.00 Hz), 1.04 (t, 6H, J=7.00 Hz), 3.40-3.33 (m, 2H), 3.53-3.46 (m, 4H), 4.43 (t, 1H, J=5.50 Hz), 4.84 (t, 1H, J=5.50 Hz), 7.50-7.37 (m, 5H), 8.19 (s, 1H), 11.5 (s, 1H). Mass Spectrum (ESI) m/e=441 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.CN1CCN(C(=O)C=CC2C3N(C4C=CC=CC=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=2)CC1>>[C:15]1([N:13]2[C:14]3[C:6]([CH:5]=[CH:4][C:3]([N:41]4[CH2:42][CH2:37][CH:38]([C:51]([F:54])([F:53])[F:52])[CH2:39][CH2:40]4)=[O:2])=[CH:7][C:8]([C:21]([F:22])([F:24])[F:23])=[CH:9][C:10]=3[N:11]=[CH:12]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Product: O=C(C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12)N1CCC(C(F)(F)F)CC1

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford, after removal of the solvent, the title compound as a white solid (40 mg, 12%), m/z 468.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH:24]([C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)[CH2:23]4)=[C:17]([F:36])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C>[OH-].[K+].C(O)C>[F:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH:24]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:23]2)=[C:17]([F:36])[C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:37])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccc(OC)cc5)C4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2CN(c3c(F)cc4cc5c(=O)c(C(=O)O)cn(C)c5nc4c3F)CCN2)cc1
Yield: 75.6 %

Procedure:
(RS)-7,9-Difluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine-3-carboxylic acid was prepared under conditions similar to Example 39, starting with (RS)-3-ethoxycarbonyl-7,9-difluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.8 g) in N aqueous potassium hydroxide (24 cc) and ethanol (25 cc). (RS)-7,9-difluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (2 g) is obtained in the form of a yellow solid, m.p. 288°-290° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.S(=O)(=O)(O)O.[OH-].[Na+].[C:29](=O)([O-])O.[Na+]>CO>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:29])=[O:11]
Reactant: O=C([O-])O
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reaction time: 30 h
Yield: 90 %

Procedure:
To 10 g (33.8 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid are added 75 ml of methanol and then 10 ml of sulfuric acid dropwise over 30 minutes. After 30 hours, the reaction medium is basified to pH 8-9 by adding aqueous 10N sodium hydroxide solution followed by saturated sodium hydrogen carbonate solution. The organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then filtered, and the solvents are evaporated off. 6.36 g of methyl (S)-2-amino-3-(4-methoxyphenyl)propionate in the form of a brown oil are obtained in a yield of 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[N:9]([O-])=O.[Na+].Cl[Sn]Cl.[OH-].[Na+]>Cl.O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccnc(Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: NNc1ccnc(Cl)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
2-Chloro-pyridin-4-ylamine, (2 g, 15.6 mmol), was dissolved in 20 mL 1M HCl and 4 mL conc. HCl and cooled to 0° C. Sodium nitrite, (1 g, 17 mmol), was dissolved in 2 mL water and added dropwise to the pyridine solution. The mixture was stirred at 0-5° C. for 2 h and then added dropwise to a suspension of SnCl2 in 35 mL conc.HCl at 0° C. The mixture was stirred at 0° C. for 1 hand then the pH carefully raised to pH9-10 with NaOH, using efficient cooling and stirring. The aqueous mixture was extracted with 10% MeOH/chloroform and the organic layer was separated, dried (sodium sulfate), and evaporated. The crude product mixture was purified by column chromatography, (silica, 5% MeOH/DCM), affording 400 mg (2-Chloro-pyridin-4-yl)-hydrazine. MS ES+144.0, 146.3
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[CH:24]=[C:23]2[NH:25][S:26]([C:29]3=[CH:30][CH:31]=[CH:32][C:21](=[C:22]23)[CH:20]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:25]1[C:23]2[CH:24]=[CH:19][CH:20]=[C:21]3[CH:32]=[CH:31][CH:30]=[C:29]([C:22]=23)[S:26]1(=[O:27])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)Nc2cccc3cccc1c23
Reactant: O=C(CCCCCCBr)NOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCCCCN1c2cccc3cccc(c23)S1(=O)=O)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 1(b), 7-bromo-heptanoic acid benzyloxyamide 0.46 g, 1.5 mmol) was reacted with 1,8-naphthalenesultam (0.3 g, 1.5 mmol) in the presence of potassium carbonate (0.2 g, 1.4 mmol) to give 7-(1,1-dioxo-2H-naphtho[1,8-cd]isothiazol-2-yl)-heptanoic acid benzyloxyamide as an amorphous solid (yield 0.4 g, 62%; purified by column chromatography using silica gel and ethyl acetate:heptane=1:1 as an eluent). MS (M+H+)=439.
Reaction SMILES: I[C:2]1[S:6][CH:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.[CH3:9][N:10](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[OH:8][CH2:7][C:4]1[CH:3]=[C:2]([C:9]#[N:10])[S:6][CH:5]=1
Reactant: OCc1csc(I)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(CO)cs1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (5-iodo-thiophene-3-yl)methanol (42 g, 176 mmol) in 150 mL of DMF is added zinc cyanide (12.4 g, 106 mmol) and tetrakis(triphenylphospine)palladium (0) (8.13 g, 7.04 mmol). The solution is heated to 80° C. After 6 h, the solution is diluted with 3 L of EtOAc. The resulting solution is washed with 1N NH4OH, H2O and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (10 g, 72 mmol) as a clear oil.
Reaction SMILES: [F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5]([CH:7]=O)[N:6]=1.[CH2:28](P(=O)(OCC)OCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[H-].[Na+].O>COCCOC>[F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5](/[CH:7]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:6]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1nc(/C=C/c2ccccc2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a stirred mixture of 2-fluoro-4-formyl-1-triphenylmethylimidazole (0.356 g.) and diethyl benzylphosphonate (0.228 g.) in 1,2-dimethoxyethane under an argon atmosphere at room temperature was added sodium hydride (0,048 g.). Stirring was continued for 18 hours and then water (15 ml.) was added. The precipitate was filtered and dried to give 2-fluoro-1-triphenylmethyl-4-(2-phenyl-trans-vinyl)imidazole (0.415 g.), m.p. 167°-170°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24](O)=[O:25])=[C:12]2[O:27][CH2:28][CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][OH:25])=[C:12]2[O:27][CH2:28][CH2:29][CH2:30][C:31]([F:32])([F:33])[F:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cn1c(C(=O)O)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CO)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
6-Benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylic acid (4.77 g, 10 mmol) was dissolved in tetrahydrofuran (50 mL), and oxalyl chloride (1.1 mL, 12 mmol) and N,N-dimethylformamide (3 drops) were added. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (1.32 g, 35 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give 6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone-(4.02 g, 84.6%) as crystals.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=O.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>CN(C)C=O.ClCCl>[Cl:1][CH2:2][C:3]1[S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1S
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1nc2ccccc2s1
Reaction time: 18 h
Yield: 65 %

Procedure:
Chloroacetyl chloride (81.6 ml) is added dropwise to a solution composed of 2-aminothiophenol (112 ml, 1.04 mol), dichloromethane (1.2 l) and three drops of dimethylformamide, while the temperature is kept below 40° C. After stirring for 18 hours, the precipitate formed is filtered off by suction and then dissolved in a minimum amount of water. This aqueous phase is extracted with pentane and the extracts are concentrated under vacuum at room temperature, giving 120 g (65%) of a flaky solid.
Reaction SMILES: Br[C:2]1[C:3]([NH:14][C@H:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:10]([O:9][C:7]([N:5]1[CH:6]=[C:2]([C:48]2[CH:47]=[CH:46][C:45]([N:42]3[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:44][CH2:43]3)=[CH:50][CH:49]=2)[C:3]([NH:14][C@H:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:4]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: COc1ccc(COC(=O)[C@H](CC(C)C)Nc2nn(C(=O)OC(C)(C)C)cc2Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(=O)[C@H](CC(C)C)Nc2nn(C(=O)OC(C)(C)C)cc2-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 90 °C

Procedure:
To 4-methoxybenzyl N-[4-bromo-1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl]leucinate (1.45 g, 2.92 mmol), 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (1.117 g, 3.65 mmol, prepared as described in Example 1) and catalyst PdCl2(dppf) (75 mg, 0.09 mmol) in DMF (30 mL) under dry nitrogen was added aqueous sodium carbonate (2.0 M, 3.3 mL, 6.6 mmol). The reaction was heated to 90° C. for 0.5 hour and an additional aliquot of PdCl2(dppf) (20 mg, 0.022 mmol) was added and the reaction mixture was heated for 1½ hour. Water was added and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 25/75) to afford 4-methoxybenzyl N-(1-(tert-butoxycarbonyl)-4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1H-pyrazol-3-yl)leucinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH3:23])[N:4]=1
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N=C(OC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (3.19 g, 10.0 mmoles) in dry dichloromethane (15 ml) and pyridine (4 ml) was cooled to 0° C. and treated dropwise with ethyl chloroformate (1.2 ml, 12.0 mmoles) under argon. After the addition was completed, the cooling bath was removed and the reaction was allowed to stir at room temperature for 1 hour. It was then diluted with ethyl acetate and the resulting solution was washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was coevaporated with toluene to remove residual pyridine. The colorless solid obtained was subjected to high vacuum and used in the next reaction without further purification (3.81 g). For analytical purposes, a small amount of the compound was recrystallized from ether-hexanes to provide colorless solid, melting point 61.5°-64.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10]([N:13]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH3:14])(=[O:12])=[O:11].C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:23])C.Cl.CCOC(C)=O>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10]([N:13]([CH2:15][O:16][CH2:17][CH2:18][C:19]([OH:23])=[O:20])[CH3:14])(=[O:11])=[O:12]
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: CN(COCCCO)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CN(COCCC(=O)O)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,4,6-Trichloro-N-(3-hydroxypropoxymethyl)-N-methylbenzenesulfonamide (363 mg, 1 mmol), 2,2,6,6-tetramethylpiperidin-1-yloxy radical (38 mg, 0.245 mmol) and [bis(acetoxy)iodo]benzene (705 mg, 2.19 mmol) were dissolved in acetonitrile/water (1:1; 8 ml) and the solution was stirred at RT for 30 min. The reaction soln. was then cooled with ice, and 2 N hydrochloric acid (4 ml) and EtOAc (40 ml) were added. The phases were separated and the organic phase was washed with water (3×20 ml) and saturated sodium chloride solution (2×20 ml), dried with Na2SO4 and concentrated i. vac. The compound was taken up in 1 N sodium carbonate soln. (30 ml) and the mixture was extracted with EtOAc (3×20 ml). The aqueous phase was then adjusted to pH 3 with 2 N hydrochloric acid and extracted with EtOAc (3×20 ml). The combined organic phases were washed with water (3×20 ml) and saturated sodium chloride solution (2×20 ml), dried with Na2SO4 and concentrated i. vac. Yield: 310 mg (82%)
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCCC(N)C1
Agent: [Pd]
Product: CC(C)(C)c1cccc(N)c1
Yield: 95 %

Procedure:
The procedure described in Example 27 is followed, using a catalyst which contains 1.0% by weight of palladium on a lithium/aluminum spinel. Starting from 3-tert-butylcyclohexylamine, there is obtained m-tert-butylaniline (boiling point=72°-73° C./0.27 mbar) in a yield of 95% of the theory.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=O)[C@H:12]2[CH2:17][C@@H:9]1[CH2:10][C@H:11]2[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:34][C:35]1[CH:39]=[C:38]([Br:40])[S:37][C:36]=1[C:41]([NH2:43])=[O:42]>O1CCCC1.O>[Br:40][C:38]1[S:37][C:36]2[C:41](=[O:42])[NH:43][C:14]([C@@H:13]3[C@H:12]4[CH2:17][C@H:9]([CH2:10][C@H:11]4[F:18])[N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:34][C:35]=2[CH:39]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]([C@H](F)C2)[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]([C@H](F)C2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution of (1R*,3S,4R*,5R)-2-(tert-butoxycarbonyl)-5-fluoro-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (352 mg) and triethylamine (0.190 mL) in tetrahydrofuran (4 mL) was added 2-methylpropyl chlorocarbonate (0.178 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction system was added a solution of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, in tetrahydrofuran (2 mL), and the mixture was stirred at 60° C. for 18 hr. Water was added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane). To the obtained pale-yellow solid (328 mg) were added 2M aqueous sodium hydroxide solution (1.81 mL) and ethanol (4.0 mL), and the mixture was stirred at 70° C. for 5 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. To the reaction system was added water (2 mL), and the precipitate was collected by filtration to give the title compound (274 mg) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:11]=[C:12]2O)=[CH:7][C:6]=1[O:23][CH3:24])=[O:4].O=P(Cl)(Cl)[Cl:28]>>[CH3:1][N:2]([CH3:25])[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:11]=[C:12]2[Cl:28])=[CH:7][C:6]=1[O:23][CH3:24])=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1C(=O)N(C)C
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1C(=O)N(C)C
Temperature: 130 °C
Yield: 70 %

Procedure:
A mixture of 1-Hydroxy-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid dimethylamide (0.1 g, 0.29 mmol) in POCl3 (4 ml) was sealed in microwave process vial (5 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. The mixture was concentrated, and the residue was treated with 1 ml MeOH. After stirred for half an hour at room temperature, the solid was collected and dried to give desired product (0.072 g, 70%). LC-MS: m/e 360 (MH+).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:13]3[C:12]([C:24]3[CH:28]=[CH:27][O:26][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO.O>[O:26]1[CH:27]=[CH:28][C:24]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[NH:10][CH:11]=2)=[CH:25]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(-c3cccs3)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1csc(-c2cnc3[nH]cc(-c4ccoc4)c3c2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 33 (28.3 mg, 0.0696 mmol) in EtOH (1.4 mL), was added 10% aqueous NaOH (0.67 mL), and the reaction mixture refluxed (oil bath 110° C.) for 0.5 h. The mixture was diluted with water (1.4 mL), and stirred for an additional 0.5 h at r.t. The precipitate was filtered off, washed with water, and dried under high vacuum to afford 34 as tan solid (15.8 mg, 85%); 1H NMR (400 MHz; CDCl3) δ 6.72 (dd, J=1.8, 0.8 Hz, 1H), 7.14 (dd, J=5.1, 3.6 Hz, 1H), 7.32-7.36 (m, 2H), 7.48 (d, J=2.5 Hz, 1H), 7.55 (t, J=1.7 Hz, 1H), 7.82 (m, 1H), 8.23 (dd, J=2.0, 0.4 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H), 9.67 (bs, 1H).
Reaction SMILES: NC1C=CC=C2C=1CNCC2.C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([S:29](=[O:32])(=[O:31])[NH2:30])[C:19]([C:25]([F:28])([F:27])[F:26])=[CH:20][CH:21]=2)[CH2:16]1)(=O)C>>[S:29]([C:18]1[C:19]([C:25]([F:26])([F:28])[F:27])=[CH:20][CH:21]=[C:22]2[C:17]=1[CH2:16][NH:15][CH2:24][CH2:23]2)(=[O:31])(=[O:32])[NH2:30]
Reactant: CC(=O)N1CCc2ccc(C(F)(F)F)c(S(N)(=O)=O)c2C1
Agent: Nc1cccc2c1CNCC2
Product: NS(=O)(=O)c1c(C(F)(F)F)ccc2c1CNCC2

Procedure:
The above prepared 8-amino tetrahydroisoquinoline compound is converted to the corresponding 8-chlorosulfonyl compound and then to the 8-sulfamoyl compound, 2-acetyl-8-sulfamoyl-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, by the procedure of Example 15. The acetyl group is removed by acid hydrolysis by the procedure of Example 15 to give 8-sulfamoyl-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline.