Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].[CH:22]([NH2:24])=O>>[O:8]=[C:7]1[NH:24][CH:22]=[N:1][C:2]2[S:3][C:4]3[CH2:15][CH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][C:5]=3[C:6]1=2
Reactant: CCOC(=O)CC1CCc2c(sc(N)c2C(=O)OCC)C1
Reactant: NC=O
Product: CCOC(=O)CC1CCc2c(sc3nc[nH]c(=O)c23)C1
Temperature: 180 °C
Yield: 68.4 %

Procedure:
Formamide (310 mL) was added to ethyl 2-amino-6-(2-ethoxy-2-oxoethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (61.2 g, 197 mmol) and the biphasic mixture was heated at 180° C. in an oil bath overnight. The heat was turned off and the reaction solution was allowed to cool. At 60° C., the reaction mixture was seeded and lots of solid quickly precipitated. Upon reaching room temperature the reaction mixture was filtered (very slowly), and rinsed with water (2×150 mL). The damp solid was placed in a vacuum oven and dried at 50° C. overnight to yield a light tan solid (39.3 g, 68.4%). 1H NMR (DMSO-d6) δ 12.31 (s, 1H), 7.99 (s, 1H), 4.09 (q, 2H), 3.06 (m, 1H), 2.87 (m, 1H), 2.75 (m, 1H), 2.40 (m, 3H), 2.19 (m, 1H), 1.89 (m, 1H), 1.47 (m, 1H), 1.19 (t, 3H); LCMS RT=2.40 min, [M+H]+=293.1.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10](O)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>CN(C)C=O>[C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10]([Cl:19])[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To a suspension of 2.2 g (10.0 mmol) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (compound (202), Example 1a, Table 2) in 2.4 ml) 55.0 mmol) of thionyl chloride is added one drop of dimethyl formamide and the mixture is stirred for 2 hours at room temperature. Excess thionyl chloride is afterwards distilled off on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system dichloromethane/hexane=1:1 and crystallisation of the pure fractions from methanol yields 0.30 g (13%) of 7-tert-butyl-3-chloro-5-methyl-3H-benzofuran-2-one, m.p. 81-86° C. (compound (208), Table 2).
Reaction SMILES: C([OH:3])C.[OH:4][C:5]1[C:6]([C:19](=NO)[CH2:20][CH2:21][C:22]2[S:23][C:24]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:25]=3[C:26]=2[CH2:27][CH2:28][CH3:29])=[CH:7][C:8]([CH3:18])=[C:9]([CH:17]=1)[O:10][CH2:11][C:12]([O:14]CC)=[O:13].O.[OH-].[Li+].Cl>O>[OH:4][C:5]1[C:6]([C:19](=[O:3])[CH2:20][CH2:21][C:22]2[S:23][C:24]3[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=[CH:30][C:25]=3[C:26]=2[CH2:27][CH2:28][CH3:29])=[CH:7][C:8]([CH3:18])=[C:9]([CH:17]=1)[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCCc1c(CCC(=NO)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Reactant: CCO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCc1c(CCC(=O)c2cc(C)c(OCC(=O)O)cc2O)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 69 %

Procedure:
To a mixture of ethanol (0.2 mL) and water (0.1 mL) was suspended ethyl 5-hydroxy-2-methyl-4-[1-hydroxyimino-3-[3-propyl-6-(trifluoromethyl)-benzothiophen-2-yl]propyl]phenoxyacetate (15 mg, 0.0295 mmol) obtained above. After the addition of lithium hydroxide monohydrate (3.7 mg, 0.0885 mmol), the suspension was heated for 1 hour under reflux, and then allowed to cool to room temperature and diluted with ice-water. The mixture was acidified by addition of 1M HCl and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane, to give the titled compound as a pale yellow crystal (9.7 mg, yield 69%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].OO.[OH:23]S(O)(=O)=O>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[C:14]([OH:23])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(OCc2ccccc2)cc1C=O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(OCc2ccccc2)cc1C(=O)O
Temperature: 65 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred suspension of 5-(benzyloxy)-2-methoxybenzaldehyde (7, 1.12 g. 4.6 mmol) in MeOH (8 mL) at room temperature was added a solution of KOH (1.04 g, 18.5 mmol) in water (1.4 mL). The mixture was heated to 65° C. and H2O2 (35 wt %; 4.0 mL, 46 mmol) was added dropwise over 105 min. The reaction mixture was stirred at 65° C. for 1 h. Then it was cooled to room temperature and acidified to pH 2 with 6N H2SO4. The precipitate was collected, washed with water and dried in vacuo to afford the title compound (1.16 g, 97%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 10.94 (br s, 1H), 7.80 (d, J=3.3 Hz, 1H), 7.44-7.37 (m, 4H), 7.35-7.32 (m, 1H), 7.19 (dd, J=9.0, 3.3 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 5.08 (s, 2H), 4.04 (s, 3H); ESI MS m/z 257 [M−H]−.
Reaction SMILES: [C:1]([N:9]=[C:10]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:22]=[CH:21][C:20]2[N+:19]([O-])=C[C:17]3[N:24]=[CH:25][N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[C:16]=3[C:15]=2[CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:17]3[N:24]=[CH:25][N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[C:16]=3[C:15]=2[CH:14]=1
Reactant: [O-][n+]1cc2ncn(-c3ccccc3Cl)c2c2cc(Cl)ccc21
Reactant: O=C=NC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1nc2ccc(Cl)cc2c2c1ncn2-c1ccccc1Cl)c1ccccc1

Procedure:
A solution of 0.644 g (3.939 mmol) benzoyl isocyanate in 10 ml CH2Cl2 is added within 10 min to 1 g (3.029 mmol) of 8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline 5-oxide (Example 71) in 10 ml CH2Cl2. The reaction mixture is heated and kept under reflux for 7 h. The solvent is evaporated, and the residue is purified by chromatography (CH2Cl2-methanol 97.5:2.5). The compound is crystallized from ethyl acetate-hexane. mp: 255-258° C.; MS: 433 (M++1); HPLC: tret=10.91 min (Grad 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[N:9]\[S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:17][CH2:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:22]1([S:19]([CH:18]([F:17])/[C:8](=[N:9]\[S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=S(=O)(CF)c1ccccc1
Reactant: CC(C)(C)S(=O)(=O)/N=C\c1cccc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)(=O)/N=C(/c1cccc(Br)c1)C(F)S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 2-methyl-propane-2-sulfonic acid 1-(3-bromo-phenyl)-meth-(Z)-ylideneamide (2.16 g, 7.49 mmol) and (fluoromethylsulfonyl)benzene (1.31 g, 7.49 mmol) in THF (50 mL), cooled to −78° C., was added LiHMDS (1M in THF; 7.87 mL, 7.87 mmol). The reaction mixture was stirred for 40 min at −78° C., followed by quenching saturated aqueous NH4Cl (10 mL) at −78° C. The mixture was extracted with EtOAc (3×), dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 3:1) afforded the title compound. MS (LC/MS): 462/464 [M+H]+; tR (HPLC conditions f): 2.20 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])[NH2:5].[CH:14]([C:16]1[CH:27]=[CH:26][C:19]2[C:20]([CH3:25])=[C:21]([C:23]#[N:24])[O:22][C:18]=2[CH:17]=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:14][C:16]2[CH:27]=[CH:26][C:19]3[C:20]([CH3:25])=[C:21]([C:23]#[N:24])[O:22][C:18]=3[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: Nc1ccc(OC(F)(F)F)c(Br)c1
Reactant: Cc1c(C#N)oc2cc(C=O)ccc12
Product: Cc1c(C#N)oc2cc(CNc3ccc(OC(F)(F)F)c(Br)c3)ccc12

Procedure:
The title compound was prepared as described in general reductive amination procedure, starting from 3-bromo-4-(trifluoromethoxy)aniline and 6-formyl-3-methylbenzofuran-2-carbonitrile, Intermediate 4. LCMS retention time=1.64 minutes (LC method 3); MS (m+1)=426.0.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1)([O-])=O>O=[Pt]=O.CO>[CH3:18][O:17][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][NH2:1])=[CH:10][CH:11]=1)=[O:16]
Reactant: COC(=O)c1ccc2[nH]cc(CC[N+](=O)[O-])c2c1
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)c1ccc2[nH]cc(CCN)c2c1

Procedure:
Combine 3-(2-nitroethyl)-5-methoxycarbonyl-1H-indole (280 mg, 1.1 mmol), PtO2 (200 mg) and 15 mL MeOH and hydrogenate at atmospheric pressure overnight. Filter reaction mixture through a pad of celite, concentrate the filtrate, and chromatograph on silica gel eluting with 5% MeOH in CHCl3 mixed with conc. NH4OH to give the title compound as an oil: ISMS 219 (M+1); 1H NMR (CDCl3) 9.01 (s, 1H), 8.36 (s, 1H), 7.88-7.85 (m, 1H), 7.32-7.24 (m, 1H), 7.05 (s, 1H), 3.91 (s, 3H), 3.05-3.01 (m, 2H), 2.93-2.89 (m, 2H), 1.22 (bs, 2H).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:48])[C@:29]([C:32]3[CH:37]=[C:36]([NH:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[O:45][CH3:46])[CH:35]=[CH:34][C:33]=3[F:47])([CH3:31])[N:30]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[F:48][C@H:28]1[CH2:27][O:26][C:25]([NH2:24])=[N:30][C@@:29]1([C:32]1[CH:37]=[C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[O:45][CH3:46])[CH:35]=[CH:34][C:33]=1[F:47])[CH3:31]
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4OC)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1Nc1ccc(F)c([C@@]2(C)N=C(N)OC[C@@H]2F)c1
Reaction time: 15 h
Yield: 82.7 %

Procedure:
A solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (49.8 mg, 76.6 μmol) in dichloromethane (2 ml) was treated at room temperature with trifluoroacetic acid (89.2 mg, 59.9 μl, 766 μmol), and the mixture was stirred for 15 hours. After evaporation at reduced pressure, the dark red residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (22 mg, 82% yield) was obtained as a white foam. MS (ISP): m/z=348.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]([CH3:10])([CH2:3][C:4]([OH:6])=[O:5])[CH2:8][C:7]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: OCc1ccccc1
Product: CC(C)(CC(=O)O)CC(=O)OCc1ccccc1

Procedure:
3,3-Dimethylglutaric anhydride (5.0 g.) and benzyl alcohol (11 ml.) were heated together at 150° C. for 16 hours. The cooled reaction mixture was partitioned between saturated sodium carbonate solution (50 ml.) and ether (50 ml.). The aqueous layer was separated, acidified with 2M hydrochloric acid and extracted with ether. The extracts were evaporated. The residual yellow oil (4.6 g.) was purified by chromatography on silica gel with methylene chloride as eluant to give benzyl hydrogen 3,3-dimethylglutarate as an oil (1.5 g.); NMR (CDCl3): 1.1 (6H,s, CH3), 2.45+2.47 (4H, 2s, COCH2), 5.12 (2H,s, OCH2), 7.37 (5H, s, aromatic H), 8.45 (1H, br.s, CO2H)ppm. This benzyl ester (1.5 g.) was dissolved in methylene chloride (15 ml.) and stirred with thionyl chloride (2.2 ml.) and N,N-dimethylformamide (DMF) (0.3 ml.) for 3 hours. The solvent was evaporated and the residue was dissolved in dry toluene (15 ml.) and the solution re-evaporated. This was repeated twice to remove excess thionyl chloride. The residual oil (1.5 g.) containing crude benzyl 4-chloroformyl-3,3-dimethylbutyrate was dissolved in methylene chloride (25 ml.). The solution was added to a cooled solution of 1,3-dipalmitin (1.4 g.) in methylene chloride (25 ml.) containing pyridine (0.32 ml.). The mixture was stirred for 2 hours at 0°-5° C. and then for 46 hours at ambient temperature. The solvent was evaporated and the residue was partitioned between ether (70 ml.) and water (3×25 ml.). The organic phase was washed with 2M hydrochloric acid, saturated sodium hydrogen carbonate solution (2×25 ml.) and finally with water (2×25 ml.), and then dried (MgSO4) and evaporated. The residual oil crystallised on treatment with ethanol to give 2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethyl 4-benzyloxycarbonyl-3,3-dimethylbutyrate as a white solid (2.5 g.).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])(=[O:5])[CH3:4].I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:20]([N:12]1[C:13]2[C:8](=[CH:7][C:6]([C:3](=[O:5])[CH3:4])=[CH:15][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:10][C:11]1=[O:16])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCI
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0.3 %

Procedure:
Sodium hydride (21 mg, 90 mmol) was slowly added into a solution of 6-acetyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (Intermediate 5, 98 mg, 45 mmol) in 3 mL of DMF at 0° C. After stirring at 0° C. for 10 min, 1-iodo-n-hexane (29 mg, 135 mmol) was added to the reaction mixture and the ice-bath was removed. The reaction was allowed to stir for 2 h before quenching with ice water. The resulting solution was then extracted with ether (3×10 mL), washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (75:25 hexane/ethyl acetate) yielded the title compound as a colorless oil (41.8 mg, 31% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([O:16]CC)=[O:15])=[CH:9][N:8]=2)[CH:6]=1.[OH-].[K+]>CCO.O>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][N:8]=2)[CH:6]=1
Reactant: CCOC(=O)c1cnc(-n2cc(F)cn2)nc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc(-n2cc(F)cn2)nc1O
Temperature: 78 °C
Reaction time: 1.5 h

Procedure:
Ethyl 2-(4-fluoro-1H-pyrazol-1-yl)-4-hydroxypyrimidine-5-carboxylate, 28-f, (1 g, 3.9 mmol) was dissolved in EtOH (7 mL) and KOH (0.67 g, 11.9 mmol) in H2O (3 mL) was added. The mixture was stirred at 78° C. for 1.5 h. Then the solvent was evaporated, and the residue was added about 10 mL of H2O and filtered. The solid was dried and washed by EtOH (5 mL) to give the title product, 28-g, (0.7 g).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].[C:8]([O-])(=O)[CH2:9][C:10](C)=[O:11]>>[OH:11][C:10]1[CH:9]=[CH:8][N:5]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[N:4]=1
Reactant: CC(=O)CC(=O)[O-]
Reactant: N=C(N)C(Cl)(Cl)Cl
Product: Oc1ccnc(C(Cl)(Cl)Cl)n1

Procedure:
The carboxylic ester compounds of the present invention may be prepared by reacting trichloroacetamidine with a selected acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carboxylic acid chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with ethyl 2-chloroacetoacetate to form 5-chloro-4-hydroxy-6-methyl-2-trichloromethyl-pyrimidine. In equation (B), the 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with trichloroacetyl chloride to form 5-chloro-6-methyl-4-trichloroacetoxy-2-trichloromethylpyrimidine. ##STR3##
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:31][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[O:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[OH:30])[C:9]=2[C:8]=1[CH3:32])=[O:6].Cl>CO.C1COCC1.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:9]3[C:8]([CH3:32])=[C:7]([C:5]([OH:6])=[O:4])[S:31][C:10]=3[N:11]=[CH:12][N:13]=2)=[C:17]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[OH:30])[CH:18]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCC[C@@H]3O)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCC[C@@H]3O)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5 ml sodium hydroxide solution (4M) was added to a mixture of 2.960 g 4-[4-Fluoro-2-((1S,2S)-2-hydroxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (cpd. 51.1) in 60 ml methanol/THF (1:1). The reaction mixture was stirred at rt for 3 hours, then acidified with aq. HCl and diluted with water. The mixture was filtered and the filtercake was dried.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[C:8]([NH:21][CH2:22][CH2:23][OH:24])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:32][Si:33]([CH3:36])([CH3:35])Cl>O1CCCC1>[CH3:32][Si:33]([CH3:36])([CH3:35])[O:24][CH2:23][CH2:22][NH:21][C:8]1[C:9]2[C:10](=[O:20])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17](=[O:19])[C:18]=2[C:5]([NH:4][CH2:3][CH2:2][O:1][Si:33]([CH3:36])([CH3:35])[CH3:32])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NCCO)ccc(NCCO)c21
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCNc1ccc(NCCO[Si](C)(C)C)c2c1C(=O)c1ccccc1C2=O
Yield: 86 %

Procedure:
In a flame dried 250 ml, three-necked flask equipped with magnetic stirring bar, reflux condenser with nitrogen inlet and rubber septum on one side neck, are placed 1.63 g (5.0 mmol) 1,4-bis(2-hydroxyethylamino)anthraquinone (C.I. Disperse Blue 23, available as Disperse Blue NSP from Inmont Corporation), 4 ml triethylamine and 50 ml tetrahydrofurane (THF) (Aldrich, freshly opened). The mixture is purged with nitrogen and stirred until the dye is at least partially dissolved and 1.55 ml (12 mmol) trimethylchlorosilane is added to the mixture during a two minute period by means of a syringe having its needle through the septum. A mild exothermic reaction occurs and a precipitate forms immediately. The color of the mixture remains deep blue throughout the reaction. After stirring overnight, the reaction mixture is filtered and the whitish solid (triethylamine hydrochloride) washed with fresh THF until it remains white. The filtrate is evaporated on a rotary evaporator and the residue recrystallized from hot hexane. 1,4-Bis(2-trimethylsilyloxyethylamino)anthraquinone is obtained in two crops of blue needles in 86% yield, m.p. 123°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][NH:10][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1cccc(F)c1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 250-mL, round-bottomed flask containing a solution of 2-(3-fluorophenyl)ethanamine (1.3 mL, 9.6 mmol) and diisopropylethylamine (1.7 mL, 9.6 mmol) in dichloromethane (32 mL) was cooled to 0° C. and treated dropwise with 4-(trifluoromethyl)benzoyl chloride (2.0 mL, 9.6 mmol) over 5 min. The ice-bath was removed after 2 h and the reaction mixture was stirred overnight. The precipitate formed was collected by filtration. The filtrate was diluted with dichloromethane (100 mL) and transferred to a separatory funnel and extracted with water (35 mL). The dichloromethane layer was separated and formation of precipitate was observed which was collected by filtration. The filtrate was concentrated to yield more solid and the combined solids were dried under vacuum to yield N-(3-fluorophenethyl)-4-(trifluoromethyl)benzamide as a white solid. MS (ESI pos. ion) m/z: 312 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]([C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](O)=[O:27])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:26](=[O:27])[C:25]2[CH:29]=[C:21]([C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:22]=[CH:23][C:24]=2[O:30][CH3:31])[CH2:7]1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1ccc(C(=O)c2ccccc2)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-benzoyl-2-methoxy-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([OH:14])=[O:13].[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([C:12]([O:14][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:3][CH:4]=2)=[O:13])=[N:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc2[nH]nc(C(=O)O)c2c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(C(=O)OCc1ccccc1)nn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A suspension of 5-methoxy-1H-indazole-3-carboxylic acid (21.5 g; 0.11 mol) and 60% NaH (10.5 g; 0.44 mol) in N,N-dimethylformamide (DMF) (200 ml) was stirred at 70° C. for 1 hour. Benzyl chloride (32.9 g; 0.26 mol) was then added slowly to the suspension and the mixture was stirred at 70° C. for 4 hours. The reaction was stopped by cooling the mixture to room temperature and pouring the mixture into water and ice. The product was extracted with ethyl acetate (3×250 ml). The combined organic phases were concentrated under reduced pressure. The crude residue thus obtained was purified by successive crystallizations from 95° ethanol, to give 18 g of benzyl 1-benzyl-5-methoxy-1H-indazole-3-carboxylate with a melting point of 107-109° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(C)=O.O>[N:24]([C:4]([C:3]1[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:5])=[N+:25]=[N-:26]
Reactant: O=C(O)c1cccnc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a solution of 2-chloronicotinic acid (1.0 g, 6.35 mmol) in a mixture of acetone (14 mL) and water (6 mL) was added triethylamine (0.97 mL, 6.98 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (1.03 g, 9.5 mmol) was then added and the resulting mixture was stirred for 1.0 hour at 0° C. To the mixture was added sodium azide (0.70 g, 10.8 mmol), and the mixture was stirred for another 3 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give desired product (550 mg, 48%). 1HNMR (CDCl3) (δ) 8.57 (d, 1H), 8.22 (d, 1H), 7.37 (t, 1H).