Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19]C(=O)C.OS(O)(=O)=O>CO.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[C:7]([C:15]([F:18])([F:16])[F:17])=[CH:6][C:5]=1[NH2:19]
Reactant: COC(=O)c1cc(-n2cnnc2)c(C(F)(F)F)cc1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-n2cnnc2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A solution of 450 mg (1.43 mmol) of 2-acetylamino-5-[1,2,4]triazol-4-yl-4-trifluoromethyl-benzoic acid methyl ester in 5 ml methanol and 1 ml water is cooled to 0° C. and treated dropwise with 0.6 ml (11.3 mmol) of concentrated H2SO4. The mixture is then heated to reflux for 30 minutes and allowed to cool to room temperature. It is poured onto ice and the resulting mixture extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. The crude product is recrystallized in ethyl acetate/hexane to give 292 mg (71%) of 2-amino-5-[1,2,4]triazol-4-yl-4-trifluoromethyl-benzoic acid methyl ester, m.p. 184-186° C.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.O[C@@H]1[C@@H](C)CC[C@@H](NC(=O)OC(C)(C)C)C1.O[C@H]1[C@H](C)CC[C@H](NC(=O)OC(C)(C)C)C1>>[OH:1][C@@H:2]1[C@@H:7]([CH3:8])[CH2:6][CH2:5][C@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1
Reactant: C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)C[C@H]1O
Agent: C[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C[C@H]1O
Agent: C[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)C[C@@H]1O
Product: C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C[C@@H]1O
Yield: 72 %

Procedure:
To a stirring solution of a mixture of (R)-tert-butyl 4-methylcyclohex-3-enylcarbamate and (S)-tert-butyl 4-methylcyclohex-3-enylcarbamate (13 g, 61.6 mmol) in THF (780 mL) at 0° C. was added 1 M borane THF complex (277 mL, 277 mmol). The solution was stirred at 0° C., allowed to reach room temperature over 1 h, and then stirred at room temperature for 20 h. The reaction was quenched very slowly with water (330 mL), diluted with ethanol (326 mL) and basified with 5 N aqueous sodium hydroxide (308 mL, 1.54 mol). To the stirring biphasic mixture was slowly added 30% hydrogen peroxide (316 mL, 3.08 mol) and the resulting mixture was heated to 45° C. for 20 h. The crude reaction was quenched with saturated aqueous sodium sulfite (573 mL) and extracted with ethyl acetate (4×1 L). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The above reaction was repeated 5 times (using 3×13 g and 2×11 g starting material). The combined crude products from all 6 reactions were purified by silica gel chromatography (0-100% ethyl acetate in hexanes). The product containing fractions were combined and concentrated under reduced pressure to afford a mixture of tert-butyl (1R,3R,4R)-3-hydroxy-4-methylcyclohexylcarbamate, tert-butyl(1R,3S,4S)-3-hydroxy-4-methylcyclohexyl-carbamate, tert-butyl (1S,3R,4R)-3-hydroxy-4-methylcyclohexylcarbamate, and tert-butyl (1S,3S,4S)-3-hydroxy-4-methylcyclohexylcarbamate (55 g, 242 mmol, 72% yield) as a solid. The 4 constituent stereoisomers were separated by preparative chiral SFC utilizing multiple injections over a series of 3 separate columns. First column: ChiralPak AD-H, 250×50 mm I.D., isocratic 35% methanol in CO2. Second column: ChiralPak AD-H, 250×50 mm I.D., isocratic 25% methanol in CO2. Third column: ChiralPak AD-H, 250×50 mm I.D., isocratic 15% ethanol in CO2. The separated isomers were characterized on an analytical scale ChiralPak AD-3 column, 150×4.6 mm I.D., 5-40% methanol (with 0.05% diethylamine) in CO, (15 min run time) and labeled as Intermediate 1 to Intermediate 4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]2[N:20]=[C:21]([C:23](O)=[O:24])[CH:22]=[C:15]2[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]2[N:20]=[C:21]([C:23]([NH:33][O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[O:24])[CH:22]=[C:15]2[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=C(O)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Reactant: NOC1CCCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of 5-[(2-nitrophenyl)sulfonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (0.116 g, 0.316 mmol) and O-(tetrahydropyran-2-yl)hydroxylamine (0.0407 g, 0.347 mmol) in methylene chloride (2.5 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.144 g, 0.379 mmol) and N-methylmorpholine (0.1 mL, 0.9 mmol). The resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue obtained purified via silica chromatography (80-100% EtOAc/hexane) to afford Intermediate 21 as a clear colorless oil (0.152 g, 100%). LC-MS: (FA) ES+466.
Reaction SMILES: [C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([OH:12])[CH:7]=[CH:6][C:4]=1[OH:5])#[N:2].[OH-].[K+].[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CO.CN(C)C=O>[C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:6][C:4]=1[OH:5])#[N:2]
Reactant: CCCCCCBr
Reactant: N#Cc1c(O)ccc(O)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(O)c(C#N)c1C#N
Temperature: 50 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
27 g (168.8 mM) of 2,3-dicyanohydroquinone and 22.2 g (337 mM) of 85%-potassium hydroxide were dissolved in a mixture solvent of 65 ml of methanol and 302 ml of dimethylformamide, followed by heating to 50° C. To the solution, 33.4 g (202.4 mM) of hexyl bromide were added dropwise in 25 minutes, followed by heating to 100° C. and stirring for 3 hours. The reaction mixture was poured into cold water and washed with ether. The water layer was acidified with 6N-hydrochloric acid to provide a pH value of 1, followed by precipitation of a crystal. The crystal was extracted with ether, and the ether layer was washed with 5%-sodium hydrogen-carbonate aqueous solution and further washed with water, followed by distilling-off of the solvent to obtain a crude product. The crude product was treated with activated carbon and recrystalized from methanol to obtain 13.1 g of 2,3-dicyano-4-hexyloxyphenol.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:9]([CH3:11])[CH3:10])[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCCC1COCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)C(=O)N1CCCC1COCc1ccccc1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 13 (4.75 g, 12.16 mmol) in CH2Cl2 (10 mL) is added TFA (10 mL). The solution is stirred for 1 h and then quenched with a saturated solution of NaHCO3 (50 mL). The mixture is extracted with CH2Cl2 (50 mL×2). The combined organic layers are washed with 50 mL portions of sat. NaHCO3, water, and brine. It is then dried over Na2SO4 and concentrated to give pure 14 as a yellow oil (3.07 g, 10.56 mmol, 87%). 1H NMR (400 MHz, CDCl3) δ0.87 (t, J=6.8 Hz, 3 H), 0.91 (d, J=6.8, 3 H), 1.65-1.79 (m, 2 H), 1.79-1.96 (m, 2 H), 1.99-2.17 (m, 1 H); 3.27-3.45 (m 1 H), 3.46-3.54 (m, 1 H), 3.59-3.62 (m, 1 H), 4.33-4.38 (m, 1 H), 4.46-4.54 (m, 2 H), 7.27-7.42 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ16.9, 19.8, 24.4, 27.2, 47.2, 56.6, 58.3, 70.1, 73.1, 127.3, 127.4, 128.2, 138.4, 173.8. HRMS calcd for C17H27N2O2 (MH+): 291.2072. Found (DCI): 291.2088 (Δ=−5.3 ppm).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@H:10]([OH:15])[C@@H:9]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:8]=2[CH:26]=1)(=[O:3])[CH3:2].O.FC(F)(F)C(O)=[O:31].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>C(#N)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][C@H:9]2[C:8]3[CH:26]=[C:4]([C:1](=[O:3])[CH2:2][OH:31])[CH:5]=[CH:6][C:7]=3[O:12][C:11]([CH3:14])([CH3:13])[C@@H:10]2[OH:15])=[O:25])=[CH:19][CH:20]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccc(F)cc1)[C@@H](O)C(C)(C)O2
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC1(C)Oc2ccc(C(=O)CO)cc2[C@H](NC(=O)c2ccc(F)cc2)[C@H]1O
Yield: 23.6 %

Procedure:
(3R,4S)-6-Acetyl-4-(4-fluorobenzamido)-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran D5 (1.83 g, 5.0 mmol) (Example 20 of WO92/22293) was dissolved in acetonitrile (25 ml), water (5 ml) and trifluoroacetic acid (0.77 ml, 10.0 mmol). [Bis(trifluoroacetoxy)iodo]benzene (4.30 g, 10.0 mmol) was added and the reaction stirred under reflux for three hours. The reaction mixture was allowed to cool and the acetonitrile was removed in vacuo, the resulting material being partitioned between water (50 ml) and dichloromethane (125 ml). The aqueous layer was extracted with further portions of dichloromethane (3×25 ml) and the combined organic extracts were dried over magnesium sulphate, filtered and the solvent removed in vacuo. The resulting yellow foam was purified by column chromatography on silica, eluting with 20% to 50% ethyl acetate in hexane to afford the title compound as a white solid (0.44 g, 24%), m.p. 216° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1.C(O[K])(C)(C)C.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>C1COCC1.CN(C=O)C>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([CH2:26][O:17][CH2:16][C:15]2[N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:18])=[CH:5][CH:6]=3)[CH:12]=[N:13][CH:14]=2)=[CH:32][CH:31]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(Cn2cncc2CO)cc1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cn2cncc2COCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.4 %

Procedure:
To a solution of 4-(5-hydroxymethylimidazol-1-ylmethyl)benzoic acid methyl ester of Example A2 (0.11 g, 0.44 mmol) in THF (4 ml), DMF (1 ml) was added portionwise tBuOK (50 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 1.5 h, then 4-chloromethylbiphenyl (90 mg, 0.44 mmol) in THF (1 ml) was added and the reaction was stirred overnight. The solvent was removed under reduced pressure, then water (10 ml) was added and the mixture was extracted with AcOEt. The organic phase was dried over MgSO4 and the resulting oil was purified by flash chromatography on silica gel (CH2Cl2/MeOH: 95/05) to give a yellow solid (20 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1.FC(F)(F)C(O[C:29](=O)[C:30](F)(F)F)=O>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:11][N:12]([CH2:13][CH2:29][CH3:30])[CH2:6][CH2:5][CH3:4])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CSc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(C)n1-2
Solvent: CN(C)C=O
Product: CCCN(CCC)CCc1nnc2n1-c1ccc(SC)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-methylthio-1-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetrapropyldiaminomethane and trifluoroacetic anhydride (in 0.2 molar excess compared to the N,N,N',N'-tetrapropyldiaminomethane) are reacted together to give 8-methylthio-1-[2-(dipropylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:19]1([CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[C:29]1([CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:26][CH2:27][NH:28][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.562 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 178 mg (0.843 mmol) of 3,3-diphenylpropylamine were dissolved in 10 ml of DMF. 162 mg (0.843 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter referred to as WSC hydrochloride) was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:20]([CH:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=[O:24])=[CH:15][CH:14]=1>O1CCCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[C:20]([CH:25]([CH:29]([CH3:30])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]([OH:24])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[CH:17][CH:18]=1
Reactant: CC(C)C(C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)C(C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
A solution of the dianion of 1,1-dimethylethyl acetoacetate (15 mL of 1M solution, 15 mmol) was added to a solution of 5,5-bis(4-fluorophenyl)-4-[2-methyl-1-(1-methylethyl)propyl]-2,4-pentadienal (4.1 g, 11.1 mmol) in tetrahydrofuran at -60° C. After stirring for 3 hours the reaction was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried with magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 5% ethyl acetate in hexane to give 3.2 g of the title compound as an oil. MS(CI): m/e =526 for M+ of C32H40F2O4.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C(=O)(O)[O-].[Na+].O>C(O)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[NH:4][C:1](=[O:3])[CH3:2])([O-:20])=[O:19]
Reactant: CC(=O)N[C@H](CS)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)N[C@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of 9.28 g (56.9 mmol) of (S)-N-acetyl-cysteine, 7.43 mL (70.5 mmol) of 1-fluoro-2-nitrobenzene and 13.66 g (163 mmol) of sodium bicarbonate was refluxed in 136 mL of ethanol and 41 mL of water for 3 hours. The mixture was cooled to room temperature and the solvent evaporated. The residue was dissolved in 136 mL of water and extracted with ether. The water solution was then acidified to pH=1with 12N hydrochloric acid (HCl). The resulting yellow precipitate was filtered to yield 13.6 g (84%) of product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:13]([CH2:17][CH2:18][CH2:19]C)[C:14](Cl)=[O:15].[C:21](=S)=S>>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH2:12][CH:13]([CH2:17][CH:18]([CH3:19])[CH3:21])[C:14]2=[O:15]
Reactant: CCCCC(Cc1ccccc1Br)C(=O)Cl
Reactant: S=C=S
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)CC1Cc2c(Br)cccc2C1=O
Reaction time: 1 h

Procedure:
A 500-ml four-necked round flask equipped with a stirrer, a Dimroth condenser, a dropping funnel, a thermometer and a NaOH trap was charged with 20.33 g (152.5 mmol) of anhydrous aluminum chloride and 70 ml of carbon disulfide. To the mixture was added dropwise a solution containing 40.2 g (132.6 mmol) of the above-obtained 3-(2-bromophenyl)-2-1-butylpropionic acid chloride dissolved in 50 ml of carbon disulfide under a nitrogen atmosphere while cooling with ice bath. After the addition was completed, the temperature in the flask was elevated to room temperature, and the mixture was stirred for 1 hour. Then, the reaction mixture was quenched by pouring onto 200 ml of ice water, which was then extracted with 100 ml of ether three times. The combined organic phase was washed with 100 ml of a saturated aqueous solution of sodium bicarbonate, and then 100 ml of a saturated NaCl aq., followed by dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give 37.4 g of the desired produce as an orange liquid. This ketone was used in the next reaction without further purification.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(O)c(Cl)c2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccc(O)c(Cl)c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(3-chloro-4-hydroxyphenyl)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and toluene was added. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 94 mg of 2-(benzamido)-4-(3-chloro-4-hydroxyphenyl)benzoic acid as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=O)[CH3:13].[CH2:15]([O:17][C:18](=[O:25])[CH2:19][C:20](=O)[CH2:21][CH2:22][CH3:23])[CH3:16].O.O.[Sn](Cl)Cl.C(Cl)Cl.CCCCCC>CCO>[CH2:15]([O:17][C:18]([C:19]1[C:20]([CH2:21][CH2:22][CH3:23])=[N:1][C:2]2[C:3]([C:12]=1[CH3:13])=[CH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)=[O:25])[CH3:16]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl[Sn]Cl
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: CCCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OCC
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
5.0 g (24.6 mmol) 1-(2-amino-4-(trifluoromethyl)phenyl)ethanone was stirred together with 2.6 ml (24.6 mmol) 3-oxo-hexanoic acid ethyl ester and 5.6 g (24.6 mmol) tin(II) chloride dihydrate for 3 h at RT. The mixture was subsequently heated to 80° C. for 16 h. After cooling to RT, the mixture was diluted with EtOH (25 ml), ice was added and the mixture was stirred for 10 min at RT. The solution was subsequently filtered off and washed with EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with an aq. Na2-EDTA sol., water and brine, dried over MgSO4 and concentrated in a vacuum. After CC (DCM/hexane 2:1) of the residue, 4.3 g (13.7 mmol, 56%) 4-methyl-2-propyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was obtained.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]([O:38]CC)=O)[CH2:31][CH2:30]2)[C:9]=1Br.O.[NH2:53][NH2:54]>CN(C=O)C>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH2:31][CH:32]([CH2:35][C:36]([NH:53][NH2:54])=[O:38])[CH2:33][CH2:34]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)CC1CCC(c2cc(N)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a 2-5 mL pressure vial was charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (0.12 mmol, 95 mg), DMF (1 mL), and hydrazine monohydrate (1 mL). The pressure vial was sealed and heated to 80° C. for 18 hours. After 18 hours, the solvents were removed in vacuo and the product taken on without further purification.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][C:17](=[O:19])[NH:16][N:15]=1.CI>CN(C=O)C>[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][C:17](=[O:19])[N:16]([CH3:1])[N:15]=1
Reactant: O=c1[nH]nc(-c2ccccc2O)o1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2O)oc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of 3.8 g of potassium t-butoxide in 60 ml of dry DMF under a N2 atmosphere was added portionwise 6 g of the product of Example 10 while maintaining the reaction temperature at 10°-20° C. with external cooling. After stirring at 25° C. for one hour, 9.6 g of methyl iodide was added dropwise at 10°-20° C. with external cooling. After stirring at room temperature for 16 hours, the suspension was poured into excess ice-water and filtered. The residue was recrystallized from 2-propanol to yield 4.6 g of the subject compound; m.p. 160°-162° C.