Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:6][O:5][C:4]([C:7]2[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17](CC4C=CC=CC=4)[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:3]1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:29])[CH2:6][O:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:27][CH:28]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccc(OCCC3CCN(Cc4ccccc4)CC3)cc2)=N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)COC(c2ccc(OCCC3CCNCC3)cc2)=N1
Yield: 86.4 %

Procedure:
A mixture of 5 parts of 4-[2-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenoxy]ethyl]-1-(phenylmethyl)piperidine and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 3.4 parts (86.4%) of 4-[2-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenoxy]ethyl]piperidine as a residue (int. 75).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32](C([O-])=O)[C:31]([CH3:37])([CH3:36])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[NH:32][C:31]([CH3:37])([CH3:36])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: OCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: CC1(C)Cn2c(cc(Cl)nc2=O)N1C(=O)[O-]
Product: CC1(C)Cn2c(cc(OCc3cc(F)c(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and tert-butyl, 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carbox-ylate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COC(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of thiophene-2-carboxylic acid (500 mg, 3.90 mmol) in acetone (20 ml), K2CO3 (593 mg, 4.29 mmol) was added, and mixture was stirred for 5 minutes, then KI (64.8 mg, 0.390 mmol) was added, followed by dropwise addition of tert-butyl 2-bromoacetate (0.634 ml, 4.29 mmol). The mixture was heated at 50° C. overnight. The solid residue was filtered out and washed with DCM; the solvent was evaporated and 2-tert-butoxy-2-oxoethyl thiophene-2-carboxylate was obtained as a clear oil (945 mg, 3.90 mmol, 100% yield, MS/ESI+ 264.9 [MNa]+) and used in the following reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a mixture of 4-bromoindole (1.96 g, 10 mmol), and 3-methoxyphenylboronic acid (1.52 g, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.83 g (82%) of the product 4-(3-methoxy-phenyl)-1H-indole as colorless syrup.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][C:44]1[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=1[CH3:50]>O.ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:42][CH2:43][C:44]2[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=2[CH3:50])=[O:13])=[CH:14][CH:15]=1)[CH3:6]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1F)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3F)cc2)c(O)n1
Temperature: 25 °C
Yield: 19 %

Procedure:
A mixture of 4-(1-(2-fluorophenoxy)ethyl)benzoic acid (260 mg, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (382 mg, 2 mmol), N-hydroxybenzotriazole (270 mg, 2 mmol), triethylamine (0.3 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(1-(2-fluorophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (75 mg, 38%). LRMS (M+H+) m/z: calcd. 394.17. found 394. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.30 (t, J=4.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.19-6.83 (m, 4H), 5.83 (s, 1H), 5.58 (q, J=6.3 Hz, 1H), 4.27 (d, J=4.8 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.56 (d, J=6.3 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH:31]1[O:33][CH2:32]1.O>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:30][CH:31]4[O:33][CH2:32]4)=[C:3]([O:21][CH3:22])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[C:14]([F:20])[CH:15]=1
Reactant: BrCC1CO1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CO1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
To a solution of 7-hydroxy-6-methoxy-4-(2-fluoro-4-chlorophenylamino)quinazoline (5.56 g, 17.4 mmol) in DMF (100 ml) containing potassium carbonate (4.8 g, 34.8 mmol) was added 1-bromo-2,3-epoxypropane (1.49 ml, 17.4 mmol). The mixture was stirred at 60° C. for 3 hours. After cooling, water (400 ml) was added The precipitate was filtered and dried under vacuum at 60° C. for 2 hours over P2O5. The product was purified by column chromatography eluting with methylene chloride followed by methylene chloride/methanol saturated with ammonia 98/2. The fractions containing the expected product were combined and evaporated to give 4-(4-chloro-2-fluorophenylamino)-7-(2,3-epoxypropoxy)-6-methoxyquinazoline (2.82 g, 43%).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=[C:31]=[N:32][CH2:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37].CN1CCCNCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:37][N:36]1[CH2:35][CH2:34][CH2:33][N:32]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([C:7]3[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)=[CH:17][CH:16]=2)=[O:15])[CH2:31][CH2:38]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)o1
Agent: CN1CCCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(C(=O)N3CCCN(C)CC3)cc2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113 %

Procedure:
To a solution of 4-(5-acetylfuran-2-yl)benzoic acid (500 g, 2.17 mmol) and HOBt (587 mg, 4.35 mol) in DMF (5 mL) was added EDCI (835 mg, 4.35 mmol). The reaction was stirred at rt for 10 min and then 1-methylhomopiperazine (1.08 mL, 8.69 mol) was added, followed by DIEA (1.52 mL, 8.69 mmol). The reaction mixture was stirred at rt for 3 h and diluted with H2O (20 mL). The mixture was extracted with DCM (3×25 mL), washed with water (2×25 mL) then brine (25 mL), dried over Na2SO4 and concentrated to give brown oil (800 mg). LCMS (ES): m/z 442 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH2:23]1[O:33][C:32]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=2[O:24]1.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:28][C:27]4[CH:30]=[CH:31][C:32]5[O:33][CH2:23][O:24][C:25]=5[CH:26]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(NCc4ccc5c(c4)OCO5)c23)c1

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3,4-methylenedioxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(3,4-methylenedioxybenzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 220-222° C.; HPLC: TRet (Grad5-40)=22.5° C.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>S(=O)(=O)(O)O>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:4]
Reactant: CCCCCCC(O)C(=O)O
Reactant: CCCCCCCCCCO
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCOC(=O)C(O)CCCCCC
Temperature: 140 °C
Yield: 80.4 %

Procedure:
A 250 mL one neck round bottom flask equipped with a Dean Stark trap, condensor and nitrogen inlet/outlet was charged with 20.0 g (0.12 moles) 2-hydroxyoctanoic acid, 79.0 g (0.50 moles) decyl alcohol, and 624 mg sulfuric acid. The mixture was heated to 140° C. for 8 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. The organic layer was collected and dried over magnesium sulfate. Excess decyl alcohol was removed by high vacuum distillation to yield 28.99 g (77.3% yield) of clear pale yellow liquid. According to GC the product is 95.0% pure.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.S(=O)(=O)(O)O.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)c1ccccc1C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
A solution of 83 g of diethyl oxalate in toluene (170 g) was cooled to −40° C. or lower. The Grignard reagent prepared as described above was added dropwise at −40° C. or lower, and this was retained at −40° C. for 2 hours. To the reaction mixture was added 234 g of 10% sulfuric acid, and an organic layer was recovered. The resulting organic layer was washed with 134 g of water, and dried with magnesium sulfate. After concentration with an evaporator, distillation under high vacuum, and silica gel column purification afforded 33.1 g of ethyl 2-(methyl-phenyl)-2-oxoacetate.
Reaction SMILES: [C:1]([C:3]([C:19]([O:21][CH2:22]C)=[O:20])=[N:4][CH:5]=[C:6]([N:13]1CCOCC1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C(C(OC)=NC=C(N1CCOCC1)C1C=CC=CC1=C=O)#N>>[C:1]([C:3]([C:19]([O:21][CH3:22])=[O:20])=[N:4][CH:5]=[C:6]([NH2:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)#[N:2]
Reactant: CCOC(=O)C(C#N)=NC=C(c1ccccc1)N1CCOCC1
Agent: COC(C#N)=NC=C(C1C=CC=CC1=C=O)N1CCOCC1
Product: COC(=O)C(C#N)=NC=C(N)c1ccccc1

Procedure:
One operates as in Example 12, but the 6.3 parts of 1-cyano-1-ethoxycarbonyl-4-morpholino-4-phenyl-2-aza-1,3-butadiene are replaced by 6 parts of 1-cyano-1-methoxy-carbonyl-4-morpholino-4-phenyl-2-aza-1,3-butadiene. 3.7 parts of 1-cyano-1-methoxycarbonyl-4-amino-4-phenyl-2-aza-1,3-butadiene are obtained. After recrystallisation from methanol, the product melts at 186°C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:32])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:24][N:23]([CH3:31])[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:32])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][N:23]([CH3:31])[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(C)cc2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A mixture of methyl [3-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethoxy]-1-methyl-1H-pyrazol-4-yl]acetate (623 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [3-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethoxy]-1-methyl-1H-pyrazol-4-yl]acetic acid (580 mg, yield 96%), which was then recrystallized from ethanol-hexane. melting point: 155–156° C.
Reaction SMILES: OB(O)[C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=[O:9].[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][C:14]=1[O:20][CH3:21].CC#N.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:3]2[CH:7]=[CH:6][S:5][C:4]=2[C:8]([OH:10])=[O:9])=[CH:15][C:14]=1[O:20][CH3:21]
Reactant: O=C(O)c1sccc1B(O)O
Reactant: COc1cc(I)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COc1cc(-c2ccsc2C(=O)O)ccc1Br
Temperature: 90 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
A solution of 3-(dihydroxyboryl)thiophene-2-carboxylic acid (1.89 g, 10.85 mmol) and 1-bromo-4-iodo-2-methoxybenzene (3.09 g, 9.86 mmol) in a 3:1 mixture of MeCN:H2O (100 mL) was treated with K2CO3 (4.09 g, 29.6). Pd(OAc)2 (66.4 mg, 0.30 mmol) and biphenyl-2-yl(dicyclohexyl)phosphine (207 mg, 0.59 mmol) were added and the mixture was stirred at 90° C. for 3 h. The mixture was cooled and concentrated, and the residue was added at 0° C. to a mixture of 10% aqueous NaOH (100 mL) and DCM. The mixture was acidified to pH=1 by addition of aqueous HCl (6 N) and the solid precipitate was collected by filtration, washed with cold H2O and DCM, then dried to afford the title compound (2.29 g, 74%). LCMS (ES+) m/z 313, 315 (M+H)+.
Reaction SMILES: NC(N)=S.[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:10][C:9]1([CH3:27])[CH3:26])(=[O:7])[CH3:6].[C:28]([N:32]=[C:33]=[S:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:33]([NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[S:34])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:10][C:9]1([CH3:27])[CH3:26])(=[O:7])[CH3:6]
Reactant: CC(C)(C)N=C=S
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: NC(N)=S
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=S)NC(C)(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Thiourea formation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with tert-butyl isothiocyanate (7.5 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 18.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)c(OCc2ccc(F)cc2)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)c(OCc3ccc(F)cc3)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-3-[(4-fluorophenyl)methoxy]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.09 (2H, s), 5.16 (2H, s), 5.69 (1H, s), 6.98-7.13 (5H, m), 7.37-7.40 (3H, m), 7.56 (1H, s), 8.03 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C23H16F2N4O2, 419; Found, 419.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC=CC=3C(F)(F)F)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[C:26]([F:25])([F:35])[F:36])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3C(F)(F)F)c(-c3ccc(Cl)cc3)c2CC1
Product: FC(F)(F)c1ccccc1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 49.3 %

Procedure:
The title compound (0.04 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-trifluoromethylbenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-trifluoromethyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H19ClF3N3, 405.12; found, m/z 406.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.45 (d, J=7.7 Hz, 2H), 7.25-7.24 (br m, 3H), 7.18-7.16 (br m, 3H), 6.46-6.44 (br m, 1H), 5.43-5.41 (s, 2H), 3.14-3.11 (br m, 4H), 2.89-2.87 (br m, 4H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([C:27]2[CH:32]=[CH:31][C:30]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[CH:29][CH:28]=2)[C:7]=1[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:5])C.Cl.[OH-].[Na+]>CCO>[CH2:36]([N:33]([CH2:34][CH3:35])[C:30]1[CH:29]=[CH:28][C:27]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=4)=[CH:11][CH:10]=3)[C:6]([C:4]([OH:5])=[O:3])=[C:7]2[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:32][CH:31]=1)[CH3:37]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(OC(F)(F)F)cc3)ccc2n1-c1ccc(N(CC)CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cc1c(C(=O)O)c2cc(Oc3ccc(OC(F)(F)F)cc3)ccc2n1-c1ccc(N(CC)CC)cc1

Procedure:
A mixture of 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-(4-trifluoromethoxyphenoxy)indole-3-carboxylic acid ethyl ester (63 mg, 0.12 mmol, see step (a) Example 75), HCl (aq, 1 M, 0.2 mL) and EtOH (1 mL) was heated at reflux for 2 h and cooled. The pH was adjusted to 4 by with NaOH (aq, 1 M) and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated and purified by chromatography to give the title compound. Yield 61 mg (89%).
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:27])=O>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:3][CH2:4][CH2:5][C:6]([Cl:27])=[O:7]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCC(=O)Cl
Yield: 99.6 %

Procedure:
Under a nitrogen atmosphere, one drop of pyridine was added to 10 g of 5,9,13,17-tetramethyloctadecanoic acid and 20 ml of methylene chloride, and 5.2 g of thionyl chloride was added dropwise thereto at room temperature. After the completion of dropwise addition, the mixture was refluxed for 1 hour and concentrated under reduced pressure to obtain 10.5 g of 5,9,13,17-tetramethyloctadecanoic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[N:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=[C:26]([C:33](O)=[O:34])[CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:26]2[CH:25]=[N:24][N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=23)=[O:34])=[O:8])[N:6]=1
Reactant: O=C(O)c1cnn2ccccc12
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnn3ccccc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Pyrazolo[1,5-a]pyridine-3-carboxylic acid. LC-MS (basic): tR=0.74 min; [M+H]+=477.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:32](=[O:33])[CH2:31][CH2:30][C@@:29]2([CH3:34])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:35])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C@@H:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:36][C:2]1([CH3:1])[C@@H:32]([OH:33])[CH2:31][CH2:30][C@@:29]2([CH3:34])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:35])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C@@H:11]([CH2:13][O:14][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:22]([CH3:23])[CH3:24])[CH3:12]
Reactant: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 27.3 g (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5-en-3-one in 500 ml tetrahydrofuran 1.24 g of lithiumaluminum hydride were added cautiously in small portions at room temperature. The reaction mixture was stirred for one hour and then cooled to 0□C. 2.5 ml water, 2.5 ml of a 1 N sodium hydroxide solution and 7.5 ml of water were added successively. The mixture was filtered over celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 18.2 g (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5-en-3β-ol as a pale yellow solid.