Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH:9](C)[C:10]([OH:12])=[CH2:11])[N:8]=1)([O-:3])=[O:2].C1NC([N+]([O-])=O)=NC=1.C1[O:26][CH:23]1C=C.C(=O)([O-])[O-].[K+].[K+].ClC1C=CC=C(C(OO)=O)C=1.C(C1C=C(SC2C=C(C)C(O)=C(C(C)(C)C)C=2)C=C(C)C=1O)(C)(C)C>C(O)C.ClC(Cl)C>[N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][CH:10]([OH:12])[CH:11]2[O:26][CH2:23]2)[N:8]=1)([O-:3])=[O:2]
Reactant: C=CC1CO1
Reactant: C=C(O)C(C)c1c[nH]c([N+](=O)[O-])n1
Agent: Cc1cc(Sc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: CCO
Product: O=[N+]([O-])c1nc(CC(O)C2CO2)c[nH]1
Yield: 33 %

Procedure:
3-(2-Nitroimidazolyl)-2-hydroxy-1-butene (11.83 gms, m.p. 90°-92° C., prepared by refluxing a mixture of azomycin, 1,3-butadiene monoxide and anydrous potassium carbonate in ethanol for 5 hours) is stirred overnight in dichlorethane with m-chloroperbenzoic acid in the presence of 3-tert-butyl-4-hydroxy-5-methylphenyl sulfide and after stirring the reaction mixture is refluxed for 1 hour. The mixture is washed with saturated sodium carbonate solution and the aqueous phase was extracted with chloroform. The combined dichloroethane and chloroform extracts are concentrated to a small volume and the product is purified by column chromatography, in which silica gel is the stationary phase and a mixture of chloroform (90%) and ethanol (10%) the eluent. The product is crystallised from ethanol as a pale yellow solid of m.p. 134°-136° C. Yield 33%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:19])=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])=O.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([OH:19])=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])/[C:5](=[N:21]\[OH:22])/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13]
Reactant: NO
Reactant: COc1ccc(C(=O)c2ccccc2F)c(O)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(/C(=N\O)c2ccccc2F)c(O)c1Cl
Reaction time: 0.75 h

Procedure:
3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone (24.6 g) is refluxed for 18 hours in 300 ml of pyridine containing 12.2 g of hydroxylamine hydrochloride. The reaction mixture is concentrated under reduced pressure and is distributed between ether and 5% HCl. The organic phase is dried and evaporated and the resulting crystalline product fused at 205° C. for 45 minutes. The product is cooled and recrystallized from toluene to give E-3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone oxime, mp 184°-186° C.
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[F:26][C:27]1([F:38])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([NH:36][NH2:37])[C:29]=2[O:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:36]([C:35]5[C:29]6[O:28][C:27]([F:26])([F:38])[O:31][C:30]=6[CH:32]=[CH:33][CH:34]=5)[N:37]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Reactant: NNc1cccc2c1OC(F)(F)O2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2ccc3c(c2)OC(F)(F)O3)nc1-c1ccnn1-c1cccc2c1OC(F)(F)O2

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=475.0 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)[CH:4]=1)#[N:2].[OH-:27].[Na+]>CO.C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)[CH:4]=1)(=[O:27])[NH2:2]
Reactant: [OH-]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C#N)ccn3)cc(C)c21
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(C(N)=O)ccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(4-cyanopyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.18 g, 3.31 mmol) in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated and then acidified to pH 5 using 1 N HCl and then concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (b, 1H), 9.20 (b, 1H), 8.20 (m, 2H), 7.70 (s, 1H), 7.44 (dd, J=5.6, 1.6 Hz, 1H), 7.33 (s, 1H), 7.15 (d, J=2 Hz, 1H), 7.00 (d, J=2 Hz, 1H), 5.46 (dd, J=9.6, 2.4 Hz, 1H), 3.03 (dd, J=15.6, 2.8 Hz, 1H), 2.44 (s, 3H), 2.08 (dd, J=15.6, 9.6 Hz, 1H). MS (ESI) m/z=343 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][CH:30]=[CH:29][C:6]=1[NH:7][C:8](=[O:28])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH2:12][CH2:11]1)=[O:4].CO.CO.[OH-].[K+].[ClH:39]>C(O)C>[ClH:39].[C:3]([C:5]1[CH:32]=[CH:31][CH:30]=[CH:29][C:6]=1[NH:7][C:8](=[O:28])[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH2:14][CH2:15]1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)c(OC)c2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: COc1ccc(C(=O)N2CCN(CC(=O)Nc3ccccc3C(=O)O)CC2)cc1OC

Procedure:
20 Grams of o-methoxycarbonyl- -[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide, 400 ml of methanol and 25 ml of 3.5N-potassium hydroxide methanol solution were mixed together and the mixture was refluxed for 8.5 hours. After completion of the reaction, the reaction mixture was allowed to stand for cooling, then an ethanol solution of hydrochloric acid was added to the mixture to adjust the pH thereof to about 1. The crystals formed were removed by filtration, and the mother liquor was cooled by ice. The crystals were collected by filtration, recrystallized from 80% water-containing methanol to obtain 13.28 g of o-carboxy- -[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloride in the form of colorless cotton fiber-like crystals. Melting point: 250.5°-251.5° C. (decomposed).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C:28]1[O:29][CH2:30][CH2:31][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[O:29][CH2:30][CH2:31][N:32]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NC1=NCCO1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NC1=NCCO1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-amino-4,5-dihydrooxazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(4,5-dihydrooxazol-2-yl)terephthalamide. MS (Q1) 456 (M)+.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH:45]([CH3:47])[CH3:46])[CH2:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:31][C:32]([C:34]3[NH:43][C:42](=[O:44])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[O:33])[CH:25]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16]>C1COCC1>[CH:1]([N:12]([OH:11])[CH:13]([CH:45]([CH3:47])[CH3:46])[CH2:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:31][C:32]([C:34]3[NH:43][C:42](=[O:44])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[O:33])[CH:25]=2)=[CH:22][CH:23]=1)(=[O:16])=[O:17])=[O:2]
Reactant: O=CO
Reactant: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)NO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)N(O)C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To formic acid (0.217 mL) was added acetic anhydride (0.054 mL, 0.576 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hr. This solution was added to a suspension of N-[(4′-{[2-(hydroxyamino)-3-methylbutyl]sulfonyl}biphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 107 (0.285 g, 0.430 mmol) and formic acid (2 mL) in THF (20 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-s (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/10→0/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and crystallized from EtOH-ethyl acetate-diethyl ether to give the title compound as a pale-yellow powder (0.077 g, 37%).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH3:10]>>[CH2:9]([O:11][CH:12]([O:17][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:13]([F:16])([F:15])[F:14])[CH3:10]
Reactant: Nc1cccnc1Cl
Reactant: CCOC(O)C(F)(F)F
Product: CCOC(Oc1ncccc1N)C(F)(F)F

Procedure:
Was prepared in a similar manner as intermediate III.1 from 2-chloropyridin-3-amine and 1-ethoxy-2,2,2-trifluoro-ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]3[CH2:14][CH2:13]3)[CH2:10][CH2:9][C:8]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:32])[CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[O:16])=[CH:7][C:6]=2[CH:33]=1.B([O-])([O-])O[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:46]([O:45][CH2:44][CH2:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]4[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]([C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH3:32])[CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:22][CH:23]=4)=[O:16])=[CH:7][C:6]=3[CH:33]=2)=[CH:41][CH:40]=1)[CH2:47][CH2:48][CH3:49]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3N(C3CC3)CC2)cc1)C1CCOCC1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of 7-bromo-1-cyclopropyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g), 4-(2-butoxyethoxy)phenyl borate (0.23 g), 1M potassium carbonate solution (1.5 ml), ethanol (1.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.05 g), and the mixture was refluxed for 3 hours under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 31) (0.25 g) as pale yellow crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH2:35][CH2:36]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(CC(F)(F)F)CC5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A solution of 49 (200 mg, 0.39 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (134 mg, 0.58 mmol) and DIPEA (0.2 mL, 1.16 mmol) and in THF (15 mL) was stirred and heated at 85° C. for 4 h in a sealed flask, then at RT (scheme 22). The reaction mixture was concentrated, diluted with a minimum of methanol in water. The pH was adjusted to 10-11 with a saturated aqueous solution of sodium bicarbonate and a few drops of 1N NaOH at the end. The suspension was shaken for 15 min and the solid was collected by filtration, rinsed with water and dried under high vacuum. The crude product was purified by Biotage (SiliaFlash 25 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 10/90 over 20 CV), to afford the title compound 84 (26 mg, 0.043 mmol, 11% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.54 (bd, J=1.4 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.1, 2.1 Hz, 1H), 7.73 (dd, J=13.5, 2.5 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.20 (dd, J=9.0, 1.4 Hz, 1H), 6.64 (dd, J=5.5, 0.8 Hz, 1H), 6.58 (bd, J=2.5 Hz, 1H), 3.55 (s, 2H), 3.15 (q, J=10.2 Hz, 2H), 2.69-2.51 (m, 5H), 2.48-2.35 (m, 4H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS 601.6 (m/z): (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[CH3:16][S:17]([C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[N:30]=[CH:29][N:28]=[C:27]3[N:31]([CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[N:32]=[CH:33][C:26]=23)=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:37]2[CH2:38][CH2:39][CH:34]([N:31]3[C:27]4=[N:28][CH:29]=[N:30][C:25]([O:24][C:23]5[CH:22]=[CH:21][C:20]([S:17]([CH3:16])(=[O:18])=[O:19])=[CH:41][CH:40]=5)=[C:26]4[CH:33]=[N:32]3)[CH2:35][CH2:36]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 60 °C
Yield: 0.7 %

Procedure:
3,6-Dichloropyridazine (0.2 mmol) was added to a mixture of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 75 mg, 0.15 mmol) and potassium carbonate (69 mg, 0.5 mmol) in dimethylformamide (1 mL). The mixture was heated to 60° C. overnight and then poured into saturated aqueous ammonium chloride solution. This mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with water and once with brine, dried (magnesium sulfate), filtered, evaporated, and purified on a silica gel column, eluting with ethyl acetate, to give 1-[1-(6-Chloro-pyridazin-3-yl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (0.5 mg, 0.7%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1([C:10]([OH:12])=[O:11])[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]([F:13])([F:14])[C:3]1([C:10]([OH:12])=[O:11])[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2
Reactant: O=C(O)C1(C(F)(F)F)CC2C=CC1C2
Agent: [Pd]
Solvent: Cc1ccccc1
Product: O=C(O)C1(C(F)(F)F)CC2CCC1C2
Yield: 32 %

Procedure:
2-Trifluoromethylbicyclo[2,2,1]hepta-5-ene-2-carboxylic acid (20) obtained in Synthesis Example 1-1-1 was stirred in a toluene solvent in the presence of 5% Pd/C catalyst at room temperature under hydrogen atmosphere to obtain 2-trifluoromethylbicyclo[2,2,1]heptane-2-carboxylic acid. In the same synthetic routes as in Synthesis Example 1-1-2 to 1-1-3 except for using the carboxylic acid as the starting material to obtain 3.9 g (four-step yield: 32%) of Q-3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][O:35][C:36]([F:39])([F:38])[F:37])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][O:35][C:36]([F:38])([F:39])[F:37])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCOC(F)(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CCOC(F)(F)F)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
151 mg (248 μmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoate (racemate) and 574 μl (7.45 mmol) of TFA were reacted according to General Method 2. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 65 mg (47% of theory)
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([Cl:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1c[nH]c2ncc(Br)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Cl)c2nc(Br)cnc21
Reaction time: 0.5 h
Yield: 79 %

Procedure:
impure 2-Bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine was dissolved in DMF (30 mL). NaH (60%, 436 mg, 10.9 mmol) was added slowly. After the addition was complete stirring was continued for 30 minutes at RT. (2-Chloromethoxy-ethyl)-trimethyl-silane (1.9 mL, 10.9 mmol) was added and the reaction mixture was allowed to warm up overnight. The reaction was quenched with H2O. The aqueous layer was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (24 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 2.62 g of 2-bromo-7-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine as a yellow liquid (79% yield for 2 steps).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5]([NH:16][CH3:17])=[N:4][CH:3]=1.[Cu][C:19]#[N:20]>CN1C(=O)CCC1.C(OCC)(=O)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:2]([C:19]#[N:20])=[CH:3][N:4]=[C:5]([NH:16][CH3:17])[C:6]=3[C:14]=2[CH:13]=1
Reactant: N#C[Cu]
Reactant: CNc1ncc(Br)c2[nH]c3ccc(F)cc3c12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CNc1ncc(C#N)c2[nH]c3ccc(F)cc3c12
Temperature: 225 °C

Procedure:
4-Bromo-8-fluoro-N-methyl-5H-pyrido[4,3-b]indol-1-amine (150 mg, 0.501 mmol) was combined with copper(I) cyanide (114 mg, 1.275 mmol) and dissolved in NMP (2.55 mL). The reaction was heated to 225° C. in a microwave for one hr. The solution was cooled to ambient temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified on silica gel (EtOAc/hexanes).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][CH:9]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>CS(C)=O.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Fc1cccc(Br)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Brc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an amount of 400 mg of imidazole was dissolved in 7.5 ml of dimethyl sulfoxide under argon atmosphere, added with 255 mg of 60% sodium hydride, and stirred at room temperature. After 1 hour, the reaction mixture was added with 0.8 ml of 3-bromofluorobenzene, and stirred at 140° C. for 21 hours. The reaction mixture was diluted with 50 ml of ethyl acetate, and washed with 20 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate (3:1 to 1:1)) to obtain 1.1 g of the title compound.
Reaction SMILES: [CH2:1](Br)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH2:12]([N:14]([CH2:26][CH3:27])[C:15](=[O:25])[C:16]1[CH:24]=[CH:23][C:21]([OH:22])=[C:18]([O:19][CH3:20])[CH:17]=1)[CH3:13]>>[CH2:1]([O:22][C:21]1[CH:23]=[CH:24][C:16]([C:15]([N:14]([CH2:26][CH3:27])[CH2:12][CH3:13])=[O:25])=[CH:17][C:18]=1[O:19][CH3:20])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: CCN(CC)C(=O)c1ccc(O)c(OC)c1
Product: CCN(CC)C(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)c(OC)c1

Procedure:
geranyl bromide was reacted with vanillic acid N,N-diethyl amide to obtain p-geranyloxy-m-methoxy-N,N-diethyl-benzamide (boiling point = 180°/0.05 mmHg);
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7]([O:9]C)=[O:8])[C@H:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[OH-].[Na+]>CO>[CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[C@H:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:3]1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C1C[C@@H](C(=O)O)[C@H](c2ccccc2)C1
Temperature: 65 °C

Procedure:
To a solution of methyl (+−)-trans-4-methylene-2-phenylcyclopentanoate prepared as in Example 20, Step A (28.4 g, 131 mmol) in methanol (400 mL) was added 5N sodium hydroxide (131 mL, 656 mmol). The reaction was heated at 65° C. for 1 h then cooled and concentrated. The residue was taken up diluted with water, acidified with 2M hydrochloric acid and extracted twice with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo to give the crude title acid (27.2 g) which was used directly in Step B.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:16]2[CH2:17][CH2:18][N:13]([CH2:11][CH3:12])[CH2:14][CH2:15]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2cccc(Cl)c2C=O)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of 2-chloro-6-fluorobenzaldehyde (5.0 g, 31.5 mmol), 1-ethylpiperazine (8.0 mL, 63.0 mmol), and potassium carbonate (5.0 g, 36.2 mmol) in anhydrous DMF (30 mL) was stirred at 90° C. overnight. DMF was evaporated. The viscous mixture was poured in water (200 mL). The mixture was extracted with diethyl ether (3×100 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 2-chloro-6-(4-ethylpiperazin-1-yl)benzaldehyde (7.4 g, 93% yield). The product was used without further purification.