Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1>C1C=CC=CC=1.C(OCC)C>[C:3]([O:7][C:6]([C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)=[O:8])([CH3:6])([CH3:4])[CH3:2]
Reactant: O=C(O)c1cc[nH]c1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1cc[nH]c1

Procedure:
0.50 g (4.50 mmol) pyrrole-3-carboxylic acid is suspended in 15 ml absolute benzene and boiled under reflux. A solution 4.07 g (18.0 mmol) 90% N,N-dimethylformamidedi-tert-butylacetal in 15 ml absolute benzene is added drop-wise within 30 min. Following another heating under reflux for 30 minutes and subsequent cooling, the reaction mixture is diluted with diethyl ether, washed with 5% sodium carbonate solution and saturated NaCl solution. Drying on sodium sulfate, filtration and concentration on the rotary evaporator leave as a crude product a yellow solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the product as a white solid.
Reaction SMILES: C(S([C:11]1[N:16]=[C:15]2[N:17]([CH2:29][C:30]3[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])[C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Br:27])[CH2:20][C:14]2=[CH:13][N:12]=1)(=O)=O)C1C=CC=CC=1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[NH:40]([C:11]1[N:16]=[C:15]2[N:17]([CH2:29][C:30]3[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])[C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Br:27])[CH2:20][C:14]2=[CH:13][N:12]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)c1cccc(CN2C(=O)N(c3ccccc3Br)Cc3cnc(S(=O)(=O)Cc4ccccc4)nc32)c1
Reactant: Nc1ccccc1
Product: COC(=O)c1cccc(CN2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 100 °C
Yield: 20 %

Procedure:
A mixture of 0.655 g (1.1 mmol) of methyl 3-[[7-benzylsulfonyl-3-(2-bromophenyl)-1,2,3,4-tetrahydro-2-oxopyrimido[4,5-d]pyrimidin-1-yl]methyl]benzoate and 0.55 ml (6 mmol) of aniline was heated at 100° C. for 2 hours. The reaction mixture was partitioned between dichloromethane(10 ml) and 2M hydrochloric acid (10 ml) and the dichloromethane layer separated, washed with saturated aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel using 1:1 ethyl acetate/hexane as the eluent. Product containing fractions were combined and evaporated to give 120 mg (20%) of methyl 3-[[7-anilino-3-(2-bromophenyl)-1,2,3,4-tetrahydro-2-oxopyrimido[4,5-d]pyrimidin-1-yl]methyl]benzoate as a white solid of melting point 79-82° C. [Mass spectrum (ESI) MH+ =546].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([O:28]C)=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([OH:28])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2-n2c(C)nnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Reaction time: 5 h
Yield: 98 %

Procedure:
To a solution of methyl [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate (for a preparation see Reference compound G)(7.4 g, 18.1 mmol) in THF (130 mL) at room temperature was added 1N NaOH (36.2 mL, 36.2 mmol). The reaction mixture was stirred at this temperature for 5 h before being quenched with 1N HCl (36.2 mL) and concentrated in vacuo. Water is then added and the aqueous layer was extracted with DCM (×3) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (7 g, 98% yield) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N#Cc1ccc(Br)cn1
Product: N#Cc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (710 mg, 2.0 mmol) and commercially available 5-bromo-2-cyano-pyridine (366 mg, 2.0 mmol) according to general procedure II. Obtained as an orange solid (730 mg, 80%). MS (EI) 457.1 [(M)+]; mp 212° C.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH2:24][CH2:23]3)[N:12]=[C:13]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)[C:6]=12.C1(C)C=CC(S([CH2:44][N+:45]#[C-:46])(=O)=O)=CC=1.O>CO>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C@@H:25]2[CH2:26][CH2:27][C@H:22]([N:11]3[C:7]4=[N:8][CH:9]=[N:10][C:5]([NH2:4])=[C:6]4[C:13]([C:14]4[CH:21]=[CH:20][C:17]([C:18]5[O:19][CH:46]=[N:45][CH:44]=5)=[CH:16][CH:15]=4)=[N:12]3)[CH2:23][CH2:24]2)[CH2:33][CH2:32]1
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(C=O)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(-c5cnco5)cc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
Sodium methoxide (130 mg, 2.41 mmol) was added in portions to a mixture of 4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzaldehyde (300 mg, 0.715 mmol) in methanol (20 mL). After 5 minutes, (p-tolylsulfonyl)methyl isocyanide (tosmic) (167 mg, 0.858 mmol) was added in portions. The solution was heated at reflux for 5 hours. Water (10 mL) was added while it was still hot. After cooling on ice for 5 minutes, the solid was filtered and washed with a mixture of methanol/water (50/50, 2 mL) then dried. The filtrate was evaporated to remove organic solvent and the solid was collected and washed with water. The combined solid was first purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase then re-crystallized twice from DMF to give cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(1,3-oxazol-5-yl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 27%). 1H NMR (DMSO-d6) δ 1.61 (m, 2H), 1.71 (m, 2H), 2.10 (m, 2H), 2.15 (s, 3H), 2.44 (m, 1H), 4.82 (m, 1H), 7.78 (m, 3H), 7.79 (m, 2H), 8.24 (s, 1H), 8.51 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=459.2, Rt 0.72 nm.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH2:1]([O:5][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Br:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: O=C(Cl)CCCCCBr
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCOC(=O)CCCCCBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled, stirred solution of 39 g (0.52 mol) of butanol and 42 g (0.52 mol) of pyridine in 550 mL of ether was added dropwise 100 g (0.47 mol) of 6-bromohexanoylchloride. The reaction mixture was stirred for 1 hour and then filtered. The filtrate was washed with water, 5% NaHCO3, and again with water. The organic layer was dried (MgSO4), the solvent was removed by rotary evaporation, and the residue was distilled at reduced pressure, bp 120°-125° C. (0.1 mm). A colorless oil was obtained, mass 111 g (94%).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][N:5]=1)[CH3:2].[CH3:15][NH:16][NH2:17]>C(O)C>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:12])[N:16]([CH3:15])[NH2:17])=[CH:6][N:5]=1)[CH3:14]
Reactant: CNN
Reactant: CCN(CC)c1ccc(N=C=S)cn1
Solvent: CCO
Product: CCN(CC)c1ccc(NC(=S)N(C)N)cn1

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 3.5 g (0.017 mole) of (2-diethylaminopyridin-5-yl) isothiocyanate with 0.86 (0.019 mole) of methylhydrazine in 150 ml of ethanol yielded 2.5 g of 4-(2-diethylaminopyridin-5-yl)-2-methyl-3-thiosemicarbazide as a solid, mp 147°-149° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>COCCOC>[F:18][C:12]1[CH:13]=[C:14]([I:17])[CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=[C:2]2[C:7]=1[CH:8]=[N:23][NH:24]2
Reactant: O=Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccc(I)cc1F
Reactant: NN
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Reaction time: 18 h
Yield: 98 %

Procedure:
To a stirred solution of 6-fluoro-2-(2-fluoro-4-iodo-phenylamino)-3-nitro-benzaldehyde (864 mg, 2.14 mmol) in DME (15 ml) was slowly added hydrazine hydrate (10 mL) at room temperature and the reaction mixture stirred for 18 hours. The organic solvent was removed in vacuo and the mixture diluted with water (50 mL). The resulting solid was collected by filtration, washed with water and dried under vacuum to yield the title compound (839 mg, 98%). LCMS (Method B): RT=3.61 min, [M+H]+=399.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C@H:15]([C:17](=[O:24])[CH2:18][C:19](OCC)=[O:20])[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:31]O.Cl>CO.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C@H:15]([C:17]3[O:24][NH:31][C:19](=[O:20])[CH:18]=3)[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(C)(C)C)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
Trans-methyl 2-(4-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.09 g, 2.80 mmol) was dissolved in MeOH (10 mL) and cooled to −40° C. Sodium hydroxide (0.112 g, 2.80 mmol) dissolved in water (1.2 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then, hydroxylamine (50% in water, 0.178 mL, 2.91 mmol) was added over 1 min and stirring continued at −40° C. for 3 h. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(4-tert-butylphenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (910 mg, 90%) was isolated as off-white foam. 1H NMR (400 MHz, cdcl3) δ 1.32 (s, 9H), 1.46-2.23 (m, 3H), 2.46-3.05 (m, 3H), 3.74 (s, 3H), 3.98-4.43 (m, 1H), 5.48-5.72 (m, 2H), 7.10-7.22 (m, 2H), 7.35-7.45 (m, 2H). MS m/z 359 (M+H)+
Reaction SMILES: [NH4+].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9])#[N:3].Cl>>[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[N:3]
Reactant: N#CCCCCC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Product: N#CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A 200-mL portion of the filtrate of the product mixture described above, containing the 5-cyanopentanoic acid ammonium salt (1.13M), was adjusted to pH 2.5 with 6 N HCl, then saturated with sodium chloride and extracted with 4×200 mL of ethyl ether. The combined ether extracts were dried over magnesium sulfate, filtered, and the solvent removed by rotary evaporation at reduced pressure. Remaining ether was removed by stirring the colorless liquid at room temperature under high vacuum (60 millitorr) for 5 h to yield 27.32 g (95% isolated yield) of 5-cyanopentanoic acid. The 5-cyanopentanoic acid was then distilled under vacuum (75 millitorr) at 110-112° C. without decomposition.
Reaction SMILES: [ClH:1].[C:2]([O:5][C@H:6]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(OC(C)(C)C)=O)=[CH:17][CH:16]=2)[N:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@H:7]1[C:36]1[CH:41]=[CH:40][C:39]([NH:42]C(OC(C)(C)C)=O)=[CH:38][CH:37]=1)(=[O:4])[CH3:3].CCOCC>O1CCOCC1>[ClH:1].[ClH:1].[C:12]([O:11][C@H:10]1[C@H:6]([O:5][C:2](=[O:4])[CH3:3])[C@H:7]([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[CH:40][CH:41]=2)[N:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](c2ccc(NC(=O)OC(C)(C)C)cc2)N(c2ccc(F)cc2)[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](c2ccc(N)cc2)N(c2ccc(F)cc2)[C@H]1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 4 N hydrogen chloride in dioxane (8 mL) was treated with the compound of Example 70B (136 mg, 0.21 mmol) followed by stirring at RT for 2 h. (During this time, the mono-deprotection product started precipitating, and ca. 4 mL of dichloromethane was added to speed the reaction by solublizing the mono-hydrochloride) The mixture was added to excess ether and the product collected by filtration and washed with ether. After drying in a vacuum oven at 50° C. for 18 h, these procedures afforded the title compound (92 mg, 84%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (m, 8 H), 6.81 (t, J=8.9 Hz, 2 H), 6.33 (m, 2 H), 5.63 (m, 2 H), 5.51 (dd, J=5.5, 1.9 Hz, 2 H), 1.79 (s, 6 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH2:34]([N:36](CC)[CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][C:42]=1[F:48])C>>[NH2:45][C:44]1[CH:46]=[CH:47][C:41]([O:40][CH2:39][CH2:38][CH2:37][N:36]([CH3:34])[C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]5[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=5[F:31])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[C:42]([F:48])[CH:43]=1
Reactant: CCN(CC)CCCOc1ccc(N)cc1F
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: CN(CCCOc1ccc(N)cc1F)c1nccc(-c2c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn3ccccc23)n1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo-[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-{[3-(diethylamino)-propyl]oxy}-3-fluoroaniline in a manner analogous to Example 27, Step D. HRMS calcd for C37H34F3N7O2: 665.2726; found: 666.2804 (M+H+).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>COCCOC>[Cl:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccccc1Cl
Yield: 80.2 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (60 mg, 0.147 mmol) in DME (3 ml)/2M Na2CO3 (256 uL, 0.513 mmol) was treated with 3-chlorophenylboronic acid (34 mg, 0.219 mmol) and Pd[PPh3]4 (34 mg, 0.029 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white crystalline solid (52 mg, 80%). LC-MS m/e 441.24 (M+H+)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18](=[O:19])[N:20]([CH3:22])[CH3:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CN(C)C(=O)CCl
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (2 g, 10 mmol), 2-chloro-N,N-dimethylacetamide (1.33 g, 11 mmol) and cesium carbonate (9.8 g, 30 mmol) ) in dimethylformamide (20 mL) was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate (150 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 1.4 g of 5-dimethylcarbamoylmethoxy-1H-indole-2-carboxylic acid ethyl ester as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[C:13](=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:27])[N:6]=1)[CH2:3][CH3:4].Cl[C:29]1[C:30]2[CH:37]=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:32]1[C:31]2[NH:35][CH:36]=[CH:37][C:30]=2[C:29]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:23])[F:24])[CH:16]=3)[C:13](=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:27])[N:6]=2)[CH2:3][CH3:4])=[N:34][CH:33]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 38.3 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (38 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (18 mg, 0.12 mmol, 1.2 equiv) and diisopropylethylamine (35 μL, 0.20 mmol, 2.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 19 mg of the title compound (38% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH2:33][OH:34])[CH:24]=[C:25]([S:27]([F:32])([F:31])([F:30])([F:29])[F:28])[CH:26]=1)([O-])=O>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:18][C:21]2[CH:22]=[C:23]([CH2:33][OH:34])[CH:24]=[C:25]([S:27]([F:32])([F:28])([F:29])([F:30])[F:31])[CH:26]=2)=[N:3][CH:4]=1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: O=[N+]([O-])c1cc(CO)cc(S(F)(F)(F)(F)F)c1
Product: COc1cc(F)ccc1-c1nc(Nc2cc(CO)cc(S(F)(F)(F)(F)F)c2)ncc1F

Procedure:
Intermediate 60.4 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and [3-nitro-5-(pentafluoro-λ6-sulfanyl)phenyl]methanol. The batch was purified by chromatography (DCM/EtOH 9:1) to give the desired product.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:19])[CH:8]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[F:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:21][NH2:22])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: NN
Reactant: Fc1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc(F)ccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-6-fluoro-4-(o-chlorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 6-fluoro-4-(o-chlorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([CH:17]=3)[NH2:16])[N:10]=2)[CH:7]=1.C(#N)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:20])([F:19])[F:21])=[C:15]([NH:16][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[CH:17]=3)[N:10]=2)[CH:7]=1
Reactant: Nc1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
A 20 mL vial is charged with 5-(6-chloroimidazo[1,2-a]pyrazin-2-yl)-2-(trifluoromethyl)aniline (0.813 g, 2.6 mmol), acetonitrile (14 mL) and pyridine (0.420 mL). The mixture is added trimethylacetyl chloride (0.640 mL, 5.2 mmol) and stirred for 20 min at 80° C. The acetonitrile solution is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (256 mg, 25% yield). LCMS m/z=397.5 [M+H]+, tR=2.62 min. (compound same as Example 85)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=3)[CH:4]=[N:3]1.S(Cl)(Cl)=O.[CH3:25]O>>[CH3:25][O:19][C:18](=[O:20])[CH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[CH:16]2
Reactant: Cn1cc(-c2cnc3ccc(CC(=O)O)cc3c2)cn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc2ncc(-c3cnn(C)c3)cc2c1
Temperature: 60 °C

Procedure:
To a solution of [3-(1-methyl-1H-pyrazole-4-yl)-quinolin-6-yl]-acetic acid (2.4 g, 8.6 mmols) and methanol (12 mL) at 0° C. was added thionyl chloride (2 eq., 17.2 mmols) in a dropwise fashion. The reaction mixture was then heated to 60° C. for one hour. The solvent was removed under vacuum and used in the next step without further purification. MS m/z: 282 (M+H+).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32].[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:52](O)=[O:53])(=[O:50])[CH3:49]>>[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:52]([NH:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32])=[O:53])(=[O:50])[CH3:49]
Reactant: Cc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1
Reactant: CCCCCC(C(C)=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O

Procedure:
The amount of 2-acetylheptanoic acid in dichloromethane from Example 17A is reacted analogously to Example 23A with 680 mg (5.0 mmol) of 1-hydroxy-1H-benzotriazole, 1.52 g (15.0 mmol) of 4-methylmorpholine, 960 mg (5.0 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 1.22 g (5.00 mmol) of 6-(1-aminoethyl)-3-(4-methylbenzyl)-1,2,4-triazin-5(4H)-one (Example 8A) to give 2-acetyl-N-{1-[3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}heptanamide.