Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C1CCC(c2cccnc2F)CC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
4-(2-Fluoropyridin-3-yl)cyclohexanone (0.05 g, 0.26 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.19 g, 0.78 mmol), and cesium carbonate (0.25 g, 0.78 mmol) were mixed in NMP (1 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 140° C. for 48 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was partially purified by silica gel chromatography. The impure product was then dissolved in a minimal amount of DCM, and hexanes were added until a precipitate formed. The resulting suspension was partially concentrated and filtered to give 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 412.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9](O)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.Cl.[CH:33]1([N:36]2[CH2:41][C:40]3([CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[O:39][CH2:38][C:37]2=[O:47])[CH2:35][CH2:34]1>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([N:44]2[CH2:45][CH2:46][C:40]3([O:39][CH2:38][C:37](=[O:47])[N:36]([CH:33]4[CH2:34][CH2:35]4)[CH2:41]3)[CH2:42][CH2:43]2)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Reactant: NC(=O)C(O)c1c(F)cc(Br)cc1F
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)C(c1c(F)cc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 40 °C
Reaction time: 3 h
Yield: 16.1 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-hydroxyacetamide (4.56 g, 17.1 mmol) and triethylamine (7.17 mL, 51.4 mmol) in anhydrous acetonitrile (25 mL) was added neat methanesulfonyl chloride (1.7 mL, 22.3 mmol). The reaction mixture was stirred vigorously at 40° C. for 3 h, at which point the reaction had proceeded to completion. To the mesylate intermediate was added more triethylamine (7.2 mL, 51.4 mmol) followed by 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (4.23 g, 17.1 mmol). The reaction was heated at 90° C. for 3 h until starting material was consumed. The reaction was diluted with water (25 mL) then the phases were separated and the aqueous phase was extracted with ether (3×25 mL). The combined ether phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (65-100% of 10% methanol in dichloromethane:dichloromethane) provided the title product (1.26 g, 16% yield). MS(ES)+ m/e 458 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.59-0.69 (m, 2 H) 0.75-0.86 (m, 2 H) 1.61-1.74 (m, 2 H) 1.85-1.95 (m, 2 H) 2.21 (s, 1 H) 2.53-2.64 (m, 2 H) 2.66-2.76 (m, 3 H) 2.79 (br. s., 1 H) 3.96 (s, 2 H) 4.68 (s, 1 H) 5.64 (br. s., 1 H) 7.16-7.26 (m, 2 H) 7.35 (br. s., 1 H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:8][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:9][CH2:10][CH2:11][CH2:12]2
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1)CCCN2
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.5 %

Procedure:
NBS (28 g, 158 mmol) was added to a solution of 1,2,3,4-tetrahydroquinoline (20 g, 150.16 mmol) in carbon tetrachloride (200 mL). The resulting solution was stirred for 3 h at 0° C., extracted with dichloromethane (3×50 mL) and concentrated in vacuo to give a residue, which was applied onto a silica gel column with 1% ethyl acetate in petroleum ether to give 6-bromo-1,2,3,4-tetrahydroquinoline as a yellow solid (11 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:34][CH2:35][CH3:36].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:34][CH2:35][CH3:36])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: CCCI
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A suspension of 0.50 g of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5, potassium carbonate (0.76 g), and 1-iodopropane (0.47 g) in DMF is heated to 100° C. for 6 hrs and stirred at room temperature overnight. The reaction mixture is filtered, and the solvent is evaporated at reduced pressure leaving a light brown solid. The solid is stirred with ethyl acetate for an hour and filtered. The solvent is evaporated from the filtrate under reduced pressure, leaving 0.12 g of the title compound as a yellowish-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:18](O)([CH3:20])[CH3:19])[CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH3:9].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][C:2]([CH3:23])([CH3:22])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([C:18]([CH3:20])=[CH2:19])[CH:12]=1)[CH3:9]
Reactant: Cc1cc(CN(C)C/C=C/C#CC(C)(C)C)cc(C(C)(C)O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)c1cc(C)cc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 52 %

Procedure:
Compound 17 (1.08 g; 3.45 mmol) was dissolved in pyridine (50 ml). While the solution was stirred at room temperature, phosphorus oxychloride (5.28 g; 34.5 mmol) was added dropwise. The mixture was heated for 2.5 hours at 100° C. while being stirred, and left to cool to room temperature. The mixture was poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 ml×2) and with saturated brine (×1), and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.53 g of the target compound (yield: 52.0%).
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].Br[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:37]1[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])=[C:30]2[C:34]([NH:33][CH:32]=[N:31]2)=[N:35][CH:36]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 38.2 %

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 6-bromo-9H-purine (24 mg, 0.12 mmol, 1.2 equiv) and diisopropylethylamine (35 μL, 0.20 mmol, 2.0 equiv). After stirring for 24 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: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].C(O)(=O)C>CCCCCC>[C:2]1([NH:1][CH2:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Nc1ccccc1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)CCNc1ccccc1

Procedure:
A mixture of 20 ml of aniline, 22 ml of methyl acrylate and 2 ml of acetic acid is refluxed for 8 hours. After concentrating the reaction mixture under vacuum, the resulting oil is distilled off under reduced pressure (b.p.=132° C. at 333.3 Pa and then b.p.=110° C. at 6.66 Pa). The product obtained is taken up in hexane and the precipitate formed is filtered off by suction. 25 g of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:35][C:11]3[C:12](=[O:34])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@@H:24](OS(C)(=O)=O)[CH2:23]5)=[C:18]([O:32][CH3:33])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:36][NH:37][CH3:38]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:35][C:11]3[C:12](=[O:34])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@H:24]([N:37]([CH3:38])[CH3:36])[CH2:23]5)=[C:18]([O:32][CH3:33])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CNC
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N1CC[C@@H](OS(C)(=O)=O)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N1CC[C@H](N(C)C)C1
Temperature: 75 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Dissolve methanesulfonic acid (R)-1-{4-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-phenyl}-pyrrolidin-3-yl ester (0.504 g, 0.952 mmol) in 2 M dimethylamine in THF (10 mL). Stir the mixture at 75° C. overnight in a sealed pressure tube. Dilute the mixture with EtOAc (50 mL) and wash with saturated NaHCO3 (2×20 mL) and brine (20 mL). Dry the solution with Na2SO4, filter, and concentrate. Purify the crude material by chromatograghy, eluting with 2% NH3—H2O/50% CH3OH/EtOAc to give 0.293 g (64%) of 2-(4-chloro-phenyl)-6-[4-((S)-3-dimethylamino-pyrrolidin-1-yl)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])=[CH:15][CH:14]=1)[OH:12]>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:41])([CH3:42])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])=[CH:17][CH:18]=1)[OH:12]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
Trifluoroacetic acid (0.05 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-4-yl]-hydroxy-acetic acid methyl ester (Example 154-(2); 7.0 mg, 0.011 mmol) in dichloromethane (0.28 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 to 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (5.0 mg, 86%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[CH:31]1([CH2:30][NH:29][S:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:2]3[N:7]=[C:6]([N:8]4[C:17]5[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=5)[CH2:11][CH2:10][CH2:9]4)[CH:5]=[CH:4][N:3]=3)=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH2:32][CH2:33]1
Reactant: Nc1ccc(S(=O)(=O)NCC2CC2)cc1
Reactant: Oc1ccc2c(c1)CCCN2c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: O=S(=O)(NCC1CC1)c1ccc(Nc2nccc(N3CCCc4cc(O)ccc43)n2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
The reaction flask containing 2,4-dichloropyrimidine (372 mg, 2.5 mmol), 6-methoxy-1,2,3,4-tetrahydroquinoline (489 mg, 3 mmol) and diisopropylethylamine (0.52 mL, 3 mmol) in n-butanol (10 mL) was heated at 40° C. overnight. The solvent was evaporated, and the residue was purified by flash column chromatography to give 2-Chloro-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (551 mg, 80%). This intermediate (250 mg, 0.91 mmol) was then dissolved in dichloromethane and treated with BBr3 (1 M in dichloromethane) (1 mL, 1 mmol) at −78° C. The reaction mixture was slowly warmed up to room temperature and stirred for 1 hr, poured into water, extracted with dichloromethane. The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography to give 2-Chloro-4-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (154 mg, 65%). To a stirred solution of 2-chloro-4-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (29 mg, 0.11 mmol) and 4-amino-N-(cyclopropylmethyl)benzenesulfonamide (27 mg, 0.12 mmol) in DMF (0.5 mL) was added p-toluenesulfonic acid (2 M in dioxane) (55 μL, 0.11 mmol). The reaction mixture was stirred at 90° C. overnight, then purified by HPLC to give the title compound (27 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)=[C:10]2[C:27]([O:29]CC)=[O:28])=[CH:5][CH:4]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 56 h
Yield: 106 %

Procedure:
To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.72 g, 1.7 mmol) in EtOH (30 ml) was added 10% palladium on activated carbon (1 g). The resulting suspension was stirred under an atmosphere of H2 for 56 h and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid (0.70 g, 95%), which was used without-further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[CH3:20][N:21]=[C:22]=[O:23]>CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH:15][C:22]([NH:21][CH3:20])=[O:23])=[O:13]
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CN=C=O
Solvent: CO
Product: CNC(=O)NNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
To a suspension of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinohydrazide (200 mg; 0.54 mmol) in methanol (10 mL) was added (methylimino)(oxo)methane (61 mg; 1.07 mmol) (methyl Isocyanate). After few minutes the reaction mixture became homogeneous, and then an yellow colored solid, 2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-N-methylhydrazinecarboxamide (50 mg) was separated out. The filtrate upon concentration gave 158 mg which was also pure. (208 mg, 90%) MS m/z: 429 M+1
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:24][C:21]([F:22])([F:23])[C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc2cccc(C(F)(F)F)c2o1
Product: FC(F)(F)c1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 52.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (77 mg, 0.38 mmol) and 2-(but-3-ynyl)-7-(trifluoromethyl)benzo[d]oxazole (90 mg, 0.38 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1 to DCM/MeOH 99:1) to yield 63 mg (0.20 mmol, 53%) of 7-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[N:12][C:11]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9](=[O:23])[N:8]3[N:24]=[CH:25][N:26]=[C:7]3[C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:27][C@@H:28]1[O:33][C@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(#N)C>[CH3:27][C@H:28]1[CH2:29][N:30]([CH:1]([C:4]2[CH:13]=[N:12][C:11]3[N:10]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:9](=[O:23])[N:8]4[N:24]=[CH:25][N:26]=[C:7]4[C:6]=3[CH:5]=2)[CH3:2])[CH2:31][C@@H:32]([CH3:34])[O:33]1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(C)=O)cnc32)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(C)N4C[C@@H](C)O[C@@H](C)C4)cnc32)cc1
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
9-Acetyl-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 81, 67 mg, 0.19 mmol), (2S,6R)-2,6-dimethylmorpholine (0.060 mL, 0.49 mmol), ACN (1 mL) and acetic acid (0.020 mL, 0.35 mmol) were combined and stirred for 10 minutes. Sodium cyanoborohydride (18 mg, 0.29 mmol) was added and the mixture was stirred for 3 days at 50° C. The mixture was filtered. Purification (HPLC, 10-65% ACN in water) afforded the title compound (26 mg, 23%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.19 (d, J=6.27 Hz, 3H), 1.23 (d, J=6.27 Hz, 3H), 1.92 (d, J=7.03 Hz, 3H), 2.34 (td, J=11.01, 2.32 Hz, 2H), 3.32 (d, J=11.42 Hz, 1H), 3.57 (d, J=11.42 Hz, 1H), 3.77 (s, 3H), 4.12 (d, J=7.03 Hz, 2H), 4.54 (q, J=6.86 Hz, 1H), 5.75 (s, 2H), 6.85 (d, J=8.66 Hz, 2H), 7.62 (d, J=8.66 Hz, 2H), 8.40 (s, 1H), 8.74 (s, 1H), 8.95 (s, 1H). [M+H]=449.3.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:2]([C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(O)c2ncccc12
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCc2ccccc2)c2ncccc12
Reaction time: 4.5 h
Yield: 57.1 %

Procedure:
27 g of 5-acetyl-8-hydroxyquinoline hydrochloride are dissolved in 540 ml of anhydrous dimethylformamide and 50 g of powdered potassium carbonate are added thereto. 18.4 g of benzyl chloride are added to the mixture at 50° C. under an argon atmosphere, and the mixture is stirred at the same temperature for 4.5 hours and then further stirred at room temperature for 1.5 hours. After the reaction, water is added to the mixture, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, a saturated sodium chloride solution, dried and then evaporated under reduced pressure to remove ethyl acetate. The residue is recrystallized from ethanol. 19.1 g of 5-acetyl-8-benzyloxyquinoline are obtained as brownish prisms. 6.35 g of said product are further recovered from the mother liquor.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][N:6]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:24]=1[CH3:40].Cl.O1CCOCC1.CN1C(=O)CCC1>>[CH3:1][C:2]1([CH3:21])[O:3][CH2:4][CH2:5][N:6]([C:8]2[CH:9]=[C:10]([NH:20][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][C:31]=4[F:33])[N:26]=[C:25]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)[C:24]=3[CH3:40])[C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[N:12][CH:13]=2)[CH2:7]1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: CC1(C)CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Nc1cc(N2CCOC(C)(C)C2)cnc1N1CCOCC1
Temperature: 160 °C

Procedure:
Prepared according to Procedure K, method 2 using 5-(2,2-dimethylmorpholino)-2-morpholinopyridin-3-amine (62 mg, 0.213 mmol; described herein), 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (58 mg, 0.213 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (50 μL, 0.21 mmol), and NMP (310 μL, 3.2 mmol), and heating in a microwave for 3 h at 160° C. Purification afforded N-(5-(2,2-dimethyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.70 (1H, d, J=4.7 Hz), 7.86-8.04 (4H, m), 7.54-7.66 (2H, m), 7.38 (1H, ddd, J=6.7, 4.7, 2.0 Hz), 7.19 (1H, dd, J=13.7, 7.8 Hz), 6.45 (1H, d, J=2.3 Hz), 3.93 (4H, t, J=4.3 Hz), 3.78-3.87 (2H, m), 3.02-3.31 (6H, m), 2.88 (2H, s), 2.21 (3H, s) 1.24-1.34 (6H, m). Mass Spectrum (ESI) m/e=529.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7](=[O:9])[CH3:8])[N:6]=1.[BrH:11].BrBr>C(O)(=O)C>[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7](=[O:9])[CH2:8][Br:11])[N:6]=1
Reactant: Br
Reactant: CC(=O)c1nc(C)oc1C
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1nc(C(=O)CBr)c(C)o1
Temperature: 100 °C

Procedure:
2.8 g (0.02 mol) of 2,5-Dimethyl-4-acetyl-oxazole are dissolved in 30 ml of glacial acetic acid, and 3 ml of a 35% strength solution of hydrogen bromide in glacial acetic acid are added. The mixture is heated to 100° C. and, over the course of 1 hour, a solution of 3.2 g (0.02 mol) of bromine in 10 ml of glacial acetic acid is added. After a further 2 hours the solvent is removed, and the residue is triturated with 50 ml of ether and filtered off with suction.