Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl>[CH2:33]([O:32][C:30]([N:14]1[CH2:17][CH:16]([CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)C(C(=O)OCC)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To 3.40 g (8.91 mmol) of diethyl (1-benzhydryl-3-azetidinyl)malonate dissolved in 30 ml of dichloromethane was added 1.91 ml (13.36 mmol) of benzyl chloroformate, followed by overnight stirring at room temperature. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (250 ml, 3-5% methanol-dichloromethane) to yield 2.64 g (84%) of the title compound.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:12].S(=O)=O.[Li].[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>O1CCCC1.CCOCC.C1C=CC=CC=1>[F:12][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[S:17]([Cl:20])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: Fc1cccc(C(F)(F)F)c1Br
Agent: O=S=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=S(=O)(Cl)c1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65 %

Procedure:
2-bromo-1-fluoro-3-trifluoromethylbenzene (1.0 eq.) was taken up in tetrahydrofuran (0.5 M) and diethyl ether (0.5 M) and cooled to −78° C. nbutyllithium (2.5M, 1.0 eq.) was added dropwise and the reaction stirred for 40 minutes. A volume of sulfur dioxide equal to the volume of THF was condensed and diluted with two volumes of ether. The lithium salt of the benzene was canulated into the sulfur dioxide and the reaction was allowed to slowly warm to room temperature. The solvent was removed and the resulting salt was washed with ether then taken up in hexanes (1.0M) and cooled in and ice bath. Sulfuryl chloride (1.06 eq.) was added and the reaction warmed to room temperature and stirred for 5 hours. The solvent was removed to give 2-fluoro-6-trifluoromethylbenzenesulfonyl chloride as a white, oily solid in 65% yield. The product was used crude. 1H NMR (400 MHz, DMSO-D6) □ ppm 7.46 (m, 1H), 7.52 (m, 2H).
Reaction SMILES: [CH2:1]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl>>[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]1=[O:16]
Reactant: CCCCCCn1c(=O)[nH]c2ccccc21
Reactant: ClCCCCCl
Product: CCCCCCn1c(=O)n(CCCCCl)c2ccccc21

Procedure:
The compound may be prepared according to the procedure described in J. Het. Chem. 18, 85 (1981) from 3-n-hexyl-2,3-dihydro-1H-benzimidazol-2-one and 1,4-dichlorobutane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[CH:15]1(/[CH:20]=[N:21]/[S@@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(Cl)Cl.C1COCC1>[CH:15]1([C@@H:20]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[NH:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)[S@@](=O)/N=C/C1CCCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N[C@H](c1ccccn1)C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
A solution of 2-bromopyridine (11.8 mL, 19.5 g, 123.5 mmolin dry THF (50 mL) was added carefully to i-PrMgCl.LiCl (1.3 M in THF, 95.0 mL, 123.5 mmol). The resulting solution was stirred at rt for 3 h after which it was added dropwise, over 45 min, to a −48° C. solution of (R,E)-N-(cyclopentylmethylene)-2-methylpropane-2-sulfinamide (19.1 g, 95.0 mmol) in dry CH2Cl2 (250 mL). The resulting mixture was stirred at −48° C. for 1 h before being allowed to slowly warm up to rt over 16 h. The reaction was quenched by addition of saturated aq NH4Cl (200 mL). H2O (200 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine (150 mL). The organic layer was dried (Na2SO4) and was concentrated under reduced pressure yielding the crude product (28.6 g, 5:1 d.r. (RS,S)—(RS,R)) as a clear red oil. The crude product was purified by repeated flash chromatography on silica gel using 1:19 MeOH-EtOAc as eluent in combination with trituration of the obtained solids with cyclohexane which eventually gave the pure product (8.80 g, 33%) as a white solid; 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (d, J=4.5 Hz, 1H), 7.63 (dt, J=1.0, 7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.16 (dd, J=4.5, 7.5 Hz, 1H), 4.26 (dd, J=5.0, 8.5 Hz, 1H), 3.95 (d, J=5.0 Hz, 1H), 2.44-2.31 (m, 1H), 1.94-1.83 (m, 1H), 1.68-1.44 (m, 5H), 1.44-1.32 (m, 1H), 1.30-1.17 (m, 1H), 1.13 (s, 9H).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1.N1C=CC=CC=1>C1C=CC=CC=1>[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([Cl:3])=[O:15])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(F)ccc1C(=O)c1ccccc1C(=O)O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1cc(F)ccc1C(=O)c1ccccc1C(=O)Cl

Procedure:
Thionyl chloride (1.5 ml) was added to a solution of 2-(4-fluoro-2-methoxybenzoyl)benzoic acid (mp 119°-120° C.) (3.66 g) and pyridine (0.03 ml) in benzene (50 ml), followed by refluxing for an hour. The solvent was distilled off to give 2-(4-fluoro-2-methoxybenzoyl)benzoyl chloride (IRνmaxNujol : 1795 cm-1). A solution of this product in methylene chloride (40 ml) was added to a solution of ethyl 4-isopropylaminocrotonate (Reference Example I) (3.6 g) and triethylamine (3.0 ml) in methylene chloride (40 ml), followed by stirring at room temperature for 16 hours. After removing the solvent, ethyl acetate was added to the residue. The mixture was washed with water, dil. hydrochloric acid, water, sodium hydrogen carbonate solution and water in turn. The ethyl acetate layer was dried over anhydrous sodium sulfate and distilled to give the title compound (5.50 g) as pale brown oily substance.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][C:8]=1[C:15]#[N:16].[F:17][C:18]([F:26])([F:25])[C:19](=O)[CH2:20][C:21](=O)[CH3:22]>C(O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21]([CH3:22])=[CH:20][C:19]([C:18]([F:26])([F:25])[F:17])=[N:14]2)=[CH:9][C:8]=1[C:15]#[N:16]
Reactant: N#Cc1cc(NN)ccc1F
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1-c1ccc(F)c(C#N)c1
Yield: 55.4 %

Procedure:
To a suspension of 4-fluoro-3-cyanophenylhydrazine tin chloride (20 g, 53.6 mmol) in ethanol (150 mL) was added 1,1,1-trifluoro-2,4-pentanedione (8.18 g, 53.6 mmol). The reaction was brought to reflux overnight. The next day the ethanol was evaporated and the residue partitioned between ethyl acetate and HCl (1 N). The aqueous phase was extracted with ethyl acetate (4×20 mL). The organic phase is washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography gave 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-methylpyrazole (8 g, 56% yield) as pure compound: MS (CI): 270 (M+H)+ (100%).
Reaction SMILES: Br[C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH:11]=[CH:10][C:9](=[O:12])[CH2:8]C1)=O.C(N(CC)CC)C.[CH:25]([OH:27])=O>CN(C=O)C.C(O[Pd]OC(=O)C)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:3]2[C:2]=1[C:25](=[O:27])[N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:4]12
Reactant: O=C1C=CN(C(=O)c2cccc(Cl)c2Br)CC1
Reactant: O=CO
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCN2C(=O)c3c(Cl)cccc3C2C1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
A mixture of 1-(2-bromo-chlorobenzoyl)-2,3-dihydro-4-pyridinone (Preparation 3) (300 mg, 0.954 mmol), triethylamine (0.39 mmol, 0.54 ml), formic acid (0.05 ml, 1.3 mmol) and di(triphenylphosphine) diacetoxypalladium (47 mg, 0.063 mmol) in DMF (3 ml) was heated to 80° C. for 2 h. The cooled solution was filtered through celite, diluted with water, extracted twice with ethyl acetate, the extracts dried over sodium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound as a colourless oil (70 mg). MS (+CI) m/z 235/237 [M+H]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:30]([CH3:31])=[CH:29][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:26]([CH3:27])=[CH:25][N:24]([CH3:28])[C:21]4=[N:22][CH:23]=3)[S:17][C:13]=2[C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2N=C(C3C=C4C(C)=CNC4=NC=3)SC=2C=1C1C=CC(Cl)=CC=1)C(OC)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:30]([CH3:31])=[CH:29][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:26]([CH3:27])=[CH:25][N:24]([CH3:28])[C:21]4=[N:22][CH:23]=3)[S:17][C:13]=2[C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(c3)c(C)cn4C)sc2c1-c1ccc(Cl)cc1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4[nH]cc(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3cnc4c(c3)c(C)cn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Preparation (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetate: To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate (12 mg, 0.022 mmol) in DMF (5 mL) was added cesium carbonate (11 mg, 0.033 mmol). The reaction solution was stirred at room temperature for 5 minutes, iodomethane (4.7 mg, 0.033 mmol) was added. The reaction solution was stirred for 30 minutes and quenched with water. Volatiles were removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give crude product which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C30H30ClN3O3S: 548.17 (M+H+); Found: 548.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=O)[CH2:12]1)=[O:10].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:30][C:31]1[C:32]([C:37]([NH:39][NH2:40])=O)=[N:33][CH:34]=[CH:35][CH:36]=1.Cl>ClCCl.CO.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:37]([C:32]3[C:31]([CH3:30])=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:39][N:40]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C1CN(C(=O)c2ccc(F)cc2Cl)CCN1
Reactant: Cc1cccnc1C(=O)NN
Agent: CC[O+](CC)CC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: Cc1cccnc1-c1nnc2n1CCN(C(=O)c1ccc(F)cc1Cl)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
A solution of 4-[(2-chloro-4-fluorophenyl)carbonyl]-2-piperazinone (0.257 g, 1 mmol, e.g. prepared as described in Intermediate 2) in dry Dichloromethane (DCM) (2 ml) was stirred at room temperature under argon. Triethyloxonium tetrafluoroborate (0.190 g, 1.000 mmol) was added and the reaction solution was stirred for 3 hours. 3-Methyl-2-pyridinecarbohydrazide (0.166 g, 1.100 mmol, e.g. prepared as described in Intermediate 22) was added to the solution and stirred for 1 h. The solvent was then evaporated in vacuo and n-butanol (2.000 ml) was added to the residue. The solution was heated at reflux for 18 hours and then allowed to cool to room temperature. The solvent was then evaporated in vacuo and the residue was partitioned between Dichloromethane and brine. The organic layer was dried over sodium sulphate, filtered and the solvent was evaporated in vacuo to give a yellow solid. The solid was then purified by flash chromatography (Biotage SP4, 25+M cartridge) using a gradient of 0 to 10% MeOH/NH3 in Dichloromethane as the eluent. The solvent was then evaporated in vacuo and the remaining residue was purified by mass-directed automated (preparative) HPLC (MDAP) to yield the crude product. The product was then dissolved in methanol (2 mL) and to this was added HCl in diethyl ether (1 mL), the solvent was then evaporated in vacuo and dried in a vacuum-oven yielding 7-[(2-chloro-4-fluorophenyl)carbonyl]-3-(3-methyl-2-pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.108 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.[C:22](O)(=[O:24])[CH3:23].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:22]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)O
Reactant: NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Reaction time: 1 h
Yield: 89.8 %

Procedure:
6-(5-Aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (38 mg, 0.13 mmol), acetic acid (0.015 mL, 0.27 mmol) and triethyl amine (0.056 mL, 0.40 mmol) are mixed in 2.5 mL of acetonitrile. Then TBTU (52 mg, 0.16 mmol) is added and the mixture is stirred for 1 hrs. All the solvents are removed and the residue is first purified by flash column chromatography and then filtered through a StratoSpheres SPE cartridge (PL-HCO3 MP SPE) to remove the HOBt. The filtrate is concentrated and dried to give 38 mg of the titled product.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([O:18][CH3:19])=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[I:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([O:18][CH3:19])=[CH:11][C:12]([O:16][CH3:17])=[C:13]([NH:14][S:27]([C:24]3[CH:25]=[CH:26][C:21]([I:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH:15]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: COc1cc(OC)c(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Product: COc1cc(OC)c(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(I)cc1

Procedure:
The title compound was prepared from 5-(cis-3,5-dimethyl-1-piperazinyl)-2,4-bis(methyloxy)aniline (D25) and 4-iodobenzenesulfonyl chloride using a similar procedure to that described for Example 81. MS (ES+) m/e 532 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C4CCCCO4)[CH:19]=3)=[C:16]([CH3:31])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:32]C4CCCCO4)[CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[CH2:39]([NH:41][CH2:42][CH2:43][OH:44])[CH3:40].[F:45][C:46]([F:51])([F:50])[CH2:47][CH2:48]I>>[CH2:39]([N:41]([CH2:48][CH2:47][C:46]([F:51])([F:50])[F:45])[CH2:42][CH2:43][O:44][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)=[C:16]([CH3:31])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:32])[CH:14]=3)[O:9]2)=[CH:4][CH:3]=1)[CH3:40]
Reactant: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(I)cc2)Oc2ccc(OC3CCCCO3)cc21
Reactant: FC(F)(F)CCI
Reactant: CCNCCO
Product: CCN(CCOc1ccc(C2Oc3ccc(O)cc3C(C)=C2c2cccc(O)c2)cc1)CCC(F)(F)F

Procedure:
The title compound was synthesized as described in general procedures F, I and J (z=1) using Intermediate 3 and 2-(ethylamino)ethanol in general procedure F, and 1,1,1-trifluoro-3-iodopropane in general procedure I. 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.20 (d, 2H), 7.13 (t, 1H), 6.78 (d, 2H), 6.75-6.71 (m, 1H), 6.68 (d, 1H), 6.66-6.62 (m, 1H), 6.62-6.60 (m, 1H), 6.46 (s, 2H), 5.84 (s, 1H), 3.93 (t, 2H), 2.76 (t, 2H), 2.70 (t, 2H), 2.57-2.49 (m, 2H), 2.45-2.31 (m, 2H), 2.03 (s, 3H), 0.94 (t, 3H). LCMS: 514.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](O)=[N:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[N:7]2.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)=[N:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[N:7]2
Reactant: Oc1nc(-c2cncnc2)nc2cccc(Br)c12
Reactant: NCc1ccccn1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cccc2nc(-c3cncnc3)nc(NCc3ccccn3)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
To a stirred suspension of 5-bromo-2-(pyrimidin-5-yl)quinazolin-4-ol (2.0 g, 6.5 mmol) in DMF (20 mL) was added diisopropylethyl amine (3.4 ml, 19 mmol) followed by PyBroP (3.7 g, 7.9 mmol). After 5 min stirring at room temperature, 2-aminomethylpyridine (1.0 mL, 9.8 mmol) was added to the reaction. Upon completion of addition, the reaction mixture was warmed to 80° C. where it stirred for 2 h (during which time reaction became a clear solution). At the conclusion of this period, the reaction mixture was quenched by the addition of cold water and then extracted into 50% ethyl acetate and hexane mixture (200 mL). The organic extracts were dried, concentrated, purified by column chromatography using ethyl acetate and hexanes as eluent to yield the crude produce. The crude product was further purified by trituration with ethyl acetate and hexane to yield 5-bromo-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (0.5 g, 20% yield). 1H NMR (400 MHz, CDCl3, δ): 5.07 (d, J=4.4 Hz, 2H); 7.26 (m, 1H); 7.41 (d, J=7.6 Hz, 1H); 7.53 (t, J=8 Hz, 1H); 7.71-7.73 (m, 2H); 7.86 (dd, J=0.8 Hz, 8.4 Hz, 1H); 8.65 (d, J=4 Hz, 1H); 9.30 (s, 1H); 9.38 (br s, 1H); 9.75 (s, 2H). ES-MS: [M++1]=393 and [M++3]=395.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[Cl:38][CH2:39][C:40]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[O:41]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CCl)c3ccccc32)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.5 g) in dichloromethane (30 ml) is added triethylamine (0.96 ml) and further thereto is added dropwise chloroacetyl chloride (0.55 ml) under ice-cooling. The mixture is stirred for 5 minutes. The reaction solution is concentrated and to the resulting residue is added water. The precipitated crystal is collected by filtration, washed with water, and dried to give 5-(2-chloroacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.4 g) as white powder.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:28](=[N:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:43]=[C:42]([CH3:44])[O:41][N:40]=3)=[CH:35][CH:34]=2)[C:29]([NH2:31])=S)[CH:25]=[C:24]([CH3:45])[N:23]=1.CN([CH:49]=[O:50])C>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([CH:28]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:43]=[C:42]([CH3:44])[O:41][N:40]=3)=[CH:35][CH:34]=2)[C:29]2[NH:31][C:49](=[O:50])[N:2]([C:4]3[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=3[C:6]([OH:8])=[O:7])[N:3]=2)[CH:25]=[C:24]([CH3:45])[N:23]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: CN(C)C=O
Reactant: COc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc(C)n1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc(C)n1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
After adding 39 mg of 2-hydrazinobenzoic acid hydrochloride and 57 μl of triethylamine to a solution of 90 mg of 2-(2-methoxy-6-methylpyridin-4-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]thioacetamide (Example (19b)) in 3 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of a methanol:THF=1:1 mixed solvent. After adding 41 μl of acetic acid and 64 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 4 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 2-(3{(2-methoxy-6-methylpyridin-4-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}benzoic acid (35 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7](C=O)=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].Cl.[CH3:15][OH:16]>>[F:1][C:2]1[CH:9]=[C:8]([CH2:15][OH:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CO
Reactant: N#Cc1cc(C=O)ccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1ccc(CO)cc1F

Procedure:
To a solution of 2-fluoro-5-formylbenzonitrile (350 mg, 2.4 mmol) in methanol (11 ml), at 0° C., was added sodium borohydride (107 mg, 2.8 mmol). The reaction mixture was allowed to warm to room temperature over 1 h, before addition of hydrochloric acid (1M, 30 ml). The mixture was extracted with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (354 mg).
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[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].C1(C2[O:40][CH2:39][CH:38]([O:41][NH2:42])[CH2:37][O:36]2)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[OH:36][CH2:37][CH:38]([O:41][NH:42][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])[CH2:39][OH:40]
Reactant: NOC1COC(c2ccccc2)OC1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC(CO)CO)c(=O)n(C)c1=O
Temperature: 50 °C

Procedure:
Phenyl 6-(2-fluoro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (compound 2A, 100 mg, 0.2 mmol, 1 eq) and O-(2-phenyl-1,3-dioxan-5-yl)hydroxylamine (79 mg, 0.404 mmol, 2 eq) (see, Vonhoff et al., Helv. Chim. Acta, 81(9), 1998; 1710-1725; European Patent Application No. EP1666485) were mixed in THF and subjected to microwave irradiation at 100° C. for 45 minutes. The reaction was complete by LCMS. Upon cooling, the intended product precipitated as a tan solid. 62 mg (51%). This solid was then dissolved in methanol (2 ml) and THF (2 ml) with ethylene glycol (100 μl). p-Toluenesulfonic acid (18 mg, 1 eq) was added and the mixture heated at 50° C. for 30 minutes. Purification by HPLC chromatography afforded the title compound as a white solid. 28 mg (53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.96 (s, 3H) 3.22 (s, 3H) 3.42-3.58 (m, 4H) 4.00-4.08 (m, J=1.67, 0.78, 0.78, 0.78, 0.78 Hz, 2H) 4.75 (t, J=5.94 Hz, 2H) 5.76 (s, 1H) 7.53-7.62 (m, 1H) 7.80 (dd, J=9.73, 1.39 Hz, 1H) 11.99 (s, 1H) 12.23 (s, 1H) [M+H] calc'd for C16H18FIN4O6, 509. found, 509.