Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[S:21][CH:22]=[CH:23][N:24]=1)CCC>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2c(F)cccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2nccs2)nc2c(F)cccc2c1Cl

Procedure:
Prepared according to Procedure E using 2,4-dichloro-8-fluoro-3-methylquinoline (250 mg, 1.087 mmol), 2-tributylstannylthiazole (0.34 mL, 1.087 mmol) and tetrakis(triphenylphosphine)palladium(0) (126 mg, 0.109 mmol) in toluene (4 mL) and heating at reflux overnight. After purification 2-(4-chloro-8-fluoro-3-methylquinolin-2-yl)thiazole was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:1][N:2]([C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1
Reactant: CNc1nc(-c2ccccc2)cs1
Reactant: CCOC(=O)CCc1ccc(OCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCCCN(C)c2nc(-c3ccccc3)cs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To an ice-cooled solution of N-methyl-4-phenyl-2-thiazolamine (0.30 g, 1.7 mmol) in N,N-dimethylformamide (5 mL) was added 60% sodium hydride (72 mg, 1.8 mmol), and the mixture was stirred for 30 min. Ethyl 4-[(3-bromopropyl)oxy]benzenepropanoate (0.57 g, 1.8 mmol), was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=15:1) to give the title compound (0.58 g, yield 80%). oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[N:4]([CH2:13][CH2:14][CH3:15])[C:3]1=[O:16].[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1/[CH:22]=[CH:12]/[C:5]1[N:4]([CH2:13][CH2:14][CH3:15])[C:3](=[O:16])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=1[N+:9]([O-:11])=[O:10])[CH3:18]
Reactant: CCOc1ccccc1C=O
Reactant: CCCn1c(C)c([N+](=O)[O-])c(=O)n(C)c1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCn1c(/C=C/c2ccccc2OCC)c([N+](=O)[O-])c(=O)n(C)c1=O
Yield: 75.1 %

Procedure:
A mixture of 3,6-dimethyl-5-nitro-1-propyl-1H-pyrimidine-2,4-dione (6.25 g, 27.5 mmol), 2-ethoxybenzaldehyde (4.24 mL, 30.3 mmol), piperidine (2.83 mL, 28.6 mmol) and 3 Å molecular sieves (8.75 g) in ethanol (125 mL) was refluxed for 5 hours. The resulting suspension was filtered and the filtrate was evaporated under reduced pressure. The residue was triturated with isopropyl ether and the precipitate collected by filtration and dried under vacuum to yield 6-[(E)-2-(2-ethoxyphenyl)vinyl]-3-methyl-5-nitro-1-propyl-1H-pyrimidine-2,4-dione (7.42 g, 75%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]=[CH:22][N:23]([CH3:25])[CH3:24])=[CH:3][CH:4]=3)=[N:9][CH:10]=[N:11]2)=[CH:14][CH:15]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc(-c2ncnn2-c2ccc(F)cc2)cc1
Solvent: CO
Product: CN(C)C=Nc1ccc(-c2ncnn2-c2ccc(F)cc2)cc1

Procedure:
A solution of 5.0 g. of 5-(p-aminophenyl)-1-(p-fluorophenyl)-1H-1,2,4-triazole in 20 ml. of dimethylformamide dimethylacetal is heated to reflux for 1.5 hours while the methanol formed is collected by distillation. The reaction mixture is cooled, 15 ml. of ether is added and the mixture is cooled further, giving 5.5 g. of the desired product, mp. 159°-161° C.
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:20].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[CH3:1][C:6]([O:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:17])[C:10]=1[Cl:16])[C:7](=[O:18])[C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([CH3:19])[CH2:14]2)([CH3:14])[C:7]([OH:18])=[O:20]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1O
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)(Oc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2)C(=O)O

Procedure:
To a refluxing solution of 2-cyclopentyl-2-methyl-6,7-dichloro-1,5-indandiol (Example 5, Step C), (15.6 g., 0.05 mole) in acetone (500 ml.) in an inert atmosphere is added solid sodium hydroxide (12.6 g., 0.25 mole). Chloroform (7.6 g., 0.69 mole) in acetone (50 ml.) is added dropwise during a ten-minute period. The reaction mixture is refluxed for 5 hours, then evaporated to dryness at reduced pressure. The residue is dissolved in water, filtered and acidified with hydrochloric acid affording α,α-dimethyl-(1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.N1CCCCC1>CCO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])/[C:8]/2=[CH:20]\[C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)=[O:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2c(c1)/C(=C/c1ccc(F)cc1)C(=O)N2

Procedure:
To a solution of methyl-2-oxindole-5-carboxylate (4.764 g) in EtOH (100 mL) was added 4-fluoro-benzaldehyde (4.72 mL) in one portion, followed by piperidine (790 μL). The mixture was refluxed for 3 hours and the yellow precipitate was collected by filtration. The yellow product was used for the next step without further purification.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1)[NH2:2].Cl.[O-:11][C:12]#[N:13].[K+]>O>[F:9][C:5]1[N:4]=[C:3]([NH:1][NH:2][C:12]([NH2:13])=[O:11])[CH:8]=[CH:7][CH:6]=1
Reactant: N#C[O-]
Reactant: NNc1cccc(F)n1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NNc1cccc(F)n1
Temperature: 35 °C

Procedure:
A solution was prepared by admixing 55 g (0.43 m) of 2-hydrazino-6-fluoropyridine in 240 ml of water with 40 g of concentrated hydrochloric acid in 60 ml of water. The mixture was stirred at 35° C. until a clear solution formed. To this reaction mixture was added 37 g (0.46 m) of potassium cyanate in 100 ml of water. After the addition was completed, the reaction mixture was stirred for 21/2 hours at room temperature and then cooled to 10° C. on an ice bath. The 2-(6-fluoro-2-pyridinyl)hydrazinecarboxamide product was isolated by filtration and washed with methylene chloride in quantitative yield. The product melted at 210°-212° C. and upon analysis, was found to have carbon, hydrogen and nitrogen contents of 42.42, 4.23 and 32.83 percent, respectively, as compared with the theoretical contents of 42.35, 4.14 and 32.93 percent, respectively, as calculated for the above named compound.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].BrC1C=CC(S([O:17][C@@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)(=O)=O)=CC=1.[CH2:34]([CH:37]1[CH:46](O)[C:45]23[N:48]=[CH:49][CH:50]=[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]3[N:39]([CH3:51])[CH2:38]1)[CH:35]=[CH2:36]>CN1C(=O)CCC1.CCOC(C)=O.Cl>[CH2:34]([CH:37]1[CH:46]([O:17][C@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)[C:45]23[N:48]=[CH:49][CH:50]=[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]3[N:39]([CH3:51])[CH2:38]1)[CH:35]=[CH2:36]
Reactant: C=CCC1CN(C)C2=CC=CC3=CC=NC32C1O
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=CCC1CN(C)C2=CC=CC3=CC=NC32C1O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 44 %

Procedure:
Cs2CO3 (8.20 g, 25.20 mmol) and 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (3.80 g, 8.18 mmol) were added in sequence to a solution of 3-allyl-1-methyl-3H-pyrrolo[2,3-e]quinolin-4-ol (1.50 g, 6.29 mmol) in NMP (42 mL). The mixture was heated at 60° C. for 12 h, then cooled and diluted with EtOAc and aqueous HCl (1 N). The organic layer was separated, washed with brine and dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified on silica gel (gradient elution, 20-100% EtOAc/petrol ether) to afford the title compound (1.30 g, 44%) as a solid. LCMS (ES+) m/z 466 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].[Cl-].[NH4+]>C(OCC)C.CCCCCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=2)[OH:21])[CH:7]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Fc1cc(F)c(Br)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1cccc(F)c1)c1cc(Br)c(F)cc1F
Temperature: -70 °C

Procedure:
A total of 2.02 g of 1,5-dibromo-2,4-difluorobenzene obtained in Production Example II-5-a was dissolved in 38 ml of diethyl ether, and 4.9 ml of a 1.58 M solution of n-butyllithium in hexane was added under stirring at −70° C. After stirring for 1 hour, 4.9 ml of m-fluorobenzaldehyde was added and the mixture was stirred for 15 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extracting with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 0.96 g of the title compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[F:17][C:18]([F:52])([F:51])[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:22]=[C:21]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]3[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=3)[CH:36]=2)[N:20]=1>C1COCC1>[CH2:1]([NH:8][S:47]([C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([C:37]2[CH:36]=[C:35]([C:21]3[N:20]=[C:19]([C:18]([F:17])([F:51])[F:52])[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=4)[N:22]=3)[CH:40]=[CH:39][N:38]=2)[CH:42]=1)(=[O:48])=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccccc1)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of benzylamine (0.32 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.49 g, 85%). MS (ISP) 614.8 [(M+H)+]; mp 202.5° C.
Reaction SMILES: C(=O)(O)[O-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Br)[C:7]=1[CH2:14]Br.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:16]([N:23]1[CH2:14][C:7]2[C:8](=[CH:9][CH:10]=[CH:11][C:6]=2[Br:5])[CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1cccc(Br)c1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Solvent: CC#N
Product: Brc1cccc2c1CN(Cc1ccccc1)C2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Postassium bicarbonate (204 g, 2.04 mol) was suspended in CH3CN (12 L), and the mixture was heated to 80° C. Solutions of 1-bromo-2,3-bis(bromomethyl)benzene (280 g, 0.82 mol in 500 mL CH3CN) and benzylamine (87.5 g, 0.82 mol in 500 mL CH3CN) were added concurrently via addition funnels over 1 hour. The reaction mixture was then stirred at 77° C. for 16 hours. The contents of the reaction flask were cooled and filtered; the solvent was removed by evaporation; and the mixture was partitioned between 1M K2CO3 and EtOAc. The organic phases were washed with brine, dried with anhydrous Na2SO4, filtered, and evaporated. Flash column chromatography (gradient elution: heptane to 10% EtOAc in heptane) gave the title compound as a pale oil. 1H NMR (CDCl3) δ (ppm) 7.41-7.39 (m, 2H), 7.37-7.34 (m, 2H), 7.32-7.27 (m, 2H), 7.10-7.03 (m, 2H), 4.02 (s, 2H), 3.97 (s, 2H), 3.91 (s, 2H). LRMS (ESI) m/z 289 [(M+H)+; calcd for C15H15BrN: 289].
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[C@@H:18]([CH3:23])[CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:25].O1CCOCC1.Cl.Cl.Cl.CC1CCN(CCN2CCC(N)CC2)CC1>>[ClH:25].[ClH:25].[ClH:25].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[C@@H:18]([CH3:23])[CH2:17]2)[CH2:10][CH2:9]1
Reactant: C[C@H]1CN(CCN2CCC(NC(=O)OC(C)(C)C)CC2)CC[C@@H]1O
Agent: CC1CCN(CCN2CCC(N)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O

Procedure:
It is prepared by BOC-cleavage of tert-butyl ester 16 (3.07 g, 8.98 mmol) with 4M−HCl in dioxane (11.2 ml, 44.8 mmol) as described for amine 7.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:12][CH2:13][CH2:14][N:15]([CH2:20][CH2:21][OH:22])[C:16](=[O:19])[CH2:17]O>N1C=CC=CC=1>[C:1]([O:22][CH2:21][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:16](=[O:19])[CH2:17][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(CO)N(CCO)CCO
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)CC(=O)N(CCOC(=O)CCCCCCCC)CCOC(=O)CCCCCCCC

Procedure:
106 g (0.6 mole) of pelargonoyl chloride was added dropwise with stirring to a solution of 32.6 g (0.2 mole) of N,N-bis(hydroxyethyl)hydroxyacetamide in 60 ml of pyridine. The precipitated pyridine hydrochloride was filtered, washed with benzene, and discarded. The benzene solution of product was water washed, dried over sodium sulfate, and passed through an activated alumina column to remove any acid. The benzene was stripped off an a rotary evaporator. The yield of product was essentially quantitative. Its structure was established by infrared and nuclear magnetic resonance spectroscopy. It had nD30 1.4537 and d430 0.9745.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[C:8]2=[N:14][N:15]=[CH:16][N:7]2[C:6]1=[O:17])[CH:2]([CH3:4])[CH3:3].[Br:18]N1C(=O)CCC1=O>C1COCC1>[Br:18][C:11]1[NH:12][C:13]2[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6](=[O:17])[N:7]3[CH:16]=[N:15][N:14]=[C:8]3[C:9]=2[N:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Cn1c(=O)n2cnnc2c2nc[nH]c21
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n2cnnc2c2nc(Br)[nH]c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-isobutyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (9.4 mg, 40 mmol) in THF (5 ml) was added N-bromosuccinimide (8 mg, 44.7 mmol). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified by preparative LCMS (method A) to provide the desired product. LCMS calculated for C10H12BrN6O (M+H): 311.0; found 310.9, 313.0.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:26])[CH:11]=[C:12]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.CO.[Li+].[OH-].Cl>O>[CH:14]1[C:13]2[C:12](=[CH:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[O:26])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCCCCNC(=O)C=C1c2ccccc2Sc2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCNC(=O)C=C1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.8 %

Procedure:
6-(2-(9H-thioxanthen-9-ylidene)acetamido)hexanoic acid methyl ester (381 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (249 mg, 68% yield) as a white solid. LC-MS (m/z) 368 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:62][C:63]1[CH:68]=[CH:67][C:66]([C@H:69]([CH3:73])[C:70](O)=[O:71])=[CH:65][CH:64]=1>>[NH2:16][C:14](=[O:15])[CH:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:70](=[O:71])[C@H:69]([C:66]2[CH:67]=[CH:68][C:63]([Cl:62])=[CH:64][CH:65]=2)[CH3:73])[C:7]1=[O:12])[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1
Reactant: NC(=O)C(c1ccc(Cl)cc1)n1ccc2c(N)cccc2c1=O
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C(=O)Nc1cccc2c(=O)n(C(C(N)=O)c3ccc(Cl)cc3)ccc12)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-2-(4-chlorophenyl)acetamide (100 mg, 0.3 mmol), N,N-dimethylformamide (1 mL, 10 mmol), N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (200 mg, 0.6 mmol) and (S)-2-(4-chlorophenyl)propanoic acid (68 mg, 0.37 mmol) and the reaction stirred at room temperature over night. The solvent was removed and the residue purified by flash chromatography (12 g silica gel, 0-10% MeOH/DCM) followed by preparative HPLC (reverse phase) to obtain the product as an off white solid. MS m/z=477.1 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 9.97 (s, 1H), 8.12-8.10 (d, J=8.18 Hz, 1H), 8.03 (s, 1H), 7.75-7.70 (dd, J=8.18&5.63 Hz, 1H), 7.59 (s, 1H), 7.501-7.34 (m, 9H), 7.03-7.00 (d, J=8.01 Hz, 1H), 6.71 (s, 1H), 6.40-6.38 (d, J=8.27 Hz, 1H), 4.00-3.94 (q, J=6.97 Hz, 1H), 1.44-1.41 (d, J=7.11 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cc(Br)ccc12
Reactant: Nc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(Nc2ncnc3cc(Br)ccc23)nc1

Procedure:
Heat a mixture of 7-bromo-4-chloro-quinazoline (200 mg, 0.821 mmol) and 2-amino-5-trifluoromethyl-pyridine (239 mg, 1.48 mmol) at 230° C. for 2 minutes. Cool and partition the solid residue between EtOAc and 10% NaOH. Dry the EtOAc layer (Na2SO4), remove the solvent under reduced pressure, and purify via flash chromatography to yield (7-bromo-quinazolin-4-yl)-(5-trifluoromethyl-pyridin-2-yl)-amine as a yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:43])([F:42])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:42])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 was used as the starting compound and 4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]butyl bromide was used instead of 3,3-diphenyl bromide. Thus, ethyl 4-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]butyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Br:26][C:23]1[CH:24]=[CH:25][C:16]([NH:15][C:10](=[O:11])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-(trifluoromethyl)phenyl)acetyl chloride (23.4 mmol assuming quantitative yield in previous step, Intermediate 5: step a) in DCM (50 mL) in an ice bath was added methyl 2-amino-5-bromobenzoate (4.90 g, 21.3 mmol) followed by triethylamine (6.51 mL, 46.8 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl then water. The organic phase was dried (Na2SO4), filtered, and concentrated and the residue was purified by flash column chromatography (50-70% DCM-heptanes). Some of the title compound was obtained in pure form from the column, along with mixed fractions containing the title compound and the starting aniline. The mixed fractions were left to stand in DCM:heptanes (1:1) overnight, forming crystalline needles of the title compound, which were collected by vacuum filtration and combined with clean fractions from the column.