Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5][S:6][CH2:7][C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.CN1CCOCC1.[Br:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH2:44])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH:30]=[CH:31][CH:32]=1>O1CCCC1.C(Cl)Cl.CO>[Br:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH:44][C:8](=[O:10])[CH2:7][S:6][S:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CC(C)(C)SSCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)SSCC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 19.8 %

Procedure:
A solution of 2.7 grams of disulfide acid from Example 74 in 25 mL of tetrahydrofuran was cooled in an ice bath. A 1.9 mL portion of isobutylchloroformate followed by a 1.6 mL portion of N-methyl morpholine were added. After stirring for 5 minutes at 0° C., 1.0 grams of N-(3-bromophenyl)4,6-quinazolindiamine was added. The mixture was stirred for 3 hours at 0° C. and then allowed to warm to room temperature. The reaction was quenched with water and the tetrahydrofuran was evaporated under vacuum. Addition of methylene chloride followed by washing the methylene chloride layer with water and evaporation of the solvent gave a crude product. Silica gel chromatography with methanol in methylene chloride gave 0.3 grams white solid of product.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10]([OH:12])=O)[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].Cl.[CH2:15]([O:18][C:19]1[C:28]([CH3:29])=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][C:20]=1[CH3:30])[CH:16]=[CH2:17].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)C>[CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:21]=[C:20]([CH3:30])[C:19]([O:18][CH2:15][CH:16]=[CH2:17])=[C:28]([CH3:29])[CH:27]=2)=[O:12])[S:8][CH:9]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: C=CCOc1c(C)cc(C(=O)NN)cc1C
Reactant: Cc1c(CC(C)C)csc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOc1c(C)cc(C(=O)NNC(=O)c2scc(CC(C)C)c2C)cc1C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
A solution of 4-isobutyl-3-methyl-thiophene-2-carboxylic acid (100 mg, 0.5 mmol), 4-allyloxy-3,5-dimethyl-benzoic acid hydrazide hydrochloride (192 mg, 0.75 mmol) and NEt3 (0.28 mL) in DMF (10 mL) is cooled at 0° C. and TBTU (200 mg, 0.6 mmol) is added. The mixture is stirred for 15 h while warming from 0° C. to rt. The mixture is diluted with diethyl ether (50 mL) and washed with 1M aq. NaOH (2×20 mL), 1M aq. HCl (2×20 mL) and brine (10 mL). The organic phase is dried (Na2SO4), filtered and evaporated to give 160 mg of 4-allyloxy-3,5-dimethyl-benzoic acid N′-(4-isobutyl-3-methyl-thiophene-2-carbonyl)-hydrazide; LC-MS: tR=1.05 min, [M+1]+=400.83.
Reaction SMILES: P(Cl)(Cl)[Cl:2].[F:5][C:6]([F:23])([F:22])[C:7]1[CH:16]=[C:15](O)[C:14]2[C:9](=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:12][CH:13]=2)[N:8]=1>>[F:5][C:6]([F:23])([F:22])[C:7]1[CH:16]=[C:15]([Cl:2])[C:14]2[C:9](=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: Oc1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Reactant: ClP(Cl)Cl
Product: FC(F)(F)c1cc(Cl)c2cccc(C(F)(F)F)c2n1

Procedure:
A mixture of 100 parts by volume of phosphorus trichloride and 40 parts of 2,8-bis-(trifluoromethyl)-4-hydroxyquinoline is refluxed for 8 hours. Most of the excess phosphorus trichloride is then distilled off, the residue is poured onto 200 parts of ice-water and the pH is brought to 12-13 with 12 N sodium hydroxide solution. The mixture is then extracted with methylene chloride, the extract is dried over sodium sulfate and the solvent is stripped off under reduced pressure. 40.2 parts=94% of theory of 2,8-bis-(trifluoromethyl)-4-chloroquinoline of melting point 40°-42° C. are obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][OH:21])[CH:16]=2)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:20]=[O:21])[CH:16]=2)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2cc(CO)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCc1ccc2cc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
The compound (255 mg) obtained in Example 121-2 was dissolved in chloroform (5.0 ml) and then added with manganese dioxide (chemically processed product) (366 mg), followed by stirring overnight at room temperature. After completion of the reaction, the solution was filtrated through Celite and the solvent was then distilled off, thereby obtaining the subject compound (245 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[N:13]=2)[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)O)=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[NH:10][C:8]([C:5]2[C:4]([NH:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[N:13]=3)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[O:9])=[CH:35][CH:34]=1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Reactant: Cc1cc(C)nc(Nc2cc(Br)cnc2C(N)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(NC(=O)c2ncc(Br)cc2Nc2cc(C)cc(C)n2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide (1.65 g, 5.14 mmol) in toluene (20 ml) was added bis(4-methoxyphenyl)methanol (1.32 g, 5.39 mmol) and p-toluenesulfonic acid monohydrate (0.098 g, 0.51 mmol). The reaction mixture was heated to reflux with a Dean-Stark apparatus attached. After 2 hours, the reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (600 mL). This mixture was washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-60% ethyl acetate/hexanes). The isolated product was dissolved in 25 mL hot ethyl acetate (˜50° C.). The mixture was allowed to cool to ambient temperature, and then it was diluted dropwise with hexanes (100 mL). After 4 hours, the mixture was filtered, and the collected solids were dried under reduced pressure to afford N-[bis(4-methoxyphenyl)methyl]-5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide. MS ESI calc'd. For C28H28BrN4O3 [M+H]+ 547 and 549. found 547 and 549. 1H NMR (500 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.68 (d, J=2.0 Hz, 1H), 9.26 (d, J=8.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.27 (d, J=8.5 Hz, 4H), 6.88 (d, J=8.5 Hz, 4H), 6.66 (s, 1H), 6.55 (s, 1H), 6.19 (d, J=9.0 Hz, 1H), 3.71 (s, 6H), 2.36 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:17][CH2:18][CH:19]=[C:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]=2[CH2:24][O:23][C:22]2[CH:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:34][C:21]1=2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:17][CH2:18][CH:19]=[C:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[N:30][C:25]=3[CH2:24][O:23][C:22]3[CH:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:34][C:21]2=3)[CH2:8][CH2:7]1
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(Oc3ccccc3Cl)CC1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
4-(2-Chloro-phenoxy)-piperidine hydrochloride (0.067 g, 0.268 mmol) was dissolved in a mixture of acetonitrile (1.32 mL) and water (0.17 mL). To this mixture was added 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.050 g, 0.134 mmol) and potassium carbonate (0.074 g, 0.536 mmol). The mixture was stirred at room temperature for 24 hrs and then concentrated in vacuo. The resulting white solid was suspended in ethyl acetate (5 mL) and an equal volume of water was added. The product was extracted into ethyl acetate (2×5 mL). The pooled organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford an oil. The residue was purified by silica gel chromatography (ethyl acetate to 87/10/3 ethyl acetate/methanol/triethylamine gradient) to afford the title compound (46 mg, 68%).
Reaction SMILES: Br[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:18]([CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:19]>CN(C)C=O.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>[C:18]([CH2:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([F:11])[C:5]([C:6]#[N:7])=[CH:8][C:9]=2[CH3:10])[CH:24]=[CH:23][CH:22]=1)#[N:19]
Reactant: N#CCc1cccc(B(O)O)c1
Reactant: Cc1cc(C#N)c(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(F)cc1-c1cccc(CC#N)c1
Temperature: 150 °C
Yield: 91.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium (10 mg, 0.1 mmol) was added into the solution of 4-bromo-2-fluoro-5-methylbenzonitrile (110 mg, 0.5 mmol), K2CO3 70% aqueous solution (1 mL) and 3-(cyanomethyl)phenylboronic acid (96 mg, 0.6 mmol) in 10 ml N,N-dimethyl formamide, the solution was heated at 150° C. under microwave condition for 20 minutes, and the reaction mixture was partitioned with 20 mL water and 50 mL ethyl acetate, the aqueous layer was extracted with ethyl acetate (100 mL×2), and the combined organic layer was washed by saturated solution of sodium bicarbonate, sodium chloride, and dried by sodium sulfate, and concentrated by give quantitative products 3′-(cyanomethyl)-5-fluoro-2-methylbiphenyl-4-carbonitrile 3 (114 mg, 88% yield, confirmed by LCMS: 251.10) without purification for next steps.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[Cl:27])[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[C:10]4[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2C1
Yield: 57 %

Procedure:
In analogy to Example 22A, the title compound was prepared from ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (250 mg, 0.88 mmol) and 3,4-dichloroaniline (150 mg, 0.93 mmol) to yield 324 mg (64% purity, 57% yield), which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:23]([N:25]3[C:33]5C(=C[C:30]([C:34]6[C:35](C7C=CC(F)=C(C)C=7)=[N:36]C=CC=6)=[CH:31][CH:32]=5)C=N3)=[O:24])[N:18]=[CH:17]4)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:48].[ClH:49]>>[ClH:49].[NH2:36][C@@H:35]1[CH2:34][CH2:30][CH2:31][CH2:32][C@H:33]1[NH:25][C:23]([N:19]1[C:20]2[C:16](=[CH:15][C:14]([C:13]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:48])[CH:4]=4)=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:22][CH:21]=2)[CH:17]=[N:18]1)=[O:24]
Reactant: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)n3ncc4cc(-c5cccnc5-c5ccc(F)c(C)c5)ccc43)c2)ccc1F
Agent: Cl
Product: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)N[C@@H]3CCCC[C@H]3N)c2)ccc1F

Procedure:
1H NMR (300 MHz, DMSO-d6): δ 8.82 (d, J=5.2 Hz, 1H), 8.71 (s, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.42 (d, J=0.7 Hz, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.16 (d, J=8.8 Hz, 3H), 7.95-7.81 (m, 1H), 7.80 (s, 1H), 7.48 (d, J=6.7 Hz, 1H), 7.33 (dd, J=8.7, 1.6 Hz, 1H), 7.16-6.89 (m, 2H), 3.75-3.52 (m, 2H), 3.46 (dd, J=8.0, 4.0 Hz, 1H), 2.12 (s, 3H), 1.94-1.78 (m, 1H), 1.75-1.55 (m, 3H), 1.50-1.35 (m, 1H), 1.31-1.02 (m, 2H).LCMS: rt 4.63 min (A), purity 92%, MS (m/e) 444 (MH+-HCl).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=2)[CH2:3][CH2:2]1.C(N)CN>C(O)C.[Pd]>[CH:1]1([CH2:4][O:5][C:6]2[N:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(OCC2CC2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: NCCN
Product: Nc1ccc(OCC2CC2)nc1
Reaction time: 2.5 h
Yield: 23.7 %

Procedure:
To a solution of 2-(cyclopropylmethoxy)-5-nitropyridine (2.0 g) in ethanol (10.0 mL) was added Pd/C (0.500 g) and ethylene diamine (5.0 mL). The reaction mixture was subjected for hydrogenation in Parr apparatus under 40 psi for 2-3 h. The reaction mass was quenched in water and extracted with DCM and concentrated the organic layer to afford 0.400 g of the desired product. 1HNMR (CDCl3): δ 0.31-0.32 (m, 2H), 0.43-0.46 (m, 2H), 1.07-1.12 (m, 1H), 3.62 (d, J=6.6 Hz, 2H), 4.25 (s, 2H), 6.24 (d, J=6.6 Hz, 1H), 6.89 (s, 1H), 7.05 (dd, J=3.0 Hz & 2.4 Hz, 1H); MS [M+H]+: 165.13.
Reaction SMILES: [C:1]1([SH+]C2C=CC=CC=2)C=CC=C[CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH:19]=[O:20]>O1CCCC1>[CH3:25][O:24][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[CH:23]=1)[CH:19]1[O:20][CH:1]1[CH3:2]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: c1ccc([SH+]c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C2OC2C)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a -78= C. solution of diphenylsulfonium ethylide (1.0 mole) in tetrahydrofuran (one liter) is slowly added 3,5-dimethoxybenzaldehyde (1.0 mole). The reaction mixture is stirred at -78° C. for 3 hours and then allowed to warm to room temperature. It is then added to ether-water and the ether phase separated. The ether phase is washed with water, dried (MgSO4) and evaporated. Fractional distillation of the residue gives the title product.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])O1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:17]([NH:19][CH:20]1[CH2:22][CH2:21]1)=[O:18]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:12]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[N:13]1[C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:17]([NH:19][CH:20]1[CH2:21][CH2:22]1)=[O:18]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1N1C(=O)Cc2ccccc2C1=O
Temperature: 150 °C
Yield: 56.3 %

Procedure:
A suspension of 1H-isochromene-1,3(4H)-dione (400 mg) and 3-amino-N-cyclopropyl-4-methylbenzamide (514 mg) in toluene (3 ml) was heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 60 minutes. The reaction mixture was diluted with ethyl acetate and washed with 2N HCl, water, brine, dried (magnesium sulfate) and concentrated to a foam which was purified by column chromatography with a gradient of iso-hexane to 70% ethyl acetate/iso-hexane to yield 3-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide as a solid (464 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.09 (s, 3H), 2.85 (m, 1H), 4.33 (d, 1H), 4.41 (d, 1H), 7.42 (d, 1H), 7.49-7.55 (m, 2H), 7.65 (s, 1H), 7.74 (t, 1H), 7.80 (d, 1H), 8.09 (d, 1H), 8.39 (d, 1H); Mass Spectrum: M+H+ 335.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[CH:12]=[C:13]([OH:19])[C:14]([OH:18])=[CH:15][C:16]=1[CH3:17])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:27](Br)[C:28]([OH:30])=[O:29].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]2[O:18][CH:27]([C:28]([OH:30])=[O:29])[O:19][C:13]=2[CH:12]=1)(=[O:10])=[O:9]
Reactant: O=C(O)C(Br)Br
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1S(=O)(=O)c1ccccc1Cl)OC(C(=O)O)O2
Reaction time: 15 h

Procedure:
23 g (77 mmol) of 4-(2-chlorophenylsulphonyl)-5-methyl-1,2-benzenediol are added to a finely particulate suspension of 50.9 g (385 mmol) of freshly calcined potassium carbonate in 180 ml of dry dimethylformamide and there is added dropwise thereto, in the course of 15 minutes, a solution of 8.50 g (39 mmol) of dibromoacetic acid in 80 ml of dimethylformamide. The mixture is then stirred for 15 hours at 80°. Subsequently, the reaction mixture is poured onto ice and adjusted to pH 1-2 with concentrated hydrochloric acid. The aqueous phase is extracted once more with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried with sodium sulphate and concentrated by evaporation. The resulting brown oil is stirred with 150 ml of ethyl acetate at 0° until crystallisation occurs. The crude 5-(2-chlorophenylsulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid so obtained is recrystallised twice from acetonitrile, resulting in the form of sand-coloured crystals having a melting point of 211°-213.5°.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH:7]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:5][OH:6].[H-].[Na+].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Br>CN(C=O)C>[CH3:1][O:2][N:3]=[C:4]([CH:7]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:5][O:6][CH2:36][C:35]1[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:34]=1[F:33]
Reactant: CON=C(CO)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=C(COCc1ccc(F)cc1F)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Treat a solution of the hydroxy-oxime (200 mg, 0.44 mmol) of Step 4 in DMF at 0° C. with NaH (12 mg, 0.48 mmol). Stir the resulting mixture for 30 mins at 0° C. Add 2,4-difluorobenzylbromide (60 μL, 0.465 mmol) in one portion and remove cooling bath. Stir the reaction for 12-18 hours at room temperature. Quench the reaction with H2O and extract with EtOAC (3×30 mL). Dry the combined organic layers over MgSO4, filter and concentrate under reduced pressure to give the crude compound as a yellow oil. Purify by silica gel chromatography (column: 2.5 cm×15 cm; pack column in 50% EtOAc/Hexane and elute using a gradient of 50-100% EtOAc/Hexane) to obtain 128 mg (0.22 mmol, 50% ) of the title compound as a pale oil. HRMS (FAB, M+H+): m/e cal'd for [C30H33N2O3Cl2F2 ]+ : 577.1836, found 577.1832.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[CH3:13][O:11][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2cc[nH]c2c1
Reaction time: 3 h

Procedure:
To a solution of 6-indole carboxylic acid (0.91 g, 5.67 mmol) in 33 mL of 2:1 THF/MeOH is added (trimethylsilyl)diazomethane (5.0 mL of a 2.0M solution in hexanes, 10.0 mmol). The mixture is stirred for 3 h and concentrated in vacuo to give the title compound (0.87 g, 4.97 mmol). The crude product is used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.70 (bs, 1H), 8.20 (s, 1H), 7.82 (dd, 1H), 7.67 (d, 1H), 7.45 (m, 1H), 6.60 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[O:10][CH3:11].Cl.Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=2[O:10][CH3:11])[CH2:22][CH2:21]1
Reactant: COc1ccc(Br)cc1CCl
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)cc1CN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 235 %

Procedure:
A mixture of 1.1 g of 2-(chloromethyl)-4-bromoanisole, 1 g of 1-(2-pyrimidyl)piperazine dihydrochloride and 2.0 mL N,N-diisopropylethylamine in 10 mL chloroform was heated at reflux temperature for 2 hr, cooled to room temperature, washed with 1N NaOH and water. The solvent was removed by evaporation under reduced pressure to yield 3.6 g of 2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-4-bromoanisole as a white solid which was used in the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[S:27]1[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH:29][CH2:28]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:29]2[CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][S:27][CH2:28]2)=[O:23])=[CH:20][CH:19]=1)[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C1CSCN1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC=CCCCNc1ccc(C(=O)N2CSCC2C(=O)OCC)cc1

Procedure:
One-tenth mole of 4-(4-pentadecenylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1.[OH-].[Na+:24]>C(O)C>[Na+:24].[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O-:20])=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3ccnc(NC)n3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1nccc(-c2cc3cc(C(=O)[O-])ccc3[nH]2)n1
Yield: 100 %

Procedure:
25 g of ethyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate were admixed with 200 ml of ethanol and 24.5 g of 33% sodium hydroxide solution, and heated to from 65° C. to 70° C. for 4 h. After cooling, the mixture was filtered with suction and the precipitate was washed with 15 ml of ethanol/water (9:1). 24.5 g (87.6% of theory) of 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid sodium salt were obtained (98.1 HPLC area %). LCMS: [M+H]⊕269.10
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#N)=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C[OH:20].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]([CH:8]=[O:20])=[N:6][CH:7]=1
Reactant: CO
Reactant: N#Cc1ncc(F)cn1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ncc(F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 5-fluoropyrimidine-2-carbonitrile (Method 6, 1.0 g, 8.1 mmol) in anhydrous THF at −78° C. was added a solution of DIBAL-H (8.1 mL) over a period of 20 minutes. The resulting mixture was stirred at this temperature for 2 hours whereupon MeOH was added. The solution was allowed to warm to room temperature whereupon a solution of conc. HCl was added. The resulting mixture was stirred for 2 hours at ambient temperature and the aqueous layer was washed with EtOAc (3×). The combined organic extracts were washed with brine and dried (MgSO4). Evaporation of the solvent afforded the titled compound (780 mg, 76%). MS: [M+H]+ 127.