Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][CH2:16][CH:17]4[CH2:19][CH2:18]4)=[CH:4][CH:3]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCC1CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-cyclopropylmethyl-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[F:54][C:55]([F:73])([F:72])[C:56]1[CH:57]=[C:58]([NH:62]C2C=CC=CC=2C(O)=O)[CH:59]=[CH:60][CH:61]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[F:54][C:55]([F:72])([F:73])[C:56]1[CH:57]=[C:58]([NH:62][C:29]2[CH:30]=[CH:31][CH:2]=[CH:3][C:4]=2[C:5]([NH:7][CH:8]([C:10]2[N:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[N:12][CH:11]=2)[CH3:9])=[O:6])[CH:59]=[CH:60][CH:61]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: O=C(O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Nc3cccc(C(F)(F)F)c3)nn2)cc(OC)c1OC
Yield: 80 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid (240 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave 2-{[3-(trifluoromethyl)phenyl]amino}-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (297 mg, 80%) as a yellow solid. MS m/z 568 (M+1).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[NH2:17])=[N:3][C:4]=2[CH:10]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: Nc1ccccc1CCl
Agent: Cl
Product: Nc1ccccc1CSc1nc2cc(Cl)ccc2[nH]1
Yield: 63 %

Procedure:
The title compound was prepared by the method of Example 1 using 2.50 g of 2-mercapto-5-chlorobenzimidazole instead of 2-mercaptobenzimidazole and 2.42 g of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. The basic extraction used 5% sodium hydroxide instead of sodium carbonate. Washing the solid residue from the dichloromethane extract with additional dichloromethane gave 2.47 g of the title compound. Anal. Calc'd. for C14H12N3ClS: C, 58.03; H, 4.17; N, 14.10; S, 11.06; Cl, 12.23. Found: C, 57.33; H, 4.06; N, 14.27; S, 10.99; Cl, 12.74.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[NH:23][N:22]=[C:21]([CH:24]=O)[CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:24][C:21]3[CH:20]=[C:19]([CH3:18])[NH:23][N:22]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: Cc1cc(C=O)n[nH]1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(C)[nH]n3)CC2)cc1
Yield: 30.1 %

Procedure:
Compound 36 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-methylpyrazole-3-carbaldehyde were used.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C>O.[Cu].CN(C)C=O>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2cc(Cl)ccc2C(=O)O)cc1

Procedure:
A mixture of 15 g. of 2,4-dichlorobenzoic acid, 10 g. of p-methylphenol, 0.5 g. of copper powder and 20 g. of anhydrous potassium carbonate in 200 ml. of dimethylformamide is heated to 165° C and maintained thereat with stirring and under a nitrogen atmosphere. After monitoring via tlc indicates the reaction is substantially complete, the reaction mixture is diluted with water, treated with charcoal, filtered and the clear filtrate acidified. The precipitate is isolated by suction filtration, washed neutral and dried to give 2-(p-methylphenyloxy)-4-chlorobenzoic acid.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([NH2:4])[CH3:3].O.[C:7]1([C:13]([CH:15]=O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+]>C(O)C>[CH3:3][C:2]1[CH:1]=[N:5][C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:15][N:4]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: CC(N)CN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cnc(-c2ccccc2)cn1

Procedure:
To a stirred solution of propylenediamine (2.94 g, 0.04 mol) in ethanol was added phenylglyoxal-monohydrate (5.00 g, 0.03 mol) at 0° C. within 30 minutes. After stirring for 1.5 hours at room temperature KOH (2.10 g, 0.04 mol) was added and the reaction mixture was refluxed for 12 hours. Then the solvent was removed under vacuum and the residue was extracted with ether. The organic phases were washed with brine and dried over MgSO4. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (7:3→3:7) as eluent. After flash chromatography the product was recrystallized from hexane. White solid. Yield: 780 mg, 15%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.57 (s, 3H), 7.38-7.50 (m, 3H), 7.91-7.99 (m, 2H), 8.43-8.49 (m, 1H), 8.87 (d, J=1.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=21.2, 126.6, 128.9, 129.4, 136.5, 140.9, 143.8, 149.8, 151.9; (ESI): m/z=170.94 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH2:11])[CH2:5]2.[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH:20]=O)([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)Cl>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][CH2:20][CH2:19][NH:18][C:17](=[O:22])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: NC1Cc2ccc(Br)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-Bromo-2,3-dihydro-1H-inden-2-amine (0.21 g, 1.0 mmol) in 16 mL of DCM/MeOH (7/1, v/v) was added tert-Butyl(2-oxoethyl)carbamate (160 mg, 1.0 mmol) and NaBH(OAc)3 (297 mg, 1.4 mmol), and the mixture was stirred at RT for 3 hours. DCM was added to the mixture, and then washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give the title product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[F:8][CH:9]([F:36])[C:10]([NH:12][C@H:13]([CH2:34][F:35])[C@H:14]([OH:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:11].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:33][C@H:14]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[C@H:13]([NH:12][C:10](=[O:11])[CH:9]([F:8])[F:36])[CH2:34][F:35])=[O:6]
Reactant: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Reactant: O=C(Cl)CCCBr
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](OC(=O)CCCBr)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
4-Bromobutanoyl chloride (29.6 μL, 0.255 mmol) is added dropwise to a stirred solution of 2,2-difluoro-N-{(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-[4-(6-{[(methylsulfonyl)amino]methyl}pyridin-3-yl)phenyl]ethyl}acetamide (100.0 mg, 0.232 mmol), N,N-diisopropylethylamine (48.4 μL, 0.278 mmol), and 4-dimethylaminopyridine (11.3 mg, 0.093 mmol) in N,N-dimethylformamide (1.00 mL) at rt. The reaction mixture is stirred for 1 hour before being concentrated. The residue was purified by CombiFlash (4 g column) eluting with 0-100% ethyl acetate to yield the title compound (80.0 mg, 59%) as a yellow foam. MS (ESI+) m/z 581.7 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12](I)=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1)=[CH2:17].C(N(CCCC)CCCC)CCC>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:1][C:2]1[CH:14]=[CH:13][C:12]([CH:17]=[CH:16][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])=[CH:22][CH:23]=2)=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Reactant: CC(C)COC(=O)c1cc(I)ccc1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C=Cc2ccc(O)c(C(=O)OCC(C)C)c2)cc1

Procedure:
Isobutyl 2-hydroxy-5-iodobenzoate (70.2 g, 0.22 mol) and 4-ethenyl-N-(3-methyl-2pyridinyl)benzensulfonamide (54.8 g, 0.20 mol) were suspended in a solution of tributylamine (55.5 g, 0.3 mol) and palladium(II) acetate (0.44 g 0.0022 mol) in dimethylacetamide (200 ml)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([Cl:16])[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O.[NH2:24][NH2:25]>C(O)C>[Cl:16][C:6]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][N:3]=[C:2]2[NH:24][N:25]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=12
Reactant: NN
Reactant: O=C(c1ccccc1)c1c(Cl)nnc(-c2ccccc2)c1Cl
Solvent: CCO
Solvent: O
Product: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Temperature: 40 °C
Reaction time: 1 h
Yield: 8.5 %

Procedure:
A mixture of (3,5-dichloro-6-phenylpyridazin-4-yl)(phenyl)methanone (150 mg, 0.46 mmol) and hydrazine hydrate (27 mg, 0.55 mmol) in ethanol (0.5 mL) was stirred at 40° C. for 1 h in a sealed tube. The reaction mixture was cooled and filtered, and the residue was washed with diethyl ether. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, gradient 0 to 20% ethyl acetate/isohexane) yielding Compound 9 as a white solid (12 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:10][CH2:9][C:8]1=[O:29])=[O:5])[CH3:2].CO>[Fe].C(O)(=O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8](=[O:29])[CH2:9][CH2:10]2)=[O:28])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc(N)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
The mixture of 1-ethoxycarbonylmethyl-5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (667 mg), iron powder (469 mg), methanol (10 ml) and acetic acid (1 ml) was refluxed for 1 hour. The reaction mixture was cooled to ambient temperature and it was filtered through a bed of celite followed by the removal of methanol. The residue was diluted with chloroform and to the mixture was added saturated sodium bicarbonate aqueous solution followed by stirring for 10 minutes. The resulting mixture was filtered through a bed of celite and the organic layer was washed with brine. Drying the filtrate, and the removal of chloroform obtained a crude product. The crude product was triturated with a mixture of diisopropyl ether and n-hexane (1:1) to give 5-(4-aminobenzoyl)-1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (610 mg) as a slightly brown powder.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][C:27](Br)=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[C:15]1=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCN2C(=NCCC2)CC1>O>[CH2:6]([O:13][N:14]1[C:15](=[O:29])[C:16]2[CH:17]=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]3[C:21]=2[C:22](=[CH:25][CH:26]=[CH:27]3)[C:23]1=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C1c2cccc3c(N4CCCC4)ccc(c23)C(=O)N1OCc1ccccc1

Procedure:
Pyrrolidine (3 mL) was added to 2-benzyloxy-6-bromo-benzo[de]isoquinoline-1,3-dione (0.8 g, 2.1 mmol, from Example M) in the presence of DBU (0.05 mL). The mixture was refluxed for 2 hours and poured into water (50 mL). The precipitate formed was filtered and dried to give 0.8 g of 2-benzyloxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.1 mmol) in the presence of 10% Pd/C (0.2 g) in DMA (30 mL) gave 0.27 g of the title compound, mp 268-270° C.;
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].O>CC(C)=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(C)cn(CCCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
A stirred solution of methyl 3-methyl-1 H-indole-6-carboxylate (0.5 g, Reference Example 30) in acetone (35 ml) was treated with 1-bromo-3-phenylpropane (0.577 g) and sodium hydroxide (0.116 g). The mixture was stirred at room temperature for 12 hours then poured into water (35 ml) and then extracted three times with ethyl acetate (50 ml). The combined extracts were washed with dilute hydrochloric acid (50 ml, 1N) then with saturated sodium bicarbonate solution (50 ml), then dried over magnesium sulphate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (50:1, v/v) to yield the title compound (0.58 g).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>O1CCCC1>[CH3:13][O:14][C:15]1[C:20]([Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:16]=1
Reactant: COc1ccc(C(F)(F)F)cn1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ncc(C(F)(F)F)cc1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To butyl lithium (7.2 ml, 1.6M in hexanes, 11.5 mmol) in tetrahydrofuran (12.0 ml) at −78° C. was slowly added diisopropylamine (1.14 g, 11.3 mmol) in tetrahydrofuran (4.0 ml), and the resulting solution allowed to warm to 0° C. over 45 mins. A mixture of 2-methoxy-5-trifluoromethylpyridine (2.00 g, 11.3 mmol) and trimethylsilyl chloride (3.2 ml, 25.2 mmol) in tetrahydrofuran (8.0 ml) was then slowly added and the mixture stirred for 30 mins. at 0° C., before being quenched with water (50 ml). The mixture formed was extracted with ethyl acetate (2×70 ml), and the extracts washed with brine (50 ml), dried (Na2SO4) and concentrated to give the product as an orange oil (1.36 g, 48% yield).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][N:6]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCN1CCNCC1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Product: CCN1CCN(c2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1

Procedure:
The title compound was prepared from 4-bromo-1-(benzenesulfonyl)-1H-indole and 4-ethylpiperazine according to Method 1 to afford 129 mg (48%) of a white solid: 1H NMR (CD3OD) δ 7.94-6.81 (m, 10H), 3.69-3.62 (m, 4H), 2.34-3.26 (partly hidden) (m, 4H), 3.14-3.04 (m, 2H), 1.40 (t, J=7 Hz, 3H); MS (ESI) 370.1 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:21][CH:22]=[CH2:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].CN(C)C=O.S(Cl)([Cl:31])=O>C1C=CC=CC=1>[Cl:31][CH2:2][CH2:3][N:4]([CH2:21][CH:22]=[CH2:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: O=S(Cl)Cl
Reactant: C=CCN(CCO)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: C=CCN(CCCl)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
16.7 parts by weight of N-hydroxyethyl-N-allyl-2,6-dinitro-4-trifluoromethylaniline is dissolved in 50 parts by weight of benzene. After adding 1 part by weight of dimethylformamide and dripping in 30 parts by weight of thionyl chloride at room temperature the whole is boiled for two hours under reflux. The volatile constituents are distilled off from the reaction mixture at 20 mm Hg, the residue is taken up in ethyl acetate, the solution is washed with ice-water, then with 10% sodium bicarbonate solution and finally again with water and the organic phase is dried over sodium sulfate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[CH:20]=1>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[C:18]([OH:27])=[O:17])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1ccc(-c2ccc(O)cc2)cc1
Product: COc1ccc(-c2ccc(OCc3cccc(C(=O)O)c3)cc2)cc1

Procedure:
3-(4′-Methoxy-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-hydroxy-4′-methoxybiphenyl (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 73 mg. Mass spectrum (ES) MH+=335.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]N)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:19]1(=[O:35])[N:23]([CH2:24][CH2:25][CH2:26][C:27](=O)[CH3:28])[C:22](=[O:30])[C:21]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:20]12.Cl.CCCCCC>C(O)C>[CH3:28][C:27]1[NH:15][C:12]2[C:13]([C:26]=1[CH2:25][CH2:24][N:23]1[C:22](=[O:30])[C:21]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:20]3[C:19]1=[O:35])=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:10][CH:11]=2
Reactant: NNc1ccc(NC(=O)c2ccc(F)cc2)cc1
Reactant: CC(=O)CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: Cc1[nH]c2ccc(NC(=O)c3ccc(F)cc3)cc2c1CCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 6.6 %

Procedure:
To a solution of 5.33 gm (21.7 mMol) 4-(4-fluorobenzoyl)aminophenylhydrazine and 5.03 gm (21.8 mMol) 5-phthalimidyl-2-pentanone in 100 mL ethanol were added 2 mL concentrated hydrochloric acid and the reaction mixture was heated at 80° C. for 14 hours. To the reaction mixture were then added an additional 3 mL concentrated hydrochloric acid and heating continued for an additional 6 hours. The reaction mixture was then cooled to 0° C. and 100 mL hexane were slowly added. The solid which formed was filtered and washed with hexane and provided, after drying, 6.67 gm of the desired compound. The mother liquor was concentrated under reduced pressure and then subjected to silica gel chromatography, eluting with 1:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide an additional 0.63 gm of product. Overall yield was 7.3 gm (76%).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[F:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:20])[N:9]=2)[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: C[O+](C)C
Reactant: COC(=O)c1ccc(F)c2[nH]ncc12
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(F)c2nn(C)cc12
Reaction time: 5 h
Yield: 66.8 %

Procedure:
To a solution of methyl 7-fluoro-1H-indazole-4-carboxylate (2.93 g, 15.1 mmol) in ethyl acetate (60 mL) was added trimethyloxonium tetrafluoroborate (2.90 g, 19.6 mmol) at room temperature, and the mixture was stirred for 5 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (2.10 g, yield 67%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:52]=[CH:51][C:50]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])=[CH:49][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:47]4[CH:48]=[CH:49][C:50]([NH:53][S:54]([CH3:57])(=[O:55])=[O:56])=[CH:51][CH:52]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccc(NS(C)(=O)=O)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 62 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (94 mg, 0.32 mmol), sodium carbonate (33 mg, 0.32 mmols), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (31 mg, 0.04 mmol) and 3 ml 1,2-dimethoxyethane and 0.75 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50% hexane-ethyl acetate) to obtain 65 mg (62% yield, 82% purity) of the title compound.