Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]3[S:26][C:27]4[CH2:28][NH:29][CH2:30][CH2:31][C:32]=4[C:19]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[CH3:34][N:35]([CH:42]([CH3:44])[CH3:43])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]3[S:26][C:27]4[CH2:28][N:29]([C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:35]([CH3:34])[CH:42]([CH3:44])[CH3:43])[CH2:30][CH2:31][C:32]=4[C:19]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: N#Cc1cnc2sc3c(c2c1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1)CCNC3
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A solution of 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c′]dipyridine-3-carbonitrile from Example 90A (80 mg, 0.17 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (47 mg, 0.24 mmol) in DMF (2 mL) was treated with DIPEA (89 mg, 0.69 mmol) and TBTU (83 mg, 0.26 mmol). The mixture was stirred at rt overnight and then directly purified by preparative HPLC to yield 63 mg (61%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Br)cn2)C1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35.9 %

Procedure:
5-Bromo-2-fluoropyridine (1.76 mg, 10 mmol) and 3.62 g (10 mmol) of tert-butyl pyrrolidin-3-ylcarbamate were dissolved in 20 ml of N,N-dimethylformamide. Potassium carbonate (1.38 g, 10 mmol) was added to the solution, and the mixture was stirred at 100° C. for 6 hr. Ethyl acetate (60 ml) and 8.5 ml of water were added to the reaction solution, and the organic layer was washed five times with 30 ml of water. The organic layer was dried over anhydrous sodium sulfate and was filtered. The solvent was then removed by distillation, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give 1.23 g (yield 36%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[C:29](=[O:31])[CH3:30])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Nc2ccncc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 8 h

Procedure:
4-tert-Butyl-N-[4-chloro-2-(pyridin-4-ylamino)-phenyl]-benzenesulfonamide (103 mg, 0.25 mmol) dissolved in DCM (5 mL) was treated with acetic anhydride (26 mg, 0.25 mmol) and triethylamine (51 mg, 0.5 mmol), and the reaction mixture was allowed to stir overnight. The volatiles were evaporated and the product was purified by HPLC to afford the title compound. MS: (M+H)/z=458.
Reaction SMILES: C([O-])(=[O:3])C.[K+].Cl[C:7]1[C:8](F)=[CH:9][C:10](I)=[C:11](N(CC(F)(F)F)C(C2C=NN([CH:21]3[CH2:26]C[CH2:24][CH2:23][O:22]3)C=2)=O)[CH:12]=1.O>CN(C=O)C.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>[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=1.[CH3:26][C:21](=[O:3])[O:22][CH2:23][CH3:24]
Reactant: CC(=O)[O-]
Reactant: O=C(c1cnn(C2CCCCO2)c1)N(CC(F)(F)F)c1cc(Cl)c(F)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=CCCCC1
Product: CCOC(C)=O
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
The catalyst Pd(PPh3)4 (630 mg, 0.55 mmol) and potassium acetate (890 mg, 9.0 mmol) are added to a solution of N-(5-chloro-4-fluoro-2-iodophenyl)-1-(tetrahydro-2H-pyran-2-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (2,2 g, 4.5 mmol) in 10 mL of anhydrous DMF placed in a microwave reactor under nitrogen. The reactor is sealed and the reaction mixture is stirred for 15 minutes at 90° C. under microwave irradiation. A further amount of catalyst Pd(PPh3)4 (630 mg, 0.55 mmol) and of potassium acetate (890 mg, 9.0 mmol) are added to the reaction medium, which is stirred for 15 minutes at 110° C. under microwave irradiation. The mixture is cooled, poured into water and extracted with EtOAc. The organic phase is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated to dryness. After purification by flash chromatography on silica (DCM/EtOAc: 100/0 to 95/5) and then (cyclohexene/EA: 90/10) and DCM (100%), 260 mg of a white solid are obtained (yield: 57%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:1][CH:2]1[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]1=[O:20])=[O:33])=[CH:26]2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c(C(=O)NC3N=C(c4ccccc4F)c4ccccc4NC3=O)cc2c1

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (50 mg, 0.186 mmol) was suspended in 1 ml of methylene chloride. 5-Methoxyindole-2-carboxylic acid (36.9 mg, 0.207 mmol) was added to the suspension followed by the addition of 38.5 mg (0.2 mmol) of EDC. The mixture was brought to pH 8 with 60 μl of triethylamine. The solid which formed after 3 min. was filtered after 5 hours and washed with chloroform. The filtrate was applied to a 2000 μ preparative TLC plate and eluted with 90:10:1 chloroform:methanol:water (CMW). The product was extracted from silica with methanol and evaporated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[CH2:17][N:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:15](=[O:28])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37](=[O:45])[C:38]([C:42](O)=[O:43])=[CH:39][NH:40][CH:41]=2)=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH2:17][C:18]3[C:9]([O:8][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:42]([C:38]5[C:37](=[O:45])[C:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)=[CH:41][NH:40][CH:39]=5)=[O:43])=[N:7][CH:6]=4)=[CH:10][CH:11]=[N:12][C:13]=3[NH:14][C:15]2=[O:28])=[CH:21][CH:22]=1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)nc4)ccnc3NC2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)c5c[nH]cc(-c6ccc(F)cc6)c5=O)nc4)ccnc3NC2=O)cc1
Yield: 31.8 %

Procedure:
A solution of 5-[(6-aminopyridin-3-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.26 mmol; 1.00 eq.), 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (67.97 mg; 0.29 mmol; 1.10 eq.), pybop (179.26 mg; 0.34 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (131.72 μl; 0.79 mmol; 3.00 eq.) was stirred at room temperature for 4 days. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 49 mg (26%) of 284 as a tan solid. LC-MS (M+H=593, obsd.=593).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(COc2ccc(OC[C@H]3CCCN3C(=O)OC(C)(C)C)cc2)c1
Yield: 53.2 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 3-methoxy-benzyl bromide (120 mg, 0.6 mmol) to afford the title product (110 mg, 53% yield); LCMS; 100% APCI+, Calcd: 413.56; Found m/z: 414.29 (M+1); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.46 (m, 2H), 3.69-3.91 (m, 1H), 3.82 (s, 3H), 4.02-4.18 (m 2H), 4.99 (s, 2H), 6.82-6.90 (m, 5H), 6.96-7.05 (m, 2H), 7.26-7.30 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH3:22])[CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].CI.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH3:22])[CH:9]=[CH:10][C:11]=2[N:13]([CH3:30])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2n1COC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-4-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (7.8 g), methyl iodide (1.7 mL), potassium carbonate (2.9 g) and N,N-dimethylformamide (14 mL) was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were washed with diethyl ether-hexane to give the title compound (6.85 g, yield 85%) as colorless needle crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][CH:3]=1.[O-:10][C:11]#[N:12].[K+]>C(O)(=O)C.O>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:11]([NH2:12])=[O:10])[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: Cc1ccc(N)cc1O
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(NC(N)=O)cc1O
Temperature: 0 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
5-Amino-o-cresol (1 g, 8.12 mmol) was dissolved in glacial acetic acid (4.1 mL) and H2O (8.41E) ata 35° C. The potassium cyanate solution was added slowly with stirring until a with precipitate of the product appears. The rest is added quickly with vigorous agitation. After 24 h, the reaction mixture was diluted with H2O, cooled to 0° C. and filtered with suction, washed with H2O and dried under high vacuum to afford the product (1.3 g, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:10]=1.[CH2:27]([N:29]([CH2:44][CH3:45])[CH2:30][CH2:31][N:32]([CH2:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])[CH3:33])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[C:35]([CH2:34][N:32]([CH2:31][CH2:30][N:29]([CH2:44][CH3:45])[CH2:27][CH3:28])[CH3:33])[CH:36]=2)=[C:3]([C:9]2[CH:10]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=3)[N:12]=[CH:13][N:14]=2)[CH:4]=1
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Reactant: Nc1ccc(Cl)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
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: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11.8 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 6-(2-amino-5-chlorophenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine 65b (200 mg, 0.53 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (130 mg, 0.49 mmol, 1.00 equiv), HATU (300 mg, 0.79 mmol, 1.50 equiv), and N,N-diisopropylethylamine (270 mg, 2.09 mmol, 5.00 equiv). The resulting solution was stirred for 2 days at 25° C. in an oil bath. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with 2×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of saturated NH4Cl, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 36.1 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 8.73 (s, 1H), 8.60 (d, J=9.3 Hz, 1H), 8.41 (s, 1H), 8.19 (m, 1H), 7.92 (m, 3H), 7.64 (m, 7H), 7.14 (s, 1H), 4.73 (d, J=5.7 Hz, 2H), 3.35 (s, 2H), 3.14 (d, J=6.9 Hz, 4H), 1.18 (t, J=7.2 Hz, 6H). MS (ES, m/z): 625 [M+H]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]1([CH2:15][C:16]2[N:20]([CH3:21])[C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>C1COCC1>[Br:8][C:17]1[CH:18]=[C:19]([S:22]([NH2:25])(=[O:24])=[O:23])[N:20]([CH3:21])[C:16]=1[CH2:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Cn1c(CC2CCCCC2)ccc1S(N)(=O)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(S(N)(=O)=O)cc(Br)c1CC1CCCCC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To a solution of NBS (68.7 mg, 386 μmol) was added a solution of compound 25e (104 mg, 410 μmol) in THF at −78° C. and stirred for 2 h at −78° C. Water (30 mL) was added and the reaction mixture was extracted with EA (150 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA=3/1) to give compound 25f (134 mg, 61%).
Reaction SMILES: C[C:2]1[C:3]([Br:12])=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][NH:7][C:6]=2[N:11]=1.[Cl:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:15]=1[CH2:16]Br.[C:24](#N)C>C(Cl)Cl>[Br:12][C:3]1[CH:2]=[N:11][C:6]2[NH:7][CH2:8][CH2:9][N:10]([CH2:16][C:15]3[C:18]([F:23])=[CH:19][CH:20]=[C:21]([F:22])[C:14]=3[Cl:13])[C:5]=2[C:4]=1[CH3:24]
Reactant: Cc1nc2c(cc1Br)NCCN2
Reactant: Fc1ccc(F)c(CBr)c1Cl
Reactant: CC#N
Solvent: ClCCl
Product: Cc1c(Br)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2
Yield: 23 %

Procedure:
1,2,3,4-Tetrahydro-6-methyl-7-bromo pyrido[2,3-b]pyrazine (0.15 g, 1 mmol), 2-chloro 3,6-difluoro-benzyl bromide (0.16 g, 1.05 mmol), KI (0.016 mmol, 0.01 g) in acetonitrile was subjected to microwave irradiation at 130° C. for 20 min. The solvent was stripped off and the crude residue was re-dissolved in CH2Cl2, washed with aqueous NaHCO3 solution. Upon drying, the residue was chromatographed, eluting with a mixture of hexanes-EtOAc (7:3) to furnish pure desired product (0.086 g 23%). The undesired N-alkylation product was also obtained and the structural differentiation was based on NOE NMR experiment.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[C:10]1([CH3:29])[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl.[CH2:31]([Cl:34])[CH2:32]Cl>>[C:10]1([CH3:29])[CH:11]=[CH:12][C:13]([S:16]([NH:19][CH:20]2[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[C:32]([CH:31]([C:7]([CH:6]([Cl:5])[C:24]4[CH:23]=[C:22]5[C:27](=[CH:26][CH:25]=4)[CH2:28][CH:20]([NH:19][S:16]([C:13]4[CH:12]=[CH:11][C:10]([CH3:29])=[CH:15][CH:14]=4)(=[O:17])=[O:18])[CH2:21]5)=[O:8])[Cl:34])[CH:23]=3)[CH2:28]2)(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: ClCCCl
Reactant: Cc1ccc(S(=O)(=O)NC2Cc3ccccc3C2)cc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(S(=O)(=O)NC2Cc3ccc(C(Cl)C(=O)C(Cl)c4ccc5c(c4)CC(NS(=O)(=O)c4ccc(C)cc4)C5)cc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25.4 g (0.19 mol) of anhydrous aluminium chloride are suspended in 80 ml of ethylene chloride and 11.1 g (0.095 mol) of chloroacetyl chloride are added. 22.8 g (0.079 mol) of 2-p-toluenesulphonamido-indane are then added and the mixture is stirred for 2 hours at room temperature. The product is then decomposed by means of ice and hydrochloric acid and the reaction product is isolated from the organic phase and recrystallised from ethyl acetate/cyclohexane.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Cl:21])=[C:16]([OH:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]#[N:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Cl:21])=[C:16]([O:22][CH2:24][C:25]#[N:26])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: Oc1c(Cl)ccc2c1c1ccccc1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1c(Cl)ccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 85 °C
Reaction time: 12 h
Yield: 113.9 %

Procedure:
A mixture of 9-benzyl-3-chloro-9H-carbazol-4-ol (0.227 g, 0.739 mmol), bromoacetonitrile (0.177 g, 1.48 mmol), potassium carbonate (0.204 g, 1.48 mmol), and DMF (2 mL) is heated at 85° C. for 4 h, then allowed to cool and stir at room temperature for 12 h. Additional bromoacetonitrile (0.177 g) and potassium carbonate (0.204 g) are added and the mixture is heated again at 85° C. for 2 h. After cooling, the mixture is combined with that from another experiment run in the same manner (starting with 0.15 g of 9-benzyl-3-chloro-9H-carbazol-4-ol) and the combined mixtures are partitioned between ethyl acetate-aq. ammonium chloride/brine and brine. The organic layer is dried over magnesium sulfate and concentrated to dryness. Chromatography on silica gel (55 mL) using ethyl acetate-hexane (10/90) gave 0.292 g of [(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]acetonitrile as a clear liquid. 1H NMR (CDCl3) δ5.07, 5.50, 7.11, 7.15, 7.25-7.47, 7.50, 8.34.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=O)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.B.CSC.[ClH:30]>O1CCCC1.C(O)C>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:23])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1.[ClH:30]
Reactant: NC(=O)Cc1ccc(CS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCO
Product: NCCc1ccc(CS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.25 h

Procedure:
A solution of 2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-acetamide (1.36 g, 3.64 mmol) in tetrahydrofuran (30 ml) was refluxed and a solution of borane-dimethylsulfid complex (2M in tetrahydrofuran, 9.11 mmol) was added. The mixture was refluxed for 2 h. The mixture was allowed to come to room temperature and was adjusted to pH=1 using a solution of HCl in ethanol (2M). After stirring the mixture for 15 min the solvents were evaporated under reduced pressure. A slurry of the resulting white powder in diethyl ether was stirred for 15 min. The remaining solid was collected, washed with diethyl ether, and dried in a vacuum oven to give white crystals of 2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-ethylamine×HCl (1.22 g, 84.7%).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:2]1.C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[C:29]1([CH2:34]Cl)[S:33][CH:32]=[CH:31][CH:30]=1>C(O)C>[C:29]1([CH2:34][S:27][C:26]([N:2]2[C@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:28])[S:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Reactant: ClCc1cccs1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1cccs1
Yield: 62 %

Procedure:
In the same manner as described in Example 53, ethyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2.24 g), triethylamine (1.20 g), carbon disulfide (0.73 ml), ethanol (50 ml) and 2-thenyl chloride (1.59 g) are reacted and treated. The product is recrystallized from ethyl acetate-n-hexane to give the title compound (2.57 g, 62%) as colorless needles, m.p. 206°-207° C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(F)cc3)sc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a 50 ml eggplant-shaped flask were added 1.00 g (3.37 mmol) 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1, 0.68 g (6.75 mmol) triethylamine, 30 mg (0.25 mmol) DMAP and 25 ml THF, and then added dropwise 0.53 g (3.37 mmol) p-fluorobenzoyl chloride dissolved in 5 ml THF. The resulting mixture was stirred at room temperature for 2 hours, elevated to 35-40° C. and allowed to react for 10 hours, filtrated, washed with THF, the mother liquid was concentrated under a reduced pressure to give a pale brown oily crude product, separated with 50 ml ethyl acetate and 10 ml 1N HCl, the organic layer separated was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was recrystallized with ethyl acetate/petroleum ether (1:2) to obtain a 1.10 g product as a white solid in a yield of 78.0%, mp: 164-165 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.77 (3H, s, OCH3), 4.22 (2H, s, CH2), 6.76 (2H, d, J=7.84 Hz, ArH), 6.94 (2H, t, 3JFH=3JHH=8.40 Hz, ArH), 7.24˜7.36 (7H, m, ArH), 7.71 (2H, dd, 3JHH=7.56, 4JFH=5.32 Hz, ArH), 11.62 (1H, br, CONH); EI-MS m/e (%): 418.2 (M+, 100), 123.0 (86); HREI-MS Calcd. for C24H19FN2O2S: 418.1151. found: 418.1138. Anal. Calcd. for C24H19FN2O2S: C, 68.88; H, 4.58; N, 6.69. found: C, 68.77; H, 4.48; N, 6.84.