Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=3)[N:24]=2)[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)(Cl)Cl.CN(C)C=O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:1][CH2:2][CH2:3][O:4][S:5]([C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=4)(=[O:7])=[O:6])=[CH:27][CH:26]=3)[N:24]=2)[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCCO)cc1
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(-c3cn4cc(Br)ccc4n3)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 12.2 %

Procedure:
To 10 mL of a solution of 639 mg (corresponding to 2.95 mmol) of 2-hydroxyethyl-p-toluenesulfonate in tetrahydrofran, 388 mg (corresponding to 1.34 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine and 780 mg (corresponding to 2.97 mmol) of triphenylphosphine were added. Further, 6 mL of N,N-dimethylformamide was added thereto to completely dissolve the contents. To the reaction mixture, 0.58 mL (corresponding to 2.95 mmol) of diisopropylazodicarboxylate was added. After the reaction mixture was stirred at room temperature for 17 hours, the reaction solution was concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=65/35). Insoluble matter in chloroform was filtered out of fractions containing a target compound. Further, the resulting crude product was purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 79.7 mg (corresponding to 164 μmol) of 6-bromo-2-[4′-(2″-p-toluenesulfonyloxyethoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1-3, Step 4).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH:15](C(O)=O)[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]>O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C(=O)O)C(=O)O)cc2s1
Solvent: O
Product: CCOC(=O)c1cc2ccc(CC(=O)O)cc2s1
Temperature: 200 °C
Yield: 99 %

Procedure:
[2-(ethoxycarbonyl)-1-benzothien-6-yl]malonic acid (0.60 g, 1.95 mmol) was suspended in H2O (4 mL) before heating at 200° C. in a microwave reactor for 60 seconds. The suspension was diluted with H2O (50 mL) and the products extracted into EtOAc (3×75 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give 0.51 g of product (white solid, 99%). 1H NMR (DMSO-d6) δ 12.42 (br s, 1H), 8.15 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.91 (s, 1H), 7.35 (dd, J=8.4, 1.8 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.71 (s, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]([C:11]([O:13][CH3:14])=[O:12])[S:4][CH2:3]1.[ClH:15].[NH2:16]O.CCOCC>C(#N)CC>[ClH:15].[NH2:16][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[S:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)C1SCC(=O)C1C(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CCC#N
Product: COC(=O)c1scc(N)c1C(=O)OC

Procedure:
3-Oxo-4,5-bismethoxycarbonyltetrahydrothiophene (2.65 g) was dissolved in propionitrile (5 ml) and hydroxylamine hydrochloride (1 g) was added. The mixture was heated under reflux on the steam bath for 11/2 hours by which time it was almost solid. Ether was added to the cooled mixture and the title compound was filtered off. Yield 2.37 g (77.5%) M.P.166°-169° dec. 3-Amino-4,5-bismethoxycarbonylthiophene was liberated from the title compound by treatment with aqueous ammonia followed by bulk distillation (220° C., 0.1 mm Hg) and exhibited 'H n.m.r. δ (CDCl3) 6.40 (1H,s), 4.40 (2H, brs), 3.90, 3.94 (2×3H,s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[C:19]([OH:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[CH:16][C:15]=1[CH3:25])=O.Cl(O)(=O)(=O)=O.[C:31](O)(=[O:33])[CH3:32]>[Pd]>[C:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:14]1[C:19]([OH:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[CH:16][C:15]=1[CH3:25])(=[O:33])[CH3:32]
Reactant: CC(=O)O
Reactant: COc1cc(C)c(C(=O)CCCCCCCCCCO)c(O)c1OC
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1cc(C)c(CCCCCCCCCCCOC(C)=O)c(O)c1OC

Procedure:
To a solution (200 ml) of 6-(11-hydroxy-1-oxoundecyl)-2,3-dimethoxy-5-methylphenol (14 g) in acetic acid is added 5% palladium-on-carbon (50% hydrate; 3 g) and 70% perchloric acid (0.1 ml), and catalytic reduction is carried out at ambient temperature and atmospheric pressure. After completion of the absorption of hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane, and the dichloromethane layer is washed with 5% aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Removal of the solvent by distillation gives a colorless oil of 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methylphenol (15 g).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH:13]([CH3:16])[S:12][CH:11]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH:13]([CH3:16])[S:12][CH:11]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:25])[CH3:24]
Reactant: CC1SC(c2cccnc2)N(CCO)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCN1C(=O)C(C)SC1c1cccnc1
Yield: 77 %

Procedure:
Pyridine (0.5 ml) was added to a solution of 3-(2-hydroxyethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4-one (0.5 g, 2.1 mmol) in acetic anhydride (2 ml) under ice-cooling. Then, the mixture was kept cooling for 2 hours. The resulting mixture was concentrated by evaporation under reduced pressure, and subjected to medium-pressure chromatography (hexane-acetone), giving 3-(2-acetoxy-ethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4-one (0.45 g, 77% yield)
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:40])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15](C3SC=CN=3)=[O:16])=[CH:13][C:12]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][C:31]([CH3:39])([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]4)=[N:26][CH:27]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2].C[C:42]([CH3:45])([O-])C.[K+]>CS(C)=O>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[S:7][C:8]2[C:14]([C:15](=[O:16])[NH:10][C:6]3[S:7][CH:42]=[CH:45][N:5]=3)=[CH:13][C:12]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:29][CH2:30][C:31]([CH3:39])([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)=[N:26][CH:27]=3)=[CH:11][C:9]=2[N:10]=1)=[O:40])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C(=O)c3nccs3)c2s1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(C(=O)Nc3nccs3)c2s1
Yield: 8 %

Procedure:
Ethyl 1-(5-(2-(3-ethylureido)-7-(thiazole-2-carbonyl)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (185 mg, 0.31 mmol) was dissolved in DMSO (2 ml) with stirring and potassium-t-butoxide (174 mg, 1.56 mmol) was added. The reaction was allowed to stir at rt for 1 h. The reaction was filtered and purified by preparative HPLC to afford Compound 145 as a solid (7 mg, 95% purity by HPCL) (4%) 1H NMR (DMSO-d6): δ 9.00-8.95 (2H, m), 8.63 (1H, s), 8.19 (1H, s), 7.65 (1H, d, J=3.59 Hz), 7.37 (1H, d, J=3.57 Hz), 6.93 (1H, t, J=5.58 Hz), 4.34 (2H, dt, J=13.73, 4.50 Hz), 3.41 (2H, dd, J=11.79, 3.40 Hz), 3.25 (2H, p, J=6.76 Hz), 2.06 (2H, dt, J=13.53, 3.67 Hz), 1.44 (2H, ddd, J=13.50, 9.94, 4.01 Hz), 1.23 (3H, s), 1.15 (3H, t, J=7.18 Hz). MS: 567 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]
Reactant: Oc1ccccc1Cl
Reactant: C[C@H](CCl)CBr
Product: C[C@H](CCl)COc1ccccc1Cl

Procedure:
Prepared by Procedure U and Scheme AK using 2-chlorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.O1CCCC1.[CH3:14][NH2:15]>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:15][CH3:14])[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: CN
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNC1CCN(C)CC1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A mixture of 1-methyl-4-piperidone (20 g, 0.18 mol) in methanol:tetrahydrofuran (100 mL, 1:1) and methyl amine (2 M in tetrahydrofuran, 3 mole excess) was placed in a Parr shaker with 5% Pd/C and hydrogenated for two hours at 60 psi and 70° C. The catalyst was filtered and the filtrate concentrated on the rotary evaporator. The crude material was distilled at 44-45° C. at 0.3 mm Hg to give 20 g (87%) of 1-methyl-4-methylaminopiperidine. Anal. Calc'd for C7H16N2: C, 65.57; H, 12.58; N, 21.85. Found: C, 65.49; H, 12.44; N: 21,49.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH2:12]/[CH:13]=[CH:14]/[CH2:15][C:16]([O:18]C)=[O:17])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+]>CO.O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH2:12]/[CH:13]=[CH:14]/[CH2:15][C:16]([OH:18])=[O:17])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C/C=C/CC(=O)NCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)C/C=C/CC(=O)NCCc1ccccc1
Yield: 83.4 %

Procedure:
The product of step (a) (13.9 g., 48 mmoles) and sodium bicarbonate (4.05 g., 48 mmoles) in methanol (300 ml) and water (60 ml) was heated at reflux for 8 hr. The solution was evaporated to dryness and the residue partitioned between water and ethyl acetate. The aqueous phase was separated, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. Evaporation of the organic extracts gave the sub-title compound (9.9 g) mp 101°-103°.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].C(N(CC)CC)C>O1CCCC1.CN(C1C=CN=CC=1)C>[C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14](=[O:16])[CH3:15])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cn(C(C)=O)c2ccccc12
Reaction time: 3 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 1H-indol-3-yl acetate (8 g, 45.69 mmol) in tetrahydrofuran (150 mL). To this was added acetic anhydride (46.6 g, 456.86 mmol). Addition of triethylamine (9.25 g, 91.49 mmol) was next. To the mixture was added DMAP (1.11 g, 9.10 mmol). The resulting solution was allowed to react, with stirring, for 3 hours while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was diluted with 300 mL of ethyl acetate The resulting mixture was washed 2 times with 150 mL of NaCl(aq.). The mixture was dried over Na2SO4. The residue was purified by eluting through a column with a 20:1 petroleum ether/ethyl acetate solvent system. This resulted in 6.6 g (67%) of 1-acetyl-1H-indol-3-yl acetate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:24])[CH2:22][CH3:23])=[C:3]([C:12]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: CCC(=O)Cl
Reactant: Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Product: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 from 3-amino-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Example 68) and propionyl chloride. m.p.: 188-190° C. (recrystallized from ethyl acetate) 1H-NMR (CDCl3) δ: 11.68 (1 H, br s), 10.88 (1 H, br s), 8.70 (1 H, d, J=5.4 Hz), 8.54 (1 H, d, J=9.1 Hz), 8.37 (1 H, d, J=2.0 Hz), 7.58 (1 H, dd, J=2.1, 5.3 Hz), 7.40 (1 H, d, J=2.0 Hz), 7.06 (1 H, dd, J=1.1, 9.1 Hz), 2.63 (2 H, q, J=7.6 Hz), 1.37 (3 H, t, J=7.6 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@@H:8]([OH:10])[CH3:9])[C:5]([F:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>[Pd].C(Cl)Cl>[F:11][C:5]1[C:6]([C@@H:8]([OH:10])[CH3:9])=[N:7][CH:2]=[CH:3][CH:4]=1
Reactant: [H][H]
Reactant: C[C@H](O)c1nc(Br)ccc1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](O)c1ncccc1F
Yield: 64.8 %

Procedure:
(1S)-1-(6-Bromo-3-fluoro-pyridin-2-yl)ethanol (1.3 g, 5.9 mmol), triethylamine (1.6 mL, 11.5 mmol) and palladium on carbon (0.64 g, 0.34 mmol) were mixed in DCM (25 mL). The flask was evacuated/filled with hydrogen gas in 4 cycles and then left at 2.5 atm pressure hydrogen gas at room temperature for 24 h. The mixture was filtered and the solid washed with DCM. The filtrate was washed with water and Brine and dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent DCM:methanol gradient) to yield 0.54 g (65% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH:4]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C-:26]#[N:27].[Na+]>CS(C)=O>[C:26]([CH2:8][CH:4]1[CH2:5][C:6](=[O:7])[N:2]([CH3:1])[CH:3]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)#[N:27]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(C)C2c2ccccc2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1C(=O)CC(CC#N)C1c1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 42 g. of 1-methyl-2-phenyl-3-tosyloxymethyl-pyrrolidin-5-one in 72.5 ml. of dimethylsulfoxide was slowly added 5.7 g of sodium cyanide at 45° C. The reaction was stirred for 3 hours at 100° C. and then set at ambient temperature for 18 hours. After decanting into 1500 ml. of ice water, the product was extracted with 2:1 chloroform-ether, dried (Na2SO4) filtered, and concentrated in vacuo to provide 19.0 g. of light yellow crystals.
Reaction SMILES: C(N[C:6]([NH:8][S:9]([CH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:11])=[O:10])=[O:7])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>>[CH3:25][O:24][C:22]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:13]=1[CH2:12][S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10])=[O:23]
Reactant: CCCCNC(=O)NS(=O)(=O)Cc1c(C(=O)OC)cccc1[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CS(=O)(=O)N=C=O

Procedure:
A suspension of 8.4 g of the product from Example 5 and 0.1 g of 1,4-diazabicyclo[2.2.2]octane (DABCO) in 75 ml xylenes was heated to reflux temperature. To this stirred solution was added 2 ml of phosgene at a rate that maintained the temperature above 130°. When the addition was complete, the turbid solution was heated at reflux temperature for 15 minutes, allowed to cool, and then filtered under an atmosphere of nitrogen. Removal of the solvent from the filtrate afforded the product as a viscous brown oil which was dissolved in dry methylene chloride and carried on to the next step without purification. The infrared spectrum of this intermediate displayed a characteristic isocyanate absorption at 2215 cm-1 and a carbonyl stretching absorption at 1730 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH:16]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH:19]=4)[CH2:14][CH2:13]3)[C:6]=2[CH:27]=1.[CH3:28][CH2:29][CH2:30]CCC.C(Br)C=C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH2:30][CH:29]=[CH2:28])[CH:19]=4)[CH2:16][CH2:17]3)[C:6]=2[CH:27]=1
Reactant: CCCCCC
Reactant: Clc1ccc2scc(CCN3CC=C(c4c[nH]c5ccccc45)CC3)c2c1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCn1cc(C2=CCN(CCc3csc4ccc(Cl)cc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (392 mg, 1 mmol) (obtained from example 32, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and was washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and allyl bromide (183 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Yellow semi-solid. Yield: 156 mg (36%); 432 (M+H); 1H NMR: δ 7.90(1H, s, NH), 7.78(3H,m), 7.26(6H, m), 6.21(1H, s), 5.99(1H, m), 5.13(2H, m), 4.71(2H, m), 3.40(2H, s), 3.15(2H, m), 2.92(4H, m), 2.68(2H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.[CH2:27]([NH2:30])[CH2:28][NH2:29]>>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:14]2[CH2:13][N:12]([C:4]3[CH:3]=[C:2]([NH:29][CH2:28][CH2:27][NH2:30])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH2:18][CH2:17][CH2:16][C:15]=2[CH:19]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCCN(c1cc(Cl)c3ccccc3n1)C2
Reactant: NCCN
Product: CS(=O)(=O)c1ccc2c(c1)CCCN(c1cc(NCCN)c3ccccc3n1)C2
Temperature: 150 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
The mixture of 2-(4-chloroquinolin-2-yl)-7-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (55.6 mg, 0.144 mmol) and ethane-1,2-diamine (1 mL) was heated with stirring in a 10 mL microwave process vial for 2 hours at 150° C. under microwave irradiation. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give 27.5 mg of product as a light-yellow solid (yield was 46.5%). MS obsd. (ESI+) [(M+H)+] 411. 1H NMR (400 MHz, CD3OD) δ ppm 7.82-7.73 (m, 4 H), 7.53 (d, J=7.6 Hz, 1 H), 7.45-7.40 (m, 1 H), 7.12-7.08 (m, 1 H), 5.98 (s, 1 H), 4.96 (s, 2 H), 4.16 (s, 2 H), 3.41 (t, J=6.4 Hz, 2 H), 3.16 (brs, 2 H), 3.06 (s, 3 H), 2.97 (t, J=6.4 Hz, 2 H), 1.96 (brs, 2 H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[Cl:18][C:19]1[C:24]([CH:25]=[CH:26][C:27](O)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([F:33])([F:32])[F:31])[N:20]=1>>[Cl:18][C:19]1[C:24]([CH:25]=[CH:26][C:27]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([F:31])([F:32])[F:33])[N:20]=1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Yield: 89.9 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (228 mg, 0.795 mmol) was reacted with 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (200 mg, 0.795 mmol) to give the title compound (340 mg, 90%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])[CH:8]=[C:9]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[F:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[C:7]1[CH:8]=[C:9]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1cc(-c2cncs2)cc(-c2ccc(C)cc2F)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3cncs3)c2)c(F)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 2′-fluoro-4′-methyl-5-thiazol-5-yl-biphenyl-3-carboxylic acid methyl ester (0.327 g, 1 mmol) in THF (10 mL) was added a solution of LiOH—H2O (1.2 mmol) in H2O (15 mL) at 0° C. The reaction was allowed to warm to room temperature and THF was removed under reduced pressure. The aqueous solution was acidified to pH=2, and the solid was collected by filtration and dried to yield 2′-Fluoro-4′-methyl-5-thiazol-5-yl-biphenyl-3-carboxylic acid as a white solid (75%), MS (M+H)=314.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([OH:9])[CH3:8].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:10][S:11]([O:9][C@@H:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:8])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H](OS(C)(=O)=O)c1ccccn1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a stirred solution of 0.27 g (2.2 mmol) of commercially available (1R)-1-pyridin-2-ylethanol in 5 mL of anhydrous dichloromethane was added 0.53 g (4.3 mmol) of 4-(dimethylamino)pyridine followed by 0.20 mL (2.6 mmol) of methanesulfonyl chloride. The resulting mixture was stirred with gradual warming to ambient temperature over 1 h. The resulting mixture was quenched with water and extracted with dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the title compound as a yellow oil (0.35 g, 81% yield).
Reaction SMILES: Br[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][C@H:27]([CH3:45])[O:28][C:29]1[CH:30]=[C:31]([OH:44])[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[OH:44][C:31]1[CH:32]=[C:33]([C:2]2[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[CH:4][CH:3]=2)[CH:34]=[C:29]([O:28][C@@H:27]([CH3:45])[CH2:26][O:25][CH3:24])[CH:30]=1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1C(=O)OCc1ccccc1
Reactant: COC[C@H](C)Oc1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C(=O)OCc3ccccc3)n2C(=O)OC(C)(C)C)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
2-Benzyl 1-t-butyl 5-bromo-1H-pyrrole-1,2-dicarboxylate (8.75 g, 23.0 mmol) synthesized in Example (780 and 3-[(1S)-2-methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (7.11 g, 23.1 mmol) synthesized in Example (78d) were dissolved in a mixed solvent of 1,4-dioxane (92 mL) and water (23 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (570 mg, 0.698 mmol) and potassium carbonate (7.95 g, 57.5 mmol) were added, followed by stirring at 55° C. for 3 hours under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (200 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=15%-35%) to afford the desired compound (8.32 g, yield 75%) as a brown oil.