Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[C:13]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:19])[CH2:12][CH2:11]3)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][CH:38]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:13]1([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]4[CH:38]=[N:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)=[CH:7][N:6]=3)[CH:9]=2)[C:14]1=[O:18]
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CCOC(=O)CC1(C)CCc2cc(-c3ccc(N)cn3)ccc2C1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(C)CCc2cc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)cn3)ccc2C1=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
Pd2(dba)3 (0.068 g, 0.074 mmol) and BINAP (0.046 g, 0.074 mmol) were added to a solution of 3G (0.5 g, 1.478 mmol) in 10 mL of toluene under argon atmosphere, followed by cesium carbonate (1.44 g, 4.43 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (0.334 g, 1.478 mmol). The mixture was degassed for 10 min. The reaction mixture was stirred at 100° C. for 6 h and allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and water. The separated organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography using 8% ethyl acetate in hexane to afford the title compound 3H (0.4 g, 53%) as a solid. 1H NMR (300 MHz, DMSO-d6): δ 9.34 (s, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.51 (d, J=2.2 Hz, 1H), 8.08-7.91 (m, 4H), 7.88-7.63 (m, 3H), 4.01 (q, J=7.1 Hz, 2H), 3.08 (m, 2H), 2.85 (d, J=15.9 Hz, 1H), 2.50-2.29 (m, 2H), 1.93 (m, 1H), 1.19 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). ESI-MS m/z: 484 (M+H)+.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[CH:10][C:9]=1[CH3:23])([O-])=O>C(O)C.O.[Fe]>[OH:22][C:18]1[CH:17]=[C:16]([S:15][C:11]2[CH:10]=[C:9]([CH3:23])[C:8](=[CH:13][C:12]=2[CH3:14])[NH2:5])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Sc1cccc(O)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(Sc2cccc(O)c2)c(C)cc1N
Temperature: 60 °C

Procedure:
6.3 ml of glacial acetic acid (0.11 moles) are added to a solution of 20 g of the product obtained in Example 4 (0.076 moles) in 328 ml of ethanol and 33 ml of H2O; 29.7 g of Fe in powder form (0.53 moles) are carefully added to the reaction mixture kept under stirring at 60° C. The temperature is brought to 90° C. and the mixture is kept under stirring for 1.5 hours.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]#[N:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][OH:25])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[C:17]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[N:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:9]=[C:10]2[C:19]1[N:23]=[C:22]([CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[S:21][N:20]=1)#[N:18]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cccc2c(-c3nsc(CO)n3)cn(CC3CCCCC3)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1nc(-c2cn(CC3CCCCC3)c3c(C#N)cccc23)ns1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 1-cyclohexylmethyl-3-(5-hydroxymethyl-[1,2,4]thiadiazol-3-yl)-1H-indole-7-carbonitrile (416 mg, 1.18 mmol) in dichloromethane (40 ml) was added methanesulfonyl chloride (0.110 ml, 1.42 mmol) and triethylamine (0.214 ml, 1.53 mmol) sequentially. The reaction was allowed to stir for 1 h and then poured into a separating funnel. The organics were washed with 2M aqueous sodium carbonate solution (20 ml), brine (20 ml), dried over magnesium sulfate, filtered, and the solvent removed in vacuo to afford methanesulfonic acid 3-(7-cyano-1-cyclohexylmethyl-1H-indol-3-yl)-[1,2,4]thiadiazol-5-ylmethyl ester (503 mg, 1.17 mmol) which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C([Mg]Cl)C.[Cl:18][CH2:19][C:20](Cl)=[O:21].C1COCC1>C(OCC)C.C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([C:3]([C:20](=[O:21])[CH2:19][Cl:18])=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:11]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=C(Cl)CCl
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C(=O)CCl)c[nH]c2c1
Yield: 19.9 %

Procedure:
A mixture of 14 g (80 mmol) methyl indole-6-carboxylate, 40 mL (84 mmol) ethylmagnesium chloride (2M) in diethyl ether, 240 mL (240 mmol) zinc chloride (1M) in diethyl ether, 9.5 g (84 mmol) chloroacetyl chloride in 680 mL DCM was stirred at room temperature for 19 h. THF was added and diethyl ether and DCM were removed by evaporation. The mixture was treated with NH4Cl aq. and ethyl acetate. The aqueous phase was extracted with THF/ethyl acetate and the combined organic layers were washed with NaCl aq., dried with Na2SO4 and evaporated. The residue was washed with ethyl acetate and dried under vacuum at 50° C. to yield 4 g (20%) of the title compound as light yellow solid. MS (m/e): 250.1 (M−H).
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([O:38][CH3:39])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=O)C.[OH-].[Li+]>O1CCCC1.CO.O>[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([O:38][CH3:39])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(OC)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(S(=O)(=O)c2ccc3[nH]ccc3c2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A mixture of the product of step D (25 mg, 0.04 mmol), lithium hydroxide (14 mg, 0.32 mmol) in tetrahydrofuran (1.25 mL), methanol (0.62 mL) and water (0.31 mL) was stirred at ambient temperature for 8 h. The reaction was quenched with aqueous ammonium chloride (15 mL) and extracted with dichloromethane. The organic extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) to give tert-butyl 8-((1H-indol-5-yl)sulfonyl)-6-methoxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (18 mg, 83%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.62 (s, 1H), 8.33 (s, 1H), 7.77-7.62 (m, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.35-7.30 (m, 1H), 6.70-6.64 (m, 1H), 4.53 (s, 2H), 4.02 (s, 3H), 3.80 (t, J=5.4 Hz, 2H), 2.92-2.76 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[CH2:8]([NH2:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:8]([NH:20][C:2](=[O:7])[CH2:3][O:4][CH2:5][CH2:6][OH:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1COCCO1
Product: CCCCCCCCCCCCNC(=O)COCCO
Temperature: 100 °C

Procedure:
In a glass reaction vessel 10.2 grams (0.1 mole) of 2-p-dioxanone was admixed with 18.5 grams (0.1 mole) of dodecyl amine and heated to 100° C. on a steam bath until reaction was completed within the period of 1 hour. The resulting liquid product was then poured on a glass plate and cooled to room temperature whereupon a pale yellow solid was formed. IR=6.06 mu.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9])=[C:6]([S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16])[CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:30][CH3:31])[N:23]=1>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9])=[C:6]([S:15]([NH:18][C:19]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:30][CH3:31])[N:23]=2)=[O:20])(=[O:16])=[O:17])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: COCCOC(=O)c1c(F)cccc1S(=O)(=O)N=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOC(=O)c1c(F)cccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
7.1 g of β-methoxyethyl 6-fluoro-2-isocyanatosulfonylbenzoate in 20 ml of methylene chloride were added over 10 minutes at 25° C. to a stirred mixture of 4 g of 2-amino-4,6-dimethoxy-1,3,5-triazine in 40 ml of DMF under nitrogen; the temperature rose to 32° C. After the mixture had been stirred for 14 hours at 25° C., the solvent was removed under reduced pressure and the residue was stirred with ether and twice with 3N HCL. It was then taken up in acetone, insoluble mater was separated off and the filtrate was concentrated to dryness. 7 g of the compound shown in the title, of melting point 179° C.-182° C. were obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)OCC>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]2)=[CH:17][CH:18]=1)#[N:21]
Reactant: N#Cc1ccc(F)cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2ccc(C#N)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 29.9 %

Procedure:
(S)-tert-butyl 2-methylpiperazine-1-carboxylate (1 g, 4.99 mmol), 4-fluorobenzonitrile (0.605 g, 4.99 mmol), and K2CO3 (0.897 g, 6.49 mmol) were combined into a vial equipped with a stir bar. The reaction was heated to 110° C. for 48 h. Cooled to RT, diluted with EA and filtered. Concentrated to a clear oil and purified on silica gel (80 g, 10-20% EA in Hex) to give a clear oil (450 mg, 30% yield) which became a crystalline solid upon sitting. [M+H] calc'd for C17H23N3O2, 301. found, 301.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH:3]([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:19]([O:21][CH3:22])=[O:20])=[O:8])[CH2:2]1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>C(O)(=O)C.ClCCl>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:1]1[CH2:6][CH2:5][S:4][CH:3]([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:19]([O:21][CH3:22])=[O:20])=[O:8])[CH2:2]1
Reactant: COC(=O)c1n[nH]c2ccc(NC(=O)C3CNCCS3)cc12
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1n[nH]c2ccc(NC(=O)C3CN(Cc4ccccc4F)CCS3)cc12
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
In a flask, dichloromethane (5 mL) and acetic acid (3 drops) was added to methyl 5-(thiomorpholine-2-carboxamido)-1H-indazole-3-carboxylate (0.320 g, 1 mmol) and 2-fluorobenzaldehyde (0.248 g, 2 mmol). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (0.636 g, 3 mmol) was added in one portion. The reaction was stirred for an additional 16 hours. Saturated sodium bicarbarbonate (20 mL) was added. The reaction was stirred for an additional 5 minutes and was extracted with dichloromethane (30×1 mL). The extracts were combined, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by flash column chromatography to give 250 mg product. LC-MS: 429.1.2 [M+H].
Reaction SMILES: CC1(C)P([C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14](OC)[C:13]=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)C(C)(C)CC2(OCCO2)C1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:46]([OH:50])[CH2:47][CH2:48][CH3:49].ClC1C=CC=CC=1OC>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:46]([O:50][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:47][CH2:48][CH3:49]
Reactant: COc1ccc(OC)c(P2C(C)(C)CC3(CC2(C)C)OCCO3)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Reactant: CCCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCOc1ccccc1OC
Temperature: 110 °C
Yield: 62 %

Procedure:
In a nitrogen-atmosphere glovebox, a 40-mL scintillation vial equipped with a magnetic stir bar was charged with palladium(II) acetate (3.2 mg, 0.014 mmol, 0.01 equivalents), 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane (8.6 mg, 0.015 mmol, 0.011 equivalents) and cesium carbonate (686 mg, 2.10 mmol, 1.5 equivalents). The solids were then slurried in toluene (2.8 mL) and n-butanol (385 μL, 4.21 mmol, 3 equivalents). 2-Chloroanisole (178 μL, 1.40 mmol, 1 equivalent) was added by syringe, then the vial was sealed with a polytetrafluoroethylene (PTFE) screw cap septum and heated to 110° C. for 19 hours. After cooling the reaction to room temperature, the vial was brought outside the glovebox. The reaction mixture was diluted with ethyl acetate (2 mL) and filtered through a pad of diatomaceous earth. After the vial was rinsed with ethyl acetate (2×2 mL) and filtered, the filter cake was washed with ethyl acetate (2 mL). The ethyl acetate was carefully removed on a rotary evaporator. A weight percent (wt %) analysis was then performed on the crude concentrate to determine an assay yield of 62% (literature reference: Wolter M, et al. Org. Lett. 2002; 4: 973-976). 1H NMR (400 MHz, CDCl3) δ ppm 6.96-6.84 (m, 4H), 4.03 (t, J=6.8 Hz, 2H), 3.87 (s, 3H), 1.91-1.78 (m, 2H), 1.57-1.44 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH:10]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCC1CCCCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-chlorothiophene-2-carboxylic acid (3.01 g, 19.0 mmol), cyclohexylmethyl bromide (3.51 g, 19.8 mmol) and potassium carbonate (2.81 g, 20.33 mmol) was stirred under Ar at +85° C. for 3 days and cooled to room temperature. Reaction mixture was diluted with water and extracted with hexanes three times. Combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (2%-15% EtOAc—hexanes gradient) gave cyclohexylmethyl 5-chlorothiophene-2-carboxylate as a colorless oil. Yield (4.76 g, 97%); 1H NMR (400 MHz, CDCl3) δ 7.56-7.60 (m, 1H), 6.90-6.94 (m, 1H), 4.08 (d, J=6.10 Hz, 2H), 1.64-1.82 (m, 6H), 1.10-1.34 (m, 3H), 0.97-1.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[O-:36][C:37]#[N:38].[K+].C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:34][CH:35]=1)[C:37]([NH2:38])=[O:36]
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(N)=O)cc2)c1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
4-Amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (237.2 mg, 0.50 mmol) was dissolved in acetic acid-water (1:2, 1.8 ml) to which was subsequently added dropwise an aqueous solution (0.5 ml) of potassium cyanate (81.1 mg, 0.90 mmol) After 3 hours of stirring at room temperature, the reaction solution was mixed with saturated sodium bicarbonate aqueous solution, alkanized with 10% sodium hydroxide aqueous solution and then extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, and dried on anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=10:1) and recrystallized from ethyl acetate-ether to obtain 125.6 mg (48.4%) of the title compound in a colorless powder form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[S:25])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccc(Br)c2)COCC(=S)N1

Procedure:
A solution of 5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (18 g, 67 mmol) in dry THF was treated with Lawesson's reagent (27 g, 67 mmol) in one portion at room temperature. The mixture was refluxed for 2 h. The title compound was obtained by chromatography on silica gel (PE/EtOAc=30:1 to 10:1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]([N:41]1[C:46](=[O:47])[C:45]([CH2:48]OS(C)(=O)=O)=[CH:44][C:43]([C:54]2[CH:59]=[CH:58][C:57]([F:60])=[C:56]([CH3:61])[CH:55]=2)=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN1CCNCC1>>[CH2:34]([N:41]1[C:46](=[O:47])[C:45]([CH2:48][N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[CH:44][C:43]([C:54]2[CH:59]=[CH:58][C:57]([F:60])=[C:56]([CH3:61])[CH:55]=2)=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccccc3)n2)ccc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccccc3)n2)ccc1F
Yield: 81.3 %

Procedure:
Following the procedure of Example 1 (10), 2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 81.3%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[Br:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1.C(O)(=O)C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.CO>[Br:7][C:8]1[C:9]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1
Reactant: Clc1ncc(Br)cn1
Reactant: [Li]c1cccs1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: Clc1ncc(Br)c(-c2cccs2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Thienyl lithium (1.0 M in THF, 26 mL, 26 mmol) was diluted with anhydrous THF (65 mL) and the mixture cooled down to −78° C. under a nitrogen atmosphere. 5-Bromo-2-chloropyrimidine, dissolved in 10 mL of tetrahydofuran, was added to the reaction mixture dropwise. The reaction was allowed to stir for 1 h and then warmed to −20° C. Acetic acid (1.5 mL) and methanol (1.2 mL) were successively added to the reaction mixture. The reaction was stirred for 15 min and a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.9 g, 20 mmol) in 10 mL of THF was added. The reaction was stirred for an additional 15 min and then the cooling bath was removed. The mixture was stirred for 1 h and then cooled to 0° C. with an ice bath. 5 N sodium hydroxide (5.2 mL) was added to the reaction mixture and stirred for 5 min. The reaction was then diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography on silica gel using 5% ethyl acetate in hexanes as an eluent to obtain a yellow solid. Yield=3.6 g. MS (M+H)+ 275/277.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39]COC)[CH2:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.CO>O1CCCC1.Cl>[Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([OH:39])[CH2:36][CH2:37][CH2:38]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(C(=O)O)cc3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc(C(=O)O)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 80 °C

Procedure:
A solution of 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid (Example 16A) (700 mg, 1.122 mmol) in tetrahydrofuran (9.3 mL) and 10% aqueous HCl solution (1.9 mL) was heated to 65° C. for 24 hours. An additional 3 mL 10% aqueous HCl solution and 3 mL methanol were added, and the reaction was heated to 80° C. for 3 hours. The reaction was removed from the heat bath and allowed to slowly cool to room temperature. The reaction was diluted with 5 mL water, and the solid was filtered and air-dried to yield the title compound. MS ESI(+) m/z 580.1 [M+H]+;
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[Cl:10])[NH2:6].N1C=CC=CC=1.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>ClCCl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:3]([C:2]([F:1])([F:11])[F:12])[CH:4]=1)=[O:22]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C(Cl)(Cl)Cl
Reaction time: 1 h
Yield: 79.1 %

Procedure:
The clear solution of 3-trifluoromethyl-4-chloroaniline (45 g, 0.230 mol) and pyridine (37 ml, 0.460 mol) in dichloromethane (450 ml) cooled at 0° C. to −5° C. and a solution of trichloroacetyl chloride (31 ml, 0.2876 mol) in dichloromethane (100 ml) was added drop wise maintaining temperature of the reaction mass below 0° C. The reaction mass was then stirred for 1 hour below 0° C. and quenched with water (250 ml) below 5° C. The organic phase was separated and aqueous layer was re-extracted with dichloromethane. The combined dichloromethane layer was washed with water, dried over sodium sulfate and evaporated under vacuum to obtain (62 g) of the desired product, i.e., 2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl)phenyl)acetamide.