Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N:24]=1.C(#N)C.[NH4+].[OH-]>CN(C=O)C.C(N(CC)CC)C.CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][C:23]3[NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(N3CCNCC3)nc2)cc1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1ccc(COc2ccc(N3CCN(Cc4nc5ccccc5[nH]4)CC3)nc2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
The product from Example 29C and 2-chloromethyl-1H-benzoimidazole (0.88 mg) were combined and dissolved in DMF (7 mL)/triethylamine (1.5 mL). After stirring at 23° C. for 2 hours, the mixture was treated with acetonitrile (20 mL) and then allowed to stir for 24 hours. The reaction mixture was partitioned between CH2Cl2 (100 mL)/n-butanol (5 mL) and water (800 mL)/NH4OH (5 mL). The organic phase was separated, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography to provide the title as a white solid (1.169 g (55%). mp 62-64° C.; Rf=0.26 (95:5 CH2Cl2:methanol:0.1% NH4OH); MS 400 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 12.3 (bs, NH, 1H), 7.90 (d, 1H, J=3 Hz), 7.55 (m, 1H), 7.3-7.5 (m, 8H), 7.15 (m, 2H), 6.80 (d, 1H, J=9 Hz), 5.05 (s, 2H), 3.76 (s, 2H), 3.39 (t, 4H, J=5.1 Hz), 2.57 (t, 4H, J=5.1 Hz).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH:9]([C:14](=S)[NH:15][CH3:16])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:19][NH2:20].C(O)(=O)C.CCOCC>C(O)C>[CH:1]1([CH:7]2[CH2:12][CH2:11][C:10]3[NH:20][N:19]=[C:14]([NH:15][CH3:16])[C:9]=3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=S)C1CC(C2CCCCC2)CCC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CNc1n[nH]c2c1CC(C1CCCCC1)CC2

Procedure:
0.7 g of 4-cyclohexyl 2-methylthiocarbamoyl cyclohexanone dissolved in 30 ml ethanol are added with 0.15 g hydrazine hydrate. The mixture is heated to reflux for 30 mn until the evolution of sulphydric gas has ceased. 0.3 ml acetic acid are thereafter added and the whole is refluxed for 3 hours. The mixture is evaporated off giving a yellow liquid as residue. The residue is taken up with ether; the organic solution is washed with a saturated aqueous solution of sodium bicarbonate then with water until the washings are neutral, finally dried and evaporated off. 0.6 g of 5-cyclohexyl 3-methylamino 4,5,6,7-tetrahydroindazole are thus recovered and recrystallized from the minimum amount of isopropanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CCC(=O)CC>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[CH:19][CH:18]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(=O)CC
Product: O=C1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
Dissolve 4-piperidone (17 mmol) in 3-pentanone (25 mL) and heat to reflux. Add cesium carbonate (19 mmol) and a catalytic amount of potassium iodide, followed by 4-chlorobenzyl chloride (20 mmol). Stir and reflux for 4 hours. Filter the hot suspension, wash the residue with hot acetone (4×20 mL), combine the filtrate and washings, and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]([O-:10])=O.C1COCC1.[CH3:16][NH2:17]>C(OCC)(=O)C>[CH3:16][NH:17][C:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH3:2])=[O:10]
Reactant: Cc1sccc1C(=O)[O-]
Reactant: CN
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccsc1C
Yield: 71.8 %

Procedure:
2-Methyl-3-thiophenecarboxylate chloride (60.5 g)/THF (300 ml) solution was added dropwise to a 40% aqueous solution of methylamine (400 ml) at 0° C. Ethyl acetate (21) was added thereto, and then the organic layer was washed sequentially with water, a 5N aqueous solution of hydrochloric acid, an aqueous solution of saturated sodium bicarbonate, water and brine, dried and evaporated. The resulting residue was crystallized from n-hexane, to give the title compound as awhite powder (43.5 g, yield; 71.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:40]([S:42]([NH2:45])(=[O:44])=[O:43])[CH3:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:45][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc5ccccc5c4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc5ccccc5c4)CC3)cnc12
Yield: 60.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-[4-(2-naphthyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (69 mg, 0.13 mmol) obtained in step 2 and ethanesulfonamide (68 mg, 0.65 mmol), the title compound (48 mg, 60%) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][C:42]=1[C:50]#[N:51].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C(=O)([O-])O.[Na+].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>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:30][CH2:31]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)=[CH:43][C:42]=1[C:50]#[N:51]
Reactant: N#Cc1cc(B(O)O)ccc1Cl
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(Cl)c(C#N)c2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 41.3 %

Procedure:
To 100.0 mg (0.16 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 4 ml toluene were added 3.8 mg tetrakis(triphenylphosphine)palladium(0), 35.7 mg (0.20 mmol) (4-chloro-3-cyano-phenyl)boronic acid in 1.0 ml ethanol and 29.6 mg (0.51 mmol) potassium fluoride in 1.0 ml water. The mixture was stirred at 100° C. for 6 hours, diluted with water and saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 44 mg (36%) Tert-butyl 4-{3-[(3R)-3-({1-[5-(4-chloro-3-cyanophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: Cl.N1C=CC=CC=1.[CH2:8]([C@:15]12[C@@H:28]3[N:29]([CH2:32][CH:33]4[CH2:35][CH2:34]4)[CH2:30][CH2:31][C@:20]41[C:21]1[C:22]([O:38][C@H:19]4[C:18](=[O:39])[CH2:17][CH2:16]2)=[C:23]([O:36]C)[CH:24]=[CH:25][C:26]=1[CH2:27]3)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N>>[CH2:8]([C@:15]12[C@@H:28]3[N:29]([CH2:32][CH:33]4[CH2:34][CH2:35]4)[CH2:30][CH2:31][C@:20]41[C:21]1[C:22]([O:38][C@H:19]4[C:18](=[O:39])[CH2:17][CH2:16]2)=[C:23]([OH:36])[CH:24]=[CH:25][C:26]=1[CH2:27]3)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(Cc5ccccc5)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: Cl
Agent: N
Solvent: c1ccncc1
Product: O=C1CC[C@@]2(Cc3ccccc3)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 160 °C
Reaction time: 1 h

Procedure:
12.5 g of pyridine hydrochloride and 5.2 g (12 mMol) of the compound of example 3 are mixed at room temperature, and heated to 160° C. whilst stirring. After 1 hour, a further 12.5 g of pyridine hydrochloride are added, and heating continues for a further hour at 160° C. After cooling, the mixture is taken up in ice water, rendered basic with conc. ammonia and extracted three times with methylene chloride. The organic phases are dried over Na2SO4, concentrated by evaporation and flash-chromatographed over silica gel with ethyl acetate/hexane 1:3. The following are isolated: the title compound as a colorless oil and unreacted starting material. The title compound is converted into the hydrochloride with ether/ethanol/HCl: M.p.: 260° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[C:12]2[N:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([C:21]2[C:26]([F:27])=[C:25]([O:28][CH3:29])[CH:24]=[C:23]([O:30][CH3:31])[C:22]=2F)=[CH:19][CH:20]=1)=[O:10])[CH3:7]>CC#N>[CH2:6]([O:8][C:9]([C:11]1[C:12]2[N:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([C:21]2[C:26]([F:27])=[C:25]([O:28][CH3:29])[CH:24]=[C:23]([O:30][CH3:31])[C:22]=2[Cl:4])=[CH:19][CH:20]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Yield: 82.7 %

Procedure:
Sulfuryl chloride (0.35 mL, 4.33 mmol, 1.1 equiv) in CH3CN (10 mL) was added dropwise to a cold (−30° C.) solution of 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 143.1) (1.4 g, 3.93 mmol) in CH3CN (40 mL). The reaction mixture was quenched by addition of a saturated solution of NaHCO3, allowed to warm to it and concentrated. The residue was diluted in EtOAc and a saturated solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) to provide 1.27 g of the title compound as a white solid. Title compound: ESI-MS: 391.1 [M+H]+; tR=4.71 min (System 1); TLC: Rf=0.12 (Hex/EtOAc, 3:2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([F:26])[CH:19]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].Br>CC(O)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:26])[CH:19]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: COc1ccc(Nc2ncc(Br)cc2C(=O)Nc2ccccc2)cc1F
Agent: Br
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1)c1cc(Br)cnc1Nc1ccc(O)c(F)c1
Yield: 91 %

Procedure:
This process was repeated with 5-bromo-2-(3-fluoro-4-methoxyphenylamino)-N-phenylnicotinamide (2.78 g, 6.7 mmol), HOAc (7 ml), and hydrobromic acid (48%, 23 ml, 424 mmol). Both reactions were combined, and the pH of the aqueous phase was raised to above 12, and then washed with DCM. Then, the pH of the aqueous phase was lowered to 6 with concentrated HCl, and the aqueous phase was extracted with 10:1 DCM/MeOH). The organic extracts were combined and concentrated to afford the desired 5-bromo-2-(3-fluoro-4-hydroxyphenylamino)-N-phenylnicotinamide (2.45 g, 6.10 mmol, 70% purity, 52% yield). MS (ESI pos. ion) m/z: 402 (MH+, 79Br), 404 (MH+, 81Br). Calc'd exact mass for C18H13BrFN3O2: 401 (79Br), 403 (81Br).
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[S:11])(=O)C1C=CC=CC=1>[OH-].[Na+]>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][NH:12][C:10]([NH2:9])=[S:11])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCNC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)NCCNC(N)=S
Temperature: 50 °C
Reaction time: 1 h
Yield: 1046.7 %

Procedure:
N-benzoyl-N′-(2-t-butyloxycarbonylaminoethyl)thiourea (1.50 g, 0.44 mmol) was suspended in aqueous sodium hydroxide solution (22 mL, 2.0 M) and heated to 50° C. with stirring for 1 hour, which resulted in dissolution of starting material and consequent formation of precipitate. Reaction mixture was extracted with ethyl. acetate and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford solid residue of title product (1.01 g), which was used for next step without further purification. 1H NMR (CDCl3/CD3OD) δ 1.40 (s, 9H), 3.20 (m, 4H), 3.55 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C@H:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH3:5].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[Mg]Br.[Cl-].[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=1[F:22])([OH:14])[CH:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 2 h
Yield: 94 %

Procedure:
A solution of 0.69 g (3.0 mmol) of (R)-1-chloro-3-(tert-butyldimethylsilyloxy)butan-2-one in 5 mL of toluene was cooled to 0° C., and 5.3 mL (3.3 mmol) of a solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise over a period of 15 minutes. After the completion of the dropwise addition, stirring was continued for another 2 hours, and then 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added thereto, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 3). Thereby, the title compound was obtained in a yield of 94% ((2S,3R): (2R,3R)=90:10).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>C(Cl)Cl>[CH2:2]([O:9][C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:28](=[O:29])[NH:27][CH:24]([CH3:26])[CH3:25])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)N=C=O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 87.8 %

Procedure:
L-Proline benzyl ester hydrochloride (500 mg, 2.073 mmol) was dissolved in CH2Cl2 (10 ml). Triethylamine (600 mg, 6.0 mmol) and isopropylisocyanate (210 mg, 2.48 mmol) were added. After 18 h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 3% methanol, 97% chloroform) to give a colourless oil identified as the title compound (528 mg, 1.82 mmol, 88%).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[S-].[Na+]>CN(C)C=O>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C(=O)C2CCCCC2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1)C1CCCCC1
Yield: 100.7 %

Procedure:
4-Cyclohexylcarbonyl-1-methoxybenzene (517 mg) obtained in Example 141 was dissolved in N,N-dimethylformamide (20 ml), sodium thiomethoxide (538 mg) was added, and the admixture was refluxed with heat for 1 hour under argon. The reaction mixture was partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/acetone to obtain 487 mg of the title compound (yield: 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[CH:29]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[CH:29]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(OCCCBr)cc1O
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Product: CC(=O)c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1O

Procedure:
Following the procedure of Example 1, ]α,α-bis(p-fluorophenyl)-4-piperidinemethanol and 1-[4-(3-bromopropoxy)-2-hydroxyphenyl]ethanone are reacted to give the title compound.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[N-:27]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].[ClH:34]>CN(C=O)C.C(O)C.[Pd]>[NH2:27][CH2:11][CH:12]1[O:25][C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:24])[CH2:18]3.[ClH:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: NCC1COc2ccc3c(c2O1)CC(=O)N3
Temperature: 45 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (3.0 g, 8.0 mmole) and sodium azide (1.6 g, 24.0 mmole) were placed in 300 ml of DMF and the reaction mixture was heated at 45° C. for 15 hours. Most of the DMF was removed and the residue was partitioned between dichloromethane and water. The dichloromethane layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was pure enough without further purification and was identified as the desired product, (S)-2-azidomethyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one. An aliquot amount of the azide (0.8 g, 3.2 mmole) in ethanol (50 ml) was hydrogenated with 10% palladium on carbon (100 mg) for 15 hours. The resulting mixture was acidified with 4N isopropanolic HCl until pH<3. The catalyst was then filtered off and the filtrate was concentrated. The residue was dissolved in 90% aqueous ethanol and precipitated with diethyl ether to give the (S) enantiomer of the title compound as a white solid hydrochloride, 1.25 hydrate, (0.7 g, 85%), m.p. 278°-280° C.
Reaction SMILES: [S:1]1[C:5]([C:6]([C:9]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)([CH3:8])[CH3:7])=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2>O>[CH3:19][O:18][C:16]1[CH:17]=[C:9]2[C:10](=[CH:14][CH:15]=1)[C:11](=[O:13])[C:4]1[C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=3[S:1][C:5]=1[C:6]2([CH3:7])[CH3:8]
Reactant: COc1ccc(C(=O)O)c(C(C)(C)c2cc3ccccc3s2)c1
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1sc3ccccc3c1C2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To 2-(1-benzo[b]thiophen-2-yl-1-methylethyl)-4-methoxy-benzoic acid (Compound Z4, 68 mg, 0.22 mmol), polyphosphoric acid (3.5 g) was added, and the mixture was stirred for 1 hr at 100° C. under heating. The mixture was added with water, extracted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (41 mg, 63%).
Reaction SMILES: I[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:35][O:34][CH2:33]4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:3]=1.[C:36]([O:39][CH2:40][C:41]1[C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][C:44]([F:56])=[CH:43][C:42]=1[N:57]1[CH2:69][CH2:68][N:60]2[C:61]3[CH2:62][CH2:63][CH2:64][CH2:65][C:66]=3[CH:67]=[C:59]2[C:58]1=[O:70])(=[O:38])[CH3:37].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:36]([O:39][CH2:40][C:41]1[C:42]([N:57]2[CH2:69][CH2:68][N:60]3[C:61]4[CH2:62][CH2:63][CH2:64][CH2:65][C:66]=4[CH:67]=[C:59]3[C:58]2=[O:70])=[CH:43][C:44]([F:56])=[CH:45][C:46]=1[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:35][O:34][CH2:33]4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:3]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: C[Si](C)(C)CCOCn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)nc(I)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3ncn(COCC[Si](C)(C)C)c3n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 117f (607 mg, 1.0 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 101k (482 mg, 1.0 mmol), Pd(dppf)Cl2 (82 mg, 0.10 mmol), K3PO4 (424 mg, 2.0 mmol), sodium acetate (164 mg, 2.0 mmol), water (0.5 mL), and acetonitrile (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 117g as yellow solid (600 mg, 72%). MS-ESI: [M+H]+ 836.5
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH2:24])=[O:23].Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH2:24])=[O:23])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: NC(=O)c1cccc(N)c1
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3cccc(C(N)=O)c3)c2cc1OC
Yield: 92.2 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.136 g of 3-aminobenzamide, 20 mg of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrogen chloride to adjust pH to 7. The product was collected, washed with water, and dried to give 0.321 g of 3-(3-cyano-6,7-dimethoxy-quinolin-4-ylamino)-benzamide as a solid, mp 253-255° C.; mass spectrum (electrospray, m/e): M 349.1301.