Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH3:22])=[C:14]([N+:23]([O-])=O)[C:13]=2[C:26]2[C:27]([F:33])=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].CC(O)=O>[Fe].O>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[C:15]([CH3:22])=[C:14]([NH2:23])[C:13]=2[C:26]2[C:27]([F:33])=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)c(C)c([N+](=O)[O-])c2-c2cc(C)cnc2F)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)c(C)c(N)c2-c2cc(C)cnc2F)c1
Temperature: 80 °C
Yield: 83.1 %

Procedure:
A mixture of 3-(3′-(ethylsulfonyl)-4-methyl-3-nitro-5-(trifluoromethyl)biphenyl-2-yl)-2-fluoro-5-methylpyridine (6.4 g, 13.3 mmol), iron (3.7 g, 66.3 mmol), HOAc, (32 mL), and H2O (11 mL) was heated at 80° C. for 2 h. After completion the reaction was concentrated in vacuo. The residue was reconstituted in dichloromethane (100 mL), filtered, and rinsed with dichloromethane (3×30 mL). The organic phase was washed with sat. NaHCO3 (1×100 mL) and brine (1×50 mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (1:1 hexanes/EtOAc) gave 5.0 g (83%) of the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 7.93 (s, 1H), 7.67-7.7.71 (m, 2H), 7.53 (t, 1H), 7.46-7.48 (m, 1H), 7.42 (s, 1H), 6.93 (s, 1H), 5.09 (s, 2H), 3.11 (q, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 0.85 (t, 3H). MS (ES) [m+H] calc'd for C22H20F4N2O2S, 453; found 453.3.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[S:9]1(=[O:48])[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:21]3[CH:22]=[C:23]([C:33]([NH:35][C:36]4[CH:40]=[CH:39][N:38](C(OC(C)(C)C)=O)[N:37]=4)=[O:34])[CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=3)=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][NH:10]1>C(Cl)Cl>[O:48]=[S:9]1(=[O:8])[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:21]3[CH:22]=[C:23]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=3)[C:33]([NH:35][C:36]3[CH:40]=[CH:39][NH:38][N:37]=3)=[O:34])=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][NH:10]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCNS3(=O)=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCNS3(=O)=O)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 1,1-dimethylethyl 3-{[(3-[(1,1-dioxido-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7-yl)oxy]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylate (47 mg, 0.08 mmol) in DCM (8 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo, DCM (20 mL) added and the mixture washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL), brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a white foam (39 mg).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:60][CH3:61])=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:60][CH3:61])=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1OC
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)c(=O)c2cc1OC
Yield: 94 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(6,7-dimethoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (48 mg, 94%). 1H NMR (400 MHz, DMSO-d6): δ 7.42-7.29 (m, 9H), 7.13-7.09 (m, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 2.40-2.33 (m, 2H), 2.11-2.02 (m, 2H), 2.02-1.95 (m, 1H), 1.69-1.60 (m, 1H). LCMS (Method F): RT=8.99 min, [M+H]+=428.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[O:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:41]1[N:46]2[CH:47]=[CH:48][N:49]=[C:45]2[CH:44]=[CH:43][CH:42]=1>O1CCOCC1.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.C1C=C(C([O-])=O)SC=1.[Cu+]>[N:49]1[CH:48]=[CH:47][N:46]2[C:41]([C:11]3[N:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:8]4[O:28][C:27]([CH2:29][N:30]5[CH2:31][CH2:32][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:34][CH2:35]5)=[CH:26][C:9]=4[N:10]=3)=[CH:42][CH:43]=[CH:44][C:45]=12
Reactant: Brc1cccc2nccn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2oc(CN3CCC(C(C)(C)O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(O)C1CCN(Cc2cc3nc(-c4cccc5nccn45)nc(N4CCOCC4)c3o2)CC1
Yield: 42 %

Procedure:
A mixture of 2-[1-(4-morpholin-4-yl-2-tributylstannanylfuro[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]propan-2-ol (147 mg, 0.23 mmol), 5-bromoimidazo[1,2-a]pyridine (46 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium (22 mg, 8 mol %) and CuTC (9 mg, 20 mol %) in 1,4-dioxane (2.5 mL) was purged with argon gas then subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:NH3/MeOH (2 M); gradient from 100:0 to 96:4)), followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to afford 249 as a white foam (46 mg, 42%). LCMS (Method G): RT=3.47 min, M+H+=477. 1H NMR (CDCl3, 400 MHz) 9.14 (s, 1 H); δ 7.87 (dd, J=8.5, 1.19 Hz, 2 H); 7.76 (d, J=8.9 Hz, 1 H); 7.73 (d, J=1.3 Hz, 1 H); 7.30 (m, 1 H); 6.79 (s, 1 H); 4.11 (t, J=4.7 Hz, 4 H); 3.90 (t, J=4.7 Hz, 4 H); 3.75 (s, 2 H); 3.08 (d, J=11.0 Hz, 2 H); 2.12 (t, J=11.0 Hz, 2 H); 1.78 (m, 2 H); 1.52-1.38 (m, 3 H); 1.31 (m, 1 H) and 1.19 (s, 6 H)
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.F[C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>CS(C)=O.C(OCC)(=O)C>[F:31][C:29]1[CH:30]=[CH:23][C:24]([C:25]#[N:26])=[C:27]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])=[CH:12][CH:13]=2)[CH:28]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: N#Cc1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(F)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108.6 %

Procedure:
KOtBu (0.968 g, 8.63 mmol) was dissolved into DMSO (3 ml) in a 100 ml round bottom flask. (4-aminophenyl)(morpholino)methanone (1.631 g, 7.91 mmol) in 7 ml of DMSO was added. The mixture was stirred for 15 mins at r.t. 2,4-difluorobenzonitrile (1 g, 7.19 mmol) in 3 ml DMSO was added slowly into the mixture for about 5 mins. The resulting mixture was stirred for 1.5 hrs at r.t. The mixture was diluted with ethyl acetate and extracted with aqueous NH4Cl solution. The organic layer was then washed with water (4×), brine, dried with MgSO4 and concentrated. 2.54 g crude 4-fluoro-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (80% by LC/MS) was obtained. MS (ESI) m/z 326.11 (M+H)+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]1([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][NH:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]>O.C(OCC)C>[C:8]1([C:14]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][N:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(-c2c[nH]nc2-c2ccccc2)cc1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(-c2cn[nH]c2-c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Sodium hydride (1.57 g of 50% dispersion, 32 mmol) was washed twice with hexanes, covered with DMF (100 mL), and a mixture of 3,4-diphenyl-1H-pyrazole and 4,5-diphenyl-1H-pyrazole (6.00 g, 27 mmol) was added. After gas evolution had ceased, the mixture was stirred for 10 minutes before adding methyl 8-bromooctanoate (7.10 g, 30 mmol). The mixture was stirred at room temperature for 40 minutes, diluted with water, and extracted with diethyl ether (3 times). The combined extracts were washed with water (3 times), dried over sodium sulfate, and concentrated in vacuo to leave an oil. Repeated chromatography on a column of silica gel using a mixture of hexanes and diethyl ether (2:1) as eluant provided methyl 3,4-diphenyl-1H-pyrazole-1-octanoate (6.11 g, 59%) as an oil. MS(CI): m/e=377 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.C([Li])CCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].O>C1COCC1>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]([Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:7][C:6]=1[O:8][Si:16]([CH3:18])([CH3:17])[CH3:15]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc(Br)cc1O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([Si](C)(C)C)cc1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
To a solution of 5-bromo-2-methylphenol (Intermediate 1, 3.6 g, 19.3 mmol) in THF (150 mL) at −78° C. was added n-butyl lithium (30 mL, 1.6 M solution in hexanes, 48.1 mmol) and the reaction stirred at this temperature for 30 minutes. Trimethylsilyl chloride (6.1 mL, 48.1 mmol) was then added and the solution stirred at −78° C. for 1.5 hours. The reaction was allowed to warm to room temperature and water (75 mL) was added. The mixture was extracted with diethyl ether (2×75 mL) and the combined organic extracts were dried (magnesium sulphate) and concentrated under reduced pressure to afford 2-methyl-5-(trimethylsilyl)phenoxytrimethylsilane (5 g) as a yellow oil. 1H NMR δH 0.26 (9 H, s), 0.29 (9 H, s), 2.20 (3 H, s), 6.93 (1 H, d, J=1.1 Hz), 7.04 (1 H, dd, J=7.3, 1.1 Hz), 7.16 (1 H, d, J=7.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].Br[CH:12]([CH3:14])[CH3:13]>C(O)C>[CH3:13][CH:12]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH3:14]
Reactant: Nc1ccccc1S
Reactant: CC(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Sc1ccccc1N
Temperature: 25 °C

Procedure:
To a solution of 2-aminothiophenol (90%, 100 g, 0.72 mol) and sodium hydroxide (31.7 g, 0.792 mol) in 90% aqueous ethanol (500 ml) was added dropwise 2-bromopropane (89 g, 0.72 mol) at room temperature. When the addition was complete, the reaction mixture was refluxed for 3 hours, cooled to room temperature, and then concentrated in vacuo. The residue was diluted with water (300 ml) and extracted with ether (3×500 ml). The ether extracts were washed with water and brine, dried with MgSO4 and concentrated in vacuo to yield the crude product. Distillation through a Vigreaux column gave 2-(1-methylethylthio)benzenamine: bp 94° (2.2-2.4 mm).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[CH:10][CH:11]=[CH2:12].OP(O)(O)=O>C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[CH2:9][CH2:10][CH:11]([CH3:12])[O:5][C:4]=2[CH:3]=1
Reactant: C=CC=C
Reactant: Oc1cccc(O)c1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CC1CCc2ccc(O)cc2O1
Temperature: 100 °C
Yield: 80.8 %

Procedure:
A 100 ml autoclave was charged wtih 20 g of resorcinol, 12 g of butadiene, 4 ml of H3PO4 and 60 ml of toluene, and purged with nitrogen. The mixture was then heated at 100° C. for 3.5 hours. The crude product was purified by column chromatography to give 24.1 g (yield 82%) of the desired product as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])[N:13]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reactant: CN(C)CCN
Product: CN(C)CCNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Yield: 84 %

Procedure:
The product of Example 47, and N,N-dimethylethylenediamine were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(2-dimethylamino-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (396 mg, 84% yield). 1H-NMR (CDCl3) δ 2.02-2.34 (m, 8H), 3.05 (m, 2H), 6.02 (br s, 1H), 6.39 (d, 1H, J=9.8 Hz), 7.24-7.62 (m, 9H). LC MS (m/e)=455 (MH+).
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH3:14])=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:26][C:12]1[O:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:2]([F:1])[F:15])=[CH:8][CH:7]=2)=[C:10]([CH3:14])[N:11]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ncoc1-c1ccc(C(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.4 %

Procedure:
To a solution of Example 38D (4.39 g, 21.0 mmol) in THF (100 mL) at −78° C. was added LiHMDS (1.0 M in THF, 23 ml, 23 mmol) slowly via syringe. The solution was stirred 45 min, and then solid hexachloroethane (5.46 g, 23.1 mmol) was added in one portion. The reaction was allowed to proceed for 24 hr, gradually warming to ambient temperature. The reaction was quenched with half-saturated aq NH4Cl solution, and the product was extracted with Et2O. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 0% to 20% EtOAc/hexanes eluant; SF40-240 g column) yielded 3.91 g (76%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.72 (m, 4H), 7.10 (t, J=55.7, 1H), 2.39 (s, 3H). MS (DCI+) m/z 244 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[N:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][CH:7]=1.C[Si]([C:25]#[N:26])(C)C>>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[NH:4][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:10][CH:11]=1)[C:25]#[N:26]
Reactant: C[Si](C)(C)C#N
Reactant: NS(=O)(=O)c1ccc(C=Nc2ccc(F)cc2F)cc1
Product: N#CC(Nc1ccc(F)cc1F)c1ccc(S(N)(=O)=O)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 2,4-difluoro-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a white powder (yield 100%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[C:6]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:5]=1.O.[OH-].[Li+].Cl>CO.O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][O:13][C:6]1[CH:5]=[C:4]([CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])[C:3]([OH:24])=[O:2]
Reactant: COC(=O)c1ccc(C(N)=O)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
103 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-terephthalamic acid methyl ester were dissolved in 1.2 ml of MeOH/water 3:1. 14 mg of lithium hydroxide monohydrate were added to the added to the solution, and the reaction was stirred at RT for 16 h and 2 h at 50° C. The solution was cooled to RT, then acidified with half-concentrated hydrochloric acid. The suspension was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield a white solid.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[C:14]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:25]1[CH:26]=[CH:27][C:28]2[S:34](=[O:36])(=[O:35])[CH2:33][CH2:32][C:31]([C:37]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][N:47]([CH3:54])[CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[CH:42][CH:41]=3)=[O:38])=[CH:30][C:29]=2[CH:55]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH3:54][N:47]([CH2:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([C:31]2[CH2:32][CH2:33][S:34](=[O:36])(=[O:35])[C:28]3[CH:27]=[CH:26][C:25]([C:6]4[O:7][C:8]5[C:14]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=[CH:11][C:9]=5[CH:10]=4)=[CH:55][C:29]=3[CH:30]=2)=[O:38])=[CH:41][CH:42]=1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCOc1cccc2cc(OB([O-])[O-])oc12
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOCCOc1cccc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)oc12
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 7-propoxyethoxy-benzofuran-2-yl borate (229 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (240 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol (40 ml) to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(7-propoxyethoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 144) (154 mg).
Reaction SMILES: N[C:2]1[C:3]([O:24]C)=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[C:8]([Cl:19])=[C:7]([C:20]([F:23])([F:22])[F:21])[CH:6]=2.Cl.[O:27]1CCOCC1>>[Cl:19][C:8]1[C:9]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])=[C:10]2[C:5](=[CH:6][C:7]=1[C:20]([F:21])([F:22])[F:23])[NH:4][C:3](=[O:24])[C:2](=[O:27])[NH:11]2
Reactant: C1COCCO1
Reactant: CCN(c1c(Cl)c(C(F)(F)F)cc2nc(OC)c(N)nc12)S(C)(=O)=O
Agent: Cl
Product: CCN(c1c(Cl)c(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c12)S(C)(=O)=O
Yield: 48 %

Procedure:
A mixture of N-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)-N-ethyl-methanesulphonamide (step (a) above, 70 mg, 0.18 mmol), 2M hydrochloric acid (3 ml) and dioxane (6 ml) was heated at reflux for 2 h, cooled and concentrated under reduced pressure. The residue was suspended in water, filtered and the solid was washed with water. After being dried, the title compound (33 mg, 48%) was obtained as a white solid, m.p. >300° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[N:10]=2)=[CH:5][CH:4]=1.[CH3:26][NH2:27]>>[ClH:1].[ClH:1].[CH:21]1([N:18]2[CH2:19][CH2:20][CH:15]([CH2:14][C:11]3[N:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:2][CH2:26][NH2:27])=[CH:8][CH:7]=4)[O:13][N:12]=3)[CH2:16][CH2:17]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CN
Reactant: ClCc1ccc(-c2nc(CC3CCN(C4CCCC4)CC3)no2)cc1
Product: Cl
Product: NCCc1ccc(-c2nc(CC3CCN(C4CCCC4)CC3)no2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 23, starting from 4-[5-(4-chloromethylphenyl)[1,2,4]oxadiazol-3-ylmethyl]-1-cyclopentylpiperidine and methylamine. HPLC: Rt=4.89 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:20]=[CH:19][C:18]=2[O:29][CH3:30])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[C:37]2[C:38]([F:43])=[CH:39][CH:40]=[C:41]([F:42])[C:36]=2[S:35][C:34]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:44]([C:34]2[S:35][C:36]3[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:37]=3[C:33]=2[Cl:32])=[O:45])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:29][CH3:30])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2ccncc2)cc1CNC1CCC(CNC(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(CNC(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a 3 L 3-neck RB flask equipped with a mechanical stirrer, N2 inlet and addition funnel is added [4-(2-methoxy-5-pyridin-4-yl-benzylamino)cyclohexyl]methylcarbamic acid t-butyl ester P5 (50.3 g, 118.20 mmol) and CH2Cl2 (750 mL). The resulting mixture is cooled in an ice bath and 3-chloro-4,7-difluorobenzothiophene-2-carbonyl chloride P10 (34.7 g, 129.92 mmol) in CH2Cl2 (250 mL) is added over 4 h. The reaction mixture is diluted with CH2Cl2 and washed with 1N HCl (800 mL), 1N NaOH (800 mL), H2O (500 mL) and brine (500 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo to an orange-brown solid. The crude product is ground to a fine solid, diluted with EtOAc (450 mL) and the resulting slurry is stirred for 1 h. The mixture is filtered and the filter cake is washed with EtOAc (100 mL), and dried to give {4-[(3-chloro-4,7-difluorobenzothiophene-2-carbonyl)-(2-methoxy-5-pyridin-4-ylbenzyl)amino]cyclohexyl}methylcarbamic acid tert-butyl ester P6 (66.0 g, 85%) as an off-white solid.