Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][C:16]([CH3:20])=[CH:17][C:18]([CH3:19])=[C:13]3[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[CH2:21]([C:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:23]=[N+:24]=[N-:25])=[CH:5][CH:6]=2)[C:14]2=[N:15][C:16]([CH3:20])=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1)[CH3:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCCl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a stirred solution of 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 7, 2.8 g, 9.0 mmol) and KI (1.5 g, 9.0 mmol) in DMF (50 mL) was added sodium azide (1.2 g, 18.0 mmol), and then the resulting mixture was stirred overnight at 100° C. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 2.35 g (85%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 6.90 (1H, s), 3.59 (2H, t, J=7.1 Hz), 2.99 (2H, t, J=7.1 Hz), 2.83 (2H, q, J=7.6 Hz), 2.65 (3H, s), 1.27 (3H, t, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:16][CH2:17][CH2:18][CH3:19])[N:3]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>O.C(OCC)(=O)C>[ClH:1].[ClH:1].[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH:27][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:16][CH2:17][CH2:18][CH3:19])[N:3]=2)[CH2:23][CH2:22]1
Reactant: CCCNc1nc(Cl)nc2c1ncn2C(CC)CC
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCNc1nc(N[C@H]2CC[C@H](N)CC2)nc2c1ncn2C(CC)CC
Product: Cl
Reaction time: 4 h

Procedure:
The operation is carried out as in Stage 3 of Example 3 starting from 121 mg of the product obtained in Stage 1 above and 489 mg of trans-1,4-diaminocyclohexane and the reaction medium is taken to a temperature of 140 to 150° C. for 4 hours then cooled down to 70–80° C., diluted with 20 ml of water/ethyl acetate in a proportion of 50/50 and left to settle, followed by washing with 10 ml of water and 5 ml of an aqueous solution of sodium chloride, drying and evaporating to dryness. After purification on silica eluting with methanol/ammonium hydroxide (NH4OH) in a proportion of 98/2 and salification with 1.4N hydrochloric acid in ethanol, 114 mg of expected product is obtained in the form of crystals.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.C[Al](C)C.C1N2CCN(CC2)C1.C[O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][N:33]=[C:32]([C:35]3[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([N:42]([CH3:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:36]=3)[N:31]=2)=[CH:26][N:25]=1)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][N:2]([CH3:3])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][N:33]=[C:32]([C:35]3[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([N:42]([CH3:49])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:36]=3)[N:31]=2)=[CH:26][N:25]=1)=[O:21]
Reactant: CNC
Reactant: COC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Agent: C1CN2CCN1CC2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
Dimethylamine (248 μL, 0.495 mmol) and bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]-octane (128 mg, 0.495 mmol) were stirred together in anhydrous toluene (2 mL) at 40 C under nitrogen for 1 h. 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-pyridine-2-carboxylic acid methyl ester (prepared in an analogous manner to Example 279, 80 mg, 0.198 mmol) was added and the reaction stirred at 80 C for approximately 18 h. The mixture was then allowed to cool to room temperature and diluted with EtOAc (20 mL). The solution was then washed with 2M HCl (2×6 mL), saturated aq. sodium bicarbonate (2×6 mL), dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by flash chromatography (0-3% MeOH in DCM) and the material obtained was then further purified by flash chromatography (0-80% EtOAc in heptane) to afford the title compound (10 mg, 12%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]=1[C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]=1[C:17]([NH:37][CH:33]1[CH2:36][CH2:35][CH2:34]1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCC1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)o1
Temperature: 50 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
A mixture of 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (2.5 g, 9.6 mmol, 1.0 equiv), 1,1′-carbonyldiimidazole (2.49 g, 15.37 mmol, 1.6 equiv) in DMF (20 mL) was stirred at 50° C. for 5 h. The mixture was cooled to room temperature. Cyclobutylamine hydrochloride (1.24 g, 11.52 mmol, 1.2 equiv) and Et3N (1.74 mL, 12.48 mmol, 1.3 equiv) was added, and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. Purification by chromatography (1:1 hexanes/EtOAc, then EtOAc) provided the titled compound (2.76 g, 91.56%) as a yellow solid.
Reaction SMILES: [Cl-].[Na+].[CH3:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:6]([NH2:8])=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>ClCCCl>[CH3:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:6]#[N:8]
Reactant: COC(C(N)=O)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(C#N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 20 ml. of dry 1,2-dichloroethane containing 2.0 g. of sodium chloride is added 3.32 g. of 2-methoxy-2-(2-pyridyl)-acetamide. After stirring at room temperature for 15 minutes, 1.7 ml. of phosphorus oxychloride is added. The solution is refluxed for 18 hours. The solution is then cooled and made basic with 10% aqueous sodium hydroxide solution. The aqueous phase is extracted three times with chloroform and the combined chloroform extracts are washed three times with water and once with brine and dried over magnesium sulfate. Filtration, removal of solvent and distillation in vacuo gives 2-methoxy-2-(2-pyridyl)acetonitrile, b.p. 72°-76° C./0.2 mm.
Reaction SMILES: [C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][S:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:36].[C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][S:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:44])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CSc3ccc(C#N)cc3)nc2c1)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CSc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 61 %

Procedure:
Prepared analogously to Example 9 from 2-[(4-cyanophenyl)thiomethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 61% of theory, C27H26N4O3S2 (518.66); Rf value: 0.27 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid); EKA mass spectrum: (M+H)+=519.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])=[C:25]([CH3:30])[CH:24]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: Cc1cc(F)ccc1N
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: Cc1cc(F)ccc1NS(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 18.6 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 61 μL (0.55 mmol) of 4-fluoro-2-methyl-aniline. After purification by chromatography on silica gel (dichloromethane/methanol 95/5) then trituration in diethyl ether, 19 mg (9%) of 8-(4-fluoro-2-methyl-phenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:23]=[C:9]2[CH:10]=[C:11]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:13]([C:14]([NH2:16])=O)[N:8]2[N:7]=1)[CH3:2].CO[C:27](OC)([N:29](C)C)[CH3:28].O.[NH2:35]N>CC(N(C)C)=O.O>[NH:8]1[CH:13]=[CH:14][N:16]=[N:7]1.[CH2:1]([NH:3][C:4]([NH:5][C:6]1[N:23]=[C:9]2[CH:10]=[C:11]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:13]([C:14]3[NH:35][N:29]=[C:27]([CH3:28])[N:16]=3)[N:8]2[N:7]=1)=[O:24])[CH3:2]
Reactant: COC(C)(OC)N(C)C
Reactant: NN
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(N)=O)n2n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3nc(C)n[nH]3)n2n1
Product: c1c[nH]nn1
Temperature: 90 °C

Procedure:
2-(3-Ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid amide, which may be prepared as in Example 16, (200 mg, 0.62 mmol) was suspended in DMA (8 mL) and preheated to 90° C. Dimethylacetamide-dimethylacetal (0.45 mL, 3.07 mmol) was added and the solution was heated at 90° C. for 30 minutes. The reaction was allowed to cool, diluted with water (100 mL), then extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 fractions were washed with water (3×50 mL), brine (50 mL), and dried (Na2SO4). The mixture was filtered under reduced pressure. The resultant oil was dissolved in AcOH and hydrazine hydrate (0.1 mL, 1.85 mmol) was added. The mixture was heated at 90° C. for 2 h. All solvent was then removed under high vacuum and the resulting slurry suspended in sat. NaHCO3 solution (50 mL). Crude 1-ethyl-3-[5-(5-methyl-2H-[1,2,4]triazol-3-yl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea triazole) was isolated by filtration and dried. Purification by silica gel chromatography (0.5% c.NH3 in 10% MeOH/CH2Cl2 as eluant) gave the desired product. HRMS (FAB+) calcd C17H17N9O (MH+) 364.1634, found 364.1632.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:37])[CH:5]=[C:6]([Cl:36])[C:7]=1[CH2:8][C@@H:9]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[C:27]([OH:35])[CH:26]=1)[O:10][C:11](=[O:24])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH:55]2[CH2:59][CH2:58][O:57][CH2:56]2)(=O)=O)=CC=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:37])[CH:5]=[C:6]([Cl:36])[C:7]=1[CH2:8][C@@H:9]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[C:27]([O:35][CH:55]2[CH2:59][CH2:58][O:57][CH2:56]2)[CH:26]=1)[O:10][C:11](=[O:24])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1C(=O)c2ccccc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OC2CCOC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-hydroxyphenyl)-2-(2-(1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (155 mg, 0.280 mmol) in DMF (3.8 ml), potassium carbonate (46.5 mg, 0.336 mmol) was added, and the mixture stirred at RT for 30 minutes. Tetrahydrofuran-3-yl 4-methylbenzenesulfonate (224 mg, 0.924 mmol) was added, and the mixture stirred at RT overnight. Water was added, and the aqueous phase extracted with AcOEt (2×). The organic phase was washed with brine, dried and evaporated under reduced pressure. The crude was purified through preparative HPLC (Method 2) to give 17 mg of title compound (yield 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.92 (d, J=4.41 Hz, 4H), 7.18-7.27 (m, 1H), 7.05 (m, 2H), 6.98 (d, J=7.94 Hz, 1H), 6.02 (dd, J=8.38, 4.85 Hz, 1H), 5.12 (m, 1H), 4.30-4.58 (m, 2H), 3.62-4.06 (m, 4H), 3.14-3.43 (m, 2H), 2.20 (ddd, J=13.56, 6.73, 6.62 Hz, 1H), 1.86-2.05 (m, 1H). MS/ESI+ [M+H]+=622.7
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:40])[C:29]3[N:33]=[C:32]([C@@H:34]4[CH2:38][CH2:37][CH2:36][O:35]4)[NH:31][C:30]=3[CH:39]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:40][C:28]1[C:29]2[N:33]=[C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[NH:31][C:30]=2[CH:39]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:27]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12

Procedure:
59 mg (0.23 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 70 mg (0.21 mmol) (S)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 0.12 mL (0.70 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([NH2:25])[N:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:21]=2)=[CH:16][CH:15]=1>ClCCl.N1C=CC=CC=1>[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:24]=[C:23]([NH:25][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[N:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:21]=2)=[CH:18][CH:19]=1.[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:24]=[C:23]([N:25]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[N:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:21]=2)=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(-c2cc(N)n(-c3ccccc3)n2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(N(S(=O)(=O)c3ccccc3)S(=O)(=O)c3ccccc3)n(-c3ccccc3)n2)cc1
Product: COC(=O)c1ccc(-c2cc(NS(=O)(=O)c3ccccc3)n(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of benzenesulfonyl chloride (0.913 ml, 7.15 mmol) in dichloromethane (7 ml) was added slowly to a solution of 4-(5-amino-1-phenyl-1H-pyrazole-3-yl)-benzoic acid methyl ester (1.5 g, 5.11 mmol) in pyridine (20 ml) at 5° C. The resulting solution was stirred at room temperature for 18 h. The solvent was evaporated in vacuo and the products were separated by flash chromatography, on silica gel, using 0 to 2% methanol in dichloromethane as the eluant, to yield 4-(5-benzenesulfonylamino-1-phenyl-1H-pyrazole-3-yl)-benzoic acid methyl ester, and 4-{5-[bis(Benzenesulfonyl)amino]-1-phenyl-1H-pyrazole-3-yl}-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12](=[O:16])[CH:13]=[CH:14]O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1.Cl.[NH2:21]O>C(O)C.O>[CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12]3[O:16][N:21]=[CH:14][CH:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1
Reactant: CSc1sc(C(=O)C=CO)c2c1C(=O)CC(C)(C)C2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CSc1sc(-c2ccno2)c2c1C(=O)CC(C)(C)C2
Yield: 25.1 %

Procedure:
A solution of 6,6-dimethyl-1-(3-hydroxy-1-oxoprop-2-enyl)-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one (200 mg, 0.68 mmol) in ethanol (14 mL) and water (1.6 mL) was heated to 80° C., after which hydroxylamine hydrochloride (52 mg, 0.74 mmol) was added. The mixture was heated at reflux for 4 h, after which time the solvent was removed in vacuo and the residue triturated in hexane/ether. The isoxazole (50 mg, 20%) was isolated as a colourless solid. mp 143-145° C. 1H NMR (360 MHz, CDCl3) δ 1.09 (6H, s), 2.45 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 6.28 (1H, d, J=1.9 Hz), 8.29 (1H, d, J=1.9 Hz). MS (ES+) 294 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ccsc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2ccsc12
Yield: 38.6 %

Procedure:
To a solution of intermediate 137, 7-methylbenzo[b]thiophene (1.0 g, 6.5 mmol) in CCl4 (20 mL) was added benzoyl peroxide (1.1 g, 4.54 mmol) followed by portionwise addition of NBS (1.15 g, 6.5 mmol). The reaction mixture stirred at reflux while irradiating with a 250 W lamp. The reaction mixture was stirred at reflux for 3 h. The solution was cooled, filtered and the solvent evaporated in vacuo. The residue was subjected to column chromatography on silica gel with hexanes as the eluent to afford the title compound (0.570 g, 33% yield): 1H NMR (400 MHz, CDCl3) δ: 7.80 (1H, dd, J=7.8, 1.7 Hz), 7.49 (1H, d, J=5.4 Hz), 7.40–7.33 (3H, m), 4.78 (2H, s). LCMS (M+H)+ m/z 209.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:30]=[CH:31][CH:32]=1)[C:11]([NH:13][C:14]1[S:15][C:16]2[CH2:29][CH2:28][CH2:27][CH2:26][C:17]=2[C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])=O)[CH2:4][CH3:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:5][CH2:4][CH:3]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:11]2[O:21][C:19](=[O:20])[C:18]3[C:17]4[CH2:26][CH2:27][CH2:28][CH2:29][C:16]=4[S:15][C:14]=3[N:13]=2)[CH:30]=[CH:31][CH:32]=1)[CH2:2][CH3:1]
Reactant: CCC(CC)NCc1cccc(C(=O)Nc2sc3c(c2C(=O)OC(C)(C)C)CCCC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)NCc1cccc(-c2nc3sc4c(c3c(=O)o2)CCCC4)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.6 %

Procedure:
To a mixture of 8.99 g of tert-butyl 2-({3-[(pentan-3-ylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate and 100 mL of methylene chloride was added 30 mL of TFA, followed by stirring for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and azeotropy was performed using toluene. 4.3 mL of thionyl chloride and 50 mL of toluene were added to the residue, and 0.10 mL of DMF was added dropwise thereto, followed by stirring for 1 hour at 60° C. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2), thereby obtaining 7.05 g of 2-{3-[(pentan-3-ylamino)methyl]phenyl}-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)C(=O)NNc1ccc(F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 73.5 %

Procedure:
A solution of Example 1 step c (0.41 g, 2.08 mmol), triphenylphosphine (763 mg, 2.91 mmol) and triethylamine (0.87 mL, 6.24 mmol) in THF (5 mL) at 0° C. was treated with 1,2-hexachloroethane (690 mg, 2.91 mmol). The reaction mixture was stirred at 0° C. for 40 min then at RT for 20 min, quenched with water, extracted twice with EtOAc, dried (Na2SO4), evaporated and purified twice by FCC (cyclohexane/EtOAc 1/0 to 1/1) to afford the title compound (274 mg, contaminated with 20% PPh3O, 58%) as a white solid. LCMS (method 1): Rt 2.58 min, m/z 180 [MH+].
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1([C:19]2[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].C([O-])([O-])=O.[Na+].[Na+].CCO>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>[CH2:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1([C:19]2[CH:24]=[CH:23][C:22]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=3)=[CH:21][CH:20]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1
Reactant: N#Cc1cccc(B(O)O)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: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)NCC1(c2ccc(-c3cccc(C#N)c3)cc2)CCN(CC2CC2)CC1
Temperature: 25 °C
Yield: 24.2 %

Procedure:
To a flask containing [1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-carbamic acid isobutyl ester (0.061 g, 0.13 mmol) was added Pd(PPh3)4 (0.015 g, 0.013 mmol, 10 mol %), 3-cyanophenylboronic acid (0.03 g, 0.2 mmol, 1.5 eq.) and Na2CO3 (0.212 g, 2 mmol). The mixture was suspended in toluene (3 mL), EtOH (1.5 mL) and H2O (1.0 mL) and heated to 80° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (10 mL) and saturated Na2CO3 (10 mL). The organic layer was washed with saturated Na2CO3 (3×10 mL) and saturated brine (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. This was purified by HPLC to give the title compound [4-(3′-cyano-biphenyl-4-yl)-1-cyclopropylmethyl-piperidin-4-ylmethyl]-carbamic acid isobutyl ester as a brown solid (0.014 g, 24%). MS (ESI): 446.3/447.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N:12](C)[C:13](=O)C)=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO.Cl>O.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH:12][CH3:13])=[C:5]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)N(C)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNc1cnc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
A mixture of 6-chloro-3-(N-methylacetamido)-4-phenylquinoline (0.9 g), methanol (5 ml) and conc. hydrochloric acid (5 ml) was refluxed for 5 hrs. It was diluted with water and neutralized with aqueous sodium hydroxide solution. The resultant precipitate was collected by filtration and recrystallized from methanol to give 6-chloro-3-methylamino-4-phenylquinoline as pale yellow crystals. Yield 0.65 g (83.5%). m.p. 139°-140° C.