Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[OH-].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:9])([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of 30 g of 2-(4-chlorophenoxymethyl)-2-tert.-butyloxirane, 9.8 g of 1,2,4-triazole and 1.2 g of solid potassium hydroxide in 70 ml of toluene and 7.5 ml of dimethyl sulphoxide was heated under reflux for 6 hours. After cooling to room temperature, 2 g of silica gel were added to the reaction mixture and it was then filtered. 75 ml of semi-concentrated hydrochloric acid were added to the filtrate, and the crystals which separated out thereby were filtered off with suction. Then 80 ml of water and aqueous sodium hydroxide solution were added to the crystalline solid so that the pH of the mixture was 13. It was stirred a further 2 hours at room temperature, then filtered off with suction and washed with water to neutrality. In this manner, 20 g (52% of theory) of 2-(4-chlorophenoxymethyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 84°-87° C. were obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([NH2:9])=[C:7]([S:10][CH3:11])[CH:6]=[C:5]([CH3:12])[N:4]=1.Cl[C:14](OC(Cl)(Cl)Cl)=[O:15]>O1CCOCC1>[CH3:1][S:2][C:3]1[C:8]([N:9]=[C:14]=[O:15])=[C:7]([S:10][CH3:11])[CH:6]=[C:5]([CH3:12])[N:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CSc1cc(C)nc(SC)c1N
Solvent: C1COCCO1
Product: CSc1cc(C)nc(SC)c1N=C=O
Yield: 140.2 %

Procedure:
A solution of 800 mg (4 mmol) 2,4-bis(methylthio)-3-amino-6-methylpyridine and 0.4 ml (2.3 mmol) trichloromethyl chloroformate in 20 ml anhydrous dioxane was refluxed under nitrogen overnight. The reaction mixture was cooled and filtered and the filtrate was concentrated to dryness in vacuo yielding 730 mg of the title compound (81% yield) as a tan colored solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][N:10]([C:17](=[O:20])[CH2:18]Cl)[CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl-].[NH4+]>C1COCC1>[O:20]=[C:17]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])[CH2:18]1
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)CCl)C1CCOCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCOCC2)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
tert-Butyl{2-[(chloroacetyl)(tetrahydro-2H-pyran-4-yl)amino]ethyl}carbamate (6.86 g) was mixed with THF (70 ml), and sodium hydride (55% suspended in oil) (1.4 g) was added thereto at 0° C., followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution at 0° C., followed by extraction with CHCl3. The organic layer was washed with water and saturated brine, and dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/MeOH) to obtain tert-butyl 3-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (5.25 g).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]#[N:21])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1.P(Cl)(Cl)(Cl)=O>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:19][C:20]#[N:21])[C:13]=3[CH2:12][CH2:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCc1ccccc1CCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: N#CCc1cccc2c1CCN=C2c1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 7 h
Yield: 75.2 %

Procedure:
1-(4-Nitrobenzoyl)amino-2-(2-cyanomethylphenyl)-ethane (12.7 g) was dissolved in 128 ml of xylene and 77 ml of phosphorus oxychloride. While the solution was heated with stirring over an oil bath at 140° C., 38 g of phosphorus pentoxide was added gradually. The reaction was performed for 7 hours. The upper layer of the reaction mixture was removed by decantation. Ice water was added to the residue, and an aqueous solution of sodium hydroxide was added to make it neutral. The crystals that precipitated were collected by filtration, and recrystallized from ethanol to afford 9 g of 1-(4-nitrophenyl)-3,4-dihydroisoquinoline-5-acetonitrile having a melting point of 137.7° to 138.7° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16]C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].CCO.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][NH2:16])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCC(CNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.7 %

Procedure:
To a solution of [4-(tert-butoxycarbonylamino-methyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester (11.00 g, 32 mmol) dissolved in 2:1 CHCl3:EtOH at room temperature was added 4.0 M HCl/dioxane (16.1 mL). The mixture was stirred at room temperature for 4 h then concentrated in vacuo to provide a crude white solid. The crude material was purified by silica gel chromatography using a gradient elution of 10-50% (2% NH4OH, 18% MeOH, 80% CH2Cl2)/CH2Cl2. The product-containing fractions were combined and concentrated in vacuo to provide (4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester as a white powder 3.62 g, 47%, m/z calculated for C13H26N2O2: 242.4, found: 243.3 (M+H)+.
Reaction SMILES: [C@@H:1]1([N:10]2[C:18]3[CH:17]=[CH:16][NH:15][C:14](=[O:19])[C:13]=3[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(O[C:24](=[O:26])[CH3:25])(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:2]([O:3][C@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:24](=[O:26])[CH3:25])[O:7][C@H:1]1[N:10]1[C:18]2[CH:17]=[CH:16][NH:15][C:14](=[O:19])[C:13]=2[N:12]=[CH:11]1)(=[O:3])[CH3:1]
Reactant: O=c1[nH]ccc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]ccc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 3.0 g of 1-β-D-arabinofuranosyl-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one, eight ml of acetic anhydride, 150 ml of pyridine, and 50 mg of p-dimethylaminopyridine is stirred at room temperature for 24 hours, evaporated in vacuo, co-evaporated with xylenes, and distributed between water and ethyl acetate. The ethyl acetate layer is washed with saturated NaHCO3 and dried with MgSO4. Removal of the ethyl acetate provides 1-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one. This is dissolved in 150 ml of dry pyridine, treated with 8.8 g phosphorus pentasulfide, and heated under reflux for 5 hours. The pyridine is removed in vacuo and the residue is treated with water. The precipitate is filtered, washed with water, and recrystallized from ethanol to afford 1-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-1,5-dihydro-4H-imidazo-[4,5-cl]pyridine-4-thione.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:8]1)[CH3:2].S(=O)(=O)(O)[OH:28].[OH-].[K+]>O>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:28])=[CH:13][CH:14]=2)[C:9]([NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[N:8]1)[CH3:26]
Reactant: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2ccccc12
Reactant: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2ccc(O)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture consisting of 14.1 g of the 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)indazole and 4.3 g of 95% by weight sulfuric acid was stirred for 3 hours at 80° C. To the mixture was added 13 ml of water, and the pH of the mixture was adjusted to 14 with potassium hydroxide. After the mixture was washed twice with 20 ml of chloroform, water was removed under reduced pressure. To the residue were added 12.5 g of potassium hydroxide and 0.6 ml of water, and the mixture was stirred for 8 hours at 250° C. After cooling, to the mixture was added hydrochloric acid to separate crystals. The crystals were obtained by filtration and dried to give 6.28 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-5-hydroxyindazole having the following analytical values in a yield of 40%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:25])[CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34]([C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]3[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=3)([OH:14])[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:25])[CH:3]=2)=[CH:29][C:28]=1[O:27][CH3:26])=[O:35]
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Reactant: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O
Product: CCn1cc(C(O)(C(C)c2ccc(-c3ccc(C(=O)OC)c(OC)c3)cc2Cl)C(F)(F)F)ccc1=O

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-ethyl-1H-pyridin-2-one (Example 183, step 2) was reacted with 3-methoxy-4-methoxycarbonylphenylboronic acid to give the title compound as an off-white solid. MS (m/e)=524.2 [M+H+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)=[C:8]([CH3:26])[C:6]=2[N:7]=1.[NH:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][N:40]=2)[CH:35]=[CH:34]1>>[OH:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:9]3[S:10][C:5]4[C:4]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:3][C:2]([C:38]5[CH:37]=[C:36]6[CH:35]=[CH:34][NH:33][C:41]6=[N:40][CH:39]=5)=[N:7][C:6]=4[C:8]=3[CH3:26])[CH:12]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1c(-c2cccc(C(=O)N3CCC(O)CC3)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(-c2cccc(C(=O)N3CCC(O)CC3)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 4-hydroxypiperidine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperadin-1-yl)methanone. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperadin-1-yl)methanone (72 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 29.5 mg of 425. MS (Q1) 555.2 (M)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:3]=1.[ClH:22]>C(Cl)Cl>[ClH:22].[ClH:22].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1
Reactant: Cc1ccnc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccnc(N2CCCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
tert-Butyl 4-(4-methyl-2-pyridyl)-1,4-diazepane-1-carboxylate (91 mg, 0.312 mmol) was dissolved in DCM under nitrogen. Hydrochloric acid (4N in dioxane, 1.56 ml, 6.25 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure to give 84 mg of a solid (quantitative). MS (ESI) m/z=192.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.C([O:12][C:13](=O)[C:14]([C:19]#[N:20])=[CH:15]OCC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:13](=[O:12])[C:14]([C:19]#[N:20])=[CH:15][NH:9]2)=[CH:7][CH:8]=1
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: COc1cccc(N)c1
Solvent: CCO
Product: COc1ccc2c(=O)c(C#N)c[nH]c2c1
Temperature: 256 °C
Yield: 62.4 %

Procedure:
An amount of 3-methoxy-phenylamine (45.3 g, 0.37 mol) and 2-cyano-3-ethoxy-acrylic acid ethyl ester (62.2 g, 0.37 mol), were heated at 120° C. for 0.5 hours, during which 14.4 mL of ethanol was collected by a Dean-Stark trap. To this was added a solution of biphenyl (333 mL) and phenyl ether (666 mL), and the mixture was heated at 256° C. for 6 hours, during which 22 mL of ethanol was collected by a Dean-Stark trap. The mixture was cooled to room temperature and filtered. The solid was washed with hexane and dried to give a brown solid (46.2 g, 63% yield), m.p 324-325° C.; 1H NMR (DMSO-d6) δ 12.63 (bs, 1H), 8.67 (s, 1H), 8.03 (d, J =9 Hz, 1H), 7.08 (dd, J=9 Hz, J=3 Hz, 1H), 7.01 (dd, J=3 Hz, 1H), 3.88 (s, 3H); HRMS (EI) m/z 223.04793 (M+Na); MS (ES) m/z 201.0 (M+1). Analysis for C11H8N2O2.0.1H2O: Found: C, 65.53; H, 4.09; N, 13.93. Calcd: C, 65.35; H, 4.06; N, 13.86.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:16]=[C:17]([Br:21])[CH:18]=[CH:19][CH:20]=1.[Na]>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=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1(C)C=CC=C(C)C=1>[Br:21][C:17]1[CH:16]=[C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1cccc(I)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1cccc(C)c1
Product: Brc1cccc(-n2c3ccccc3c3ccccc32)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.1 %

Procedure:
The 300 mL round bottom flask, equipped with magnetic stirrer and refluxed condenser, was charged with carbazole (7.1 g, 42.5 mmol), 3-iodobromobenzene (25.00 g, 88 mmol), Pd2(dba)3 (800 mg, 1 mol %), dppf (1′,1′-bis(diphenylphosphino)ferrocene (975 mg, 2 mol %), sodium t-buthoxide (6.3 g) and m-xylene (100 ml). The reaction mixture was heated to reflux and stirred under nitrogen atmosphere for 48 hours. Then reaction was cooled down to room temperature, filtered through silica plug and evaporated. The residue was subjected to column chromatography on silica gel, eluent gradient mixture hexane-hexane/ethyl acetate mixture 9:1, providing 7.00 g of 9-(3-bromo-phenyl)-9H-carbazole as white solid, structure was confirmed by NMR and GCMS spectroscopy.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH2:24]([Sn](CCCC)(CCCC)C=C)[CH2:25]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:15]1([N:7]2[C:8]3[C:3](=[C:2]([CH:24]=[CH2:25])[C:11]([F:12])=[C:10]([F:13])[C:9]=3[F:14])[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)[CH2:17][CH2:16]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(Br)c2c1=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Temperature: -18 °C
Yield: 87.4 %

Procedure:
5.9 g of ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 6.7 g of tributyl-vinylstannane and 0.69 g of tetrakis(triphenylphosphine)-palladium(0) are refluxed for 10 hours in 60 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is cooled to -18° C., and the solid which has precipitated is filtered off with suction, washed with toluene and dried. 4.46 g of the title compound are obtained (88% of theory).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:29]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=[O:29]
Reactant: N#Cc1c(F)cccc1I
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1c(F)cccc1I
Reaction time: 0.42 h
Yield: 83 %

Procedure:
2-Fluoro-6-iodobenzonitrile (10.274 g) was dissolved in toluene (100 ml), followed by the dropwise addition of 1.5M diisobutylaluminium hydride/toluene solution (31 ml) in nitrogen atmosphere at −70° C., and the mixture was stirred for 25 min. Subsequently, it was stirred at room temperature for further 45 min. To the mixture was added 5% sulfuric acid, and it was stirred for 1 hr. Sequentially, the resulting solution was extracted with ethyl acetate, and the resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (8.683 g, yield; 83%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:8])[O:5][C:4](=[O:18])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:25]([C:29]1[CH:34]=[C:33]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[C:32]([CH3:47])=[CH:31][C:30]=1[S:48]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([C:29]1[C:30]([S:48][C:3]2[C:4](=[O:18])[O:5][C:6]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)([CH3:8])[CH2:7][C:2]=2[OH:1])=[CH:31][C:32]([CH3:47])=[C:33]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:34]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(NS(=O)(=O)c3ccc(C#N)cc3)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(C)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1NS(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 from 4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-5,6-dihydro-pyran-2-one (prepared in Example KK; 0.09 g, 0.37 mmol), DMF (6 mL), K2CO3 (0.11 g, 0.81 mmol), and toluene-4-thiosulfonic acid S-[2-tert-butyl-4-(4-cyano-benzenesulfonylamino)-5-methyl-phenyl] ester (prepared in Example JJJJ; 0.19 g, 0.37 mmol). The mixture was stirred at room temperature overnight. After the standard work-up, the resulting residue was flash chromatographed on silica gel, eluting with 2% EtOH:EtOAc, then triturated with EtOAc:CH2Cl2 :hexanes to afford the title compound. 1H NMR (DMSO-d6) δ 1.24 (s, 9 H), 1.42 (s, 3 H), 1.87 (s, 3 H), 1.92 (m, 2 H), 2.52 (m, partially obscured by DMSO, 2 H), 2.75 (d of ABX q, 1 H), 2.95 (d of ABX q, 1 H), 6.46 (s, 1 H), 6.64 (d, 2 H), 6.70 (s, 1 H), 6.96 (d, 2 H), 7.77 (d, 2 H), 8.06 (d, 2 H), 9.15 (s, 1 H), 9.68 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:3]=1[CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[NH2:6].[CH2:15]=O>Cl.O>[Br:1][C:2]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:3]=1[CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[NH:6][CH2:15]2
Reactant: C=O
Reactant: N[C@H](Cc1cc(O)ccc1Br)C(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)[C@H]1Cc2c(Br)ccc(O)c2CN1
Temperature: 90 °C
Yield: 75 %

Procedure:
Slurry 2-bromo-5-hydroxy-(D)-phenylalanine (1.87 g, 0.00719 mol) in 0.05 M hydrochloric acid (10.7 mL) and add 37% formaldehyde solution in water (1.02 mL). Heat at 90° C. for one hour. Cool to room temperature, filter, and wash with water (2×) and acetone (2×) and dry in a vacuum oven to give the desired product (1.53 g, 75%) as a light pink solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:6]=1)=[O:4]>C1COCC1.[Pd]>[CH3:1][N:2]([CH3:19])[C:3]([C:5]1[C:9]([NH2:10])=[CH:8][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1nn(-c2ccccn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1nn(-c2ccccn2)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A solution of 4-nitro-1-pyridin-2-yl-1H-pyrazole-3-carboxylic acid dimethylamide (50 mg, 0.19 mmol) in THF (3 ml) was flushed with argon and treated with Pd/C 10% (11 mg, 0.01 mmol). The reaction vessel was evacuated and flushed with hydrogen three times and the reaction was stirred at ambient temperature overnight. The reaction mixture was filtrated and the solvent was evaporated to yield a solid material (44 mg, 99%) which was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C[CH2:13][N:14](CC)[CH2:15]C.CNC.O>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:14]([CH3:15])[CH3:13])=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of 3-(chloromethyl)benzoyl chloride (426 μL, 3 mmol) and Et3N (626 μL, 4.5 mmol) in THF (5 mL) was treated with dimethylamine (1.5 mL, 2-M in THF, 3 mmol), stirred at room temperature for 1 h, poured into water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo to give the title compound (580 mg, 98%) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.46-7.34 (4H, m), 4.59 (2H, s), 3.11 (3H, s) and 2.98 (3H, s); Anal. Calcd for C12H12N6O2.0.2H2O: C, 49.38; H, 4.28; N, 28.79. Found: C, 49.25; H, 4.09; N, 28.47.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.O>C1COCC1>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.1 %

Procedure:
Propionyl chloride (5.53 g, 0.0597 mol) was added dropwise to a solution of tert-butyl 4-(3-aminophenyl)-1-piperidinecarboxylate (15.0 g, 0.0543 mol) and TEA (16.5 g, 0.163 mol) in THF (200 mL) and the mixture was stirred at room temperature for 3 h. Water (50 mL) was added to the reaction mixture, the aqueous layer was extracted with CH2Cl2 (3×100 mL), and the combined organic extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/EtOAc (10:1) to afford the product (18.8 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H) 7.34–7.21 (m, 3H), 6.93 (d, 1H, J=7.4 Hz), 2.77 (t, 2H, J=11.5 Hz), 2.68–2.58 (m, 1H), 2.38 (q, 2H, J=7.6 Hz), 1.87–1.67 (m, 4H), 1.67–1.54 (m, 2H), 1.48 (s, 9H), 1.25 (t, 3H, J=7.5 Hz); ESMS m/e: 333.4 (M+H)+.