Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][C:36]1([CH3:47])[CH2:41][O:40][C:39]([CH:45]=[CH2:46])([C:42]([OH:44])=[O:43])[CH2:38][O:37]1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.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]>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:46]=[CH:45]/[C:39]4([C:42]([OH:44])=[O:43])[CH2:38][O:37][C:36]([CH3:35])([CH3:47])[CH2:41][O:40]4)=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC1(C(=O)O)COC(C)(C)CO1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COC(C)(C)CO4)cc3n2)N1
Temperature: 50 °C
Yield: 100 %

Procedure:
A mixture of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (198 mg, 0.371 mmol), 5,5-dimethyl-2-vinyl-[1,4]dioxane-2-carboxylic acid (69 mg, 0.371 mmol), triethylamine (112 mg, 155 μL, 1.11 mmol) and tri(o-tolyl)phosphine (23 mg, 0.074 mmol) in 1,4-dioxane (7.5 mL) was degassed with nitrogen for 5 min and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.037 mmol) was added and the mixture was heated to 80° C. for 40 min and then allowed to cool to room temperature. The suspension was filtered and evaporated to give crude title compound (0.371 mmol) which was used directly in the next stage. LCMS (m/z) 640.3 [M+H], Tr=1.94 min.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C([Li])CCC.[CH3:24][CH:25]([CH3:31])[CH2:26][CH2:27][C:28](Cl)=[O:29].C([O-])(O)=O.[Na+]>CCCCCC>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:28](=[O:29])[CH2:27][CH2:26][CH:25]([CH3:31])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
(S)-4-Benzyl-2-oxazolidinone (15.1 g, 85.0 mmol) was dissolved in THF (200 mL, 2.5 mol), cooled at −78° C. under nitrogen, and stirred for 10 minutes. 1.6 M of n-butyllithium in hexane (53.1 mL) was added dropwise and stirred for 15 minutes. 4-Methylpentanoyl chloride (12.6 g, 93.5 mmol) was added dropwise, stirred for 30 minutes at −78° C., then warmed to 0° C. for 2 hours. 150 mL of saturated NaHCO3 was added and the mixture was warmed to room temperature for 30 minutes. The mixture was extracted with DCM, washed with Na2 CO3 (5%) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Excess oxazolidinone was removed using hexanes to provide intermediate (2a) (14.5 g).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[C:25]([OH:31])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:26]1/[C:25]([OH:31])=[CH:24][C:23](=[NH:22])[C:28]([O:29][CH3:30])=[CH:27]/1
Reactant: COc1ccc(O)cc1N
Reactant: Nc1c(N)n2n(c1=O)CCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: COC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(O)=CC1=N

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 3-amino-4-methoxyphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]OC[CH2:35]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH:19]([CH2:35][CH2:34][CH3:38])[C:20]([O:22][CH3:23])=[O:21]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccs1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccs1)CCC3
Yield: 85 %

Procedure:
This compound was prepared according to the procedure C from Methyl [2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.261 g; 0.760 mmol), LHMDS 1N in THF (0.836 mL; 0.836 mmol), 1-iodopropane (0.111 mL; 1.140 mmol) in DMF (3.0 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.249 g (85%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C@@H:13]4[C:17]([CH3:19])([CH3:18])[C@@:10]([CH3:20])([CH2:11][CH2:12]4)[C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]I>CN(C)C=O>[C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C@@H:13]4[C:17]([CH3:19])([CH3:18])[C@@:10]([CH3:20])([CH2:11][CH2:12]4)[C:9]=3[N:8]2[CH3:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 55.7 %

Procedure:
A mixture of (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 4.77 g, 17.8 mmol) and methyl iodide (2.2 mL, 35.3 mmol) in N,N-dimethylformamide (30 mL) was purged with argon and then heated in a sealed tube at 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with sodium bicarbonate and extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (magnesium sulfate), filtered, evaporated and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Analytical Sales 120 g column, eluting with 25-75% ethyl acetate/hexanes followed by recrystallization from ethyl acetate to give (4S,7R)-2-phenyl-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (2.8 g) of white crystals. The filtrate was evaporated and recrystallized from ethyl acetate to give a further 0.53 g, and the resulting filtrate was evaporated, dissolved in dichloromethane, treated with decolorizing charcoal and crystallized from dichloromethane to give a further 0.77 g of product. The total yield was 4.1 g (82%). EI(+)-MS (M+H) 283.
Reaction SMILES: C(OC[C:6]1([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1)(=O)C.[CH2:17]1COCC1>>[CH2:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:11]1[CH:17]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C1CCOC1
Reactant: CC(=O)OCC1(c2cccs2)C=CC=CC1
Product: c1ccc(Cc2cccs2)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 1-(2-thienyl)benzyl acetate in THF (5 ml) was added carefully to dry liquid ammonia (100 ml). Lithium metal was added in small portions until the blue color persisted. The resulting reaction mixture was stirred for 30 min, and the reaction was quenched by addition of solid ammonium chloride. The residue, after complete evaporation of liquid ammonia, was dissolved in water (50 ml) and was extracted with methylene chloride (2×50 ml). The combined organic layer was dried over MgSO4 and filtered. Removal of the solvent gave crude product, which was purified by column chromatography using hexane as eluent to give 2-benzylthiophene (1.2 g, 68% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([O:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:6]=[CH:5][C:4]1=2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:8]=[C:7]([O:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:6]=[CH:5][C:4]2=3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: NCC1CCCc2cc(OCC(N)=O)ccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)COc1ccc2c(c1)CCCC2CNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
0.1 mol of 5-aminomethyl-5,6,7,8-tetrahydro-naphth-2-yl-oxyacetamide (Example 7), 0.11 mol of 4-chlorobenzenesulphonyl chloride and 0.11 mol of triethylamine are stirred in 200 ml of tetrahydrofuran at room temperature for 3 hours. The mixture is filtered, the filtrate is evaporated, the residue is taken up in CH2Cl2 and the mixture is washed with 1N HCl, saturated NaHCO3, 1N HCl and saturated NaCl solution, dried over Na2SO4 and evaporated. The residue is purified by flash chromatography over silica gel using CH2Cl2MeOH 5:1.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)#[CH:9].[CH3:21][C:22]([CH3:43])([CH3:42])[CH2:23][C:24]([NH:26][C:27]1[C:35](C2C=NC=CC=2)=[C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:29]2[N:28]=1)=[O:25]>O1CCCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[Cu]I>[CH3:21][C:22]([CH3:43])([CH3:42])[CH2:23][C:24]([NH:26][C:27]1[C:35]([C:9]#[C:8][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)=[C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:29]2[N:28]=1)=[O:25]
Reactant: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1cccnc1
Reactant: C#Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1C#Cc1ccc(OC(F)(F)F)cc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
Triethylamine (3 mL) was added to a mixture of bis(tri-t-butylphosphino)palladium (9.6 mg, 0.019 mmol; Strem), 1-ethynyl-4-trifluoromethoxybenzene (0.12 mL, 0.75 mmol), CuI (3.6 mg, 0.019 mmol) and the product from Example 110B (117 mg, 0.38 mmol) in anhydrous tetrahydrofuran (3 mL). The mixture was purged with a nitrogen stream for 2 minutes, and then stirred at 85° C. for 18 hours in a sealed tube. The reaction mixture was cooled and partitioned between dichloromethane (2×50 mL) and 1.0 M sodium carbonate (100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under vacuum. The resulting residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-100% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 9.12 (dd, J=6.9, 1.7 Hz, 1H), 8.65 (dd, J=4.1, 1.7 Hz, 1H), 7.58-7.60 (m, 2H), 7.41-7.44 (m, 2H), 7.17 (dd, J=6.9, 4.1 Hz, 1H), 2.29 (s, 2H), 1.07 (s, 9H); MS (APCI) m/z 417 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12]
Reactant: CCOC(=O)c1cc2c(Cl)cc(O)cc2n1C
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(Oc3ccccc3[N+](=O)[O-])cc2n1C
Temperature: 25 °C
Yield: 86.2 %

Procedure:
After 0.42 g (1.64 mmol) of ethyl 4-chloro-6-hydroxy-1-methyl-2-indolecarboxylate was added to a suspension of 0.066 g (1.64 mmol) of 60% sodium hydride and 5 ml of dimethylformamide, the suspension was stirred at room temperature until the mixture became an almost transparent solution. Then 0.35 g (2.49 mmol) of 1-fluoro-2-nitrobenzene was added to the solution at room temperature followed by stirring for 5 hours at the same temperature. The reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was isolated and purified by silica gel column chromatography to give 0.53 g (94.3%) of ethyl 4-chloro-1-methyl-6-(2-nitrophenoxy)-2-indolecarboxylate.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH2:10](Br)[C:11]#[CH:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH2:12][CH:11]=[CH2:10]
Reactant: COc1ccccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccccc1OC
Temperature: 25 °C
Reaction time: 34 h
Yield: 98.3 %

Procedure:
To a well stirred solution of guaiacol (10.0 g, 80.55 mmol) and propargyl bromide (11.5 g, 96.66 mmol) in DMF (100 mL) was added anhydrous K2CO3 (22.0 g, 161.2 mmol) and the mixture was stirred at room temperature for 34 hours. The mixture was then filtered to remove inorganic material. Filtrate was concentrated under vacuo and diluted with water (250 mL). It was then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave the product (13.0 g) as brown oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([CH:24]5[CH2:26][CH:25]5[C:27]([O:29]C)=[O:28])[N:21]([CH3:31])[C:20]=4[CH:32]=3)[C:12](=[O:33])[CH:11]=2)=[CH:6][CH:5]=1.CO.Cl>C1COCC1>[Cl:3][C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([CH:24]5[CH2:26][CH:25]5[C:27]([OH:29])=[O:28])[N:21]([CH3:31])[C:20]=4[CH:32]=3)[C:12](=[O:33])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C2CC2C(=O)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Yield: 81 %

Procedure:
Sodium hydroxide (1.811 ml) was added to a solution of methyl(1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1 (2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate (280 mg) in THF (3 ml)-MeOH (3 ml) at room temperature. The mixture was neutralized with 1 M HCl at 0° C. and extracted with EtOAc and MeOH. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resulting solid was washed with IPE and dried to give the title compound (220 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccnc1Br
Agent: O=S(=O)(O)O
Product: COc1ccc([N+](=O)[O-])nc1Br
Temperature: 60 °C
Yield: 65 %

Procedure:
2-Bromo-3-methoxypyridine (Desc. 4; 12.4 g, 66 mmol) in concentrated sulphuric acid (30 ml) was treated dropwise with fuming nitric acid (5.5 ml), and the solution heated at 60° C. for 2 hours. After cooling the solution was poured onto ice (500 ml). The solid formed was recovered by filtration, washed with water (500 ml) and sodium bicarbonate solution (500 ml) to give the title product as a yellow solid (10.0 g, 43 mmol, 65% yield).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=2[CH3:30])=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.O>[NH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=2[CH3:30])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCNC(=O)OCc3ccccc3)cc2)c(C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CCN)cc2)c(C)c1
Yield: 87.6 %

Procedure:
A mixture of methyl 4′-[2-[[(benzyloxy)carbonyl]-amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylate (650 mg), ammonium formate (500 mg) and palladium on carbon powder (400 mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 2 hours. The reaction mixture was filtrated and poured into water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give methyl 4′-(2-aminoethyl)-2-methyl-1,1′-biphenyl-4-carboxylate (380 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1COCC1.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>[C:9]1([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)s1
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: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc(-c2ccccc2)s1
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
5-bromothiophene-2-carboxaldehyde (1.0 g, 5.2 mmol) is added to a solution of tetrakis(triphenylphosphine)palladium(0) (180 mg, 0.16 mmol) in degassed THF (10 mL). The resulting solution is stirred for 5 minutes. A solution of phenylboronic acid (760 mg, 6.2 mmol) in THF (10 mL) is added followed by aqueous Na2CO3 (2M, 5.2 mL). The mixture is heated at reflux for 24 hours. The reaction mixture is allowed to cool, poured into ether, and washed twice with water. The ether layer is dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (1:1 hexanes:CH2Cl2) to yield the desired product (900 mg, 91%). 1H NMR (300 MHz, CDCl3) δ 7.38-7.45, 7.65-7.68, 7.73, 9.88.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH2:10][NH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:19]#[N:20].[C:28](OC(=O)C)(=[O:30])[CH3:29].CC1C=CC=CC=1>CO>[C:28]([N:9]1[CH2:10][C:11](=[O:16])[N:12]([CH3:15])[C:13](=[O:14])[N:8]1[C:6]1[CH:5]=[C:4]([Cl:17])[C:3]([CH:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:19]#[N:20])=[C:2]([Cl:1])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: CN1C(=O)CNN(c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)N1CC(=O)N(C)C(=O)N1c1cc(Cl)c(C(C#N)c2ccc(Cl)cc2)c(Cl)c1
Reaction time: 90 h
Yield: 42.9 %

Procedure:
A mixture of 4 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-4 methyl-3,5-dioxo-1,2,4-triazin-2(1H)-yl)benzeneacetonitrile, 12 parts of acetic acid anhydride and 36 parts of methylbenzene was stirred for 90 hours at reflux temperature. After cooling, 16 parts of methanol were added. The solvent was evaporated in vacuo. The residue was stirred in water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol. The precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 2.0 parts (42.9%) of 1-acetyl-2-[3,5-dichloro-4[(4-chlorophenyl)cyanomethyl]phenyl]-1,6-dihydro-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione; mp. 178.1° C. (compound 78).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1O[N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:10]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[S:24][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:10]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=[N+]([O-])c1ccc(C2=NOC(c3c(Cl)cccc3Cl)C2)cc1
Product: O=[N+]([O-])c1ccc(C2=NSC(c3c(Cl)cccc3Cl)C2)cc1

Procedure:
By the method of Asian. J. Chem., 2000, 12, 1358-1360, (±)-5-(2,6-dichlorophenyl)-3-(4-nitrophenyl)-2-isoxazoline can be treated with diphosphorus pentasulfide followed by aqueous quench to produce (±)-5-(2,6-dichlorophenyl)-3-(4-nitrophenyl)-2-isothiazoline. The nitrophenyl group can be reduced to the corresponding aniline with tin dichloride or iron powder and ammonium chloride. The aniline, in turn, can be treated with 2,2-dichloroacetyl chloride and triethylamine to yield (±)-2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-3-(2-isothiazolinyl)]phenyl acetamide.
Reaction SMILES: Cl[CH2:2][C:3]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])([OH:13])[CH:4]([O:6]C(=O)C(C)(C)C)[CH3:5].C[O-].[Na+].Cl>C1COCC1.CO>[O:13]1[C:3]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])([CH:4]([OH:6])[CH3:5])[CH2:2]1
Reactant: CC(OC(=O)C(C)(C)C)C(O)(CCl)c1cc(F)ccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)C1(c2cc(F)ccc2F)CO1
Reaction time: 5 h
Yield: 79 %

Procedure:
A solution of 1.70 g (5.3 mmol) of 1-chloro-2-(2,5-difluorophenyl)-3-(pivaloyloxy)butan-2-ol ((2S,3R)/(2R,3R)=94/6) in 20 mL of THF was cooled to 0° C., and 3.5 g (17.8 mmol) of a 28% solution of NaOMe in methanol was added thereto. The reaction was performed for 5 hours, and 20 mL of 1 M hydrochloric acid was added to stop the reaction. Then, extraction was performed with ethylacetate (30 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain 1.51 g of a crude product. The resulting product was purified by column on silica gel to obtain 0.838 g of the title compound (yield: 79%) ((2R,3R)/(2S,3R)=98/2 (the diastereomeric ratio was measured by HPLC under the same HPLC measurement conditions as those in Example 10, (2R,3R) 32 minutes, (2S,3R) 30 minutes). 1H-NMR (400 MHz, CDCl3) (2R,3R) δ: 1.70 (d, 3H, J=6.6 Hz), 2.80 (d, 1H, J=5.1 Hz), 3.34 (d, 1H, J=5.1 Hz), 4.17 (q, 1H, 6.6 Hz), 6.98-7.00 (m, 2H), 7.14-7.26 (m, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[CH3:49]>C(#N)C>[CH3:49][C:48]1[CH:47]=[CH:46][C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])=[CH:44][C:43]=1[Cl:42]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1Cl
Yield: 47.3 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chloro-4-methylbenzenesulfonyl chloride (0.0440 g, 0.195 mmol) to obtain 4-(4-methyl-3-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0200 g, yield 47%).