Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:10][C:11]1([CH3:42])[C:20]2[C:15](=[C:16]([C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][N:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:42])[C:20]2[C:15](=[C:16]([C:21]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:22])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:31][CH2:32][N:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:34][CH2:35]3)[CH:25]=2)[CH2:12]1
Reactant: CC1(C)CC(c2cccc(N3CCN(c4ccccc4)CC3)c2)Nc2c(C(=O)O)cccc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCN(c4ccccc4)CC3)c2)Nc2c(C(=O)NS(=O)(=O)C3CC3)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (96 mg, 0.8 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (32 mg, 0.8 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A76. A solution of 4,4-dimethyl-2-[3-(4-phenyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (50 mg, 0.11 mmol) and 1,1′-carbonyldiimidazole (37 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B76. Solution B76 was added to Solution A76 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {4,4-dimethyl-2-[3-(4-phenyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-amide (15 mg, 24%) as a white solid: MS (ESI) M+1=545.2.
Reaction SMILES: [Mg].Br[C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH3:13])=[CH:5][CH:4]=1.COB(OC)OC.Br[C:24]1[CH:25]=[CH:26][C:27]([F:32])=[C:28]([CH:31]=1)[CH:29]=[O:30].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Mg].BrC1C=CC(OCCOCCC)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:32][C:27]1[CH:26]=[CH:25][C:24]([C:3]2[CH:15]=[CH:14][C:6]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH3:13])=[CH:5][CH:4]=2)=[CH:31][C:28]=1[CH:29]=[O:30]
Reactant: CCCOCCOc1ccc(Br)cc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COB(OC)OC
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119321.9 %

Procedure:
Under an argon atmosphere, magnesium (737 mg, 30.299 mmol) was suspended in 40.5 ml of tetrahydrofuran, which was then refluxed. Under reflux, a solution of 1-p-bromophenoxy-2-propoxyethane (7.66 g, 29.56 mmol) in 13.5 ml of tetrahydrofuran was dropped and refluxed for 1.5 hours. After cooling to room temperature, the resultant sealed was stored in a refrigerator to form seeds. Under a nitrogen flow, magnesium (73.7 g, 3.0299 mol) was suspended in 4050 ml of tetrahydrofuran, which was then refluxed. Under reflux, the seeds previously prepared were added. A solution of 1-p-bromophenoxy-2-propoxyethane (766 g, 2.956 mol) in 1350 ml of tetrahydrofuran was dropped. After refluxing for 3 hours, the mixture was cooled to 14° C. A solution of trimethoxyborane (310 g, 2.99 mmol) in 1350 ml of tetrahydrofuran was dropped at −15 to −10° C. and stirred at −15 to −10° C. for 1 hour. The mixture was heated to room temperature, sealed and left stand overnight. Under a nitrogen flow, palladium (II) acetate (3318 mg, 14.78 mmol) and subsequently triphenylphosphine (15.506 g, 59.12 mmol) were added at room temperature and stirred at room temperature for 30 minutes. 5-Bromo-2-fluorobenzaldehyde (300 g, 1.478 mmol) and subsequently 1275 ml of an aqueous solution of potassium carbonate (1072 g, 7.76 mol) were added at room temperature and was heated under reflux for 5 hours. After cooling room temperature, 6.75 L of a 2N hydrochloric acid was dropped at 20-30° C. After phase separation, the water layer was extracted with 6.75 L of toluene. The organic layers were combined together and washed with 4.5 L of a 2N hydrochloric acid, two 5-L portions of a 2N aqueous sodium hydroxide solution, two 4.5-L portions of a 12.5% aqueous ammonia, 4.5 L of a 20% brine, 4.5 L of a 2N hydrochloric acid, and three 4.5-L portions of a 20% brine. After addition of 15 g or activated carbon (Shirasagi A), followed by stirring at room temperature for 20 minutes, filtration was conducted and the residue was washed with 1.3 L of toluene. Through vacuum concentration, 533.2 g of crude 2-fluoro-5-(4-propoxyethoxyphenyl) benzaldehyde was obtained as a brown oily matter, which was used in the next step without being purified. A part thereof was purified by column chromatography to yield 2-fluoro-5-(4-propoxyethoxyphenyl) benzaldehyde as white crystals.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=2)[CH:19]=[C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[N:13][CH:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:7]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=2)[CH:19]=[C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[N:13][CH:14]=1)[CH2:6][CH2:5][C:4]#[CH:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(OCCCC#C[Si](C)(C)C)cn3)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCCCOc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 4-(3-(5-(5-(trimethylsilyl)pent-4-ynyloxy)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.7 g, 1.34 mmol) in dry THF (4 mL) was added TBAF (3.8 mL, 13.4 mmol) dropwise maintaining ice-cooled conditions. The mixture was stirred for 30 min. The reaction was concentrated and then partitioned between saturated NaHCO3 solution and CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (0.6 g, 98% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]2=[O:13])[CH3:2].CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[C:8](=[O:13])[C:9]1=[O:12]
Reactant: Clc1ccccc1CBr
Reactant: CCc1cccc2c1NC(=O)C2=O
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Product: CCc1cccc2c1N(Cc1ccccc1Cl)C(=O)C2=O
Yield: 80.7 %

Procedure:
Using a method similar to Preparation 15, with 7-ethylisatin (88 mg, 0.5 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene beads(630-720 mg, 1.4-1.6 mmol, 2.2 mmol/g, Fluka) and 2-chlorobenzyl bromide (0.065 mL, 0.5 mmol) gives 121 mg (85%) of the title compound as crude material as a red-orange solid. MS (ES): m/z=300 (M+1).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:35]=[CH:34][C:23]2[NH:24][CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1.[O:36]=[C:37]1[NH:42][C:41]2[CH:43]=[C:44]([C:47](O)=[O:48])[CH:45]=[CH:46][C:40]=2[O:39][CH2:38]1>CCOC(C)=O>[Br:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([C:47]([C:44]3[CH:45]=[CH:46][C:40]4[O:39][CH2:38][C:37](=[O:36])[NH:42][C:41]=4[CH:43]=3)=[O:48])[CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1
Reactant: CCOC(=O)CC1COc2cc(Br)ccc2N1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 150 °C
Yield: 57.9 %

Procedure:
TEA (0.737 mL, 5.32 mmol) and T3P (50 wt. % in EtOAc, 2.372 mL, 3.99 mmol) were added to a solution of ethyl (7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate (Intermediate 27, 399 mg, 1.33 mmol) and 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (308 mg, 1.60 mmol) in EtOAc (7 mL). The reaction mixture was heated in a microwave reactor at 150° C. for 2 h. Additional T3P (50 wt. % in EtOAc, 1.2 mL, 2.02 mmol) and TEA (0.3 mL, 2.16 mmol) was added and the mixture was heated in a microwave reactor at 150° C. for another 2 h. EtOAc (50 mL) was added and the mixture washed with sat. aq. Na2CO3 (2×30 mL), HCl (30 mL, 0.5M) and brine, dried through a phase separator and evaporated. The compound was purified by preparative HPLC (Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% ACN in H2O/ACN/FA 95/5/0.2 buffer over 20 min with a flow of 100 mL/min, UV detection at 254/280 nm). The title compound (366 mg, 58%) was obtained after removal of solvents in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:30])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=3)[O:8][C:7](=[O:28])[C:6]=2[CH:29]=1.[CH3:31][NH2:32]>C(#N)C>[Cl:22][C:21]1[C:16]([N:15]2[C:11]([C:9]([NH:10][C:5]3[C:6]([C:7]([NH:32][CH3:31])=[O:28])=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[Cl:30])=[O:8])=[CH:12][C:13]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])=[N:14]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN
Reactant: CS(=O)(=O)Oc1cc(-c2nc3c(Cl)cc(Cl)cc3c(=O)o2)n(-c2ncccc2Cl)n1
Solvent: CC#N
Product: CNC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(OS(C)(=O)=O)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,8-dichloro-2-[1-(3-chloro-2-pyridinyl)-3-[(methylsulfonyl)oxy]-1H-pyrazol-5-yl]-4H-3,1-benzoxazin-4-one (i.e. the product of step D) (0.05 g, 0.10 mmol) in acetonitrile (3 mL) was added methylamine (2.0 M solution in THF, 0.5 mL, 1 mmol). The resulting solution was stirred at room temperature overnight. Thin layer chromatography showed the reaction to be incomplete. Methylamine (2.0 M solution in THF, 0.5 mL, 1 mmol) was added dropwise and the reaction stirred 1 hour at room temperature. Thin layer chromatography showed the reaction was complete. The reaction mixture was concentrated to dryness to yield 0.057 g of the title compound, a compound of present invention, as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(O[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C.C(OC1C=CC=CC=1)(=O)C1C=CC=C(C(OC2C=CC=CC=2)=O)C=1>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(=O)Oc1ccccc1
Agent: O=C(Oc1ccccc1)c1cccc(C(=O)Oc2ccccc2)c1
Product: O=C(Oc1ccccc1)c1ccc(O)cc1
Temperature: 180 °C

Procedure:
An aromatic polyester useful as a cross-linking agent for the prepolymer of Example 1 is produced as follows. 414 g. (3 moles) of p-hydroxybenzoic acid, 510 g (3.75 moles) of phenyl acetate and 954 g. (3 moles) of diphenyl isophthalate are charged into a fournecked resin kettle equipped with a thermometer, stirrer, distilling head and a combination nitrogen-HCl inlet tube. The reaction mixture is stirred constantly under a nitrogen atmosphere throughout the run. The reaction mixture is heated to 180°C, and HCl is then bubbled through the mixture for 7 hours, the temperature being held at 180°C. Phenyl p-hydroxybenzoate is thereby produced. The HCl flow is discontinued, the reaction mixture is heated to 200°C at a rate of 10°C/hour, 363 g. (3.3 moles) of hydroquinone is added, and the temperature is further increased to 250°C over a period of 2.5 hours. The distilling head is then heated to 190°C by external heating means to prevent condensation in the distilling head of distillate subsequently to be produced. The reaction mixture is heated to 320°C over a period of 6 hours, held at 320°C for 16 hours, heated to 340°C and held there for 3 hours. During this stage, condensation occurs between the phenyl p-hydroxybenzoate, diphenyl isophthalate and hydroquinone, accompanied by the distillation of phenol. A total of 1127 g. of distillate is collected during the entire run, the distillate containing acetic acid, phenol and the excess phenyl acetate.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C([O-])(=O)C.[Na+].[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)C=C(O)[CH:18]=[CH:17]2>C1(C)C=CC=CC=1>[C:5]([O:4][C:1]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([Br:13])[CH:15]=2)[CH:2]=1)(=[O:7])[CH3:6]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc2cc(Br)ccc2c1

Procedure:
6-bromo-2-naphthol is obtained according to the procedure of Example 1. A solution of acetic anhydride, sodium acetate, and the 6-bromo-2-naphthol in toluene is then refluxed for about 2 1/2 hours. Crude 2-acetoxy-6-bromonaphthalene is isolated therefrom by stripping the solvent from the organic layer after washing with water. The acetoxy compound is then purified by recrystallization from n-butanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[C:17]([F:18])=[C:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[C:17]([F:18])=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3ccccc3Cl)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2nc(Nc3ccccc3Cl)oc2c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 90.1 %

Procedure:
Methyl 2-(2-chlorophenyl)amino-7-fluoro-6-benzoxazolylacetate (2.12 g, 6.33 mmol) was dissolved in THF/methanol (2:1, 90 ml). To the resulting solution was added 1N NaOH (30 ml) and the mixture was stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure. The residue was acidified with 1N hydrochloric acid. The crystals thus precipitated were collected by filtration, washed with water and dried under reduced pressure, whereby 2-(2-chlorophenyl)amino-7-fluoro-6-benzoxazolylacetic acid (1.83 g, 90%) was obtained as a colorless solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cccc(Sc2ccccc2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(Sc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
(3-Phenylsulfanyl-phenyl)-methanol described in Preparation Example 93 (212 mg, 0.980 mmol), phthalimide (144 mg, 0.980 mmol), diethylazodicarboxylate (170 μl, 1.08 mmol) and triphenylphosphine (308 mg, 1.18 mmol) were dissolved in tetrahydrofuran (4 mL), and the solution was stirred overnight at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (124 mg, 0.359 mmol, 37%) was obtained as a solid.
Reaction SMILES: [P:1]([O-:5])([O-:4])([OH:3])=[O:2].[K+].[K+].C([O-])(=O)C.[Ca+2:12].C([O-])(=O)C>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:12].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:12].[Ca+2:12]
Reactant: O=P([O-])([O-])O
Agent: CC(=O)[O-]
Agent: [Ca+2]
Agent: [K+]
Product: O=P([O-])([O-])[O-]

Procedure:
Catalyst A was prepared by adding an aqueous solution of dipotassium hydrogen phosphate (1.0 mole) with vigorous stirring to an aqueous solution of calcium acetate (1.67 moles) to obtain a calcium phosphate gel having a Ca/P atomic ratio of 1.67. After standing overnight, the gel was recovered by filtration and washed by slurrying in a 3500 ml portion of water and filtered. The wash treatment was done three times. Finally, the filter cake was additionally washed by pulling 10 liters of distilled water through it. About 1/4 of the wet cake was reslurried in 1000 ml of distilled water and to the stirred slurry was added 16 g of barium nitrate dissolved in 300 ml of distilled water. The mixture was allowed to stand for 2 days with occasional stirring. Then to the well-stirred slurry was slowly added a mixture of 145 g nickel nitrate and 16 g barium nitrate dissolved in 600 ml of hot distilled water and 100 g potassium carbonate dissolved in 250 ml of distilled water. The resulting mixture was filtered to obtain a cake which was reslurried in about 3500 ml of distilled water and filtered. This operation was repeated and finally about 3 liters of distilled water was pulled through the filter cake. The cake was dried overnight at 220° F, crushed to pass a 40 mesh screen and calcined in air at 800° F for 3 hours. The cooled product was mixed with 3 weight percent polyethylene powder and pilled to 1/8-inch size at 100 psig. The pills were heated at about 800° F in hydrogen for about 20 minutes to obtain the finished catalyst. This invention catalyst, as analyzed, contained 16.3 weight percent barium and 26.9 weight percent nickel based on the total weight of the catalyst composite. The surface area of the catalyst was about 80 square meters per gram, as determined by nitrogen absorption, the pore volume was about 0.2 ml per gram as determined by water absorption, and the apparent bulk density was 0.94 gram per ml.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][NH:24][OH:25])=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1>O1CCOCC1>[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][N:24]([OH:25])[C:3]([NH:2][CH3:1])=[S:4])=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1
Reactant: CN=C=S
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: CNC(=S)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A solution of methyl isothiocyanate (1.36 g, 18.56 mmol) in 2 ml of dioxane is added dropwise to a suspension of 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine (2.01 g, 5.84 mmol) in 60 ml of dioxane and 60 ml of H20 at 0° C. The ice bath is removed. After one hour 0.5 g (6.84 mmol) additional methyl isothiocyanate is added and the reaction mixture is stored in a freezer overnight. The solids are collected by filtration and recrystallized from THF/hexane, rinsed with ether, and dried under high vacuum over P2O5 to give pure 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)thioxomethyl]-lH-indole-3-methanamine (1.32 g, 54%); mp 198°-198.5° C. (dec).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[C:10]1([CH3:22])[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH:11]=1.N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([N:18]2[CH2:19][CH2:20][N:16]([C:12]3[CH:11]=[C:10]([CH3:22])[CH:15]=[CH:14][CH:13]=3)[C:17]2=[O:21])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N2CCNC2=O)c1
Reactant: Cc1c(Br)cccc1Br
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: C1COCCO1
Product: Cc1cccc(N2CCN(c3cccc(Br)c3C)C2=O)c1
Temperature: 120 °C
Reaction time: 21.5 h
Yield: 71.4 %

Procedure:
A suspension of 1,3-dibromo-2-methylbenzene (185 mg, 0.740 mmol), 1-m-tolylimidazolidin-2-one (50 mg, 0.284 mmol), copper (I) iodide (5.40 mg, 0.028 mmol), tripotassium phophosphate (120 mg, 0.567 mmol) and (+/−)-trans-1,2-diaminocyclohexane (3.4 μL, 0.028 mmol) in 1,4-dioxane (1 mL) was purged with nitrogen and heated at 120° C. in a sealed tube. After 21.5 h, the mixture was concentrated and the residue was purified by column chromatography (eluting with a gradient from hexane to 50:50 hexane-EtOAc) to provide 1-(3-bromo-2-methylphenyl)-3-m-tolylimidazolidin-2-one as a white solid (70 mg, 70%). 1H NMR (400 MHz, chloroform-d) δ 7.51-7.54 (1 H, m), 7.49 (1 H, s), 7.34 (1 H, dd, J=8.05, 1.94 Hz), 7.24 (2 H, d, J=8.05 Hz), 7.11 (1 H, t, J=7.91 Hz), 6.90 (1 H, d, J=7.49 Hz), 3.98-4.04 (2 H, m), 3.81-3.87 (2 H, m), 2.38 (3 H, s), 2.36 (3 H, s). Mass spectrum m/z 345, 347 (M+H)+.
Reaction SMILES: C(O/[CH:4]=[CH:5]\[C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=1)C.BrN1C(=O)CCC1=O.[NH2:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1>O1CCOCC1.O>[CH3:31][C:30]1[C:25]2[N:26]([C:5]([C:6]3[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=3)=[CH:4][N:24]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccnc1N
Reactant: CCO/C=C\c1nc(SC)ncc1C#N
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc(C#N)c(-c2cnc3c(C)cccn23)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.6 %

Procedure:
10 g of 4-[(Z)-2-ethoxyvinyl]-2-(methylthio)-5-pyrimidinecarbonitrile (synthesized according to the method disclosed in International Publication WO2006/025567, pages 90-91) was dissolved in a mixed solvent of 150 mL of 1,4-dioxane and 30 mL of water and then 8.04 g of N-bromosuccinimide was added thereto under an ice-cold condition, and the mixture was stirred for 1.5 hours at room temperature. To the reaction solution, 4.89 g of 2-amino-3-picoline was added, and the mixture was further stirred for 2.5 hours. 200 mL of water was added to the reaction solution to extract with 2 L of a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The organic layer was washed with water, and dried over anhydrous magnesium sulfate. Thereafter, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in a small amount of chloroform and solidified with hexane to obtain 4.02 g of 4-(8-methylimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [1-6] (hereinafter, referred to as the compound [1-6]) as a light brown solid.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:12])[C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C[N:16]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C(N)(=O)C(N)=O>C(Cl)Cl.C(OCC)(=O)C>[C:1]1([NH:7][C:8](=[O:12])[C:9]([NH2:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)C(=O)Nc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=O)C(N)=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)C(=O)Nc1ccccc1
Reaction time: 0.08 h

Procedure:
Acid 84 (20 mg, 1.4 eq) in CH2Cl2 (1 mL) was treated with PyBOP (53 mg, 1.2 eq) and NMM (0.028 mL, 3.0 eq) and stirred for 5 minutes. To this was added a solution of oxalamide (50 mg, 1.0 eq) and NMM (0.028 mL, 3.0 eq) in CH2Cl2 (1 mL) and the mixture stirred at room temperature overnight. The mixture was diluted with ethyl acetate, the organic phase washed with 0.5N HCl, brine, saturated bicarbonate solution, and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative HPLC yielded 24 mg (38%) of N-[cyclohexyl-(1-{2-[1-cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-octahydro-indole-1-carbonyl}-2,2-dimethyl-propylcarbamoyl)methyl]-N′-phenyl-oxalamide 96 as a white solid with consistent analytical data. LCMS ret time=4.07, M+H=737.26, M−H=735.22.