Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[NH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([NH:22][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[O:7])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cccc2ccccc12)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 2-nitrobenzoyl chloride in anhydrous THF (5 mL) was added N, N-diisopropylethylamine (0.235 mL, 1.35 mmol) followed by 1-aminonaphthalene (192.9 mg, 1.35 mmol) and the solution was stirred at 40° C. for 16 hours. The solvent was evaporated to give N-naphthyl(2-nitrophenyl)carboxamide, a compound of formula (7), which was used for the next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6](Cl)=[O:7])#[N:2].O[NH:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2)=[NH:19].C(N(CC)CC)C>C(#N)C>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([C:18]3[N:17]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:7][N:19]=3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: N=C(NO)c1ccc2[nH]ncc2c1
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
3-Cyano-4-[(1-methylethyl)oxy]benzoyl chloride (D106) (545 mg, 2.437 mmol) and N-hydroxy-1H-indazole-5-carboximidamide (D2) (685 mg, 2.437 mmol) were dissolved in acetonitrile (30 ml) before adding triethylamine (0.374 ml, 2.68 mmol). The resulting mixture was stirred at room temperature for 3 h then at 80° C. for 48 h, then cooled at room temperature. The precipitate formed was filtered off and dissolved in EtOAc and washed with water, evaporated and chromatographed [0-15% EtOAc in cyclohexane] to give the title compound (170 mg, 17%) as a pink solid. MS (ES): C19H15N5O2 requires 345; found (MH+) 346
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.Br[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Br.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[O:21]1[CH2:22][CH2:23][N:1]([C@@H:2]2[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:3]2)[CH2:19][CH2:20]1
Reactant: N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: BrCCOCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CC[C@@H](N2CCOCC2)C1)OCc1ccccc1

Procedure:
A solution of EXAMPLE 111B (400 mg), 1-bromo-2-(2-bromoethoxy)ethane (0.246 mL), and triethylamine (0.595 mL) in N,N-dimethylformamide (6 mL) was stirred at 70° C. for 24 hours. The solution was cooled and poured into ethyl acetate (200 mL). The solution was extracted with 3× water, washed with brine, concentrated, and chromatographed on silica gel using 10% methanol/ethyl acetate to give the pure product.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:23])([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:25])=[O:24])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI.[Cl-].[NH4+]>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:23])([CH2:20][CH2:21][CH3:22])[N:16]([CH3:1])[S:15]2(=[O:24])=[O:25])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CCCC1(C)NS(=O)(=O)N(Cc2ccccc2)C1=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCC1(C)C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
Potassium t-butoxide (3.93 g, 35.06 mmol) was added in one portion to a solution of 2-phenylmethyl-4-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9 g, 31.87 mmol) in 250 ml of THF at 0° C. and the mixture was stirred under nitrogen at this temperature for 1 hour. To the mixture was added methyl iodide (27.14 g, 191.22 mmol) at 0° C. and the resulting mixture was allowed to stir at 0° C. for 1/2 hour and at room temperature for 11 hours. The resulting mixture was poured into 400 ml of saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo to afford 9.28 g (98%) of 2-phenylmethyl-4-methyl-4 -propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =propyl; R2 =CH3 ; R3 =methyl ) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([N:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH3:12])[CH:10]=1)=[O:4].[OH-].[Na+].Cl>CO>[C:13]([N:11]([CH3:12])[C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1)(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(N(C)C(=O)C(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(N(C)C(=O)C(C)C)c2)cc1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
5-(Isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (85 mg, 0.26 mmol)) was added to a mixture of methanol (2 mL) and 1N aqueous NaOH (2 mL) and the mixture was stirred for one hour. HCl (1N aqueous solution) was added dropwise to the stirring solution until a precipitate formed. An additional 0.5 lM of 1N HCl was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 67 mg of 5-(isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21](OS(C)(=O)=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:10][C:9]1([CH3:34])[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:10][C:9]1([CH3:33])[CH3:34])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CC(CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1)OS(C)(=O)=O
Solvent: ClCCl
Product: CCOC(=O)C=CCC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A solution of 4-benzyl-5-(3-ethoxycarbonyl-2-methanesulfonyloxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (64 g) in dichloromethane (250 ml) was stirred at 15° C. under an atmosphere of nitrogen during the dropwise addition of 1,8-diazobicyclo[5,4,0]undec-7-ene (21.3ml). After 30 minutes, a further portion of 1,8-diazobicyclo[5,4,0]undec-7-ene (9.0ml) was added and the reaction mixture stirred for 1 hour. The solvent was evaporated and the residue dissolved in ethyl acetate, washed sequentially with 2M aqueous hydrochloric acid (500 ml and 250 ml), water, 5% aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate) and evaporated to afford 4-benzyl-5-(3-ethoxycarbonyl-allyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (49 g, %) as an orange gum. Mass spectrum 404 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:8](CC3C=CC4/C(=C(\C)/C#N)/C5C=CC=CC=5OCC=4C=3)[C:7]3[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3]C1.[CH:34]1(C2NC3C(C)=CC=CC=3N=2)CC1>>[CH2:1]([C:4]1[NH:5][C:6]2[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:7]=2[N:8]=1)[CH3:3]
Reactant: C/C(C#N)=C1\c2ccc(Cn3c(C4CC4)nc4c(C)cccc43)cc2COc2ccccc21
Reactant: Cc1cccc2nc(C3CC3)[nH]c12
Product: CCc1nc2cc(C)cc(C)c2[nH]1

Procedure:
[step 1] (Z)-2-[8-(2-Cyclopropyl-4-methylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (764 mg, 89%) was obtained in the same manner as in step 1 of Example 140, using 2-cyclopropyl-4-methylbenzimidazole (342 mg, 1.98 mmol), obtained in Reference Example 28, instead of 2-ethyl-4,6-dimethylbenzimidazole.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]5[C@@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[O:26][C:25]([CH3:38])([CH3:37])[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[I-:40].[Na+].CN(C)[C@@H]1CCCC[C@H]1N(C)C>O1CCOCC1.[Cu](I)I>[Si:30]([O:29][CH2:28][C@H:27]1[O:26][C:25]([CH3:37])([CH3:38])[O:24][C@@H:23]1[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7](=[O:39])[C:6]3[C:5]4[C:13](=[CH:14][C:2]([I:40])=[CH:3][CH:4]=4)[NH:12][C:11]=3[C:10]([CH3:16])([CH3:15])[C:9]=2[CH:17]=1)([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32]
Reactant: CC1(C)O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Reactant: [I-]
Agent: I[Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N(C)C
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(I)ccc4c2C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 110 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
Under nitrogen atmosphere, 3-bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound T22-1, 300 mg, 0.47 mmol), sodium iodide (147 mg, 0.94 mmol) and copper iodide (9.40 mg, 0.047 mmol) were dissolved in dioxane (1.00 ml), added with (1R,2R)—N,N,N′,N′-tetramethyl-cyclohexane-1,2-diamine (15.4 μl, 0.094 mmol), and then stirred at 110° C. for 16 hr. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (methylene chloride/methanol) to obtain the title compound (220 mg, 70%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:1][NH:2][C:3](=[S:6])[NH:4][NH:5][C:17]([C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)=[O:18]
Reactant: CNC(=S)NN
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: CNC(=S)NNC(=O)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
To a stirred room temperature solution of 4-methyl-thiosemicarbazide (5.91 g, 5.62×10-2 mole) and pyridine (150 ml) was added 2-naphthoyl chloride (10.7 g, 5.61×10-2 mole). After stirring overnight, the pyridine was evaporated at reduced pressure. The concentrate was treated with water and the undissolved product was collected by filtration and dried by suction. Crystallization from acetone/ethanol afforded off-white needles, Mp 211° C. (decomp).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH:11][N:12]=[CH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[CH:9][C:8](=[O:23])[N:7]([CH3:24])[C:6]1=[O:25])[CH:2]([CH3:4])[CH3:3].[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.C(N(CC)CC)C>CC(N(C)C)=O>[S:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]([CH2:13][N:12]2[C:32]([C:28]3[N:27]([CH3:26])[CH:31]=[CH:30][CH:29]=3)=[C:9]3[C:10]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6](=[O:25])[N:7]([CH3:24])[C:8]3=[O:23])=[N:11]2)=[CH:15]1
Reactant: Cn1cccc1C=O
Reactant: CC(C)Cn1c(NN=Cc2csc3ccccc23)cc(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21
Temperature: 90 °C

Procedure:
1-Benzothiophene-3-carbaldehyde N-(3-isobutyl-1-methyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl)hydrazone (100 mg, 0.284 mmol) was suspended in anh. DMA (3 mL) under an atmosphere of N2 gas. To the suspension was added N-methylpyrrole-2-carboxaldehyde (37 mg, 0.34 mmol). To this suspension was added catalytic amounts of triethylamine (25 μL). The reaction mixture was placed in a preheated heating block maintained at 90° C. and heated under N2 gas for 18 h. At the end of reaction the solvent was removed in vacuo and the resulting brown oil was resuspended in DMSO (1.5 mL) and was purified by semi preparative RPHPLC eluting with MeCN/water/TFA mixtures. Yield=37 mg, Rt=2.46 min, MS: 444,(M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31](O)=[O:32])=[CH:22]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])=[CH:12][CH:13]=3)[CH2:18]2)=[O:32])=[CH:22]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)Cc1c[nH]c3ccccc13)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 290 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 140 mg indole-3-acetic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. 910 mg of a residue are obtained. The residue is purified by silica gel flash chromatography. 180 mg of the title compound are obtained after drying.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1)#[CH:27].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:27]#[C:26][C:28]2([OH:36])[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(c2ccc(I)c(Cc3ccccc3)n2)CC1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccc(C#CC3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)CC1
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A mixture of 1.42 g of 2-benzyl-3-iodo-6-(4-ethoxycarbonylpiperidino)pyridine, 520 mg of 3-ethynyl-3-quinuclidinol, 110 mg of tetrakis(triphenylphosphine)palladium(0), 3 mg of cuprous iodide, 1.3 ml of triethylamine and 6 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 80° C. for 3 hours in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 20-100% ethyl acetate/hexane and then with 2.5% methanol/ethyl acetate, to give 700 mg of the target compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C1COCC1.Cl>[OH-].[Pd+2].[OH-].CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=CC=Cc1cccs1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CCCCc1cccs1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76.2 %

Procedure:
A mixture of ethyl 5-(2-thienyl)-2,4-pentdienoate (20.20 g), 10% palladium hydroxide (Pd(OH)2) (2.04 g), THF (200 ml), MeOH (100 ml) and 1 N HCl (10 ml) was stirred at r.t. under nitrogen atmosphere for 3.5 hours. After removal of insoluble solids, the filtrate was evaporated in vacuo, and the residue was dissolved with a mixture of AcOEt and water. The organic layer was washed with saturated aqueous solution of NaHCO3, water and brine, and dried over MgSO4, and evaporated in vacuo to give ethyl 5-(2-thienyl)pentanoate (15.70 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)(O)[O-].[Na+]>CO.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1Cl
Yield: 81 %

Procedure:
To 2.0 g of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 50 mL of methanol was added 1.9 g of 2,4-dichloroaniline. After refluxing the reaction under an inert atmosphere for 2 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/hexanes. Drying in vacuo yielded 2.6 g (80%) of 4-(2,4-dichloro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile as yellow needles: melting point 206-208° C.; mass spectrum (m/e): M+H 332.8.
Reaction SMILES: [CH3:1][C@@H:2]([OH:7])[CH2:3][C@H:4]([OH:6])[CH3:5].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:6][C@H:4]([CH3:5])[CH2:3][C@H:2]([OH:7])[CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H](O)C[C@@H](C)O
Product: C[C@H](C[C@@H](C)O)OCc1ccccc1
Yield: 107 %

Procedure:
20.0 g of (2R, 4R)-(-)-pentanediol and 20.4 g of benzaldehyde were subjected to the same procedure as in Example 91 i) to obtain 39.9 g of (2R, 4R)-4-benzyloxy-2-pentanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](C)=[CH:5][CH:4]=1)[CH3:2].[CH2:10]=C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[CH3:10])[CH3:2]
Reactant: CCc1ccc(C)cc1
Reactant: C=C
Solvent: Cc1ccccc1
Product: CCc1ccccc1C

Procedure:
Data from these analyses are combined by computer program to give an overall material-balanced run result. Especially noted is the proportion of para-ethyltoluene in ethyltoluenes, PET/ET, and the ratio of toluene converted to theoretical toluene conversion if all ethylene fed reacted stoichiometrically with toluene to give ethyltoluene.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C>C1COCC1>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([B:12]([OH:17])[OH:13])=[CH:4][CH:5]=1)[CH3:11]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A one-necked, 25-mL, round-bottomed flask equipped with a reflux condenser fitted with an argon inlet adapter was charged with magnesium powder (0.255 g, 10.5 mmol, -50 mesh), 7 mL THF, and 4-bromophenetol (1.41 g, 1.00 mL, 7.00 mmol). The resulting mixture was heated to reflux for 3 h. A second one-necked, 25-mL, round- bottomed flask equipped with a rubber septum and an argon inlet needle was charged with triisopropyl borate (3.95 g, 4.85 mL, 21.00 mmol) and cooled to -78° C. while the Grignard reagent prepared above was added dropwise via cannula over ca. 5 min. The cooling bath was removed and the reaction mixture was stirred for 3 h at room temperature. A mixture of ether (50 mL) and a 10% HCl solution (59 mL) was added and the resulting organic phase was washed with a 100-mL portion of water. The organic phase was dried over MgSO4, filtered, and concentrated to provide a yellow solid which was recrystallized from ether-hexanes to provide 0.783 g (67%) of a white solid:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.C(Cl)CCl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:21][C:31](=[O:32])[CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:34])([F:22])[F:35])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(N)ccc1Oc1ncccc1-c1ccncn1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(NC(=O)Cc2cccc(C(F)(F)F)c2)ccc1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 3-methyl-4-(3-pyrimidin-4-yl-pyridin-2-yloxy)-phenylamine (30 mg, 0.11 mmol), (3-trifluoromethyl-phenyl)-acetic acid (27 mg, 0.13 mmol), and EDC (41 mg, 0.22 mmol) was added CH2Cl2 (2.0 mL). The mixture was stirred for 6 h at RT, concentrated, diluted with EtOAc, and extracted with saturated NaHCO3. The organic layer was dried over Na2SO4, filtered, concentrated and purified by reverse-phase HPLC to yield N-(3-Methyl-4-((3-(4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide. MS m/z=465 [M+1]+. Calc'd for C25H19F3N4O2: 464.45.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)#[N:25]>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:30][C:29]1[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: COC=Cc1ccc(C#N)cc1
Reaction time: 1 h

Procedure:
A suspension of 37.2 g of methoxymethyl-triphenylphosphonium chloride in 250 ml of t-butyl methyl ether is treated at room temperature while gassing with argon with 13.4 g of potassium t-butylate and stirred for 1 hour. Subsequently, the reaction mixture is treated at about 20° C. with a mixture of 9.49 g of 4-cyanobenzaldehyde and 100 ml of t-butyl methyl ether and stirred for a further 1 hour. Thereafter, the reaction mixture is partitioned in diethyl ether/water. The aqueous phase is extracted several times with diethyl ether. The organic phases are washed with water, dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with petroleum ether and toluene/hexane (vol. 3:1) gives 4-(2-methoxyvinyl)benzonitrile.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH:35][C:36](=O)[O:37]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C.CCOC(C)=O>[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH:35][C:36]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=3)[CH:8]=2)[CH2:3][CH2:2]1)=[O:37]
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1csc(-c2ccc3c(c2)NCC3)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CC3)n1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A mixture of ethyl 2-(indolin-6-yl)thiazole-4-carboxylate (28D) (56 mg, 0.14 mmol), K2CO3 (22 nmg, 0.16 mmol), and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (48 mg, 0.15 mmol) was heated to reflux in acetonitrile (3 mL) for 5.5 hours. The reaction mixture was cooled to rt and diluted in EtOAc (5 mL), washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE/EtOAc (1:1), to provide 22 mg (34%) of the desired product ethyl 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)indolin-6-yl)thiazole-4-carboxylate (28E): 1H NMR (300 MHz, CDCl3) δ 8.67 (1H, s), 8.12 (1H, s), 7.68 (2H, m), 7.52 (1H, m), 7.38 (1H, m), 7.25 (2H, m), 4.43 (2H, q), 4.22 (2H, m), 3.18 (2H, m) 1.45 (3H, t). LC/MS (APCI): m/z 451.1 (M+H).