Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:27])[CH:20]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: NCCN1CCCCC1
Reactant: Cn1ncc2cc(NC(=O)Nc3cccc(Oc4ccnc(C(=O)O)c4)c3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1ncc2cc(NC(=O)Nc3cccc(Oc4ccnc(C(=O)NCCN5CCCCC5)c4)c3)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.2 %

Procedure:
4-[3-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]-pyridine-2-carboxylic acid (0.07 g, 0.17 mmol) was dissolved in DMF (2.5 mL), followed by sequential addition of 1-(2-aminoethyl)piperidine (0.02 g, 0.17 mmol), 1-hydroxybenzotriazole (0.05 g, 0.38 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (0.05 g, 0.26 mmol), and N-methylmorpholine (0.04 g, 0.38 mmol). The mixture was stirred at room temperature for 12 h, and the solvent was removed in vacuo. The crude residue was dissolved in CH2Cl2 (10 mL), and washed with H2O (3 mL). The solvent was removed in vacuo, and the crude product was purified by preparative HPLC. The isolated product was washed with aq. Na2CO3 to give 0.07 g (78%) of the title compound. 1H-NMR (CD3OD) δ 8.51 (d, 1H), 7.91 (s, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 7.50-7.46 (m, 2H), 7.41-7.36 (m, 2H), 7.26 (dd, 1H), 7.10 (dd, 1H), 6.81-6.77 (dd, 1H), 4.03 (s, 3H), 3.60 (t, 2H), 2.78-2.71 (m, 6H), 1.69-1.51 (m, 6H); MS LC-MS (M+H)+=514.3, RT=2.62 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:41])[CH3:22])=[CH:29][CH:28]=1)[C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:39])[CH3:40])=[CH:34][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 20.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.0 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.91 g) as starting materials, 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][C:5]2=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH2:17]([N:21]1[C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:33])[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([N:21]1[C:25]2[CH:26]=[C:27]([C:2]3[N:6]4[CH2:7][CH2:8][CH2:9][C:5]4=[N:4][C:3]=3[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:33])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cn1c(N)nc2ccc(B(O)O)cc21
Reactant: Fc1ccc(-c2nc3n(c2Br)CCC3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccc(F)cc4)nc4n3CCC4)cc21
Temperature: 90 °C
Reaction time: 0.13 h
Yield: 31.3 %

Procedure:
Bubble nitrogen through a solution of 3-bromo-2-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (750 mg, 2.67 mmol) in dimethoxyethane (20 ml). Add bis(triphenylphosphine)palladium(II) chloride (175 mg, 0.095 mmol) and stir at room temperature for 3 minutes. Add (1-isobutyl-2-amino-1H-benzimidazol-6-yl)boronic acid (750 mg, 3.211 mmol) by 2M aqueous sodium carbonate (2.7 mL, 5.40 mmol). Heat at 90° C. for 16 hours. Cool to room temperature, dilute with water (50 ml), and extract with ethyl acetate (150 ml). Dry over magnesium sulfate and concentrate under reduced pressure. Subject the residue to HPLC (Xterra MS C18 5 μm, 19×100 mm; Solvent A: 10 mM ammonium carbonate at pH 9; Solvent B: acetonitrile; Gradient: from 35 to 50% B in 8 minutes and then 50 95% B in 1 minute; Flow rate: 20 mL/min) to provide 1-isobutyl-2-amino-6-(2-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-1H-benzimidazole (325 mg, 31%). MS (ES): m/z=390 (M++H) The free base is treated with two equivalents of methanesulfonic acid essentially as previously described to provide the title compound (50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][O:19][CH3:20])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:34].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][O:19][CH3:20])=[N:15][C:16]([Cl:34])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: COCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: COCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP12), chlorination of 1-iodo-3-methoxymethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (720 mg; 1.274 mmol) and purification by FC (DCM/MeOH=60/1) gave the expected product 1-chloro-3-methoxymethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as an orange oil (254 mg; 42%). LC-MS: tR=1.09 min.; [M+H]+=474.42 g/mol.
Reaction SMILES: C([O:3][C:4](=O)[C@@:5]([NH2:24])([CH2:22][CH3:23])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)C.[BH3-][C:27]#N.[Na+]>ClCCl.C(O)=O>[CH2:22]([C@@:5]([NH:24][CH3:27])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)[CH2:4][OH:3])[CH3:23]
Reactant: [BH3-]C#N
Reactant: CCCCCCCOc1ccc(CC[C@](N)(CC)C(=O)OCC)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=CO
Product: CCCCCCCOc1ccc(CC[C@](CC)(CO)NC)cc1

Procedure:
(R)-2-amino-2-ethyl-4-(4-heptyloxy-phenyl)-butyric acid ethyl ester (175 mg; 0.5 mmol) is dissolved in dichloromethane (2) and formic acid (100 μl), p-formaldehyde (100 μl; 30% in water) and NaBH3CN are added. After 1 hour at RT the reaction mixture is extracted with saturated aqueous NaHCO3 solution and the organic layer is dried over MgSO4 and purified on silica gel using n-hexanetethyl acetate (1/1→1/9) as mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[N:22]=[C:21](C)[N:20]=3)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6].NC1N=CN=C(C[OH:37])C=1.ClC1C=C(C=C(Cl)C=1N1C=C2C(Cl)=NC=CC2=N1)C#N>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:18][C:19]3[CH:24]=[C:23]([CH2:25][OH:37])[N:22]=[CH:21][N:20]=3)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6]
Reactant: Nc1cc(CO)ncn1
Reactant: Cc1cc(Nc2nccc3nn(-c4c(Cl)cc(C#N)cc4Cl)cc23)nc(C)n1
Agent: N#Cc1cc(Cl)c(-n2cc3c(Cl)nccc3n2)c(Cl)c1
Product: N#Cc1cc(Cl)c(-n2cc3c(Nc4cc(CO)ncn4)nccc3n2)c(Cl)c1
Yield: 37 %

Procedure:
Following the procedure described for 3,5-dichloro-4-[4-(2,6-dimethylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]benzonitrile, (6-amino-pyrimidin-4-yl)-methanol and 3,5-dichloro-4-(4-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile were reacted to afford the title compound as a pale yellow solid (70 mg, 37% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 9.22 (s, 1H), 8.70 (s, 2H), 8.49 (s, 2H), 8.00 (d, J=6.4 Hz, 1H), 7.25-7.22 (m, 1H), 5.61 (t, J=5.7 Hz, 1H), 4.53 (d, J=5.8 Hz, 2H). LCMS (Method D): RT=2.05 min, m/z: 412 [M+H+].
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:15]([N:6]1[CH:7]=[C:2]([I:1])[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]1=[O:8])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCn1cc(I)c(C)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-iodo-4-methyl-3-nitro-2-pyridone (8.0 g, 28.6 mmol) and sodium hydride (1.03 g, 43 mmol) in DMF (150 mL) was stirred at rt for 1 hour. n-Hexyl bromide (8.03 mL, 57.2 mmol) was added, and the mixture was stirred for 24 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed, dried, filtered and evaporated. Chromatography of a portion of the residue over silica gel (20% petroleum ether/methylene chloride) gave 1-hexyl-5-iodo-4-methyl-3-nitro-2-pyridone.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:21](=[O:24])[CH2:22]Cl)=[C:15]([CH:20]=1)[N:16]([CH3:19])[CH:17]=[O:18]>C(N(CC)CC)C.ClCCl>[C:1]([O:9][CH2:22][C:21]([C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:20][C:15]=1[N:16]([CH3:19])[CH:17]=[O:18])=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(C=O)c1cc(Cl)ccc1C(=O)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C=O)c1cc(Cl)ccc1C(=O)COC(=O)c1ccccc1

Procedure:
A solution of benzoic acid (18.8 g) in triethylamine (28.5 ml) and dichloromethane (110 ml) at 0° was added dropwise over 1 hour to the solution of 5'-chloro-2'-(2-chloroacetyl)-N-methylformanilide at 0° under nitrogen. The mixture was stirred for a further hour whilst maintaining the temperature at 0 to 5° and then heated under reflux overnight. After cooling, the reaction mixture was washed with water (2×100 ml), dried over magnesium sulphate, and the solvent removed by distillation to give the novel compound 2-[4-chloro-2-(N-methylformamido)phenyl]-2-oxoethyl benzoate in the form of a gum.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Temperature: -70 °C

Procedure:
6,7-Dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (12 g., 0.04 mole) is dissolved in dimethylformamide (30 ml.), and potassium carbonate (5.5 g., 0.04 mole) is added and the mixture stirred and heated on a steam bath for 30 minutes. Ethyl 7-bromoheptanoate is added dropwise over 10 minutes with stirring and heating on a steam bath for two hours. The mixture is poured into a mixture of ice and water (300 g., total) and then extracted with ether. The ether extract is dried over Na2SO4, filtered and the ether removed at reduced pressure. The residue is dissolved in petroleum ether and cooled to -70° C. to obtain ethyl 7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoate, 17.7 g., m.p. 47°-50° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH2:14]/[CH:15]=[CH:16]/[C:17]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[C:12]([O:28][CH3:29])[C:11]([CH3:30])=[C:10]2[C:6]=1[C:7](=[O:31])[O:8][CH2:9]2)(=[O:3])[CH3:2].[OH-].[Li+].Cl>CO.O>[C:1]([O:4][C:5]1[C:13]([CH2:14]/[CH:15]=[CH:16]/[C:17]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[C:12]([O:28][CH3:29])[C:11]([CH3:30])=[C:10]2[C:6]=1[C:7](=[O:31])[O:8][CH2:9]2)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(C)c1/C=C/Cc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C)c2c(c(OC(C)=O)c1C/C=C/c1c(C)cccc1C(=O)O)C(=O)OC2

Procedure:
A solution of methyl (E)-2-[3-(4-acetoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-prop-1-en-1-yl]-3-methylbenzoate (0.1 g) and lithium hydroxide (0.06 g) in methanol (1 ml) and water (1 ml) was heated at 70° C. for 48 hours. The solution was cooled and poured into water, then acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was dried and evaporated to give (E)-2-[3-(4-acetoxy-1,3-dihydro -6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-prop -1-en-1-yl ]-3-methylbenzoic acid, mp 180°-3° C. (ethyl acetate/cyclohexane).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])(=O)=O.CN(C=O)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O.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>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Reactant: OB(O)c1ccccc1F
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccc2F)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
To a stirred solution of dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate T9.2 (1.60 g, 4.7 mmol) in DMF (9.4 mL, 4.7 mmol) at 23° C. was added 2-fluorophenylboronic acid (0.98 g, 7.0 mmol, commercially available from Aldrich), potassium carbonate (1.9 g, 14 mmol), and then tetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol). The reaction mixture was heated to 90° C. and the reaction was stirred for 22 hours. The reaction was then cooled to room temperature, diluted with water, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield T19.1 as a colorless oil (1.10 g, 82% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1ccc(N)cc1[N+](=O)[O-]
Temperature: 8 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
4-Ethylaniline (10.3 mL, 82.5 mmol) was added dropwise to sulfuric acid (96%, 63 mL), cooled to 8° C., maintaining the temperature below 10° C. After the addition, the reaction mixture was cooled to −5° C., before the addition of a mixture of nitric acid (100%, 4 mL) and sulfuric acid (96%, 10 mL), keeping the temperature below 0° C. The reaction mixture was then stirred at the same temperature for 1 h. The reaction mixture was poured into ice (200 mL) and the precipitate filtered and washed with water. The solid was suspended with water (100 mL) and neutralized with ammonium hydroxide (35%). The precipitate was filtered and dried in the oven to obtain a light-brown solid (10 g, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:7]=[CH:8][CH2:9][CH:10]=1)[C:4]([OH:6])=[O:5].[Al]>C1C2C(CCCC2)CCC1.CCCCCC.[Rh]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC1=CCC=CC1C(=O)O
Agent: [Rh]
Agent: *O[SiH2]*
Agent: [Al]
Solvent: C1CCC2CCCCC2C1
Solvent: CCCCCC
Product: Cc1ccccc1C(=O)O

Procedure:
To a suspension of 2-methyl-1,4-dihydrobenzoic acid (0.085g, 0.50 mmol; 81% pure, from Aldrich Chemical Company) in decalin (5 mL) under a nitrogen atmosphere is added a polysiloxane matrix material containing a homogenous dispersion of rhodium and aluminum (0.100 g). The solution is heated to reflux for 19 hours. On cooling the reaction mixture is diluted with hexane (25 mL) and extracted with aqueous sodium hydroxide (5%) solution (2×5 mL). The basic aqueous solution is acidified and extracted with chloroform (3×4 mL). The combined organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated using a rotary evaporator to give 2-methylbenzoic acid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][C:2]1=[O:11].C(N(C(C)C)CC)(C)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:2](=[O:11])[CH2:3]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CNc2ccccc2N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 3,4-dihydroquinoxalin-2(1H)-one (1.0 g, 6.7 mmol; J. Med. Chem. 758, 1994) and N,N-diisopropyl-N-ethylamine (1.7 mL, 10.1 mmol) in dichloromethane (30 mL) under an atmosphere of nitrogen, acetic anhydride (0.76 mL, 8.1 mmol) was added and stirred at room temperature overnight. The resultant solution was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1% methanol in chloroform. Collection and concentration of appropriate fractions provided the acetylation product.
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH3:26][O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O>C1COCC1.O>[CH3:2][O:3][CH:4]=[CH:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:28]=1[O:27][CH3:26]
Reactant: COc1cccc(C=O)c1OC
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1cccc(OC)c1OC
Reaction time: 0.25 h
Yield: 83 %

Procedure:
THF (15 mL) was added to a mixture of methoxymethyltriphenylphosphonium bromide and sodium amide (mfd. by Aldrich Chemical Co.; 3.0 g, 6.9 mmol) at room temperature and stirred for 15 minutes. To the resulting orange-colored suspension was added a solution of 2,3-dimethoxybenzaldehyde (997 mg, 6.00 mmol) in THF (5 mL), and stirred for 3 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by the use of a silica gel column (silica gel 50 mL; hexane/ethyl acetate=1/0 to 15/1) to obtain 2-(2,3-dimethoxyphenyl)ethenyl methyl ether (808 mg, 83%) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)[CH2:9][OH:10])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>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(OCC)(=O)C>[NH2:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[CH:12]=1)[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(Br)c1
Reactant: OB(O)c1cccnc1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: NC(CO)c1cccc(-c2cccnc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of [1-(3-bromo-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (160 mg, 0.51 mmol) in ethyleneglycoldimethylether (10 mL) in a sealed tube were added pyridine-3-boronic acid (82 mg, 0.66 mmol), cesium carbonate (500 mg, 1.53 mmol) and water (2 mL). Argon was bubbled through the solution for 10 min, and Pd(PPh3)4 (30 mg, 0.025 mmol) was added. The reaction mixture was heated at 100° C. for 6 h. The reaction mixture was cooled down to room temperature, and ethyl acetate (20 mL) was added. The reaction mixture was washed with saturated NH4Cl (2×10 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated in vacuo, and the crude product was diluted in CH2Cl2 (8 mL) and trifluoroacetic acid (2 mL). The reaction mixture was agitated for 1 h and concentrated in vacuo. The residue was purified by solid phase extraction (SCX cartridge, silca gel benzene sulfonic acid linked) to give the title product (110 mg, 100% yield) as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[C:6](=[O:14])[CH2:5]2.[C:15]1([C:20](Cl)=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[C:6](=[O:14])[CH:5]2[C:20](=[O:21])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(C(=O)c2cccs2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a stirred solution of 0.75 g (3.6 mmole) of 5-chloro-1-acetyl-2-oxindole and 0.96 ml (7.9 mmole) of 4-(N,N-dimethylamino)pyridine in 20 ml of N,N-dimethylformamide, cooled to ca. 0° C., was added a solution of 0.4 ml (3.7 mmole) of 2-thenoyl chloride in 5 ml of N,N-dimethylformamide, dropwise, during a few minutes. The reaction mixture was stirred for 30 minutes at ca. 0° C. and then for 3.5 hours at room temperature, and then it was poured into 500 ml of ice-cold 2N hydrochloric acid. The resulting solution was extracted with ethyl acetate, and the extracts were washed with water, followed by saturated sodium chloride solution, and then they were dried using magnesium sulfate. Evaporation of the dried ethyl acetate solution gave 1.1 g of crude product. The latter was purified by column chromatography using silica gel and eluting with dichloromethane-ethyl acetate mixtures, followed by recrystallization from a small volume of toluene, to give 250 mg of the title compound, m.p. 168°-170° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][NH2:13]>C(OCC)C>[CH3:12][NH:13][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CN
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCOCC
Product: CNc1nc(SC)ncc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Through a 5° C. solution of 14.5 g (78.1 mmol) of 4-chloro-2-(methylthio)-5-pyrimidinecarbonitrile in 800 mL of diethyl ether is bubbled methylamine gas for a period of 15 minutes. The reaction mixture is allowed to warm to room temperature, set overnight, and filtered. The solids are washed with diethyl ether, then efficiently with 50 mL of water, and dried to give 12.0 g (81%) of the title compound: mp 189-190° C.