Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][C:5]([O:13][CH3:14])=[C:4]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH:3]=1.C(O)(=O)C.[CH:28](N)=[NH:29]>COCCO>[CH3:14][O:13][C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[O:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)[N:1]=[CH:28][NH:29][C:8]2=[O:10]
Reactant: N=CN
Reactant: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1N
Solvent: COCCO
Solvent: CC(=O)O
Product: COc1cc2c(=O)[nH]cnc2cc1OCC1CCN(C)CC1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A solution of ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1 g, 50 mmol) in 2-methoxyethanol (160 ml) containing formamidine acetate (5.2 g, 50 mmol) was heated at 115° C. for 2 hours. Formamidine acetate (10.4 g, 100 mmol) was added in portions every 30 minutes during 4 hours. Heating was prolonged for 30 minutes after the last addition. After cooling, the volatiles were removed under vacuum. The solid was dissolved in ethanol (100 ml) and methylene chloride (50 ml). The precipitate was removed by filtration and the filtrate was concentrated to a final volume of 100 ml. The suspension was cooled to 5° C. and the solid was collected by filtration, washed with cold ethanol followed by ether and dried under vacuum overnight at 60° C. to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (12.7 g, 70%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.[NH4+].[Cl-]>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1

Procedure:
1-chloromethyl-4-nitro-benzene Compound 1i (5.0 g, 29 mmol) and piperidine (5.8 mL, 58 mmol) were combined in THF (30 mL) at ambient temperature. The reaction was refluxed for 4 hours, then diluted with aqueous 10% NH4Cl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to provide 1-(4-nitro-benzyl)-piperidine Compound 1j (5.0 g) as a pale yellow oil requiring no further purification (see, Mitsuru Shiraishi, et al., J. Med. Chem., 2000, 43, 2049-2063). 1H NMR (DMSO-d6) δ 8.18 (d, 2H); 7.59 (d, 2H); 3.57 (s, 2H); 2.43-2.25 (m, 4H); 1.58-1.32 (m, 6H).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6]C1=O)([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[OH:6][C:7]1([CH2:8][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:14][O:13][C:12]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: CC(C)N1CC2(COc3ccc([N+](=O)[O-])cc3OC2)OC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)NCC1(O)COc2ccc([N+](=O)[O-])cc2OC1

Procedure:
A mixture of 0.15 mole of the oxazolidinone from Step B above and 15 g. (0.38 mole) of sodium hydroxide in 100 ml. of water and 200 ml. of 95% ethanol is refluxed, the solution evaporated to a small volume and the product extracted with diethyl ether. Evaporation of the solvent gives 3-hydroxy-3-isopropylaminomethyl-7-nitro-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH:10]([OH:20])[N:9]=1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:9][CH:10]([O:20][C:26]([C:25]3[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=3)=[O:27])[C:11]2=[O:19])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1Nc2ccccc2C(c2ccccc2F)=NC1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OC1N=C(c2ccccc2F)c2ccccc2N(C(=O)c2ccc(Cl)cc2)C1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A suspension of 1,3-dihydro-5-(2-fluorophenyl)-3-hydroxy-2H-1,4-benzodiazepin-2-one (610 mg, 2.25 mmole) in 25 ml of methylene chloride was treated with 4-chlorobenzoyl chloride (0.314 ml, 2.48 mmole) at room temperature. 4-Dimethylaminopyridine (303 mg, 2.48 mmole) was added and within minutes the reaction mixture became homogeneous. The reaction mixture was protected from moisture and stirred at room temperature overnight. An additional equivalent each of 4-chlorobenzoyl chloride and 4-dimethylaminopyridine were added and stirring was continued for 8 hours at 40°-45° C. The reaction mixture was diluted to 150 ml with methylene chloride and washed in succession with 10% citric acid solution (3×50 ml), saturated sodium bicarbonate solution (3×50 ml) and brine (50 ml). Rotoevaporation of the dried (MgSO4) organic phase gave a foam which on trituration with ether afforded a beige solid. Recrystallization from ethyl acetate afforded 612 mg of the title compound as a white powder in analytical purity: m.p. 198°-199° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[H][H]>CO.[Pd].C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: CCOC(=O)C(=CCCc1ccccc1)CCCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(CCCc1ccccc1)CCCc1ccccc1
Yield: 98 %

Procedure:
A solution of ethyl-2-(3-phenylpropyl)-5-phenyl-2-pentenoate in methanol (10 mL) was added to a suspension of 10% palladium on carbon (0.112 g) in methylene chloride (10 mL) and the mixture was hydrogenated under 60 psi of hydrogen for 6 h. The catalyst was removed by filtration through a pad of celite and the solvent was removed under reduced pressure to give ethyl-2-(3-phenylpropyl)-5-phenyl-pentanoate (0.787 g, 98%). The crude product was not purified further but used directly in the next step. 1H NMR (300 MHz, CDCl3): δ 1.25 (t, 3 H, J=7.1), 1.60 (m, 8 H), 2.39 (m, 1 H), 2.61 (t, 4 H, J=7.3), 4.14 (q, 2 H, J=7.1), 7.24 (m, 10 H).
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[N+:13]([CH3:16])([O-:15])=[O:14].C(NCC)C>C1COCC1>[I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([OH:12])[CH2:16][N+:13]([O-:15])=[O:14])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccn2c(I)cnc2c1
Solvent: CCNCC
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1ccn2c(I)cnc2c1
Temperature: 55 °C

Procedure:
To a solution of 3-Iodo-imidazo[1,2-a]pyridine-7-carbaldehyde (150 mg, 0.54 mmol) in THF (10 ml) was added nitromethane (88 μl, 1.63 mmol), diethylamine (6 μl, 0.05 mmol) and sieves (300 mg). The reaction mixture was heated at 55° C. for 2 hours before being cooled. The sieves were filtered off and the resulting solution partitioned between EtOAc and H2O. The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to afford a crude product that was used as is (116 mg). MS: [M+H]+=334.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12]([CH3:18])([C:15]([OH:17])=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([C:15]([C:12]3([CH3:18])[CH2:11][CH2:10][N:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][CH3:2])[N:8]=4)[CH2:14][CH2:13]3)=[O:17])[CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: CCc1nccc(N2CCC(C)(C(=O)O)CC2)n1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Product: CCc1nccc(N2CCC(C)(C(=O)N3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)n1

Procedure:
In a similar process as described in Example 39 using 1-(2-ethylpyrimidin-4-yl)-4-methyl-piperidine-4-carboxylic acid and 1-(4-bromophenylsulphonyl)-piperazine the following was produced 1-(4-bromophenylsulphonyl)-4-[1-(2-ethylpyrimidin-4-yl)-4-methyl-piperidin-4-ylcarbonyl]piperazine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][C:29]([OH:34])=[CH:28][CH:27]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:23][C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][C:29]([O:34][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:28][CH:27]=2
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (110 mg, 0.34 mmol), (prepared as described for the starting material in Example 9), and 2,3-dimethyl-5-hydroxyindole (66 mg, 0.41 mmol), (Arch. Pharm. 1972, 305, 159), in DMF (1.5 ml) containing potassium carbonate (70 mg, 0.51 mmol) was heated at 100° C. for 2 hours. After cooling, the residue was purified by chromatography, eluting with methanol/methylene chloride (1/9) followed by 2.5M ammonia in methanol/methanol/methylene chloride (5/10/85) to give 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (50 mg, 33%).
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]([OH:15])=O)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[C:9]([CH:8]1[CH2:1][C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13](=[O:15])[CH2:12]1)([OH:11])=[O:10]
Reactant: O=C(O)CC(Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Product: O=C1CC(C(=O)O)Cc2ccccc21
Yield: 91.1 %

Procedure:
A solution of 2-benzylsuccinic acid (78.37 g, 0.376 mol) in sulfuric acid (98%, 300 mL) was stirred at 60° C. for 20 min, then poured onto ice (2 kg), followed by extraction with diethyl ether (2 L, twice). The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated under vacuum to obtain a solid. The solid was recrystallized from ethyl acetate to obtain the title compound (65.14 g, yield 91%). 1HNMR (DMSO-d6) δ 12.4–12.2 (bs, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.50 (m, 1H), 7.34–7.28 (m, 2H), 3.21–3.07 (m, 3H), 2.73 (m, 2H). See also U.S. Pat. No. 5,739,135; J. Med. Chem. 1982, 25, 535–538; Org. Prep. Proc. Int. 1987, 19, 447–449.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
In the same manner, P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (500 mg., 1.22 mmol) and ethyl bromoacetate (408 mg, 2.44 mmol) are reacted together with potassium carbonate (253 mg, 1.83 mmol) in 2-butanone (10 ml) to yield ethoxycarbonylmethyl P-ethyl-2-nitro-5-(2-chloro-4-tri-fluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6]C(=O)OC(C)(C)C)[CH2:2]1.[F:14][CH2:15][C:16](=O)[CH2:17][F:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:14][CH2:15][CH:16]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH2:6])[CH2:2]1)[CH2:17][F:18]
Reactant: O=C(CF)CF
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N[C@@H]1CCN(C(CF)CF)C1
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g) and 1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.853 g). After stirring for one hour, the reaction was quenched with saturated aqueous NaHCO3 solution (5 mL). The mixture was extracted with dichloromethane (25 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL) and methanol (1 mL) and stirred for one hour. The mixture was concentrated to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:39])[C@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:12][C:13](=[O:31])[C@H:14]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:15][C:16](=[O:23])[C@H:17]([CH2:19][C:20](=[O:22])[NH2:21])[NH2:18].ClC1C=CC([O:47][C:48](=O)[CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=C(Cl)C=1Cl.C(N1CCOCC1)C>CN(C)C=O>[CH3:8][O:9][C:10](=[O:39])[C@H:11]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH:12][C:13](=[O:31])[C@H:14]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:15][C:16](=[O:23])[C@H:17]([CH2:19][C:20](=[O:22])[NH2:21])[NH:18][C:48](=[O:47])[CH2:49][NH:50][C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52]
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)OC(C)(C)C

Procedure:
A solution of asparaginyl-phenylalanyl-phenylalanine methyl ester trifluoroacetate (0.88 g, 1.59 mmole, described by H. U. Immer et al., U.S. Pat. No. 3,917,578, issued Nov. 4, 1975), t-butoxycarbonyl-glycine trichlorophenyl ester (0.56 g, 1.59 mmole) and N-ethylmorpholine (0.203 ml, 1.59 mmole) in dimethylformamide (9 ml) is stirred at 0° C. for 1 hour and at 25° C. for 20 hours. The solution is evaporated and the residue is crystallized from methanol to give the title compound, mp 211°-214° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:21])[CH2:3][N:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20].[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:24]([O:23][C:22]([NH:1][CH:2]([CH3:21])[CH2:3][N:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20])=[O:26])[CH3:25]
Reactant: CC(N)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)NC(C)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
4.2 g of 2-(2-aminopropyl)-4-phenyl-1(2H)-isoquinolone, 2.7 g of ethyl chlorocarbonate, 4.1 g of potassium carbonate and 60 ml of ethanol were mixed and stirred at room temperature for 3 hours. The solvent was then distilled off, and the residue was extracted with dichloromethane. The crystals obtained by distilling off the solvent were recrystallized from ethanol to obtain 3 g (57% yield) of 2-(2-ethoxycarbonylaminopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 182° C. as colorless prisms.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:33]>ClCCl>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH2:26][O:27][C:28]3=[O:33])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(OCC)c1ccc(C=Nc2cccc3c2COC3=O)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 84.5 %

Procedure:
To a stirred mixture of 4-(diethoxymethyl)benzaldehyde (3.75 g, 18 mmol) and anhydrous sodium sulfate (21.3 g, 150 mmol) in anhydrous dichloromethane (300 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.24 g, 15 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give 4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (4.3 g, yield 84%) as a light yellow solid. LC-MS (ESI) m/z: 340(M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1([NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=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>[CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:31]3[CH:30]=[C:29]([C:28](=[O:45])[NH:27][CH:24]4[CH2:26][CH2:25]4)[CH:34]=[CH:33][C:32]=3[CH3:35])[CH:14]=2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(Br)cc12
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: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Temperature: 80 °C

Procedure:
A mixture of the product of step i) (0.37 g), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.29 g) [prepared as described in US2005020590] and potassium carbonate (0.27 g) in degassed N,N-dimethylformamide (8 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (0.115 g) and the mixture heated at 80° C. under nitrogen for 24 hours. The reaction mixture was concentrated to dryness and the crude product purified (SiO2, 2% methanol in dichloromethane as eluent) to give the sub-title compound (0.44 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]C(C)(C)C.[CH3:16][S:17]SC>C1COCC1>[CH3:16][S:17][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: CSSC
Reactant: Brc1cccc2cc[nH]c12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CSc1cccc2cc[nH]c12
Temperature: 0 °C
Yield: 56.1 %

Procedure:
To a solution of 7-bromo-1H-indole (3.0 g, 15.3 mmol) in THF (60 mL) at −78° C. was added tBuLi (1.7 M, 33.8 mL, 57.4 mmol) and the mixture was allowed to warm to 0° C. The reaction was re-cooled to −78° C. and a solution of dimethyl disulfide (2.0 mL, 22.9 mmol) was added and the reaction was allowed to warm to 0° C. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield the crude product. This material was purified by chromatography over silica gel eluting with ethyl acetate in hexanes (0→2%) to afford pure 7-(methylthio)-1H-indole (1.4 g, 55%). 1H NMR (400 MHz, CDCl3) δ=2.50 (s, 3 H), 6.58 (dd, J=3.03, 2.02 Hz, 1H), 7.09 (t, J=7.58 Hz, 1H), 7.18-7.31 (m, 2H), 7.56 (d, J=7.83 Hz, 1H), 8.45 (br. s., 1 H); MS (ES+): m/z 164.15 [MH+].
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2].[Li]CCCC.[CH3:24][S:25]S(C)(=O)=O>C1COCC1.CCCCCC>[CH2:1]([N:3]([S:25][CH3:24])[C:4]([C:6]1[C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[Si:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])[CH3:2]
Reactant: CSS(C)(=O)=O
Reactant: CCNC(=O)c1c([Si](C)(C)C)sc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(SC)C(=O)c1c([Si](C)(C)C)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of the product of Example 8 (1.1 g, 4 mmol) in 20 mL THF at <-60° C. under a positive nitrogen atmosphere was added dropwise 2.5M of n-BuLi in hexane (2.2 mL) at <-60° C., and the solution was stirred for 0.5 h. A solution of methyl methanethiolsulfonate (0.6 g, 4.8 mmol) in 2 mL THF was added at <-60° C. After 1 h at ambient temperature, the solution was poured into ice water and extracted with methylene chloride. The organic layer was washed with brine, dried, and concentrated in vacuo. The residue was purified on a silica gel column using 8% ethyl acetate-hexane to give 1 g of the desired product as a viscous yellow oil, a yield of 76.9%. nD24 1.5886.
Reaction SMILES: [CH:1]1([C:5](O)=O)[CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CC=CC=1.[CH3:26][NH:27][C:28](=[S:31])[NH:29][NH2:30]>CN(C)C=O>[CH3:26][N:27]1[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:30][N:29]=[C:28]1[SH:31]
Reactant: O=C(O)C1CCC1
Reactant: CNC(=S)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(S)nnc1C1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
5 g of cyclobutyl carboxylic acid (49.9 mmol) were dissolved in 50 ml of dimethylformamide. Within 10 min. 12.15 g of 1,1′-carbonyldiimidazol (74.91 mmol) were added in portions. After stirring for 1 h at room temperature 23 ml of pyridin were added followed by the addition of 10.5 g of 4-methyl-3-thiosemicarbazide (99.88 mmol). The solution was stirred at room temperature for 72 h and then poured into 600 ml of ice water. Stirring was continued for 30 min. before the aqueous layer was extracted three times with 50 ml dichloromethane and three times with 50 ml ethyl acetate each. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated, thereby yielding 5.2 g of the crude title product which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:7]([N+:18]([O-])=O)[CH:6]=1)[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:7]([NH2:18])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Reaction time: 6 h

Procedure:
To a solution of 5.84 g (20 mmol) of Compound 10 in 50 mL ethyl acetate and 30 mL methanol, 100 mg of 10% Pd/C was added, and the mixture was hydrogenated at 30 psi for 6 h. The catalyst was removed by filtration through a pad of Celite, the solvent was evaporated to dryness resulting in a dark purple solid which was recrystallized from ether-hexane. The mother liquid was evaporated, and the resulting solid was suspended in hexane and filtered to give additional yield of Compound 11
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2[NH:9][CH:10]=N[C:7]=2[CH:6]=1)[NH2:4].[C:14](C1C=C2C(=CC=1)NC=C2)#N>>[OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[NH:9][CH:10]=[CH:14]2)[NH2:4]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: NC(=NO)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from 5-cyanoindole (2 g; 14.07 mmol) as a brown solid (2.4 g, 97%). HPLC (Method A), Rt 0.95 min (Purity: 88.8%). LC/MS (Method B): 176.1 (M+H)+.