Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCOCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (90 mg, 0.30 mmol, 1.00 equiv) in DMF (10 mL) was added 2-chloro-1-(morpholin-4-yl)ethan-1-one (73.35 mg, 0.45 mmol, 1.50 equiv) and potassium carbonate (83 mg, 0.60 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. After completion of the reaction, the solids were removed by filtration and the filtrate was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 19 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]-1-(morpholin-4-yl)ethan-1-one (30.8 mg) as a white solid. MS (ES, m/z): 430 (M+H+). 1H NMR (400 MHz, CD3OD-d6): δ 8.23 (s, 1H), 4.05-4.08 (m, 1H), 3.67-3.68 (m, 6H), 3.59-3.60 (m, 2H), 3.40 (s, 2H), 3.08 (t, 2H), 3.01 (t, 2H), 2.52-2.59 (m, 3H), 2.34 (s, 3H), 2.16-2.19 (m, 2H), 1.93-1.96 (m, 2H), 1.45-1.57 (m, 4H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]=O>[N+:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1

Procedure:
Under argon, to a solution of 3-iodonitrobenzene (3.00 g, 12.0 mmol) in pyridine (15 mL) were added ethyl 3-(4-hydroxyphenyl)propionate (2.81 g, 14.5 mmol), copper oxide (3.35 g, 42.2 mmol), and potassium carbonate (4.16 g, 30.1 mmol), and the resulting solution was heated to reflux for 40 hours. The reaction solution was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and once insoluble matter had been filtered off, and the filtrate was extracted with ethyl acetate out. The ethyl acetate layer was washed with 1 M hydrochloric acid, water and a saturated sodium bicarbonate solution, and then washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1→6:1), to thereby yield 1.12 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>CN(C)C=O.O>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(O)ccc2c2oc3ccccc3c12
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc2c(c1)[nH]c(=O)c1c3ccccc3oc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 133.6 %

Procedure:
In dry N,N-dimethylformamide was dissolved 6.0 g of 3-hydroxy-5H-benzofuro[3,2-c]quinolin-6-one, and 1.1 g of 2-dimethylaminoethyl chloride hydrochloride and 6.02 g of sodium bicarbonate were added to the solution. The mixture was stirred for 16 hours at 120° C. Into the reaction mixture were poured chloroform and water, and the insolved materials were filtered out. The organic layer was washed with water, dried over magnesium sulfate anhydride, and evaporated under reduced pressure. The residue was washed with ether, and recrystallized from chloroform and ethyl acetate to obtain 3.29 g of 3-(2-dimethylaminoethoxy)-5H-benzofuro[3,2-c]quinolin-6-one.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].[CH3:19][Si:20]([CH3:25])([CH3:24])[CH2:21][C:22]#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.COC(C)(C)C.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.[Cu]I>[CH3:19][Si:20]([CH3:25])([CH3:24])[CH2:21][C:22]#[C:23][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16]
Reactant: C#CC[Si](C)(C)C
Reactant: COc1nn(C)c(=O)n1Cc1cc(Br)ccc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: COC(C)(C)C
Product: COc1nn(C)c(=O)n1Cc1cc(C#CC[Si](C)(C)C)ccc1C
Temperature: 80 °C
Reaction time: 9 h
Yield: 34 %

Procedure:
A mixture of 624 mg (2.0 mmol) of 4-(5-bromo-2-methylbenzyl)-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 299 of the present invention), 700 mg (6.3 mmol) of 3-(trimethylsilyl)-1-propyne, 63 mg (0.095 mmol) of PdCl2(PPh3)2, 32 mg (0.17 mmol) of copper (I) iodide, 104 mg (0.40 mmol) of triphenylphosphine and 1.0 g of triethylamine in 6 ml of acetonitrile was stirred at 80° C. under an atmosphere of nitrogen for 9 hours. After cooling to room temperature, the reaction mixture was diluted with tert-butyl methyl ether, washed with water, dried and concentrated. The residue was subjected to silica gel column chromatography (eluted with hexane:ethyl acetate=2:1) to obtain 0.30 g (0.68 mmol) of 4-{5-(3-trimethylsilyl-1-propynyl)-2-methylbenzyl}-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 527 of the present invention).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][C:14](=[CH2:18])[C:15](Cl)=[O:16].O>C(OCC)C>[CH3:13][C:14]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:18])[CH:15]=[O:16]
Reactant: C=C(C)C(=O)Cl
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C=O)N1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, pyrrolidine (3.55 g, 0.05 mole) was dissolved in ethyl ether (50 ml). Triethylamine (5.06 g, 0.05 mole) was added and the solution cooled to and maintained at 0° C. 2-Methylacryloyl chloride (5.22 g, 0.05 mole), dissolved in ethyl ether (50 ml) was added to the reaction and the solution stirred overnight. Water (50 ml) was added, the layers were separated and the aqueous layer extracted with ethyl ether. The extracts were concentrated and the resulting product dried (6.77 g). The structure was confirmed by NMR.
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([N+:24]([O-])=O)[C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:19]1[C:3]([NH:4][C:5]2[S:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([Cl:1])[C:22]([Cl:23])=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2c([N+](=O)[O-])ccc(Cl)c2Cl)sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2c(N)ccc(Cl)c2Cl)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(2,3-dichloro-6-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(6-amino-2,3-dichloroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=1[CH3:23])[CH:12]=[CH:11]2)/[C:4]([OH:6])=[O:5].[H][H]>CO.ClCCl.[Pd]>[CH3:1][O:2][CH:3]([CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=1[CH3:23])[CH:12]=[CH:11]2)[C:4]([OH:6])=[O:5]
Reactant: CO/C(=C\c1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 60.9 %

Procedure:
A suspension of 80 mg of (Z)-2-methoxy-3-[1-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-1H-indol-5-yl]-acrylic acid in 5 ml of methanol and 2 ml of dichloromethane and 30 mg of Pd/C 10%) was hydrogenated at 22° C. and 1 bar until hydrogen uptake ceased (3 h). The mixture was filtered, the filtrate evaporated and the residue was purified by preparative HPLC (RP-18, CH3CN/H2O, gradient) to give 49 mg of the title compound as a yellow oil. MS: (M−H)− 389.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[N:6]=[CH:7][NH:8][C:4]=2[C:3]=1[CH3:12].C([N:15]=[C:16](S)[N:17](C(OCC1C=CC=CC=1)=O)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])C.[C:39]([O:42][CH2:43][CH3:44])(=[O:41])C>CO>[CH2:43]([O:42][C:39]([N:15]=[C:16]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[NH:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[N:6]=[CH:7][NH:8][C:4]=2[C:3]=1[CH3:12])=[O:41])[C:44]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: Cc1cc(N)c(C)c2[nH]cnc12
Reactant: CCN=C(S)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Solvent: CO
Product: Cc1cc(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)c(C)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 430 mg of 5-amino-4,7-dimethylbenzimidazole in 100 mL of ethyl acetate and 10 mL of methanol are added 19 of ethyl N,N-bis(benzyloxycarbonyl)pseudothiourea and 855 mg of mercuric acetate and the mixture is stirred at room temperature for 15 hours. The mixture is rotary evaporated and the residue is purified by flash column chromatography on silica gel, eluting with 5% methanol/ethyl acetate to provide 1.01 g of 5-[N2,N3-bis(benzyloxycarbonyl)guanidino]-4,7-dimethybenzimidazole as a glassy solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(C1C=CC(NC(C2C=C(OC)C3OCCCOC=3C=2)C2N[C:22](=[O:24])N(C3N=CSC=3C(O)=O)N=2)=CC=1)(=N)N.CO[C:48](=[O:78])[N:49]=[C:50](SC)[C:51]([C:65]1[CH:70]=[C:69]([O:71][CH3:72])[C:68](OC)=[CH:67][C:66]=1[F:75])=[N:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:63]=C(C)O[N:60]=2)=[CH:55][CH:54]=1.Cl.C[O:81][C:82]([C:84]1[CH:89]=[CH:88][CH:87]=[C:86]([NH:90][NH2:91])[N:85]=1)=[O:83].COC(=O)N=C(SC)C(C1C=C(OC)C2OCCCOC=2C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1.COC(C1SC=NC=1NN)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:59]([C:56]1[CH:57]=[CH:58][C:53]([NH:52][CH:51]([C:65]2[CH:70]=[C:69]([O:71][CH3:72])[CH:68]=[C:67]([O:24][CH3:22])[C:66]=2[F:75])[C:50]2[NH:49][C:48](=[O:78])[N:90]([C:86]3[N:85]=[C:84]([C:82]([OH:81])=[O:83])[CH:89]=[CH:88][CH:87]=3)[N:91]=2)=[CH:54][CH:55]=1)(=[NH:60])[NH2:63]
Reactant: COC(=O)c1cccc(NN)n1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Reactant: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)cc2c1OCCCO2
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)OCCCO2
Agent: COC(=O)c1scnc1NN
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3cccc(C(=O)O)n3)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Examples (180a) to (180b), except that [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester and 6-hydrazinopyridine-2-carboxylic acid methyl ester hydrochloride (Example (174a)) were used instead of respectively {2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and 4-hydrazinothiazole-5-carboxylic acid methyl ester in Example (180a), to give the title compound as a yellow solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:5][CH2:6][O:7][C:8]1[CH:29]=[CH:28][C:11]([CH2:12][O:13]/[N:14]=[C:15](/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)\[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:10][CH:9]=1.CO.Cl>O1CCCC1>[CH3:3][N:4]([C:30]1[N:31]=[CH:32][CH:33]=[CH:34][N:35]=1)[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:13]/[N:14]=[C:15](/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)\[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:28][CH:29]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCCN(C)c2ncccn2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCOc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of methyl E-4-[4-[2-(methyl-2-pyrimidylamino)ethoxy]benzyloxyimino]-4-phenylbutyrate (1.22 g) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-[2-(methyl-2-pyrimidylamino)ethoxy]benzyloxyimino]-4-phenylbutyric acid (1.09 g, yield 92%) as colorless crystals. m.p. 72-73° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([CH2:18][C:19](=O)[CH3:20])[N:11]=1.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.C(OCC)(=O)C>[Cl-].[Zn+2].[Cl-].O>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([C:18]2[C:29]3[C:28](=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=3)[NH:31][C:19]=2[CH3:20])[N:11]=1
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2[nH]c(C)c(-c3nc(OC)cc(OC)n3)c2c1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To 80 ml of toluene were added 8.0 g (40 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone and 7.7 g (44 m moles) of 4-metoxyphenylhydrazine hydrochloride. Thereto was added 6.0 g (44 m moles) of zinc chloride. Refluxing was made for 2 hours with heating. The reaction mixture was allowed to cool. Thereto were added ethyl acetate and water to dissolve the whole reaction mixture. The oily layer was washed with water, separated and dried over Glauber's salt. The resulting organic layer was concentrated under reduced pressure using an rotary evaporator to obtain, as an orange solid, 8.0 g (26.7 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-5-methoxy-2-methylindole. Yield: 67% Recrystallization from toluene was made.
Reaction SMILES: CS/[C:3](/[N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)=[O:15])[C@@H:10]([C:27]([O:29][CH3:30])=[O:28])[CH2:9]1)=[CH:4]\[N+:5]([O-:7])=[O:6].C(O)C.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[N+:5](/[CH:4]=[C:3](/[N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)=[O:15])[C@@H:10]([C:27]([O:29][CH3:30])=[O:28])[CH2:9]1)\[N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)([O-:7])=[O:6]
Reactant: C1CCNCC1
Reactant: COC(=O)[C@H]1CN(/C(=C/[N+](=O)[O-])SC)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Solvent: CCO
Product: COC(=O)[C@H]1CN(/C(=C/[N+](=O)[O-])N2CCCCC2)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Temperature: 85 °C
Yield: 70.5 %

Procedure:
To a stirred solution of methyl (3R,4S)-1-[(Z)-1-(methylthio)-2-nitrovinyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxylate (81.0 mg, 0.000187 mol) in ethanol (3.0 mL, 0.051 mol) was added piperidine (92.8 uL, 0.000934 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 17 h 45 min. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 0-8% MeOH/CH2Cl2 to give the product as a yellow solid (62 mg, 71% in yield). MS (ESI): (M+H)+=471.1.
Reaction SMILES: C(OC(N[CH:12]1[NH:16][C@@H:15]([CH3:17])[C:14]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([OH:18])[O:13]1)=O)C1C=CC=CC=1.[OH2:27].Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:14]([O:27][C:12]([NH:16][C@@H:15]([CH3:17])[C:14]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])=[O:18])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O
Reactant: C[C@@H]1NC(NC(=O)OCc2ccccc2)OC1(O)c1ccc(F)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
In tetrahydrofuran (70 mL) was dissolved (4S)-2-(benzyloxycarbonyl)amino-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (14.0 g) prepared in Example 12, and water (50 mL) and conc. hydrochloric acid (20 mL) were added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with toluene, the aqueous layer was discarded, and the organic layer was washed with water three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=3/1) to give the title compound (11.7 g) as a pale yellow syrup in a yield of 92%.
Reaction SMILES: C(NC(C)C)(C)C.[CH:8]1([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.CCCCCC>[CH:8]1([CH:13]([C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)CC1CCCC1
Reactant: O=C1CCCCC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(C1CCCC1)C1(O)CCCCC1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
Diisopropylamine (12.7 g, 0.125) was dissolved in 150 mls of dry THF and cooled to -70° C. under N2. n-Bulb (80 ml of 1.6M solution in hexane, 0.125 moles) was added and the solution stirred for 5 minutes at -70° C. Methyl cyclopentaneacetate (17 g, 0.125 mole) in 50 mls of THF was added at -70° C. over 15 minutes and the reaction was stirred at -70° C. for 15 more minutes. A solution of cyclohexanone (11.3 g, 0.115 moles) in THF (50ml) was then added at -70° C. over 1/2 hour and stirred in the cold for 1 hour. The reaction was warmed to room temperature over 1 hour and quenched with 5 mls of 1N HCl. The solvent was removed on the rotary evaporator and ethyl acetate added. The solution was then washed with saturated NaHCO3 and the layers were separated. The organic layer was dried over Na2SO4. The drying agent was filtered and the filtrate stripped to give a residue which was chromatographed on silica gel using 7% ethyl acetate/hexane to give 27.8 g (92% yield) of the title compound.
Reaction SMILES: C[O:2][CH:3](OC)[C:4](=O)[CH3:5].[CH2:9]([C:16]1[C:17]([NH2:28])=[N:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C:16]1[NH:21][C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][N:18]2[C:3](=[O:2])[C:4]([CH3:5])=[N:28][C:17]=12)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Reactant: COC(OC)C(C)=O
Product: Cc1nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn-2c1=O

Procedure:
Synthesized using method B with 1,1-dimethoxypropan-2-one and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. Exact mass calculated for C20H18N3O+ m/z+316.14, found m/z+316.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C.C(N(C(C)C)C(C)C)C>CO>[NH2:19][C:18]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=2[CH3:10])[N:9]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: Cc1c(Br)cccc1NN
Reactant: CCOC=C(C#N)C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1c(Br)cccc1-n1ncc(C#N)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
(3-Bromo-2-methylphenyl)hydrazine (CAS no. 459817-67-5) (10 g, 49.74 mmol) was suspended in MeOH (100 mL) under nitrogen at 0° C. 2-(Ethoxymethylene)malononitrile (6.07 g, 49.74 mmol) added portionwise over 5 mins and the mixture stirred at ˜0° C. for 2 hours. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. No reaction. The starting material was NMRed and found to be a salt, so N-ethyl-N-isopropylpropan-2-amine (17.33 mL, 99.47 mmol) was added and stirred for a further 16 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc, and washed sequentially with water ×2 and saturated brine. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product, 5-amino-1-(3-bromo-2-methylphenyl)-1H-pyrazole-4-carbonitrile (12.60 g, 91%). m/z (ES+) (M+H)+=279.25; HPLC tR=1.95 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][C:23]=1[F:32]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][C:23]=3[F:32])=[O:15])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(O)c1ccc(CN)c(F)c1
Reactant: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1

Procedure:
Prepared from 2-(Benzo[1,3]dioxol-5-yloxy)-nicotinic acid and and 2-(4-Aminomethyl-3-fluoro-phenyl)-propan-2-ol.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[SH:9][CH2:10][C:11](O)=O.[OH-].[Na+]>Cl>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:11]1[CH2:10][SH:9]
Reactant: Nc1ccccc1N
Reactant: O=C(O)CS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: SCc1nc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
To 1,2-phenylenediamine (1.88 g, 17 mmol) in 50% v/v hydrochloric acid (20 ml) was added 2-mercaptoacetic acid (1.3 ml, 1.7 g, 19 mmol). The reaction mixture was heated, under nitrogen, at 60° C. then at 90° C. for 48 hours. Additional 2-mercaptoacetic acid (400 μA, 530 mg, 6 mmol) was added in this time. A sample was analyzed by HPLC. The reaction mixture was cooled and neutralized to pH 5 with 40% v/v NaOH. The resulting solid was washed with water (50 ml) and dried under vacuum to yield (1H-Benzo[d]imidazol-2-yl)-methanethiol 1.95 g, 93% yield, Rt=7.6 min, purity >95% together with disulfide (Rt=8.0 mins) 4%. 1H NMR (d6-DMSO, 400 MHz) 14.3 ppm (bs, 0.5H), 7.46 ppm (m, 2H), 7.13 (m, 2H), 4.17 ppm (s 0.1H). MS (Electrospray+) 164 m/z (M+), 131 m/z (M-SH).