Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=O.I.CS[CH:23]([NH2:25])[NH2:24].O>N1C=CC=CC=1>[NH2:25][C:23]1[NH:24][C:12]([C:11]2[CH:16]=[CH:17][N:18]=[CH:19][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[N:14][N:15]=1
Reactant: CSC(N)N
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Agent: I
Solvent: c1ccncc1
Solvent: O
Product: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1
Temperature: 140 °C
Yield: 43 %

Procedure:
A reaction mixture of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (100 mg, 0.27 mmol, 1 eq) and C-Methylsulfanyl-methanediamine hydroiodide (86 mg, 0.39 mmol, 1.45 eq) in pyridine (2 mL) in a sealed tube was heated at 140° C. for 4 hrs. After cooling the mixture was poured into water, extracted with EtOAc, and the combined organic fractions were dried over anhydrous MgSO4. After filtration and solvent evaporation the resulting residue was subjected to silica gel column chromatography (EtOAC:Hex=1:1) to give the desired product (46 mg). [4.99 min; 397(M+1)]
Reaction SMILES: C(OC[O:5][CH:6]1[CH2:24][CH:23]2[N:8]([C:9](=[O:45])[N:10](CC3C=CC(OC)=CC=3)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH:18]3[C:20]([C:26]([NH:28][S:29]([C:32]4([CH3:35])[CH2:34][CH2:33]4)(=[O:31])=[O:30])=[O:27])([NH:21][C:22]2=[O:25])[CH2:19]3)[CH2:7]1)C.ClCCl.FC(F)(F)C(O)=O.O>C(OCC)(=O)C.CO>[OH:5][CH:6]1[CH2:24][CH:23]2[N:8]([C:9](=[O:45])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH:18]3[C:20]([C:26]([NH:28][S:29]([C:32]4([CH3:35])[CH2:34][CH2:33]4)(=[O:31])=[O:30])=[O:27])([NH:21][C:22]2=[O:25])[CH2:19]3)[CH2:7]1
Reactant: CCOCOC1CC2C(=O)NC3(C(=O)NS(=O)(=O)C4(C)CC4)CC3C=CCCCCCN(Cc3ccc(OC)cc3)C(=O)N2C1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC1(S(=O)(=O)NC(=O)C23CC2C=CCCCCCNC(=O)N2CC(O)CC2C(=O)N3)CC1
Yield: 29.8 %

Procedure:
The acetal compound 22a (0.301 g, 0.465 mmol) was deprotected using 2:1:0.1 dichloromethane/trifluoroacetic acid/H2O (6.2 ml) at rt for 4 h, then conc onto silica and flash chromatography using 9:1 ethyl acetate/methanol gave the product as a colorless foam (0.065 g, 30%). LR-MS: Calcd for C21H33N4O6S: 469. Found: 469 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].Cl(O)(=O)=O.[CH3:25][S:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:34][CH2:33][C:32]2[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:36][CH:35]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: [O-][Cl+2]([O-])O
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 4-methylsulfonyl-benzylamine hydrogen chloric acid salt (59 mg, 0.32 mmol). The title compound was obtained as a yellow solid (54 mg, 39% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.51 (1H, m), 8.99 (2H, s), 8.48 (1H, s), 7.89 (2H, dd), 7.55 (2H, dd), 4.51 (2H, m), 3.18 (3H, s). MS m/z: 515.97, 517.99 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[S:32]
Reactant: COc1ccc(C2CCOCC2)cc1NC(=O)c1ncc[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCOCC2)cc1NC(=S)c1ncc[nH]1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
0.41 g of 1H-Imidazole-2-carboxylic acid [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-amide (1.36 mmol) were taken up in toluene (25.0 ml) and treated with 1.65 g of Lawesson reagent (4.08 mmol). The reaction mixture was heated to reflux for 16 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with methylene chloride. The combined organic phases were dried on sodium carbonate, evaporated and the residue was dried under high vacuum to yield 0.179 g of 1H-imidazole-2-carbothioic acid [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-amide (41%) as a yellow solid; M.p.: 189–190° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30]2[O:31][CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[N:34]=2)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[S:19][C:18]([CH3:28])=[N:17][C:16]=2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH2:29][C:30]2[O:31][CH:32]=[C:33]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[N:34]=2)=[O:15])=[CH:22][CH:23]=1
Reactant: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2Cc2nc(-c3ccc(F)cc3)co2)c(-c2ccc(F)cc2)s1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCNCC2Cc2nc(-c3ccc(F)cc3)co2)c(-c2ccc(F)cc2)s1
Reaction time: 2 h
Yield: 12.1 %

Procedure:
4-{1-[5-(4-Fluorophenyl)-2-methyl-tliiazol-4-yl]-methanoyl}-3-[4-(4-fluoro-pbenyl)-oxazol-2-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (0.130 g) was dissolved in trifluoroacetic acid (10 ml) and stirred at rdom temperature for 2 hours. The reaction mixture was then evaporated to dryness at reduced pressure and the residue was chromatographed over silica gel. Elution with a gradient of 0 to 10% [9:1 methanol/conc. ammonia solution] in dichloromethane provided the title compound as a pale yellow gum (0.013 g), mass spectrum (API+) 481 [MH+], C25H22F2N4O2S requires 480.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH2:13]([O:12][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:14]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCc1cccc([N+](=O)[O-])c1

Procedure:
A 300-milliliter flask equipped with a reflux condenser and a magnetic stirring bar was charged with 17.1 grams (0.1 mole) of 3-nitrobenzyl chloride in 150 milliliters of ethanol. To this stirred solution was added 6.8 grams (0.1 mole) of sodium ethoxide. The reaction mixture was heated to reflux and maintained at reflux for 21 hours. The reaction mixture was then cooled and concentrated on a rotary evaporator at 55° C. The residue was suspended in 250 milliliters of methylene chloride and transferred to a separatory funnel wherein it was washed consecutively with 100 milliliter portions of water, 1 Normal hydrochloric acid, water, 1 Normal sodium hydroxide, and water, respectively. The organic phase was separated, dried over magnesium sulfate, and concentrated on a rotary evaporator at 55° C., leaving a dark brown liquid. The dark brown liquid was charged to a distillation flask and distilled at a pressure of 2.0 millimeters of mercury. A main fraction (14 grams) was collected, said fraction having a boiling point of 112°-115° C. at 2 mm Hg pressure. This main fraction was identified by NMR spectroscopy as 1-(ethoxymethyl)-3-nitrobenzene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CCN(CC)CC.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:21]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(O)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
Into a round bottom flask containing 3-hydroxybenzaldehyde (0.658 g, 5.23 mmol) and DMAP (0.0646 g, 0.52 mmol), first 10 mL of anhydrous CH2Cl2 and then 0.89 mL of NEt3 (0.634 g, 6.27 mmol) were added. After the reaction mixture was stirred under nitrogen at 0° C. for 10 minutes, 5 mL of a CH2Cl2 solution of TBSCl (0.976 g, 6.28 mmol) were added. The reaction mixture was stirred for 2.5 h at room temperature and, then it was filtered through silica gel-florisil, rinsed with CH2Cl2 and the organic phase dried under Na2SO4. After evaporating the solvent, 1.1308 g (4.79 mmol) of pure product was obtained in a 92% yield.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[N:7]=1.[OH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([C:23]2[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:12][CH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:7][N:6]2[CH:8]=1
Reactant: Cc1cc(C(=O)Nc2cccc(O)c2)n(C)n1
Reactant: OCc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(CO)cn4n3)c2)n(C)n1
Temperature: 150 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
To a solution of (6-iodoimidazo[1,2-b]pyridazin-2-yl)methanol (400 mg, 1.45 mmol) in N,N-dimethylformamide (4.0 mL) were added N-(3-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (504 mg, 2.18 mmol) and potassium carbonate (402 mg, 2.91 mmol), and the mixture was stirred at 150° C. for 16 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol=100/0→10/1) to give the title compound (70 mg, 13%) as a white powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][N:9]1C(=O)C2=CC=CC=C2C1=O)[CH2:4][CH2:5][F:6])[CH3:2].O.NN>C(O)C>[NH2:9][CH2:8][CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][F:6]
Reactant: CCN(CCF)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN(CCN)CCF
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a stirred solution of compound 21 (752 mg, 2.85 mmol) in anhydrous ethanol (30 mL) was added, under argon, hydrazine monohydrate (324 μL, 6.68 mmol). The mixture was refluxed for 1 h. After cooling to room temperature, the white precipitate was filtered and washed with ethanol (10 mL). The filtrate was evaporated under vacuum and the residue was chromatographed (Al2O3, CH2Cl2/EtOH/NH4OH, 80/19/1, v/v/v) to give compound 22 (213 mg, 1.59 mmol) as an orange-coloured oil. Yield 56%; Rf (Al2O3, CH2Cl2/EtOH/NH4OH, 80/19/1, v/v/) 0.41; IR (CCl4) ν 1034, 1453, 1684, 2700-3000 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.01 (t, 3H, J=7.1 Hz), 2.59 (m, 4H), 2.74 (td, 2H, 3JH-F=26.5 Hz, J=5.3 Hz), 2.78 (t, 2H, J=5.3 Hz), 4.30 (se, 2H), 4.46 (td, 2H, 2JH-F=47.5 Hz, J=5.0 Hz).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH3:27])[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](N1C=C(CO)C=N1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].ICC.CC1C(CCOC)=C(C)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:27][CH3:28])[CH:22]=[N:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: OCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: COCCc1c(C)nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCOCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 87 %

Procedure:
This compound is a slightly yellow solid and has been obtained as described in 2b for 1-trityl-4-methoxymethylpyrazole, starting from 1-trityl-4-hydroxymethylpyrazole (1.250 g; 3.67 mmol), sodium hydride (221 mg; 5.51 mmol) and iodoethane (1.5 mL; 18.35 mmol), as described in example 2a for 3,5-dimethyl-4-methoxyethyl-1-tritylpyrazole. Yield: 87% (1.174 g, 3.19 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1.[N+:11]([N:14]=[C:15]1[NH:19][CH2:18][CH2:17][NH:16]1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Cs+]>C(#N)C>[Cl:1][C:2]1[C:7]([CH2:8][N:16]2[CH2:17][CH2:18][NH:19][C:15]2=[N:14][N+:11]([O-:13])=[O:12])=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)c(CCl)c1
Reactant: O=[N+]([O-])N=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cnc(Cl)c(CN2CCNC2=N[N+](=O)[O-])c1
Yield: 90 %

Procedure:
2-chloro-3-chloromethyl-5-methylpyridine (1.3 g, 0.0076 moles) was added to a well-stirred material comprising of 2-nitroimino-1, 3-diazacyclopentane (1.18 g, 0.00912 moles), potassium carbonate (1.16 g, 0.0083 moles), cesium chloride (0.04 g, 0.00024 moles) in acetonitrile (10 ml) solvent at room temperature. The reaction mixture was refluxed for 5 hours. Solvent was removed under reduced pressure and the mass diluted with water (25 ml). The mass was then extracted with methylene chloride (2×50 ml) and the layers were separated. Organic layer was dried over sodium sulphate and solvent removed under reduced pressure. The residue obtained was subjected to chromatographic purification on silica gel to give 1-(2-chloro-5-methyl-3-pyridylmethyl)-2-nitroiminoimidazolidine in 90% yield. NMR (CDCl3+DMSO d6): δ2.38 (s, 3H, CH3), 3.58 (t, 2H, N—CH2), 3.74 (t, 2H, N—CH2), 4.52 (s, 2H, CH2), 7.54 (s, 1H, aromatic), 812 (s, 1H, aromatic), 8.86 (1H, NH). Mass: M+. 269.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26]([CH2:32][CH3:33])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34](C1(C(O)=O)CCNCC1)CC.C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][C:26]([CH2:32][CH2:33][CH3:34])([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Reactant: CCCC1(C(=O)O)CCNCC1
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Yield: 4 %

Procedure:
Compound was prepared in a manner similar to that of 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid using 4-Propyl-piperidine-4-carboxylic acid (0.185 g, 1.08 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.3 g, 0.9 mmol) and Acetic acid (0.18 mL, 3.1 mmol) in Methanol (1.8 mL, 44 mmol) and Sodium cyanoborohydride (84.101 mg, 1.3383 mmol) to give 16 mg 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-propyl-piperidine-4-carboxylic acid (4%). ESI-LCMS 466 (M+H). 1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 7.54-7.88 (m, 3H), 7.31-7.43 (m, 1H), 7.14-7.25 (m, 1H), 6.98-7.12 (m, 1H), 4.12-4.40 (m, 2H), 3.33-3.50 (m, 2H), 2.82-3.08 (m, 2H), 2.05-2.42 (m, 3H), 1.74-1.95 (m, 2H), 0.94-1.64 (m, 12H), 0.82 (s, 13H).
Reaction SMILES: [NH:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[CH:3]=[CH:2]1)[N:10]=[CH:9][CH:8]=[CH:7]3.[CH2:14]1[O:17][C@H:15]1[CH3:16]>>[N:1]1([CH2:14][C@@H:15]([OH:17])[CH3:16])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[CH:3]=[CH:2]1)[N:10]=[CH:9][CH:8]=[CH:7]3
Reactant: c1cnc2ccc3cc[nH]c3c2c1
Reactant: C[C@H]1CO1
Product: C[C@H](O)Cn1ccc2ccc3ncccc3c21

Procedure:
(S)-1-(1H-Pyrrolo[2,3-f]quinolin-1-yl)-2-propanol was prepared according to the method described in Example 1 using 1H-pyrrolo[2,3-f]quinoline and (S)-propylene oxide to produce 0.36 g (17% yield) of the product as a pale yellow oil: IRνmax (Nujol)/cm−1 3106, 1361, 1117, 826, 805 and 731; NMR δH (400 MHz, CDCl3) 1.36 (3H, d, J 6.0 Hz), 2.75 (1H, br), 4.44 (2H, m), 4.56 (1H, m), 6.63 (1H, d, J 3.0 Hz), 7.19 (1H, d, J 3.0 Hz), 7.30 (1H, dd, J 8.5 and 4.0 Hz), 7.70 (1H, d, J 8.5 Hz), 7.86 (1H, d, J 9.0 Hz), 8.53 (1H, d, J 9.0 Hz) and 8.66 (1H, d, J 4.0 Hz).
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].I[C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:12]([CH2:18][CH2:19][CH3:20])=[N:11][C:10]=1[C:21]#[N:22].Cl.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)CC>[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:12]([CH2:18][CH2:19][CH3:20])=[N:11][C:10]=1[C:21]#[N:22]
Reactant: Nc1ccccc1B(O)O
Reactant: CCCc1nc(C#N)c(I)n1CC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCCO
Solvent: O
Product: CCCc1nc(C#N)c(-c2ccccc2N)n1CC(C)C
Temperature: 100 °C
Yield: 119.2 %

Procedure:
Triphenylphosphine (19 mg, 0.0735 mmol), water (2.9 mL), n-propanol (14.3 mL), aqueous sodium carbonate (9.8 mL of 2 M), and palladium (II) acetate (5.50 mg, 0.0245 mmol) were added to a mixture of 5-iodo-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile (2.59 g, 8.17 mmol) and 2-aminophenylboronic acid hydrochloride (1.70 g, 9.80 mmol). The reaction vessel was evacuated and filled with nitrogen three times and then heated under nitrogen at 100° C. for 24 hours. The work-up procedure described in Example 4 was followed with the modification that the reaction mixture was partitioned between chloroform and brine, and the extractions of the aqueous fraction were carried out with chloroform. After the organic fractions were combined, 2.75 g of 5-(2-aminophenyl)-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile were obtained as a brown solid.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1.[F:17][C:18]([F:28])([F:27])[O:19]C1C=CC(O)=CC=1>>[F:17][C:18]([F:28])([F:27])[O:19][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2o1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Product: O=C(O)c1cc2cc(OC(F)(F)F)ccc2o1

Procedure:
93 mg of 5-(trifluoromethoxy)benzofuran-2-carboxylic acid were prepared as described for 5-(trifluoromethyl)benzofuran-2-carboxylic acid, using 4-(trifluoromethoxy)phenol instead of 4-(trifluoromethyl)phenol.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[C:32]([CH3:34])[CH:33]=2)[C:29]#[N:30])=[O:25])=[N:6][C:7]([O:17]CC[Si](C)(C)C)=[N:8][C:9]=1[O:10]CC[Si](C)(C)C)([CH3:3])=[CH2:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:17])[NH:6][C:5]=1[C:24]([C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:29]#[N:30])=[O:25])([CH3:3])=[CH2:2]
Reactant: C=C(C)c1c(OCC[Si](C)(C)C)nc(OCC[Si](C)(C)C)nc1C(=O)c1cc(C)cc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)c1c(C(=O)c2cc(C)cc(C#N)c2)[nH]c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of 3-[5-isopropenyl-2,6-bis-(2-trimethylsilanyl-ethoxy)-pyrimidine-4-carbonyl]-5-methyl-benzonitrile (0.636 g, 1.28 mmol) in dichloromethane (10 mL) at 0° C. was added TFA (2 mL). Reaction mixture was stirred at 0° C. for 30 min, concentrated and purified by flash column chromatography (silica gel, 0 to 10% methanol/dichloromethane) to give a yellow solid (0.311 g, 82%). 1H NMR (300 MHz, CD3OD): δ 8.11 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 4.91 (s, 1H), 4.75 (s, 1H), 2.49 (s, 3H), 1.82 (s, 3H). Mass spectrum: 296.1 (M+H)+.
Reaction SMILES: O[CH:2]([CH:25]1[S:29][C:28](=[O:30])[NH:27][C:26]1=[O:31])[CH2:3][C@H:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([O:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[O:15][C:16]=2[CH3:17])[CH2:5]1.C(N(CC)CC)C.S(Cl)(C)(=O)=O>ClCCl>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[N:13][C:12]=1[CH2:11][O:10][C@@H:6]1[CH2:7][CH2:8][CH2:9][C@H:4]([CH2:3][CH:2]=[C:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])[CH2:5]1
Reactant: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC(O)C4SC(=O)NC4=O)C3)c(C)o2)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC=C4SC(=O)NC4=O)C3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
344 mg of 5-{1-hydroxy-2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dione are dissolved in 20 ml of dichloromethane, and 0.13 ml of triethylamine and and 0.12 ml of mesyl chloride are added. The mixture is stirred at room temperature for two hours, and another 0.13 ml of triethylamine and and 0.12 ml of mesyl chloride are added. The mixture is stirred at room temperature for 12 hours. 100 ml of dichloromethane are added, the mixture is washed with saturated sodium bicarbonate solution and dried over magnesium sulfate and the solvent is then removed under reduced pressure. The resulting residue is dissolved in 10 ml of tetrahydrofuran and, at −78° C., 0.22 ml of a 2.7 M solution of n-butyllithium in n-hexane is added. The mixture is stirred at 0° C. for 30 minutes, 20 ml of 1N hydrochloric acid are then added and the mixture is extracted three times with in each case 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 81 mg of 5-{2-[Cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethylidene}thiazolidine-2,4-dione as a white solid.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.C(O)(=O)C.[Br:19]N1C(=O)CCC1=O>ClCCl>[Br:19][C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: c1ccc2c(c1)OCCc1ccsc1-2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1cc2c(s1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine (440 mg, 2.2 mmol) and acetic acid (10 ml) in dichloromethane (10 ml) at 0° C., was added N-bromosuccinimide in portions. Reaction mixture was stirred for 18 hours, allowing solution to raise to room temperature before being concentrated in-vacuo. Residue was dissolved in ethyl acetate and sat. sodium carbonate solution. Organic phase was washed with water and brine, dried (Na2SO4) and concentrated in-vacuo to give 2-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine.
Reaction SMILES: [O:1]=[C:2]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17]C(=O)OC(C)(C)C)=[O:9].Cl>CCOC(C)=O>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)NCc1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)CCCCCC(=O)NCc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Into a solution of tert-butyl (2-(7-oxo-7-((pyridin-3-ylmethyl)amino)heptanamido)phenyl)carbamate (1.2 g, 2.73 mmol) in EtOAc (50 mL) were passed HCl (gas) at 0° C. The mixture was stirred for 30 min at 0° C. under HCl (gas). A white solid precipitated and was filtered. The white solid was collected and poured into a solution of 5% Na2CO3 in water (100 mL). The resulting mixture was extracted by EtOAc (100 mL×2). The organic layers were combined, dried with anhydrous Na2SO4 and concentrated under reduce pressure. The crude solid was recrystallized in EtOAc to afford the desired compound (0.6 g, yield 64.6%) as an off-white solid.