Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C1C=CC=CC=1.C(=O)C1C=CC=C(C=O)C=1.CC1SC2C=CC(F)=CC=2N=1.C(OC(=O)C)(=O)C.[F:37][C:38]1[CH:39]=[CH:40][C:41]2[S:45][C:44](/[CH:46]=[CH:47]/[C:48]3[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=3)[CH:51]=[O:52])=[N:43][C:42]=2[CH:56]=1.[BH4-].[Na+]>C1(C)C(C)=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:37][C:38]1[CH:39]=[CH:40][C:41]2[S:45][C:44](/[CH:46]=[CH:47]/[C:48]3[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=3)[CH2:51][OH:52])=[N:43][C:42]=2[CH:56]=1
Reactant: O=Cc1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Agent: Cc1nc2cc(F)ccc2s1
Agent: O=Cc1cccc(C=O)c1
Agent: [BH4-]
Solvent: Cc1ccccc1C
Solvent: OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: OCc1cccc(/C=C/c2nc3cc(F)ccc3s2)c1

Procedure:
An alternate procedure for preparing this benzyl alcohol comprises condensing isophthalaldehyde with 2-methyl-5-fluorobenzothiazole in the presence of acetic anhydride and zinc chloride in hot xylene followed by the reduction of the 3-(5-fluorobenzothiazol-2-yl-trans-ethenyl)benzaldehyde product with sodium borohydride to provide the appropriate benzyl alcohol.
Reaction SMILES: [C:1]1([CH2:11][CH:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][C:13]2=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1.CO>[C:1]1([CH2:11][CH:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][C:13]2=[S:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CO
Product: S=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Temperature: 160 °C

Procedure:
A suspension of 200 mg (0.73 mmol) of 3-naphthalen-1-ylmethyl-imidazo[1,2-a]pyridin-2-one and 250 mg (0.62 mmol) of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) in 20 mL of toluene is heated at 160° C. for 1 h under microwave condition. The resulting mixture is dissolved in methanol and absorbed on silica gel. The slurry is dried under reduced pressure and is purified by flash chromatography on silica gel. The compound is eluted 5˜10% methanol in dichloromethane solution to give the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Br-:10].[Br-:11].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:10][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([Br:11])[C:6]=1[OH:9]
Reactant: [Br-]
Reactant: COc1ccc(O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Br)c(O)c(Br)c1
Yield: 101.2 %

Procedure:
To 4-methoxyphenol (10.00 g, 80.6 mmol) in CH2Cl2 (70 mL), add a stirred solution of benzyltrimethylammonium tribromide (69.10 g, 177.2 mmol) in CH2Cl2 (500 mL) and MeOH (200 mL). Stir the reaction for 12 hours and remove the solvent in vacuo. Add methyl tert-butyl ether (MTBE) (600 mL) and collect the precipitate (benzyltrimethylammonium bromide) by filtration and wash with MTBE (200 mL). Filter the organics through Celite® and concentrate to provide the subtitled product (23.0 g, >95%) as an orange solid that may be used without purification. 1H NMR (DMSO-d6) δ 3.69 (s, 3H), 7.14 (s, 2H), 9.32 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.Cl.N1C=CC=CC=1>>[NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: COc1cc([N+](=O)[O-])cnc1N
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ncc([N+](=O)[O-])cc1O
Temperature: 150 °C
Yield: 50.3 %

Procedure:
Into a 500 mL round bottom flask were combined 2-amino-3-methoxy-5-nitropyridine (0.300 g, 0.00177 mol) and solid pyridine hydrochloride (8.8 g, 0.076 mol). The solid mixture was heated at 150° C. (upon which the solids fused; the evolution of a gas was also apparent). The mixture was held at 150° C. for three hours upon which reaction was deemed complete by LC-MS. After allowing to cool to 80° C., the mixture was poured on to ice and the aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×100 mL), dried (Na2SO4), filtered and concentrated under vacuum to leave a crude residue. The residue was purified by column chromatography on silica gel using a methanol:methylene chloride (0-10%) gradient as eluent to give the product as a solid (0.138 g, 49 %) which was used directly in the next step. LC-MS 1.28 min. m/z=155.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][NH:6]1)=[O:4].CC(C[AlH]CC(C)C)C.CO.O.[CH3:20][C:21]#[N:22]>C1(C)C=CC=CC=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>[NH:22]1[CH2:20][CH:21]1[CH:1]1[O:2][CH:3]([OH:4])[CH:5]2[N:6]1[CH2:7]2
Reactant: CC#N
Reactant: COC(=O)C1CN1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: OC1OC(C2CN2)N2CC12
Temperature: -78 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a flame dried Schlenk tube equipped with a magnetic stirring bar, a rubber septum and a N2 inlet was added aziridine-2-carboxylic acid methyl ester 1d (1.01 g, 10 mmol) dissolved into 25 ml of anhydrous toluene. The reaction flask was cooled to −78° C., at which point 13 ml of a 1.5M solution of DIBAL in toluene was added slowly via syringe to the reaction mixture over a period of 30 minutes. The reaction was allowed to stir for 5 hours or until completed by TLC. MeOH was added via syringe to the reaction mixture over a period of 15 minutes while maintaining a temperature of −78° C. After the addition of MeOH, the reaction mixture was allowed to warm to room temperature and stir for 30 minutes. A few drops of saturated aqueous Na2SO4 were used to cause precipitation of aluminum salts, which were filtered off after stirring for another 30 minutes. The filtrate was concentrated under reduced pressure to yield a thick clear oil, which was pure enough by NMR to use in subsequent transformations. An analytically pure sample can be obtained by subjecting the crude product to flash column chromatography (silica gel; 20% water in MeCN, Rf=0.32) to yield the title compound as a colourless oil in 76% yield. The compound is water soluble. 1H NMR (CDCl3 with D2O present, 400 MHz) δ: 5.33 (s, 0.5H), 5.27 (s, 1H), 4.92 (s, 1H), 4.91 (s, 0.5H), 2.62 (dd, J=5.2 Hz, 3.2 Hz, 1H), 2.53 (dd, J=5.6 Hz, 3.6 Hz, 0.5H), 2.47-2.43 (m, 1H), 2.39 (quintet, J=3.2 Hz, 0.5H), 2.29 (d, J=3.6 Hz, 0.5H), 2.10 (d, J=6.4 Hz, 0.5H), 1.86 (d, J=6.4 Hz, 1H), 1.76 (d, J=5.2 Hz, 1H), 1.70 (dd, J=5.2 Hz, 3.6 Hz, 1.5H), 1.26 (d, J=3.2 Hz, 1H), 1.21 (d, J=3.2 Hz, 0.5H) ppm. 13C NMR (CDCl3, 100 MHz) δ: 96.6 (major), 95.7 (minor), 95.6 (minor), 94.8 (major), 44.8 (minor), 44.0 (major), 31.9 (minor), 31.6 (major), 28.0 (major), 27.6 (minor), 21.3 ppm.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1[C:23]([O:24][CH2:25][CH3:26])=[N:22][CH:21]=[CH:20][C:10]=1[C:11]([N:13](C(C)C)C(C)C)=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:13]=[C:11]([OH:12])[C:10]3[C:9]([C:3]=2[CH:4]=1)=[C:23]([O:24][CH2:25][CH3:26])[N:22]=[CH:21][CH:20]=3
Reactant: CCOc1nccc(C(=O)N(C(C)C)C(C)C)c1-c1cc(Br)ccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1nccc2c(O)nc3ccc(Br)cc3c12
Reaction time: 2 h

Procedure:
To a solution of 3-(2-amino-5-bromophenyl)-2-ethoxy-N,N-diisopropylisonicotinamide (17.9 g, 43 mmol) in THF (213 mL) at 0° C. was added sodium bis(trimethylsilyl) amide (1.0 M in THF, 85 mL, 85 mmol). The solution was stirred for 2 hr and monitored by LCMS. Another 10 mL of sodium bis(trimethylsilyl) amide was added and stirred for an additional 30 min. The solution was quenched with methanol and concentrated to a slurry which was subsequently triturated with water and filtered to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]([CH:23]=[O:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:25](=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:25])[CH:18]=[C:17]([CH:23]=[O:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1cc(C=O)cc(C=O)c1
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C=Cc1cc(C=O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A solution of 2.87 g of methyl (RS)-(4-cyano-phenylamino)-(3,5-diformyl-phenyl)-acetate in 20 ml of dioxan and 1.3 ml of DMF was treated with 3.18 g of methyltriphenylphosphonium bromid and 1.84 g of potassium carbonate. The suspension was heated for 3 days to 100° C. It was left to cool to room temperature, filtered and concentrated. The crude product was isolated by extraction isoliert and purified by chromatography on silica gel. There were obtained 1.31 g of methyl (RS)-(4-cyano-phenylamino)-(3-formyl-5-vinyl-phenyl)-acetate as a light yellow solid.
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCC)C(=O)OCC
Yield: 89.1 %

Procedure:
Reaction and post-treatment were carried out according to Reference example 12(a) using 2.16 g of diethyl butylmalonate, 2.44 g of 4-benzyloxybenzyl chloride and 480 mg of sodium hydride (55% oil suspension) to obtain 3.67 g of the desired compound as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.[OH-].[K+].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[S:18]>O.O1CCCC1>[CH3:15][N:16]([CH3:20])[C:17]([O:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][C:6]([O:12][C:17](=[S:18])[N:16]([CH3:20])[CH3:15])=[CH:5]2)=[CH:10][CH:11]=1)=[S:18]
Reactant: CN(C)C(=S)Cl
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=S)Oc1ccc2ccc(OC(=S)N(C)C)cc2c1
Temperature: 10 °C
Yield: 75.1 %

Procedure:
To a mixture containing 32 grams of 2,7-dihydroxynaphthalene and 26.3 grams of potassium hydroxide in 140 ml of water which had been cooled to 10° C. was slowly added 56.8 grams of dimethylthiocarbamoyl chloride in 88 ml of tetrahydrofuran. The temperature was maintained below 12° C. throughout the addition. The solid which formed was filtered, washed with water, reslurried in methanol and filtered to produce 50.2 grams of dimethyl-thiocarbamic acid O-(7-dimethylthiocarbamoyloxy-naphthalen-2-yl) ester. After drying this was placed in a round bottom flask and heated under a nitrogen atmosphere at 250° C. for 1.5 hours. The mixture was cooled and the solid recrystallized from ethyl acetate to give 17 grams of dimethyl-thiocarbamic acid S-(7-dimethylcarbamolysulfanyl-naphthalene-2-yl) ester. This was added to a mixture of 50 ml of ethanol and a solution of 22.4 grams of potassium in 32 mil of water, and then heated at reflux for 30 minutes. The mixture was cooled, diluted with 300 ml of water and acidified with hydrochloric acid. The solid which formed was filtered and dried yielding 8.5 grams of naphthalene-2,7-dithiol (9).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][CH2:9][C:10]([N:12]([CH2:14][CH:15](OC)OC)[CH3:13])=[O:11])[CH2:4][CH2:3]1.Cl.[H][H]>[Pt].CO.O>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:15][CH2:14][N:12]([CH3:13])[C:10](=[O:11])[CH2:9]2)[CH2:6][CH2:7]1
Reactant: COC(CN(C)C(=O)CN[C@H]1CC[C@H](O)CC1)OC
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: O
Solvent: CO
Product: CN1CCN([C@H]2CC[C@H](O)CC2)CC1=O
Temperature: 50 °C

Procedure:
82 g platinum on charcoal (5%) are added to a solution of 822 g (trans)-1-hydroxy-4-{[N-(2,2-dimethoxy-ethyl)-N-methyl-amino]-carbonylmethylamino}-cyclohexane in 4500 ml of methanol and 450 ml of water. After the addition of 499 ml concentrated hydrochloric acid hydrogenation with hydrogen is begun immediately. During the hydrogenation process the mixture is heated to 50° C. After 3 h it is filtered.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][C:12]([CH3:15])=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][C:12]([CH3:15])=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8])=[C:16]=[S:17]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1ncn(-c2ccc(N)cc2C#N)n1
Solvent: ClCCl
Product: Cc1ncn(-c2ccc(N=C=S)cc2C#N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
Step G (3): Dichloromethane (100 mL) was added to a flask charged with 5-amino-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (6.59 g, 33.1 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (7.68 g, 33.1 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture was concentrated and the crude products were purified using silica gel chromatography (0-5% EtOAc/chloroform) linear gradient to afford 5-isothiocyanato-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (5.19 g, 15.88 mmol, 56% yield) as a yellow solid. LC-MS (M+H)+ 242.0.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24]C(=O)[O-])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[CH2:3][CH2:2]1.[ClH:28]>ClCCl>[ClH:28].[ClH:28].[ClH:28].[O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[CH2:3][CH2:2]1
Reactant: O=C([O-])NC1CCC(CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reaction time: 3 h

Procedure:
To a mixture of trans-tert-butyl-(4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylcarbamate (0.49 g, 1.14 mmol) in dichloromethane (8 ml) was added at room temperature hydrochloric acid solution (4M in dioxane, 4.27 ml, 17.1 mmol) and the mixture was allowed to stir for 3 h, the solvent was evaporated, diethyl ether (20 ml) was added and the mixture was allowed to stir for 30 min at room temperature. The precipitate was collected by filtration, washed with diethyl ether and dried to yield the title compound as a white solid (0.5 g, 100%), MS (ISP) m/z=331.3 [(M+H)+], mp 287.5° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.C1(C)C=CC(S(O[C@@H:35]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]2)(=O)=O)=CC=1>>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][C@H:35]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)[CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1

Procedure:
Analogously to Method I, 0.665 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.822 g of tert-butyl 3(R)-(toluene-4-sulphonyloxy)pyrrolidine-1-carboxylate are reacted. The title compound is obtained as a white foam. Rf=0.14 (1:1 EtOAc-heptane). Rt=4.91.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3o2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1
Temperature: 50 °C

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (155 mg), acetic acid (4.0 mL) and 10% palladium on carbon (40 mg) in methanol (10 mL) is shaken under an hydrogen atmosphere (5 bar) at 50° C. The catalyst is filtered off and the filtrate is concentrated in vacuo to give the title compound. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9](Cl)=[O:10])[CH3:2].C(OC1C=CSC=1C(O)=O)C.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[C:31]([CH2:39][CH2:40][CH3:41])=[N:32][N:33]([CH3:38])[C:34]=1[C:35]([NH2:37])=[O:36].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([NH:29][C:30]1[C:31]([CH2:39][CH2:40][CH3:41])=[N:32][N:33]([CH3:38])[C:34]=1[C:35]([NH2:37])=[O:36])=[O:10])[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: CCOc1ccsc1C(=O)Cl
Agent: CCOc1ccsc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1sccc1OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Ethoxythiophene-2-carbonyl chloride 2, prepared from the reaction of 3-ethoxythiophene-2-carboxylic acid (2.79 g, 16.2 mmol) with oxalyl chloride, was added to a solution of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide 1 (2.08 g, 11.4 mmol), DMAP (28 mg, 0.23 mmol) and Et3N (1.64 g, 16.2 mmol) in anhydrous CH2Cl2 (30 mL) at 0° C., and stirred at r.t. for 24 h. The mixture was washed with 1 N HCl and dried with MgSO4. Chromatography (silica gel, hexane:ethyl acetate=3:1) gave a white solid; mp: 103-104° C.; 1H NMR (DMSO-d6) δ 0.87 (t, J=7 Hz, 3 H), 1.39 (t, J=7 Hz, 3 H), 1.56 (sxt, J=7 Hz, 2 H), 2.43 (t, J=7 Hz, 2 H), 3.88 (s, 3 H), 4.32 (q, J=7 Hz, 2 H), 7.18 (d, J=6 Hz, 1 H), 7.66 (s, br. 1 H), 7.75 (s, br. 1 H), 7.81 (d, J=6 Hz, 1 H), 8.87 (s, 1 H); MS (m/z): 337 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[C:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH2:29][N:30]([CH3:40])[C:31](=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[H][H]>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH2:29][N:30]([CH3:40])[C:31](=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Yield: 26.8 %

Procedure:
In a manner similar to that of Example 1(g), starting with 1 g (1.8 mmol) of N-[6-benzyloxy-4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methyloctanamide (obtained in Example 75) in ml of dioxane and 1 ml of triethylamine under 3 atm of hydrogen, 270 mg (27%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=3[O:20][CH3:21])[N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH:41][C:2]3[N:22]=[C:5]4[CH:6]=[CH:7][CH:8]=[C:9]([C:10]5[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=5[O:20][CH3:21])[N:4]4[N:3]=3)=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: COc1cc(C(F)(F)F)ccc1-c1cccc2nc(Cl)nn12
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nn12

Procedure:
7-[5-(2-Methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-5-(2-Methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.5 g, 1.5 mmol), and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.6 g, 2.0 mmol). Product was isolated as a foam (0.27 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.69 (d, J=7.99 Hz, 1H), 7.56-7.51 (m, 2H), 7.41 (d, J=7.99 Hz, 1H), 7.32-7.28 (m, 2H), 7.06-7.02 (m, 1H), 6.97-6.93 (m, 1H), 6.75 (brs, 1H), 3.86 (s, 3H), 3.62-3.48 (m, 4H), 2.91-2.77 (m, 4H) 1.52 (s, 9H). MS=554 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:22])[C:19]=1[O:20]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:16])[CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:22])[C:19]=1[OH:20])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:16])[CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CS(=O)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)c(O)c(Cl)c1)N1CS(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
3-(3,5-dichloro-4-methoxybenzoyl)-1-oxo-2,3-dihydro-1,3-benzothiazole (336 mg) was dissolved in N,N-dimethylformamide (6 mL) and lithium chloride (400 mg) was added to the solution, and then the mixture was stirred at 120° C. for 16 hours. To the reaction solution, 1N hydrochloric acid was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from ethyl acetate-methanol to obtain the title compound (220 mg) as a brown crystal.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH:12]([C:18]([CH3:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([CH3:20])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(O)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Product: CCOC(=O)c1sc(-c2ccc(O)cc2)nc1C
Reaction time: 1 h

Procedure:
A mixture of 4-hydroxy thiobenzamide (100 g, 0.653 mol) and ethyl 2-chloroacetoacetate (118.3 g, 0.719 mol) in denatured spirit (DNS) (500 mL) was heated at about 60° C. to 65° C. for about 2.5 hours. The reaction mixture was cooled to about 0° C. to 5° C. and stirred for about 1 hour at the same temperature. The solid obtained was filtered, washed with denatured spirit and dried to obtain the title compound. (Yield: 156 g, 90.7%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH2:30]([O:29][CH2:28][CH2:27][NH:26][C:24]([C:7]1[C:6](=[O:32])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:39]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:40])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])[CH3:31]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Reactant: O=C(Cl)N1CCOCC1
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Step 2 of Example 373 and was obtained as a white solid: ES+ MS: 556 (M+H+).