Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11].[CH3:26][C@@H:27]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[NH:28]1>>[F:1][C:2]1[CH:7]=[C:6]([N:28]2[C@H:27]([CH3:26])[CH2:31][CH2:30][S:29]2(=[O:33])=[O:32])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(I)cc3F)CC2)c(C)c1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4[C@H](C)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 55.8 %

Procedure:
Using (2,6-difluoro-4-iodophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (743 mg) described in Preparation Example 158 and (R)-3-methylisothiazolidine 1,1-dioxide (220 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (421 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: NS(=O)(=O)c1ccc(N=Cc2ccc(Cl)c(Cl)c2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 3,4-dichlorobenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a white powder (yield 52%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>CN1CCCC1=O>[N:10]1([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: c1c[nH]cn1
Solvent: CN1CCCC1=O
Product: N#Cc1ccnc(-n2ccnc2)c1
Temperature: 150 °C
Yield: 24.4 %

Procedure:
A mixture of 2-chloro-4-cyanopyridine (4.0 g, 28.9 mmol), imidazole (7.9 g, 115 mmol) and N-methyl-2-pyrrolidinone (50 ml) was heated at 150° C. for 58 hours. The solvent was removed by distillation and the residue was partitioned between chloroform and water. The organic layer was separated and the aqueous layer was extracted with chloroform (2×100 ml). The organic layers were combined and the solvent was removed in vacuo. The residue was triturated with ether and a solid was collected by filtration. The solid residue was purified by column chromatography eluting with hexanes/acetone (1/1) to afford 1.2 g (24%) of 2-(1-imidazolyl)-4-cyanopyridine as a tan solid, m.p. 146°-147° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][S:19]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:21])=[O:20]
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCCC3)cs2)C1
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of 3-hydroxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (290 mg, 1.14 mmol) (obtained as described in Reference Example 26(2)) in methylene chloride (9 ml) were added methanesulfonyl chloride (0.30 ml, 5.12 mmol) and triethylamine (0.70 ml, 5.12 mmol) in an ice bath, and the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (335 mg, yield 89%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].O.Cl[CH:15]([F:17])[F:16]>C(O)(C)C.[OH-].[Na+]>[Br:8][C:7]1[CH:6]=[C:5]([Br:9])[CH:4]=[C:3]([S:10]([CH:15]([F:17])[F:16])(=[O:12])=[O:11])[C:2]=1[NH2:1]
Reactant: FC(F)Cl
Reactant: Nc1c(Br)cc(Br)cc1S(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Nc1c(Br)cc(Br)cc1S(=O)(=O)C(F)F
Temperature: 40 °C

Procedure:
A solution of 2-amino-3,5-dibromobenzenesulfinic acid (7.98 g; 0.025 mol) in a mixture of isopropyl alcohol (100 ml) and sodium hydroxide (8.0 g of 50% aqueous) and water (2 ml) is warmed to 40° C. Chlorodifluoromethane is added slowly through a gas inlet tube over a period of 3 hours. The reaction mixture exotherms to 55° C. The reaction mixture is poured into water (500 ml) and the solution is extracted with methylene chloride (2×100 ml). The combined extracts are washed with saturated NaHCO3 (100 ml), saturated NaCl (100 ml), then dried over MgSO4. The solvent is evaporated under vacuum yield 0.9 g of the title product, m.p. 84°-88° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.O.[SH2:12].[Na].Cl>CN(C)C=O>[S:8]1[C:7]2[C:2](=[S:12])[NH:3][CH:4]=[CH:5][C:6]=2[CH:10]=[CH:9]1
Reactant: S
Reactant: Clc1nccc2ccsc12
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: S=c1[nH]ccc2ccsc12
Temperature: 0 °C

Procedure:
adc) 4.85 g of 7-chloro-thieno[2,3-c]pyridine were dissolved in 15 ml of dimethylformamide and 3.18 g of sodium hydrogen sulfide monohydrate were added under argon. The mixture was heated to 110°-115° for one hour, an additional 1.06 g of sodium hydrogen sulfide monohydrate were added and the mixture was held at the temperature indicated above for an additional hour. The mixture was poured on to 150 ml of ice-water and acidified with 1N aqueous hydrochloric acid solution. After stirring at 2° for a short time, the yellowish crystals were removed by filtration. After recrystallization from a toluene/ethyl acetate mixture, there was obtained pure thieno[2,3-c]pyridine-7(6H)-thione, m.p. 187°-189°.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:5].[CH2:10](Cl)[CH:11]=[C:12]([CH3:14])[CH3:13].[Cl-].CC(C)(C)CCCCCCCCCCCCCCCCC[NH3+]>O>[C:7](=[C:6]([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:4](=[O:3])[CH3:5])([CH3:9])[CH3:8]
Reactant: CC(C)=CCCl
Reactant: CC(=O)C=C(C)C
Agent: CC(C)(C)CCCCCCCCCCCCCCCCC[NH3+]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)C(CC=C(C)C)=C(C)C
Reaction time: 2 h

Procedure:
To a solution of 600 g of sodium hydroxide in 490 g of water was added 980 g of mesityl oxide together with 520 g of prenyl chloride and 25 g of trimethylstearylammonium chloride, and the mixture was reacted in a water bath under stirring for 2 hours (The reaction temperature rose to 70° C.). The reaction mixture was poured into water and extracted with ethyl ether. The ethereal solution was washed with water and dried over anhydrous sodium sulfate. The ether was distilled off under reduced pressure and the residue (1250 g) was further distilled to recover the unreacted mesityl oxide. Thereupon, as higher-boiling products, 560 g of a 2.5:1 mixture of 3-isopropenyl-6-methyl-5-hepten-2-one and 3-isopropylidene-6-methyl-5-hepten-2-one (purity 96.4%) was obtained. Based on the purity of 83.71% for the prenyl chloride used, the yield of 3-isopropenyl-6-methyl-5-hepten-2-one was 59% (410 g) and that of 3-isopropylidene- 6-methyl-5-hepten-2-one was 19% (130 g).
Reaction SMILES: C1(C2C=C(C3CC3)C=CC=2N2CCN(C(C3C=NC(F)=CC=3C)=O)CC2)CC1.COC1C=CC(CN)=CC=1.Cl[CH2:40][CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].[NH2:47][C:48]1[N:53]=[CH:52][C:51]([C:54]([N:56]2[CH2:61][CH2:60][N:59]([C:62]3[CH:67]=[CH:66][C:65]([CH:68]4[CH2:70][CH2:69]4)=[CH:64][C:63]=3[CH:71]3[CH2:73][CH2:72]3)[CH2:58][CH2:57]2)=[O:55])=[C:50]([CH3:74])[CH:49]=1>>[CH:71]1([C:63]2[CH:64]=[C:65]([CH:68]3[CH2:70][CH2:69]3)[CH:66]=[CH:67][C:62]=2[N:59]2[CH2:58][CH2:57][N:56]([C:54]([C:51]3[CH:52]=[N:53][C:48]([N:47]4[CH2:40][CH2:41][CH2:42][S:43]4(=[O:45])=[O:44])=[CH:49][C:50]=3[CH3:74])=[O:55])[CH2:61][CH2:60]2)[CH2:72][CH2:73]1
Reactant: Cc1cc(N)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Reactant: O=S(=O)(Cl)CCCCl
Agent: COc1ccc(CN)cc1
Agent: Cc1cc(F)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Product: Cc1cc(N2CCCS2(=O)=O)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1

Procedure:
Using [4-(2,4-dicyclopropylphenyl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (480 mg) described in Preparation Example 179, 4-methoxybenzylamine (2 mL) and 3-chloropropane-1-sulfonyl chloride (0.31 mL) and by the reaction and treatment in the same manner as in Example 229, the title compound (450 mg) was obtained via (6-amino-4-methylpyridin-3-yl)[4-(2,4-dicyclopropylphenyl)piperazin-1-yl]methanone.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15][CH3:16])[C:5]=2[N:6]=1.N(OCCC(C)C)=O>CN(C=O)C>[CH3:16][O:15][C:7]1[C:5]2[N:6]=[CH:2][S:3][C:4]=2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=1
Reactant: COC(=O)c1cc(OC)c2nc(N)sc2c1
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c2ncsc2c1
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 23.5 %

Procedure:
To a stirred solution of methyl 2-amino-4-methoxy-1,3-benzothiazole-6-carboxylate (100 g, 0.42 mol) in DMF (1 L) was added drop wise isoamyl nitrite (108 g, 0.92 mol) at 65° C. Then the resulting mixture was stirred at 65° C. for 20 min. TLC (EtOAc/Petroleum ether 1:4) showed the reaction was complete. After cooling to ambient temperature, the mixture was poured into ice water (1 L). The resulting mixture was extracted with EtOAc (1 L×3). The combined organic layers were washed with water (1 L×2), dried over Na2SO4 and concentrated in vacuum. The residue was purified by chromatography (silica gel, EtOAc/Petroleum ether 1:50 to 1:10) to afford the product (22 g, 23%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.050 (s, 1H), 8.285-8.281 (d, 1H), 7.592-7.587 (d, 1H), 4.110 (s, 3H), 3.965 (s, 3H).
Reaction SMILES: [Cl:1][CH:2]=[C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[O:4][Si](C(C)C)(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(#N)C>[Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:4]
Reactant: CC(C)[Si](OC(=CCl)c1ccccn1)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C(CCl)c1ccccn1
Yield: 84.6 %

Procedure:
Crude 2-{2-chloro-1-[(triisopropylsilyl)oxy]ethenyl}pyridine (117.3 g, 0.376 mol) is placed in a 4 L plastic bottle and is dissolved in acetonitrile (0.4 L). To the stirring solution is added 48% aqueous HF (170 mL, 0.45 mL/mmol) and the progress of the reaction is monitored by reverse phase analytical HPLC. After. Ca. 2 hours the reaction is judged to be complete, and the pH of the solution is carefully adjusted to ca. 8 with saturated aq. NaHCO3. The mixture is poured into a separatory funnel containing CH2Cl2 (1.5 L). The organic phase is removed and the aq. layer is extracted with CH2Cl2 (2×1.0 L). The combined organic layers are dried (Na2SO4), and concentration in vacuo affords the title compound (49.5 g) as a tan solid (after cooling). The crude material is judged to be quite pure by 1H—NMR and HPLC and is used as is in the Noyori asymmetric reduction.
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH:14][NH:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>O1CCCC1>[CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:40][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:15][N:14]=1)=[CH:8]2
Reactant: CCOC(=O)C(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture of ethyl [2-({7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}carbonyl)hydrazino](oxo)acetate (0.43 g), Lawesson's reagent (0.42 g) and tetrahydrofuran (10 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.29 g, yield 68%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 176-177° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([CH2:30][S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:31]([CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:33])=[O:32])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NS(=O)(=O)Cc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Sulfonylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with α-toluenesulfonyl chloride (12 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (25 ml) was performed according to the acylation method described in example 6.
Reaction SMILES: [Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[C:8](O)=[O:9])=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C(Cl)Cl>[Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[C:8]([Cl:18])=[O:9])=[O:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccco1
Solvent: ClCCl
Product: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1ccco1
Temperature: 0 °C

Procedure:
To an ice-cold stirred suspension of 2-dichloroacetoxyimino-2-(fur-2-yl)acetic acid (1.5 g) in dry methylene chloride (70 mls) was added dropwise a freshly prepared solution of phosphorus pentachloride (1.0 equiv.) in methylene chloride. When solution was complete the solvent was evaporated at low temperature and the residual oil azeotroped with benzene to give 2-dichloroacetoxyimino-2(fur-2-yl)acetyl chloride (syn-isomer) as a pale yellow oil which was used directly.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:17])[C:12]([O:16][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[C:13]([Cl:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: Clc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(OCCCOc2c(Cl)cc(OCc3ccccc3)cc2Cl)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a mixture of 5.0 g of 4-benzyloxy-2,6-dichlorophenol, 4.7 g of 1-bromo-3-(4-chlorophenoxy)propane and 30 ml of N,N-dimethylformamide was added 2.7 g of potassium carbonate with stirring at room temperature. After stirring at room temperature for 12 hours, the reaction solution was poured into iced water and extracted twice with 200 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to obtain a crude product. This crude product was subjected to silica gel chromatography to give 6.5 g of 4-benzyloxy-1-(3-(4-chlorophenoxy)propyloxy)-2,6-dichlorobenzene(yield: 85 %).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCCCBr
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(C2(C#N)CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3-Methoxyphenyl)acetonitrile (0.52 grams) was added to a solution of sodium hydride (0.212 grams) in DMSO (10 mL) at 0° C. The mixture was warmed to room temperature over 30 minutes. 1,5-Dibromopentane (0.722 mL) was added dropwise as a solution in DMSO (5 mL). This mixture was stirred for 16 hours, then partitioned between ethyl acetate and water. The organic phase was separated and washed with brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated. The resulting solid was chromatographed on silica gel using ethyl acetate and hexane (3:97) to give the titled compound (0.42 grams).
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH2:9]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1)[CH3:10].C(N(CC)CC)C>O1CCOCC1>[C:1]([NH:19][NH:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([O:11][CH2:9][CH3:10])=[CH:13][CH:14]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOc1ccc(C(=O)NN)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)NNC(=O)c1ccc(OCC)cc1
Yield: 90.7 %

Procedure:
29 g of ethoxalyl chloride are added, in the course of 30 minutes, to 36 g of 4-ethoxybenzhydrazide and 21.3 g of triethylamine in 360 ml of anhydrous dioxane, whilst keeping the temperature of the reaction medium at about 10° C. The stirring is continued (sic) for about two hours, whilst allowing the temperature to return to the ambient value. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure (20 mm Hg, 50° C.) and the residue is stirred in the presence of 200 ml of isopropyl ether and then filtered off. After drying (20° C., 1 mm Hg), 50.8 g of 1-ethoxalyl-2-(4-ethoxybenzoyl)-hydrazine, which melts at 126° C. after a first melting at 120° C., are obtained. Yield: 90.7%.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:26])[NH:15][CH2:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[N:20][NH:21]3)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[NH:21]1[C:22]2[C:18](=[C:17]([CH2:16][NH:15][C:14]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=3)=[O:26])[CH:25]=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cccc2[nH]ncc12)c1cc(C(F)(F)F)c(C(=O)O)s1
Reaction time: 15 h

Procedure:
A mixture of 5-[(1H-Indazol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (200 mg, 0.52 mmol), lithium hydroxide monohydrate (220 mg, 5.22 mmol), THF (4 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 160 mg (83%). MS m/e 370.0 (M+H+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.IC1C=CC=CC=1.[CH2:16]([C:20]1([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:25][C:24](=[O:26])[CH:23]=[C:22]([O:27][CH2:28][CH3:29])[CH2:21]1)[CH2:17][C:18]#[CH:19].C(C1(C2CCCC2)OC(=O)CC(=O)C1)CC#C>>[CH:30]1([C:20]2([CH2:16][CH2:17][C:18]#[C:19][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=3)[O:25][C:24](=[O:26])[CH:23]=[C:22]([O:27][CH2:28][CH3:29])[CH2:21]2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: C#CCCC1(C2CCCC2)CC(OCC)=CC(=O)O1
Reactant: Oc1cccc(I)c1
Agent: C#CCCC1(C2CCCC2)CC(=O)CC(=O)O1
Solvent: Ic1ccccc1
Product: CCOC1=CC(=O)OC(CCC#Cc2cccc(O)c2)(C2CCCC2)C1

Procedure:
The title compound was prepared analogously to Example 6, except 3-iodophenol was used for iodobenzene, and 6-but-3-ynyl-6-cyclopentyl-4-ethoxy-5,6-dihydro-pyran-2-one, described in Step 2 of that example, was used for 6-but-3-ynyl-6-cyclopentyl-dihydro-pyran-2,4-dione. 1H NMR (CDCl3): δ 1.26 (t, 2H, J=7.16 Hz), δ 1.51-1.81 (m, 8H), δ 2.10 (t, 2H, J=7.54 Hz), δ 2.36 (t, 1H, J=8.10 Hz), δ 2.48 (d, 1H, J=17.71 H), δ 2.52 (t, 2H, J=7.35 Hz), δ 2.68 (d, 1H, J=17.52 Hz), δ 3.94 (q, 2H, J=7.35 Hz), δ 5.14 (d, 2H, J=6.22 Hz), δ 6.77 (dd, 1H, J=5.65 Hz, J=2.45 Hz), δ 6.87 (s, 1H), δ 6.95 (d, 1H, J=6.59 Hz), δ 7.14 (t, 1H, J=7.91 Hz). Anal. Calcd. For C22H26O4 0.3 EtOAc: C, 73.16, H 7.52. Found: C, 73.18, H, 7.57; ESIMS (M+Na+) 377.1.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:23])[C:11]1=CN(C)C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)S([N:33]=[N+:34]=[N-])(=O)=O.CO>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:23])[C:11]1=[N+:33]=[N-:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)C=C1C(=O)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=NS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C(=O)C1=[N+]=[N-]
Temperature: 60 °C
Yield: 77 %

Procedure:
5'-O-(t-Butyldimethylsilyl)-2',3'-dideoxy-3'-(N,N-dimethylamino-methylene)-2'-oxo-uridine (1.78 g, 4.5 mmol), from Step 6, was added to the trifluoromethanesulfonyl azide solution and the reaction mixture was heated at 60° C. for 2.5 h under a nitrogen atmosphere. The solvents were evaporated in vacuo to a syrup (2.8 g) which was dissolved in 10 mL of methylene chloride and purified by flash chromatography (5 psi) on a silica gel column (2×35 cm) eluted with 200 mL of methylene chloride, 200 mL of 1% methanol in methylene chloride, 200 mL of 2% methanol in methylene chloride and 3% methanol in methylene chloride to give 1.27 g (77% yield) of the title compound. MS DCI: 367 (M+H)+.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)[N:6]=[CH:5]1.N1C=C(C=O)N=[CH:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[ClH:1].[C:27]([N:13]1[CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:41][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[N:10]([CH2:9][C:7]2[N:6]=[CH:5][NH:4][CH:8]=2)[CH2:11][C@H:12]1[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:28]
Reactant: O=Cc1c[nH]cn1
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
A solution of 115 mg (0.29 mmol) of Compound B in 2.5 mL of dichloroethane and 2.5 mL of glacial acetic acid was treated with 69 mg (0.71 mmol) of 4-imidazole-carboxaldehyde, 3A sieves and stirred at rt for 18 hrs. The mixture was treated with 122 mg (0.58 mmol) of sodium triacetoxyborohydride in one portion and stirred at rt for 30 min and filtered. The filtrate was partitioned between 100 mL of ethyl acetate and 100 mL of 1 N sodium hydroxide. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The oil was purified by reverse phase preparative HPLC (gradient of aq methanol with 0.1% TFA). The yellow foam was evaporated 3× from methanolic hydrogen chloride. The foam was dissolved in water and lyophilyzed to afford 30 mg (22%) of Compound C as a yellow lyophilate. MS: (M+H)+ =480.