Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].CN1CCCC1=O.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:19]([NH:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNC(=O)c1cccc(Br)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NNC(=O)c1cccc(Br)c1)c1ccccc1
Yield: 96 %

Procedure:
Subsequently, 5.0 g (23 mmol) of 3-bromobenzohydrazine obtained in (i) above was put in a 300-mL three-neck flask, 10 mL of N-methyl-2-pyrrolidone was added therein, and the mixture was stirred. Thereafter, a mixed solution of 10 mL of N-methyl-2-pyrrolidone and 3.2 mL (28 mmol) of benzoyl chloride was dripped to the above mixture through a 50-mL dropping funnel. After the dripping, the mixture was heated and stirred at 80° C. for 3 hours so as to be reacted. After the reaction, water was added to the reaction solution, and a solid was precipitated. The precipitated solid was collected by suction filtration to obtain another solid. The obtained solid was washed with approximately 1 L of water and collected by suction filtration. The collected solid was washed with methanol and collected by suction filtration; thus, 7.1 g of a white solid that was an object was obtained (yield: 96%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[OH-].[Na+]>CO>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([C:5]2[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[CH:12]=[CH:13][C:4]=2[C:3]([OH:21])=[O:2])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(-c2ccc(C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)ccc2C(=O)O)cc1
Yield: 66.2 %

Procedure:
Dimethyl-2-(4-toluyl)terepthalate (11.88 g) was suspended in methanol (99 ml). 5M NaOH (50 ml) was added. The reaction mixture was heated at reflux for 1.5 hours. The methanol was removed under reduced pressure. The residue was treated with ethyl acetate and water and the layers separated. The aqueous layer was washed once with ethyl acetate. The aqueous layer was then acidified with 2N HCl and extracted three times with ethyl acetate. These combined organic extracts were then dried over MgSO4, filtered and evaporated under reduced pressure gave the product (7.09 g)
Reaction SMILES: C(S[C:4]([O:6][CH2:7][O:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])=[O:5])C.S(Cl)([Cl:17])(=O)=O>>[Cl:17][C:4]([O:6][CH2:7][O:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCSC(=O)OCOC(=O)C(C)C
Product: CC(C)C(=O)OCOC(=O)Cl
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A 100 mL roundbottom flask was charged with the 2-methylpropanoic acid ethylsulfanylcarbonyloxymethyl ester (2.91 g, 14.1 mmol) and cooled to −40° C. in an acetone dry ice bath. Sulfuryl chloride (1.90 g, 14.1 mmol) was added over one minute. After 10 minutes the acetone/dry ice cooling bath was removed and replaced with an ice/water bath. After 30 minutes of stirring, the cooling bath was removed and the reaction was allowed to stir for one hour at room temperature and then placed under vacuum for 90 minutes. The material was used without purification. 1H-NMR (300 MHz, CDCl3) δ (ppm): 1.22 (d, 6H), 2.65 (m, 1H), 5.83 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10](Cl)=[N:9][C:8]([Cl:13])=[N:7][C:6]=2[N:5]([C@@H:14]2[O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]2[O:16]C(=O)C)[CH:4]=1)#[N:2].[CH3:32][OH:33]>C[O-].[Na+]>[Cl:13][C:8]1[N:9]=[C:10]([O:33][CH3:32])[C:11]2[C:3]([C:1]#[N:2])=[CH:4][N:5]([C@@H:14]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]3[OH:16])[C:6]=2[N:7]=1
Reactant: CO
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C#N)c3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: COc1nc(Cl)nc2c1c(C#N)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 34.6 %

Procedure:
5-Cyano-2,4-dichloro-7-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (5, 400 mg) was dissolved in 40 ml of methanol containing 200 mg of sodium methoxide. The solution was stirred at room temperature for 1 hr and neutralized to pH 7 with Dowex 50W-X 12 (H30) resin. The resin was filtered and the solvent was evaporated to dryness in vacuo. The residue was dissolved in water, treated with decolorizing carbon, filtered and the product slowly crystallized under an air stream. The solid was recrystallized from ethanol-water to yield 100 mg of 7, mp 194-195°. The analytical sample was dried in an Abderhalden apparatus in vacuo for 2 hr. at 110° (mp unchanged).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:11](Br)[CH2:12]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][NH2:10])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: N#CCc1ccc(Cl)cc1
Product: NCC1(c2ccc(Cl)cc2)CC1
Yield: 33 %

Procedure:
(1-(4-Chlorophenyl)cyclopropyl)methylamine is prepared from 4-chlorophenyl acetonitrile and ethylene dibromide in overall 33% yield as described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][NH:19][CH2:18][CH2:17]2.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][N:19]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][N:6]=1)[CH2:18][CH2:17]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCc3cc(OC)c(OC)cc3C2)nc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 55.3 %

Procedure:
A mixture of methyl-6-chloronicotinate (170 mg), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (205 mg), potassium carbonate (150 mg) and dioxane (5 mL) was heated in a 100° C. oil bath overnight. An additional aliquote of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (100 mg) was added and heating was continued for five hours. The reaction was partitioned between water and EtOAc. The organics were washed with water, dried, and the solvent evaporated. The residue was purified by flash chromatography eluting with EtOAc to give methyl 6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)nicotinate as a white solid (180 mg), m/e=329 (M+1).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([Si](C)(C)C)[NH:9][N:8]2C(N)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(Cl)(=O)=O)=CC=1.O.[N:31]1C=CC=C[CH:32]=1>>[C:1]1([N:7]2[C:11]([C:32]#[N:31])=[CH:10][NH:9][NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C1=CN(c2ccccc2)N(C(N)=O)N1
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: N#CC1=CNNN1c1ccccc1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
3-phenyl-5-trimethylsilanyl-1H-[1,2,3]triazole-2-carboxylic acid amide (550 mg) which is the compound prepared in the above 3) was dissolved in 2.0 ml of pyridine, 801 mg of 4-methylbenzenesulfonic acid chloride was added thereto and the mixture was stirred at 130° C. for one day. Water was added to the reaction solution, the mixture was extracted with ethyl acetate and the ethyl acetate layer washed with a saturated saline solution and dried over sodium sulfate. After the solvent was evaporated in vacuo and the residue was separated and purified by a thin-layer chromatography (hexane/ethyl acetate=5/1) to give 113 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9](F)[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:28])([C:19]([F:27])([F:26])[C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH2:17][OH:18].[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]([F:28])([C:19]([F:26])([F:27])[C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH2:17][O:18][C:9]1[C:8]([F:13])=[C:7]([F:14])[C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[C:10]=1[F:11]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)c(F)c1F
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a mixture of 2,3,4,5,6-pentafluorobenzoic acid (1 g) and 2,2,3,3,4,4,5,5-octafluoropentanol (1.18 g) in N,N-dimethylformamide (5 ml) was added 62% sodium hydride (0.39 g) at room temperature. The mixture was stirred at the same temperature for 1 hour, and thereto was added a mixture of water and ethyl acetate. The separated organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel to give 4-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-2,3,5,6-tetrafluorobenzoic acid (923.0 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].CO[CH:17](OC)[CH2:18]Br.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O>CN(C=O)C.ClC1C=CC=CC=1>[Br:7][C:8]1[C:9]2[O:14][CH:18]=[CH:17][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Oc1ccccc1Br
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: Brc1cccc2ccoc12
Temperature: 95 °C
Reaction time: 15 h
Yield: 44 %

Procedure:
A suspension of potassium carbonate (50.0 g, 362 mmol) in 100 ml of DMF was added sequentially with 2-bromophenol (20.6 g, 120 mmol) and bromoacetaldehyde dimethyl acetal (20.2 g, 120 mmol) and stirred at 95° C. for 15 hours. The reaction solution was concentrated, liquid separation was carried out with ethyl acetate-water, the organic layer was sequentially washed with an aqueous solution of 1M-sodium hydroxide and saturated sodium chloride water, and dried with anhydrous magnesium sulfate. The residue obtained by concentration was dissolved in 200 ml of chlorobenzene, added at room temperature to a solution comprising diphosphorus pentoxide (8.07 g, 56.8 mmol) and 85% phosphoric acid (27 ml), which was stirred at 95° C. for 15 hours. After cooling to room temperature, the mixture was poured over ice water, stirred, and then extracted with dichloromethane. The organic layer was washed with saturated sodium chloride water and dried with anhydrous magnesium sulfate. The residue obtained by concentration was purified by silica gel chromatography (100% hexane) to obtain an oily product (10.4 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[Cl:8][C:5]1[N:4]=[N:3][C:2]([N:1]=[CH:11][N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ccc(Cl)nn1

Procedure:
A mixture of 3-amino-6-chloropyridazine (6.39 g, 49.3 mmol) and N,N-dimethylformamide dimethyl acetal (7.67 mL, 54.3 mmol) was stirred under reflux for 75 min. Excess N,N-dimethyl-formamide dimethyl acetal was removed to afford the title compound as a beige solid (tR 1.0 min (conditions 1), MH+=185).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[Br-].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][Zn+].[NH4+].[Cl-]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C[Zn+])cc1F
Reactant: CCOC(=O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2ccc(Cc3ccc(F)c(F)c3)cc2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of Pd(dba)2 (57.5 mg, 0.100 mmole) and tfp (46.7 mg, 0.201 mmole) in anhydrous THF (10.0 mL) was stirred at room temperature for 20 minutes and then cooled to 0° C. Ethyl 7-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 9a, Step 2 (2.00 g, 5.02 mmole) was added as a solid, followed by a solution of 3,4-difluorobenzyl zinc bromide in anhydrous THF (20.0 mL-0.5 M, 0.100 mmole) added dropwise over 5 minutes. The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 24 h and was then poured into sat. NH4Cl (100 mL) and extracted with EtOAc (2×200 mL). The combined extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give 3.45 g of an orange oil. The crude product was purified by silica chromatography (92.5:7.5 hexanes:EtOAc) to give 1.81 g (91 % yield) of the product as a yellow oil: EIHRMS m/z 398.0955 (M+, C20H15F5O3, Calc'd 398.0941).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14](OCC)=[O:15])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][OH:15])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1conc1-c1ccc(F)c(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1conc1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
To a solution of ethyl 3-(3-bromo-4-fluorophenyl)isoxazole-4-carboxylate (10.47 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 75 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-(3-bromo-4-fluorophenyl)-4-isoxazolylmethanol (9.75 g, yield 96%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 93–94° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:13]2[CH2:18][CH2:17][CH2:16]/[C:15](=[CH:19]\[C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]4)=[C:22]([O:32][CH3:33])[CH:21]=3)/[C:14]2=[O:34])[CH2:11][OH:12])=[CH:6][CH:5]=1.CI.O.[C:38](=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:13]2[CH2:18][CH2:17][CH2:16]/[C:15](=[CH:19]\[C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]4)=[C:22]([O:32][CH3:33])[CH:21]=3)/[C:14]2=[O:34])[CH2:11][O:12][CH3:38])=[CH:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: COc1cc(/C=C2\CCCN(C(CO)c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H](c1ccc(F)cc1)N1CCC/C(=C\c2ccc(-n3cnc(C)c3)c(OC)c2)C1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Sodium hydride (containing mineral oil at 40%, 24 mg) was added to a solution of (E)-1-(1-(4-fluorophenyl)-2-hydroxyethyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one synthesized by the method described in Example 629 (216 mg) in THF (5 mL), and the reaction solution was stirred at room temperature for 50 minutes. Then, methyl iodide (85 mg) was added to the reaction solution, and the reaction solution was stirred at room temperature for 14 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 185 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:31])[CH:12]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:11]2[C:18]([CH3:30])=[C:19]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:10]=2[O:9]1.CS(O[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=1)(=O)=O.[ClH:47]>C(#N)C.C(OCC)(=O)C>[ClH:47].[ClH:47].[CH3:46][O:45][C:41]1[CH:40]=[C:39]([CH2:38][CH2:37][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[C:20]([CH3:23])=[C:21]([CH3:22])[C:10]4[O:9][C:8]([CH3:31])([CH3:7])[CH:12]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[C:11]=4[C:18]=3[CH3:30])[CH2:29][CH2:28]2)[CH:44]=[CH:43][CH:42]=1
Reactant: COc1cccc(CCOS(C)(=O)=O)c1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cccc(CCN2CCN(c3c(C)c(C)c4c(c3C)C(N3CCCC3)C(C)(C)O4)CC2)c1
Reaction time: 16 h
Yield: 25 %

Procedure:
To a mixture of potassium carbonate (207 mg, 1.1 mmol) and (2,2,4,6,7-pentamethyl-3-pyrrolidinyl-2,3-dihydro-1-benzofuran-5-yl)piperazine obtained in Example 134 in acetonitrile (5 ml) was added 3-methoxyphenethyl methanesulfonate (253 mg) at room temperature. After the mixture was stirred for 16 hours, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate/hexane=4/1) to obtain 186 mg as a free base. The free base was treated with 4N hydrogenchloride in ethyl acetate (10 mL) to obtain 137 mg (yield 25%) of the title compound. mp. 183–185° C. (decomposition) (ethanol-ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:19][N:20]([CH3:29])[C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([NH2:28])=[O:27])[CH2:22]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][N:20]([CH3:29])[C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([NH:28][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:27])[CH2:22]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: CN(C)[C@@H]1CCN(C(N)=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)C1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
A mixture of Example A1 (0.500 g, 1.987 mmol), (R)-3-(dimethylamino)pyrrolidine-1-carboxamide hydrochloride (0.770 g, 3.97 mmol) and Cs2CO3 (1.295 g, 3.97 mmol) and Xantphos (0.230 g, 0.397 mmol) in dioxane (10 mL) was sparged with Ar, treated with Pd2(dba)3 (0.182 g, 0.199 mmol), sparged again with Ar and heated at 100° C. overnight. The mixture was cooled to RT, treated with THF, the solids removed via filtration, washed with THF and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford (R)-3-(dimethylamino)-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (720 mg, 97%). MS (ESI) m/z: 373.1 (M+H+).
Reaction SMILES: ClCCl.C(O[C@@:8]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([C@H:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)(=O)C.[NH3:29]>C(OCC)(=O)C>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:8]([CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[C:15]([S:17]([NH2:29])(=[O:19])=[O:18])[CH3:16]
Reactant: N
Reactant: CC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=C(Cn1cncn1)c1ccc(F)cc1F)S(N)(=O)=O

Procedure:
A dichloromethane (30 ml) solution of (2R,3R)-3-chlorosulfonyl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butyl acetate (2.0 g) was cooled to -30° C., to which was introduced ammonia for 10 minutes. To the mixture was introduced nitrogen to eliminate ammonia. To the reaction mixture was added ethyl acetate (50 ml), then precipitating crystals were collected by filtration, followed by recrystallization from methanol to give 3-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)-2-butene-2-sulfonamide (isomer A, Compound 36, 0.54 g) as colorless crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1([CH3:10])[CH3:9].Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH2:6]/[C:5](=[N:12]\[OH:13])/[CH2:4][C:3]1([CH3:10])[CH3:9]
Reactant: CC1(C)CC(=O)CCC1O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1(C)C/C(=N/O)CCC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
The mixture of 4-hydroxy-3,3-dimethylcyclohexanone (1.0 equiv.), hydroxylamine hydrochloride (2.0 equiv.) and sodium bicarbonate (2.5 equiv.) in MeOH (0.7 M) was stirred at room temperature overnight. The solvent were removed and the residue was passed through a short silica gel column (50% ethyl acetate in petroleum ether) to afford the crude (E)-4-hydroxy-3,3-dimethylcyclohexanone oxime (96% yield) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:8]=1[F:16])C>CO.[Pd]>[F:16][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][CH2:5][C:4](=[O:3])[NH:13]2
Reactant: CCOC(=O)CNc1c(F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=C1CNc2c(F)cccc2N1

Procedure:
To a degassed solution of (2-fluoro-6-nitrophenylamino)acetic acid ethyl ester from Example B2 (2.1 g, 8.7 mmol) in methanol (65 ml) was added palladium on carbon (10%, 600 mg). Hydrogen gas was bubbled through the mixture for 75 mins, filtered through Celite® and reduced in vacuo. The residues was purified by flash chromatography on silica (eluant EtOAc: pet. ether 50:50); yield 1.02 g, 71%.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@@H:8]([NH:13][C@@H:14]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29](F)=[CH:28][C:27]=3F)=[CH:22][CH:21]=2)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][CH2:4]1)#[N:2].C(C1(NC(=O)[C@@H](N[C@@H](C2C=CC(Br)=CC=2)C2SC=CN=2)CC(C)C)CC1)#N.[CH3:62][S:63](C1C=CC(B(O)O)=CC=1)(=[O:65])=[O:64]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:3]1([NH:6][C:7](=[O:34])[C@@H:8]([NH:13][C@@H:14]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([S:63]([CH3:62])(=[O:65])=[O:64])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)c1nccs1)C(=O)NC1(C#N)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)NC1(C#N)CC1
Product: CC(C)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)c1nccs1)C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in similar manner to that described for (2S)-2-{(S)-[(2′,4′-difluorobiphenyl-4-yl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid (1-cyanocyclopropyl)-amide, via Suzuki cross-coupling of (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid (1-cyanocyclopropyl)-amide with 4-methanesulfonylphenylboronic acid, in the presence of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), dichloromethane complex.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](N)=[N:4][C:2]1=[O:3].[CH3:9][Si:10]([CH3:17])([CH3:16])[NH:11][Si:12]([CH3:15])([CH3:14])[CH3:13].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>ClCCl>[CH3:9][Si:10]([N:11]([Si:12]([CH3:15])([CH3:14])[CH3:13])[C:8]1[CH:7]=[CH:5][NH:4][C:2](=[O:3])[N:1]=1)([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Nc1cc[nH]c(=O)n1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Temperature: 27 °C

Procedure:
To 5.78 g of cytosine were added 112 ml of hexamethyldisilazane and 50 mg of ammonium sulfate. The mixture was heated to 115° C.-120° C. for 3 hours with stirring and the excess hexamethyldisilazane was subsequently removed. This solution was then cooled to 27° C. and a solid residue formed which was reconstituted in 35 ml of dichloromethane to form a homogenous bis-trimethylsilylcytosine solution.