Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.C(O)(C)C>CC(O)CCC.Cl>[ClH:2].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[N:5][CH:4]=2)=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCOCC1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)cnnc2cc1OCCCN1CCOCC1
Temperature: 120 °C
Yield: 106.3 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)cinnoline hydrochloride (150 mg, 0.36 mmol), (prepared as described for the starting material in Example 12), 4-chloro-2-fluoroaniline (77 mg, 0.53 mmol) in 2-pentanol (4 ml) and 5M isopropanolic hydrogen chloride (1 ml) was heated at 120° C. for 1 hour. The mixture was allowed to cool and isopropanol was added. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)cinnoline hydrochloride (185 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13](=[N:21][S@@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:9])=[CH:4][CH:3]=1.[CH2:28]([Mg]Br)[CH:29]=[CH2:30]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C@@:13]([NH:21][S@@:22]([C:24]([CH3:26])([CH3:25])[CH3:27])=[O:23])([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:30][CH:29]=[CH2:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NCCC(=N[S@](=O)C(C)(C)C)c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CC[C@](CCN[C@@H](C)c1ccc(Br)cc1)(N[S@](=O)C(C)(C)C)c1ccc(F)cc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of (R)—N-(3-((1S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl) propylidene)-2-methylpropane-2-sulfinamide (13.3 g, 29.3 mmol) in THF (300 mL) was added 1M allylmagnesium bromide (88 mL, 0.088 mol) under nitrogen at −78° C. The mixture was stirred for 2 h. The reaction was quenched with satd aq NH4Cl. The organic phase was separated and concentrated to give crude (R)—N—((R)-1-((S)-1-(4-bromophenyl)ethylamino)-3-(4-fluorophenyl)hex-5-en-3-yl)-2-methylpropane-2-sulfinamide (14 g, 100%), which was used for the next step without further purification.
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.[Br:25][C:26]1[S:30][C:29]([CH2:31]O)=[CH:28][CH:27]=1>CN(C)C=O>[Br:25][C:26]1[S:30][C:29]([CH2:31][N:20]2[CH:19]=[C:18]([Cl:17])[CH:23]=[N:22][C:21]2=[O:24])=[CH:28][CH:27]=1
Reactant: OCc1ccc(Br)s1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1Cc1ccc(Br)s1
Temperature: 40 °C
Yield: 45.2 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (2.25 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (653 mg) and 5-bromo-2-hydroxymethylthiophene (1.351 g) in dry N,N-dimethylformamide (12.5 ml) under nitrogen and then the mixture was heated at 40° C. After 2 h the temperature was increased to 80° C. After 4 h the reaction mixture was evaporated to dryness and the residue triturated with diethyl ether. The solid was collected and crystallised from acetone to give off white crystals of the title pyrimidinone (691 mg), m.p. 217°-220° C., λmax (EtOH) 243.5 nm (ε 13,810), 336 nm (ε 1,190).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C@@H:25]([CH2:35][CH:36]=[CH2:37])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:38](=[O:42])/C=C/C>ClCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C@@H:25]([CH2:35]/[CH:36]=[CH:37]/[CH:38]=[O:42])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(CCCCC)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reactant: C/C=C/C=O
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CCCCCN([C@@H](C/C=C/C=O)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Yield: 74.2 %

Procedure:
A solution of the material from Step 3 (9.5 g, 16.67 mmol) and crotonaldehyde (6.90 mL, 83 mmol) in dichloromethane (183 mL) was heated at reflux. Grubbs' 2nd Generation catalyst (0.71 g, 0.833 mmol) was added, and the reaction mixture was stirred at reflux for 4 hours. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 7.4 g of the title compound. LCMS (M+Na)=620.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6](F)[N:5]1[O:12][CH:13]([F:15])[F:14].[CH2:16]([OH:18])[CH3:17]>>[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([O:18][CH2:16][CH3:17])[N:5]1[O:12][CH:13]([F:15])[F:14]
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOC1=NC(Cl)=NC(N)N1OC(F)F
Reaction time: 0.25 h

Procedure:
1.2 g (0.0466 mol) of 97% sodium hydride were added a little at a time to 150 ml of ethanol at 20°-35° C. and dissolved by stirring for 15 minutes. Then, while stirring at 0° C., 10.0 g (0.046 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine were added, and the mixture was stirred at 0° C. for 1 hour and at 22° C. overnight. The residue from concentration under reduced pressure was taken up in methylene chloride, extracted with water and dried. Concentration yielded 10.6 g (94.6% of theory) of the title compound of melting point 63°-65° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[CH3:18][C:19](=[N:25][S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[CH2:20][C@@H:21]([CH3:24])[CH2:22][CH3:23]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[CH3:17][O:16][C:13](=[O:15])[CH2:14][C@@:19]([CH3:18])([NH:25][S@:26]([C:28]([CH3:30])([CH3:29])[CH3:31])=[O:27])[CH2:20][C@@H:21]([CH3:24])[CH2:22][CH3:23]
Reactant: COC(C)=O
Reactant: CC[C@H](C)CC(C)=N[S@@](=O)C(C)(C)C
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[C@H](C)C[C@@](C)(CC(=O)OC)N[S@@](=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 62.1 %

Procedure:
To a solution of diisopropylamine (3.1 mL, 22.2 mmol) in THF (40 mL) at −78° C. was slowly added butyllithium (14.4 mL, 1.6 M, 23 mmol). The mixture was stirred at 0° C. for 25 minutes and subsequently cooled down to −78° C. Methyl acetate (1.76 mL, 22.2 mmol) in THF (7 mL) was added. After Stirring for 20 minutes, chlorotitaniumtriisopropoxide (11 mL, 46.2 mmol) in THF (10 mL) was added and the resulting mixture was stirred at −78° C. for 20 minutes. (S)-2-Methyl-propane-2-sulfinic acid ((3S)-1,3-dimethyl-pentylidene)-amide (1.9 g, 8.9 mmol) in THF (10 mL) was added. The mixture was stirred at −78° C. overnight. The reaction was quenched by NH4Cl solution (50 mL). The mixture was filtered. The filtrate was extracted by EtOAc (3×70 mL). The EtOAc phase was reduced under reduce pressure and the residue was purified by a silica gel column (Hexane/EtOAc 1:1) to give the titled compound (1.61 g, 62% yield) as a colorless oil: 1H NMR (CDCl3) δ 3.64 (s, 3H), 2.60 (m, 2H), 1.47 (m, 2H), 1.44 (m, 1H), 1.36 (s, 3H), 1.27 (m, 2H), 1.19 (s, 9H), 0.90 (d, J=6.4 Hz, 3H), 0.81 (t, J=7.6 Hz, 3H); MS (APCI) (M+1)+ 292.2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: CCNCC(=O)O
Reactant: Cc1cccc(N=C=S)c1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2cccc(C)c2C)C1=S
Yield: 41.5 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 16.3 g of 2,3-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (10.3 g) as a light pink solid, m.p. 120°-121° C. Anal. Calcd. for. C13H16N2O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.72; H,. 6.44; N, 11.47. Mass spectrum (El, M.+) m/z 248.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[C:5]([C:8](OC)=O)=[N:6][CH:7]=1.[NH2:16][C@:17]([CH3:24])([CH:21]([CH3:23])[CH3:22])[C:18]([NH2:20])=[O:19].CC([O-])(C)C.[K+].O>C1(C)C=CC=CC=1>[CH:21]([C@:17]1([CH3:24])[C:18](=[O:19])[NH:20][C:8]([C:5]2[N:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[C:12]([OH:14])=[O:13])=[N:16]1)([CH3:23])[CH3:22]
Reactant: CC(C)[C@@](C)(N)C(N)=O
Reactant: COC(=O)c1cc(C)cnc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc(C2=N[C@](C)(C(C)C)C(=O)N2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
A stirred mixture of dimethyl 5-methylpyridine-2,3-dicarboxylate (52.25 g, 0.25 mol) and (R)2-amino-2,3-dimethylbutyramide (33.43 g, 0.2563 mol, 96.2% R isomer) in dry toluene is treated with KOt-Bu (29.4 g, 0.2625 mol) at 35° C., stirred at ambient temperatures for 10 minutes, treated with a second portion of KOt-Bu (29.4 g, 0.2625 mol) at 40° C., heated at 80°-85° C. for 1.5-2.0 hr, cooled to room temperature, treated with water and stirred until dissolution of solids is complete. The phases are separated. The aqueous phase is acidified to pH 3 with concentrated HCl, stirred at pH 3 for 10-15 min., and filtered. The aqueous filtrate is extracted with methylene chloride. The filtercake is dispersed in methylene chloride and the dispersion is filtered. The methylene chloride extracts and the methylene chloride filtrate are combined, dried over MgSO4 and concentrated to dryness in vacuo to give the title product as a white solid, 47.3 g, 68.6% yield, 98.1% pure, 97% R isomer by quantitative NMR analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(C)(C)O[C:9]2=[O:15])=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: COc1cc(CCN)ccc1O
Reactant: CC1(C)OC(=O)C(c2ccc(Br)cc2)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(CCNC(=O)C(O)c2ccc(Br)cc2)ccc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Bromo-phenyl)-2,2-dimethyl-[1,3]dioxolan-4-one (15 g, 55 mmol) is dissolved in 50 ml of ethanol. 4-(2-Amino-ethyl)-2-methoxy-phenol hydrochloride (14 g, 69 mmol) and triethylamine (7.0 g, 69 mmol) are added and the mixture is stirred for 72 hours at room temperature. The solvent is removed in vacuum and the residue is extracted with ethyl acetate and 1N hydrochloric acid. The aqueous layer is extracted twice with ethyl acetate and the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The remaining 2-(4-bromo-phenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-acetamide is purified by chromatography on silica gel. 1H-NMR (300 MHz, CDCl3): 2.71 (t, 2H, CH2CH2), 3.54 (t, 2H, CH2CH2), 3.80 (s, 3H, OCH3), 5.59 (s, 1H, CHOH), 6.16 (bs, 1H, NH), 6.52-7.35 (m, 7H, CH arom.).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1>C(O)(=O)C>[OH:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1COc2ccc(O)cc2N1
Solvent: CC(=O)O
Product: O=C1COc2cc([N+](=O)[O-])c(O)cc2N1

Procedure:
Fumic nitric acid (δ 1.52, 2.6 ml, 0.062 mole) in acetic acid (5 ml) was added dropwise under stirring to 6-hydroxy-2H-1,4-benzoxazin-3-(4H)-one (Coupler (1), 10.3 g, 0.062 mole) in acetic acid (100 ml) at room temperature. The 6-hydroxy-7-nitro-1,4-benzoxazin-3-one (6.7 g, 51%) separated as yellow prisms.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][N:19]4[C:23]([CH3:25])([CH3:24])[C:22](=[O:26])[NH:21][C:20]4=[O:27])[N:11]=3)=[CH:7][C:6]=2[CH:28]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:24][C:23]1([CH3:25])[N:19]([CH2:18][CH2:17][NH:16][C:12]2[N:11]=[C:10]([C:8]3[S:9][C:5]4[CH:4]=[CH:3][C:2]([NH:1][CH2:29][C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)=[CH:28][C:6]=4[CH:7]=3)[CH:15]=[CH:14][N:13]=2)[C:20](=[O:27])[NH:21][C:22]1=[O:26]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc(N)ccc3s2)n1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc(NCc4ccncc4)ccc3s2)n1
Temperature: 60 °C
Yield: 27.1 %

Procedure:
1-(2-(4-(5-aminobenzothiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidin-2,4-dione (300 mg, 0.758 mmol) was suspended in dichloromethane (10 mL). Isonicotinaldehyde (97.4 mg, 0.910 mmol), acetic acid (4-5 drops), and sodium triacetoxyborohydride (321 mg, 1.516 mmol) were added, and the mixture was heated to 60° C. for 16 h. The reaction was cooled to room temperature, diluted with a saturated aqueous solution of sodium bicarbonate (15 mL), and extracted with dichloromethane (4×15 mL). The organic layers were combined and then washed in turn with a saturated aqueous solution of sodium bicarbonate (10 mL), deionized water (15 mL), and a saturated aqueous solution of sodium chloride (15 mL). The organic layer was separated, dried over sodium sulfate (200 mg), filtered through a coarse frit (to remove the sodium sulfate), and concentrated in vacuo to give a white solid (100 mg). The crude material was purified by flash chromatography (MeOH/DCM) to yield the title compound as a white powder (20 mg). MS (M+H)+ 488.
Reaction SMILES: S1C2C=CC=CC=2N=C1NN=CC1OC([N+]([O-])=O)=CC=1.[N+:21]([C:24]1[S:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].[NH:31]([C:33]1[S:34][C:35]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:36]=2[N:37]=1)[NH2:32]>>[Cl:42][C:40]1[CH:39]=[CH:38][C:36]2[N:37]=[C:33]([NH:31][N:32]=[CH:29][C:27]3[S:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[S:34][C:35]=2[CH:41]=1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: NNc1nc2ccc(Cl)cc2s1
Agent: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(Cl)cc3s2)s1

Procedure:
The compound 3n was prepared according procedure described for 3a by employing 5-nitrothiophen aldehyde (157 mg, 1 mmol) and 2-hydrazino-6-chloro-benzothiazole (199 mg, 1 mmol) at 70° C. for 2 h (yield 287 mg, 85%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(=[O:5])=[O:4].Cl.[CH3:23][O:24][NH2:25]>C(O)C>[CH3:23][O:24][N:25]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]1[CH:18]=[CH:19][CH:20]=[C:7]([NH:6][S:3]([N:2]([CH3:21])[CH3:1])(=[O:5])=[O:4])[CH:8]=1
Reactant: CON
Reactant: CN(C)S(=O)(=O)Nc1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: CON=C(c1ccccc1)c1cccc(NS(=O)(=O)N(C)C)c1
Yield: 107.7 %

Procedure:
A solution of 3-[N-(dimethylaminosulfonyl)amino]-benzophenone (500 mg) and O-methylhydroxylamine hydrochloride (830 mg) in ethanol (10 ml) is refluxed for 19 hours, and the resultant mixture is concentrated in vacuum. The residue is basified with aqueous sodium hydrogencarbonate and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of silica gel, which is eluted with 3% methanol-methylene chloride. The eluate is concentrated in vacuum to give 3-[N-(dimethylaminosulfonyl)amino]benzophenone O-methyloxime (590 mg) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]1([CH3:19])[CH2:18][O:17]1>CN(C)C=O.O>[CH3:15][C:16]([OH:17])([CH3:19])[CH2:18][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A solution of 3-nitro-1H-pyrazole (prepared in Example 3, 200 mg, 1.77 mmol) in N,N-dimethylformamide (5 mL) was treated with solid potassium carbonate (352 mg, 2.55 mmol) and 2,2-dimethyl-oxirane (314 mL, 3.54 mmol) and placed in a sealed tube and heated to 100° C. for 1 h in an oil bath. After this time the reaction was cooled to 25° C. and diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were then combined and dried over sodium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix Intelliflash system (12 g column, 50% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (175 mg, 54%) as a clear colorless oil: ES-HRMS m/e calcd for C7H11N3O3 (M+H)+ 186.0873, observed 186.0873; 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (s, 6H, 2×CH3), 2.11 (br. s., 1H, OH), 4.18 (s, 2H, NCH2), 6.92 (d, J=2.4 Hz, 1H, Ar), 7.60 (d, J=2.4 Hz, 1H, Ar).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[F:27][CH:28]([F:31])[CH2:29][NH2:30].CCOC(C)=O>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:30][CH2:29][CH:28]([F:31])[F:27])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCC(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NCC(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.5 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.64 g, 1.63 mmol) in CH3CN, was added neat 2,2-difluoroethylamine (0.23 g, 1.97 mmol), dropwise. The reaction was stirred at room temperature until complete by TLC (3.5 h). The reaction was washed with a minimal amount of saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of EtOAc and hexanes (1:1, 2:1, then pure EtOAc, respectively), providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(2,2-difluoroethyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.433 g, 56% yield) 1H NMR (500 MHz, CDCl3) δ 1.99 (s, 3H), 2.00 (s, 3H), 2.03 (s, 3H), 2.06 (s, 3H), 3.83-3.86 (m, 2H), 3.95 (s, 1H), 4.02-4.09 (m, 2H), 4.18-4.23 (m, 1H), 5.05-5.11 (m, 1H), 5.21-5.30 (m, 1H), 5.72 (d, 1H, J=8.6 Hz), 5.94 (t, 1H, J=56.1 Hz), 6.63-6.73 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]([CH2:10][CH2:11][OH:12])[CH3:9].[C:13](Cl)(=[O:23])[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[C:13]([O:12][CH2:11][CH2:10][N:8]([CH3:9])[CH3:7])(=[O:23])/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC=CC(=O)Cl
Reactant: CN(C)CCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCC/C=C/C(=O)OCCN(C)C

Procedure:
Thionyl chloride (8 ml) was added to trans-2-decenoic acid (3.4 g, 0.02 mol) followed by refluxing on a hot water bath for 2 hours. An excessive thionyl chloride was evaporated in vacuo to give 2-decenoic acid chloride. Pyridine (1 ml) was added to a solution of N,N-dimethylaminoethanol (2.0 g, 0.022 mol) in tetrahydrofuran (30 ml) followed by dropping into a solution of 2-decenoic acid chloride in tetrahydrofuran (20 ml). The reaction solution was heated to reflux on a hot water bath for 3 hours, tetrahydrofuran was evaporated in vacuo, water and ethyl acetate were added to the residue to partition and an ethyl acetate layer was collected therefrom. The ethyl acetate layer was washed with water and evaporated followed by purifying by silica gel column chromatography (developer: chloroform) to give the aimed compound as a light brown oily product.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([CH:9]([C:14]([CH3:16])=[CH2:15])[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[N:8]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1OC(C)=O
Yield: 98.3 %

Procedure:
A mixture containing 6.7 g (17.2 mmol) of (2R) methyl 2-((3S,4S)-4-acetoxy-3-benzyloxycarbonylaminoazetidine-2-on-1-yl)-3-methylbut-3-enoate and 1.8 ml of triethylamine in 180 ml of methylene chloride is refluxed for 60 minutes in a nitrogen atmosphere. After cooling of the solution it is washed subsequently with 100 ml aqueous 1N hydrogen chloride solution and 100 ml of saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and evaporated in vacuo. In this way, 6.6 g (98%) of title compound as a pure, noncrystalline solid is obtained. IR spectrum in methylene chloride: 3400, 3000, 1790, 1730, 1510 and 1210 cm-1.
Reaction SMILES: Cl.[C:2]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH2:20])[CH2:14]2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:22]1[C:23]2[C:30]([CH3:31])=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(O)C>[C:2]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][C:22]1[C:23]3[C:30]([CH3:31])=[CH:29][S:28][C:24]=3[N:25]=[CH:26][N:27]=1)[CH2:14]2)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc2ncnc(NC3Cc4ccc(OC(=O)c5ccccc5)cc4C3)c12
Yield: 48.6 %

Procedure:
Using 5-benzoyloxy-2-aminoindan hydrochloride (67 mg, 0.35 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (68 mg, 0.37 mmol), triethylamine (0.52 ml, 3.7 mmol), and ethanol (6 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (70 mg, 0.17 mmol) having the following physical properties: