Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C)([O-])=O.C[C:6]([O:8][CH2:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21])=O.C(=O)(O)[O-].[Na+].Cl>[Cl-].[Zn+2].[Cl-].O.CO>[NH2:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH2:9][O:8][CH3:6])[CH2:19][S:18][C@H:13]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 10 ml of nitromethane were added 2.72 g of 7-ACA, 2.7 g of methanol, 5.0 g of zinc chloride and 4.0 g of ferric chloride. The mixture was heated at 50° C. for 30 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 150 ml of water. Then, the mixture was adjusted to pH 7.5 with sodium bicarbonate at a temperature of from 2° C. to 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was concentrated by evaporation under reduced pressure, and adjusted to pH 7 with 1N HCl. Then, the mixture was applied to the same column as used in Example 2. The elution was conducted using water as an eluent to obtain an eluate. The eluate was adjusted to pH 3.5 with 36 % hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.63 g. The yield of the desired product was 67 %.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl-].C[Al+]C.[CH3:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][N:12]=1.O>ClCCl.CCCCCC>[CH3:2][N:3]([O:4][CH3:5])[C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([CH3:10])=[N:12][CH:13]=1
Reactant: CNOC
Reactant: COC(=O)c1ccc(C)nc1
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: CON(C)C(=O)c1ccc(C)nc1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (710 mg, 7.28 mmol) was suspended in dichloromethane (50 mL). To this, dimethylaluminum chloride (a 1.04 mol/L solution in hexane, 7.00 mL, 7.28 mmol) was slowly added under a nitrogen atmosphere at 0° C. and the mixture was stirred at the same temperature for 1 hour. To this, methyl 6-methylnicotinate (1.00 g, 6.62 mmol) was added, and (7.00 mg, 1.88 mmol) was added at room temperature. Then, water was added to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give 6-methylnicotinic acid N,O-dimethylhydroxylamide (737 mg, yield: 62%).
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:18]([NH2:20])=[O:19])=[C:5]([F:28])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:28])=[CH:4][C:3]([C:1]([NH2:2])=[O:35])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccccn3)C(N)=O)c(F)cc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccccn3)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-(pyridin-2-yl)propanamide (53 mg, 0.133 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (16 mg). MS 415.1 (M+H); UV 214.4, 278.0, 302.6 nm.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].[C:11]([C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21](OCC)=[O:22])[CH:16]=[CH:17][CH:18]=1)#[N:12].C(N(CC)CC)C>C(O)C>[CH2:7]([N:9]1[C:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:11]#[N:12])=[CH:20][C:21](=[O:22])[NH:10]1)[CH3:8]
Reactant: CCOC(=O)C#Cc1cccc(C#N)c1
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1[nH]c(=O)cc1-c1cccc(C#N)c1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
Ethyl hydrazine oxalate (4.01 g, 26.7 mmol, 1.50 equiv) was added to a solution of ethyl 3-(3-cyanophenyl)prop-2-ynoate (3.55 g, 17.8 mmol, 1 equiv) and triethylamine (3.73 mL, 26.7 mmol, 1.50 equiv) in ethanol (180 mL). The reaction mixture was heated to 80° C. for 3.5 hours, then cooled to 22° C. The cooled reaction mixture was concentrated by rotary evaporation, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 3-(2-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (3.5 g, 3:1 mixture of regioisomers in favor of desired product). The mixture of regioisomers was used without separating in the next step. Calcd (M+1)+: 214.1. Found: 214.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)#[N:23]>CC(C)=O>[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)#[N:23]
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cccc(CN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c1
Reaction time: 4 h
Yield: 93.1 %

Procedure:
To a stirred solution of 1-(4-nitro-phenyl)-piperazine (35.9 g) and potassium carbonate (71.6 g) in acetone (500 mL) was added dropwise 3-cyano-benzyl bromide (34 g) at room temperature and the mixture was heated under reflux. After 4 hours, the salts were removed by filtration, washed with acetone and the filtrate was evaporated to dryness. The residue was taken in CH2Cl2 and the solution was washed with water, dried over Na2SO4, filtered and evaporated. The oily residue was crystallized from AcOEt/diisopropyl ether to give the title compound (52 g) as orange crystals.
Reaction SMILES: [CH2:1]([C:8]1([CH:17]=[CH:16][C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH2:13]1)[CH2:9][CH:10]([OH:12])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=[O:28])[CH:26]=[CH2:27].CC1C=CC(S(O)(=O)=O)=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C1(C)C=CC=CC=1>[C:25]([O:12][CH:10]([NH2:11])[CH2:9][C:8]1([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:14][C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH2:17]1)(=[O:28])[CH:26]=[CH2:27]
Reactant: NC(O)CC1(Cc2ccccc2)C=CC(Cc2ccccc2)=CC1
Reactant: C=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: Cc1ccccc1
Product: C=CC(=O)OC(N)CC1(Cc2ccccc2)C=CC(Cc2ccccc2)=CC1
Temperature: 80 °C

Procedure:
In a three-aperture flask, 10.5 g (33 mmol) of p-dibenzyl-aminophenethyl alcohol, 9.51 g (132 mmol) of acrylic acid, 0.56 g (3.3 mmol) of p-toluene sulfonate, and 30 mL of dehydrated toluene were poured, and the mixture was heated at 80° C. under an argon atmosphere with stirring. To the reaction solution, 3.8 g (18.2 mmol) of dicyclohexylcarbodimide and 2.5 g (16.5 mmol) of 4-pyrrolidinopyridine were added, and the reaction solution was further heated with stirring for 5 hours. The reaction solution was cooled to the room temperature and then diluted with toluene, followed by washing with water three times. The toluene solution was dried with anhydrous magnesium sulfate, and then the solvent was distilled away to purify the toluene solution by silica gel chromatography using a mixture solvent of hexane/ethyl acetate (4/1) as an eluent to thereby synthesize 4.05 g (yield: 33% by mass) of p-dibenzyl-aminophenethyl acrylate of the exemplified compound No. 23 represented by the following structural formula.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[CH2:28]([NH:35][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[N:10]=[C:2]([Cl:1])[CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCc2ccccc2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 2-chloro-6-methoxyisonicotinic acid (4.90 g, 26.00 mmol, prepared according to Okajima S., Yakugaku Zasshi, (1953), 73, 845-847) and 4-methylmorpholine (3.3 mL, 30.00 mmol) in tetrahydrofuran (100 mL) was added isobutyl chloroformate (3.8 mL, 28.00 mmol) at 0° C. The resulting solution was stirred at ambient temperature for 1 hour, followed by the addition of benzylamine (4.2 mL, 38.00 mmol). The reaction mixture was stirred at ambient temperature for 20 hours, diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL). The organic solution was dried over anhydrous sulphate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate and hexanes to give N-benzyl-2-chloro-6-methoxyisonicotinamide (6.20 g, 86%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 7.18 (s, 1H), 6.94 (s, 1H), 6.43 (br s, 1H), 4.58 (d, J=5.7 Hz, 2H), 3.94 (s, 3H); MS (ES+) m/z 277.4 (M+1).
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O:23][CH:24](OCC)[C:25]#[CH:26])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(=O)CCCCC1>[O:2]=[C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:26][C:25]([CH:24]=[O:23])=[C:6]2[N:7]1[CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=12
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccsc1-2
Reactant: C#CC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [OH-]
Solvent: O=C1CCCCC1
Product: O=Cc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2

Procedure:
A mixture of 0.855 g of 5,6-dihydro-3-hydroxy-2-phenylthiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) and 0.65 ml of 3,3-diethoxypropyne in 30 ml of cyclohexanone was stirred with a few crystals of p-toluenesulfonic acid at 130° for 3 hours under an inert gas and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed with 10 percent potassium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, concentrated and chromatographed on silica gel with toluene/acetonitrile (19:1). By crystallization from dioxane, there is obtained 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxaldehyde of m.p. 213°-215°.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][CH3:9])=[CH:5][N:6]=1.CS[C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([CH3:9])[C:12]([NH:13][N+:14]([O-:16])=[O:15])=[NH:17])=[CH:5][N:6]=1
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CNCc1cnc(Cl)s1
Solvent: CCO
Product: CN(Cc1cnc(Cl)s1)C(=N)N[N+](=O)[O-]
Yield: 47.9 %

Procedure:
A mixture of 1.50 g of 2-chloro-N-methyl-5-thiazolemethanamine, 1.13 g of S-methyl-N-nitroisothiourea and 6 ml of ethanol was heated under reflux for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Solvent: Chloroform/Methanol=20/1) to obtain 1.00 g of the title compound as crystals. This compound is No. 6 in Table 1. m.p.: 116.0°-117.0° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)#[N:20]>C1COCC1.CC(OC)(C)C.[NH4+].[Cl-]>[C:19]([C:21]1[CH:28]=[CH:27][C:24](/[CH:25]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
A flame dried three-neck round-bottom flask equipped with a magnetic stirring bar, a thermometer, an addition funnel and a nitrogen inlet was charged with NaH (3.96 g, 94.7 mmol) and anhydrous THF (120 mL). Tert-butyl diethylphosphonoacetate (23.2 mL, 94.7 mmol) dissolved in anhydrous THF (20 mL) was added dropwise via the addition funnel over a period of 30 min. After the completion of addition, the reaction mixture was stirred at rt for another 30 min. A solution of 4-cyanobenzaldehyde (11.3 g, 86.1 mmol) dissolved in anhydrous THF (20 mL) was added to the reaction mixture dropwise via the addition funnel over a period of 30 min. After the end of the addition, the reaction mixture was stirred at rt for 1 h, then diluted with MTBE (200 mL) and sat. NH4Cl (150 mL). The organic layer was separated, washed with 25 mL of water and 25 mL of sat. NH4Cl, dried over MgSO4, filtered and evaporated to dryness to give 20.0 g title compound as a solid (100%). 1H NMR (400 MHz, CDCl3) δ ppm 1.56 (s, 9H) 6.47 (d, J=16 Hz, 1H) 7.58 (d, J=16 Hz, 1H) 7.61 (d, J=8 Hz, 2H) 7.68 (d, J=8 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:27]C(=O)C)[C@H:17]([C:31]([OH:33])=[O:32])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O.Cl>CO>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[C@H:17]([C:31]([OH:33])=[O:32])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@H]1[C@H](C(=O)O)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C[C@@H](C(=O)O)[C@@H]2O
Temperature: 50 °C
Yield: 69.1 %

Procedure:
A solution of 784.4 mg (1.75 mmol) of 6, 5% aqueous KOH in MeOH (7 mL) was stirred and heated at 50° C. for 3 h. Reaction was cooled to rt, poured into H2O (50 mL), adjusted to pH 1 with 10% aqueous HCl, and extracted with EtOAc (3×, 100 mL). Combined organic extracts were washed with H2O (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification of the residue by flash chromatography on a 2×17 cm column of silica gel using EtOH/EtOAc (10:90) gave 491.5 mg (69%) of 7 as a white foam. Data for 7: TLC, T-4, Rf0.63. 1H NMR (500 MHz, CDCl3) δ 0.86 (2, 3H, H-18), 3.94 (d, 1H, J=8.3 Hz, H-17α), 5.04 (s, 2H, benzylic), 6.73 (d, 1H, J=2.2 Hz, H-4), 6.80 (dd, 1H, J=8.7, 2.2 Hz, H-2), 7.21 (d, 1H, J=8.7 Hz, H-1), 7.32-7.45 (m, 5H, Ar—H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>>[Cl:19][CH2:20][CH2:21][CH2:22][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: ClCCCI
Reactant: O=C1COc2cc(F)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2cc(F)ccc2N1CCCCl
Yield: 104.6 %

Procedure:
7-Fluoro-4H-benzo[1,4]oxazin-3-one (81MF763) (0.263 g, 1.57 mmol), Cs2CO3 (0.769 g, 2.36 mmol) and 3-chloro-1-iodopropane (0.354 g, 1.73 mmol) were mixed according to GP5 giving the crude title compound (0.40 g); 1H NMR (CDCl3) d 7-01-6.91 (m, 1H), 6.79-6.73 (m, 2H), 4.60 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.4 Hz, 2H, 2.18-2.11 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH:12]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:4]([F:23])[CH:3]=1.CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[S:9]([CH:12]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:4]([F:23])[CH:3]=1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CCCCC1S(=O)(=O)N(C)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 1; 250 mg) obtained in Example 1 was 1.60 g) in N,N-dimethylformamide (2.5 ml), methyl iodide (118 mg), potassium carbonate (191 mg) were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (30 ml), washed with water (30 ml×2) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1/4) to yield ethyl 6-[N-(4-chloro-2-fluorophenyl)-N-methylsulfamoyl]-1-cyclohexene-1-carboxylate (Compound 2; 250 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([CH2:22][OH:23])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@H:12]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
278.0 mg (0.8 mmol) tert. Butyl (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-hydroxymethyl-pyrrolidine-1-carboxylate are dissolved in 6 ml DCM and combined with 216 μl (1.5 mmol) triethylamine. 89 μl (1.2 mmol) methanesulphonic acid chloride are added while cooling with the ice bath. The reaction mixture is heated to RT and stirred for two hours. Then it is mixed with water and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: COC1C=CC(O)=C(C2OC3C=CC=C(CNCC4C=CC=CN=4)C=3N=2)C=1.[CH3:28][O:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][C:33]([C:38]2[O:39][C:40]3[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][NH:48][CH2:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=4)[C:41]=3[N:42]=2)=[C:32]([O:56]COC)[CH:31]=1>>[CH3:28][O:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][C:33]([C:38]2[O:39][C:40]3[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][NH:48][CH2:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=4)[C:41]=3[N:42]=2)=[C:32]([OH:56])[CH:31]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Agent: COc1ccc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)c1
Product: COc1cc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)cc1OC

Procedure:
2-(4,5-dimethoxy-2-hydroxyphenyl)-4-(2-pyridylmethyl)aminomethyl-benzoxazole (F26) was prepared in a similar manner for the preparation of 2-(5-methoxy-2-hydroxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F23) using 2-(4,5-dimethoxy-2-methoxymethoxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F17) (100 mg, 0.23 mmol) instead of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F16) in 92% (83 mg); 1H-NMR (500 MHz, CDCl3) δ3.95 (s, 3H), 3.96 (s, 3H), 4.01 (s, 2H), 4.21 (s, 2H), 6.66 (s, 1H), 7.17 (dd, 1H, J=7.5, 5.0 Hz), 7.31 (t, 1H, J=8.0 Hz), 7.37-7.40 (m, 2H), 7.41 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.67 (t, 1H, J=7.5 Hz), 8.66 (d, 2H, J=5.0 Hz), 11.27 (s, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:12]1[C:13]([Cl:28])=[C:14]([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:18][N:19]=1)[C:15]#[N:16].[Cl:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32]>C1COCC1>[Cl:28][C:13]1[C:12]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[Cl:29])=[N:19][CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[C:14]=1[C:15]#[N:16]
Reactant: COc1cccc(-c2cnc(Cl)c(Cl)c2C#N)c1
Reactant: Nc1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(-c2cnc(Nc3ccccc3Cl)c(Cl)c2C#N)c1
Reaction time: 1 h
Yield: 20.8 %

Procedure:
A 1 M solution of lithium bis(trimethylsilyl)amide (0.573 mL, 0.573 mmol) was added to a solution of 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (40 mg, 0.143 mmol, from Step 3 of Example 128) and 2-chloroaniline (36.6 mg, 0.287 mmol) in THF (2 mL) at room temperature. After 1 h at room temperature, LCMS and HPLC analysis indicated that a 1:2 mixture of two products were formed. The reaction mixture was quenched with saturated sodium bicarbonate (5 mL) and diluted with ethyl acetate (60 mL), washed with water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 5-20% ethyl acetate in hexanes, gave 3-chloro-2-(2-chlorophenylamino)-5-(3-methoxyphenyl)isonicotinonitrile as yellow solid (11 mg, 21% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.51-8.63 (1H, m), 8.35 (1H, s), 7.87 (1H, s), 7.38-7.51 (2H, m), 7.29-7.37 (1H, m), 6.97-7.16 (4H, m), 3.88 (3H, s); MS (ES+) m/z: 370 (M+H); LC retention time: 4.28 min (analytical HPLC Method A). The minor product was found to be 2-chloro-3-(2-chlorophenylamino)-5-(3-methoxyphenyl)isonicotinonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:14]=1.C(O)C.O1CCCC1>ClCCl>[CH2:13]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)[CH3:14]
Reactant: CN1CCc2c(O)cccc2C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1cccc2c1CCN(C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 5-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.5 g, 3.07 mmol), triphenylphosphine (1.0 g, 3.83 mmol) and ethanol (0.27 mL, 4.61 mmol) in dry tetrahydrofurane 0.597 mL (3.83 mmol) diethyldiazodicarboxylate was added dropwise. After the reaction mixture was stirred at r.t. overnight, it was diluted with dichloromethane, washed with water, and the product was extracted into dilute aqueous hydrochloric acid solution, which was washed with dichloromethane. The aqueous phase was made alkaline with aqueous sodium hydroxide, and extracted with dichloromethane. The dichloromethane solution was dried over Na2SO4 and evaporated. The product was purified by silicagel chromathography (System E) and recrystallised from absolute ethanol. Yield 0.586 g, 48%. 1H NMR (CDCl3): 7.07 (1H, t, 8.1 Hz), 6.64 (2H, m), 4.01 (2H, q, 7.1 Hz), 3.55 (2H, s), 2.81 (2H, t, 6.1 Hz), 2.67 (2H, t, 6.1 Hz), 2.44 (3H, s), 1.40 (3H, t, 6.8 Hz). 13C NMR (CDCl3): 156.5, 135.9, 126.1, 123.0, 118.4, 108.3, 63.3, 57.9, 52.7, 46.0, 23.8, 14.9; MS (EI+): 191 (83%), 190 (100%), 162 (15%), 160 (16%), 148 (61%), 120 (28%), 104 (48%); Rt (HPLC)=8.1 min.