Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([F:28])=[CH:23][N:22]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]2[O:34][CH2:35][C:36](=[O:40])[NH:37][C:38]=2[N:39]=1>>[Cl:20][C:21]1[N:26]=[C:25]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[O:34][CH2:35][C:36](=[O:40])[NH:37][C:38]=3[N:39]=2)[C:24]([F:28])=[CH:23][N:22]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(n1)NC(=O)CO2
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: O=C1COc2ccc(Nc3nc(Cl)ncc3F)nc2N1

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one were reacted to yield 2-chloro-5-fluoro-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 4.63 (s, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 8.33 (d, J=3.3 Hz, 1H), 10.14 (s, 1H, NH), 11.19 (s, 1H, NH); 19F NMR (282 MHz, DMSO-d6): δ −152.35; LCMS: ret. time: 26.74 min.; purity: 85.90%; MS (m/e): 296.13 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:24][C:25]1[CH:30]=[C:29]([S:31][CH3:32])[CH:28]=[CH:27][C:26]=1[NH2:33].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[NH:33][C:26]1[CH:27]=[CH:28][C:29]([S:31][CH3:32])=[CH:30][C:25]=1[F:24]
Reactant: CSc1ccc(N)c(F)c1
Reactant: COC(=O)c1ccc(CNC=O)nc1Cl
Agent: [Pd]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CNC=O)nc1Nc1ccc(SC)cc1F
Temperature: 100 °C
Reaction time: 25 h
Yield: 22.8 %

Procedure:
To a solution of 2-chloro-6-formylaminomethyl-nicotinic acid methyl ester (123 mg, 0.54 mmol) in toluene (1.6 mL) was added potassium phosphate (119 mg, 0.76 mmol), 2-fluoro-4-methylsulfanyl-phenylamine (102 mg, 0.65 mmol), tris(dibenzylideneacetone)dipalladium (12.8 mg, 0.014 mmol) and dicyclohexyl-(2′,6′-diisopropoxy-biphenyl-2-yl)-phosphane (25 mg, 0.054 mmol). The reaction mixture was degassed with argon then heated at 100° C. After 25 hours, the reaction mixture was cooled, diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride, water then brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated with ethyl acetate to afford the title compound as a bright yellow solid (43 mg, 23%). LCMS (method B): RT=3.53 min, [M+H]+=350.
Reaction SMILES: [N:1]([CH:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([C:16]([CH3:19])([CH3:18])[CH:15]=[CH:14][C:13]=3[CH3:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:19][C:16]1([CH3:18])[C:17]2[C:12]([CH:11]=[C:10]3[C:9]=2[CH:8]=[N:7][N:6]3[CH2:5][CH:4]([NH2:1])[CH3:21])=[C:13]([CH3:20])[CH:14]=[CH:15]1
Reactant: CC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2C(C)(C)C=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: CC1=C2C=c3c(cnn3CC(C)N)=C2C(C)(C)C=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
1.1 g (3.9 mmol) of (RS)-1-(2-azido-propyl)-4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 60 ml of anhydrous ethanol were hydrogenated over 110 mg of platinum oxide for 3 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 150 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 453 mg (3.9 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 4 hours and the white crystals were subsequently filtered off. 1 g (69%) of (RS)-2-(4,4,7-trimethyl-1,4-dihydroindeno[2,1-c]pyrazol-1-yl )-1-methyl-ethylamine fumarate (1:1) with m.p. 167° was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:9])[F:10])[C:3]=1[CH2:11][OH:12]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1nc(C(F)F)c(CO)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
A solution of 7.2 g (37.0 mmoles) of 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde dissolved in 100 ml of methanol was cooled to 0° C. Thereto was gradually added 2.1 g (55.5 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.8 g (yield: 52.1%) of (5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][CH:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:13](=[O:14])[CH:12]([CH3:11])[CH2:16][CH3:17]
Reactant: CCC(C)C(=O)Cl
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(C)C(=O)c1ccc(OC)c(Cl)c1Cl

Procedure:
By following the procedure described in Example 5, Step A, using as the reactants 2,3-dichloroanisole (100 g., 0.565 mole), 2-methylbutyryl chloride (.75 g., 0.62 mole), aluminum chloride (84 g., 0.62 mole) and methylene chloride (400 ml.), there is obtained 2',3'-dichloro-4'-methoxy-2-methylbutyrophenone.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2.Cl[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[CH3:20][C:19]([Si:16]([CH3:18])([CH3:17])[O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2)([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCc2cc(C#CCO)ccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc2c(c1)CCC2=O
Reaction time: 10 h
Yield: 93.3 %

Procedure:
5-(Hydroxyprop-1-yn-1-yl)-2,3-dihydro-1H-indene-1-one (1.03 g, 5.42 mmol) was dissolved in DMF and treated with chloro-tert-butyldimethylsilane (981 mg, 6.51 mmol), imidazole (443 mg, 6.51 mmol) at 0° C. The reaction mixture was allowed to reach ambient temperature. After 10 h, the reaction mixture was extracted with ethyl acetate (100 mL×3), washed with water, brine and dried over MgSO4. The organic layer was concentrated under vacuum and purified by flash column chromatography to yield the 5-(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-2,3-dihydro-1H-inden-1-one (1.54 g, 94% yield): 1H NMR (400 MHz, CDCl3): δ 7.63 (d, 1H), 7.59 (s, 1H), 7.42 (d, 1H), 4.45 (t, 2H), 3.10 (m, 2H), 2.78 (m, 2H), 2.64 (m, 2H), 1.82 (m, 2H), 0.95 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([O:26][C:27](=[O:29])[CH3:28])=[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:3].[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][C@@H:45]([NH2:52])[C:46]3[O:50][N:49]=[C:48]([CH3:51])[N:47]=3)=[CH:40][CH:39]=2)[CH:34]=[CH:35][C:36]=1[F:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][C@@H:45]([NH:52][C:2]([C:4]3[C:5]([O:26][C:27](=[O:29])[CH3:28])=[C:6]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:7]=[C:8]([C:10]4[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=4)[CH:9]=3)=[O:3])[C:46]3[O:50][N:49]=[C:48]([CH3:51])[N:47]=3)=[CH:40][CH:39]=2)[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: CC(=O)Oc1c(C(=O)Cl)cc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccccc1
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Product: CC(=O)Oc1c(C(=O)N[C@H](Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)c2nc(C)no2)cc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccccc1
Yield: 40 %

Procedure:
Acetic acid 5′-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylcarbamoyl]-4-trifluoromethyl-[1,1 ′;3′,1″]terphenyl-4′-yl ester (0.04 g ) was prepared from Acetic acid 5′-chlorocarbonyl-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-4′-yl ester (0.06 g, 0.14 mmol) [prepared from 4′-Hydroxy-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid following general procedures K & L.] and 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (0.047 g,0.14 mmol) following general procedure M.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:10](C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O.[Cl-].[Li+]>CS(C)=O.[Cl-].[Na+].O>[N+:1]([C:4]1[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ncccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 93 %

Procedure:
Diethyl (3-nitropyridin-2-yl)-malonate (12.5 g, 0.044 mol) was dissolved in DMSO (150 mL), and water (0.79 mL, 0.044 mol) and lithium chloride (4.65 g, 0.11 mol) were added at room temperature under nitrogen. The reaction was warmed to 100° C. for 12 h, and more lithium chloride (1 g) was added to the reaction. The reaction was heated for another 5 hours and cooled to room temperature. Brine (150 mL) was added, and the reaction mixture was extracted with EtOAc (3×275 mL). The extracts were combined, dried over sodium sulfate and concentrated in vacuo. The resulting residue was triturated with diethyl ether and collected by filtration to yield the title compound (8.6 g, 92% yield). 1H NMR 400 MHz (DMSO-d6): δ 8.83 (m, 1H); 8.53 (m, 1H); 7.65 (m, 1H); 4.23 (s, 2H); 4.07 (m, 2H); 1.16 (m, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][NH:24][C:25]([NH2:27])=[S:26]>O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1](=[N:23][NH:24][C:25]([NH2:27])=[S:26])([C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: O=C(c1ccccc1)c1cccc(C(O)c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: NC(=S)NN=C(c1ccccc1)c1cccc(C(O)c2ccccc2)c1
Reaction time: 48 h
Yield: 57.9 %

Procedure:
p-toluenesulfonic acid (0.007 g, 0.03 mmol) was added to a solution of 3-benzoyl benzhydrol 5 (0.396 g, 1.09 mmol) in anhydrous tetrahydrofuran (10 mL). After stirring at reflux for 10 min, thiosemicarbazide (0.199 g, 2.19 mmol) was added to the reaction mixture and stirred for 2 days under an inert atmosphere of nitrogen gas. After 2 days, tetrahydrofuran was removed under reduced pressure and water (50 mL) was added. The products were extracted with ethyl acetate (2×20 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 88:12 to 0:100) afforded 3-benzoyl benzhydrol thiosemicarbazone 6 (0.228 g, 0.631 mmol) as a white solid in a 57% yield. HRMS (ESI) calculated for C21H19N3OSH+ (M+H)+ 362.1321, found 362.1336.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])[CH3:3]>C(OCC)(=O)C>[CH:2]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])([CH3:3])[CH3:1]
Reactant: C=C(C)c1cccc(C#N)c1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C#N)c1
Reaction time: 16 h

Procedure:
To 3-(prop-1-en-2-yl)benzonitrile (1.2 gm, 8.3 mmol) in ethyl acetate (30 ml) 10% Pd/C (120 mg) was added and stirred under hydrogen atmosphere for 16 h. Then the reaction mixture was filtered and solvent evaporated to obtain 3-isopropylbenzonitrile in quantitative yield.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:19][C:20]5([CH2:21][CH2:22][N:23]([C:29]6[N:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=6)[CH2:24][CH2:25]5)[CH2:26]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(c4ncc(C(F)(F)F)cn4)CC3)C2)CC1
Reaction time: 8 h

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-chloro-5-trifluoromethyl-pyrimidine following a procedure analogous to that described for Example 15; the reaction is conducted at 45° C. overnight. LC (method 6): tR=1.09 min; Mass spectrum (ESI+): m/z=536 [M+H]+.
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][N:7]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:19][C:20]1[CH:21]=[N:22][C:23]([Cl:26])=[N:24][CH:25]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CCOCC.O.C1COCC1>[Br:19][C:20]1[C:21]([C:16]2[S:15][C:14]([N:7]([CH3:6])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[N:18][CH:17]=2)=[N:22][C:23]([Cl:26])=[N:24][CH:25]=1
Reactant: CN(c1ccccc1)c1nccs1
Reactant: Clc1ncc(Br)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccccc1)c1ncc(-c2nc(Cl)ncc2Br)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tBuLi (2.9 mL, 1.1 M solution in pentane, 3.0 mmol) was added to a stirred solution of 0.52 g (2.8 mmol) of 2-(N-Methyl-N-phenylamino)thiazole in 10 mL of Et2O at −78° C. The solution was stirred for 30 min at −78° C. before 0.59 g (3.0 mmol) of 5-bromo-2-chloropyrimidine and 10 mL of THF were added. The reaction solution was stirred for 30 min at −78° C., and then quenched by the addition of 5 mL of AcOH in 15 mL of MeOH. Solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.4 g, 6.1 mmol) was added and the reaction solution was warmed to 0° C. and stirred for 10 min, then poured into 100 mL of a 0.5 M solution of sodium ascorbate, diluted with 300 mL of water and the crude product removed by filtration and washed repeatedly with water. The residue was azeotroped with toluene and purified by flash chromatography eluting with a linear gradient of 10% EtOAc in hexane to 100% EtOAc to deliver the title compound. MS (M+H)+ 383.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C@H:20]2[O:37][C@H:36]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:11][C@H:6]1[O:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].C[O-].[Na+].[OH-].[Na+].CCOCC>CO.O.C(OC(=O)C)(=O)C.N1C=CC=CC=1.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C@H:20]2[O:37][C@H:36]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:11][C@H:6]1[O:7][CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCO[C@@H]1O[C@H](COC(C)=O)[C@H](O[C@H]2O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromoethyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-β-D-galactopyranoside (15) (740 mg; 1 mmol) was dissolved in methanol (14 ml) by heating. Sodium methoxide in methanol (0.1M; 2 ml) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium hydroxide (87 mg; 2.2 mmol) in water (2 ml) was added together with the catalyst (10% Pd/C; 120 mg) and the reaction mixture was hydrogenated (15 h) at atmospheric pressure. Filtration (Celite) and evaporation (<0.1 torr) gave a colorless, amorphous residue that was suspended in a mixture of acetic anhydride and pyridine (1:1; 10 ml). The reaction mixture was stirred (75°; 3 h), cooled and poured into ether (50 ml). The ether solution was washed (water, sat. sodium hydrogen carbonate solution, water), dried (sodium sulfate) and evaporated (<0.1 torr) which gave 33 as a crystalline residue that was pure by TLC (SiO2, ethyl acetate:isooctane 3:1). Yield: 650 mg (98%). Recrystallization from methanol-water gave an analytical sample (needles): mp 133°-135°; [α]D22 +81.4° (c 0.9; CHCl3); 1H-NMR (CDCl3, TMS) δ 5.57 (d, 1H, H4'), 5.39 (dd, 1H, J3',4' =3.2 Hz, H3'), 5.20 (dd, 1H, J2',3' =11.0 Hz, H2'), 5.18 (dd, 1H, J2,3 =10.8 Hz, H2), 5.01 (d, 1H, J1',2' =3.5 Hz, H1'). 4.82 (dd, 1H, J3,4 =2.6 Hz, H3), 4.48 (d, 1H, J1,2 =7.9 Hz, H1), 4.06 (d, 1H, H4), 3.92, 3.59 (dq, 1H each, J=9.7 and 7.1 Hz, CH3 --CH2 --O), 2.13, 2.11, 2.08, 2.075, 2.06, 2.04, 1.99 (s, 3H each, CH3 --CO), 1.22 (t, 3H, J=7.1 Hz, CH3 --CH2 -- O) ppm. 13C-NMR (CDCl3, TMS) δ 170.7, 170.6, 170.5, 170.4, 170.1, 169.7, 169.1 (CH3 --CO), 100.9 (Cl), 99.4 (Cl'), 77.2, 72.8, 71.9, 68.8, 68.6, 67.9, 67.4, 67.1 (C2-C5, C2'-C5'), 65.4 (CH2 --CH3), 62.1, 60.5 (C6, C6'), 21.0, 20.8, 20.7, 20.6 (CH3 --CO), 15.1 (CH2 --CH3) ppm.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(OC)(OC)OC>[Cl-].[Zn+2].[Cl-].S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 0.93 g of ferric chloride, 5.25 g of zinc chloride and 3.13 ml of trimethyl borate. The mixture was heated at 50° C. for 5 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.89 g. The yield of the desired product was 70%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[C:26]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]1([C:2]2[N:7]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:24]=[CH:23][C:17]5[O:18][C:19]([F:22])([F:21])[O:20][C:16]=5[CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[CH:5]=[CH:4][C:3]=2[CH3:25])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1C1=CCCCC1
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (110 mg, 0.300 mmol) was dissolved in 3 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. Cyclohexenylboronic acid (49.1 mg, 0.390 mmol), 0.4 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 17 mg, 0.015 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The organic layer was evaporated to dryness and the residue was purified on silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield N-(6-cyclo-hexenyl-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide. ESI-MS m/z calc. 412.2. found; 413.0 (M+1)+. Retention time 1.79 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[N:30]([CH2:36][CH2:37][O:38][CH3:39])[C:29]=2[CH:40]=1>>[F:19][C:18]1[C:9]([NH:8][C:6]2[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=[C:2]([NH:24][C:25]3[CH:26]=[CH:27][C:28]4[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[N:30]([CH2:36][CH2:37][O:38][CH3:39])[C:29]=4[CH:40]=3)[N:7]=2)=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: COCCN1C(=O)CCCc2ccc(N)cc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CCOC)C(=O)CCC3)ncc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide and 8-amino-1-(2-methoxyethyl)-1,3,4,5-tetrahydrobenzo[b]azepin-2-one in an analogous manner to Example 195 (microwave: 120° C., 2 hours) to afford a white solid (30 mg, 50%). Mp: 142-4° C. LCMS (m/e) 547 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.03 (s, 1H), 8.35 (s, 1H), 7.56 (s, 1H), 7.47 (br s, 1H), 7.36 (m, 1H), 7.28 (m, 1H), 7.20 (m, 1H), 7.01 (br s, 2H), 3.40 (m, 2H), 3.26 (s, 3H), 2.94 (d, J=5 Hz, 3H), 2.66 (br m, 2H), 2.23 (br s, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][CH:6]=1.C(O)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:19][CH3:20]>>[CH3:3][O:4][C:5]1[N:10]=[N:9][C:8]([C:11](=[O:13])[CH:19]([CH3:20])[C:18]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC
Reactant: COC(=O)c1ccc(OC)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)C(=O)c1ccc(OC)nn1
Yield: 52.5 %

Procedure:
Ethyl 3-(6-methoxypyridazin-3-yl)-2-methyl-3-oxopropionate is prepared by the fractional addition, over a period of 20 minutes, of sodium hydride (19.2 g) (50% in mineral oil) to a solution of methyl 6-methoxypyridazine-3-carboxylate (50 g) in ethyl propionate (220 g) at a temperature of about 98° C. The reaction mixture is maintained under reflux for a further 30 minutes. It is subsequently cooled to a temperature of about 20° C., and ethanol (10 cc) is added with care, followed by distilled water (800 cc). The aqueous phase is removed, washed by decantation with diisopropyl ether (3 × 250 cc), pure acetic acid (250 cc) is added (pH = 5-6) and the aqueous phase is washed again with ethyl acetate (3 × 150 cc). The organic phases are combined, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (30 mm Hg) to give ethyl 3-(6-methoxypyridazin-3-yl)-2-methyl-3-oxopropionate (37.2 g) in the form of a yellow oil.