Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([O:15][CH3:16])[CH2:11][CH2:10]2)[C:5](/[CH:17]=[CH:18]/[C:19](OCC)=[O:20])=[C:4]([CH3:24])[N:3]=1.CCCCC=CCCCCC.C(N(CC)CC)C>COC(C)(C)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:24])[C:5]2[CH:17]=[CH:18][C:19](=[O:20])[N:8]([C@H:9]3[CH2:14][CH2:13][C@H:12]([O:15][CH3:16])[CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@H](OC)CC1
Agent: CCCCC=CCCCCC
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CO[C@H]1CC[C@H](n2c(=O)ccc3c(C)nc(N)nc32)CC1

Procedure:
A solution of (E)-ethyl 3-(2-amino-4-(trans-4-methoxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate (674 mg, 2.02 mmol) thiophenol (621 ul, 6.05 mmol), 1,5-diazabicyclo5,4,0)undec-5-ene (1.81 mL, 12.1 mmol) and triethylamine (1.69 mL, 12.1 mmol) in N′,N-dimethylformamide (15 mL) was heated in the microwave for 30 minutes at 100° C. then in an oil bath at 100° C. overnight. The reaction mixture was diluted with methyltertbutylether and washed with saturated sodium carbonate, brine, 0.1 N hydrochloric acid, brine, dried (MgSO4), filtered and concentrated. The combined aqueous layer was extracted with dichloromethane (2×). The organic layer was dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/methanol (0-5%) to afford 2-amino-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (482 mg, 83%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]([C:30]3[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=3)=[O:29])[CH:25]=2)[CH:20]=[CH:19]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:34]([C:33]3[CH:32]=[CH:31][C:30]([C:28]([NH:27][C:24]4[CH:25]=[C:26]5[C:21]([CH:20]=[CH:19][NH:18]5)=[CH:22][CH:23]=4)=[O:29])=[CH:37][CH:36]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3cc[nH]c3c2)cc1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5cc[nH]c5c4)cc3)[nH]c2c1

Procedure:
Compound 664 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(6-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C25H22N4O3: 427.17; found: 426.99.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][S:8][CH:7]([CH2:10][C:11]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:18]([OH:20])=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:6]1)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][S:8][CH:7]2[CH2:10][C:11]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18](=[O:20])[N:6]12)=[O:4]
Reactant: COC(=O)C1CSC(CC(NC(=O)OC(C)(C)C)(C(=O)O)c2ccccc2)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CSC2CC(NC(=O)OC(C)(C)C)(c3ccccc3)C(=O)N21
Yield: 23 %

Procedure:
To a solution of compound 15 (3 g, 7.3 mmol) and p-TsOH.H2O (0.3 g, 1.6 mmol) in toluene (150 mL) was heated to reflux for 1 h. The solution was washed with NaHCO3 solution and brine, dried over Na2SO4. After concentration, the residue was purified by column chromatography on silica gel (PE: EA=10:1) to give compound 16 (660 mg, 23.1%). 1H NMR (400 MHz, CDCl3) δ1.41 (s, 9 H), 3.04-3.07 (m, 1 H), 3.24-3.37 (m, 1 H), 3.39-3.41 (m, 1 H), 3.48-3.50 (m, 1 H), 3.74 (s, 3 H), 5.04 (bs, 1 H), 5.25 (bs, 1 H), 5.42 (bs, 1 H), 7.31-7.40 (m, 3H), 7.53-7.54 (m, 2H). MS (M+): 393. The stereochemistry was identified by NOE experiment.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C([Sn](CCCC)(CCCC)[C:34]1[CH:35]=[N:36][C:37]2[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:41]=[N:40][C:38]=2[CH:39]=1)CCC>COCCOC.C(OCC)(=O)C.[Cu]Br.CSC.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>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17]([C:34]4[CH:39]=[C:38]5[N:40]=[CH:41][N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:37]5=[N:36][CH:35]=4)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:3])=[O:4]
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2c(c1)ncn2COCC[Si](C)(C)C
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CSC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc2cc(-c3nc(N4CCOCC4)c4cc(CN5CCN(S(C)(=O)=O)CC5)sc4n3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (90 mg) in 1,2-dimethoxyethane (10 mL) was added 6-tributylstannanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-]pyridine (219 mg) and copper(I)bromide-dimethylsulfide (84 mg) and the reaction stirred at room temperature for 10 min. Then, tetrakis(triphenylphosphine)palladium (0) (12 mg) was added and the reaction heated at reflux for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2×30 mL), aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-thieno[2,3-d]pyrimidine as a white solid.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([N+:13]([O-])=O)[C@H:10]([CH:16]([F:18])[F:17])[CH2:9]1)C1C=CC=CC=1>CO>[F:17][CH:16]([F:18])[C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[NH2:13]
Reactant: O=[N+]([O-])[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)F
Solvent: CO
Product: N[C@@H]1CNC[C@H]1C(F)F

Procedure:
A mixture of trans-1-benzyl-3-(difluoromethyl)-4-nitropyrrolidine (25 g, 0.097 mol) and Pd (OH)2/C (4 g) in MeOH (200 mL) was placed under a hydrogen atmosphere (50 psi) at rt overnight. The mixture was filtered to yield trans-4-(difluoromethyl)pyrrolidin-3-amine in solution. Boc2O was added at 0° C. and the resulting mixture was stirred at 0° C. for 4 hrs, then concentrated and purified by column chromatography (100% EtOAc) to give the title compound (14 g, 61% yield) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]([CH3:25])=[CH2:24])[C:3]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]([CH3:25])=[CH2:24])[C:3]=1[O:26][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: C=C(C)Cc1c(O)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)Cc1c(OCC(=O)OC)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
First, 1.0 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2-methyl-2-propenyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione was dissolved in 15 ml of N,N-dimethylformamide, to which 0.43 g of potassium carbonate and 0.4 ml of methyl bromoacetate were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The organic layer was dried and concentrated. The residue was subjected to silica gel chromatography, which afforded 1.0 g of 1-[4-chloro-6-fluoro-3-methoxycarbonylmethyloxy-2-(2-methyl-2-propenyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=O)[NH:10]2.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:5]=2[O:4][C:3]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:2]=2[F:1])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)ccc2c1Oc1ccc(F)cc1F
Product: COc1ccc2nc(Cl)ccc2c1Oc1ccc(F)cc1F
Yield: 87.5 %

Procedure:
A solution of 5-(2,4-difluoro-phenoxy)-6-methoxy-1H-quinolin-2-one derivative (0.3 g) in 10 mL of POCl3 was refluxed for 1.5 hours. POCl3 was removed under vacuum, the residue was stirred with saturated aqueous sodium bicarbonate solution, the product was extracted with methylene chloride, and the organic layer was dried (MgSO4). Solvent removal gave 0.28 g (87.5%) of 2-chloro-5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline as pure white crystals.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[S:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:9].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[S:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:20])=[O:9]
Reactant: COC(=O)CS(=O)C1CCCCC1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)C1CCCCC1Cl
Temperature: 5 °C
Reaction time: 4 h

Procedure:
The compound of Example 24 (3.5 g, 0.0112 mole) was dissolved in methylene chloride and cooled to 5° C. with an ice bath. 3-Chloroperoxybenzoic acid (85%, 2.3 g 0.0112 mole) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and concentrated in a rotary evaporator to give the crude product as a solid. The product was purified by silica gel chromatography. The structure was supported by NMR.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N+:24]([O-:26])=[O:25]>CC(O)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:23][N+:24]([O-:26])=[O:25])=[CH:11][C:10]=1[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C

Procedure:
A mixture of 4-benzyloxy-3-cyclopentyloxybenzaldehyde (6.3 g, 21.3 mmol) in AcOH (13 mL) and CH3NO2 (5.8 mL, 106.5 mmol) was created. NH4OAc (3.3 g, 42.5 mmol) was added and the mixture was heated under reflux for 2 h. After cooling to r.t., the mixture was extracted with CH2Cl2. The organic layer separated and washed with water, sat.
Reaction SMILES: Cl.Cl.[N:3]1[N:11]2[C:6]([O:7][CH2:8][CH2:9][CH2:10]2)=[C:5]([C@H:12]([NH2:14])[CH3:13])[CH:4]=1.[F:15][C:16]([F:34])([F:33])[C:17]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][C@@H:25]([C:30](O)=[O:31])[CH2:24][CH2:23][C:22]=2[N:21]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN1CCCC1=O>[N:3]1[N:11]2[C:6]([O:7][CH2:8][CH2:9][CH2:10]2)=[C:5]([C@H:12]([NH:14][C:30]([C@H:25]2[CH2:24][CH2:23][C:22]3[N:21]=[C:20]([C:17]([CH3:19])([CH3:18])[C:16]([F:34])([F:33])[F:15])[CH:29]=[CH:28][C:27]=3[CH2:26]2)=[O:31])[CH3:13])[CH:4]=1
Reactant: CC(C)(c1ccc2c(n1)CC[C@H](C(=O)O)C2)C(F)(F)F
Reactant: C[C@@H](N)c1cnn2c1OCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](NC(=O)[C@H]1CCc2nc(C(C)(C)C(F)(F)F)ccc2C1)c1cnn2c1OCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
A 2 mL vial was charged with (R)-1-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)ethanamine dihydrochloride (35 mg, 0.15 mmol), (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (38 mg, 0.13 mmol), N-methylpyrrolidinone (200 μL) and N,N-diisopropylethylamine (93 μL, 0.53 mmol). A solution of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (61 mg, 0.16 mmol) in N-methylpyrrolidinone (300 μL) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and purified by reverse-phase HPLC (20-75% MeCN in 10 mM Et2NH/H2O) to afford the product as a foam (31.0 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=7.9 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.20 (s, 1H), 4.78 (app pentet, J=7.3 Hz, 1H), 4.27 (app t, J=5.2 Hz, 2H), 4.04 (t, J=6.2 Hz, 2H), 2.93-2.73 (m, 4H), 2.61-2.52 (m, 1H), 2.19-2.10 (m, 2H), 2.03-1.94 (m, 1H), 1.85-1.72 (m, 1H), 1.54 (s, 6H), 1.29 (d, J=6.9 Hz, 3H); m/z=437.4 (M+1)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([CH3:34])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:22][CH2:23][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[CH3:34])=[O:17])[CH2:19][CH2:20]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Product: Cc1cc(N2C[C@H](C)CS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 58.9 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (110 mg) described in Preparation Example 4 and (4-bromo-2-methylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 124 and by the reaction and treatment in the same manner as in Example 4, the title compound (150 mg) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[C:20]([Br:21])=[CH:19][N:18]2[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=[C:17]2[CH:16]=1)(C)(C)C>C(Cl)Cl>[Br:21][C:20]1[C:15]([NH2:14])=[CH:16][C:17]2[N:18]([CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (15 ml) was added to a solution of (6-bromo-2-phenyl-imidazo[1,2-a]pyridin-7-yl)-carbamic acid tert-butyl ester (2.75 g, 7.1 mmol) in CH2Cl2 (15 ml), and the mixture was stirred at r.t. overnight. The mixture was then washed (water, 2×50 ml), dried (Na2SO4), and the solvent was evaporated to give a first crop of the desired product. The water layer was made alkaline by addition of NaOH (conc. 14 ml), and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and evaporated to give a second crop of the desired product. The combined crops (2.02 g, 99%) were used in the next step without further purification. MS (m/e)=288.0 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:34])[CH:22]([O:31]C=O)[C:23]4[S:27][C:26]([NH:28]C=O)=[N:25][CH:24]=4)[C:18](=[O:35])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.P(Cl)(Cl)(Cl)=O.C(OCC)C>CO>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:34])[CH:22]([OH:31])[C:23]4[S:27][C:26]([NH2:28])=[N:25][CH:24]=4)[C:18](=[O:35])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC=O)c3cnc(NC=O)s3)[C@H]2SC1
Agent: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC=O)c3c[nH]c(=NC=O)s3)[C@H]2SC1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3cnc(N)s3)[C@H]2SC1

Procedure:
To a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-formylamino-1,3-thiazol-5-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-formylimino-2,3-dihydro-1,3-thiazol-5-yl)acetamido]-3-cephem-4-carboxylic acid, (1.5 g.) in methanol (30 ml.) was added phosphorus oxychloride (1.06 g.) under ice-cooling and stirring, and the mixture was stirred for 1 hour at the same temperature and then further stirred for 4 hours at room temperature. To the reaction mixture was added diethyl ether (150 ml.), and the precipitates were collected by filtration and then dried. Thus obtained pale yellow powder (1.30 g.) was added to water (30 ml.), and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid. The resulting solution was treated with an activated charcoal, washed with ethyl acetate and then adjusted to pH 7 with a 5% sodium bicarbonate aqueous solution. The solution was washed with ethyl acetate, adjusted to pH 3 with 10% hydrochloric acid and then filtered. The aqueous solution was adsorbed on a HP-20 (neutral resin) column, which was washed with water and then eluted with an aqueous methanol solution. The eluates containing the object compound were collected and then methanol was distilled off under reduced pressure. The remaining aqueous solution was lyophilized to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-5-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-(2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)acetamido]-3-cephem-4-carboxylic acid, (0.63 g.), mp. 130° to 200° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][S:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]2[CH3:19])[C:5]2[CH2:10][S:9][CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)CSC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CSC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 2,4-dichloro-5,7-dihydrothieno[3,4-d]pyrimidine (300 mg, 1.45 mmol) and Et3N (294 mg, 2.9 mmol) in DMF (5.0 mL) at 0° C. was added 3-(S)-methylmorpholine (161 mg, 1.59 mmol) dropwise. After the addition was complete, the mixture was stirred overnight at rt. The solvent was removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated to give the crude product which was purified by preparative TLC (Eluent: petroleum ether/ethyl acetate=2/1) to provide 2-chloro-5,7-dihydro-4-((S)-3-methylmorpholino)thieno[3,4-d]pyrimidine as a light yellow solid (283 mg, 72%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=O.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12]>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:16]=[C:14]([CH2:13][C:11]#[N:12])[S:15][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: N#CCC(N)=S
Product: N#CCc1nc(-c2ccncc2)cs1
Yield: 46 %

Procedure:
This compound was synthesized from 2-bromo-1-(pyridin-4-yl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (0.23 g, yield 46%): 1H NMR (300 MHz, MeOD) δ 8.59 (m, 2H), 8.24 (s, 1H), 7.98 (m, 2H), 4.44 (s, 2H). MS (ESI) m/z: Calculated for C10H7N3OS: 201.01. found: 202.2 (M+H)+.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:40]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@@H:19]([CH2:22][O:23][C:24](=[O:31])[NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:18]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]1)=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][C@@H:4]([C@@H:40]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:41]1[CH:42]=[C:43]([F:48])[CH:44]=[C:45]([F:47])[CH:46]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@@H:19]([CH2:22][O:23][C:24](=[O:31])[NH:25][CH2:26][C:27]([F:30])([F:28])[F:29])[N:18]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:17]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(Cl)cc2)c2cc(F)cc(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(Cl)cc2)c2cc(F)cc(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: 25 °C

Procedure:
The product from step 2 (150 mg, 0.19 mmol) and triphenylphosphine (74 mg, 0.28 mmol) were dissolved in THF (4 mL) and to the solution was added water (1 mL). The mixture was heated to reflux under a nitrogen atmosphere for 12 h. The mixture was cooled to ambient temperature and the solvents were removed in vacuo. The residue was purified on a 12 g silica gel column eluting with a gradient of 0-10% methanol:chloroform. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=774.7.
Reaction SMILES: [OH:1][C@@H:2]([CH3:41])[CH2:3][CH2:4][CH:5]1[O:40][CH2:39][CH2:38][O:37][CH:6]1[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[C:17]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13]=1[C:14]([OH:16])=[O:15].[CH:42]1C=CC=CC=1.[N+](=C)=[N-].CN(N=O)C(N)=O>C(O)(=O)C.C(OCC)C>[OH:1][C@@H:2]([CH3:41])[CH2:3][CH2:4][CH:5]1[O:40][CH2:39][CH2:38][O:37][CH:6]1[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=[C:17]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:13]=1[C:14]([O:16][CH3:42])=[O:15]
Reactant: C[C@H](O)CCC1OCCOC1CCC/C=C/c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)O
Reactant: c1ccccc1
Agent: C=[N+]=[N-]
Agent: CN(N=O)C(N)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1c(/C=C/CCCC2OCCOC2CC[C@H](C)O)cc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a suspension of 48 g. of 2-(10(S)-hydroxy-6-ethylenedioxy-trans-undecenyl)-4,6-dibenzyloxybenzoic acid in 300 ml. of benzene is added a stoichiometric excess of diazomethane in 250 ml. of diethyl ether. The diazomethane is freshly prepared from N-methylnitrosourea. The solution becomes light yellow and is stirred for 15 minutes after the addition of the diazomethane. Acetic acid is then added to the mixture to decompose the excess diazomethane, and the solvents are removed to provide 48.8 g. of light yellow oil. The oil is purified by chromatography on 1250 g. of SilicAR, CC-7, an absorbent silica gel obtainable from Mallinckrodt Chemical Works, using a chloroform solvent. About 41 g. of a colorless oil of methyl 2-(10(S)-hydroxy-6-ethylenedioxy-trans-undecenyl)-4,6-dibenzyloxybenzoate are obtained. This oil analyzes as containing 72.92 wt. % carbon and 7.24 wt. % hydrogen, as compared to theoretical values of 73.17 wt. % carbon and 7.32 wt. % hydrogen.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[OH:10])=[CH:5][CH:4]=1.CN1C(C(C2C=CC=CN=2)O)=CN=C1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(O)c2cccnc2)cc1
Agent: Cn1cncc1C(O)c1ccccn1
Product: COc1ccc(C(=O)c2cccnc2)cc1

Procedure:
The title compound was prepared analogously to the method in Intermediate 25: step b using (4-methoxyphenyl)(pyridin-3-yl)methanol (Intermediate 31: step a) in place of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH2:11]([OH:15])[CH2:12][CH2:13][OH:14]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[O:14][CH2:13][CH2:12][CH2:11][OH:15]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: OCCCO
Product: NCc1ccc(Cl)cc1OCCCO

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 1,3-propane-diol analogously to the preparation of Intermediate 113.1 as a colorless solid; ES-MS: M+=216.1; HPLC: AtRet=2.23 min.