Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][CH2:20][OH:21])=[O:12]>>[OH:21][CH2:20][CH2:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)N1CCCCC1CCO
Reactant: C1CCNCC1
Product: O=C(CCCN1CCCCC1)N1CCCCC1CCO
Reaction time: 3.5 h

Procedure:
Piperidine (0.83 ml) was added to the crude (0.975 g) of 4-chloro-1-[2-(2-hydroxyethyl)piperidino]-1-butanone. After being stirred for 3.5 hours at 70~80° C., the reaction mixture was concentrated, thereby yielding a crude (1.097 g) of the entitled compound as light yellow syrup.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([Br:10])[CH:3]=1.CN([CH:14]=[O:15])C.[Cl-].[NH4+].C[CH2:19][O:20]CC>>[Br:10][C:4]1([CH:3]=[CH:2][CH:7]=[C:6]([CH:14]=[O:15])[CH2:5]1)[CH:19]=[O:20]
Reactant: CCOCC
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Product: O=CC1=CC=CC(Br)(C=O)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
step 1—n-BuLi (2.6 mL of a 1.6 M solution, 1.1 equiv) was added slowly to a solution of the 1,3-dibromo-5-methoxy-benzene (1.0 g, 3.8 mmol, CAS Reg. No. 74137-36-3) in Et2O (20 mL) cooled to −78° C. under an N2 atmosphere. The solution was stirred for 45 min, and DMF was added via syringe. The solution was warmed slowly to RT, added to saturated ammonium chloride, and extracted with ether. The organic phase was washed with brine and dried (MgSO4), filtered and evaporated to afford 0.80 g (98%) of 1-bromo-3-formyl-benzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:16]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[CH2:17].C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:17]=[CH:16][N:18]1[C:19](=[O:28])[C:20]2[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cc1ccccc1C=CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 20 h
Yield: 25.8 %

Procedure:
A mixture of 3-bromo-phenyl acetic acid tert-butyl ester (5.64 g, 20.80 mmol), N-vinyl phthalimide (3.60 g, 20.80 mmol), diisopropylethylamine (3.63 g, 28.08 mmol), palladium acetate (107 mg, 0.478 mmol), and tri-o-tolylphosphine (475 mg, 1.56 mmol) in acetonitrile (10 mL) was stirred at 90° C. for 20 h. The reaction was cooled to room temperature and ice water (50 mL) was added. EtOAc (50 mL) was added and the organic solution was washed with 5.5% HCl followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (hexanes:EtOAc 9:1 to 4:1) provided the title compound (1.95 g). MS 381 (M+18).
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH:18]4[CH2:20][CH2:19]4)[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[CH3:34][C:35]1([NH:39][CH3:40])[CH2:38][NH:37][CH2:36]1>>[CH:18]1([N:8]2[C:7]3[N:6]=[C:5]4[CH:21]=[C:22]([N:37]5[CH2:38][C:35]([CH3:34])([NH:39][CH3:40])[CH2:36]5)[C:2]([F:1])=[CH:3][C:4]4=[CH:13][C:12]=3[C:11](=[O:14])[C:10]([C:15]([OH:17])=[O:16])=[CH:9]2)[CH2:19][CH2:20]1
Reactant: CNC1(C)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Product: CNC1(C)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)C1
Yield: 79.3 %

Procedure:
1-Cyclopropyl-7-fluoro-8-(3-methyl-3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.58 g of 7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.34 g of 3-methyl-3-(methylamino)azetidine dimethanesulphonate. 1.57 g of 1-cyclopropyl-7-fluoro-8-(3-methyl-3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 330° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:32]=[N:33][N:34]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20]([NH:21][C:22](=[O:30])[C:23](=[N:28][OH:29])[C:24](=O)[CH2:25]Cl)[C:19](=[O:31])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1.[NH2:35][C:36]([NH2:38])=[S:37].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:3]2[N:4]([N:32]=[N:33][N:34]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20]([NH:21][C:22](=[O:30])[C:23]([C:24]4[N:35]=[C:36]([NH2:38])[S:37][CH:25]=4)=[N:28][OH:29])[C:19](=[O:31])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1
Reactant: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NO)C(=O)CCl)[C@H]3SC2)nn2nnnc12
Reactant: NC(N)=S
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4cc(N)c5nnnn5n4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)thiomethyl]-7-(4-chloro-2-hydroxyimino-3-oxobutyramido)-3-cephem-4-carboxylic acid (5.12 g; 0.01 mole) was dissolved in anhydrous N,N-dimethylacetamide (25 ml). Thiourea (0.76 g; 0.01 mole) was added, and the mixture was stirred at room temperature for 3 hours. The resulting solution was dropped under stirring into ethyl acetate (250 ml). A gummy material precipitated; the supernatant mother liquors were discarded and the residue was carefully triturated with fresh ethyl acetate until a powder was obtained. The powder was collected by filtration and dried. There was thus obtained a N,N-dimethylacetamide solvate of the hydrochloride salt of the desired product. This material was dissolved in aqueous NaHCO3 and washed five times with ethyl acetate, then with diethyl ether. Nitrogen was bubbled in for 15 minutes, charcoal was added, the charcoal was filtered off and the solution made acidic with 2 N HCl. The crystalline precipitate was collected and thoroughly washed with water and then with ethyl alcohol, yielding 3.8 g of the title compound, identical by TLC, IR, NMR to the product prepared in Example 7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.C([N:15]([CH:18](C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:44][O:45]NOOC>CN(C=O)C>[CH3:44][O:45][N:15]([CH3:18])[C:9]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([CH3:8])=[CH:5][N:4]=1)=[O:11]
Reactant: CONOOC
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cnc(C(=O)O)c(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ncc(C)nc1N
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-Amino-5-methyl-pyrazin-2-carboxylic acid (0.48 g, 3.12 mmol) is dissolved in anhydrous DMF (10 ml) under N2. The brown solution is cooled to 0° C., and diisopropylethylamine (1.48 ml, 7.9 mmol), EDC.HCl (0.75 g, 3.8 mmol), HOBt (0.58 g, 3.8 mmol) and N,O-dimethoxyhydroxylamine hydrochloride (0.37 g, 3.8 mmol) are added and the reaction is stirred at 0° C. for 1 hour and at room temperature for 4 hours. The solvent is concentrated in vacuo, and the residue is diluted with EtOAc and aq. NaHCO3. The phases are separated and the aqueous layer washed with EtOAc. The organic layers are combined, washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-5% MeOH in DCM) yields 3-amino-5-methyl-pyrazin-2-carboylic acid methoxy-methyl-amide as a pale yellow solid. [M+H]+ 197.
Reaction SMILES: [CH3:1][NH:2][C:3](=[NH:6])[S:4]C.[O:7](C(OC(C)(C)C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O.[CH2:22](Cl)Cl>C([O-])(O)=O.[Na+].O>[CH3:1][N:2]([CH3:22])[C:3](=[N:6][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])[SH:4]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CNC(=N)SC
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)C(S)=NC(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
44 (1.04 g, 10.0 mmol) and BOC2O (2.18 g, 10.0 mmol) were dissolved in a biphasic solution of CH2Cl2 (40 mL) and sat. NaHCO3 (40 mL) and the two layers stirred vigorously. After 24 h, the reaction mixture was diluted with CH2Cl2 (60 mL), water (60 mL) and the organic layer separated. The organic layer was washed with water (2×100 mL), dried (Na2SO4) and concentrated. The product oil was purified over silica gel (20% EtOAc/Hexane) to give a mixture of isomers of the product mono-BOC protected S—Me-isothiourea as a sticky oil (1.85 g, 90%). 1H-NMR (DMSO-d6) 9.45 (s, 0.4H), 8.97 (s, 1H), 3.17 (s, 3H), 3.06 (s, 1.2H), 2.33 (s, 1.2H), 2.23 (s, 3H), 1.45 (s, 9H), 1.39 (s, 3.6H).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19]C)=[O:18])[CH:5]=2.[Li+].[OH-].Cl>CO.C1COCC1.O.O>[Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (20 g, 60 mmol) and LiOH (3.8 g, 160 mmol) in MeOH/THF/H2O (1:1:1, 300 mL) was heated at 90° C. for 2 h. The reaction mixture was cooled in an ice/H2O bath, neutralized with 1M HCl (˜160 mL) diluted with H2O (250 mL) and stirred for 1 h at rt. The precipitates were collected by filtration rinse with H2O and dried to yield 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (quant.) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][NH2:50])[CH2:44][CH2:43]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:50][CH2:49][CH2:48][N:45]2[CH2:46][CH2:47][O:42][CH2:43][CH2:44]2)=[O:33])=[CH:18][CH:17]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCN4CCOCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-morpholino-1-ethanamine (66 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (162 mg, yield 100%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1
Reactant: CN1CCCN(c2nnc3ccc(F)cn23)CC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of Intermediate A (183 mg, 1.12 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 149 mg, 2.24 mmol) and the mixture stirred at RT for 0.5 h. A solution of Intermediate 69a (400 mg, 1.12 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.5 h. The cooled mixture was diluted with water and extracted with DCM (3×20 mL) and DCM-MeOH (4:1, 2×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-25% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (179 mg, 41%). LCMS (Method 3): Rt 0.44 min, m/z 393 [MH+].
Reaction SMILES: [C:1]1([P:7](=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([Cl:24])([Cl:23])[Cl:22]>C(Cl)(Cl)=O>[Cl-:22].[Cl-:22].[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH:21]([Cl:24])([Cl:23])[Cl:22]
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: [Cl-]
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1

Procedure:
In accordance with the invention, triphenylphosphine oxide is reacted (e.g., chlorinated) with phosgene in chloroform as a solvent to form a triphenylphosphine dichloride-chloroform adduct. The resulting adduct is reduced with hydrogen in the presence of chloroform as the solvent or alternatively without a solvent.
Reaction SMILES: C[C:2]1[N:3]=[CH:4][C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:6][C:7]=1C.[CH3:17]C1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]2[N:47]=[CH:46][CH:45]=[N:44]2)[C:35]=1[C:36](O)=[O:37].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]2[N:47]=[CH:46][CH:45]=[N:44]2)[C:35]=1[C:36]([N:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([N:9]([C:5]3[C:4]([CH3:17])=[N:3][CH:2]=[CH:7][N:6]=3)[CH2:10]2)[CH2:15]1)=[O:37]
Reactant: Cc1ncc(N2C[C@@H]3CCNC[C@@H]32)nc1C
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1nccnc1N1C[C@@H]2CCN(C(=O)c3c(F)cccc3-n3nccn3)C[C@@H]21

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(3-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 31) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H20FN7O, 393.43; m/z found 394.1 [M+H]+. 1H NMR (CD3OD): 7.99-7.79 (m, 4H), 7.72-7.59 (m, 2H), 7.38-7.21 (m, 1H), 4.63-4.01 (m, 4H), 3.82-3.24 (m, 3H), 2.74-2.25 (m, 4H), 2.16-1.29 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.C([O:23][C:24](=O)[C:25](=[O:30])[CH2:26][C:27](=[O:29])[CH3:28])C>C(O)C>[C:27]([C:26]1[CH:14]([C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:12]=2[F:11])[N:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)[C:24](=[O:23])[C:25]=1[OH:30])(=[O:29])[CH3:28]
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=Cc1cccc(F)c1F
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CCO
Product: CC(=O)C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cccc(F)c1F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and 2,3 Difluorobenzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2,4-Dioxo-pentanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[N:8][C:9]=2[N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:4]([CH2:28][CH3:29])[N:3]=1.C(=O)(O)[O-].[Na+].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.O>C1(C)C=CC=CC=1.CCO.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>[CH2:28]([N:4]1[C:5]2=[N:6][C:7]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[N:8][C:9]([N:11]3[CH2:12][CH:13]4[O:18][CH:16]([CH2:15][CH2:14]4)[CH2:17]3)=[C:10]2[C:2]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[N:3]1)[CH3:29]
Reactant: CCn1nc(Br)c2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCn1nc(-c2cccnc2)c2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Yield: 104.1 %

Procedure:
To a solution of 3-bromo-1-ethyl-6-(4-nitrophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (100 mg)(0.21 mmol) in toluene/EtOH (1:1) (2.0 mL) was added Pd(PPh3)4 (12 mg) (10 mol %), aqueous sodium bicarbonate solution (2.0 M) (0.135 mL) and 3-pyridine boronic acid (32 mg) (0.26 mmol). The reaction was heated in the microwave for 20 minutes at 140 C. The reaction was cooled and added water and then extracted three times with EtOAc. Organics were dried (MgSO4) and filtered off through a pad of Magnesol and concentrated in vacuo. to give a yellow oil 100 mg. MS m/z=458 (M+H)
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I.C[N:16]([CH:18]=[O:19])C>>[ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([CH3:9])([CH3:13])[C:18]([NH2:16])=[O:19])[CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CI
Reactant: N#CCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C(N)=O)C1CCNCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 3 g of pyridin-4-ylacetonitrile hydrochloride in 50 ml of DMF is cooled to 0° C., 2.6 g of 60% sodium hydride in oil are added in small portions and the mixture is left stirring for 2 hours at RT. The reaction mixture is cooled on an ice bath, 6 g of methyl iodide are added dropwise and the mixture is left stirring overnight at RT. The reaction mixture is poured over a water/ice mixture, extracted with ether, the organic phase washed with a saturated NaCl solution, dried over MgSO4, filtered and the solvent evaporated off under vacuum. The residue is chromatographed on H silica gel, eluting with DCM and then with the DCM/MeOH (98/2; v/v) mixture. 2.39 g of the expected product are obtained in the form of an oil which crystallizes.
Reaction SMILES: C(O)(=[S:3])C.[C:5]([OH:12])(=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9].C1(=O)OC(=O)C=C1>>[C:8]([OH:10])(=[O:9])[CH3:7].[SH:3][CH:7]([CH2:6][C:5]([OH:12])=[O:11])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CC(O)=S
Agent: O=C1C=CC(=O)O1
Product: CC(=O)O
Product: O=C(O)CC(S)C(=O)O
Yield: 83 %

Procedure:
Another synthesis for forming thiomalic acid is by the reaction of thioacetic acid and maleic acid as cited in Flett and Garner's, "Maleic Anhydride Derivatives", (J. Wiley, New York 1952) page 225. The example given here uses thioacetic acid plus maleic acid to give mercaptosuccinic acid acetate having the formula ##STR1## and the yield is 83% of that required by theory for the latter but no yield is given for the subsequent alkaline hydrolysis of this acetate to disodium thiomalate and sodium acetate and the eventual acidification to give thiomalic acid. This procedure is impractical in that the thioacetic acid preparation is expensive and is not commercially available on a large scale at an economical price, and thus is a drawback to this process. Moreover, once thiomalic acid is obtained by alkaline hydrolysis of the acetate and acidification, it must still be isolated from the water solution containing inorganic salts, just as in the sulfide process of the British patent already discussed.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH:2]=C.[BH4-].[Na+].C(Cl)Cl.C[OH:36]>C(=O)=O.CC(C)=O>[OH:36][CH2:2][CH2:1][O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C=CCOCc1cccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)c1
Reactant: CO
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(-c2cccc(COCCO)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
3-(3′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (260 mg, 0.664 mmol) was dissolved in DCM/methanol (4:1, 7.5 mL) and was cooled to −78° C. in dry ice-acetone bath. O3 was bubbled through the solution for 15 min. Thin layer chromatography (TLC) confirmed the completion of the reaction at this stage. The DCM was evaporated in vacuo; ethanol (5 mL) was added and the solution was cooled in ice-water bath to 0° C. NaBH4 (175 mg, 7 eq.) was added and the reaction was stirred at the temperature of 0˜5° C. for one hour then at room temperature for 1.5 hour. The reaction mixture was quenched with saturated NaHCO3 aqueous solution. The aqueous phase was extracted with DCM (3×8 mL), the combined organic phases were washed with brine (5 mL), dried over sodium sulfate and concentrated. The crude residue was purified on silica gel eluting with 20˜50% ethyl acetate in hexane to give the product (134 mg, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.59 (d, 3H), 7.52 (d, 1H), 7.41 (t, 1H), 7.32 (d, 3H), 4.85 (s, 2H), 4.45 (s, 2H), 3.77 (br, 2H), 3.62 (t, 2H), 3.12 (s, 2H), 2.48 (br, 1H), 1.72 (m, 4H), 1.5 (m, 6H).
Reaction SMILES: C([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:5][CH:4]=1)C.ClCC1C=C[C:30]([O:33]C)=CC=1>>[CH3:30][O:33][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:23][CH:24]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: COc1ccc(CCl)cc1
Product: COCOc1cc(SCc2ccc(OC)cc2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 1-(chloromethyl)-4-methoxybenzene instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:11]1=[O:26])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:27][C:28](OC(C)=O)=[O:29].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:28]([O:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=2)[C:11]1=[O:26])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:29])[CH3:27]
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H](C(=O)OC(C)(C)C)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Compound 93-1 (350 mg, 0.932 mmol) was dissolved in CH2Cl2 (4.66 ml) and cooled to 0° C., Ac2O (0.176 ml, 2 eq), pyridine (0.151 ml, 2 eq), and DMAP (11 mg, 0.1 eq) was added. The mixture was stirred for 2 hours, diluted with EtOAc, washed with CuSO4 solution, water, dried and concentrated to give 370 mg of compound 93-2.