Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[S:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C[CH2:33][N:34](C(C)C)C(C)C.CN>C(Cl)Cl.C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([NH:34][CH3:33])=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)s5)cn34)ccnc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3c2)s1
Yield: 18.8 %

Procedure:
To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carbonyl chloride (0.150 g, 0.33 mmol) and Hunig's Base (0.17 ml, 1.00 mmol) in DCM (2.5 mL) was added methanamine (0.17 ml, 0.33 mmol) in THF dropwise. The solution was stirred at room temperature for 3 hours, at which point an additional 1.5 equivalents of amine were added. The solution was concentrated in vacuo and purified via flash chromatography eluting with 3-8% MeOH:NH4OH in DCM. There remained an impurity, so the product was triturated with MeCN, filtered and washed with DCM to yield 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-methylthiophene-2-carboxamide (0.0276 g, 19% yield) as an amorphous tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[N+:11]=[N-:12].C[O-].[Na+]>CO>[N:10]([C:13](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1])[C:14]([O:16][CH3:17])=[O:15])=[N+:11]=[N-:12]
Reactant: O=Cc1ccccc1Br
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1ccccc1Br)N=[N+]=[N-]
Temperature: 0 °C
Yield: 18636.4 %

Procedure:
A solution of 75 ml (624 mmol) of 2-bromobenzaldehyde and of 252 g (2.2 mmol) of methyl azidoacetate in 160 ml of methanol is added dropwise over 3 h, at a temperature of −10 to −8° C., under nitrogen and with mechanical stirring, to a solution of 476 ml of sodium methoxide (30% in methanol) in 950 ml of methanol. Stirring is maintained for 2 h at a temperature below 5° C. The mixture is poured onto 1.5 kg of ice. The precipitate is collected by filtration, washed with water and dried under reduced pressure with light excluded. 116 g (0.41 mol) of solid are obtained, which solid is used quickly in the following stage.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1)=[O:6].[OH-].[K+]>C(O)C>[O:6]=[C:5]1[NH:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:14]#[N:15]
Reactant: N#Cc1cccc(NC(=O)NCCCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cccc(N2CCNC2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
110.00 g (490 mmol) 1-(2-chloro-ethyl)-3-(3-cyano-phenyl)-urea are dissolved in 2000 ml of ethanol at 50° C. and a solution of 42.00 g (640 mmol) potassium hydroxide in 390 ml of ethanol is added within 1.5 hours. The reaction mixture is stirred for 16 hours at ambient temperature, then the precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.O>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccccc1Oc1ccccc1
Reaction time: 1 h

Procedure:
Add 2-Phenoxy-benzoic acid (1 g, 4.67 mmol), in several portions, to a suspension of Lithium aluminium hydride (372 mg, 9.33 mmol) in dry THF (20 ml) at room temperature and stir. After 1 h, add aqueous 1M HCl dropwise carefully, then pour into H2O and extract three times with Et2O. Combine the organic phases, dry over Na2SO4 and concentrate at vacuum to yield pure (2-Phenoxy-phenyl)-methanol as courless oil. Add aqueous concentrated HBr (16 ml) to a solution of (2-Phenoxy-phenyl)-methanol (900 mg, 4.5 mmol) in CH2Cl2 (5 ml) and stir at room temperature. After 1 h. separate the organic phase and wash the aqueous one with CH2Cl2. Combine organic phases, wash with H2, dry over Na2SO4 and concentrate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with hexane:CH2Cl2, 2:1 to afford 1-Bromomethyl-2-phenoxy-benzene as colourless oil. 1H-NMR (CDCl3, 200 MHz): δ 7.44-7.01 (m, 8H), 6.84 (d, J=1.2 and 8.0 Hz, 1H), 4.60 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[N:10]1([C:16]([S:18][CH3:19])=[S:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:13]1[CH2:14][CH2:15][N:10]([C:16]([S:18][CH3:19])=[S:17])[CH2:11][CH2:12]1
Reactant: Cc1ccccc1CCl
Reactant: CSC(=S)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CSC(=S)N1CCN(Cc2ccccc2C)CC1
Yield: 28.2 %

Procedure:
1.405 g (10 mmol.) of 2-methylbenzyl chloride, 1.76 g (10 mmol.) of methyl 1-piperazinecarbodithioate, 1.06 g (10 mmol.) of anhydrous sodium carbonate and 14 ml of ethanol. The mixture was refluxed under heating for 2.5 hours. Ethanol was distilled off under reduced pressure. The residue was mixed with water and ether. The organic solvent portion was taken out, and to the portion was added 15 ml of 3-N hydrochloric acid. The aqueous portion was neutralized with 1-N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was purified over a silica gel column to give 790 mg of methyl 4-(2-methylbenzyl)-1-piperazinecarbodithioate as a white crystalline product, yield 28.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[C:12]([CH2:17][N:18]([CH2:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=3)[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:13][CH:14]=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[NH:48][C:49](N1C=CN=C1)=[O:50]>CN(C=O)C>[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[NH:48][C:49]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]([CH2:17][C:12]2[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:9])[CH3:10])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:25][C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH2:24][CH2:23]1)=[O:50]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)C2CCNCC2)c(C)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)C2CCN(C(=O)Nc3ncc[nH]3)CC2)c(C)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a warm (70° C.), stirred, solution of {3-[1-(4-Chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-(3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (0.141 g, 0.30 mmol) and DIPEA (0.32 mL, 1.84 mmol) in DMF (3 mL) was added imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 1.5 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (30 mL) and washed with water (5×10 mL). The organic phase was dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 157 mg (85%) of COMPOUND 275 as a white solid. 1H NMR (CDCl3) δ 1.28-1.39 (m, 2H), 1.58 (s, 6H), 1.65-1.71 (m, 2H), 2.24 (s, 3H), 2.29 (s, 3H), 2.56-2.65 (m, 3H), 3.36 (s, 2H), 3.68 (s, 2H), 4.10-4.14 (m, 2H), 6.68 (s, 2H), 6.83-6.85 (m, 2H), 7.07-7.10 (m, 2H), 7.17-7.21 (m, 2H), 7.81 (d, 1H, J=6.9 Hz), 8.09 (s, 1H), 8.50 (d, 1H, J=3.3 Hz); 13C NMR (CDCl3) δ 18.78, 19.21, 28.81, 31.76, 43.11, 45.08, 55.15, 55.65, 58.55, 122.21, 127.81, 129.21, 132.10, 132.30, 133.51, 134.67, 139.48, 143.61, 145.93, 147.15, 147.46, 149.05, 155.28, 156.16, 158.91; ES-MS m/z 572 (M+1) & 574 (M+1). Anal. Calcd. For C32H38N7OCl.0.4CH2Cl2: C, 64.20; H, 6.45; N, 16.18; Cl, 10.53. Found: C, 63.83; H, 6.43; N, 15.88; Cl, 10.92.
Reaction SMILES: C([C@H:3]([S:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[CH3:42][NH2:43]>>[CH3:34][N:33]1[C:29]([C:27]([NH:26][C:22]2[CH:21]=[C:20]([C:19]#[C:18][C:16]3[CH:15]=[N:14][CH:13]=[C:12]([CH:17]=3)[C:10]([N:9]=[S@@:7]([CH2:3][C:4]([NH:43][CH3:42])=[O:5])(=[O:8])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:11])[CH:25]=[CH:24][CH:23]=2)=[O:28])=[CH:30][C:31]([CH3:35])=[N:32]1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Reactant: CN
Product: CNC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate and methylamine were reacted to give the title compound.
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10](=O)[CH3:11])([O-])=O.[N+](C(OC1C=CC=CC=1)C(=O)C)([O-])=O>[Ni].CO>[CH3:11][CH:10]1[NH:3][C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[O:8][CH2:9]1
Reactant: [H][H]
Reactant: CC(=O)COc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Agent: CC(=O)C(Oc1ccccc1)[N+](=O)[O-]
Solvent: CO
Product: CC1COc2ccccc2N1
Temperature: 40 °C

Procedure:
Reaction conditions: 220 bar of hydrogen, reaction temperature 60° C. with a residence time of about 60-90 minutes. The space velocity was about 2 g of o-nitrophenoxyacetone per g of catalyst used and hour. The catalyst used was a nickel sponge metal catalyst from H. C. Starck, Amperkat Ni—Mo 3706 (exchange of the water under which the catalyst is stored for methanol). The yields in this step were 95+%; at least 100 g of nitrophenoxyacetone were converted per gram of theoretically dry catalyst. Good mixing was ensured by stirring. In order to prevent precipitation of the reactant solution, it was heated to 40° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:42]=[CH:41][C:34]2[O:35][C:36]([CH3:40])([CH3:39])[O:37][CH2:38][C:33]=2[CH:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:22]1([S:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:28][C@@H:29]([C:31]3[CH:42]=[CH:41][C:34]4[O:35][C:36]([CH3:39])([CH3:40])[O:37][CH2:38][C:33]=4[CH:32]=3)[OH:30])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Reactant: O=S(=O)(c1ccc(C#CCCOCCCCCCBr)cc1)C1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCC#Cc3ccc(S(=O)(=O)C4CCCC4)cc3)ccc2O1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
To a stirred solution of 1-{4-[(6-bromohexyl)oxy]but-1-ynyl}-4-(cyclopentylsulfonyl) benzene (280 mg) in DMF (10 ml) were added (1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (WO 0266422 A1) (170 mg) and diisopropylethylamine (165 μl). The mixture was heated at 50° for 22 h before being allowed to cool to room temperature. The mixture was dissolved in EtOAC, washed with brine, dried (MgSO4) and evaporated to dryness. The residual oil was purified on a silica bond elut SPE cartridge (10 g), gradient 0% to 30% [MeOH-aqueous ammonia (10:1)] in DCM (Gradmaster™). The appropriate fractions were evaporated to give the title compound (127 mg) LCMS RT=2.87 min
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]=[C:13]([S:22][CH3:23])[N:12]=1.C[C:25]1[CH:30]=[CH:29][C:28]([N:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH2:32])=[CH:27][CH:26]=1>O1CCOCC1>[CH3:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([S:22][CH3:23])[NH:12][C:11]2=[N:32][N:31]([C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)N(N)c1ccc(C)cc1
Reactant: CSc1nc(Cl)c2cc(C)ccc2n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N(N=c1[nH]c(SC)nc2ccc(C)cc12)c1ccccc1

Procedure:
N,N-Diisopropylethylamine (0.104 mL, 0.6 mmol) was added to a solution of 11b (0.071 g, 0.3 mmol) and 10a, (0.057 g, 0.3 mmol) in 5 mL of dioxane and the solution was heated at reflux for 48 h; during which a white precipitate fell out. The white slurry was filtered and the precipitate was washed with dioxane to give 12 as a white solid. (0.110 g, 100%). mp. 229.7° C.;
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([Cl:13])[CH:3]=1.CO.[BH4-].[Li+].[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([Cl:13])[CH:3]=1
Reactant: COC(=O)c1cc(F)c(Br)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(F)c(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
To a solution of methyl 4-bromo-2-chloro-5-fluorobenzoate (18.00 g, 67.28 mmol) in tetrahydrofuran (100 mL) was added methanol (3.0 mL, 74.15 mmol), followed by the addition of lithium borohydride solution (4.0 M in tetrahydrofuran, 33.7 mL, 134.80 mmol) at 0° C. over 30 min. The reaction mixture was stirred for further 10 min at 0° C., and then at ambient temperature for 20 h; 5% sodium hydroxide solution (100 mL) was added to the reaction mixture slowly at 0° C. After stirring for 30 min. the reaction mixture was extracted with ethyl acetate (200 mL×3). The organic layer was washed with brine, and concentrated in vacuo to afford the title compound as a pale yellow solid (16.00 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=6.0 Hz, 1H), 7.30 (d, J=9.0 Hz, 1H), 4.69 (s, 2H), 2.08 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: Nc1cc(Cl)ccc1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 51 %

Procedure:
Starting from 2-amino-4-chlorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (110 mg; 51% yield).
Reaction SMILES: CON(C)[C:4]([C:6]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].OS([O-])(=O)=O.[K+]>C1COCC1.O.CCOCC>[CH:4]([C:6]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C=O)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 1-{[methoxy(methyl)amino]carbonyl}-cyclopentylcarbamate (3.34 g, 12.27 mmol) in anhydrous THF (112 mL) at 0° C. under an atmosphere of nitrogen was added LAH (698 mg, 18.40 mmol), portionwise. The reaction was stirred at 0° C. for 30 min, treated with KHSO4 (3.4 g) in water (72 mL), diluted with Et2O, and stirred for 5 min. The layers were separated, and the aqueous was extracted with Et2O three times more. The combined organic extracts were washed twice each with aqueous 1N HCl solution, saturated aqueous NaHCO3 solution, and brine, dried over MgSO4, and concentrated in vacuo to afford the product as a sticky solid.
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C[Si](CC(N)=O)(C)C.[F:44][C:45]([F:69])([F:68])[C:46]([NH:48][C:49]1[S:50][CH:51]=[C:52]([C:54](=[N:58][O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)[C:55](O)=[O:56])[N:53]=1)=[O:47].P(Cl)(Cl)(Cl)=O>O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[F:68][C:45]([F:44])([F:69])[C:46]([NH:48][C:49]1[S:50][CH:51]=[C:52]([C:54](=[N:58][O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)[C:55]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:9]([O:11][CH2:12][C:13]4[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=4)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]23)=[O:56])[N:53]=1)=[O:47]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: O=C(O)C(=NOCc1ccc(F)cc1)c1csc(NC(=O)C(F)(F)F)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)C(=NOCc1ccc(F)cc1)c1csc(NC(=O)C(F)(F)F)n1
Yield: 91.8 %

Procedure:
A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (2.5 g.), bis(trimethylsilyl)acetamide (4.5 g.) and trimethylsilylacetamide (6.8 g.) in tetrahydrofuran (50 ml.) and a solution of 2-[2-(2,2,2-trifluoroacetamido)thiazole-4-yl]-2-(4-fluorobenzyloxyimino)acetic acid (syn isomer, 3.2 g.), phosphoryl chloride (15 g.) and N,N-dimethylformamide (0.7 g.) in ethyl acetate (32.8 ml.) were treated in a similar manner to that of Example 1-(1) to give 4-nitrobenzyl 7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(4-fluorobenzyloxyimino)acetamido]-3-cephem-4-carboxylate (syn isomer, 4.85 g.).
Reaction SMILES: [C:1]([CH2:3]Br)#[N:2].[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[C:6]1=[O:15])[CH2:12]2.[Cl-]>C1(C)C=CC=CC=1>[C:6]([O:15][C:6]1([CH2:3][C:1]#[N:2])[CH:7]2[CH2:13][CH:11]3[CH2:10][CH:9]([CH2:14][CH:5]1[CH2:12]3)[CH2:8]2)(=[O:15])[C:5]([CH3:14])=[CH2:12]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: N#CCBr
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1(CC#N)C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
A three-neck flask under nitrogen is charged with 100 mL toluene and 1 gm of cyanomethylbromide (CNCH2Br) and cooled with an ice bath. A slight molar excess of Mg is added to the toluene and the mixture stirred until completion of formation of the Grignard reagent. A molar equivalent of 2-adamantanone is then added to the reaction mixture and stirring continued for 30 minutes or more while warming to room temperature. The reaction mixture is then again cooled with an ice bath and a slight molar excess of methacrylol chloride is added dropwise. When the acid chloride addition is complete, the ice bath is removed and stirring continued at room temperature until reaction completion. The resulting 2-cyanomethyl-2-adamantyl methacrylate can be isolated and purified by extraction and/or chromatography.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].N1C[CH2:15][CH2:14][CH2:13]1.CC(C)=O>C(#N)C.CC(=O)OCC>[CH3:13][C:14]1([CH3:15])[CH2:1][C:2](=[O:3])[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)[O:11]1
Reactant: C1CCNC1
Reactant: CC(=O)c1cc(O)ccc1O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2cc(O)ccc2O1
Temperature: 45 °C

Procedure:
A reaction mixture of 100 g (0.65 mol) of 2,5-dihydroxyacetophenone in 1 l of acetonitrile, 130 ml (1.55 mol) of pyrrolidine and 290 ml (3.95 mol) of acetone was heated to 45° C. for 8 h. The solvents were then stripped off in vac. and the residue was dissolved in 1 l of EA. The organic phase was washed twice with dilute hydrochloric acid, stirred with activated carbon and dried over magnesium sulfate and largely concentrated. After stirring the residue with petroleum ether and filtering off the precipitate with suction, 102 g of 2,2-dimethyl-6-hydroxychroman-4-one, m.p. 158° C., were obtained.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[S:11]1[CH:15]=[CH:14][C:13]([C:16](Cl)=O)=[CH:12]1.N1C=CC=CC=1>O1CCOCC1>[S:11]1[CH:15]=[CH:14][C:13]([CH2:16][NH:10][C:9]2[N:1]=[CH:2][N:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[N:5]3)=[CH:12]1
Reactant: O=C(Cl)c1ccsc1
Reactant: Nc1ncnc2nc[nH]c12
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: c1nc(NCc2ccsc2)c2[nH]cnc2n1

Procedure:
In the other version of the process, 1 mole equivalent of adenine is heated in a conventional manner (Phytochemistry 16, (1977) 1865) with from 1 to 10, preferably from 2 to 5, mole equivalents of thiophene-3-carbonyl chloride in the presence of a proton acceptor (e.g. pyridine), possibly in a solvent, such as dioxane, at as high as 200° C., and the mixture is worked up in a conventional manner and if necessary recrystallized, for example as described above.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([NH:15][C:16](=[O:38])[CH2:17][N:18]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:37]=[CH:36][C:28]3[N:29]=[C:30]([S:32](=[O:35])(=[O:34])[NH2:33])[S:31][C:27]=3[CH:26]=2)[N:20]=[N:19]1)[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([S:8][CH2:9][C@H:10]([NH:15][C:16](=[O:38])[CH2:17][N:18]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:37]=[CH:36][C:28]3[N:29]=[C:30]([S:32](=[O:34])(=[O:35])[NH2:33])[S:31][C:27]=3[CH:26]=2)[N:20]=[N:19]1)[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CSCc1ccccc1)NC(=O)Cn1cc(COc2ccc3nc(S(N)(=O)=O)sc3c2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1nc2ccc(OCc3cn(CC(=O)N[C@@H](CSCc4ccccc4)C(=O)O)nn3)cc2s1
Temperature: 25 °C

Procedure:
Compound 141 (5.0 mg, 0.0087 mmol, 1 equiv) in a THF/H2O mixture (1:1, 1 mL) was treated with LiOH (0.4 mg, 0.010 mmol, 1.2 equiv) and irradiated in a Biotage Emrys Optimizer microwave reactor (250 W) at 100° C. for 10 min. After cooling the contents of the tube to room temperature, the solvent was removed and the crude product was purified by HPLC. Yield: 3 mg, 63%.