Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH2:10][CH2:11]1)[CH2:8][C:7]2=[O:22])=[O:5])[CH3:2].B.[Na]>C(O)C>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([CH2:10][CH2:11]1)[CH2:8][CH:7]2[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCC(NCc3ccccc3)(CC1)CC2=O
Agent: B
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C12CCC(NCc3ccccc3)(CC1)CC2O
Temperature: 0 °C

Procedure:
Ethanol (2 mL) was added to 4-(benzylamino)-2-oxobicyclo-[2.2.2]octane-1-carboxylic acid ethyl ester (200 mg, 0.66 mmol) and then the resulting mixture was stirred. The resulting mixture was cooled to 0° C., sodium boron hydride (38 mg, 1 mmol) was added thereto, the temperature thereof was raised up to room temperature and then the mixture was stirred for 30 minutes. After quenching the reaction mixture with a 18% aqueous ammonium chloride solution, the mixture was made uniform with water and acetonitrile and then quantitatively analyzed (according to the LC technique). As a result, the yield of the desired product was found to be 83% (the internal standard substance used was 1,2,4-trimethylbenzene).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:25](OCC)([O:28]CC)[CH2:26][Cl:27])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11]>C(C(C)=O)C(C)C>[CH3:6][O:7][N:8]=[C:9]([C:25](=[O:28])[CH2:26][Cl:27])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: CCOC(CCl)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)CC(C)C
Product: CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Yield: 64.9 %

Procedure:
70% Perchloric acid (0.75 ml), 7-(2-methoxyimino-3,3-diethoxy-4-chlorobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 1.82 g) and methyl isobutyl ketone (7.3 ml) were treated in a similar manner to that of Example 47 to give 7-(2-methoxyimino-3-oxo-4-chlorobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 0.98 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([OH:16])=[CH:11][CH:12]=[CH:13][C:14]=1[CH3:15].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]3[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=3[O:16][C:2]=2[CH:7]=1
Reactant: Cc1cccc(O)c1-c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1cccc2oc3cc(Cl)ccc3c12
Yield: 83.4 %

Procedure:
A mixture of 2′,4′-dichloro-6-methyl-biphenyl-2-ol (8.75 g, 34.7 mmol), K2CO3 (25 g, 180 mmol) and CuO (17 g, 214 mmol) in 200 mL of pyridine was refluxed under nitrogen for 2 hours. Pyridine was eliminated by distillation. To the residue were added 200 mL of water and 200 mL of methylenechloride, the resulting mixture was filtered through Celite. The organic phase was washed with water, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (cyclohexane/ethyl acetate, 5/1) to give 6.27 g of beige solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33]>>[Cl:33][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([Cl:32])[C:26]=1[NH:25][C:19]1[C:18]2[C:23](=[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:15]([O:34][CH3:35])=[CH:16][CH:17]=2)[O:22][C:21](=[O:24])[CH:20]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: C1CCNCC1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN1CCCCC1

Procedure:
The title compound was prepared from piperidine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.31 (br s, 1H), 8.55 (s, 2H), 7.85 (d, 1H), 7.04 (d, 1H), 4.20 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.90-2.30 (br, 6H), 1.75-1.35 (m, 12H); MS (ESI): 505.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]#[N:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:27]=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O.[Zn+2].[Br-].[Br-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12]([N:11]=3)=[CH:13][CH:14]=[C:15]([C:25]3[NH:30][N:29]=[N:28][N:26]=3)[CH:16]=4)=[CH:7][C:6]=2[CH:27]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)N(C)c1nc2cc(C#N)ccc2nc1-c1cc2cc(F)ccc2o1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N(C)c1nc2cc(-c3nnn[nH]3)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 130 °C
Reaction time: 48 h
Yield: 36.9 %

Procedure:
To a solution of 2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile (150 mg, 0.42 mmol) in DMSO (30 ml) and water (2 ml) was added ZnBr2 (46.9 mg, 0.21 mmol) and NaN3 (81.3 mg, 1.25 mmol), and the resulting mixture was stirred for 48 h at 130° C. The reaction mixture was quenched with water (100 ml) and adjusted to pH 3 with HCl (2N), extracted with ethyl acetate (4×60 ml), and the organic layers combined and concentrated in vacuo to give the residue, which was purified by silica gel column chromatography (12% methanol in dichloromethane) to afford 3-(5-fluorobenzofuran-2-yl)-N-methyl-N-(propan-2-yl)-7-(1H-tetrazol-5-yl)quinoxalin-2-amine as a yellow solid (62.6 mg, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:8])=[CH:5][S:6][CH:7]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19]([C:13](=[CH:12][NH:8][C:4]1[C:3]([O:2][CH3:1])=[CH:7][S:6][CH:5]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:20])[CH3:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cscc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cscc1OC)C(=O)OCC

Procedure:
4-Methoxy-3-thiopheneamine (11.8 g, 0.091 mol) and diethyl ethoxymethylenemalonate (19.75 g, 0.091 mol) in toluene (300 ml) was heated under reflux in an atmosphere of nitrogen for 18 hours. The solvent was evaporated under reduced pressure to give a buff-coloured solid, this was washed with petroleum ether (b.p. 40°-60°) and the title compound collected by filtration, 25.23 g, m.p. 100°-102°.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C1(C(O)=O)CCC=CC1.C(Cl)(=O)C(Cl)=O.[F:25][C:26]([F:37])([S:33]([O-:36])(=[O:35])=[O:34])[CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29].[C:38]1([S+:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C.[Cl-].Cl>C(Cl)Cl>[F:37][C:26]([F:25])([S:33]([O-:36])(=[O:34])=[O:35])[CH:27]([O:32][C:7]([CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:8])[C:28]([F:29])([F:31])[F:30].[C:51]1([S+:44]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reactant: O=C(Cl)C1CC=CCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)C1CC=CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])C1CC=CCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Cyclohexenecarbonyl chloride prepared by reaction of 4.2 g (0.03 mole) of 3-cyclohexenecarboxylic acid with 5.1 g (0.04 mole) of oxalyl chloride was dissolved in 12 g of methylene chloride. A solution of 3-cyclohexenecarbonyl chloride in methylen chloride, as prepared above, was added dropwise to a mixed solution of 15 g (0.03 mole) of triphenylsulfonium 1,1,3,3,3-pentafluoro-2-hydroxypropane-1-sulfonate prepared in accordance with the method described in Japanese Patent Laid-Open Publication No. 2007-145804, 2.4 g (24 millimoles) of triethylamine, 0.1 g (1 millimole) of N,N′-dimethylaminopyridine, and 60 g of methyle chloride. The mixture was then stirred at room temperature for 5 hours. After stirring, 30 g of 5% dilute hydrochloric acid was added to quench the reaction. An organic layer was isolated and washed with water. After washing with water, the organic layer was concentrated. To the organic layer, methyl isobutyl ketone was added, and the mixture was washed with water. After then, the washed organic layer was concentrated, and diisopropyl ether was added to perform recrystallization. The crystal was filtered off, collected, and dried under reduced pressure at 50° C. to obtain 14 g of triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(3-cyclohexenecarbonyloxy)propane-1-sulfonate (PAG intermediate) which was a target compound as a white crystal (yield: 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:28][CH2:29][CH2:30][N:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][C:32]1=[O:42])[CH2:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:22])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>C(#N)C>[C:46]([O:45][C:43](=[O:44])[N:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:50])[CH2:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:18][CH2:19][CH2:14][CH2:15][CH2:16][CH3:17])[C:12]1=[O:22])[CH2:28][CH2:29][CH2:30][N:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:32]1=[O:42])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N(CCCCN(CCCn1c(=O)[nH]c2ccccc2c1=O)C(=O)OC(C)(C)C)CCCn1c(=O)[nH]c2ccccc2c1=O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCn1c(=O)n(CCCN(CCCCN(CCCn2c(=O)c3ccccc3n(CCCCCC)c2=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(=O)c2ccccc21
Reaction time: 3 h

Procedure:
(4-{tert-butoxycarbonyl-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl)-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]carbamic acid tert-butyl ester (3 g, 4.3 mmol) was dissolved in 120 mL acetonitrile. Potassium carbonate (3.45 g, 25.0 mmol) and 1-bromohexane (3.5 g, 21.1 mmol) were added thereto and stirred for 3 hours under reflux. The solvent was concentrated under reduced pressure, and silica gel column-chromatography of the remaining residue was performed to give the title compound of colorless oil form (3.7 g, 99%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][C@H:7]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[N:8]([C:15](=[O:25])[CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])[C@H:9]2[CH3:14])(=[O:3])[CH3:2].[CH3:35][Mg]Cl>C1COCC1>[Si:28]([O:27][CH2:26][C@H:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[C:1]([OH:3])([CH3:35])[CH3:2])[C@H:9]([CH3:14])[N:8]1[C:15](=[O:25])[CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:30])[CH3:29]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Solvent: C1CCOC1
Product: C[C@H]1c2cccc(C(C)(C)O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
Dissolve 1-((1S,3R)-5-acetyl-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (68 mg, 130 μmol) in THF (1.3 mL). Cool to 0° C., add MeMgCl (87 μL, 261 μmol, 3M in Et2O). Stir 30 min at 0° C. and 30 min at room temperature. Add MeMgCl (87 μL, 261 μmol, 3M in Et2O) at rt. Stir 60 min. Add water and extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound as a white foam (0.054 g, 100 μmol). MS (m/z): 536.2 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[CH2:32][OH:33])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[H-].[Na+].[CH2:49](Br)[CH:50]=[CH2:51]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[CH2:32][O:33][CH2:51][CH:50]=[CH2:49])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(-c5ccccc5CO)nn4)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCc1ccccc1-c1cn(Cc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)nn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-(hydroxymethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.052 g, 0.082 mmol) in DMF (3 mL) was added 60% NaH (8.23 mg, 0.206 mmol) at 0° C. After 10 min allyl bromide (0.071 ml, 0.823 mmol) was added at once and stirred for 30 min at 0° C. and 1 h at rt. Then, quenched with EtOH, diluted with ether (50 mL), washed with water (3×5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-((allyloxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as yellow paste which was used in the next step without purification. LCMS (M+H)=672.7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#N)[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2].[PH2]([O-])=[O:21].[Na+]>O.N1C=CC=CC=1.C(O)(=O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]=[O:21])[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(C#N)cc12
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(C=O)cc12
Temperature: 100 °C

Procedure:
(2-Chloro-7-cyano-naphthalen-1-yl)-acetic acid ethyl ester (5.53 g, 20.20 mmol) is dissolved in a mixture of water (70 ml), pyridine (130 ml) and glacial acetic acid (70 ml). Sodium hypophosphite (17.13 g, 161.62 mmol) and Raney nickel (13 g) are added at RT. The reaction mixture is heated to 100° C. for 1 h. TLC analysis indicates complete consumption of starting material. The reaction mixture is cooled to RT, filtered through Celite and concentrated on a rotary evaporator. The residue is taken up in 2 M aqueous HCl. Extraction with EtOAc, removal of solvent and purification by FCC (hexane/EtOAc 5:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.28 (t, J=8.8 Hz, 3H), 4.22 (q, J=8.8 Hz, 2H), 4.39 (s, 2H), 7.68 (d, J=9.9 Hz, 1H), 7.83 (d, J=9.9 Hz, 1H), 7.95-8.03 (m, 2H), 8.48 (s, 1H), 10.2 (s, 1H). ES−-MS: 275.3, 277.3 [M+H]+.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>CC(O)C>[CH3:15][C:2]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc2ncccn2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In a thermally controlled reactor, stir a mixture of 2-bromo-1-[4-(trifluoromethyl)phenyl]propan-1-one (500 g, 1.78 mol, 1 equiv), IPA (5 L), 2-aminopyrimidine (205 g, 2.13 mol, 1.2 equiv), and sodium bicarbonate (298.8 g, 3.55 mol, 2 equiv) at 80° C. for 18 hours. Cool the suspension, and concentrate in vacuo. Dilute the resulting mixture in DCM (5 L), and wash with brine (2 L). Re-extract the brine wash with DCM (2.5 L); combine all the organic phases; and dry over MgSO4; filter; and collect the filtrate. Concentrate the filtrate to dryness under reduced pressure, and slurry the resulting red gum in Et2O (1.5 L). Collect the resulting solid by filtrate, and air dry for 45 min to give the title compound as a fine, off white solid (108 g, 22% yield). MS (m/z) 278 (M+1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][C:5](=[NH:19])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[C:22](OCC)(=[O:29])[CH2:23][C:24](OCC)=[O:25].C[O-].[Na+]>COCCO>[OH:29][C:22]1[N:19]=[C:5]([CH2:4][CH2:3][C:2]([F:20])([F:21])[F:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]([F:17])([F:18])[F:16])=[CH:11][CH:12]=2)[C:24](=[O:25])[CH:23]=1
Reactant: N=C(CCC(F)(F)F)Nc1ccc(OCC(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=c1cc(O)nc(CCC(F)(F)F)n1-c1ccc(OCC(F)(F)F)cc1

Procedure:
A mixture of 4,4,4-trifluoro-N-[4-(2,2,2-trifluoroethoxy)phenyl]butanimidamide (20.9 g), diethyl malonate (20.2 mL), sodium methoxide (10.8 g) and 2-methoxyethanol (400 mL) was heated under reflux overnight, and the reaction mixture was concentrated under reduced pressure. Similarly, a mixture of 4,4,4-trifluoro-N-[4-(2,2,2-trifluoroethoxy)phenyl]butanimidamide (22.6 g), diethyl malonate (21.8 mL), sodium methoxide (11.7 g) and 2-methoxyethanol (400 mL) was heated under reflux overnight, and the reaction mixture was concentrated under reduced pressure. The obtained residues were combined, and partitioned between diethyl ether and water. The aqueous layer was separated, to the organic layer was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained solid was suspended in diisopropyl ether. The precipitate was collected by filtration, washed with diisopropyl ether, and dried to give the title compound (41.6 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].S(C)C>O1CCCC1>[CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C#N
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1CN
Temperature: 70 °C
Reaction time: 15 h
Yield: 42.7 %

Procedure:
To a stirred solution of 2-methyl-4-nitrobenzonitrile (407 mg, 2.510 mmol) in tetrahydrofuran was added 2M BH3.SMe2 in tetrahydrofuran (2.1 mL). The reaction mixture was stirred for 15 h at 70° C. The mixture was cooled to room temperature, then quenched by water. The mixture dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to give (2-methyl-4-nitrophenyl)methanamine (178 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].I[CH2:34][C:35]([NH2:37])=[O:36]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[N:29][CH2:34][C:35](=[O:36])[NH2:37])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=N)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=NCC(N)=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl sulfoximide (500 mg, 0.00108 mol) in DMF(2.5 mL) was added Sodium hydride (170 mg, 0.0036mol) at 25-30° C. under nitrogen atmosphere. Reaction mixture was stirred at 40-45° C. for 3 hr. Reaction mixture was cooled to 0-5° C. and to this was added iodoacetamide (240 mg, 0.0013 mol) and stirred for 12 hr at 25-30° C. Subsequent work up and column purification (100-200 mesh silica gel, 2% methanol in chloroform) gave 90 mg of titled product in 16% yield.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:10][O:11][C:12](=[O:16])[C@@H:13]([CH3:15])[NH2:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:16])[C@@H:13]([CH3:15])[NH:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NCc1ccccc1
Temperature: 22 °C
Reaction time: 19 h
Yield: 80.5 %

Procedure:
Benzaldehyde (19 mL, 19 g, 0.18 mol) was added to a solution of D-alanine methyl ester hydrochloride (25 g, 0.18 mol) in dry CH2Cl2 (300 mL). The solution was stirred at 22° C. for 19 h. The reaction mixture was cooled with an ice-water bath and solid sodium triacetoxyborohydride (46 g, 0.22 mol) was added in portions over ˜15 min. The cooling bath was removed and the milky white solution was stirred at 22° C. for 7 h. The solvent was removed by rotary evaporation under reduced pressure and the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL). The aqueous layer was extracted with EtOAc (˜50 mL). The aqueous layer was adjusted to pH ˜10 with 1 N NaOH (450 mL) and the milky aqueous layer was extracted immediately with EtOAc (3×250 mL). The combined organic layers were washed with brine (˜250 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford N-benzyl-D-alanine methyl ester (28 g, 80%) as a colorless semi-solid.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([O:10][CH3:11])[N:5]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[N+:8]([O-:1])[CH:7]=[C:6]([O:10][CH3:11])[N:5]=1
Reactant: COc1cncc(Cl)n1
Reactant: OO
Solvent: CC(=O)O
Product: COc1c[n+]([O-])cc(Cl)n1

Procedure:
Hydrogen peroxide (1.5 ml. of 30%) is added to a solution of 10 mmole of 2-chloro-6-methoxypyrazine in 5 ml. acetic acid. The solution is heated at 60°-75° C. for 10-15 hours. The solution is concentrated to quarter volume, diluted with water and extracted with chloroform, washed, dried and evaporated to give 2-chloro-6-methoxypyrazine 4-oxide which may be crystallized from a suitable solvent such as ethanol.
Reaction SMILES: [CH2:1]([C:11]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl-:37].[Ca+2].[Cl-].Cl>C(Cl)Cl>[CH2:1]([C:11]([Cl:37])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [Cl-]
Reactant: CCCCCCCCCCCCCCC(O)(CCCCCCCCCC)CCCCCCCCCC
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(Cl)(CCCCCCCCCC)CCCCCCCCCC

Procedure:
One mole of di-n-decyl-n-tetradecylcarbinol is added to 0.2 liters of methylene chloride and 0.32 moles calcium chloride. Approximately 1.5 moles of HCl gas is slowly bubbled through the solution. The product mixture is then washed with 1 liter of a 10% sodium carbonate solution. The organic layer is dried with magnesium sulfate and the methylene chloride is evaporated off to give di-n-decyl-n-tetradecyl-methylchloride.