Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2](=[CH2:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].C(Cl)C=C[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1([CH:8]=[CH:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCC=Cc1ccccc1
Reactant: C=C(C)CCC(C)=O
Solvent: CCO
Product: CC(=O)CCC=Cc1ccccc1

Procedure:
The synthesis was similar to that used for 5-methyl-5-hexen-2-one. Materials that were used: cinnamyl chloride (100 g, 0.655 mole, Acros Organic), pentadione (72 g, 0.72 mole), and ethanol (460 mL). Product, 70-75° C., 0.1 mmHg, 48 g (42%). 1H-NMR (CDCl3, δ): 2.15 (s, 3H); 2.16 (m, 2H); 2.60 (m, 2H); 6.17 (m, 1H), 6.42 (d, 1H), 7.2-7.33 (m, 5H).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]2[C:28]([CH3:33])=[N:29][CH:30]=[C:31]([CH3:32])[C:20]=12>C(Cl)(Cl)Cl>[CH3:33][C:28]1[N:21]2[C:22]3[C:27]([C:19]([CH2:18][CH2:17][N:13]4[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:11][CH2:12]4)=[C:20]2[C:31]([CH3:32])=[CH:30][N:29]=1)=[CH:26][CH:25]=[CH:24][CH:23]=3
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: Cc1cnc(C)n2c1c(CCCl)c1ccccc12
Solvent: ClC(Cl)Cl
Product: Cc1cnc(C)n2c1c(CCN1CCC(NC(=O)c3ccccc3)CC1)c1ccccc12
Yield: 48.7 %

Procedure:
An intimate mixture of powdered 4-benzoylaminopiperidine (4.08 g) and 5-(2-chloroethyl)-1,4-dimethylpyrimido[1,6-a]indole (5.18 g. described in Example 12) is heated at 150°-160° C. for 30 minutes. After cooling, the melt is dissolved in chloroform, washed with 10% sodium hydroxide and repeatedly with water. The organic phase is dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel using chloroform-methanol (35:1). The eluates are evaporated and the residue is crystallized from ethanol-diethyl ether to give 4.15 g of the title compound, mp 233°-234° C. The title compound is coverted to the dihydrochloride salt and crystallized from methanol; mp 247° C.; ir (nujol) 3255, 2450 and 1625 cm-1 ; uv(MeOH) λmax 256, 297, 309 and 322 nm; ε=33700, 6000, 9050 and 10880, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C([BH3-])#N.[Na+]>CO>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:18][CH2:11][CH2:10][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9]
Reactant: COC(=O)CN
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)CNCCN(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a solution of N-t-butoxycarbonylsarcosinal (1.50 g) and glycine methyl ester hydrochloride (1.63 g) in methanol (60 ml) was added a solution of sodium cyanoborohydride (544 mg) in methanol (10 ml) at ambient temperature. The mixture was stirred overnight at the same temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml), and the solution was washed with 1 M sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (chloroform as eluent) to give N-[2-(N-t-butoxycarbonyl-N-methylamino)ethyl]glycine methyl ester (1.04 g) as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[CH3:23])(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[CH3:23])(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccncc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cnccc2C)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (127 mg) in ethyl acetate (2 mL) and 2-propanol (0.5 mL) was added 4N hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine as a pale-yellow oil (yield 97 mg, 97%). A solution of the obtained 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (30 mg) in ethanol (2 mL) and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 103 mg, 81%).
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]2[N:25](CC3C=CN=CC=3)[C:26]([S:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=3)=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=2)=[O:21])(=[O:16])[O:9]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].[CH3:50][C:51]#[N:52]>>[C:1]1([O:7][P:8]([CH2:17][CH2:18][NH:19][C:20]([O:22][CH:23]([C:24]2[NH:25][C:26]([S:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=3)=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=2)[CH2:3][C:2]2[CH:1]=[CH:6][N:52]=[CH:51][CH:50]=2)=[O:21])(=[O:16])[OH:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC#N
Reactant: CC(C)c1nc(COC(=O)NCCP(=O)(Oc2ccccc2)Oc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)c1nc(C(Cc2ccncc2)OC(=O)NCCP(=O)(O)Oc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of phosphonate 31 (11 mg, 0.015 mmol) in CH3CN (0.5 mL) was added 1N LiOH (46 μL, 0.046 mmol) at 0° C. See Scheme 21 (FIG. 23). After the reaction mixture was stirred for 2 h at 0° C., Dowex 50WX8-200 (26 mg) was added and stirring was continued for an additional 30 min. The reaction mixture was filtered, rinsed with CH3CN, and concentrated under reduced pressure to give {2-[5-(3,5-dichloro-phenylsulfanyl)-4-isopropyl-1-pyridin-4-ylmethyl-1H-imidazol-2-ylmethoxycarbonylamino]-ethyl }-phosphonic acid monophenyl ester 32 (10 mg, 100%) as a colorless oil. 1H NMR (300 MHz, CD3OD) δ 8.52 (d, 2H), 7.28 (m, 6H), 6.79 (m, 4H), 5.60 (s, 2H), 5.29 (s, 2H), 3.29 (m, 3H), 1.83 (m, 2H), 1.31 (d, 6H). 31P NMR (300 MHz, CD3OD) δ 20.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:20])([CH3:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([C:21]#[C:22][CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[CH:4][N:3]=1.[CH3:30][CH2:31]CC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:21]=[C:22]([CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[N:8]([C:9]3([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH2:19][CH2:31][CH2:30][CH2:20]3)[C:6]=2[N:7]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCOC(C#Cc1cnc(Cl)nc1NC(C)(C)CNC(=O)OC(C)(C)C)OCC
Agent: [F-]
Product: CCOC(OCC)c1cc2cnc(Cl)nc2n1C1(CNC(=O)OC(C)(C)C)CCCC1

Procedure:
tert-butyl N-[[1-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]methyl]carbamate is synthesized by treating tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamate with TBAF using similar experimental conditions as described for the synthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) 4534 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([O:14]COCC)([CH2:12][F:13])[CH2:10][F:11].[Li]CCCC.[B:24](OC)(OC)[O:25]C.CC(=O)OCC>C1COCC1>[F:11][CH2:10][C:9]1([CH2:12][F:13])[O:14][B:24]([OH:25])[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]1=2
Reactant: COB(OC)OC
Reactant: CCOCOC(CF)(CF)c1cc(C)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)C(CF)(CF)OB2O
Reaction time: 0.17 h
Yield: 32.4 %

Procedure:
To a solution of 1-bromo-2-(2-(ethoxymethoxy)-1,3-difluoropropan-2-yl)-4-methylbenzene (1.8 g, 5.10 mmol) in THF (15 mL) at −78° C. was slowly added n-BuLi (5.1 mL, 12.75 mmol). After stirring for 10 min, a solution of B(OMe)3 (1.06 g, 10.2 mmol) in dry THF (5 mL) was added dropwise. The mixture was stirred at −78° C. for 0.5 h, and then dry ice bath was removed. The solution was acidified with HCl (4 N) and extracted with EA (100 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (5:1 to 3:1) to give the desired compound (350 mg, yield 32%) as white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)([CH3:13])[CH3:12]>C1COCC1>[CH2:12]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH2:11][CH3:13]
Reactant: [Li]C(C)(C)C
Reactant: c1ccc2sccc2c1
Solvent: C1CCOC1
Product: CCCc1cc2ccccc2s1

Procedure:
2-n-Propylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 9.7 mmoles, 5.7 ml), n-bromopropane (9.7 mmoles, 0.88 ml) and THF (20 ml). 1.11 g (85%) of a light yellow liquid was isolated.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:7][C:8]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:9]=1[C:10]#[N:11].Cl[C:26]1[CH:27]=[C:28]2[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1>>[C:10]([C:9]1[CH:12]=[C:13]([CH:14]=[CH:15][C:8]=1[O:7][C:6]1[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:4]([F:3])[CH:5]=1)[CH2:16][O:17][C:26]1[CH:27]=[C:28]2[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cc(F)cc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 2-(3-fluoro-5-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH:10](O)[CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][C:5]1([CH3:17])[C:6]2[C:14](=[CH:13][C:12]3[CH:11]=[CH:10][CH2:9][C:8]=3[CH:7]=2)[C:2]([CH3:18])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CC(O)C3
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)C=CC3
Yield: 60.9 %

Procedure:
A 1 L round bottom flask fit with a magnetic stirrer, condenser, thermometer, and nitrogen inlet was charged with anhydrous toluene (7 mL, Aldrich), the crude 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indan-2-ol (31.0 g, 0145 mol), pyridine (31.6 mL, 0.39 mol, Aldrich), and p-toluenesulfonyl chloride (30.4 g, 0.16 mol, Aldrich). The mixture was heated to reflux and cooled for GC analysis periodically for a total reflux time of 2 hours. The reaction was then quenched in 5% HCl (250 mL) and extracted into diethyl ether (200 mL). The ether extract was washed with 5% HCl (200 mL), 5% aqueous sodium bicarbonate (until neutral to pH paper), Water (2×200 mL), and dried over anhydrous magnesium chloride. Removal of solvents by rotary evaporation gave 23.0 g of crude product which was purified by chromatography on silica gel (60 g silica gel/hexane eluent) to give 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indene (17.5 g, 92-99+% pure by GC). 1HNMR (CDCl3, 500 MHz) δ7.44 (s, 1H); 7.36 (s, 1H); 6.82 (br d, J=5.5 Hz, 1H); 6.47 (br d, J=5.5 Hz, 1H); 3.51 (s, 2H); 1.70 (s, 4H); 1.32 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[I:14][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[O:9][CH3:10]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: COc1cc(OC)c([N+](=O)[O-])cc1I
Temperature: 25 °C

Procedure:
To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in glacial acetic acid (30 mL) is added benzyltrimethylammonium dichloroiodate (1.90 g) and anhydrous zinc chloride (1.0 g) and the mixture is stirred at room temperature under an atmosphere of argon. Additional benzyltrimethylammonium dichloroiodate (0.4 g) is added after 5 hours and again after 24 hours. Additional zinc chloride (0.5 g) and glacial acetic acid (15 mL) is added after 24 hours. The mixture is permitted to stir at room temperature for 3 days and is then filtered, diluted with 5% aqueous sodium bisulfite, and extracted three times with ethyl acetate. These pooled organic extracts are washed successively with 5% aqueous sodium bisulfite, saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is triturated with hexanes to provide the desired product as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a solution of 4-fluorophenylmagnesium bromide (110.0 mmol, 55.0 mL of 2.0 M solution) in 150.0 mL THF at 0° C. was added 1-benzyl-4-piperidone (55.0 mmol, 10.2 mL) dropwise. The resulting solution was stirred under argon atmosphere for 1.5 h and then quenched with 100.0 mL of saturated NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with 100.0 mL of Et2O. The combined organic extracts were washed with brine, separated and dried over Na2SO4. The solution was filtered and the solvent was removed in vacuo to obtain a yellow oil which was purified by passing through a silica gel column with 4:1 hexane/EtOAc followed by 1:1 hexane/EtOAc as the eluting system. 1-Benzyl-4-(4-fluoro-phenyl)-piperidin-4-ol was obtained as a pale yellow oil in 89% yield (13.9 g). It was dissolved in 150.0 mL of toluene and p-toluenesulfonic acid monohydrate (50.0 mmol, 9.5 g) was added. The resulting suspension was heated to reflux for 8 h. After the suspension was cooled, it was basified with 3 N NaOH solution and was extracted with Et2O (2×50 mL). The organic extracts were combined, washed with brine and the oraganic layer was dried over Na2SO4. The solvent was removed in vacuo to obtain 1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine as a yellow viscous oil (12.0 g, 92% yield) which was used in the next step without further purification.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[P:7]([O-:12])([O:10][CH3:11])[O:8][CH3:9]>C1C=CC=CC=1>[CH3:9][O:8][P:7]([CH:2]([OH:1])[C:3]([Cl:6])([Cl:5])[Cl:4])(=[O:12])[O:10][CH3:11]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: COP([O-])OC
Solvent: c1ccccc1
Product: COP(=O)(OC)C(O)C(Cl)(Cl)Cl

Procedure:
In another process, Pesticide Manufacturing and Toxic Materials Control Encyclopedia, edited by Marshall Sittig, Noyes Data Corporation, Park Ridge, N.J. 1980, 75 grams of chloral are dropped into 60 grams of dimethyl phosphite at an initial temperature of 25° C. The temperature slowly rises to 50° C. and is kept at 50° C. to 60° C. by external cooling. After cooling the oil is dissolved in benzene, and the benzene solution is washed with a sodium bicarbonate solution and dried with anhydrous sodium sulfate. After the solvent has been distilled off, an oil is left which is almost completely solidified. After washing with an icy mixture of ether and petroleum ether, the trichloro-α-hydroxyethyl phosphonic dimethyl ester is obtained in the form of colorless needles with a melting point of about 81° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C@@H:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25]Br>CC(=O)CC>[CH3:21][C@@H:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC[C@H](C)CCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC[C@H](C)CCCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 10 h
Yield: 91.3 %

Procedure:
A reaction vessel was charged with 1.1 g of 4-hydroxy-4'-bromobiphenyl, 20 ml of 2-butanone, 1.2 g of potassium carbonate and 0.95 g of (S)-4-methylhexyl bromide, and the mixture was refluxed with stirring until TLC showed the disappearance of the starting materials. It took 10 hours for this. The reaction liquid was filtered to remove solids and the filtrate was concentrated. The residue was dried under reduced pressure to obtain 1.4 g (93%) of (S)-4-(4-methylhexyl)oxy-4'-bromobiphenyl.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:14]([CH2:15][CH2:16][CH3:17])[C:12]1[C:11]([C:19]([F:21])([F:20])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {5-(methyl-propyl-amino)-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M74) (0.54 g, 0.95 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (230 mg, 54%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][S:14][CH3:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH:20]([CH3:22])[CH3:21].C(Cl)CCl>O1CCOCC1.CN(C1C=CN=CC=1)C>[CH2:19]([O:17][C:16](=[O:18])[C@H:11]([CH2:12][CH2:13][S:14][CH3:15])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CO
Reactant: CSCC[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)Cc1ccccc1)C(=O)OCC(C)C
Temperature: 23 °C
Reaction time: 17 h

Procedure:
N-Phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolved in 3.0 mL dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol), and catalytic DMAP (0.015 g). After stirring for 17 hours at 23° C., the mixture was evaporated at reduced pressure to an oil, the residue was diluted in EtOAc and washed with 0.1 N HCl and saturated sodium bicarbonate. Chromatography on silica gel using 98:2 CHCl3/MeOH as eluant provided the pure product.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=2[CH3:23])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.[OH-:24].[Na+]>O>[NH2:1][C:2]1[N:3]([C:16]2[C:17]([CH3:23])=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:2][CH2:6][C:7]([OH:15])=[O:24])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12
Reactant: Cc1c(O)cccc1-n1nc2c(c1N)c(=O)[nH]c1ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1c(OCCC(=O)O)cccc1-n1nc2c(c1N)c(=O)[nH]c1ccccc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-amino-2-(3-hydroxy-2-methylphenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (100 mg), 1N aqueous sodium hydroxide solution (326 μl) and water (3 ml) was added dropwise γ-propiolactone (25 μl) at 80° C. The mixture was stirred at 80° C. for 2 hours, after stirring, cooled to room temperature, and the insoluble materials were filtered off. pH of the filtrate was adjusted to about 2 by adding 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and dried to obtain the target compound (8 mg).
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[F:6][C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1>O.Cl.C(OCC)C>[N:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=1)=[N+:14]=[N-:1]
Reactant: NNc1cccc(F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
Sodium nitrite (262 mg) dissolved in 1.0 ml of water was dropped, under cooling with ice, into a solution of 500 mg of 3-fluorophenylhydrazine hydrochloride in 2.5 ml of concentrated hydrochloric acid and 3.0 ml of diethyl ether. Temperature of the reaction solution was raised to room temperature followed by stirring for 3 hours. The reaction solution was diluted with diethyl ether, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 252 mg of the title compound as a brown oily crude product.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>CO.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(Oc2ccccn2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Oc2ccccn2)cc1-c1ccccc1

Procedure:
A solution of the resultant ester from Example 6B (1.0 equivalent) in aqueous methanol is treated with NaOH (2.0 equivalents) and stirred until the reaction is deemed complete by TLC analysis. The mixture is acidified, diluted with water, and extracted into ethyl acetate which is dried and evaporated. Chromatography on silica gel provides the title product.