Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](Cl)(Cl)=[S:10].C(N(CC)CC)C>C1COCC1>[SH:10][C:9]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: Nc1cccnc1N
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Sc1nc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 9.8 %

Procedure:
To a solution of 2,3-diaminopyridine (286 mg, 2.62 mmol) in THF (10 ml) were added thiophosgene (300 mg, 2.62 mmol) and triethylamine (265 mg, 2.62 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=10:1) to provide 39 mg (yield 10%) of 2-mercaptoimidazolo[4,5-b]pyridine.
Reaction SMILES: [ClH:1].[ClH:2].Cl[CH2:4][C:5]1[N:6]=[C:7]([CH2:10][N:11]([CH3:13])[CH3:12])[S:8][CH:9]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[OH:26])[N:22]=[CH:21][N:20]=[CH:19]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:17]1[CH:18]=[C:23]([NH:22][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH2:4][C:5]4[N:6]=[C:7]([CH2:10][N:11]([CH3:13])[CH3:12])[S:8][CH:9]=4)=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][N:20]=2)[CH:24]=[CH:25][C:16]=1[Cl:2]
Reactant: COc1cc2cncnc2cc1O
Reactant: CN(C)Cc1nc(CCl)cs1
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 50 h
Yield: 30 %

Procedure:
N-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride hydrochloride (0.050 g, 0.220 mmol) and 4-[3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-ol (0.074 g, 0.220 mmol) were suspended in DMF (4 mL) and potassium carbonate (0.152 g, 1.10 mmol) was added. The mixture was stirred at room temperature for 50 h and then at 70° C. for 3.5 h. An additional portion of N-{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride hydrochloride (0.019 g, 0.084 mmol) was added and the mixture was stirred at 70° C. for a further 25 h. The reaction mixture was concentrated in vacuo. and the residue was partitioned between ethyl acetate and brine. The organic portion was washed with 1 N aqueous sodium hydroxide, brine, dried over sodium sulfate, filtered and concentrated in vacuo. to afford a brown solid. Recrystallization from ethyl acetate/diethyl ether afforded the title compound as a pale brown solid (0.016 g, 0.033 mmol, 15% yield). 1H NMR (400 MHz; CDCl3): 2.37 (s, 6H); 3.79 (s, 2H); 4.00 (s, 3H); 5.34 (s, 2H); 7.00 (s, 1H); 7.15 (br s, 1H); 7.34-7.37 (m, 2H); 7.55 (d, 1H); 7.57 (d, 1H); 7.96 (d, 1H); 8.66 (s, 1H); MS (EI) for C22H21Cl2N5O2S: 490 (MH+).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])C[CH2:12][CH3:13].[CH:15]1([O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH:24]=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C([Mg]Br)C.[Cl-].[NH4+:36]>O1CCCC1.CC#N.CCCCCC>[CH:15]1([O:20][C:21]2[CH:22]=[C:23]([CH:24]([NH2:36])[CH2:12][CH3:13])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: [Li]CCCC
Reactant: [NH4+]
Agent: CC[Mg]Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC#N
Product: CCC(N)c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice bath cooled stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (2.5M, 4.1 mL, 19.5 mmol) in tetrahydrofuran (5 mL) under nitrogen, was added a hexane solution of butyl lithium (7.2 mL, 18 mmol) via syringe. The ice bath was removed and the solution was stirred for 30 minutes at room temperature. This solution then was added dropwise to an ice bath cooled solution of 3-cyclopentoxy-4-methoxybenzaldehyde (3.3 g, 15 mmol) in tetrahydrofuran (5 mL) and the mixture stirred for 20 minutes. An ethereal solution of ethylmagnesium bromide (3M, 10 mL, 30 mmol) then was added dropwise. The reaction solution was allowed to reach room temperature and then was stirred at room temperature. The reaction progress was monitored by HPLC (Waters Nova-Pak/EC 18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 35/65, CH3CN/0.1% H3PO4 (aq)) and after 3 hours no starting material remained. The reaction mixture was slowly poured into a saturated solution of ammonium chloride (100 mL). The resulting mixture was extracted with methylene chloride (3×20 mL) and the combined extracts were dried over magnesium sulfate and concentrated in vacuo to yield 5.6 g of product which was further purified by flash column chromatography (silica gel, 250/10/1, methylene chloride/methanol/ammonium hydroxide) to afford 2.5 g (67%) of the product as an oil: 1H NMR (CDCl3) δ 6.91-6.77 (m, 3H), 4.85-4.74 (m, 1H), 3.83 (s, 3H), 3.74 (t, J=6.8 Hz, 1H), 2.02-1.15 (m, 12H), 0.86 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3) δ 148.8, 147.5, 138.8, 118.4, 113.3, 111.8, 80.3, 57.4, 56.0, 32.7, 32.4, 10.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=O)[C:3]=1[N+:10]([O-:12])=[O:11].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Temperature: 95 °C
Reaction time: 3 h
Yield: 180.4 %

Procedure:
A mixture of 4,6-dimethyl-3-nitro-2(1H)-pyridinone (step 1, 10.0 g, 29.7 mmol) in phosphorus oxychioride (35 mL, 187.3 mmol) was stirred at 95° C. for 3 h, then cooled to 45° C. The excess amount of phosphorus oxychloride was removed by distillation under reduced pressure at 45° C. The residue was cooled to room temperature, and diluted with dichloromethane (75 mL). The resulting solution was cooled to 0° C., and 2N hydrochloric acid (50 mL) was added dropwise into the solution. The organic layer was separated, and washed with 2N hydrochloric acid (4×25 mL), 2N aqueous NaOH (2×50 mL) and brine (50 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 10.0 g (90%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.07 (1H, s), 2.56 (3H, s), 2.35 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.COC(=O)C1C=CC(N)=C([C:87]([F:90])([F:89])[F:88])C=1>N1C=CC=CC=1>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([C:87]([F:90])([F:89])[F:88])[CH:10]=1
Reactant: COC(=O)c1ccc(N)c(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C(F)(F)F)c1
Yield: 74 %

Procedure:
This compound was synthesized in analogy to example 20, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 20, intermediate c), 4-amino-3-trifluoromethyl-benzoic acid methyl ester and using pyridine as a base to afford the title compound as a colorless solid (74%).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])/[CH:2]=[CH:3]/[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CCN(CC)CC.Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22](/[C:3](/[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:2]\[C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH:23]=1
Reactant: Brc1cccnc1
Reactant: CCOC(=O)/C=C/CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C(/CC(=O)OCC)c1cccnc1
Temperature: 40 °C
Yield: 87.1 %

Procedure:
To a solution of 15 mL (85.6 mmol) of diethyl (2E)-pent-2-enedioate in 5 mL of anhydrous DMF are added, under a stream of argon, 0.62 g (2.8 mmol) of Pd(OAc)2, 1.7 g (5.56 mmol) of P(OTol)3 and 5.5 mL (39.7 mmol) of Et3N, the medium is then heated to 40° C. and 4 mL (39.75 mmol) of 3-bromopyridine are added. The medium is then heated for 24 hours at 90° C., and then taken up in 100 mL of EtOAc, washed with 100 mL of water, dried over Na2SO4, concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 9.12 g of diethyl (2Z)-3-(pyridin-3-yl)pent-2-enedioate are obtained in the form of a yellow wax.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(COC)OC.C(Cl)[Cl:32]>>[ClH:32].[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([Cl:32])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: ClCCl
Solvent: COCCOC
Product: Cl
Product: O=C(Cl)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A cold solution of 25 g. 4-(8-cyclohexyloctylamino)benzoic acid in 500 ml. dimethoxyethane-methylene chloride (4:1) is prepared and dry hydrochloric acid is bubbled through the solution until no more precipitate forms. The solution is treated with 25 ml. thionyl chloride and refluxed until all of the precipitate has dissolved. The solvents are evaporated to yield an orange, semi-crystalline mass.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]1)[CH3:2].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[OH:26])[CH:21]=O)[CH3:16].[CH3:27][C:28]1(C)OC(=O)CC(=O)[O:29]1>CCO>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[CH2:27][C:28](=[O:29])[NH:14][C:13]3[N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:1][CH3:2])[N:10]=[CH:11][C:12]2=3)[CH:23]=[CH:24][C:25]=1[OH:26])[CH3:16]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCc1ccccc1-n1nccc1N
Reactant: CCOc1cc(C=O)ccc1O
Solvent: CCO
Product: CCOc1cc(C2CC(=O)Nc3c2cnn3-c2ccccc2CC)ccc1O
Temperature: 75 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To 2-(2-Ethyl-phenyl)-2H-pyrazol-3-ylamine 3 (25.9 mmol) in EtOH (150 mL) was added 3-Ethoxy-4-hydroxy-benzaldehyde 5 (28.5 mmol), followed by Meldrum's Acid 4 (28.5 mmol). The reaction mixture was heated to 75° C., then after 2 hours, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was treated with water (100 mL) and the product was extracted with dichloromethane (200 mL). The organic extract was dried over anhydrous magnesium sulfate and the solvent was removed at reduced pressure. The residue was purified by column chromatography t to provide (11 mmol) of 4-(3-Ethoxy-4-hydroxy-phenyl)-1-(2-ethyl-phenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-b]pyridin-6-one 6. 1H NMR (300 MHz, CDCl3/TMS) δ 7.44-7.35 (m, 3H), 7.30-7.25 (m, 2H), 5.57 (d, J=2.1 Hz, 1H), 3.57 (br s, 2H), 2.49 (q, J=7.6 Hz, 2H), 1.10 (t, J=7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3/TMS) δ 145.20, 142.60, 139.62, 135.93, 129.47, 129.41, 127.88, 126.55, 88.70, 24.04, 14.34.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].COCCOC.[F:15][C:16]([F:22])([F:21])[S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[F:15][C:16]([F:22])([F:21])[S:17]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])(=[O:19])=[O:18]
Reactant: O=C1CCC(=O)N1O
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: ClCCl
Product: O=C1CCC(=O)N1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 71.6 %

Procedure:
N-Trifluoromethanesulfonyloxysuccinimide was prepared by the following procedure. To a dried flask equipped with a stirrer, under nitrogen, were added N-hydroxysuccinimide (2.10 g, 18.2 mmol), 60 mL of dried DME, and trifluoromethanesulfonyl chloride (2.00 mL, 18.7 mmol). The mixture was cooled in ice, and triethylamine (3 mL, 22 mmol) was added dropwise by syringe. After warming the reaction mixture to room temperature, 150 mL of methylene chloride was added and the organic layer was washed with water (3×100 mL) and dried. Evaporation of the solvent left 3.80 g of a white solid. Recrystallization from methylene chloride-hexane gave 3.22 g (71.6%) of N-trifluoromethanesulfonyloxysuccinimide: mp 122°-123°. A doubly recrystallized sample was prepared: mp 126°-127°; ir (KBr) 1695 (s), 1440 (s), 1230 (m), 1210 (m), 1140 (m), 1120 (m), 1030 (m), 790 (s), 590 (s); uv (CH3CN) 234 nm (shoulder) (ε=130); nmr (CDCl3) 2.85 (s); 19F nmr -71.54 ppm (s); mass spectrum 246.9781 (calcd for C5H4NO5F3S: 246.9762). Anal. Calcd for C5H4NO5F3S: C, 24.30; H, 1.63; N, 5.67; O, 32.37; F, 23.06; S, 12.97. Found: C, 24.16; H, 1.57; N, 5.95.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([O:13][C:14](=[O:30])[CH2:15][N:16]([C:18](=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])[CH3:17])[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].Cl[C:33]1[C:42]2[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=2)[N:36]=[C:35]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[OH:50])[N:34]=1.C(N(CC)CC)C>C(Cl)Cl.O>[OH:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[C:35]1[N:34]=[C:33]([N:10]2[CH2:11][CH2:12][N:7]([C:5]([CH:4]([O:13][C:14](=[O:30])[CH2:15][N:16]([C:18](=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH3:21])[CH3:17])[CH2:3][CH:2]([CH3:31])[CH3:1])=[O:6])[CH2:8][CH2:9]2)[C:42]2[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=2)[N:36]=1
Reactant: CC(C)CC(OC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C)C(=O)N1CCNCC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)C(CC(C)C)OC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The amine was taken up in 1 mL CH2Cl2 and treated with 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (53 mg, 0.19 mmol) and 49 μL of triethylamine, and stirred at room temperature for 3 h. The reaction mixture was diluted with 10 mL of CH2Cl2 and 10 mL of water. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid 1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carbonyl}-3-methyl-butyl ester. LC/MS: m/z 677.4 (M+H)+ at 3.25 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].[OH-].[Na+].C([O:10][C:11](=O)[C:12](=[CH:16]OCC)[N+:13]([O-:15])=[O:14])C>O>[OH:10][C:11]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:16][N:4]=[C:3]([S:2][CH3:1])[N:5]=1
Reactant: CCOC=C(C(=O)OCC)[N+](=O)[O-]
Reactant: CSC(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ncc([N+](=O)[O-])c(O)n1

Procedure:
104.5 gm of S-methyl-isothiourea (0.75 mol) and 53.3 gm (1.333 mol) of sodium hydroxide solution are stirred together for 10 minutes in 350 ml of water. 114.5 gm (0.605 mol) of ethyl-ethoxymethylene-nitroacetate are then slowly added thereto, the temperature being kept at 20° C. by cooling. The precipitate is extracted and washed with a little ice-cold water. It is dissolved in approximately 9 liters of hot water and acidified with concentrated hydrochloric acid with cooling. The precipitated product is extracted and washed with ether.
Reaction SMILES: [F:1][C:2]([F:28])([C:6]([F:27])([F:26])[C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])C(O)=O.[Br:29]Br.FF>>[F:1][C:2]([Br:29])([F:28])[C:6]([F:27])([F:26])[C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13]
Reactant: BrBr
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Yield: 142.9 %

Procedure:
Perfluorononanoic acid 100 g (0.215 mole), bromine 21.0 g (0.129 mole) and Freon 113 (500 ml) were mixed in the plastic reactor. The mixture was treated with fluorine in the same manner as described in Example 1. Approximately 1.7 fold excess fluorine was used, producing 92 grams of perfluorooctyl bromide (86% yield). Thus, using approximately half the amount of bromine as used in Example 1 produced a lower yield of the perfluoroalkyl halide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]([C:20]#[C:21][C:22]([O:24][CH3:25])=[O:23])=[O:19]>[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:19])/[C:20](/[O:15][C:6]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:21]/[C:22]([O:24][CH3:25])=[O:23]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COC(=O)C#CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: COC(=O)/C=C(\Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)OC

Procedure:
A mixture of 5 parts of 2,4-di-t-butylphenol, 3.55 parts of acetylene dicarboxylic acid dimethyl ester and four drops of benzyl-trimethylammonium hyroxide were heated on a steam bath for 20 min. The 2,4-di-t-butylphenoxyfumaric acid dimethyl ester formed was hydrolysed by heating with 2.8 parts of sodium hydroxide in 15 parts by volume of water and 8 parts by volume of methanol. The hydrolysis was complete when one layer was obtained. The methanol was boiled off and the solution was cooled and acidified with concentrated hydrochloric acid. The crude 2,4-di-t-butylphenoxyfumaric acid was liberated as an oil, and was extracted into ether. This acid was purified by extraction with sodium bicarbonate solution which was washed well with ether. Acidification of the sodium bicarbonate solution gave the purified fumaric acid which was extracted again into ether. The dried ether extracts were evaporated to give the fumaric acid as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:10]1[CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:13]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:39](=O)[CH2:40][CH:41]([CH3:43])[CH3:42].CC(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:10]1[CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=2)[CH:13]=[C:14]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:20][CH:19]=2)[CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH:15]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(NCc2ccc(C(C)(C)C)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC(C)CC=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(CCC(C)C)Cc2ccc(C(C)(C)C)cc2)c1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 2-[5-(4-tert-Butyl-benzylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester, compound 37a, (0.06 g, 0.11 mmol), isovaleraldehyde (0.36 mL, 3.3 mmol), AcOH (0.01 mL) in DCM (10 mL) was stirred at room temperature overnight. NaCNBH4 (0.01 g, 0.16 mmol) added and resulting solution was stirred 30 min. The crude product was purified by TLC plate to give the title compound at 50% yield. Calcd MW 595.8. Found MH+ 596.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([NH:19][C:12]([C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:14])[CH:16]([CH3:18])[CH3:17]
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Reactant: CC(C)CN
Product: COc1ccc(C2(C(=O)NCC(C)C)CC2)cc1
Yield: 97 %

Procedure:
Prepared in a similar manner to Example 35a starting from 1-(4-methoxyphenyl) cyclopropanecarboxylic acid and isobutyl amine. Yield: 97%. MS+H (248).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][N:12]([CH3:25])[CH2:13][CH2:14][CH2:15][C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][CH:17]=1.[OH-].[Na+]>O.ClCCl>[CH3:25][N:12]([CH3:11])[CH2:13][CH2:14][CH2:15][C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][C:17]=1[CH:3]=[O:4]
Reactant: CN(C)CCCc1c[nH]c2c1CCCC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Dimethylformamide (0.8 g) and 13 mL of dichloromethane was cooled to −9° C. Phosphorus oxychloride (1.7 g) was. rapidly added via a dropping funnel. 3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indole (2 g) was added in portions with vigorous stirring. The mixture was warmed to room temperature and then refluxed for 10 minutes. It was then cooled to 5° C., and diluted with 20 mL of water. The pH was adjusted to 10 with 10N sodium hydroxide. The layers were separated. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to give 1.8 g (80%) of 3-(3-dimethylaminopropyl)-2-formyl-4,5,6,7-tetrahydro-1H-indole as a dark oil which solidified.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N:18]1C=CC=CC=1.C[CH2:25][OH:26]>>[CH3:25][O:26][N:18]=[C:11]([C:3]1[CH:4]=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: c1ccncc1
Reactant: CCCCCC(=O)c1cc(C#N)c(=O)[nH]c1C
Reactant: CCO
Product: CCCCCC(=NOC)c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
A mixture of 1,2-dihydro-6-methyl-2-oxo-5-(1-oxohexyl)-3-pyridinecarbonitrile (0.80 g, 0.0038 mol) and pyridine (2.0 ml) were heated and stirred at reflux overnight in EtOH (30.0 ml). The solution was allowed to cool to room temperature and the solvent was removed on the rotary evaporator. The pasty residue was triturated with H2O, filtered and recrystallized (EtOH-H2O) giving 0.5 g (56%) m.pt. 159°-165° C. One more recrystallization gave the analytical sample m.pt. 170°-171° C.
Reaction SMILES: [CH3:1][CH:2]([NH2:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]>>[NH3:10].[NH2:10][CH:2]([CH3:1])[CH2:3][C:4]1[CH2:9][CH:8]=[CH:7][CH2:6][CH:5]=1
Reactant: CC(N)Cc1ccccc1
Agent: [Li]
Product: CC(N)CC1=CCC=CC1
Product: N

Procedure:
12 g. (0.09 moles) of α-methylphenethylamine is reduced by treatment with 4 g. of lithium in 0.5 l. of ammonia according to procedure of Example 1(a) to yield 1-(2-aminopropyl)-1,4- cyclohexadiene.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].CN1[CH2:18][CH2:17][O:16]CC1.[Cl:19][C:20]1[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27]C=1)C(Cl)=O>C(Cl)Cl>[C:4]([C@@H:5]([NH:6][C:17](=[O:16])[C:18]1[CH:27]=[CH:26][CH:22]=[C:21]([CH2:20][Cl:19])[CH:29]=1)[CH2:7][CH2:8][S:9][CH3:10])([O:3][CH3:2])=[O:11]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1c(Cl)cccc1C(=O)Cl
Reactant: CN1CCOCC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CCl)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of (S) methionine methyl ester hydrochloride (10.56 g, 52.9 mmol) and 4-N-methylmorpholine (21.34 g, 211.6 mmol) under nitrogen in 200 mL of methylene chloride at 0° C. was added 3-chloro-methyl benzoyl chloride (10.00 g, 52.9 mmol) dropwise via syringe. After addition the cooling bath was removed and the resulting solution was stirred for 16 h at 20° C. The methylene chloride solution was extracted with 125 mL each of water, 2% potassium hydrogen sulfate, saturated sodium hydrogen carbonate, and saturated sodium chloride. The methylene chloride was dried over magnesium sulfate and concentrated in vacuo to the title compound as an oil. 1HNMR (300 MHz, CDCl3)δ 7.85 (1H, s), 7.76 (1H, d, J=8 Hz), 7.56 (1H, d, J=8 Hz), 7.45 (1H, t, J=8 Hz), 6.96 (1H, d, J=7 Hz), 4.94 (1H, q, J=5 Hz), 4.62 (2H, s), 3.81 (3H, s), 2.60 (2H, t, J=8 Hz), 2.30 (1H, m), 2.15 (1H, m), 2.12 (3H, s).