Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(OC(=O)CC)(=O)CC.C(OC(=O)CCC)(=O)CCC.C1(=O)OC(=O)CC1.C1(=O)OC(=O)CCC1.C1(=O)OC(=O)CCCC1.[C:52]([F:59])([F:58])([F:57])[C:53](Cl)([Cl:55])[F:54]>[Zn]>[C:52]([C:53]([CH2:1][OH:3])([F:54])[Cl:55])([F:59])([F:58])[F:57]
Reactant: FC(F)(F)C(F)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Agent: CCC(=O)OC(=O)CC
Agent: CCCC(=O)OC(=O)CCC
Agent: O=C1CCC(=O)O1
Product: OCC(F)(Cl)C(F)(F)F

Procedure:
This reaction may be run as described with addition of both reagents in the same reaction vessel or the acid anyhydride may be added alone to produce CF3CClFCH2OC(═O)CH3, which may be isolated. And then the reactive metal may be added to the CF3CClFCH2OC(═O)CH3 to produce the HFO-1234yf. In this process the carboxylic acid anhydride is selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, succinic anhydride, glutaric anhydride, and adipic anhydride. The reactive metal powder is as described previously herein. The reductive dehydroxychlorination can be done without neutralizing the product mixture from the reaction of CFC-114a with zinc and an aldehyde. Or the reductive dehydroxychlorination may be done after first isolating the CF3CClFCH2OH, and then esterification by reaction with a carboxylic acid anhydride and a reactive metal to form CF3CClFCH2OC(═O)CH3. Any of these dehydroxychlorinations produce Composition C as described above.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([NH:25][C:26]([C@@H:28]3[C@H:33]4C[C@H:30]([CH2:31][CH2:32]4)[NH:29]3)=[O:27])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.NC1C(C2OC(NC([C@@H]3CCCN3)=O)=NN=2)=NC(C2C=CC(S(C(C)C)(=O)=O)=CC=2)=CN=1>>[NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([NH:25][C:26]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)=[O:27])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:18])[CH3:19])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)[C@H]4N[C@H]5CC[C@@H]4C5)o3)n2)cc1
Agent: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)[C@@H]4CCCN4)o3)n2)cc1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)[C@@H]4CCCCN4)o3)n2)cc1

Procedure:
Compound IA-160 (1R,4S,6S)—N-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]-5-azabicyclo[2.2.1]heptane-6-carboxamide 1H NMR (400.0 MHz, DMSO) d 1.18 (d, 6H), 1.34-1.45 (m, 2H), 1.55-1.76 (m, 4H), 2.68 (br d, 1H), 3.44-3.52 (m, 1H), 3.64 (s, 0.6H), 3.76 (s, 0.4H), 4.25 (s, 0.6H), 4.33 (s, 0.4H), 7.88 (d, 1.2H), 7.90 (br s, 2H), 7.92 (d, 0.8H), 8.31 (d, 0.8H), 8.53 (d, 1.2H), 9.00 (d, 1H), 10.43 (s, 0.4H) and 10.86 (s, 0.6H) ppm; MS (ES+) 484.3 Compound IA-217 (25)-N-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]pyrrolidine-2-carboxamide 1H NMR (400.0 MHz, DMSO) d 1.18 (d, 6H), 1.67-1.72 (m, 1H), 2.04-2.21 (m, 2H), 3.00 (br s, 2H), 3.35-3.41 (m, 1H), 3.45-3.59 (m, 3H), 4.28-4.34 (m, 1H), 7.82 (br s, 2H), 7.88-7.92 (m, 2H), 8.44-8.53 (m, 2H), 9.00-9.01 (2×s, 1H) and 10.87 (s, 1H) ppm; MS (ES+) 458.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[C:9]=2[O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.Cl.C[CH2:39][O:40]C(C)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[C:9]=2[O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]([O:40][CH3:39])=[O:26])=[C:23]([C:29]([F:30])([F:31])[F:32])[CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc2cc(O)ccc2c(Oc2ccc(C=O)c(C(F)(F)F)c2)c1-c1cccc(F)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2c(-c3cccc(F)c3)c(C)cc3cc(O)ccc23)cc1C(F)(F)F
Temperature: -20 °C
Reaction time: 3 h

Procedure:
A stirring solution of 286 (0.30 g, 0.62 mmol) in CH2Cl2 (10 mL) was chilled to −20° C. under N2 and BBr3, 1 M in CH2Cl2 (2.86, 2.86 mmol, 1 M), was added drop wise. The resulting orange-brown reaction was stirred at −20° C. for 3 h and the reaction then poured onto ice followed by 1 N HCl (20 mL) and EtOAc (100 mL).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:14][CH3:15])=[N:7]2.[C:16]([Cu])#[N:17].O.C(N)CN>CN(C=O)C>[C:16]([C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:14][CH3:15])=[N:7]2)#[N:17]
Reactant: N#C[Cu]
Reactant: COc1ccc2nc(SC)ccc2c1Br
Solvent: NCCN
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nc(SC)ccc2c1C#N
Temperature: 150 °C
Yield: 86.8 %

Procedure:
A mixture of 5-bromo-6-methoxy-2-methylthioquinoline (6.1 g, 21 mmol) and CuCN (3.7 g, 41 mmol) in DMF (80 mL) was heated at 150° C. for 14 hours. The mixture was cooled and treated sequentially with 2:1 H2O/ethylenediamine (15 mL). The mixture was extracted with 1:1 EtOAc/hexane. The organic layer was worked-up. HPLC (1:8 EtOAc/hexane) gave 4.2 g (87%) of 5-cyano-6-methoxy-2-methylthioquinoline as a light yellow solid, (M+) 230(100).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1Br.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22]>>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1[CH:21]([OH:22])[C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1cccc(C=O)c1
Reactant: COC(OC)c1cc2c(cc1Br)OCO2
Product: COc1cccc(C(O)c2cc3c(cc2C(OC)OC)OCO3)c1
Yield: 79 %

Procedure:
2-bromo-4,5-methylenedioxybenzaldehyde dimethylacetal and 3-methyoxybenzaldehyde are reacted in the same manner as described in Example 1-(1), whereby 2-(3-methoxy-α-hydroxybenzyl)-4,5-methylenedioxybenzaldehyde dimethylacetal is obtained as pale yellow syrup. Yield: 79%
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:5].[Br:35]N1C(=O)CCC1=O.O.C(Cl)Cl>C(#N)C>[NH2:1][C:2]1[C:33]([Br:35])=[CH:32][C:31]([CH3:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][CH:25]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)=[O:5]
Reactant: Cc1ccc(N)c(C(=O)N(CCc2cccc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)c(N)c(C(=O)N(CCc2cccc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 75 °C
Yield: 71.4 %

Procedure:
2-Amino-N-(4-tert-butyl-benzyl)-5-methyl-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (60 mg, 0.128 mmol) was dissolved in acetonitrile (2 ml) and N-bromosuccinimide (23 mg, 0.128 mmol) was added. The reaction was heated to 75° C. for 4 h. The reaction mixture was cooled to RT and partitionated between water and methylene chloride. The aqueous layer was extracted with methylene chloride and the combined organic phase was dried (MgSO4), filtered and concentrated in vacuo to give the desired product (50 mg, 71%) as a light brown oil. MS (ISP) 547.3 (M+H)+.
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][C:50]([Br:52])=[CH:51][C:46]=4[NH:45][C:44]3=[O:53])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>>[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:38][CH2:39][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][C:50]([Br:52])=[CH:51][C:46]=4[N:45]([S:59]([CH3:58])(=[O:61])=[O:60])[C:44]3=[O:53])[CH2:41][CH2:42]2)[CH2:33][CH2:32]1)=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4cc(Br)ccc43)CC2)CC1
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4cc(Br)ccc43)CC2)CC1

Procedure:
Example 12 was repeated except that the 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-5-bromo-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Referential Example 12 and that acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][CH2:5][O:4][C:3]1=[CH:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1.Cl.C[OH:16]>>[CH3:1][C:2]1([CH3:13])[CH2:6][CH2:5][O:4][C:3]1([OH:16])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: CC1(C)CCOC1=Cn1cncn1
Reactant: CO
Agent: Cl
Product: CC1(C)CCOC1(O)Cn1cncn1
Yield: 93 %

Procedure:
30 g (0.17 mole) of (3,3-dimethyl-tetrahydrofuran-2-ylidene)-(1,2,4-triazol-1-yl)-methane and 100 g of concentrated hydrochloric acid are stirred in 300 ml of methanol at room temperature for 4 hours. The reaction mixture is concentrated in vacuo, the residue is taken up in water, the pH value is adjusted to 7 to 8 with dilute sodium hydroxide solution and the mixture is extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate and concentrated in vacuo. 30.7 g (93% of theory) of 3,3-dimethyl-2-hydroxy-2-(1,2,4-triazol-1-yl-methyl)-tetrahydrofuran of melting point 93°-95° C. are obtained. ##STR101##
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(C(C)=O)C>[C:1]1([S:7][CH2:8][CH2:9][CH2:10][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: ClCCCSc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: c1ccc(SCCCN2CCNCC2)cc1

Procedure:
To 1000 ml methyl ethyl ketone are added 3-phenylthio-1-chloro-propane (1 mole), sodium iodide (1 mole) and anhydrous piperazine (4 moles). The resulting mixture is refluxed during 24 hours, with stirring, after which the solvent is evaporated in vacuo, the residue is taken up into water and ether. The ether phase is washed with water, dried and concentrated. The residue is distilled in vacuo. B.p. = 140° C./0.05 mm Hg. N.M.R.: consistent.
Reaction SMILES: C([CH:3]([CH:6]([OH:10])[CH2:7]CC)[CH2:4][OH:5])C.[N-:11]=[C:12]=[O:13]>C(C(C)=O)CCCC>[NH2:11][C:12]([O:10][CH2:6][CH3:7])=[O:13].[NH2:11][C:12]([O:5][CH2:4][CH3:3])=[O:13].[N-:11]=[C:12]=[O:13].[N-:11]=[C:12]=[O:13]
Reactant: CCCC(O)C(CC)CO
Agent: [N-]=C=O
Solvent: CCCCCC(C)=O
Product: CCOC(N)=O

Procedure:
The half-blocked diisocyanate product of Part A is reacted with 2-ethyl-1,3-hexanediol, 18.2 g, in 22.8 g methyl amyl ketone at 60°-80° C. until no infrared absorption for isocyanate is observed.
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:39])[CH2:29][N:30](C)[C:31](=O)OC(C)(C)C)(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH3:31][NH:30][CH2:29][C:28]([NH:27][CH2:26][CH2:25][NH:24][C:1](=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22])=[O:39]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)CN(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)CNC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
tert-Butyl (2-((2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-2-oxoethyl)(methyl)carbamate was taken up in 2 mL of EtOAc and 2 mL of saturated HCl in EtOAc was added. The resulting reaction mixture was stirred at room temperature for 2 h. Enough saturated aqueous Na2CO3 was added to adjust the pH=8. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford 530 mg of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2-(methylamino)acetamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide (99% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>ClCCl>[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CO[Si](CCCN)(OC)OC
Solvent: ClCCl
Product: CO[Si](CCCNC(=O)c1ccc(I)cc1)(OC)OC
Reaction time: 1 h

Procedure:
4-Iodo-N-[3-(trimethoxysilyl)propyl]-benzamide (1) was prepared, as illustrated in FIG. 5, where a solution of 3-aminopropyltrimethoxysilane (1.78 mL, 10 mmol) in 10 mL of dichloromethane was added dropwise to a suspension of 4-iodobenzoyl chloride (1.33 g, 5 mmol) in 20 mL of dichloromethane at 0° C. The mixture was stirred for 1 hour and solvent was evaporated in vacuo. The residue was purified by column chromatography on silica using 2% methanol in chloroform. The solvent was removed by rotary evaporation to give a viscous oil. 1H NMR (300 MHz, CDCl3): δ 0.70 (t, J=8.1 Hz, 2H), 1.73 (m, 2H), 3.42 (m, 2H), 6.64 (br, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 6.81, 22.78, 42.54, 50.89, 98.41, 128.78, 134.44, 137.91, 167.03. HRMS calculated for C13H20INO4Si 409.0206, found 410.0295 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+]>C1COCC1.O>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[C:8]1[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(C2CCCN2C(=O)OC(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 34B (2.7 g) in THF (50 mL) was added lithium hydroxide (0.2 g) in water (5 mL). The mixture was stirred at ambient temperature overnight and partitioned between ethyl acetate and 0.5 M hydrochloric acid. The extract was washed with water, dried over magnesium sulfate, filtered and concentrated. The concentrate was flash chromatographed on silica gel with ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7](=[O:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:39])([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)C>[N:13]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([NH:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:20][CH:19]=2)=[O:18])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(CCCCCn1ccnc1)Nc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(NC(=O)CCCCCn2ccnc2)cc1
Reaction time: 0.5 h

Procedure:
To 20 ml of ethanol were added 1.37 g of p-hydroxy-6-(1-imidazolyl)hexaneanilide and 0.69 g of anhydrous potassium carbonate and the mixture was stirred for 30 minutes with heating under reflux. After cooling, 1.26 g of ethyl 6-bromo-2,2-dimethylhexanoate was added thereto and the mixture was reacted overnight with heating under reflux. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue followed by extracting with chloroform. After the chloroform layer was successively washed with a 1N aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting residue was subjected to silica gel column chromatography. The product was eluted out using a chloroform-methanol liquid mixture (50:1 in a volume ratio). The solvent was removed by distillation under reduced pressure. The resulting crystals were recrystallized from a solvent mixture of n-hexane-ethyl acetate to obtain ethyl 6-[p-[6-(1-imidazolyl)hexanamido]phenoxy]-2,2-dimethylhexanoate as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([NH:20][CH2:21][C:22]3[CH:36]=[CH:35][C:25]([CH2:26][NH:27]C(=O)OC(C)(C)C)=[CH:24][CH:23]=3)=[O:19])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2.FC(F)(F)C(O)=O>ClCCl>[NH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:11]([N:6]3[CH2:5][C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[CH2:7]3)=[O:12])=[CH:38][CH:37]=2)=[O:19])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)c2ccc(NC(=O)N3Cc4ccc(F)cc4C3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(CNC(=O)c2ccc(NC(=O)N3Cc4ccc(F)cc4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 4-((4-(5-fluoroisoindoline-2-carboxamido)benzamido)methyl)benzylcarbamate (392 mg, 0.756 mmol) was dissolved in dichloromethane, treated with trifluoroacetic acid (582 μl, 7.56 mmol), stirred for 3 hours at ambient temperature and then concentrated to dryness. The resulting solid was triturated with ether, collected and dried under vacuum to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.01 (q, J=5.6 Hz, 2H), 4.46 (d, J=6.0 Hz, 2H), 4.76 (d, J=7.9 Hz, 4H), 7.08-7.29 (m, 2H), 7.32-7.44 (m, 5H), 7.67 (d, J=8.7 Hz, 2H), 7.76-7.86 (m, 2H), 8.12 (s, 2H), 8.63 (s, 1H), 8.91 (t, J=6.2 Hz, 1H); MS (ESI(+)) m/e 419 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH2:19][OH:20])=[N:9][N:10]=2)[CH:7]=1.N1C=CN=C1.CN(C1C=CC=CN=1)C.Cl[Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38]>CC1CCCO1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH2:19][O:20][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCCSc1ccccc1-c1nnc2ccc(Br)cn12
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CC1CCCO1
Product: CC(C)[Si](OCCSc1ccccc1-c1nnc2ccc(Br)cn12)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
To a slurry of alcohol of Example 6 (51.3 g, 0.146 moles) in 2-methyltetrahydrofuran (257 ml) was added imidazole (11.9 g, 0.175 moles) and dimethylaminopyridine (1.79 g, 0.015 moles). Chlorotriisopropylsilane (33.9 g, 0.175 moles) was added over 10 minutes and the resultant mixture heated at 50° C. for 18 hours. The reaction was cooled to 20° C. and washed with 1M hydrochloric acid solution (257 ml) and the aqueous extracted with 2-methyltetrahydrofuran (103 ml). The combined organics were washed with 10% w/w sodium chloride solution, then distilled under reduced pressure, and replaced with n-heptane to give a final volume of 513 ml. The resultant slurry was cooled to 5° C. and granulated for 18 hours. The solid was collected by filtration to give the title compound as a white solid (63.0 g, 87%).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]1[C:30]2[C:25](=[C:26]([O:31]C)[N:27]=[CH:28][CH:29]=2)[N:24]([CH3:33])[CH:23]=1>O1CCCC1>[CH:1]1([CH2:6][CH2:7][O:8][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=2[C:22]2[C:30]3[CH:29]=[CH:28][NH:27][C:26](=[O:31])[C:25]=3[N:24]([CH3:33])[CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCC1CCCC1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3F)cn(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCCC2CCCC2)c2cc[nH]c(=O)c21
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 40.5 %

Procedure:
2-cyclopentylethanol (0.137 g, 1.196 mmol) in tetrahydrofuran (5 mL) was treated with NaH (0.029 g, 1.196 mmol) at ambient temperature, stirred for 5 minutes and treated with the product from Example 17C (0.1 g, 0.299 mmol). The reaction mixture was heated at 60° C. for 12 hours and partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. The resulting residue (0.15 g) was treated with 4 M HCl in dioxane (15 mL), heated at 70° C. for 12 hours, cooled, concentrated and the residue was purified by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-100%) to give the title compound (0.05 g, 0.121 mmol, 34.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (d, J=5.0 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.79 (dd, J=8.7, 2.4 Hz, 1H), 7.57 (s, 1H), 7.33 (d, J=8.7 Hz, 1H), 6.94-6.86 (m, 1H), 6.42 (d, J=6.5 Hz, 1H), 4.31-3.99 (m, 5H), 3.20 (s, 3H), 1.85 (dd, J=14.6, 7.3 Hz, 1H), 1.79-1.63 (m, 4H), 1.62-1.39 (m, 4H), 1.11 (dd, J=12.0, 7.9 Hz, 2H). MS (ESI+) m/z 415.1 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[N:1]1([CH2:7][C:8]([N:10]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C(=O)CN1CCCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)CN1CCCCC1)c1ccc(N)cc1

Procedure:
Prepared analogously to Example Id by catalytic hydrogenation of 4-(N-piperidinomethylcarbonyl-N-methyl-amino)-nitrobenzene in methanol over palladium/charcoal.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([OH:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[OH-].[K+]>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:19][CH2:3][CH2:2][CH2:1][OH:4]
Reactant: CCCCCCCCCCCCCCO
Reactant: CC1CO1
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCOCCCO

Procedure:
Propylene oxide was bubbled into 685 g of myristyl alcohol in the presence of potassium hydroxide catalyst until three moles of propylene oxide were added per mole of myristyl alcohol, thus obtaining a pale, yellow liquid (PPG-3 myristyl ether) as the major product.
Reaction SMILES: C(CC1(CC)CCC(C=C)CC1=O)(OC)=O.[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25]N)[CH3:18].C(Cl)(C)=O>CO>[NH:25]1[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: CCc1ccccc1NN
Agent: C=CC1CCC(CC)(CC(=O)OC)C(=O)C1
Solvent: CO
Solvent: CC(=O)Cl
Product: c1ccc2[nH]ccc2c1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
The more polar ketone isomer of 2-carbomethoxymethyl-5-ethenyl-2-ethylcyclohexanone (5.084 g, 22.66 mmol) and the 2-ethylphenylhydrazine (3.086 g, 22.66 mmol) were heated at reflux in 97 ml of methanol under nitrogen for 48 hours. The reaction was then cooled to 0° C., treated with 45.32 mmol (3.56 g, 3.22 ml) of AcCl and refluxed an additional 45 minutes. Cooling, concentration and flash chromatography afforded 2.772 g (8.52 mmol, 38%) of indole as an orange oil. Rf =0.47 in 15% ethyl acetate/petroleum ether on TLC.