Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:8][CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.O>O1CCCC1>[CH2:11]([N:10]1[C:6]([CH2:5][CH2:4][C:3]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)[OH:18])=[CH:7][N:8]=[CH:9]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CCc1cncn1Cc1ccccc1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: O
Solvent: C1CCOC1
Product: OC(CCc1cncn1Cc1ccccc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
1-benzyl-5-imidazole propionic acid methyl ester (6,4 g) in tetrahydrofuran is heated at 60° C. and to this is then added dropwise p-chlorophenylmagnesium bromide prepared above. After the addition is complete, the reaction mixture is refluxed for an additional 3 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated, toluene is added and the mixture is made acidic with hydrochloric acid. The precipitated product is filtered, washed with ether and dried. Yield 12,2 g; m.p. 210°-213° C. M.p. of nitrate 157°-160° C. (made in water-ether mixture). M.p. of hydrochloride (from ethylacetate) 178°-187° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH2:20])[CH2:8][C@@H:7]1[CH3:21])=[O:5])[CH3:2].[F:22][C:23]([F:39])([F:38])[C:24]1[CH:25]=[C:26]([CH2:34][C:35](O)=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH:20][C:35](=[O:36])[CH2:34][C:26]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:24]([C:23]([F:38])([F:22])[F:39])[CH:25]=2)[CH2:8][C@@H:7]1[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N)C[C@@H]1C
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](NC(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-4-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (150 mg, 0.50 mmol) and 3,5-bis-trifluoromethylphenylacetic acid (138 mg, 0.51 mmol) in 1.5 ml anhydrous dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (192 mg, 0.66 mmol) and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with 50 ml ethyl acetate and was washed with 0.1N HCl (2×10 mL), 0.1N NaOH (2×10 mL) and brine (1×10 mL). The organic phase was dried (MgSO4), filtered and concentrated, and the the residue was chromatographed using 20:1 hexanes:ethyl acetate. The title compound crystallized out of the combined fractions (129 mg, 46%). mp 157-9° C.; MS m/z 549 (M++1); 1H NMR (CDCl3) δ 1.07 (d, 3H), 7.70-7.78 (m, 3H).
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=3)[C:22]([O:24]CC[Si](C)(C)C)=[O:23])=[CH:16][CH:15]=2)[CH3:8])=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:2]=[CH:3][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]([CH3:39])([CH3:40])[CH3:41])=[CH:36][CH:37]=3)[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)[CH3:8])=[CH:5][CH:6]=1
Reactant: CC(=NOCCOc1ccc(C[C@H](Oc2ccc(C(C)(C)C)cc2)C(=O)OCC[Si](C)(C)C)cc1)c1ccc(-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=NOCCOc1ccc(C[C@H](Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1)c1ccc(-c2ccccc2)cc1
Yield: 67 %

Procedure:
The reaction was carried out according to Reference example 7 using 2-trimethylsilylethyl (S)-3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy]ethoxy]phenyl]-2-(4-t-butylphenoxy)propionate (300 mg) obtained from Reference example 10 and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.20 ml). The resulting residue was purified by chromatography on a silica gel column (eluant; methylene chloride/methanol=24/1˜19/1), and then the obtained compound was filtered off and washed with isopropyl ether and hexane to afford the target compound (170 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:9]2[CH2:11][O:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:21]>CO>[NH2:21][CH2:11][C@H:9]([OH:10])[C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CO1
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl (S)-2-cyclohexyl-1-((R)-oxiran-2-yl)ethylcarbamate (0.20 g, 0.74 mmol) in MeOH (15 mL) at rt, ammonium hydroxide (5 mL) was added. The resulting clear solution was stirred at rt overnight, and completion of reaction was confirmed by LC-MS. Solvent was removed under vacuum to leave tert-butyl (2S,3S)-4-amino-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (0.21 g, quant.), which was used for the next step without purification; M/S m/z 287 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH:10]=[C:11]2[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]2[CH2:13]4)[CH2:17]3)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28].C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[C:27]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH:10]=[C:11]2[CH:12]3[CH2:20][CH:16]4[CH2:15][CH:14]([CH2:19][CH:18]2[CH2:17]4)[CH2:13]3)[CH:5]=[CH:6][CH:7]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(COC=C2C3CC4CC(C3)CC2C4)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(COC=C2C3CC4CC(C3)CC2C4)c1
Reaction time: 0.08 h

Procedure:
[(3-Acetoxyphenyl)methoxymethylene]adamantane (1b) was prepared as described in the previous application. Hydroxy alkene 1a (0.75 g, 2.8 mmol) was dissolved in 10 mL of CH2Cl2 and pyridine (5.2 g, 65.8 mmol) under N2. The solution was cooled in an ice bath and a solution of acetyl chloride (2.6 g, 33 mmol) in 1 mL of CH2Cl2 was added dropwise via syringe. After 5 min at 0° C., TLC on silica with 20% ethyl acetate/hexane showed complete acetylation of 1a. After removal of the solvent, the solid residue was washed with 30 mL of ether. The ether was washed with 3×25 mL of water, dried over MgSO4, and evaporated to dryness. The product was chromatographed on silica using 20% ethyl acetate/hexane affording 0.45 g of 1b as an oil: 1H NMR (CDCl3) δ 1.79-1.96 (m, 12H), 2.27 (s, 3H), 2.66 (s, 1H), 3.26 (s, 1H), 3.29 (s, 3H), 6.99-7.36 (m, 4H); 13C NMR (CDCl3) δ 20.90, 28.13, 30.07, 31.99, 36.99, 38.89, 39.01, 57.59, 120.34, 122.14, 126.55, 128.66, 132.19, 136.90, 142.59, 150.42, 169.04; MS m/e (rel intensity) 312 (100, M), 270 (25), 255 (19.3), 213 (20.7), 163 (12.2), 121 (30.7), 43 (30); IR (neat) 3006, 2925, 2856, 1725, 1600, 1438, 1362, 1218, 1100 cm-1 ; Anal. Calcd. for C20H24O3 : C, 76.92; H, 7.69, Found: C, 76.96; H, 7.85. ##STR22##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: ClCc1ccccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
The whole of the 2-benzyloxybenzyl alcohol thus obtained was dissolved in 500 ml of tetrahydrofuran, and 85 ml of thionyl chloride were added dropwise, whilst ice-cooling, to the resulting solution. The reaction mixture was then allowed to stand overnight at room temperature, after which it was concentrated by evaporation under reduced pressure to give a dark colored oil. This product was dissolved in toluene, and the solution was decolorized by treating it with silica gel for chromatography followed by filtration. The filtrate was concentrated by evaporation under reduced pressure to give 2-benzyloxybenzyl chloride as a yellow oil, which was used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.Br[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CCOC(=O)CCBr
Reactant: COc1cc(Cl)ccc1S
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCSc1ccc(Cl)cc1OC

Procedure:
4-Chloro-2-methoxythiophenol (5.78 g, 33 mmol), triethylamine (5.0 mL, 36 mmol) and ethyl 3-bromopropanoate (4.6 mL, 36 mmol) were dissolved in ethyl acetate (50 mL) and refluxed for 2 h. Water was added and the liquid phases were separated. The aqueous phase was extracted two times with ethyl acetate. The combined organic fractions were washed with 1 M aq. HCl and then concentrated in vacuo. Purification by flash chromatography (SiO2; heptane: dichloromethane (1:1, 0:1)) afforded the sub-title compound as a yellow solid. Yield: 3.0 g (30%). Estimated purity: 75% (NMR).
Reaction SMILES: [F:1][C:2]([F:37])([C:12]([F:36])([F:35])[C:13]([F:34])([F:33])[C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][SiH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].C([Br:41])C=C>C1C=CC=CC=1.Cl[Pd]Cl>[F:37][C:2]([F:1])([C:12]([F:35])([F:36])[C:13]([F:33])([F:34])[C:14]([F:31])([F:32])[C:15]([F:29])([F:30])[C:16]([F:28])([F:27])[C:17]([F:26])([C:22]([F:23])([F:24])[F:25])[C:18]([F:20])([F:19])[F:21])[CH2:3][CH2:4][Si:5]([Br:41])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C=CCBr
Reactant: CC(C)[SiH](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F)C(C)C
Agent: Cl[Pd]Cl
Solvent: c1ccccc1
Product: CC(C)[Si](Br)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F)C(C)C
Temperature: 60 °C
Yield: 205.9 %

Procedure:
In an oven-dried round-bottom flask equipped with a stir bar and cooled under N2, (3,3,4,4,5,5,6,6,7,7,8,8,9,10,10,10-hexadecafluoro-9-trifluoromethyldecyl)diisopropylsilane (4.86 g, 7.94 mmol) was dissolved in 10 mL anhydrous benzene (benzene dried by boiling off 10% by volume prior to use). To this mixture was added allyl bromide (1.44 g, 11.9 mmol, 1.5 eq.) and PdCl2 (30 mg). The solution was heated to 60° C. for 15 hr, then cooled, and concentrated via rotary evaporation. The resulting suspension was dissolved in pentane, filtered to remove residual catalyst, and then solvent was removed to yield ((3,3,4,4,5,5,6,6,7,7,8,8,9,10,10,10-hexadecafluoro-9-trifluoromethyldecyl)diisopropylsilyl)-bromide (11.3 g) as a pale brown liquid. The bromide was treated under anhydrous conditions with 1.2 eq. (based on initial silane) of ethynylmagnesium bromide and heated to 40° C. for 6 hr. The reaction was quenched with water and dilute sulfuric acid, pentane was added, and the organic layer was separated. The organic layer was washed with water (6×50 mL), dried over MgSO4, filtered, and concentrated via rotary evaporation. Further purification via flash chromatography using hexane yielded pure ((3,3,4,4,5,5,6,6,7,7,8,8,9,10,10,10-hexadecafluoro-9-trifluoromethyldecyl)diisopropylsilyl)-acetylene (4.1 g, 6.5 mmol, 82%) as a colorless liquid. Analysis of the product provided the following data: 1H-NMR (200 MHz, CDCl3) δ=2.4 (s, 1H), 2.2 (m, 2H), 1.0 (m, 14H), 0.8 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2].[Br:16][C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@@H:21]2O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:21]2[C:22]3[C:18](=[C:17]([Br:16])[CH:25]=[CH:24][C:23]=3[F:26])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O)cc1
Reactant: O[C@H]1CCc2c(Br)ccc(F)c21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Br)ccc(F)c32)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
(1S,2S)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (Intermediate 4, 6.51 g, 31.57 mmol), (S)-4-Bromo-7-fluoro-indan-1-ol (Intermediate 8, 7.29 g, 31.57 mmol) and triphenyl phosphine (9.11 g, 34.72 mmol) are dissolved in dry tetrahydrofuran (50 mL) and cooled to −20° C. under nitrogen atmosphere. Di-tert-butyl azodicarboxylate (8.00 g, 34.72 mmol) is added and the mixture stirred for 30 minutes at −20° C. then allowed to warm to room temperature and stirred overnight. The solvent is removed under vacuum and the residue purified by flash chromatography (0-10% ethyl acetate in cyclohexane) to give the title compound (Yield 8.23 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1.C(N(CC)CC)C>O.C(Cl)Cl>[O:11]=[C:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
A methylene chloride solution (6 ml) of dimethyl sulfoxide (2.0 ml, 28.2 mmol) was added dropwise to a methylene chloride solution (30 ml) of oxalyl chloride (1.7 ml, 19.5 mmol) at −60° C. over a period of 10 minutes and stirred at −60° C. for another 10 minutes. Then, a methylene chloride solution (140 ml) of tert-butyl 4-hydroxycyclohexylcarbamate (2.56 g, 11.9 mmol) was added dropwise thereto over a period of 35 minutes, and the resulting mixture was stirred at −60° C. for 40 minutes. After triethylamine (8.4 ml, 60.3 mmol) was added thereto at −60° C., the resulting mixture was warmed up to room temperature spontaneously. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain tert-butyl 4-oxocyclohexylcarbamate (2.23 g, 87%).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=2)[CH2:17][CH2:16]1.C=O.C(O)(=O)C>CO>[CH3:1][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)c1cnc(C2CCNCC2)cn1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cnc(C2CCN(C)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
Sodium triacetoxyborohydride (530 mg, 2.50 mmol) was added to methyl 5-(piperidin-4-yl)pyrazine-2-carboxylate (221 mg, 1.00 mmol), formaldehyde (37% aqueous solution, 1.50 ml, 20.00 mmol) and acetic acid (0.11 ml, 2.00 mmol) in methanol (5.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was quenched with water (5 mL) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 5-(1-methylpiperidin-4-yl)pyrazine-2-carboxylate (239 mg, 100%) as a yellow waxy solid. This was used directly with no further purification.
Reaction SMILES: Cl.[Si]([O:9][CH:10]([CH2:14][S:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([OH:13])=[O:12])(C(C)(C)C)(C)C>O1CCCC1>[C:17]([S:16][S:15][CH2:14][CH:10]([OH:9])[C:11]([OH:13])=[O:12])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)SSCC(O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)SSCC(O)C(=O)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A 1 N aqueous hydrochloric acid solution (300 μl) was added to a solution of 2-(tert-butyldimethylsilyloxy)-3-(tert-butyldisulfanyl)propionic acid prepared by the method known in the literature (J. Am. Chem. Soc. 2008, 130, 4919) (Compound 24) (30.0 mg, 0.092 mol) in tetrahydrofuran (THF) (300 μl) at room temperature, and the mixture was stirred at 60° C. for 16 hours. The reaction solution was purified by Reverse-phase silica-gel chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford 3-(tert-butyldisulfanyl)-2-hydroxypropanoic acid (H-tBuSSlac-OH) (Compound SP666) (7.4 mg, 54%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[CH2:11][CH2:10]1)(=O)[CH3:7].[NH2:24][C:25]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:29][C:26]=1[C:27]#[N:28]>ClCCl>[CH2:36]([O:35][C:30]1[C:31]([O:33][CH3:34])=[CH:32][C:25]([N:24]=[C:6]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])[CH2:11][CH2:10]2)[CH3:7])=[C:26]([CH:29]=1)[C:27]#[N:28])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc(N)c(C#N)cc1OCc1ccccc1
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorous oxychloride (0.81 ml, 0.0086 mol) was added to a solution of 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane (4.02 g, 0.0157 mol) in dichloromethane (25 ml) and the mixture stirred for 30 minutes at room temperature. A solution of 2-amino-5-benzyloxy-4-methoxybenzonitrile (2 g, 0.0078 mol) in dichloromethane (25 ml) was then added and the reaction stirred for 18 hours at 40° C. On cooling, the reaction mixture was poured carefully in to ice/water (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to give a brown oil. The crude product was purified on silica gel eluting with a solvent gradient of methanol:dichloromethane (2:98 to 10:90 v/v) to give the subtitle compound. Rf 0.67 (0.880 aqueous ammonia:methanol:dichloromethane 1:7:92, v/v). MS m/z 492 (MH)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[CH2:13][C:14]#[N:15])=[CH:6][CH:5]=1.[CH3:20][N:21]([CH2:25][CH2:26]Cl)[CH2:22][CH2:23]Cl.Cl>CS(C)=O>[C:14]([C:13]1([C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:26][CH2:25][N:21]([CH3:20])[CH2:22][CH2:23]1)#[N:15]
Reactant: CN(CCCl)CCCl
Reactant: N#CCc1ccccc1Sc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(C#N)(c2ccccc2Sc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2.3 g of 99% sodium hydride are slowly added to a mixture, under nitrogen, of 4.3 g of 2-(4-fluorophenylthio)-benzyl cyanide in 30 mls of dimethylsulfoxide. After total addition, the mixture is stirred for an additional five minutes and then a mixture of 3.9 g of 95% mechlorethamine hydrochloride in 20 ml of dimethylsulfoxide is added portionwise over a 40 minute span. After this addition, the reaction is stirred for 1 hour in a hot water bath at 70° C. and then permitted to stand at ambient temperature for 16 hours. The cooled reaction mixture is poured onto 150 ml of crushed ice and the diluted mixture is extracted thrice with 60 ml portions of ether. The combined ether extracts are washed with 25 ml of saturated sodium chloride solution and dried, leaving a solid. The solid is recrystallized from cyclohexane, leaving the pure product, 4-cyano-4-[2-(4-fluorophenylthio)phenyl]-1-methylpiperidine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15](Br)[CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:2]=1[O:1][CH2:10][CH2:2][CH2:3][CH3:4])[CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccc(C(F)(F)F)cc1OCCCC

Procedure:
2-Hydroxy-4-trifluoromethyl-benzoic acid (755 mg) was reacted with butylbromide (0.96 ml) and K2CO3 (1.15 g) in DMF solution as described above to yield title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([NH:20][NH2:21])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC1CCCCN1C(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)NN
Reaction time: 16 h

Procedure:
2-Methoxycarbonylmethyl-piperidine-1-carboxylic acid tert butyl ester (8.14 g) in ethanol (150 ml) was treated with hydrazine hydrate (19 ml) and the mixture boiled for 16 h. Solvent was removed at reduced pressure and the residue azeotroped with toluene to give the title compound (8.34 g)
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[CH:23]=[C:22]2[CH3:33])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH:40]([NH2:43])[CH2:41][CH3:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:33][C:22]1[N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:9]3[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:15][CH:16]=2)[C:29]2[C:24]([CH:23]=1)=[CH:25][C:26]([C:30](=[O:31])[NH:43][CH:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:41][CH3:42])=[CH:27][CH:28]=2
Reactant: CCC(N)c1ccccc1
Reactant: Cc1cc2cc(C(=O)O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCC(NC(=O)c1ccc2c(c1)cc(C)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2-methyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1[CH:10]=[C:9]([C:11](OCC)=[O:12])[CH:8]=[CH:7][N:6]=1)[CH3:4]>C(O)C.ClCCl>[CH2:3]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][N:6]=1)[CH3:4]
Reactant: CCOC(=O)c1ccnc(CC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCc1cc(CO)ccn1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
5.36 g of sodium borohydride are added portionwise to a solution of 5.08 g of ethyl 2-ethylpyridine-4-carboxylate in 53 ml of ethanol, under an inert atmosphere of argon at a temperature in the region of 0° C. The reaction mixture is refluxed with stirring for 3 hours and then concentrated to dryness under reduced pressure. The residue thus obtained is taken up in 500 ml of dichloromethane and then washed with 500 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. 3.16 g of 2-ethyl-4-(hydroxymethyl)pyridine are thus obtained.