Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6])#[N:2].C([Sn]([N:29]=[N+:30]=[N-:31])(CCCC)CCCC)CCC>O1CCCC1>[NH:29]1[C:1]([CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6])=[N:2][N:31]=[N:30]1
Reactant: CC(C)(C)OC(=O)NC(CC#N)C(=O)O
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1nnn[nH]1)C(=O)O
Reaction time: 72 h
Yield: 84.9 %

Procedure:
17.5 g (82 mmol, 1 equiv. ) of 3-cyano-2- (1,1-dimethylethoxy) methanamido-propionic acid 26 was dissolved in 125 mL of tetrahydrofuran and 40.5 g (129 mmol, 1.5 equiv. ) tributyltin azide was added. The reaction mixture was brought to reflux and held there for 3 days. The reaction mixture was cooled and the volatiles removed in vacuo on a rotary evaporator. The residue was dissolved in 300 mL of 0.5M sodium hydroxide and this aqueous solution was washed with ethyl acetate (4×100 mL). The aqueous layer was passed through a 125 mL bed of Dowex 50X8-400 ion exchange resin and the resin washed with four column volumes of 1:1 methanol:water. The volatiles were removed in vacuo on the rotary evaporator to yield 17.9 g of the product as a white solid (85% yield). 1H-NMR (CD3OD): 4.55 p.p.m (m, 1H); 3.40 p.p.m. (m, 2H); 1.40 p.p.m. (s, 9H). This material is suitable for use in solid-phase peptide synthesis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>O.C(=S)=S>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:19](=[O:21])[CH3:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: COc1ccc(-c2ccccc2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 4′-methoxybiphenyl (0.05 mol) and AlCl3 (0.06 mol) were dissolved in boiling CS2 (60 mL) with stirring. Acetyl chloride (0.1 mol) was added dropwise and reflux continued for 1 hour. The mixture was poured onto crushed ice (150 mL) containing water (50 mL) and HCl (50 mL). The organic phase was separated and the CS2 removed by distillation. The residue was recrystallised from aqueous isopropanol to give the title compound. δC (CDCl3, 62.9 MHz): 26.6, 55.4, 114.4, 126.6, 128.4, 129.0, 132.2, 135.3, 145.4, 159.9 and 198.0
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[N:26]1([C:30]2[C:35]([C:36]#[N:37])=[C:34]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46]O)=[CH:40][CH:39]=3)[C:33]([C:48]#[N:49])=[C:32]([S:50][CH2:51][C:52]3[N:53]=[C:54]([C:57]4[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=4)[S:55][CH:56]=3)[N:31]=2)[CH2:29][CH2:28][CH2:27]1>CN(C=O)C.ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:46][CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([C:34]2[C:33]([C:48]#[N:49])=[C:32]([S:50][CH2:51][C:52]3[N:53]=[C:54]([C:57]4[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=4)[S:55][CH:56]=3)[N:31]=[C:30]([N:26]3[CH2:27][CH2:28][CH2:29]3)[C:35]=2[C:36]#[N:37])=[CH:39][CH:40]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCC2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
101 mg (0.536 mmol) of N-(tert-butoxycarbonyl)-beta-alanine were initially charged in 2 ml of DMF/dichloromethane (1:1). 44.5 mg (0.232 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 10.9 mg (0.89 mmol) of 4-dimethylaminopyridine and 100 mg (0.179 mmol) of 2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 8) were added, and the mixture was then stirred at RT overnight. The crude product was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 118 mg (90% of theory) of the target compound.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH:17]1[C:25](=[O:26])[CH:24]2[CH:19]([CH:20]3[O:27][CH:23]2[CH2:22][CH2:21]3)[C:18]1=[O:28].C(N(CC)CC)C>ClCCl>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:26][C:25]1[CH:24]2[CH:19]([C:18](=[O:28])[C:17]=1[C:10]1[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:8])[CH:20]1[O:27][CH:23]2[CH2:22][CH2:21]1)=[O:6]
Reactant: Cc1cc(C)c(C2C(=O)C3C4CCC(O4)C3C2=O)c(C)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)C3C4CCC(O4)C3C2=O)c(C)c1
Reaction time: 0.03 h

Procedure:
A solution of pivaloyl chloride (0.055 g, 0.57 mmol) in dichloromethane (2 ml) is added dropwise to a solution of (1RS,2SR,6RS,7SR)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (0.12 g, 0.42 mmol) in dichloromethane (2 ml) at room temperature and the reaction mixture is stirred for 2 minutes. A solution of triethylamine (0.08 ml) in dichloromethane (1 ml) is added and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give (1RS,2SR,6RS,7SR)-5-oxo-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-3-en-3-yl 2,2-dimethylpropionate as a colourless oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:21]1[CH2:26][C@@H:25]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:24][N:23]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:22]1)=[O:19])(=[O:3])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>N1C=CC=CC=1>[CH3:2][C:1]1[O:3][C:6]([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C:18]([N:20]([CH2:42][CH:43]([CH3:44])[CH3:45])[C@H:21]2[CH2:26][C@@H:25]([C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[O:28])[CH2:24][N:23]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[CH2:22]2)=[O:19])=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)CCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1nnc(CCn2c(C(=O)N(CC(C)C)[C@H]3C[C@@H](C(=O)N4CCOCC4)CN(C(=O)OC(C)(C)C)C3)nc3ccccc32)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.2 %

Procedure:
tert-Butyl (3S,5R)-3-[({1-[3-(2-acetylhydrazino)-3-oxopropyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (292 mg) was dissolved in pyridine (5 ml), and trifluoromethanesulfonic anhydride (2301) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 15 hr, and concentrated. The residue was diluted with 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (117 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].[H-].[Na+].[CH3:18]I>COCCOC>[CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15]
Reactant: CI
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2
Temperature: 30 °C

Procedure:
A stirred suspension of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (12.2 g., 0.05 mole) and sodium hydride (1.43 g., 0.06 mole) in anhydrous 1,2-dimethoxyethane (500 ml.) is heated in an inert atmosphere at 80°-85° C. for one hour, cooled to 30° C. and treated with methyl iodide (8 ml.) The reaction mixture is refluxed for 15 minutes, then the solvent is distilled at reduced pressure. The crude product is poured into water (500 ml.), extracted into ether, washed with water and dried over magnesium sulfate. After evaporation of the ether the product is crystallized from methylcyclohexane affording 8.2 g. of 2,2-dimethyl-5-methoxy-6,7-dichloro-1-indanone which melts at 142° C.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][OH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][O:15][P:1]([Cl:5])([Cl:3])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC(CO)CCCCCCC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(CCCCCCC)COP(=O)(Cl)Cl
Temperature: -10 °C
Yield: 34.7 %

Procedure:
With nitrogen substitution, 540 ml of toluene and 138.0 grams (0.9 moles) of phosphorus oxychloride were added and cooled to −10 degrees C. To this mixture, a solution of 243.5 grams (0.9 moles; 1.0 in molar ratio) of 2-heptylundecanol and 91.1 grams (0.9 moles) of triethylamine was dripped, and the mixture was reacted for 12 hours at 0 degrees C. The mixture was then heated to 25 degrees C., and a triethylamine hydrochloride was removed by filtering to obtain 1003.9 grams of a toluene solution of (2-heptylundecyl)dichlorophosphate (34.7% in concentration).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:32]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:33])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: Cc1ccc(C(OC2CN(C(=O)NC3CCCCC3)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]azetidine hydrochloride (151) (0.56 mmol) and cyclohexyl isocyanate (0.56 mmol) using the procedure described for compound (10). The desired product was obtained as a white foam (230 mg, 91%).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1.Cl>CCOCC>[C:10]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16])(=[O:15])[CH3:9]
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1nc2ccccc2c(=O)o1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)Nc1ccccc1C(=O)C1CCCCC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Cyclohexylmagnesium bromide (240 ml of a 2M solution in ether) in ether (200 ml) was added dropwise to a solution of 2-methyl-4H-3,1-benzoxazin-4-one (100 g) in ether (1100 ml) at -10° C. over 2 h. The mixture was stirred at this temperature for 2 h, then at ambient temperature for 30 min. After cooling to -10° C. the suspension was treated with 2M HCl (600 ml), keeping the temperature below 0° C. After stirring for 15 min the layers were separated, and the ethereal layer washed sequentially with water (500 ml), 5% sodium hydroxide solution (2×500 ml) and finally water (2×500 ml). The organic layer was separated, dried (MgSO4), evaporated in vacuo and chromatographed on silica gel using petrol:ethyl acetate (2:1) to give (2-acetamidophenyl) cyclohexyl methanone (28 g). Mp 66° C. 1H NMR (CDCl3, 360 MHz) δ 1.25-1.89 (10H, m), 2.23 (3H, s), 3.33 (1H, m), 7.13 (1H, d of t, J=6 and 1 Hz), 7.53 (1H, d of t, J=6 and 1 Hz), 7.92 (1H, d, J=6 Hz), 8.76 (1H, d, J=6 Hz), 11.73 (1H, brs).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][N:13]1[S:25]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[C:42]3[C:37](=[C:38]([F:46])[C:39]([F:45])=[C:40]([F:44])[C:41]=3[F:43])[NH:36][CH:35]=2)[CH2:30][CH2:29]1)(=[O:27])=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[S:25]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[C:42]3[C:37](=[C:38]([F:46])[C:39]([F:45])=[C:40]([F:44])[C:41]=3[F:43])[NH:36][CH:35]=2)[CH2:30][CH2:29]1)(=[O:27])=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)N2CCC(c3c[nH]c4c(F)c(F)c(F)c(F)c34)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOCc1ccccc1)[C@H]1CNCCN1S(=O)(=O)N1CCC(c2c[nH]c3c(F)c(F)c(F)c(F)c23)CC1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of N-benzyloxy-4-tert-butoxycarbonyl-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (24.40 g, 36.40 mmol) [prepared as described in Step 4 above] in methylene chloride (90 ml) was added trifluoroacetic acid (60 ml). The reaction mixture was stirred for 2 h, concentrated in vacuo, and partitioned between ethyl acetate (500 ml) and sat. sodium bicarbonate (200 ml). The aqueous layer was washed with ethyl acetate and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was dissolved in ethyl acetate (40 ml) and slowly added to hexane (200 ml) with vigorous stirring. The resulting slurry was filtered to afford 20.65 g of N-benzyloxy-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([CH:28]1[S:32][CH:31]([C:33](O)=[O:34])[CH2:30][CH2:29]1)[CH2:26][CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:25]([CH:28]1[S:32][CH:31]([C:33]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:16]=[CH:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:13][N:14]=3)=[CH:23][CH:22]=2)=[O:34])[CH2:30][CH2:29]1)[CH2:26][CH3:27]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCC1CCC(C(=O)O)S1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)C3CCC(CCC)S3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 2.6 g of 5-propyl-tetrahydrothiophene-2-carboxylic acid (prepared as shown in Scheme 1) and 3.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:8](=[O:17])[C:9]([CH3:16])([S:11][C:12]([F:15])([F:14])[F:13])[CH3:10])=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:8]([OH:17])[C:9]([CH3:16])([S:11][C:12]([F:13])([F:15])[F:14])[CH3:10])=[CH:23][CH:24]=1
Reactant: CC(C)(SC(F)(F)F)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(SC(F)(F)F)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
10 g (0.026 mol) of 1-(4-chlorophenoxy)-3-methyl-1-(1,2,4-triazol-1-yl)-3-trifluoromethylthio-butan-2-one (Example 1) were dissolved in 100 ml of methanol and 1 g (0.025 mol) of sodium borohydride was added in portions to the solution. The reaction mixture was further stirred at room temperature for 30 minutes and was thereafter introduced into water. The mixture was extracted with methylene chloride, and the organic phase was dried over sodium sulphate and concentrated in vacuo. The residue crystallized after a short time. 9.5 g (95% of theory) of 1-(4-chlorophenoxy)-3-methyl-1-(1,2,4-triazol-1-yl)-3-trifluoromethylthio-butan-2-ol of melting point 85°-87° C. were obtained.
Reaction SMILES: C(Cl)(=O)C.[C:5](Cl)(=[O:9])[O:6][CH2:7][CH3:8].[C:11]1([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][C:19]2[NH:20][CH2:21][CH2:22][N:23]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:7]([O:6][C:5]([N:23]1[CH2:22][CH2:21][N:20]=[C:19]1[CH2:18][CH:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9])[CH3:8]
Reactant: c1ccc(C(CC2=NCCN2)c2ccccc2)cc1
Reactant: CCOC(=O)Cl
Solvent: CC(=O)Cl
Product: CCOC(=O)N1CCN=C1CC(c1ccccc1)c1ccccc1

Procedure:
In place of acetyl chloride in Example 53, ethyl chlorocarbonate was reacted with 2-(2,2-diphenyl ethyl)-2-imidazoline to give 1-ethoxycarbonyl-2-(2,2-diphenyl ethyl)-2-imidazoline having a melting point of 78° to 80° C.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[C:10]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(O)=O.[Na+]>CC(O)=O>[N+:6]([C:13]1[CH:12]=[CH:11][C:10]([CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)=[CH:15][CH:14]=1)([O-:9])=[O:7]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Temperature: 25 °C

Procedure:
A solution of conc. H2SO4 (2.65 mL) in AcOH (40 mL) and a solution of conc. HNO3 (2.1 mL) in AcOH (20 mL) are added sequentially and dropwise to a solution of 4-phenylpiperidine in AcOH (40 mL), maintaining the temperature below 20° C. Then, conc. H2SO4 (40 mL) is added (no cooling applied; internal temperature reaches 60° C.). The reaction mixture is allowed to cool to RT, poured onto ice/water (100 g), neutralized by addition of solid NaHCO3 (150 g), and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by trituration in Et2O to afford the title compound as a yellow solid. ESI-MS: 207.1 [MH]+; tR=2.42 min (system 1).
Reaction SMILES: [H-].[Na+].C(OC([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)=O)(C)(C)C.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C1COCC1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:18][CH2:17][CH2:16][CH:13]2[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COCCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
NaH (60% dispersion in oil, 98 mg, 2.4 mmol, 1.2 equiv.) was added to a solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (468 mg, 2.0 mmol) in THF (10 mL) at 0° C. under Ar protection. The mixture was warmed to room temperature and stirred at that temperature for 3 h. 1-(Bromomethyl)-4-methoxybenzene (353 μL, 2.4 mmol, 1.2 equiv.) was added at room temperature. After stirring for 20 h, the reaction was quenched with saturated aqueous NH4Cl solution. The mixture was extracted three times with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed, and the residue was purified by CC (SiO2, hexane/EtOAc 10:1 to 4:1) to afford the product (268 mg, 38%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.22 (d, 2H, J=8.4 Hz), 6.85 (d, 2H, J=8.8 Hz), 4.40 (s, 2H), 4.05 (m, 2H), 3.76 (m, 4H), 3.45 (t, 2H, J=6.0 Hz), 2.65 (m, 2H), 1.62-1.50 (m, 5H), 1.44 (s, 9H), 1.08 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:20]=[C:18]1[NH:17][C:16](=[O:21])[C:15](=[CH:14][C:11]2[CH:10]=[CH:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)=[CH:13][CH:12]=2)[S:19]1
Reactant: Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 96.5 %

Procedure:
In a manner similar to that of Example 1(d), by reacting 1.2 g (2.3 mmol) of 5-(3′-aminobiphenyl-4-ylmethylene)thiazolidine-2,4-dione with 430 μl (3 mmol) of phenylacetyl chloride, 920 mg (97%) of the expected product are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10])#[N:2].[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])#[N:2]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1ccccc1C#N
Yield: 85 %

Procedure:
A solution of 2-cyanobenzensulfonylchloride (2.0 g, 10 mmol), dimethyl amine (1.18 g, 10 mmol, 40 wt % in water) and triethylamine (1.5 mL, 10 mmol) were stirred together at room temperature for 30 min. The resulting slurry was diluted with ethyl acetate and filtered. The filter cake was washed with ethyl acetate and the combined filterate was washed with water, dried (Na2SO4) and concentrated to give the title product as orange plates (1.78 g, 85% yield). 1HNMR (300 MHz, CDCl3) δ: 8.02 (1H, dd, J=8.05, 1.46 Hz), 7.87 (1H, dd, J=7.32, 1.47 Hz), 7.79–7.76 (2H, m), 2.86 (6H, s). LCMS calcd for C9H11N2O2S (M+H): 211.05; found: 211.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-:13].[K+:14]>>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([F:9])=[C:6]([O-:13])[CH:7]=1.[K+:14]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Agent: [K+]
Product: O=[N+]([O-])c1cc(F)c([O-])cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 1-chloro-4,5-difluoro-2-nitrobenzene (5.12 g, 26.5 mmol) and 15% aqueous KOH (19.9 g) solution was stirred at reflux for 3 hours, then cooled to rt, and filtered to give the title compound as a yellow crystalloid (5.67 g, 93.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]>CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)c(F)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(O)CCc1ccc(C(F)(F)F)c(F)c1
Reaction time: 4 h
Yield: 81.4 %

Procedure:
10% NIX was added to a stirred solution of 3-(3-fluoro-4-(trifluoromethyl)phenyl)-acrylic acid (I-77a: 5.5 g, 0.0234 mol) in methanol. The resulting mixture was stirred under hydrogen atmosphere for 4 hours. The reaction was monitored by TLC (5% methanol in CHCl3). The catalyst was filtered through celite bed and the solvent distilled under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 4.5 g of the product (81.8% yield).