Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:66]=[CH:65][C:7]([O:8][P:9]2([O:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-])=O)=[CH:58][CH:57]=3)[N:14]=[P:13]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:12]=[P:11]([O:45][C:46]3[CH:51]=[CH:50][C:49]([N+:52]([O-])=O)=[CH:48][CH:47]=3)([O:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-])=O.NC1C=CC=CC=1.[H][H]>O=[Pt]=O.C1COCC1>[NH2:1][C:4]1[CH:66]=[CH:65][C:7]([O:8][P:9]2([O:55][C:56]3[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=3)[N:14]=[P:13]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[N:12]=[P:11]([O:45][C:46]3[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=3)([O:35][C:36]3[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=3)[N:10]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OP2(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=N2)cc1
Agent: O=[Pt]=O
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(OP2(Oc3ccc(N)cc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=N2)cc1

Procedure:
A 1000-mL stirrer-equipped autoclave was charged with 40.0 g (0.041 mol) of hexakis(4-nitrophenoxy)cyclotriphosphazene (2), aniline (75 mL), and 0.1 g of PtO2 catalyst. The mixture was agitated vigorously under 50 psi of hydrogen pressure at 50° C. until no further pressure drop was recorded (~30 h). The reaction mixture was filtered and the filtrate was poured slowly into toluene (1000 mL). Impure 3 precipitated from solution. After filtration, the crude 3 was recrystallized from o-dichlorobenzene and from THF to yield 30 g (92%) of pure 3, mp 189°-190° C. A 31P NMR spectrum in THF showed a singlet at 11.2 ppm, which indicated complete conversion of NO2 to NH2 groups.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[CH:5][CH:4]=1)#[N:2].[S].[CH2:31](N)[CH2:32][NH2:33]>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([CH2:17][NH:16][CH2:15][CH2:14][CH2:13][C:12]([NH:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:33][CH2:32][CH2:31][N:2]=2)=[CH:8][CH:7]=1)=[O:29])(=[O:20])=[O:19]
Reactant: N#Cc1ccc(CCNC(=O)CCCNCS(=O)(=O)c2cccc(Cl)c2Cl)cc1
Reactant: NCCN
Agent: [S]
Product: O=C(CCCNCS(=O)(=O)c1cccc(Cl)c1Cl)NCCc1ccc(C2=NCCN2)cc1

Procedure:
Analogously to 13b), 4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}butyramide was prepared from 0.297 g (0.654 mmol) of N-[2-(4-cyanophenyl)ethyl]4-[(2,3-dichloro-benzenesulphonyl)methylamino]butyramide, 42 mg (1.31 mmol) of sulphur and 1.8 ml of ethylenediamine.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20]C=CC=2)[CH:6]=[CH:5][C:4]([C@:7]2([CH3:15])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:14])=[CH:3][CH:2]=1.[CH2:22](C1C=CC(C(C(OCC)=O)=O)=CC=1)C(C)C.C1C=CC([C@@H](N)CO)=CC=1.C(C1C=CC([C@@H](C)C(OC)=O)=CC=1)C(C)C>>[OH:13][C:9]1[C:10](=[O:12])[O:11][C@:7]([CH3:15])([C:4]2[CH:3]=[CH:2][C:1]([CH2:16][CH:21]([CH3:20])[CH3:22])=[CH:6][CH:5]=2)[C:8]=1[OH:14]
Reactant: CCOC(=O)C(=O)c1ccc(CC(C)C)cc1
Reactant: C[C@@]1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Agent: COC(=O)[C@H](C)c1ccc(CC(C)C)cc1
Agent: N[C@@H](CO)c1ccccc1
Product: CC(C)Cc1ccc([C@@]2(C)OC(=O)C(O)=C2O)cc1
Yield: 15 %

Procedure:
(R)-(−)-3,4-Dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone was synthesized in, an analogous manner used for the production of (s)-(+)-5-[(1,1′-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with ethyl 4-isobutylbenzoylformate. (R)-(−)-Phenylglycinol was used to resolve the methyl (R)-(−)-2-(4-isobutylphenyl)propionate enantiomer, of which 1.2 g, (5 mmol) was converted into 190 mg (15% yield) of (R)-(−)-3,4-dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone as a white crystalline material: mp 180-181° C. dec. (CHCl3/hexanes); [α]25D−137° (c=1.27; MeOH); 1H NMR (acetone-d6) δ 7.44-7.14 (m, 4H), 2.48 (d. 2H, J=7.1 Hz), 1.87-1.82 (m, 1H), 1.83 (s, 3H), 0.88 (d, 6H, J=6.5 Hz). Anal Calcd for C15H18O4: C, 68.68; H, 6.92. Found: C, 68.52; H, 7.01.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:22][CH2:23][NH2:24])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccc(OCc2ccccc2)cc1-c1cccc(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1ccc(OCc2ccccc2)cc1-c1cccc(F)c1

Procedure:
80 mg, 0.25 mmol of 29 was added to a 25 mL oven-dried flask containing 5 mL freshly distilled DCM, under argon atmosphere. Acetic anhydride (21 μL, 0.22 mmol) and triethyl amine (35 μL) were then added to the solution and the resultant mixture stirred at room temperature for 3 h. The reaction mixture was then quenched by addition of saturated ammonium chloride, and extracted into DCM. The combined organic layers were dried (Na2SO4) and concentrated to a crude mixture, which was purified by column chromatography (Silica gel, 3:1 hexane:EtOAc) to give the desired product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH:13]=1>O1CCOCC1>[N:12]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)=[O:4])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C(CBr)c1cccc(Br)c1
Solvent: C1COCCO1
Product: O=C(Cn1cnc2ccccc21)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 2-bromo-1-(3-bromophenyl)ethanone (120 mg, 0.432 mmol) in dioxane (2 mL) was added benzoimidazole (102.0 mg, 0.864 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (4:96) as eluent to give the sub-title compound in 53% yield (71.8 mg, 0.227 mmol).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([C@:16]12[CH2:24][CH2:23][C@@H:22]3[C@:25]4([CH3:34])[C:30]([CH2:31][CH2:32][C@H:21]3[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[OH:35])=[CH:29][C:28](=[O:33])[CH2:27][CH2:26]4)#[CH:15]>CC(C)=O>[C:14]([C@:16]12[CH2:24][CH2:23][C@@H:22]3[C@:25]4([CH3:34])[C:30]([CH2:31][CH2:32][C@H:21]3[C@@H:20]1[CH2:19][CH2:18][C:17]2=[O:35])=[CH:29][C:28](=[O:33])[CH2:27][CH2:26]4)#[CH:15]
Reactant: C#C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C#C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CCC2=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A small excess of Jones reagent (8 N chromic acid in sulphuric acid) is added to a solution of 300 mg of 13-ethinyl-17β-hyroxy-10-methyl-gon-4-en-3-one in 4 ml of acetone at 0° C. The reaction mixture is stirred for a further 5 minutes at 0° C and the excess reagent is destroyed by adding isopropyl alcohol. The reaction mixture is diluted with ethyl acetate, washed with water, sodium bicarbonate solution and saturated sodium chloride solution, dried and evaporated. The residue is chromatographed on silica gel; elution with a mixture of hexne/ethyl acetate (3:1) gives 13-ethinyl-10-methyl-gon-4-ene-3,17-dione, which is identical to the product of Examples 1C and 3.
Reaction SMILES: C[Si:2]([CH3:11])([O:7][CH2:8][CH2:9][SH:10])[O:3][CH2:4][CH2:5][SH:6].C(N(CC)CC)C.ClC([SiH3])(Cl)Cl.[SH:24][CH2:25][CH2:26][OH:27]>CCOCC>[CH3:11][Si:2]([O:3][CH2:4][CH2:5][SH:6])([O:7][CH2:8][CH2:9][SH:10])[O:27][CH2:26][CH2:25][SH:24]
Reactant: OCCS
Reactant: C[Si](C)(OCCS)OCCS
Agent: [SiH3]C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](OCCS)(OCCS)OCCS

Procedure:
The 2-[methyl-bis(2-sulfanylethoxy) silyl]oxyethanethiol (2) was synthesized according to the same procedure as 2-[dimethyl(2-sulfanylethoxy)silyl]oxyethanethiol (1), using triethylamine (8.08 g, 0.080 mol), trichloromethylsilane (3.98 g, 0.027 mol), and 2-mercaptoethanol (6.24 g, 0.080 mol) in ether (400 mL). 2-[methyl-bis(2-sulfanylethoxy) silyl]oxyethanethiol (2) was obtained as a clear, colorless, foul-smelling liquid (6.81 g, 93.2%). The product was purified by distillation under reduced pressure and obtained as a clear, colorless, foul-smelling liquid (4.53 g, 62.0%), Bp=128-129° C. at 0.25 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:12][C:7]1[CH:6]=[C:3]([C:2]([OH:1])=[CH:9][C:8]=1[O:10][CH3:11])[CH:4]=[O:5]
Reactant: [Br-]
Reactant: COc1ccc(C=O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
A mixture of 2-hydroxy-4-methoxy-benzaldehyde (3.64 g, 20 mmol) and tetrabutylammonium tribromide (6.40 g, 20 mmol) in anhydrous dichloromethane (200 mL) was stirred at room temperature for 24 hours. The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography, using a Biotage 40M cartridge; eluting with 5% ethyl acetate/95% hexane to give 3-bromo-6-hydroxy-4-methoxy-benzaldehyde as a white solid (3.50 g, 76%).
Reaction SMILES: N1C=CC=CC=1.C([O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C(C)=C.O>C1COCC1>[C:14]1([C:13]([OH:12])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=C(C)C(=O)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The procedure of Example 2 was repeated except that 3.96 g (0.05 mol) of dry pyridine was used in place of triethylamine and the reaction was carried out in THF. It was confirmed when the reaction solution was examined by means of thin-layer chromatography that triphenylmethyl methacrylate was quantitatively formed. After the amine salt was removed by filtration, the solvent and excess pyridine were evaporated. The intended product was obtained as a syrup. An attempt to recrystallize it from ether and n-hexane failed, since hydrolysis took place due to water contained in the solvents for recrystallization and triphenylmethyl alcohol was formed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].CS([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1)(=O)=O.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Temperature: 50 °C
Yield: 87.8 %

Procedure:
To 3,4-dichlorophenol (13.8 g) dissolved in a 60 ml THF/60 ml DMSO mixture was added 9.5 g of t-BuOK. The temperature rose to about 40° C. and then 19.8 g of 2,5-bis(methylsulfonyl)pyridine was added. The reaction mixture was warmed to 50° C. and the temperature maintained at 50° C. for 1 hour. The reaction mixture was cooled, poured into approximately 3 volumes of water and the solid collected. The solid was dried on a porous plate and then recrystallized from CH2Cl2 /ethanol to give 23.5 g of 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)pyridine as shiny white plates, m.p. 120°-121° C.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[Cl:17])[CH2:15][CH:16]=1
Reactant: Clc1ccccc1CBr
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Agent: Cl
Product: Clc1ccccc1CN1CC=C(c2cc3ccccc3s2)CC1
Yield: 11.9 %

Procedure:
4-(Benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.99 mmol) was reacted with 2-chlorobenzyl bromide (0.24 ml, 1.5 mmol) as exemplified in Example 1. The crude product was triturated with methanol to give the title compound as a pale yellow brown solid (40 mg, 12%) m.p. 105°-106° C.; (Found: C, 69.29; H, 5.17; N, 4.23. C20 H18ClNS. 0.5H2O requires C, 68.85; H, 5.49; N, 4.01%). δH (CDCl3), 2.66 (2H, m, NCH2CH2), 2.80 (2H, m, NCH2CH2), 3.27 (2H, m, NCH2CH2), 3.77 (2H, s, NCH2Ar), 6.20 (1H, m, NCH2CH), 7.13 (1H, s, ArH), 7.25 (4H, m, ArH), 7.36 (1H, d of d, J 7.7Hz, J 1.4Hz, ArH), 7.53 (1H, d of d, J 7.5Hz, J 1.6Hz, ArH), 7.66 (1H, d of d, J 6.9Hz, J 1.5Hz, ArH), 7.73 (1H, d of d, J 8.7Hz, J 1.7Hz, ArH). m/z (ES+) 340 (M+1)+.
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:14]([O:16][CH2:17]Cl)[CH3:15].C(OCC)(=O)C>CN(C)C=O>[CH2:14]([O:16][CH2:17][O:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)[CH3:15]
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCOCc1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
4.56 g of piperonyl alcohol and 1.20 g of 60% sodium hydride were suspended in 30 ml of N,N-dimethylformamide. After stirring for 30 minutes under ice-cooling, 2.28 ml of chloromethyl ethyl ether was added thereto, and the mixture was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution. The mixture was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:20), to give 4.98 g of the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCCC(Oc1ccc(-c2ccc(Cl)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
This compound is made in a substantially similar manner to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl ester and 4-chlorophenylboronic acid as starting materials in step D. MS (ES): 492.3 [M−H]−.
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][CH2:5][CH2:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CC(C)([O-])C.[K+].[H][H]>CO>[CH3:1][O:2][CH2:3][NH:4][CH2:5][CH2:6][C@@H:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[OH:8]
Reactant: COCNCCC(=O)c1cccs1
Reactant: [H][H]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COCNCC[C@H](O)c1cccs1
Reaction time: 12 h

Procedure:
A degassed methanol solution (4 mL) containing RuCl2((R)-3,5-xylylBINAP) ((2R)-DAIPEN) (10 mg), 3-methoxymethylamino-1-(2-thienyl)-1-propanone (160 mg), potassium tert-butoxide (100 mg) and methanol (10 mL) were charged in a glass autoclave under an argon gas flow. After deaeration and replacement by argon, hydrogen was introduced to a predetermined pressure. The resulting solution was hydrogenated at 20□ for 12 hours. Upon completion of hydrogenation, the reaction mixture was concentrated to give the objective compound as an oily product (161 mg, 95% ee; purity: 95.8% by HPLC assay).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[Li]CCCC.[C:31](=[O:33])=[O:32]>>[CH2:1]([O:8][C:9]1[C:10]([F:17])=[C:11]([F:16])[C:12]([F:15])=[C:13]([CH:14]=1)[C:31]([OH:33])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Product: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1F
Reaction time: 7.5 h

Procedure:
To a solution of 1-benzyloxy-2,3,4-trifluorobenzene in appropriate inert solvent is added strong base (such as LDA, n-BuLi, LiHDMS) at low temperature (−50-−80° C., prefer −78° C.) under nitrogen atmosphere. The stirring is maintained at this temperature for several hours (0.5-12 h, prefer 0.5-2 h). The mixture is transferred to a bottle with dry ice and the resulting mixture is stirred for some time (such as 3-12 h, prefer 5-10 h). 5-Benzoxy-2,3,4-trifluorobenzoic acid is obtained after conventional workup.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][N:23]([CH:31]([CH3:33])[CH3:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:15]([C:34]3[C:35]4[CH:42]([CH:43]([CH3:45])[CH3:44])[CH2:41][CH2:40][C:36]=4[N:37]=[CH:38][N:39]=3)[CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:31]([N:23]([CH2:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[N:15]([C:34]3[C:35]4[CH:42]([CH:43]([CH3:45])[CH3:44])[CH2:41][CH2:40][C:36]=4[N:37]=[CH:38][N:39]=3)[CH2:14][C:11]3([CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:21]=12)[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN(C(=O)OC(C)(C)C)C(C)C)cccc43)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)C1CCc2ncnc(N3CC4(CCNCC4)c4c(CN(C(=O)OC(C)(C)C)C(C)C)cccc43)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 783.4 %

Procedure:
A solution of tert-butyl (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl(isopropyl)carbamate (0.088 g, 0.14 mmol) in MeOH (1 mL) was treated with ammonium formate (0.027 g, 0.43 mmol) and Pd/C (0.0077 g, 0.0072 mmol) and heated to reflux for 7 hours and stirred at room temperature overnight. The reaction was filtered through glass filter paper, and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (5% MeOH/DCM, then 5% 7N NH4 in MeOH/DCM) to yield pure tert-butyl isopropyl((1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)carbamate (0.57 g, 76%). LCMS (APCI+) m/z 520.2 [M+H]+; Rt=3.80 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br>CO>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: CO
Product: Nc1cc(Cl)c(Br)cc1C(=O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 2-amino-4-chlorobenzoic acid (10.0 g, 58.5 mmol) in methanol (150 mL) was added bromine (15.7 mL) at −78° C., and the reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with ice water (100 mL) and aq. sodium thiosulfate, and extracted with ethyl acetate (150 mL×3). The organic layers were separated, combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (9 g, 62%).
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1.O>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[N:9][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C[C@H](N)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: C[C@H](N=C1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
To a solution of (S)-1-phenylethanamine (1.921 g, 15.85 mmol) in benzene (8.81 ml) were added molecular sieves in water and 1-benzylpiperidin-4-one (2.50 g, 13.21 mmol). The reaction was stirred at room temperature for 5 hrs. The product mixture was filtered and concentrated under reduced pressure to give a yellow oil, which was standing under vacuum at 45° C. for 14 hrs to remove the residual reactant, yielding (S)—N-(1-benzylpiperidin-4-ylidene)-1-phenylethanamine (3.24 g, 11.08 mmol, 84.0% yield) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ 7.33-7.25 (m, 10H), 4.81-4.76 (m, 1H), 3.54 (s, 2H), 2.72-2.33 (m, 8H), 1.47 (d, J=6.6 Hz, 3H). LCMS (method K) m/z 291.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:16][CH:13]1[CH2:15][CH2:14]1)=[O:8]
Reactant: O=C(Cl)/C=C/c1cccc(Br)c1
Reactant: NC1CC1
Solvent: Cc1ccccc1
Product: O=C(/C=C/c1cccc(Br)c1)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A solution of trans 3-bromocinnamoyl chloride (12.2 g) in dry toluene (150 ml) was added dropwise (rapidly) with rapid stirring to a solution of cyclopropylamine (6.3 g) in dry toluene (150 ml). The reaction mixture was stirred at room temperature for 2 hours, then at 30°-35° C. for an additional hour; and the solvent and excess amine were removed under reduced pressure. The residue was triturated with water to remove cyclopropylamine hydrochloride. The product was filtered, washed with dilute hydrochloric acid and then with water. It was then recrystallized from ethanol:water (1:10) to give white crystalline trans 3-bromo-N-cyclopropylcinnamamide (12 g), m.p. 110°-111° C. Elemental analysis, NMR and 1R data were all consistent with the assigned structure. TLC gave one spot run on silica gel with 5:1 and with 3:1 hexane:ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[N+:42]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([OH:38])[CH:30]=4)=[CH:24][CH:23]=3)[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)=[CH:8][CH:7]=1.O.NN>[Pd].C(O)C>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:12]3([C:9]4[CH:10]=[CH:11][C:6]([O:5][C:4]5[CH:39]=[CH:40][C:41]([NH2:42])=[C:2]([OH:1])[CH:3]=5)=[CH:7][CH:8]=4)[CH:13]4[CH2:21][CH:17]5[CH2:16][CH:15]([CH2:20][CH:19]3[CH2:18]5)[CH2:14]4)=[CH:27][CH:26]=2)=[CH:30][C:31]=1[OH:38]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C3(c4ccc(Oc5ccc([N+](=O)[O-])c(O)c5)cc4)C4CC5CC(C4)CC3C5)cc2)cc1O
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(C3(c4ccc(Oc5ccc(N)c(O)c5)cc4)C4CC5CC(C4)CC3C5)cc2)cc1O
Reaction time: 24 h
Yield: 67 %

Procedure:
A mixture of 2,2-bis(4-(3-hydroxy-4-nitrophenoxy)phenyl)adamantane (3.00 g, 5.05 mmol), 10% Pd/C (0.06 g) and ethanol (60 mL) were heated to reflux. Then, 20 mL of hydrazine hydrate was added dropwise into the suspension solution over a period of 1 hour. After the mixture was refluexed for another 24 h. The reaction solution was then filtered to remove Pd/C. The crude product was recrystallized from ethanol to give 1.81 g (67.1%) of 2,2-bis(4-(4-amino-3-hydroxyphenoxy)phenyl)adamantane. mp>160° C. (decompose); IR (KBr): 3415, 3298, 2912 cm−1, MS (EI) m/z 534 (M+, 100); Anal. Calcd. for C34H34N2O4: C, 76.40; H, 6.36; N, 5.24. Found: C, 76.21; H, 6.45; N, 5.22.