Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].CC([O-])=O.[Na+].Cl.[NH2:18][OH:19]>CO.[Cl-].[Na+].O>[OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[C:9](=[N:18]/[OH:19])/[CH3:10]
Reactant: NO
Reactant: CC(=O)c1cccc(C)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: C/C(=N\O)c1cccc(C)c1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
1-(2-hydroxy-3-methylphenyl)ethanone (Step 46.1) (900 mg, 5.87 mmol) was dissolved in MeOH (15 mL) and NaOAc (771 mg, 9.40 mmol) and hydroxylamine hydrochloride (612 mg, 8.81 mmol) were successively added. The resulting mixture was heated up and stirred at 60° C. for 2 hr. The reaction mixture was poured into brine and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product (964 mg, 5.25 mmol, 89% yield) as a colorless solid. tR: 0.94 min (LC-MS 2); ESI-MS: 166 [M+H]+, ESI-MS: 164 [M−H]− (LC-MS 2); Rf=0.66 (hexane/EtOAc 1:1).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:4][C:3]=1[O:34][CH3:35].[C:36](Cl)(=[O:38])[CH3:37]>N1C=CC=CC=1>[C:36]([O:1][C:2]1[C:3]([O:34][CH3:35])=[CH:4][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:6][C:7]=1[O:8][CH3:9])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1O
Solvent: c1ccncc1
Product: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-[2-{5-(4-hydroxy-3,5-dimethoxyphenyl)-(2E,4E)-2,4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (1 g) and pyridine (10 ml) was added slowly acetyl chloride (0.48 ml) at 5° to 10° C. After 1 hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was treated with a mixture of fumaric acid (83 mg) and methanol (8 ml) and concentrated under reduced pressure to give white crystals. The crystals were recrystallized from ethanol to give 1-[2-{5-(4-acetoxy-3,5-dimethoxyphenyl)-(2E,4E)-2,4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine 1/2fumarate (0.25 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[CH:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.N#N.[CH:26]1([C:29]#[CH:30])[CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>C1COCC1.CCOC(C)=O.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]1([C:29]#[C:30][C:2]2[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][N:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: Cn1cnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Reactant: C#CC1CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cnnc1C(=NOCc1cccc(C#CC2CC2)n1)c1ccccc1
Reaction time: 0.05 h
Yield: 190.3 %

Procedure:
To a stirred solution of N-[(6-bromopyridin-2-yl)methoxy]-1-(4-methyl-4H-1,2,4-triazol-3-yl)-1-phenylmethanimine (0.125 g, 0.33 mmol, 1 eq.) in 3 ml dry THF “degassed” with N2, was added Cyclopropylacetylene (0.95 g, 0.1 mmol, 3 eq.) followed by N-ethyldiisopropylamine (0.216 g, 1.67 mmol, 5 eq.), Copper Iodide (0.012 g, 0.06 mmol, 0.2 eq.) and Tetrakis(triphenylphosphine)palladium (0.077 g, 0.06 mmol, 0.2 eq.). The reaction was microwaved 120° C./normal/fixed hold/pre stir 100 s for 180 s. The reaction was diluted with EtOAc and filtered through a “celite” plug. The solvent was evaporated and the residue purified by chromatography on silica gel to give N-{[6-(cyclopropylethynyl)pyridin-2-yl]methoxy}-1-(4-methyl-4H-1,2,4-triazol-3-yl)-1-phenylmethanimine (0.068 g, 56% yield) as a yellow viscous oil.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH:4]([CH3:7])[CH2:5][CH3:6].COC(=O)[C@H]([C@H](CC)C)N.OCCN.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[C:27]([CH2:34][CH3:35])[CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]2[NH:8][C@@H:3]([CH:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:33]2)=[C:27]([CH2:34][CH3:35])[CH:26]=1)#[N:24]
Reactant: CCc1cc(C#N)ccc1N=C=S
Reactant: CCC(C)[C@H](N)CO
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: NCCO
Product: CCc1cc(C#N)ccc1N=C1N[C@@H](C(C)CC)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Cyano-2-ethylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-cyano-2-ethylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2-ethylphenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8]CSC)=[O:7].[OH-].[Na+]>C(O)C>[CH3:1][S:2][CH2:3][S:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7]
Reactant: CSCOC(=O)C(SCSC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSCSC(C(=O)O)c1ccccc1
Reaction time: 8 h

Procedure:
2.9 gms. of DL-α-[[(methylthio)methyl]thio]benzene acetic acid, (methylthio)methyl ester are dissolved in 10 ml. of ethanol. 20 ml. of 1 N alcoholic sodium hydroxide solution are added and the mixture is permitted to stand overnight. This is then concentrated, the residue is dissolved in water, the aqueous solution is extracted once with ether, then acidificed and the oil is extracted with ether. After drying with magnesium sulfate and evaporating the solvent 1.8 gms. of DL-α-[[(methylthio)methyl]thio]benzeneacetic acid are obtained as an oil.
Reaction SMILES: C(OC([C:6]1[C:7]([OH:28])=[N:8][C:9]2[N:10]([N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:11]=1)=O)C.P(=O)(O)(O)O>>[OH:28][C:7]1[CH:6]=[CH:11][N:10]2[N:12]=[CH:13][C:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)=[C:9]2[N:8]=1
Reactant: CCOC(=O)c1cn2ncc(-c3ccc(Sc4ccccc4)cc3)c2nc1O
Agent: O=P(O)(O)O
Product: Oc1ccn2ncc(-c3ccc(Sc4ccccc4)cc3)c2n1
Yield: 50.3 %

Procedure:
In the same manner as in Example 3 except that 0.39 g of 6-ethoxycarbonyl-5-hydroxy-3-(4-phenylthiophenyl)-pyrazolo[1,5-a]pyrimidine obtained in Example 2 and 5 ml of 85% phosphoric acid were used, 0.16 g of the title compound was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:34]1([C:40]([NH2:43])([CH3:42])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Br:44][C:45]1[C:53]2[C:48](=[N:49][CH:50]=[C:51]([C:54]3[CH:55]=[C:56]([CH:60]=[CH:61][CH:62]=3)[C:57](O)=[O:58])[CH:52]=2)[O:47][C:46]=1[C:63]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=1>CN(C=O)C.CCOC(C)=O>[Br:44][C:45]1[C:53]2[C:48](=[N:49][CH:50]=[C:51]([C:54]3[CH:55]=[C:56]([CH:60]=[CH:61][CH:62]=3)[C:57]([NH:43][C:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([CH3:42])[CH3:41])=[O:58])[CH:52]=2)[O:47][C:46]=1[C:63]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1)c1ccccc1
Reaction time: 1 h
Yield: 85 %

Procedure:
DIEA (210 μL, 1.20 mmol) was added to a stirring solution of HATU (228 mg, 0.600 mmol), 2-phenylpropan-2-amine (69.1 μL, 0.480 mmol), 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (165 mg, 0.400 mmol) in DMF (4 mL) at room temperature. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with Et2O to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (180 mg, 0.340 mmol, 85% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.78-8.86 (1H, m), 8.60 (1H, s), 8.34-8.38 (1H, m), 8.27 (1H, s), 8.19-8.26 (2H, m), 7.99 (1H, d, J=7.93 Hz), 7.89 (1H, d, J=7.93 Hz), 7.61 (1H, t, J=7.63 Hz), 7.46-7.55 (2H, m), 7.42 (2 H, d, J=7.32 Hz), 7.30 (2H, t, J=7.78 Hz), 7.18 (1H, t, J=7.17 Hz), 1.72 (6H, s). LC-MS retention time: 1.97 min; m/z (MH+): 529, 531. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][NH:11][C:12](=[O:16])[C:13]([OH:15])=[O:14].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>C1COCC1>[C:17]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)C(=O)NCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCNC(=O)C(=O)O
Reaction time: 6 h

Procedure:
To 730.7 g (5 moles) of diethyl oxalate was added dropwise at room temperature a solution of 61.1 g (1 mole) of ethanolamine in 500 ml of acetone and, after the addition finished, treatment of the mixture by distillation under reduced pressure to remove the formed ethanol and the acetone and an excess amount of diethyl oxalate yielded ethyl 2-hydroxyethyloxamate. A mixture of 80.5 g (0.5 moles) of this ethyl 2-hydroxyethyloxamate, 50.6 g (0.5 moles) of triethylamine (hereinafter, referred to as TEA), 20.0 g of water, and 1000 ml of dioxane was warmed under reflux for 8 hours and treated with solvent removal followed by dehydration yielded a triethylamine salt of 2-hydroxyethyloxamic acid. A mixture of 11.7 g (0.05 moles) of this triethylamine salt of 2-hydroxyethyloxamic acid and 5.1 g (0.05 moles) of TEA was treated with dehydration by molecular sieve and then, dissolved with warming into 300 ml of THF. To this THF solution was added dropwise under a refluxing condition during 0.5 hours a solution of 5.2 g (0.05 moles) of methacrylic acid chloride in 30 ml of THF and, after the addition finished, the mixture was further stirred under the condition for 6 hours and treated with fractional extraction to get methacryloyloxyet hyloxamic acid of the following structure: ##STR17## Besides, identification of the methacrylolyloxyethyloxamic acid 1 was carried out with 13C-NMR spectra analysis (ppm, in CDCL3) and the results were 17.93 for (2), 38.86 for (6); 62.35 for (5), 120.59 for (1), 138.86 for (3), 158.01 for (7), 160.56 for (8), and 167.06 for (4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH:15]([CH2:17][C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(O)[CH2:19][CH:20]=[CH2:21])[CH3:16])[C:11](=[O:14])[O:12]C)[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+]>>[CH2:19]([C:18]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:14][C:11](=[O:12])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])[CH:15]([CH3:16])[CH2:17]1)[CH:20]=[CH2:21]
Reactant: C=CCC(O)(CC(C)N(C(=O)OC)[C@@H](C)c1ccc(Br)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: C=CCC1(c2ccc(F)cc2)CC(C)N([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C

Procedure:
To a solution of methyl (S)-1-(4-bromophenyl)ethyl(4-(4-fluorophenyl)-4-hydroxyhept-6-en-2-yl)carbamate (20 mg, 0.043 mmol) was added NaH at 0° C. The mixture was stirred and heated to reflux for 1 h. The mixture was cooled to rt and quenched with water. The organic phase was extracted by EtOAc and concentrated to give the crude product which was purified by preparative TLC to give three isomers of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-4-methyl-1,3-oxazinan-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:16][C:17](=[O:25])[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:26]>CC(O)C>[NH2:26][C:20]1[C:19]2[N:18]([C:17](=[O:25])[NH:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:23]=[CH:22][N:21]=1
Reactant: O=c1[nH]c(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(=O)[nH]c(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 110 °C

Procedure:
A solution of 1-(3-benzyloxy-phenyl)-8-chloro-2H-imidazo[1,5-a]pyrazin-3-one (100 mg, 0.28 mmol) in i-PrOH (4 mL) was saturated with NH3 at −20° C. and heated 110° C. in a sealed tube for 48 hours. The light brown reaction mixture was partitioned in water and DCM and separated. The aqueous layer was washed with DCM (3×) and the combined organic layers were washed with brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 8% MeOH in DCM], resulting in the title compound as a pale brown solid; 1H NMR (DMSO-d6, 400 MHz) δ=5.16 (s, 2H), 5.86 (brs, 2H), 6.70 (d, J=5.2 Hz, 1H), 7.01 (d, J=4.8 Hz, 1H), 7.07-7.14 (m, 2H), 7.24 (brt, J=2 Hz, 1H), 7.32-7.49 (m, 7H); MS (ES+): m/z=333.21 (100) [MH+], HPLC: tR=2.05 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][OH:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1>C(Cl)Cl>[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]
Reactant: C1=COCCC1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC1CCCCO1
Yield: 67.2 %

Procedure:
In methylene chloride were dissolved 15 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol and 1.5 g of p-toluenesulfonic acid, and to the solution was dropwise added, under stirring, 8.7 g of 2,3-dihydropyran, at 0°-5° C. and over a period of 30 min. The resulting solution was further stirred at 0°-5° C. for 30 min., and then washed with an aqueous sodium carbonate solution in a separatory funnel. The solution was concentrated after the washing, and the concentrated solution was purified over a silica gel column to give 13 g of 1-(2-tetrahydropyranyl)oxy-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene (yield 68%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.[Cl-].[NH4+]>CN(C)C=O>[Si:11]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2[nH]ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Yield: 99.7 %

Procedure:
A solution of 4-hydroxyindole (3.0 g, 22.5 mmol), t-butyldimethylsilyl chloride (5.09 g, 33.8 mmol) and imidazole (3.83 g, 56.3 mmol) in dimethylformamide (60 mL) was stirred at room temperature for 24 hours. Aqueous ammonium chloride was added (100 ml) and extracted several times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and evaporated to give a crude oil. Flash chromatography (10% ethyl acetate/hexanes) yielded the desired product (5.55 g, 100%) as a white solid. NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][S:12](=[O:15])(=[O:14])[NH:11][C:10](=[O:16])[NH:9]2)=[CH:4][CH:3]=1.[CH3:17][O-].[Na+].CI>CO.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][S:12](=[O:15])(=[O:14])[N:11]([CH3:17])[C:10](=[O:16])[NH:9]2)=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C1NC(c2ccc(Cl)cc2)CS(=O)(=O)N1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CO
Product: CN1C(=O)NC(c2ccc(Cl)cc2)CS1(=O)=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Using a method similar to that described by A. Etienne et al. (Bull. Soc. Chim. Fr., 1974, 1395) 5-(4-chlorophenyl)-1,1-dioxo-[1,2,4]thiadiazinan-3-one DE3 is treated with sodium methoxide (1 equivalent) in methanol. Add methyl iodide (1.2 equivalent) in DMF and allow to stir for 12 h. Pour the mixture into ice water and collect the precipitate of the title compound DE4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a solution of 150 mg (0.35 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-4-[(t-butyldimethylsiloxy)-methyl]-1,1'-biphenyl (Step G) in 2 mL of dry tetrahydrofuran under a nitrogen atmosphere was added by syringe 0.52 mL (0.53 mmol) of 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran. The reaction mixture was stirred for one hour then diluted with 100 mL of ethyl acetate. The mixture was washed with water (3×20 mL), then saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give an oil which was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (55:45) to afford 101 mg (93%) of the product as a white solid. FAB-MS: calculated for C19H23NO3 313; found 314 (M+H). 1H NMR (200 MHz, CDCl3): 1.40 (s, 9H), 2.50 (s, 2H), 4.20 (s, 2H), 4.70 (s, 2H), 7.18-7.45 (s, 8H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:4]=2[O:3]1>CO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:4]2[O:3][C:2]([CH3:1])([CH3:17])[C:7](=[O:8])[N:6]([CH3:9])[C:5]=2[CH:10]=1
Reactant: CN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)C(C)(C)Oc2ccc(N)cc21
Reaction time: 3 h
Yield: 94.6 %

Procedure:
A mixture of 2,2,4-trimethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (290 mg, 1.23 mmol, 1 equiv.) in 10 mL of MeOH in the presence of 29 mg of Pd/C was hydrogenated at room temperature for 3 h. The reaction mixture was then filtered through a pad of celite and the filtrate was concentrated to give 240 mg (Yield=95%) of product as a pale brown solid which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]([CH2:24][C:25]([O:27]CC)=[O:26])[C:10](=[O:30])[CH2:9]1)=[O:7].[OH-].[Na+]>C(O)C>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]([CH2:24][C:25]([OH:27])=[O:26])[C:10](=[O:30])[CH2:9]1)=[O:7]
Reactant: CCOC(=O)CN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To an ice-cooled solution of (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-(ethoxycarbonylmethyl)-5-(1H-indol-3-ylmethyl)piperazin-2-one (0.88 g) in ethanol (20 ml) was added 1N sodium hydroxide solution (1.58 ml). The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1 hour and 45 minutes. The mixture was concentrated under reduced pressure, and water and 1N hydrochloric acid (1.58 ml) were added to the residue under ice-cooling. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. After evaporation in vacuo, n-hexane was added to the crystalline residue and the resulting crystals were collected by filtration, washed with n-hexane, and dried to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-(carboxymethyl)-5-(1H-indol-3-ylmethyl)piperazin-2-one (0.76 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>CC#N>[N:16]([CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11]1)=[C:17]=[S:18]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NCCCN1CCC(c2ccccc2)CC1
Solvent: CC#N
Product: S=C=NCCCN1CCC(c2ccccc2)CC1

Procedure:
A solution of 4-phenyl-1-piperidinepropanamine (Example 5 intermediate) (3.2 g, 14.7 mmol) and 1,1'-thiocarbonyldiimidazole (2.8 g, 15.7 mmol) in MeCN (100 mL) was stirred for 2 h. The reaction mixture was chromatographed by vacuum filtration over silica (MeCN) to furnish 1-(3-isothiocyanatopropyl)-4-phenylpiperidine as an amber oil which crystallized upon standing (1.25 g, 33%). mp 50-55° C.; MS (ESI) m/z 261 (MH+); IR (KBr) 2113 cm-1. 1H NMR (CDCl3) δ 7.23 (m, 5H), 3.63 (t, 2 H, J=6.3 Hz), 3.08 (m, 2H), 2.55 (t, 2H, J=7.2 Hz), 2.50 (m, 1H), 2.15 (m, 2H), 1.95 (t, 2H, J=6.9 Hz), 1.86 (m, 4H). Anal. Calcd. for C15H20N2S.0.5 C2H3N: C, 66.28; H, 7.82; N, 12.08. Found: C, 66.68; H, 7.75; N, 12.22.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:18]([CH2:19][CH:20]=[CH2:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH2:22][CH:23]=[CH2:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C>[Si:1]([O:8][C:9]1[C:10]([CH2:22][CH2:23][CH3:24])=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][C:18]=1[CH2:19][CH2:20][CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: C=CCc1cc(C(=O)OC)cc(CC=C)c1O[Si](C)(C)C(C)(C)C
Solvent: CCO
Product: CCCc1cc(C(=O)OC)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Yield: 89.8 %

Procedure:
A solution of 5.0 g (14.45 mmol) of the product of Step C in 250 mL ethanol containing 5% Rh/C (0.25 g) was shaken under a 40 psi pressure of hydrogen. Upon completion of reduction, the mixture was filtered through Celite, the filter cake was washed with methanol and dichloromethane. Removal of solvents afforded 4.55 g (90%) of the title compound.