Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:4][C:3]=1[C:22]([O:24]C)=O.C([O-])=O.[NH4+].[CH:30]([NH2:32])=O>>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([C:6]3[C:2]4[N:1]=[CH:30][NH:32][C:22](=[O:24])[C:3]=4[S:4][C:5]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: COC(=O)c1sc(-c2ccccc2)c(-c2ccc3[nH]ccc3c2)c1N
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: O=c1[nH]cnc2c(-c3ccc4[nH]ccc4c3)c(-c3ccccc3)sc12

Procedure:
A mixture of EXAMPLE 8B (95 mg, 0.27 mmol) and ammonium formate (68 mg, 1.08 mmol) in formamide (5 mL) was heated at 170° C. for 4 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC on a C18 column using 0-70% acetonitrile/0.1% trifluoroacetic acid in water to give 40 mg of the title compound. 1H NMR (DMSO-d6) δ 12.57 (br, 1H), 11.14 (s, 1H), 8.15 (s, 1H), 7.53 (s, 1H), 7.30-7.36 (m, 7H), 6.93 (dd, J=8.2, 1.5, 1H), 6.41 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][NH:6][CH3:7])[CH3:2].[Cl:9]([O-:13])(=[O:12])(=[O:11])=[O:10].CS[C:16]1[S:20][CH:19]=[CH:18][S+:17]=1>O1CCCC1>[Cl:9]([O-:13])(=[O:12])(=[O:11])=[O:10].[S:17]1[CH:18]=[CH:19][S:20][C:16]1=[N+:6]([CH3:7])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:8]
Reactant: CCOC(=O)CNC
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C[N+](C)=c1sccs1
Temperature: 25 °C

Procedure:
To 30 ml of tetrahydrofuran, 1.4 g of N-methylglycine ethyl ester was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration and recrystallized from acetone-ethyl ether, whereby 1.7 g (yield: 67%) of N-(1,3-dithiol-2-ylidene)-N-methyl-N-ethoxycarbonylmethylammonium perchlorate (Compound No. 1) was obtained as crystals having a melting point of from 104° to 105° C.
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[O:18]=[O+][O-].O=O>ClCCl.CO>[N:16]1[C:17]2[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=[O+][O-]
Reactant: C(=C1CCCc2cccnc21)c1ccccc1
Agent: O=O
Solvent: CO
Solvent: ClCCl
Product: O=C1CCCc2cccnc21
Temperature: 0 °C

Procedure:
A solution of (2) in dichloromethane (100 mL) and methanol (500 mL) was cooled to −78° C. and charged with ozone/oxygen (3 psi, 1.5 ampere). The dark brown solution turned yellow after several hours. When (2) was consumed (TLC), ozone/oxygen flow was stopped. The reaction mixture was purged with nitrogen for 10 m. Methyl sulfide (6 mL) was added, and the mixture was stirred for 30 m at 0° C. The solvents were removed under vacuum and the residue was dissolved in 1 N HCl (500 mL) and washed with diethyl ether (4×150 mL). The aqueous layer was basified to pH ˜7 with NaOH (s), and extracted with ethyl acetate (2×200 mL). The pooled ethyl acetate layers were dried over magnesium sulfate. The mixture was filtered and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 90% EtOAc 10% hexane to give 6,7-Dihydro-5H-quinolin-8-one (3) as a solid. The aqueous layer was extracted with chloroform/isopropanol (3:1) several times. The pooled chloroform/isopropanol layers were dried over magnesium sulfate. The mixture was filtered and the solvents were removed under vacuum to give (3). The combined weight of (3) was 17.9 g (122 mmol, 89% over 2 steps).
Reaction SMILES: C([BH3-])#N.[F:4][C:5]1[CH:55]=[CH:54][C:8]([C:9]([N:11]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:52]=[CH:51][C:28]4[N:29]([C:32]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:30]=[N:31][C:27]=4[CH:26]=3)[CH:22]=[CH:21][C:20]=2[F:53])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:7][CH:6]=1.C(O[C:59]1(O[Si](C)(C)C)[CH2:61][CH2:60]1)C.C(O)(=O)C>CO>[CH:59]1([N:15]2[CH2:16][CH2:17][CH:12]([N:11]([CH2:18][C:19]3[CH:24]=[C:23]([C:25]4[CH:52]=[CH:51][C:28]5[N:29]([C:32]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)([C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)[C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:30]=[N:31][C:27]=5[CH:26]=4)[CH:22]=[CH:21][C:20]=3[F:53])[C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:55][CH:54]=3)[CH2:13][CH2:14]2)[CH2:61][CH2:60]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F)C1CCNCC1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F)C1CCN(C2CC2)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
Solid supported cyanoborohydride (2.5 mmol/g, 46 mg) was added to a solution of 4-fluoro-N-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-N-piperidin-4-yl-benzamide (20 mg, 0.029 mmol), (1-ethoxy-cyclopropoxy)-trimethylsilane (25 mg, 0.145 mmol) and acetic acid (1.74 mg, 0.029 mmol) in 1 mL of methanol. The mixture was stirred at 45° C. for 2 h and then at 75° C. overnight. The mixture was cooled and filtered and the filtrate concentrated in vacuo to provide the crude product. Chromatography provided 14 mg of product. LC/MS: Retention time, 3.20 min; (M+H)=730.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].C(S)[CH2:14][S:15]([O-])(=O)=O.[Na+]>CS(C)=O.CO>[OH:12][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[S:15][CH3:14]
Reactant: O=S(=O)([O-])CCS
Reactant: O=[N+]([O-])c1ccc(Cl)c(CO)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CSc1ccc([N+](=O)[O-])cc1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
To a solution of 4-chloro-3-(hydroxymethyl)nitrobenzene (20 g, 0.10 mol) in DMSO (160 mL) and MeOH (80 mL), MeSNa (8.2 g, 0.12 mol) was added portionwise at 0° C., and the mixture was stirrred for 2 h at room temperature. The mixture was poured into ice water (300 mL) and the yellow precipitate was collected by filtration and washed with ether (150 mL) gave the title compound (21 g, quantitative).
Reaction SMILES: [I:1]Cl.[CH3:3][CH:4]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])[CH3:5].C([O-])(=O)C.[Na+]>C(O)(=O)C>[I:1][C:11]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([CH:4]([CH3:5])[CH3:3])[CH:12]=1
Reactant: CC(C)c1ccccc1N
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(I)ccc1N
Reaction time: 1 h

Procedure:
Iodine monochloride (12.9 cm3) was added at room temperature to a stirred solution of 2-[prop-2-yl]-aniline (27.0 g) and sodium acetate (16.4 g) in acetic acid (250 cm3). After 1 hour, volatile material was removed in vacuo and the residue was partitioned between ethyl acetate (200 cm3) and 10% sodium carbonate solution (50 cm3). The dried (MgSO4) organic extract was filtered and evaporated in vacuo to afford an oil which was chromatographed on silica (Merck "MK 60.9385") eluting with hexane. Combination and evaporation of the product containing fractions gave the product as a crude dark unstable oil (38 g) which was not characterised fully but was used directly in Preparation 84.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH3:28])[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[N:35][NH:36]2)=[CH:32][CH:31]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([NH:29][C:2]3[N:3]=[C:4]([NH:27][CH3:28])[C:5]4[C:10]([C:11]5[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=5)=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:38]=2)[CH:34]=[N:35]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CNc1nc(Cl)nc2c1c(-c1ccncc1)cn2S(=O)(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CNc1nc(Nc2ccc3cn[nH]c3c2)nc2[nH]cc(-c3ccncc3)c12
Temperature: 115 °C
Yield: 33.9 %

Procedure:
To a mixture of 2-chloro-N-methyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.041 g, 0.091 mmol) in nBuOH (0.8 mL) was added 6-aminoindazole (0.024 g, 0.18 mmol) and TMSCl (0.03 mL, 0.23 mmol). After heating at 115° C. for 48 h, the mixture was purified by preparative HPLC to give N2-(1H-indazol-6-yl)-N4-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (0.011 g), MS (MH 357.1), λ=214.5, 247.5, 306.8.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH:9]([CH3:12])[N:8]1C(OCC=C)=O)=[O:6])([CH3:3])[CH3:2].[BH4-].[Na+]>C(#N)C.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:1]([NH:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH:9]([CH3:12])[NH:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)N1C(C)CC[C@@H]1C(=O)NC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NC(=O)[C@H]1CCC(C)N1
Temperature: 50 °C

Procedure:
(R)-Allyl 2-(isopropylcarbamoyl)-5-methylpyrrolidine-1-carboxylate (450 mg, 1769 μmol) was dissolved in acetonitrile (13 mL) and sodium borohydride (268 mg, 7078 μmol) and tetrakis(triphenylphosphine)palladium(0)(102 mg, 88 μmol) were added at ambient temperature. The reaction mixture was heated to 50° C. for 4 h, then filtered through a pad of silica gel and washed with chloroform to remove impurities. The silica was washed again with methanol to obtain the title compound as a mixture of diastereomers (˜60:40). Found MS (ES+): 171(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27]Br>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27][O:16][N:15]=[CH:14][C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:11][C:5]1[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Reactant: Cc1cccc(C=CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Oc2ccccc2C=NOCC=Cc2cccc(C)c2)n1
Yield: 64.5 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 4.2 g of 3-methylcinnamyl bromide were dissolved in 30 ml of acetonitrile containing 2.7 g of anhydrous potassium carbonate, and the solution was heated for 5 hours under stirring and reflux. After the reaction mixture was allowed to cool down, the acetonitrile was distilled out under reduced pressure and the resulting residue was dissolved in 200 ml of ethyl acetate. The ethyl acetate solution was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate: 4:1) to obtain 5.2 g of O-(3-methylcinnamyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as crystals.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)O)[CH:20]=[CH:19]2>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:22]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Reactant: COc1ccc2cc(C(O)c3ccccc3)ccc2c1
Product: COc1ccc2cc(C(C3=C(O)C(C)(c4ccccc4)C3=O)c3ccccc3)ccc2c1

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (6-methoxy-naphthalen-2-yl)-phenyl-methanol to give the title compound as a colorless solid. MS: 419.3 ([M−H]−).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].Br[C:13]([F:20])([F:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>CC(N(C)C)=O>[F:19][C:13]([F:20])([O:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CN(C)C(=O)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)C(=O)C(F)(F)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 33.5 %

Procedure:
A mixture of 2-nitro-5-fluoro-phenol (3.0 g, 19.1 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (3.9 g, 19.1 mmol) and Na2CO3 (2.1 g, 19.8 mmol) in 30 mL of DMAC was heated to 100° C. overnight. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles. Purification by chromatography on silica gave the product (1.8 g, 6.4 mmol, 38% yield) as a yellow oil that solidified upon standing.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][CH:25]([NH:28][CH3:29])[CH2:24]4)=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:30]1([CH2:36][C:37]([OH:39])=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:1]1([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:15])[NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][CH:25]([N:28]([CH3:29])[C:37](=[O:39])[CH2:36][N:30]5[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)[CH2:24]4)=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNC1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)cc3)cc2)C1
Reactant: O=C(O)CN1CCCCC1
Product: CN(C(=O)CN1CCCCC1)C1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)cc3)cc2)C1

Procedure:
1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with piperidin-1-ylacetic acid by method E. This resulted in the product with the molecular weight of 519.69 (C30H41N5O3); MS (ESI): 520 (M+H+).
Reaction SMILES: Cl.C(O)C.C(OC([NH:12][C@H:13]1[CH2:18][C@H:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:16][CH2:15][C@H:14]1[NH:23][C:24]([C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=2)=[O:25])=O)(C)(C)C>O1CCOCC1>[ClH:35].[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][C@@H:14]1[CH2:15][CH2:16][C@@H:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:18][C@@H:13]1[NH2:12])=[O:25])=[CH:34]2
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(C)(C)O)CC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](N)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 4N hydrogen chloride solution in dioxane (10 ml) was added to an ethanol solution (5 ml) of (1R*,2S*,4R*)-N2tert-butoxycarbonyl-N1-[(5-Chloroindol-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-1,2-cyclohexanediamine, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure to obtain the title compound (100 mg) as a colorless oil.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:10]([C@@H:12]1[N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15][N:14]([CH2:28][CH2:29][CH3:30])[C:13]1=[O:31])[OH:11])C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:10]([C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([CH2:28][CH2:29][CH3:30])[C:13]1=[O:31])[OH:11]
Reactant: CCCN1CCN(C(=O)OCc2ccccc2)[C@@H]([C@@H](O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCN1CCN[C@@H]([C@@H](O)[C@@H](N)Cc2ccccc2)C1=O
Yield: 91 %

Procedure:
To a solution of 3-(S)-(2-(S)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)-4-benzyloxycarbonyl-1-propylpiperazin-2-one Isomer-2 (215 mg, 0.35 mmol) in methanol (10 mL/mmol) add palladium hydroxide (172 mg) in one portion and stir the mixture under 1 atmosphere of hydrogen gas for 24 h. Filter through a filtering agent, wash with methanol and concentrate to give the title compound as an oil (Isomer-2) (94 mg, 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>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:18]([C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1)=[CH2:19]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCn1ncc(Br)c1-c1csc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1cnn(CC)c1-c1csc(C(=O)OC)c1
Temperature: 90 °C
Yield: 89.9 %

Procedure:
A mixture of methyl 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (200 mg, 0.64 mmol), Pd(Ph3P)4 (73.3 mg, 0.06 mmol), and tributyl(ethenyl)stannane (302 mg, 0.95 mmol) was heated at 90° C. for 1 h under N2 in a sealed tube. The mixture was purified on Silica (10P/0-20% EtOAc in Hex) to give the title compound (151 mg, 76%): LC-MS (ES) m/z 263 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15]([CH2:18][CH2:19][OH:20])=[CH:16][O:17][C:13]=2[CH:12]=1.CCN(C(C)C)C(C)C.[O:32](S(C)(=O)=O)[S:33]([CH3:36])(=O)=[O:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15]([CH2:18][CH2:19][O:20][S:33]([CH3:36])(=[O:34])=[O:32])=[CH:16][O:17][C:13]=2[CH:12]=1
Reactant: OCCc1coc2cc(Oc3nc4ccccc4s3)ccc12
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1coc2cc(Oc3nc4ccccc4s3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 105.3 %

Procedure:
To a solution of 2-[6-(benzothiazol-2-yloxy)-benzofuran-3-yl]-ethanol (0.32 g, 1.0 mmol) in DCM (15 mL) was added 4-dimethylaminopyridine (13 mg, 0.10 mmol), DIEA (0.22 mL, 1.2 mmol) and Ms2O (0.22 g, 1.2 mmol) and the resulting solution was stirred (rt, 15 min). The reaction mixture was diluted with DCM (40 mL). The organic layer was washed with saturated NH4Cl (2×50 mL), brine (2×50 mL), dried, filtered and concentrated in vacuo to provide the title compound as a clear oil (0.41 g, 100%). MS (ESI): mass calcd. for C18H15NO5S2, 389.5; m/z found, 390.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([Cl:12])=[C:4]([C:13]([OH:15])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:22]1([O:28][CH2:29][CH3:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([Cl:12])=[C:4]([C:13]([C:25]2[CH:26]=[CH:27][C:22]([O:28][CH2:29][CH3:30])=[CH:23][CH:24]=2)=[O:15])[CH:3]=1
Reactant: CCOc1ccccc1
Reactant: CC1Cc2c(Cl)c(C(=O)O)cc(Br)c2O1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)c2cc(Br)c3c(c2Cl)CC(C)O3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of compound 88 (2.4 g, 8.23 mmol) in CH2Cl2 (50 mL) were added oxalyl chloride (0.87 mL, 9.88 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (45 mL) and cooled to 0° C. To the mixture was added phenetole (1.1 mL, 8.28 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (1.1 g, 8.28 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min, warmed up to room temperature and stirred at the temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (50 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 89 was carried on to the next step without further purification (3.15 g).
Reaction SMILES: C(O[CH2:5][C:6]1[C@H:7]2[CH2:20][CH2:19][C@H:18]([CH3:21])[C@H:8]2[C@H:9]([O:12][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[O:10][CH:11]=1)(=O)C.[H][H]>C(OCC)(=O)C.N1C=CC=CC=1.[C].[Pd]>[CH2:16]([O:15][CH:13]([O:12][C@H:9]1[C@@H:8]2[C@@H:18]([CH3:21])[CH2:19][CH2:20][C@@H:7]2[C:6]([CH3:5])=[CH:11][O:10]1)[CH3:14])[CH3:17]
Reactant: [H][H]
Reactant: CCOC(C)O[C@@H]1OC=C(COC(C)=O)[C@H]2CC[C@H](C)[C@@H]12
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@@H]1OC=C(C)[C@H]2CC[C@H](C)[C@@H]12

Procedure:
5.0 g of this colorless oily substance, i.e., (1S, 4aS, 7S, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran, was dissolved in a mixed solvent of 100 mS of ethyl acetate and 3 mι of pyridine, and after 150 mg of 10% palladium carbon was added, the reaction mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere of 1 atm. After the catalyst was filtered by celite, extraction was carried out by adding 100 mι of ethyl acetate to the reaction mixture solution. The organic layer was washed with 100 mι of 2N hydrochloric acid solution and saturated sodium chloride solution, and was then dried by magnesium sulfate. After filtration, the solvent was distilled off under a reduced pressure, and a colorless oily substance was obtained (1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4, 7-dimethylcyclopenta[c]pyran.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12](Br)[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[C:32]([Si:36]([CH3:42])([CH3:41])[O:37][CH2:38][C:39]#[CH:40])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>C(#N)C.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.[Cu]I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([C:40]#[C:39][CH2:38][O:37][Si:36]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:41])[CH3:42])[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCC#Cc1nc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)cs1
Temperature: 100 °C
Yield: 16 %

Procedure:
Under argon, 500 mg (0.916 mmol) of 2-amino-4-(2-bromo-1,3-thiazol-4-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)pyridine-3,5-dicarbonitrile and 0.186 ml (0.916 mmol) of tert-butyl(dimethyl)(prop-2-yn-1-yloxy)silane were initially charged in 10 ml of acetonitrile, and 105 mg (0.092 mmol) of tetrakis(triphenylphosphine)palladium(0), 35 mg (0.183 mmol) of copper(I) iodide and 0.255 ml (1.832 mmol) of triethylamine were added in succession. The mixture was then heated under reflux at 100° C. for 4 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC. This gave 239 mg of the target compound in a purity of 38% (yield: 16%). The batch obtained in this manner contained the desilylated compound in a proportion of 62%. The mixture was used without further purification for the subsequent hydrogenation.