Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([NH:28][C:29]2[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=2)[CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:12][C:13]1[CH:18]=[C:17]([C:2]2[S:6][C:5]([CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:3]=2)[CH:16]=[C:15]([NH:28][C:29]2[N:34]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:32]=[CH:31][N:30]=2)[CH:14]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: NS(=O)(=O)Cc1ncc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CS(N)(=O)=O)s2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
The product of Step 4 (102 mg, 0.396 mmol), N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 3, 1.50 mg, 0.396 mmol), and PdCl2(dppf).CH2Cl2 (29 mg, 0.040 mmol) were combined in a flask, sealed, and purged with nitrogen (2×). Dioxane (2.4 mL) and aqueous Na2CO3 (2 M, 0.593 mL, 1.187 mmol) were added, and the reaction was purged again with nitrogen (2×). The mixture was stirred in an oil bath at 100° C. overnight. The dark brown reaction was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (dry load, 25-100% ethyl acetate in hexanes) provided an orange solid that was triturated with CH2Cl2 and filtered to afford 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanesulfonamide (120 mg, 71%) as a colorless solid. MS ESI: [M+H]+ m/z 430.0. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.83 (d, J=4.9, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.50 (s, 1H), 7.28 (d, J=4.9, 1H), 7.20 (s, 1H), 7.17 (s, 2H), 4.73 (s, 2H), 2.32 (s, 3H). rhSYK activity=+++
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4]>C(Cl)(Cl)Cl.CO>[Br:1][C:7]1[CH:6]=[C:5]([CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: BrBr
Reactant: CCc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1ccc(O)c(Br)c1
Temperature: 25 °C

Procedure:
8.41 ml of bromine in 100 ml of CHCl3 were added dropwise within 2 hrs. to a solution, cooled to 0° C., of 20 g of 4-ethylphenol in 200 ml of CHCl3 and 100 ml of MeOH. The reaction mixture was left to warm to room temperature and was concentrated. The product was isolated by extraction. There were obtained 33.14 g of 2-bromo-4-ethyl-phenol as a light brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH:17]([CH2:19][OH:20])[OH:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:28][C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1CCC(N=C=NC2CCCCC2)CC1.CCOC(C)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH:17]([CH2:19][O:20][C:33](=[O:34])[C@H:29]([CH:30]([CH3:31])[CH3:32])[NH:28][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[OH:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)CO
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 49 %

Procedure:
1-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (17.95 g. 61.6 mmol), Boc-L-valine (6.69 g, 30.8 mmol), DMAP (0.38 g, 3.1 mmol), and DCC (7.10 g, 34.4 mmol) in 240 mL CH2Cl2 and 60 mL DMF were stirred at rt under N2 for 18 h. The EtOAc. The organic solution was washed with 50 mL saturated NH4Cl. The aqueous phase was reextracted with 50 mL EtOAc. The organic phases were combined, washed successively with 50 mL saturated NaHCO3 and 50 mL brine, dried over Na2SO4, and concentrated under vacuum. Flash column chromatography of the crude material on silica gel (eluent 2/1 petroleum ether—EtOAc, and then EtOAc) gave 7.41 g (49%) of the title compound (alternative nomenclature: 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propanol).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:34])[C:18]([C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[C:21]=1[CH2:30][CH2:31][CH2:32][CH3:33])=[O:19])=[CH:7]2.[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:37][N:36]=[N:35][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:34])[C:18]([C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[C:21]=1[CH2:30][CH2:31][CH2:32][CH3:33])=[O:19])=[CH:7]2
Reactant: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC#N)ccc3c2)c2ccccc2n1C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)c2ccccc2n1C
Temperature: 100 °C
Reaction time: 4.25 h
Yield: 90.3 %

Procedure:
A mixture of 2-butyl-1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (1.79 g, 3.45 mmol), prepared in the previous step, sodium azide (673 mg, 10.35 mmol) and ammoniun chloride (554 mg, 10.36 mmol) in 100 mL of DMF was stirred under nitrogen at 100° C. for 4.25 h. The reaction was diluted with water, made basic by the addition of 20 mL of 1 N NaOH and extracted multiple times with ethyl acetate. The aqueous layer was acidified with 40 mL of 1 N HCl. A brown oil separated. The oil was partitioned between the aqueous layer and methylene chloride. The organic layer separated and the aqueous layer was extracted three times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in 20 mL of 1 N NaOH and then acidified with 30 mL 1 N HCl. The solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (1.75 g, 89%) as an off-white solid, mp 147-149° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][Cl:23]>CN(C)C=O.C(OCC)(=O)C>[Cl:23][CH2:22][CH2:21][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCCCl)c2ccccc12
Temperature: 60 °C
Yield: 103.1 %

Procedure:
To a solution of 4-hydroxy-1-naphthaldehyde (8.6 g, 50 mmoles) and potassium carbonate (13.8 g, 100 mmoles) in N,N-dimethylformamide (DMF)(40 mL) was added 1-bromo-2-chloroethane (7.4 g, 50 mmoles). The mixture was heated at 60° C. overnight. The solution was diluted with ethyl acetate (500 mL), extracted with water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated to obtain 12.1 g product (52% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]([O:22]CC=C)=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1>C1COCC1.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>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]([OH:22])=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)c1cc(C(=O)OCc2ccccc2)c2ccccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cc(C(=O)O)n2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of indolizine-1,3-dicarboxylic acid 3-allyl ester 1-benzyl ester (300 mg, 0.895 mmol) in THF (6 mL) were added Pd(PPh3)4 (34.5 mg, 0.09 mmol) and morpholine (260 mg, 8.95 mmol). The reaction mixture was stirred at RT under nitrogen atmosphere for 30 min. The reaction mixture was diluted in EtOAC, extracted twice with HCl 1N and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give the desired compound which was used without further purification in the next step TLC, Rf (CH2Cl2/MeOH 9:1)=0.4: MS (LC/MS): 294.0 [M−H]−; tR (HPLC conditions a): 3.62 min.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]([Br:15])[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCCc1ccc(Br)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCC(Br)c1ccc(Br)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A solution of 4-bromo-2-fluorophenethyl acetate (2.72 mmol) in carbon tetrachloride (6 mL) was degassed with a stream of nitrogen for five minutes, at which point the solution was treated with N-bromosuccinimide (2.99 mmol) and azobisisobutyronitrile (0.272 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred at 80° C. for 8 h, at which point the reaction was cooled to room temperature and was stirred overnight. The resulting mixture was concentrated to dryness in vacuo. Purification of the crude material by silica gel chromatography (0-50% ethyl acetate/hexanes) afforded the title compound as a beige oil (790 mg, 77% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 2.00 (s, 3 H) 4.57 (dd, J=11.62, 7.07 Hz, 1 H) 4.67 (dd, J=11.75, 7.20 Hz, 1 H) 5.52 (t, J=7.07 Hz, 1 H) 7.45-7.55 (m, 1 H) 7.59-7.70 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:3](/[C:9](=[N:15]\[H])/[NH:10][O:11][C:12](=O)[CH3:13])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CC(O)=O.C([O-])(O)=O.[Na+]>O>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[N:15]=[C:12]([CH3:13])[O:11][N:10]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: [H]/N=C(/NOC(C)=O)c1nc(Br)cnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(-c2nc(Br)cnc2N)no1
Temperature: 70 °C
Yield: 66 %

Procedure:
A mixture of (E)-3-amino-6-bromo-N-(ethanoyloxy)pyrazine-2-carboximidamide (8.405 g, 22.71 mmol) and AcOH (30 mL) was heated to 70° C. for 2 hours. The reaction mixture was allowed to cool, diluted with water and then neutralised with solid NaHCO3. The resultant dark coloured precipitate was filtered off (3.83 g, 66% Yield). 1H NMR (400.0 MHz, DMSO) d 2.68 (s, 3H), 7.31 (br s, 2H) and 8.34 (s, 1H) ppm; MS (ES+) 258.80
Reaction SMILES: Cl[C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[O:4][CH2:5][C:6]1[N:7]([CH3:28])[C:8]2[C:13]([C:14]=1[C:15](=[O:27])C(N(C)C1CCN(C)CC1)=O)=[CH:12][CH:11]=[CH:10][CH:9]=2.B.[CH2:35]1[CH2:39]O[CH2:37][CH2:36]1>>[Cl:33][C:31]1[CH:30]=[CH:29][C:3]([O:4][CH2:5][C:6]2[N:7]([CH3:28])[C:8]3[C:13]([C:14]=2[CH:15]([OH:27])[CH2:8][N:7]2[CH2:6][CH2:5][CH:35]([CH3:39])[CH2:36][CH2:37]2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:2][CH:32]=1
Reactant: C1CCOC1
Reactant: CN1CCC(N(C)C(=O)C(=O)c2c(COc3ccc(Cl)cc3Cl)n(C)c3ccccc23)CC1
Agent: B
Product: CC1CCN(CC(O)c2c(COc3ccc(Cl)cc3)n(C)c3ccccc23)CC1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a round bottom flask was charged with 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-N-(1-methylpiperidin-4-yl)amino]-1,2-ethanedionyl]-1H-indole (0.3349 g, 0.686 mmol) and placed in an ice bath Borane-tetrahydrofuran complex (4.11 ml of a 1.0 M borane solution in THF, 4.11 mmol) was added slowly and the ice bath was removed. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was stirred for about one hour and then 0.33 ml of a 1:1 tetrahydrofuran:methanol solution was added. Sodium hydroxide (1.74 ml of a 5.0 N solution) was then added and the resulting mixture was heated to reflux and maintained at this temperature overnight.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.O>[OH:6][CH:7]([C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)c1ccccc1)c1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C(O)c1ccncc1
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-2-pyridin-4-yl-ethanone (0.81 mg, 2.46 mmol) prepared in Step 2 in 5 mL of tetrahydrofuran was added a solution of 1.0 M tetra-n-butyl ammonium fluoride in THF (7.4 mL) and the resulting mixture was stirred for 1 hour. After the reaction was complete, the reaction materials were diluted with 50 mL of ethyl acetate and 50 mL of water to dissolve salts, followed by separation of layers. The obtained organic layer was successively washed twice with 50 mL of a brine solution. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography, to give 68 mg (yield: 13%) of 2-hydroxy-1-phenyl-2-pyridin-4-yl-ethanone of the following formula.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BrH:12]>CS(C)=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: CS(C)=O
Product: Cc1cc(Br)cc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (1.23 g, 8.14 mmol, 1.0 eq) in 15 mL of DMSO was added 40% HBr (6.00 mL, 44.7 mmol, 5 eq). The resulting mixture was stirred at room temperature overnight. A white precipitate formed during the course of the reaction. The reaction mixture was quenched with saturated aqueous NaHCO3 resulting in a white solid that was filtered and dried in vacuo to yield 950 mg in 51% yield of Ivi-a as white solid. LCMS m/z=229.9 (M+1) (Method B) (retention time=1.20 min),
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][C:20]=1[NH2:28]>>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:28][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:19]=3[CH3:18])[NH:25][N:24]=[CH:23]4)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Cc1cc2[nH]ncc2cc1N
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cc3cn[nH]c3cc2C)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxylic acid (Intermediate 21) and 6-methyl-1H-indazol-5-yl-amine (Bionet), the title compound was obtained as a pale brown solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[S-:15][C:16]#[N:17].[Na+]>C(O)C>[S:15]([CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[C:16]#[N:17]
Reactant: N#C[S-]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: [Na+]
Solvent: CCO
Product: CCO[Si](CCCSC#N)(OCC)OCC

Procedure:
After a solution of chloropropyltriethoxysilane and sodium thiocyanate react in ethanol to form a thiocyanatopropyltriethoxysilane suspension, salt resulting from the reacting step is removed from the ethanol-containing centrifugate and washed. The first embodiment for manufacturing thiocyanatopropyltriethoxysilane includes adding the wash ethanol to the solution in the reacting step, distilling the centrifugate to remove ethanol, and removing solids from a thiocyanatopropyltriethoxysilane residue resulting from the distilling step. The ethanol from the distilling step may be used to wash the salt separated in the centrifugating step. The second embodiment in the process for manufacturing thiocyanatopropyltriethoxysilane includes distilling a thiocyanatopropyltriethoxysilane suspension to form distilled ethanol and a thiocyanatopropyltriethoxysilane residue, and centrifugating the residue to separate salt resulting from the reacting step from the centrifugate to obtain a thiocyanatopropyltriethoxysilane product. The distilled ethanol can be used to wash the salt, and the ethanol from the washing step can be added to the solution in the reacting step.
Reaction SMILES: Br[C:2]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH2:17][CH3:18])[CH:3]=1.[CH3:19][N:20](C)C=O>[C-]#N.[Zn+2].[C-]#N.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.O>[C:19]([C:2]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH2:17][CH3:18])[CH:3]=1)#[N:20]
Reactant: CCOC(=O)c1cc(OCC)c(Br)cc1OCC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1cc(OCC)c(C#N)cc1OCC
Temperature: 80 °C
Yield: 81 %

Procedure:
Ethyl 4-bromo-2,5-diethoxybenzoate (0.615 g, 1.94 mmol), zinc cyanide (0.137 g, 1.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.157 g, 0.136 mmol) were combined under nitrogen in a flame-dried Schlenk tube. Dimethylformamide (7 mL) was added and the reaction mixture was put through three freeze-pump-thaw cycles and then put under a nitrogen atmosphere and heated at 80° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the resulting mixture was extracted with diethyl ether (100 mL, 2×50 mL). The combined organic phases were washed with brine (3×50 mL) and then dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 33% ethyl acetate in hexanes) gave ethyl 4-cyano-2,5-diethoxy-benzoate as an off-white solid (0.416 g, 81%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(F)cc1

Procedure:
For example: Acryloyl chloride and 4-fluorophenol react in dichloromethane in the presence of triethylamine to give 4-fluorophenyl acrylate 10 (R=4-fluorophenyl). Compound 10 is then added to a solution of 9 in ethanol and diethylamine to give 11 (R=4-fluorophenyl) after usual workup.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2)=[O:1]
Reactant: O=C1CC2CCC(CCCCCO)C2C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCCC1CCC2CC(=O)CC12

Procedure:
The procedure followed is the same as that described in Example 13 substituting the starting material prepared in Example 11, 2-(5-hydroxypent-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxypentyl)-2(1H)-pentalenone} (0.3 g, 1.4 mmoles), and pyridinium dichromate (0.80 g, 2.1 mmoles) dissolved in methylene chloride (5 ml). The crude product is chromatographed on silica gel leaving a clear, colorless oil (0.14 g, 0.67 mmoles).
Reaction SMILES: Br/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH2:9]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:9]([N:16]1[CH2:17][CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][CH:2]1[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: COC(=O)/C=C(/C)Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In toluene (250 ml), N,N′-dibenzylethylenediamine (12 ml) and triethylamine (12 ml) were dissolved, followed by the dropwise addition of methyl 3-bromocrotonate (7.0 ml) under ice cooling. The resulting mixture was stirred at room temperature for 24 hours. After the addition of triethylamine (2.0 ml), the resulting mixture was stirred at room temperature for 71 hours. The insoluble matter was filtered off and the filtrate was distilled under reduced pressure. The residue was added with 10% hydrochloric acid (300 ml) and crystals so precipitated were removed by filtration. Ethyl acetate was added to the filtrate. Potassium carbonate was added to the water layer so separated to make it alkaline. Ethyl acetate was added to the resulting mixture. The organic layer so separated was washed with saturated saline and dried over anhydrous potassium carbonate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1), whereby the title compound (1.07 g, 62%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36].C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C.C(N(CC)CC)C.C(O)(=O)C>[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C:12]([N:14]1[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:16][C@H:15]1[CH3:29])=[O:13]
Reactant: COC(=O)CCN
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCNCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (0.075 g, 0.18 mmol) in methanol (2 mL) was added 3-amino-propionic acid methyl ester hydrochloride salt (0.063 g, 0.45 mmol) and the pH of the solution was adjusted to 5–6 with triethylamine and acetic acid. The reaction mixture was stirred at ambient temperature for 1 hour. To the resulting reaction mixture was added sodium cyanoborohydride (0.023 g, 0.36 mmol), and the pH of the solution was again adjusted to pH 5 with acetic acid and triethylamine. The reaction mixture was stirred at ambient temperature overnight, diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.035 g).