Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1COCC1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: O=Cc1ccc(I)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Ic1ccc(CNc2ccccn2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2.00 g (8.62 mmol) 4-iodo-benzaldehyde are added to 0.811 g (8.62 mmol) 2-amino-pyridine in 20 mL THF and the mixture is stirred for 1 h at 50° C. After that time, 4.57 g (21.5 mmol) sodium triacetoxyborohydride are added and the mixture is stirred for 1 h at 50° C. Subsequently, water is added and the mixture is extracted with EtOAc. The organic layer is dried over magnesium sulphate and the solvent is removed in vacuo. The residue is purified by RP-HPLC to yield the desired product.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[C:11]([NH:15][S:16]([C:19]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:18])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([NH:15][S:16]([C:19]1[CH:24]=[C:23]([NH:25][CH:1]=[O:2])[CH:22]=[CH:21][C:20]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:18])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.5 ml of formic acid are carefully added at 0° C. to 13 ml of acetic anhydride. The mixture is subsequently heated at 50°-60° C. for 2 h. A solution of 16.0 g (0.056 mol) of N-tert-butyl-5-amino-2-methoxycarbonylbenzenesulfonamide in 50 ml of DMF is then added dropwise at 0° C. The cooling bath is removed and the mixture is stirred for a further 4 h at room temperature. The reaction mixture is then taken up in 800 ml of ethyl acetate and washed with three times 150 ml of water. The organic phase is dried over magnesium sulfate, the solvent is distilled off, and the residue is recrystallized from ethyl acetate/n-heptane. The product is N-tert-butyl-5-formylamino-2-methoxycarbonylbenzenesulfonamide (14.23 g, 82% of theory) which melts at 113°-114° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1.[CH:15]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:15]([N:28]1[CH2:33][CH2:32][N:31]([CH2:3][C:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:7][CH:8]=2)[CH2:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)cs2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloromethyl-2-phenylthiazole monohydrochloride (2.46 g), 1-benzhydrylpiperazine (2.52 g) and potassium carbonate (1.4 g) in N,N-dimethylformamide (40 ml) was stirred at 70° C. for 2 hours. After the reaction mixture was poured into ice-water, it was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated to give an oil of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-phenylthiazole, which was transformed into its hydrochloride in a conventional manner, followed by recrystallization from ethanol to obtain white crystals (2.7 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-phenylthiazole dihydrochloride, mp 215°-218° C.
Reaction SMILES: N1C2C(=CC=CC=2)C(C2CCC(=O)CC2)=C1.O1[C:21]2([CH2:26][CH2:25][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][C:34]=4[F:36])[NH:29][CH:28]=3)[CH2:23][CH2:22]2)[O:20]CC1>>[F:36][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[C:27]([CH:24]1[CH2:23][CH2:22][C:21](=[O:20])[CH2:26][CH2:25]1)=[CH:28][NH:29]2
Reactant: Fc1cccc2[nH]cc(C3CCC4(CC3)OCCO4)c12
Agent: O=C1CCC(c2c[nH]c3ccccc23)CC1
Product: O=C1CCC(c2c[nH]c3cccc(F)c23)CC1
Yield: 110.1 %

Procedure:
This compound was prepared in the manner described above for 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-4-fluoro-1H-indole (4.0 g) to afford 3.7 g (63%) of the title compound as a white solid: mp 104-106° C.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[H-].[Na+]>C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:13]=[CH:12][N:11]=1
Reactant: O=C(NCCCl)Nc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1c1ccnc(Cl)c1
Yield: 91 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(2-chloroethyl)-3-(2-chloro-pyridin-4-yl)urea (I-33a: 7.0 g, 30.042 mmol) in dry THF (40 mL) was reacted with 60% NaH (1.08 g, 45.06 mmol) in dry THF (30 mL) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 5.40 g of the product (92% yield).
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[S:29][CH2:30][CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.ClCCl.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[S:29]1[CH2:30][CH2:31][N:32]=[C:28]1[C:26]1[NH:27][C:23]([C:8]2[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH:9]=2)[O:5][C@@H:4]([CH3:33])[CH2:3][OH:2])=[CH:24][CH:25]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCCS3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCCS3)[nH]2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-thiazole (88 mg, 0.18 mmol) synthesized in Example (25c) was dissolved in dichloromethane (5 mL), and cooled to −78° C., a 1.0 mol/L boron tribromide dichloromethane solution (0.22 mL, 0.22 mmol) was added under nitrogen atmosphere. After the temperature was raised naturally and the solution was stirred at room temperature for 1 hour, subsequently a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, followed by extraction with dichloromethane (60 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-100%) to afford the desired product (46 mg, yield 54%) as a pale yellow solid.
Reaction SMILES: COP([CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(OC)=O.[Br-].[Mg+2].[Br-].CCN(CC)CC.[Cl:24][C:25]1[C:26]([NH:33][C@@H:34]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]2)=[N:27][CH:28]=[C:29]([CH:31]=O)[CH:30]=1>C1COCC1.C(OCC)(C)=O.O>[Cl:24][C:25]1[C:26]([NH:33][C@@H:34]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]2)=[N:27][CH:28]=[C:29](/[CH:31]=[C:7](\[F:13])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Reactant: CCOC(=O)C(F)P(=O)(OC)OC
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 7.5 °C
Yield: 92.1 %

Procedure:
To a mixture of ethyl (dimethoxyphosphoryl)(fluoro)acetate (2.08 g) and magnesium bromide (1.9 g) in THF (20 ml) was added dropwise to a Et3N (1.32 ml) with stirring at 0-15° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at same condition for an hour. A solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (2.0 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at 0-15° C. for 4 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (3:7). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (2.34 g)
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][OH:28])[N:24]=[CH:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].[I-].[K+]>CN(C)C=O.O>[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][O:28][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:24]=[CH:23]1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
58.0 mmol of sodium hydride (60% dispersion in paraffin) are added in portions to a solution of 30.0 mmol of (1-trityl-1H-imidazol-4-yl)methanol [33769-07-2] in 300 ml of N,N-dimethylformamide at 20° C. The mixture is stirred at 20° C. for 1.5 hours. 50.0 mmol of ethyl bromoacetate [105-36-2] and 6.00 mmol of potassium iodide are added, and the mixture is stirred at room temperature for 16 hours. A further 58.0 mmol of sodium hydride and 50 mmol of ethyl bromoacetate are added and the mixture is stirred again for 16 hours. The reaction mixture is poured into water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried with magnesium sulphate and evaporated. The title compound is obtained as a brown oil from the residue by flash chromatography (SiO2 60 F). Rf=020 (ethyl acetate-heptane 2:1), Rt=4.32 (gradient I).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[C:13](=[O:19])[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[C@H:13]([OH:19])[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C2CC2)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C(C2CC2)=C[C@H]1CO[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-cyclopropyl-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 263, 3.82 g, 10.01 mmol) following the procedure described for Intermediate 8. The desired product was obtained as a colorless oil (3 g, 78%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[N-:11]([C:14]#[N:15])[C:12]#[N:13].[Na+]>O>[CH2:1]([NH:9][C:14]([NH:11][C:12]#[N:13])=[NH:15])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CNC(=N)NCCc1ccccc1
Temperature: 50 °C

Procedure:
48.25 g (0.398 moles) of phenethyl amine is charged to a 500 mL three neck round bottom flask equipped with a stirring shaft and a dropping funnel. The flask is cooled in an ice bath as 38.59 g (0.398 moles) of concentrated hydrochloric acid is added dropwise. After the addition of the acid, the ice bath is replaced by a heating mantle and the mixture is heated to 50° C. 37.20 g (0.418 moles) of sodium dicyanamide is added to the flask with stirring. The mixture is heated to 100° C. and stirred for 6.5 hours then cooled in an ice bath. 150 mL of water are added and the white, crystalline precipitate is collected on a Buchner funnel. The product is recrystallized from water yielding 55.5 g of 1-phenethyl-3-cyanoguanidine (74.1% of theoretical) melting point at 111°-112° C.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[CH:11][CH:10]=1.OCCI>CN(C)C=O>[OH:4][CH2:2][CH2:1][N:16]1[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[N:19]=[C:15]1[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=1
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Reactant: CC(C)(C)[O-]
Agent: OCCI
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C(F)(F)F)cn2CCO)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At an internal temperature of 0°-50°, 35.0 g of potassium tert.-butoxide are added to a solution of 35 g of 2-(4-methoxyphenyl)-4-(trifluoromethyl)-imidazole in 200 ml of dimethylformamide. After 20 minutes, a solution of 14.7 ml of 2-hydroxyethyl iodide in 100 ml of dimethylformamide is added dropwise within a period of 5 minutes, the mixture is then stirred for 120 hours at room temperature and the solvent is removed in a rotary evaporator; the residue is taken up in water and extracted several times with ethyl acetate. The organic phases are combined, the solvent is removed and the residue is chromatographed on silica gel with the solvent mixture ethyl acetate/hexane 1:1 and 1-(2-hydroxyethyl)-2-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole is isolated from the main fractions in the form of a crystallising oil.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2>>[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: Brc1cccc2cc[nH]c12
Reactant: CCC1(O)CCc2cc(F)ccc21
Product: CCC1(c2c[nH]c3c(Br)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-bromoindole, the title compound is prepared as in example 1. 51 mg (16%). NMR (400 MHz, CDCl3): δ 0.82 (t, 3H), 2.12 (m, 1H), 2.21 (m, 1H), 2.30 (m, 1H), 2.59 (m, 1H), 2.97 (m, 2H), 6.82 (m, 2H), 6.90 (s, 1H), 6.99 (m, 2H), 7.12 (d, 1H), 7.28 (d, 1H), 8.08 (s, 1H, NH).
Reaction SMILES: [Na+].[CH2:2]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH3:17])=[C:7]([C:18]([O-])=[O:19])[C:6]=1[C:21]([O-])=[O:22])[CH3:3].[Na+].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:28]([F:38])[CH:27]=1>C(O)(=O)C.O>[CH2:16]([O:15][C:8]1[C:7]2[C:18](=[O:19])[N:25]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:28]([F:38])[CH:27]=3)[C:21](=[O:22])[C:6]=2[C:5]([O:4][CH2:2][CH3:3])=[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)[CH3:17]
Reactant: CCOc1c(C(=O)[O-])c(C(=O)[O-])c(OCC)c2ccccc12
Reactant: CCOC(=O)Cc1ccc(N)cc1F
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
A mixture of 1,4-bis(ethyloxy)-2,3-naphthalenedicarboxylic acid sodium salt (526 g, 1.51 mol) and ethyl (4-amino-2-fluorophenyl)acetate (539 g, 2.73 mol) in glacial acetic acid (5100 mL) was heated to reflux for 6 hours, with reaction progress monitored by 1H-nmr spectroscopy. The reaction mixture was allowed to cool to room temperature, stirred for 18 hours, diluted with water (14 L) and stirred for a further 30 minutes. The product was isolated by filtration, washed with water (5 L) and dried in a vacuum oven at 60° C. to give the desired product as an off-white solid (587 g, 84% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@H:17]([NH:26][CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[CH2:16][C@@H:15]1[CH2:42][CH3:43])=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@H:17]([N:26]([C:1](=[O:3])[CH3:2])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[CH2:16][C@@H:15]1[CH2:42][CH3:43])=[O:13])([CH3:10])[CH3:9]
Reactant: CC[C@H]1C[C@@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nc(OC)ccc2N1C(=O)OC(C)C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.6 %

Procedure:
Add acetic anhydride (0.023 mL, 1.205 mmol) to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (125 mg, 0.241 mmol) and pyridine (0.097 mL, 1.205 mmol) in dichloromethane (2 mL), and stir at room temperature for 14 h. Remove the solvent under reduced pressure and purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (105 mg, 78%). 1H NMR (CDCl3, 300 MHz): δ 0.66-0.72 (m, 3H), 1.20-1.29 (m, 7H), 1.33-1.69 (m, 3H), 2.01-2.21 (m, 3H), 2.26-2.33 (m, 1H), 3.82, 3.86 (s, 3H), 4.22-4.28 (m, 1H), 4.81-5.01 (m, 2H), 6.59, 6.65 (d, J=8.7 Hz, 1H), 7.61-7.73 (m, 4H). MS (ES+): 562 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].IC.[C:11](=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccccc1S
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A deoxygenated solution of 2-fluorothiophenol (10 g, 78 mmol) in anhydrous DMF (10 mL) was treated with iodomethane (4.9 mL, 78 mmol) and potassium carbonate (10.8 g, 78 mmol). The reaction mixture was stirred at room temperature for 1 hour. A thin layer chromotography (100% hexanes) sample indicated that the reaction had not gone to completion, so an additional equivalent of base and iodomethane were added and the reaction mixture was stirred overnight at room temperature. The reaction was acidified with 10% aqueous citric acid and extracted with hexanes (2×125 mnL). The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide the desired compound as a pale yellow oil (yield: 6.68 g; 60%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl[CH2:14][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2)=[O:16]>CN(C=O)C.[I-].[K+]>[O:10]1[CH2:11][CH2:12][N:7]([CH2:14][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20]3)=[O:16])[CH2:8][CH2:9]1
Reactant: C1COCCN1
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Cc2cc(C(=O)CN3CCOCC3)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
Potassium carbonate (800 mg, 5.8 mmol) followed by potassium iodide (30 mg, 0.2 mmol) and morpholine (500 μl, 5.7 mmol) were added to a solution of 5-(2-chloroacetyl)oxindole (1.05 g, 5 mmol), (J. Med. Chem. 1991, 1860), in DMF (20 ml) and the mixture was stirred for 1 hour at ambient temperature. The solvent was removed by evaporation and the residue was purified by reverse phase column chromatography on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water/methanol (a gradient from 100/0 to 30/70). The purified product was then purified by chromatography on silica eluting with methylene chloride/methanol (95/5) to give 5-(2-morpholinoacetyl)oxindole (673 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][CH:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)Cc2ccc(Br)cc2C(O)C1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 7-bromo-3,3-dimethyl-3,4-dihydro-1(2H)-naphthalenone (7.8 g) in dry ethanol (50 ml) at 0° C., was treated with sodium borohydride (1.5 g). The mixture was stirred and allowed to warm to room temperature over 18 hours, and the ethanol removed in vacuo. The residue was partitioned between ethyl acetate and water, and the organic layers were dried and evaporated to give the alcohol as a gum (7.0 g)
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][C:6]1([CH3:19])[CH3:18])(=[O:3])[CH3:2]>CO.[H][H].[OH-].[OH-].[Pd+2]>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCN(Cc2ccccc2)CC1(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC1CCNCC1(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 4-acetylamino-1-benzyl-3,3-dimethyl piperidine (1.8 g, 6.92 mmol) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) at 35° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-acetylamino-3,3-dimethylpiperidine. Yield 1.0 g (90%), C9H18N2O, m/z 171 (M+1).
Reaction SMILES: [NH2:1][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].[CH2:15]([O:19][C:20](=[O:30])/[CH:21]=[CH:22]\[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:19][C:20](=[O:30])[C@H:21]([CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])[CH2:16][CH2:17][CH3:18]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Product: CCCCOC(=O)C[C@H](NCCC[Si](OCC)(OCC)OCC)C(=O)OCCCC

Procedure:
221.0 g (1.0 mol) of 3-aminopropyl-triethoxysilane and 228.0 g (1.0 mol) of maleic acid di-n-butyl ester were reacted by the same procedure used in Example 1. The viscosity of the clear, pale yellow liquid was about 30 mPa.s (23° C). Base titration showed an amine equivalent weight of about 462 g (theory: 449 g).