Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].I[CH2:33][CH3:34]>CC(=O)CC>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:33][CH3:34])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCI
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 65 %

Procedure:
3.0 g (9 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzoic acid, 4 g (30 millimoles) of potassium carbonate and 2 9 g (18.9 millimoles) of iodoethane in 27 ml of butan-2-one were refluxed until conversion was complete (monitored by thin layer chromatography). When the mixture had cooled, the solid was filtered off, the filtrate was evaporated down and the residue was recrystallized from methanol to give 2.1 g (65%) of the title compound of melting point 137°-138° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: c1cc(C2CCCN2)cs1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccsc1

Procedure:
The title compound, white solid, m.p. 120° C. and MS: m/e=328.1 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-3-yl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: I[C:2]1[C:10]2[O:9][N:8]=[C:7]([NH2:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:12].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][CH:22]2[CH2:45][CH2:44][C:25]3([C:33]4[C:28](=[CH:29][C:30](B5OC(C)(C)C(C)(C)O5)=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:43])[CH2:24][CH2:23]2)[CH2:15][CH2:14]1>>[NH2:11][C:7]1[C:6]2[CH:5]=[CH:4][C:3]([CH3:12])=[C:2]([C:30]3[CH:29]=[C:28]4[C:33]([C:25]5([CH2:24][CH2:23][CH:22]([O:21][CH2:20][CH2:19][N:16]6[CH2:15][CH2:14][O:13][CH2:18][CH2:17]6)[CH2:45][CH2:44]5)[C:26](=[O:43])[NH:27]4)=[CH:32][CH:31]=3)[C:10]=2[O:9][N:8]=1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C32CCC(OCCN3CCOCC3)CC2)OC1(C)C
Reactant: Cc1ccc2c(N)noc2c1I
Product: Cc1ccc2c(N)noc2c1-c1ccc2c(c1)NC(=O)C21CCC(OCCN2CCOCC2)CC1

Procedure:
Obtained as a white solid (16%, exact isomeric form not determined) from 7-iodo-6-methyl-1,2-benzisoxazol-3-amine (preparation 24) and 4-(2-morpholinoethoxy)-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclohexane-1,3′-indolin]-2′-one (preparation 15) following the experimental procedure as described in example 1 followed by purification by flash chromatography (97:3 dichloromethane/methanol).
Reaction SMILES: [C:1](Cl)(=[O:28])[O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15](=[O:27])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1F.[NH:30]1[CH2:33][CH2:32][CH2:31]1>C(Cl)Cl.CO>[N:30]1([C:1]([O:2][CH2:3][CH2:4][N:5]2[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/2=[N:14]\[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[N:30]2[CH2:33][CH2:32][CH2:31]2)=[O:28])[CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)c1cn(CCOC(=O)Cl)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reactant: C1CNC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cn(CCOC(=O)N2CCC2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2N2CCC2)s1
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a solution of Example 61B (174 mg, 0.384 mmol) in CH2Cl2 (1.4 mL) was added azetidine (110 mg, 1.920 mmol) in methanol (0.5 mL) and the mixture was stirred for 2 hr. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) to obtain the title compound (38 mg, 0.074 mmol, 19.38%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (m, 9H) 1.99-2.12 (m, 2H) 2.18-2.29 (m, 2H) 3.78 (t, J=7.29 Hz, 4H) 3.87 (t, J=7.46 Hz, 4H) 4.35 (dd, J=14.24, 4.75 Hz, 4H) 6.57 (d, J=8.82 Hz, 1H) 7.27 (s, 1H) 7.51 (dd, J=8.65, 1.86 Hz, 1H) 7.87 (d, J=1.70 Hz, 1H); MS (DCI) m/z 511 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4](=[O:7])[CH2:5][CH3:6].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:1][O:2][C:3](=[O:8])[C:4](=[O:7])[C:5]([CH3:6])=[CH:11][N:12]([CH3:13])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)C(=O)OC
Product: COC(=O)C(=O)C(C)=CN(C)C
Reaction time: 8 h

Procedure:
Methyl-2-ketobutyrate (5 g, 43 mmol) was added at ambient temperature to dimethylformamide dimethyl acetal (5.13 g, 43 mmol, 5.72 ml). The solution was stirred overnight under nitrogen and then the volatile components were removed in vacuo at 40° C. The yellow residue was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)C#N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].CN(C=[O:31])C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)=[O:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(Cl)c2)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of (48) (7.56 g, 21.88 mmol) in anhydrous DMF (100 ml) in a water bath under an atmosphere of nitrogen, was portionwise added 60% sodium hydride (1.05 g, 26 mmol). After 30 min, oxygen gas was bubbled into the reaction mixture for 4 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and purified by silica gel column chromatography (eluent, ether:hexane (1:4)) to afford 5.87 g (80%) of a white solid. m.p. 119-120° C.; 1H NMR (200 MHz, CDCl3) δ: 1.19 (6H, d, J=7.1 Hz), 2.38 (3H, s), 2.80 (1H, m), 3.93 (3H, s), 4.06 (3H, s), 7.40-7.61 (3H, m).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCCl)c(OC)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 12.6 g (71.4 mmol) of 4-bromo-1-chlorobutane (purity: 99 wt. %), 8.5 g (60.4 mmol) of potassium carbonate (purity: 98 wt. %), and 300 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85° C. for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (gel: Wako gel C-200, eluent: n-hexane), to give 13.6 g (isolated yield: 90.0%, purity: 99% in terms of area percentage by high performance liquid chromatography) of methyl 4-(4-chlorobutoxy)-3-methoxybenzoate as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[OH:26][CH2:27][C:28](CO)([CH2:31][OH:32])[CH2:29][OH:30].C(=O)([O-])[O-].[K+].[K+].C(O)=O>CN(C)C=O>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:28]([CH2:31][OH:32])([CH2:29][OH:30])[CH2:27][OH:26])=[O:7]
Reactant: OCC(CO)(CO)CO
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(=CCCC(=O)OCC(CO)(CO)CO)CCCC(C)CCCC(C)CCCC(C)C
Reaction time: 10 h

Procedure:
Under reduced pressure of 60-70 mmHg and nitrogen gas stream, 250 g (0.71 mol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise at 78-83° C. to a solution of 157 g (1.15 mol) of pentaerythritol and 1.58 g (1.15 mmol) of potassium carbonate in dry N,N-dimethylformamide (700 mL). After the reaction mixture was stirred at the same temperature for 10 hours, formic acid was added at 75° C. to adjust the pH to 4. After the resulting solution was subjected to vacuum concentration, the residue was diluted with t-butylmethylether (1.5 L), and the resulting insoluble matter was separated by filtration. The filtrate was washed with 10% sodium bicarbonate aqueous solution twice, and decolorized with activated carbon (8 g). After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate mixture) to obtain the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C:8]3([CH2:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH:23]4[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[CH2:15][CH2:16][CH2:17][C:6]=1[C:7]=23)(=O)C.C[O-].[Na+]>CO>[OH:4][C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C:8]3([CH2:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH:23]4[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[CH2:15][CH2:16][CH2:17][C:6]=1[C:7]=23
Reactant: COc1ccccc1C1CNCCN1CCCCC12CCCc3c(OC(C)=O)ccc(c31)NC2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C1CNCCN1CCCCC12CCCc3c(O)ccc(c31)NC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A methanol solution of 121 mg (0.25 mmol) of 6-acetoxy-2a-[4-(2-methoxyphenylpiperazinyl)butyl]-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H) -one was mixed with 30 mg of methanol solution of sodium methoxide and the mixture was stirred at a room temperature for 3 hours. By evaporating the solvent under a reduced pressure and recrystallizing the resulting residue from chloroform-ethyl acetate, the title compound was obtained quantitatively.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:7][NH:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([I:16])=[CH:11][N:10]=1)[CH3:2].[CH:30](OCC)(OCC)OCC>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:7][N:8]1[C:9]2=[N:10][CH:11]=[C:12]([I:16])[CH:13]=[C:14]2[N:15]=[CH:30]1)[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOc1cc(CNc2ncc(I)cc2N)ccc1OCc1ccc(OC)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOc1cc(Cn2cnc3cc(I)cnc32)ccc1OCc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
To a stirred suspension of N2-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodopyridine-2,3-diamine (3.99 g, 7.88 mmol) in ethanol (50 mL) was added triethyl orthoformate (2.67 g, 18.02 mmol) and p-toluenesulfonic acid monohydrate (0.075 g, 0.39 mmol). As the mixture was heated to reflux, a brown solution was obtained. After 30 min, the mixture was allowed to cool to room temperature, resulting in the formation of a precipitate. The solids were isolated by filtration, washed with ethanol, and dried to provide 2.50 g (61%) of 3-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-iodo-3H-imidazo[4,5-b]pyridine as a tan solid.
Reaction SMILES: C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.[Br:19][C:20]1[CH:25]=[C:24]([C:26]#[C:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[N:23]=[C:22]([NH2:38])[CH:21]=1.[CH3:39][N:40]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH:41]([CH3:45])[C:42](O)=[O:43].C(=O)([O-])O.[Na+]>CCOC(C)=O.N1C=CC=CC=1>[C:49]([O:48][C:46](=[O:47])[N:40]([CH:41]([C:42](=[O:43])[NH:38][C:22]1[CH:21]=[C:20]([Br:19])[CH:25]=[C:24]([C:26]#[C:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:37])[CH3:36])[CH:29]([CH3:31])[CH3:30])[N:23]=1)[CH3:45])[CH3:39])([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)[Si](C#Cc1cc(Br)cc(N)n1)(C(C)C)C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C(=O)Nc1cc(Br)cc(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (70 ml of a 50 wt.-% solution in EtOAc, 118 mmol) is added to a mixture of 4-bromo-6-{2-[tris(propan-2-yl)silyl]ethynyl}pyridin-2-amine B1 (10.4 g, 29.5 mmol), 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (12 g, 59 mmol) and pyridine (20 ml) at −20° C. The mixture is stirred for 3 h at that temperature. 200 ml of a saturated aqueous sodium hydrogencarbonate solution is added and the mixture extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 11.1 g (70%). HPLC-MS: M+H=538/540; tR=.2.05 min (METHOD—1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:13][C:14](=[O:28])[CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17].Cl>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][CH2:13][C:14](=[O:28])[CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCl)CC(=O)OCCCc1ccccc1
Reactant: OCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
2-(1-Piperidinyl)ethanol (15 mL, 113 mmol) in THF (50 mL) was added dropwise to a suspension of sodium hydride (7 g, 175 mmol) in THF (200 mL) at 0° C. The mixture was then stirred for 1 h at room temperature, cooled to 0° C., 3-phenylpropyl 4-chloroacetoacetate (22 mL, 103 mmol) in THF (50 mL) was added dropwise and the reaction mixture was then stirred for 18 h whilst warming to room temperature. 1N Hydrochloric acid was added until the mixture was acidic and the aqueous layer was then separated. The organic layer was extracted twice more with 1N hydrochloric acid. The combined acid layers were made basic to pH 8 with sodium hydrogen carbonate and extracted with chloroform. The combined extracts were washed with brine, dried and evaporated to give the title compound (24 g) as an oil. Electrospray MSm /z 348 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.[CH3:17][CH:18]([CH3:22])[CH2:19][CH:20]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:20]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:5][CH2:6]1)[CH2:19][CH:18]([CH3:22])[CH3:17]
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CCN1CCC2(CC1)OC(=O)Nc1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Spiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (A4) (22 mg, 0.10 mmol) was dissolved in anhydrous 1,2-dichloroethane (750 μL) in a scintillation vial and treated with 3-methylbutanal (va) (9 mg, 0.10 mmol), followed by sodium triacetoxyborohydride (30 mg, 0.14 mmol). The reaction was stirred at room temperature for 1 hour, then quenched with methanol (500 μL) and stirred at room temperature for an additional 30 minutes. The reaction was filtered (Whatman 0.45 μm PTFE) and subjected to reverse-phase HPLC purification [2-99% CH3CN gradient over 13 min with 0.1% TFA (aq), 35 mL/min, 1.0 mL injected] to provide 1′-isopentylspiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (compound no. 76). LC/MS m/z 289.0 [M+H]+, retention time 1.55 min (RP-C18, 10-99% CH3CN/0.05% TFA).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:9]2[CH2:10][CH2:11][CH:6]([C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)[CH2:7][CH2:8]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: c1nc(C2CCNCC2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(CN2CCC(c3c[nH]cn3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5 g of 4-(4-imidazolyl)piperidine in 75 cm3 of dimethyl formamide, 2 g of potassium carbonate and 1.5 g of p-fluorobenzyl chloride are added. The mixture is then heated to 80° C. with stirring for 2 hours. The mixture is filtered and the filtrate evaporated under reduced pressure. The residue is recrystallized in acetonitrile. White crystals, M.p. 232° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].CO[C:15]([CH3:17])=[CH2:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][CH:15]([CH3:17])[CH3:16]
Reactant: C=C(C)OC
Reactant: COC(=O)c1cc(Cl)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)ccc1NC(C)C
Temperature: 25 °C
Reaction time: 84 h
Yield: 79.7 %

Procedure:
To a solution of 500 mg of 2-amino-5-chlorobenzoic acid methyl ester (2.69 mmol) were added slowly 380 μl of 2-methoxypropene (4.04 mmol), 154 μl of acetic acid (2.69 mmol) and 951 mg of sodium triacetoxyborohydride (4.04 mmol). The reaction mixture was stirred at RT for 3.5 d, then 1N NaOH solution was added and the mixture was extracted with DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The remaining residue was purified by column chromatography (silica gel; heptane 100% to heptane/EtOAc 9:1) to give 488 mg (80%) of a yellow liquid. MS (ISP) 228.1 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[C:37](=[O:46])[CH2:36][S:35]2)[CH:32]=1)(=[O:26])[CH3:25]>>[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[C:37](=[O:46])[C:36](=[C:14]3[N:13]([CH3:12])[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15]3)[S:35]2)[CH:32]=1)(=[O:26])[CH3:25]
Reactant: CSc1sc2c([n+]1C)CCCC2
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1cccnc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-ium p-toluenesulfonate with 2-(5-acetyl-2-ethylaminophenylimino)-3-pyridin-3-ylmethyl-thiazolidin-4-one. MS(ESI): 520 (MH+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1.[NH2:17][OH:18]>C(O)C>[OH:18][N:17]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1
Reactant: NO
Reactant: O=C1CCC(COC(=O)N2CCCC2)CC1
Solvent: CCO
Product: O=C(OCC1CCC(=NO)CC1)N1CCCC1

Procedure:
To a solution of pyrrolidine-1-carboxylic acid 4-oxo-cyclohexylmethyl ester (2 mmol) in ethanol (10 mL) was added hydroxylamine (10 mmol) and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide pyrrolidine-1-carboxylic acid 4-hydroxyimino-cyclohexylmethyl ester. Pyrrolidine-1-carboxylic acid 4-hydroxyimino-cyclohexylmethyl ester was dissolved in a 2N ammonia methanol solution (10 mL) and then Raney nickel was added. After 12 hours stirring under hydrogen atmosphere, the reaction mixture was filtered and concentrated under reduced pressure to provide pyrrolidine-1-carboxylic acid 4-amino-cyclohexylmethyl ester. To a solution of pyridine-2-yl-methanol (2 mmol) in THF (10 mL) was added CDI (2 mmol). After 2 h stirring at room temperature, pyrrolidine-1-carboxylic acid 4-amino-cyclohexylmethyl ester was added and the resulting mixture was stirred for additional 2 hours at 60° C. The reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate), thereby completing the preparation of a target compound (310 mg, 43% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[CH3:23][CH:24]1[O:29][CH:28]([CH3:30])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]3[CH2:25][CH:24]([CH3:23])[O:29][CH:28]([CH3:30])[CH2:27]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: CC1CNCC(C)O1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CC(C)OC(C)C2)c2nccc(C)c2c1
Yield: 55.1 %

Procedure:
A mixture of 5.5 g (0.015 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 1.85 ml (0.018 mole) of 2,6-dimethylmorpholine in 90 ml of benzene was heated under reflux for 24 hr. Triethylamine (2 ml) was added and the mixture was heated under reflux for an additional 2 hr, allowed to cool, and filtered. The filtrate was washed with water, dried and concentrated. TLC(silica gel--ethyl acetate) demonstrated a mixture of the unchanged bromo compound, Rf(silica--ethyl acetate)=0.63, and the product, Rf=0.08. A solution of the residue, 1.3 ml (0.01 mole) of 2,6-dimethylmorpholine, and 1.5 ml of triethylamine in 80 ml of benzene was heated under reflux for 40 hr, allowed to cool, filtered, washed with water, dried and concentrated. The residue was chromatographed over 200 g of silica gel with 1 liter each of the following solutions of methanol in ethyl acetate: 1.5%, 2%, 3% to afford 3.7 g of crude product. Recrystallization from hexane afforded 3.3 g of the title compound, mp 87°-90°. The NMR spectrum confirmed the presence of hexane.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH2:14]1[CH:18]2[CH2:19][NH:20][CH2:21][CH:17]2[CH2:16][N:15]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(O)(C)C>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:20]2[CH2:19][CH:18]3[CH2:14][N:15]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][CH:17]3[CH2:21]2)=[CH:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC2C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-[(2S)-Oxiranylmethoxy]benzonitrile (4.36 g, 0.025 mol; prepared as described in International Patent Application WO 99/31100) and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (6.2 g, 0.025 mol; see Preparation A above) were mixed in isopropanol and stirred at 60° C. overnight. The solvent was evaporated and the product was purified by flash chromatography on silica, eluting with ethyl acetate, 10% MeOH. This gave 1.2 g (88%) of the sub-title compound.