Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[O:12](N1C(=O)CCC1=O)[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CCCC)=O.C(N(CC)CC)C>O.CC(C)=O>[C:13]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])(=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 92.5 %

Procedure:
Similarly, as in example 2, the title compound was prepared using L-lysine monohydrochloride (7.30 g, 40 mmol) and succinimidyl caprate (10.7 g, 40 mmol) in the presence of triethylamine (16.8 ml, 120 mmol) in 35 ml of water and 36 ml of acetone. The product was washed with cold water and with cold ethanol then dried giving 9.04 g (78%) of the desired compound. Infrared: 1580-1590 cm-1 (ionized carboxyl), 1520-1540 and 1640 cm-1 (amide bands).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=2)=[CH:8][CH:9]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.38 g of methyl α-[p-(p-chlorophenoxy)phenyl]acetate in 15 ml of carbon tetrachloride is added 0.92 g of N-bromosuccinimide and a small drop of concentrated HBr. The mixture is maintained at reflux for 72 hours and cooled to room temperature. Filtration through 50 g of aluminum oxide, evaporation of the solvent and bulb-to-bulb distillation of the residue (166° at 0.05 mm) affords the product as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[NH:15]1[C:14]([C:11]2([NH2:10])[CH2:13][CH2:12]2)=[N:18][N:17]=[N:16]1
Reactant: O=C(NC1(c2nnn[nH]2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1(c2nnn[nH]2)CC1

Procedure:
[1-(1H-tetrazol-5-yl)-cyclopropyl]-carbamic acid benzyl ester was dissolved in MeOH (5 ml). The solution was passed through a H-Cube hydrogenator at 0 bar, 30° C. and 1 ml/min with 10% Pd/C as a catalyst. The elute was concentrated to afford 48 mg of 1-(1H-tetrazol-5-yl)-cyclopropylamine as a solid product, m/z 126.5 [M+1]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:15])[N:23]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:29][CH:30]=4)[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:21][CH3:22]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(S(N)(=O)=O)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with p-aminomethylbenzenesulfonamide (0.31 g, 1.4 mmol). Purification using silica gel, eluting with 4:1 CH2Cl2 /acetone, afforded a solid that recrystallized from CH2Cl2 /Et2O/hexane to give 109 as a white solid (m.p. 190-194° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH2:6]3)[CH2:4]2.CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1.CN(C1C=CN=CC=1)C.O>[CH3:27][S:28]([O:1][CH2:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])([CH2:6]3)[CH2:4]2)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(CO)(C3)C2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC12CC3CC1CC(COS(C)(=O)=O)(C3)C2
Yield: 99.2 %

Procedure:
To a stirred solution of tert-butyl [1-(hydroxymethyl)tricyclo[3.3.1.03,7]non-3-yl]carbamate (0.65 g, 2.45 mmol) obtained in step VI in THF (10 mL) at ice bath temperature, was sequentially added Et3N (1.0 mL, 7.35 mmol), DMAP (20 mg, 0.16 mmol), and methanesulfonyl chloride (0.29 mL, 3.7 mmol). After stirring the reaction at the same temperature for 0.5 h, it was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain title compound {3-[(tert-butoxy carbonyl)amino]tricyclo[3.3.1.03,7]non-1-yl}methyl methane sulfonate as a viscous liquid (0.84 g) in 100% yield. m/z (M+1) 358; 1H NMR (CDCl3) 300 MHz δ 4.76 (s (br), 1H), 4.02 (s, 2H), 3.01 (s, 2H), 2.99 (s, 3H), 2.54-2.44 (m, 1H), 2.42-2.35 (m, 1H), 2.20-1.87 (m, 4H), 1.82 (dd, J=2.2, 10.5 Hz, 1H), 1.76-1.58 (m, 4H), 1.57-1.48 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])[CH:6]=1.C[N:18]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:18])=[O:12])[CH:6]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cccc(Cn2cc(Br)cn2)c1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Cn2cc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
To a solution of 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzoic acid (0.20 g, 0.711 mmol) in THF (3.5 mL) at 0° C. was added N-methylmorpholine (0.086 g, 0.854 mmol), and isobutyl chloroformate (0.107 g, 0.783 mmol) slowly. The reaction was stirred at 0° C. for 1.5 h and ammonium hydroxide (0.249 g, 7.11 mmol) was slowly added. The reaction was allowed to warm to room temperature where it stirred overnight. At the conclusion of this period, the reaction mixture was partitioned between DCM and water. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (0.188 g, 94%). LCMS, [M+H]+=280.0.
Reaction SMILES: [Si:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:14](#[N:17])[CH:15]=[CH2:16]>>[Si:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][CH2:15][C:14]#[N:17])[CH2:10][CH2:9]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CC#N
Reactant: CC(C)(C)[Si](C)(C)N1CCNCC1
Product: CC(C)(C)[Si](C)(C)N1CCN(CCC#N)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 160.3 g (0.8 mol) of 1-t-butyldimethylsilylpiperazine (Synthesis Example 1) and heated at 70° C. Once the internal temperature became steady, 46.7 g (0.88 mol) of acrylonitrile was added dropwise over 2 hours. Stirring was continued for 4 hours at the temperature. On distillation of the reaction solution, 194.1 g of a fraction having a boiling point of 145-147° C./0.4 kPa was collected.
Reaction SMILES: [C:1]1([S:7]([C@@H:10]2[CH2:14][C@@H:13]([C:15]([OH:17])=O)[C@H:12]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:27][CH2:28][C:29]#[N:30].C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:28]([CH2:29][NH:30][C:15]([C@@H:13]1[CH2:14][C@@H:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[CH2:11][C@H:12]1[C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])=[O:17])#[N:27]
Reactant: N#CCN
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N1CCOCC1
Reaction time: 8 h

Procedure:
A mixture of (1R,2R,4S)-4-benzenesulfonyl-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid (0.1 mmol) and amino-acetonitrile hydrochloride (0.12 mmol) in dimethylformamide (0.5 ml) was subsequently treated with diisopropylethyl amine (0.5 mmol), 1-hydroxybenzotriazole hydrate (0.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.2 mmol) and stirring was continued at 22° C. overnight. The mixture was purified by preparative HPLC on a RP-18 column using a gradient of a mixture of acetonitrile and water to give (1R,2R,4R)-4-benzenesulfonyl-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid cyanomethyl-amide as a white solid. MS: 406.5 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](B(O)O)[CH:8]=1.Br[C:17]1[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=[O:24])=[CH:19][CH:18]=1>CO.C1(C)C=CC=CC=1.ClCCl.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>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:17]2[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=[O:24])=[CH:19][CH:18]=2)[CH:8]=1
Reactant: O=CC=Cc1ccc(Br)cc1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=CC=Cc1ccc(-c2cccnc2)cc1

Procedure:
2M aq. Na2CO3 (1 mL) and a solution of 3-pyridinylboronic acid (148 mg, 1.20 mmol) in methanol (1 mL) were added to a solution of 4-bromocinnamaldehyde (211 mg, 1.00 mmol, prepared as described in Tetrahedron 1998, 54, 10761) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.030 mmol) in toluene (2 mL) and the mixture was heated to reflux for 36 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded the title compound. MS 210 (M+H)+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:15]1[CH:20]=[CH:19]C=C[N:16]=1)(OC)=O.[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH3:19][C:20]1[CH:23]=[CH:22][C:21]([CH2:25][OH:24])=[N:16][C:15]=1[CH3:11]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccccn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1ccc(CO)nc1C
Reaction time: 8 h

Procedure:
Diisobutyl aluminum hydride (4.45 mL, 25 mmol) was added to the carbomethoxypyridine from Step 3 (1.4 g, 8.4 mmol ) in THF (40 mL) at -78° C. The mixture was stirred overnight with slow warming to +4° C. The reaction was quenched with solid tartaric acid followed by aqueous sodium potassium tartrate and stirred 1/2 hour. Neutralization with saturated aq. NaHCO3 and extraction with EtOAc (3×) gave after treatment with brine and evaporation 1.12 g (97%) of the title compound.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.Cl.[O:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][NH2:22])[CH2:16]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[I:1][C:2]1[C:7]([C:8]([NH:22][NH:21][CH:17]2[CH2:18][CH2:19][CH2:20][O:15][CH2:16]2)=[O:10])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: NNC1CCCOC1
Reactant: COc1nccc(I)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc(I)c1C(=O)NNC1CCCOC1
Yield: 58.2 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (3.0 g) obtained in Step C of Example 6, tetrahydro-2H-pyran-3-ylhydrazine dihydrochloride (2.44 g), DIEA (5.63 mL), EDCI hydrochloride (2.47 g) and HOBt (1.74 g) in DMF (50 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.36 g).
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2O[Si](C(C)(C)C)(C)C)[N:5]([CH3:20])[C:4]1=[O:21].[Cl-].[NH4+]>C1COCC1.[Zn]>[CH3:20][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][C:4]1=[O:21]
Reactant: CSC1C(=O)N(C)c2cccc(O[Si](C)(C)C(C)(C)C)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CN1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 1.2 g (3.7 mmol) of 3-methylsulfanyl-4-(t-butyldimethylsilyloxy)-methyl-1,3-dihydro-indol-2-one in THF (25 mL) was stirred with saturated ammonium chloride solution (20 mL), and activated zinc dust (5 g) was added. The mixture was stirred for 60 h at rt. The organic phase was separated, dried over MgSO4 and concentrated to give 1.16 g of impure 4-t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one as an off-white solid: 1H NMR (DMSO-d6): δ 0.11 (s, 6H), 0.86 (s, 9H), 3.42 (s, 2H), 4.67 (s, 2H), 6.74 (d, J=7.7 Hz, 1H), 695 (d, J=7.7 Hz, 1H) 7.18 (t, J=7.7 Hz, 1H), 10.40 (s, 1H). A solution of 0.64 g (2.3 mmol) of 4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in DMF dimethylacetal (5 mL) was heated to 100° C. for 1 h. The excess DMF dimethylacetal was removed under high vacuum, and the resulting dark oil was chromatographed on silica gel, eluting with EtOAc, to give 0.34 g (44%) of 3-dimethylaminomethylene-4-(t-butyldimethyl-silyloxy)methyl-1,3-dihydro-indol-2-one as a white solid: 1H NMR (DMSO-d6): δ −0.03 (s, 6H), 0.81 (s, 9H), 3.29 (s, 6H), 4.64 (s, 2H), 6.66 (d, J=7.3 Hz, 1H), 6.73 (d, J=7.3 Hz, 1H), 6.79 (t, J=7.3 Hz, 1H), 7.76 (s, 1H), 9.97 (s, 1H) ); APCI−MS m/z 333 (M+1)+. A solution of 0.115 g (0.34 mmol) of 3-dimethylaminomethylene-4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in ethanol (10 mL) was treated with 0.076 g (0.34 mmol) N-methylsulfanilamide hydrochloride. The solution was refluxed for 0.5 h and cooled to rt. The resulting yellow precipitate was isolated by filtration, washed with ethanol and dried to yield 0.048 g (38%) of the title compound: 1H NMR (DMSO-d6): δ 2.37 (d, J=5.0 Hz, 3H), 4.67 (s, 2H), 5.3 (bs, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 7.33 (q, J=5.0 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 8.32 (d, J=12.2 Hz, 1H), 10.67 (s, 1H), 11.26 (d, J=12.2 Hz, 1H); APCI−MS m/z 358 (M−1)−. Anal. Calcd for C17H17N3O4S: C, 56.81, H, 4.77; N, 11.69, S, 8.92. Found C, 56.89, H, 4.81; N, 11.70; S, 8.84.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][C:23]2[N:24]=[CH:25][N:26]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[CH:27]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N(Cc1c[nH]cn1)C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)cn1)C1CCN(Cc2ccccc2)CC1
Yield: 24 %

Procedure:
To a solution of tert-butyl (1-benzyl-4-piperidinyl)((1H-imidazol-4-yl)methyl)carbamate (1.3 g) obtained in Example 83b) in DMF (30 ml) was added sodium hydride (0.22 g) under ice-cooling, and mixed at room temperature for 1 hour. Subsequently, 2-(trimethylsilyl)ethoxymethyl chloride (1.3 ml) was added under ice-cooling, and then mixed at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and water, and the organic layer was collected by separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate:hexane=1:1) to obtain the title compound as a pale yellow oil (4.9 g, 24%).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=[O:29])[C:10](=[CH:25]OCC)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[C:14]=2[S:21]([CH3:24])(=[O:23])=[O:22])=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:31]O>C(O)C>[CH:6]1([C:9]2[O:29][N:31]=[CH:25][C:10]=2[C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[C:14]=2[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:8][CH2:7]1
Reactant: CCOC=C(C(=O)c1ccc(F)c(F)c1S(C)(=O)=O)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1c(C(=O)c2cnoc2C2CC2)ccc(F)c1F
Reaction time: 2.5 h
Yield: 58.7 %

Procedure:
Sodium acetate (0.31 g) was added with stirring to a mixture of 3-cyclopropyl-1-[3,4-difluoro-2-(methylsulphonyl)phenyl]-2-ethoxymethylenepropane-1,3-dione (1.1 g) and hydroxylamine hydrochloride (0.26 g) in ethanol. The mixture was stirred for 2.5 hours. The mixture was evaporated to dryness and the residue was suspended in ethyl acetate, washed with water, dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness. The residue was triturated with n-hexane and filtered to give 5-cyclopropyl-4-(3,4-difluoro-2-methylsulphonylbenzoyl)isoxazole (compound 283, 0.59 g) as an orange solid, m.p.115°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:27][CH2:28][CH:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:30][CH2:31]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(c2ccccc2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(c4ccccc4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 60.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.6 g) and 5-amino-2-(4-phenylpiperidin-1-yl)benzonitrile (0.65 g), the title compound (0.7 g) was obtained, melting point: 186–188° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:39]=[C:38]4[C:34]([C:35]([CH3:40])=[N:36][NH:37]4)=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)[N:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:39]=[C:38]4[C:34]([C:35]([CH3:40])=[N:36][NH:37]4)=[CH:33][CH:32]=3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(COc4ccc(-c5ccc6c(C)n[nH]c6c5)cc4)nc(N)n3)CC2)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1n[nH]c2cc(-c3ccc(OCc4cc(N5CCC6(CC5)CN[C@H](C(=O)O)C6)nc(N)n4)cc3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (70 mg, 0.11 mmol) in MeOH (3 mL) is added 4 N NaOH (3 mL), and the reaction mixture was stirred at RT for 4 h. The reaction mixture was then concentrated in vacuo. The residue was diluted with water (5 mL) and the pH adjusted to 6-7. The precipitated solid was collected by filtration, and the filter cake was washed with cold water, then dried to afford the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][NH:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1.[N-:34]([C:37]#[N:38])[C:35]#[N:36].[Na+]>O.CC(O)C.C(Cl)Cl>[C:35](/[N:34]=[C:37](/[N:15]1[CH2:16][C@@:12]2([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11][C@H:10]([NH:9][C@H:8]3[CH2:7][CH2:6][O:5][CH2:4][C@H:3]3[O:2][CH3:1])[CH2:17][C@H:13]2[CH2:14]1)\[NH2:38])#[N:36]
Reactant: N#C[N-]C#N
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CNC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(/C(N)=N/C#N)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 120 °C

Procedure:
A mixture of Example 1 (HCl salt, 50 mg, 0.0865 mmol), sodium dicyanamide (10.32 mg, 0.116 mmol) in 5% water in i-PrOH (1.2 mL) in a sealed tube was flushed with Ar and heated at 120° C. for 5 h. After cooling to rt, the mixture was diluted with DCM, filtered and evaporated. The residue was purified by CombiFlash (eluent: 10% 7N NH3 in methanol in DCM) to give the product as a colorless gel. 1H-NMR (400 MHz, CDCl3): δ 1.54-1.92 (m, 5H), 2.37 (br. s., 1H), 2.71 (br. s., 1H), 3.07-4.23 (m, 19H), 4.66-4.96 (m, 2H), 5.80 (m, 2H), 7.73 (s, 1H), 8.71 (br. s., 1H); LC/MS: C25H32F3N7O3: m/z 536.2 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](O)[CH:11]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][C:12]1[CH:11]=[CH:10][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1)=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)c1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccccn1
Reaction time: 17 h
Yield: 63 %

Procedure:
4.92 g, 40 mmoles, picolinic acid and 5.84 g, 42 mmoles p-nitrophenol were suspended/dissolved in 200 ml CH2Cl2. Then 8.24 g, 40 mmoles, DCC was added in 20 ml CH2Cl2 with vigorous stirring. Stirring was continued in room temperature for 17 h. Then the mixture was filtered and the filter cake washed with 30-40 ml CH2Cl2. The raw product was first treated with 100 ml Et2O with stirring in ice-bath and filtered. Recrystallization from 250 ml iPrOH gave 6.24 g, 63% product. M.p. 154°-6° C. (dec.). M.p. (Fife and Przystas, loc. cit.) 145°-7° C. Anal. C,H,N,O.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:17])[CH:13]=2)[N:8]=1.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:17])[C:13]=2[N+:18]([O-:20])=[O:19])[N:8]=1
Reactant: Cc1ccc2nc(Cl)ccc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc2nc(Cl)ccc2c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 98 %

Procedure:
Sulfuric acid(7.2 mL) was added to 2-chloro-6-methyl-quinoline (1.15 g, 6.5 mmol). To the resulting solution was added nitric acid(3.1 mL), and the mixture was heated at 100° C. for 20 minutes. After cooling, the mixture was poured into ice-water. The resulting yellow solid was collected by filtration and dried under vacuum to give 2-chloro-6-methyl-5-nitro-quinoline (1.42 g, 98%).