Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH:10]=O>CO.O.[Pd]>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(CNC1CCCC1)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of cyclopentanamine (5 g) in methanol (20 mL) was added 2,2-dimethoxyacetaldehyde 60% in water (8.86 mL) and the mixture stirred at ambient temperature for 5 h. A slurry of palladium on carbon (10%, 200 mg) in methanol (5 mL) was added and the mixture hydrogenated at 5 bar for 16 h. It was filtered and concentrated in vacuo to afford N-(2,2-dimethoxyethyl)cyclopentanamine (9.44 g) as a oil. 1H NMR (400 MHz, CDCl3) δ 4.47 (t, J=5.6 Hz, 1H), 3.39 (s, 6H), 3.05 (quintet, J=6.8 Hz, 1H), 2.72 (d, J=5.4 Hz, 2H), 1.89-1.80 (m, 2H), 1.73-1.62 (m, 2H), 1.58-1.48 (m, 2H), 1.36-1.27 (m, 2H)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH2:17][NH2:18])([C:13]([F:16])([F:15])[F:14])[C:7]=2[CH:19]=1.C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH2:17][NH:18][C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[O:36])([C:13]([F:15])([F:16])[F:14])[C:7]=2[CH:19]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of [6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methylamine hydrochloride (60 mg, 0.20 mmol) in THF (1 mL), triethylamine (66 μL, 0.47 mmol) and 4-fluorophenyl isocyanate (32 mg, 0.24 mmol) were sequentially added at room temperature. The reaction solution was stirred overnight at room temperature and then concentrated. The residue was purified by thin-layer silica gel column chromatography (ethyl acetate/hexane=1/1), whereby the objective compound (24 mg, 28%) was obtained as a white solid.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:22])=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:38])([OH:30])=[O:29]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 59.5 %

Procedure:
410 mg (0.79 mmol) (R)-1-[6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 100 ml methanol were hydrogenated in the presence of 50 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded 160 mg (59%) (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid as colorless oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([C:20]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]3[NH:29][C:30]([C:32]3[NH:33][C:34]4[C:39]([CH:40]=3)=[CH:38][C:37]([Cl:41])=[CH:36][CH:35]=4)=[O:31])=[O:21])[S:19][C:13]=2[CH2:12]1)=O)(C)(C)C.C(O)C.Cl>ClCCl>[ClH:41].[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([C:20]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]3[NH:29][C:30]([C:32]3[NH:33][C:34]4[C:39]([CH:40]=3)=[CH:38][C:37]([Cl:41])=[CH:36][CH:35]=4)=[O:31])=[O:21])[S:19][C:13]=2[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 182.4 %

Procedure:
(±)-cis-N1-[[5-[2-(tert-Butoxycarbonylamino)-ethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N2-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine (450 mg) was dissolved in dichloromethane (5 ml), and a saturated ethanol solution (30 ml) of hydrochloric acid was added to stir the mixture at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and solids deposited were collected by filtration to obtain the title compound (367 mg) as a pale yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[Br-].[CH2:37]([O:39][C:40](=[O:44])[CH2:41][CH2:42][Zn+])[CH3:38].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>[F:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[S:24]([NH:23][C:19]1[C:18]([F:35])=[C:17]([C:9]2[N:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH2:42][CH2:41][C:40]([O:39][CH2:37][CH3:38])=[O:44])[N:7]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:26])=[O:25]
Reactant: CCOC(=O)CC[Zn+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Temperature: 25 °C
Yield: 64 %

Procedure:
To solid N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (1 g, 1.85 mmol) was added 3-ethoxy-3-oxopropylzinc bromide 0.5M solution in THF (31.5 ml, 15.77 mmol) at RT. Bis(tri-t-butylphosphine)palladium (0) (0.095 g, 0.186 mmol) was added to reaction mixture. The reaction was stirred at RT for several hours. The reaction was check by LCMS. The reaction mixture was quenched into sat'd NH4Cl and stirred for several hours. A white/grey ppt was filtered. The EtOAc was added to filtrate. The EtOAc was separated contained form the water layer. The water layer was rewashed with EtOAc and the organic extracts combined, dried over MgSO4, filtered, and concentrated to dryness to give an orange oil. The crude product was added to a silica gel column and eluted with EtOAc with DCM (20% to 60%) and collected fractions to obtain ethyl 3-{4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoate (1.12 g, 64%). MS (ESI): 605 [M+H]+.
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6](Cl)=[O:7])[CH3:2].[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1.O>N1C=CC=CC=1>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:6](=[O:7])/[CH:5]=[CH:4]/[O:3][CH2:1][CH3:2])=[C:12]([CH3:17])[CH:11]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCO/C=C/C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCO/C=C/C(=O)Nc1ccc(Br)cc1C

Procedure:
Trans-3-ethoxypropenoyl chloride (0.74 g) was added at 0° to a stirred solution of 4-bromo-2-methylaniline (0.93 g) in pyridine (10 cm3). After 0.5 hours water (40 cm3) was added, the solid material was filtered off, washed with water (30 cm3) and dried. The product was recrystallised from ethyl acetate to afford trans-N-(4-bromo-2-methylphenyl)-3-ethoxypropenamide, m.p. 163°-164°, (1.3 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH2:27][C:28]([O:30]CC)=[O:29])[CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O>O1CCOCC1.O>[C:15]([O:14][C:12](=[O:13])[CH2:11][C@H:10]([C:19]1[O:23][N:22]=[C:21]([CH2:24][N:25]([CH2:27][C:28]([OH:30])=[O:29])[CH3:26])[N:20]=1)[CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)CN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CN(CC(=O)O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 120.7 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-([(2-ethoxy-2-oxoethyl)(methyl)amino]methyl}-1,2,4-oxadiazol-5-yl)hexanoate (preparation 132) (1.00 g, 2.21 mmol) in dioxan (20 ml) and H2O (20 ml) was treated with LiOH.H2O (193 mg, 2.21 mmol) and the reaction mixture stirred at room temperature for 19 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with brine. The aqueous was extracted with EtOAc (×3). The combined organic extracts were dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a white foam (1.13 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[C:54]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH:55]=2)[CH:50]=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:58]([O:57][C:54]1[CH:55]=[C:56]2[C:51]([CH:50]=[CH:49][CH:48]=[C:47]2[NH:46][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:52][CH:53]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: Nc1cccc2ccc(OCc3ccccc3)cc12
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2ccc(OCc3ccccc3)cc12
Reaction time: 18 h

Procedure:
To N-(tert-butoxycarbonyl)glycine (527 mg, 3.01 mmol) in dry CH2Cl2 (5 mL) under argon were added PYBOP (1.65 g, 3.16 mmol), 1-amino-7-benzyloxynaphthalene, as described above in Step J, (750 mg, 3.01 mmol), and N,N-diisopropylethylamine (0.55 mL, 3.16 mmol). The reaction mixture was stirred for 18 hrs, then partitioned between CH2Cl2 (200 mL) and 10% aqueous citric acid (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was sufficiently pure for use in the next reaction.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].Br[CH2:15][C:16]1[CH:20]=[CH:19][O:18][N:17]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]([N:5]([CH2:15][C:16]1[CH:20]=[CH:19][O:18][N:17]=1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: BrCc1ccon1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1N(Cc1ccon1)C(=O)CCl

Procedure:
A mixture of 6.1 g N-chloroacetyl-2,6-dimethylaniline and 5 g 3-bromomethylisoxazole (prepared as in Example 6 above) in 200 ml dry dimethylformamide was treated with 1.5 g sodium hydride as in Example 3 above. After workup, the solid product was purified by column and high-pressure liquid chromatography to yield a pure product, m.p. 78°-81° C. This product is shown as Compound 2 in Table I. C14H15ClN2O2 : calc., %C 60.32, %H 5.39, %N 10.05; found, %C 60.72, %H 5.71, %N 8.85.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7](=[CH2:24])[CH:8](O)[CH:9]([NH:20][CH:21]=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2].C(Cl)Cl.S(Br)([Br:30])=O>O>[C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:24][Br:30])=[CH:8][CH:9]([NH:20][CH:21]=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: C=C(CCOC(C)=O)C(O)C(NC=O)C(=O)OCc1ccccc1
Reactant: O=S(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCC(=CC(NC=O)C(=O)OCc1ccccc1)CBr
Reaction time: 2 h

Procedure:
10.5 g (31.3 mmol) of benzyl 6-acetoxy-2-formylamino-3-hydroxy-4-methylenehexanoate are dissolved in 100 ml of abs. CH2Cl2. Then 2.91 ml (37.6 mmol) of thionyl bromide are added to this solution at room temperature. After 2 hours, 80 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and twice with water. The aqueous phases are extracted twice with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated by evaporation, giving benzyl 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoate as a yellowish-brown oil which is further reacted without purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30]Cl)=[CH:27][C:21]=3[CH2:20][S:19](=[O:34])(=[O:33])[C:18]=2[CH:35]=1)=[O:13].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30][NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:33])(=[O:34])[C:18]=2[CH:35]=1)=[O:13]
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCCN3CCOCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-Morpholin-4-yl-ethylamine (0.18 mL, 1.44 mmol) and tetrabutylammonium iodide (0.075 g, 0.2 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.5 g, 1.2 mmol) in dry DMF (1 mL). The reaction mixture was then stirred at 120° C. for 3 h in an atmosphere of nitrogen. It was treated with cold water and the solid that precipitated was filtered, washed with water, and dried. The solid was treated with a methanolic HCl solution (10 mL), and refluxed at 70° C. for 3 h. The reaction mixture was concentrated and treated with an aqueous sodium bicarbonate solution. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.150 g, (24.19%); 1H NMR (DMSO-d6): δ 2.40 (t, 4H, 2CH2), 2.50-2.60 (m, 4H, 2CH2), 3.10 (m, 4H, 2CH2), 3.15-3.20 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 4.50 (t, 1H, NH), 5.15 (s, 2H, CH2), 6.10 (t, 1H, NH), 6.7 (s, 2H, 2Ar), 8.10 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS: m/e (EI+) 524 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:24])=[C:14]([CH:23]=1)[NH:15][C:16](=[O:22])[C:17]([O:19]CC)=O)#[N:9]>CO>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:24])=[C:14]([CH:23]=1)[NH:15][C:16](=[O:22])[C:17]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:19])#[N:9]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)ccc1O
Solvent: CO
Product: CN1CCN(C(=O)C(=O)Nc2cc(C#N)ccc2O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a mixture of 1.2 g of N-methylpiperazine and 20 ml of methanol was added gradually 2 g of ethyl 5-cyano-2-hydroxyoxanilate and after stirring the mixture for 3 hours at room temperature, crystals formed were recovered by filtration, washed successively with isoporpnaol and ether, and dried to provide 2 g of 1-(5-cyano-2-hydroxyoxanilyl)-4-methylpiperazine.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)=[O:14])[CH2:21][CH2:20]1)=[O:18]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (116 mg, 0.50 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-amino-cyclohexanecarboxylic acid methyl ester (80 mg, 0.50 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by 1-hydroxybenzotriazole (74 mg, 0.55 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol, 1.15 eq) and N,N-diisopropylethylamine (192 μL, 1.12 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexanecarboxylic acid methyl ester as an off-white solid (127 mg, 66% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:4]([C:6]2[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:3])[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NC2CC2)nn1
Yield: 66 %

Procedure:
As described for example 81, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (89 mg, 0.25 mmol) was converted, using cyclopropylamine instead of aminomethylcyclopropane, to the title compound (61 mg, 66%) which was obtained as a white foam. MS: m/e=368.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:15])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH3:14])[C:6]=2[N:7]=1.ClCCl.[Br:19]Br>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:15])[C:5]2[CH:11]=[C:10]([Br:19])[C:9](=[O:12])[N:8]([CH2:13][CH3:14])[C:6]=2[N:7]=1
Reactant: CCn1c(=O)ccc2c(C)nc(N)nc21
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCn1c(=O)c(Br)cc2c(C)nc(N)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.70 g, 13.2 mmol) was added to dichloromethane (100 mL), and then bromine (0.75 mL, 1.10 equiv.) was added slowly. This reaction mixture was stirred for 3 h at room temperature. After that, the solvent was evaporated nearly 80% volume of reaction mixture under vacuum, and then acetone was added to give 3.54 g 2-Amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a tan solid. LC/MS: Calculated for C10H11BrN4O (283.12). Found: 285.15 (M+2). HPLC analytical purity: 97.7%.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[ClH:10].Cl.[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH2:39][CH2:40][CH2:41]O)(=[O:38])=[O:37])=[CH:32][CH:31]=3)[N:21]=2)[CH2:16][CH2:15]1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[ClH:10].[ClH:10].[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH2:39][CH2:40][CH2:41][F:7])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[N:21]=2)[CH2:16][CH2:15]1)[CH3:13]
Reactant: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCO)cc3)cc3ccccc23)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCF)cc3)cc3ccccc23)CC1
Temperature: -78 °C

Procedure:
Diethylaminosulfur trifluoride (DAST, 0.14 ml) was added to anhydrous methylene chloride (3 ml), and the resulting mixture was stirred at −78° C. in nitrogen atmosphere, to which was then added a solution of 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxypropyl)sulfonylphenyl]isoquinoline (0.31 g) obtained in Example 352 in methylene chloride (5 ml), and the mixture was further stirred for 6 hr. DAST (0.09 ml) was further added thereto, and the resulting mixture was further stirred overnight. The bulk temperature was raised to room temperature. The reaction solution was diluted with chloroform, followed by the addition of a 10% aqueous solution of sodium carbonate. The organic layer was separated, and then it was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.23 g of the free compound of the title compound as a pale brown viscous oil.
Reaction SMILES: C[Si:2]([CH3:12])([CH3:11])[N:3]([CH2:8][CH:9]=C)[Si:4]([CH3:7])([CH3:6])[CH3:5].[Cl:13]C([SiH3])Cl>C1(C)C(C)=CC=CC=1>[CH3:7][Si:4]([CH3:5])([CH3:6])[N:3]1[CH2:8][CH2:9][CH2:12][Si:2]1([Cl:13])[CH3:11]
Reactant: [SiH3]C(Cl)Cl
Reactant: C=CCN([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1C
Product: C[Si](C)(C)N1CCC[Si]1(C)Cl
Temperature: 65 °C

Procedure:
N-trimethylsilyl-2-chloro-2-methy-1-aza-2-silacyclopentane (cyclic APMCS, which may be referred to as c-APMCS) was prepared as follows. To a 300 mL nitrogen purged bottle equipped with stir bar was added 20.1 g (0.1 mol) of N,N-bis(trimethylsilyl)allyl amine, 11.5 g (0.1 mol) of dichloromethylsilane, and 0.81 mL of 2.4 wt % Karsted's Catalyst in xylene. The solution was stirred for 72 hrs, then heated at 65° C. for 2 hrs, and heated at 100° C. for a further 3 days. The product was distilled at 85-90° C. at 25 mm Hg. GC/MS confirmed structure. Proton NMR was also used to determine structure.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:32])[CH2:30][CH3:31])[O:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.369 g, 1.3 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Propionyl chloride (450 μl, 5.2 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. Ethyl acetate was added to the residue and undissolved salts were removed by filtration. The filtrate was then applied to a silica gel column (4.8×13 cm) and eluted with methanol. After evaporation of the solvent, the product was eluted to a Chromatotron plate (4 mm silica gel) with a mixture of hexane:acetone (75:25). The product containing fractions were combined, concentrated, and further chromatographed on the Chromatotron (2 mm silica gel plate) with a mixture of chloroform:acetone (95:5). Product containing fractions were applied to preparative silica gel plates (20×20×0.2 cm) which were then developed in chloroform:acetone (85:15). Final purification was achieved by a third run on the Chromatotron (2 mm silica gel plate) with a mixture of hexane:acetone (80:20). Lyophilization afforded 0.178 g of 6-(cyclopropylmethylamino)-9-((2R,5S)-5-((propanoyloxy)methyl)-tetrahydro-2-furyl)-9H-purine as an oil (39% yield).