Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=1)=C=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]([NH:36][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:41][CH:40]=3)=[O:35])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccc(C(F)(F)F)cc3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and 1-isocyanato-4-(trifluoromethyl)benzene (31.3 mg, 0.17 mmol) according to General Procedure G to give 18 mg (22.1%) of white solid. Anal. Calcd. for C26H30F3N5O m/z 458.2, found: 486.3 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.53 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.25 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 3.64 (m, 1H), 3.51 (m, 2H), 3.05 (m, 1H), 2.70 (m, 1H), 2.12 (m, 1H), 1.99 (m, 3H), 1.83 (m, 3H), 1.67 (m, 3H), 1.39 (m, 6H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7](O)[CH3:8])(=[O:4])[CH:2]=[CH2:3].[C:10]([O:14][CH2:15][CH2:16][CH2:17]O)(=[O:13])[CH:11]=[CH2:12]>>[CH2:12]=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:8][CH2:7][CH2:6][O:5][C:1]([CH:2]=[CH2:3])=[O:4])=[O:13].[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:8][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])(=[O:13])[CH:11]=[CH2:12]
Reactant: C=CC(=O)OCC(C)O
Reactant: C=CC(=O)OCCCO
Product: C=CC(=O)OCCCCCCOC(=O)C=C

Procedure:
HPA—an isometric mixture of 2-hydroxypropyl acrylate and 3-hydroxypropyl acrylate (available as ROCRYL 430 from Rohm and Haas, Philadelphia, Pa.)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O>CS(C)=O.C(O)C.[Pd]>[O:15]=[C:13]1[NH:8][C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:11]2[CH2:18][CH2:17][CH2:16][CH:12]12
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Pd]
Solvent: CS(C)=O
Solvent: CCO
Product: O=C1Nc2ccccc2N2CCCC12

Procedure:
1.5 ml of o-fluoro-nitrobenzene and 8.2 g of L-proline were stirred at 60° C. for 3 hours in 50 ml DMSO. The mixture was then evaporated in vacuo to give a yellow oil. This oil was dissolved in 250 ml 96% ethanol and was hydrogenated at normal pressure at room temperature using 2 g 5% Pd/C as catalyst. After completion of hydrogen uptake, the mixture was filtered and evaporated in vacuo to give the title compound. M.p. 169°-172° C.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([CH3:13])=[CH:6][C:3]=1[CH2:4]Cl.C(O)(=[O:16])C.C1N2CN3CN(C2)CN1C3.Cl>O>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([CH3:13])=[CH:6][C:3]=1[CH:4]=[O:16]
Reactant: Cc1cc(CCl)c(C)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: Cc1cc(C=O)c(C)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The mixture constituted by 2,5-dimethyl-3-nitrobenzyl-chloride (A) prepared according to M. J. Winchester and F. D. Popp, J. Het. Chem. 12, p. 547 (1975) (610 g), acetic acid (1280 ml, water (1280 ml) and hexamethylene tetramine (855 g) was heated with reflux under stirring for 2 hours. 1037 ml of concentrated hydrochloric acid were then added in 10 minutes and the mixture was again heated with reflux for 20 minutes. This mixture, cooled to 0° C., gave a solid which was filtered off, dried and recrystallised from cyclohexane (4 liters) to give 290.5 g (53%) of yellow needles corresponding to the aldehyde of formula B, melting point: =90°-93° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>O1CCCC1>[Cl:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
To a solution of morpholine (3.6 mL, 41 mmol) and triethylamine (5.2 g, 51 mmol) in tetrahydrofuran (100 mL) was added chloroacetyl chloride (3.0 mL, 38 mmol) at 0° C., and the mixture was stirred at 0° C. for 20 minutes. The reaction solution was concentrated and ethyl acetate was added thereto. The resulting mixture was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated to obtain the title compound (4.0 g, yield 64%) as an oily matter.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:8]([C:7]1[C:2]([NH:29][CH:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
2-Chloro-3-nitro-pyridine (5 g, 33.3 mmol), anhydrous N,N-dimethylformamide (50 mL), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (6.7 g, 33.3 mmol) and anhydrous sodium carbonate (7.1 g, 66.6 mmol) were combined with stirring under nitrogen. The reaction mixture was heated at 90° C. overnight. Then it was poured into water and the resulting yellow solid was filtered off and found to be tert-butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (8.5 g, 26.4 mmol, 79.4% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([O:22]C)[C:19]([O:24]C)=[C:18]([O:26]C)[CH:17]=1)=[O:15]>>[OH:2][C:3]1[C:4]2[CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([OH:26])[C:19]([OH:24])=[C:20]([OH:22])[CH:21]=3)[O:15][C:5]=2[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Reactant: COc1cc(O)cc(OC)c1
Product: Oc1cc(O)c2cc(-c3cc(O)c(O)c(O)c3)oc2c1
Yield: 62 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone: Yield 62% following procedures A.2 and A.5; m.p. 260° C. (dec.); IR 3442, 3326, 1600, 1539, 1470, 1313, 1197, 1072, 1037 cm−1; 1H NMR (500 MHz, δ ppm, DMSO-d6) 9.67 (s, 1H), 9.22 (s, 1H), 8.97 (s, 2H), 8.29 (s, 1H), 6.81 (s, 1H), 6.69 (s, 2H), 6.37 (s, 1H), 6.14 (s, 1H); 13C NMR (75 MHz, δ ppm, CD3OD) 158.3, 157.3, 155.0, 151.9, 147.4, 134.8, 123.8, 113.1, 104.8, 98.7, 97.7, 90.8.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:25][C:26]1([CH3:51])[CH:35]=[C:34]([CH3:36])[C:33]2[N:32]=[CH:31][N:30]=[C:29]([N:37]3[CH2:43][C:42]4[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:41]=4[O:40][CH2:39][CH2:38]3)[C:28]=2[CH2:27]1>>[NH2:16][C@@H:13]1[CH2:14][CH2:15][N:11]([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:45]3[CH:46]=[CH:47][C:41]4[O:40][CH2:39][CH2:38][N:37]([C:29]5[C:28]6[CH2:27][C:26]([CH3:25])([CH3:51])[CH:35]=[C:34]([CH3:36])[C:33]=6[N:32]=[CH:31][N:30]=5)[CH2:43][C:42]=4[CH:44]=3)[CH:6]=2)(=[O:9])=[O:10])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: CC1=CC(C)(C)Cc2c1ncnc2N1CCOc2ccc(B(O)O)cc2C1
Product: CC1=CC(C)(C)Cc2c1ncnc2N1CCOc2ccc(-c3cnc(N)c(S(=O)(=O)N4CC[C@@H](N)C4)c3)cc2C1

Procedure:
Synthesized according to the method of example 5 using (R)-tert-butyl 1-(2-amino-5-bromopyridin-3-ylsulfonyl)pyrrolidin-3-ylcarbamate (reagent preparation 25) and [4-(6,6,8-trimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1 and BOC group deprotection. 1H NMR (400 MHz, d6-DMSO): 8.54 (s, 1H), 8.48 (br s, 1H), 8.01 (d, 1H), 8.58 (d, 1H), 7.47 (dd, 1H), 7.02 (d, 1H), 6.76 (br s, 2H), 5.99 (d, 1H), 4.60 (s, 2H), 4.32 (m, 2H), 383 (m, 2H), 3.40-3.32 (m, 4H), 3.30-3.26 (m, 2H), 2.90 (m, 1H), 2.70 (s, 2H), 1.97 (s, 3H), 1.89 (s, 6H), 1.63 (m, 1H), 0.93 (s, 6H); MS (EI) for C29H35N7O3S: 562 (MH+).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.C1COCC1.Cl>C(Cl)Cl.[I-].[Zn+2].[I-]>[NH2:6][CH2:5][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)([OH:17])[CH3:16]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(C)(O)CN)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
Into a 100 mL single-neck flask, 28.5 mL of trimethylsilyl cyanide was added dropwise to 10 g of 4′-methoxyacetophenone and 2.28 g of zinc iodide while stirring under a nitrogen atmosphere at room temperature. The reaction was allowed to stir at this temperature overnight. In the morning, the mixture was diluted with methylene chloride (100 mL) and the organic layer was backwashed once with sat. Na2HCO3, dried over MgSO4, and concentrated under reduced vacuum to yield 13 g. as a tan oil. Because of possible stability problems, this material was used immediately and placed into 200 mL THF in a 500 mL single-neck flask. While stirring at room temperature under a nitrogen atmosphere, 70 mL of BH3-THF complex was added syringe wise and the reaction was stirred overnight. In the morning, 10 mL of concentrated hydrochloric acid was added dropwise at room temperature and severe foaming was present. The mixture was then concentrated under reduced vacuum. The resulting HCl salt was liberated while being stirred in 1N NaOH and the free amine was extracted into ethyl acetate. This organic layer was washed with H2O, dried over Na2SO4, and concentrated under reduced vacuum to yield 7.31 g. of a 2 spot material. This material was purified via silica gel chromatography employing the Water's prep. 2000 and eluting with a solvent of methylene chloride/methanol 9:1 to yield intermediate title compound (3.01 g, 24%) as an oil as the top spot. (FD) M.S. 180.3 (M*−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:5]([CH3:7])=O.[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:34])/[CH:30]=[C:31](\[NH2:33])/[CH3:32])#[N:20]>C(O)(C)C>[CH3:7][C:5]1[NH:33][C:31]([CH3:32])=[C:30]([C:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:19]#[N:20])=[O:34])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: C/C(N)=C/C(=O)OCCCCCCCC#N
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCC#N)C1c1cccc([N+](=O)[O-])c1
Yield: 64.7 %

Procedure:
6.7 g (26.8 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid methyl ester and 6.0 g (26.8 mmol) of 3-amino-crotonic acid-(7-cyanoheptyl)ester are boiled in 50 ml of isopropanol for 12 hours. The precipitate which separates is suction filtered and chromatographed on silica gel with dichloromethane/methanol (98:2). The main fraction yields 7.9 g (65%) of yellow crystals melting at 151°-152° C. after concentration of the fraction by evaporation under vacuum and recrystallisation of the residue from tert.-butyl-methyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])(=[O:30])=[O:29])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3F)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and the 2-fluoro-benzenesulfonyl chloride (92 mg, 0.63 mmol) was dissolved in pyridine (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide (113 mg, yield: 44%) as yellow solid. MS (ESI+APCI) M+1=445.1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[N:18]1([C:23]2[CH2:27][CH2:26][CH2:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([C:24]2[CH2:25][CH2:26][CH2:27][C:23]=2[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: C1=C(N2CCCC2)CCC1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1=C(N2CCCC2)CCC1)c1cccnc1Cl
Reaction time: 21 h

Procedure:
Dissolve 2-chloronicotinoyl chloride (0.10 mole) in CHCl3 (90ml). Add the resulting solution to a 5° C solution of triethylamine (0.10 mole) and an enamine, 1-(1-pyrrolidinyl)-1-cyclopentene (0.10 mole), dissolved in CHCl3 (90ml). Allow C-acylation to proceed for 21 hrs., while the temperature of the reaction mixture rises to 25° after the second hour. Monitor the course of the reaction by thin-layer chromatography as needed. Wash the resulting solution with water, aqueous NaHCO3 solution, and with water. After drying, carefully evaporate solvent to obtain the enaminoketone, (2-chloro-3-pyridinyl)[2-(1-pyrrolidinyl)-1-cyclopenten-1-yl]methanone, m.p. 102.5°-104.0° C., after recrystallization from ethyl acetate. This compound is referred to in Examples 1 and 3 below as Compound 1.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:8](=[O:20])[CH2:7]1)(=[O:5])[CH3:4].[C:21](OCC)(=[O:27])[C:22](OCC)=[O:23]>CS(C)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH:10]=[CH:11][N:6]3[C:3](=[O:5])[CH:4]=[C:21]([OH:27])[C:22]([OH:23])=[C:7]3[C:8]2=[O:20])=[CH:14][CH:15]=1
Reactant: CC(=O)N1C=CN(Cc2ccc(F)cc2)C(=O)C1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1c2c(O)c(O)cc(=O)n2ccn1Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of anhydrous DMSO and sodium hydride (0.24 g, 60% oil dispersion, washed 3× with hexane) under an atmosphere of nitrogen was heated with stirring at 50° C. for 3 h. After cooling to room temperature, a solution of 4-acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one (0.5 g, 2.0 mmol; Example 2, Step 3) in anhydrous DMSO (5 mL) was added over a period of 10 min and the resultant mixture stirred at room temperature for 30 min. The mixture was then treated with diethyl oxalate (0.29 mL, 2.1 mmol) and stirred at room temperature overnight. The product mixture was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH3:23]C(C)([O-])C.[Na+].IC>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCOCC1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CCOCC1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
To a 20 mL vial containing 2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (0.0907 g, 0.279 mmol) was added DMSO (0.5 mL); placed in a dry ice-acetone bath and then added sodium tert-butoxide (0.030 g, 0.307 mmol) followed by DMSO (0.5 mL) and iodomethane (0.019 ml, 0.307 mmol). The dry ice-acetone bath was removed and the mixture was allowed to warm up to room temperature and stirred for 16 h. The reaction was diluted with 10 mL of water and vigorously stirred at room temperature. Collected rust/orange solids by vacuum filtration, washed with additional water and dried under high vacuum affording 2-chloro-6a-methyl-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (46.0 mg, 48.4% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (d, J=0.76 Hz, 3H) 2.48-2.72 (m, 2H) 3.17-3.34 (m, 1H) 3.41-3.77 (m, 5H) 3.94-4.19 (m, 6H) 4.61 (tt, J=12.38, 4.29 Hz, 1 H) 7.98-8.14 (m, 1H). MS [M+H] found 339.3.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)(=[O:28])=[O:27])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 2-thiophenesulfonyl chloride (530 mg). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(2-thiophenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (759 mg).
Reaction SMILES: [Na:1].OC[O:4][PH:5]([C:7](=[O:14])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:6].C(O)=[O:16]>>[Na:1].[O:14]=[C:7]([P:5]([OH:4])([OH:6])=[O:16])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CCC(=O)[PH](=O)OCO
Reactant: O=CO
Agent: [Na]
Product: COC(=O)CCC(=O)P(=O)(O)O

Procedure:
A solution of the product of Example 9 (5.0 g, 0.0215 mol) in formic acid (50 ml) was refluxed for 21/2 hours. The solution was evaporated in vacuo. Toluene (~25 ml) was added to the residue and was evaporated to dryness. This procedure was repeated twice. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][OH:15])=[N:3]1.C[N+]1([O-])CCOCC1.CC(O)C>C(#N)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH:14]=[O:15])=[N:3]1
Reactant: Cn1cc2c([C@@H]3C[C@H]3CO)cccc2n1
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CC(C)O
Product: Cn1cc2c([C@@H]3C[C@H]3C=O)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
Trans-[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanol (500 mg, 2.47 mmol), 4 Å molecular sieves (200 mg), 4-methylmorpholine N-oxide (724 mg, 6.18 mmol) and tetra-n-propylammonium perruthenate(VII) (43.6 mg, 0.124 mmol) were dissolved in acetonitrile (25 mL), and the mixture was stirred at room temperature for 2 hr. 2-Propanol was added, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (382 mg, yield 77%).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].[H-].[Na+].O>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][CH2:2][CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCCO3)[nH]2)c1
Temperature: 0 °C
Reaction time: 19 h
Yield: 71.9 %

Procedure:
N-(2-Chloroethyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (177 mg, 0.349 mmol) synthesized in Example (18b) was dissolved in tetrahydrofuran (5 mL), and cooled to 0° C. Sodium hydride (40 mg, 0.917 mmol) was added, and the temperature was raised to room temperature, followed by stirring for 19 hours. After the reaction solution was cooled to 0° C., water (5 mL) was added, and extraction was carried out with ethyl acetate (10 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=50%-100%) to afford the desired compound (118 mg, yield 72%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[S:32](Cl)([CH3:35])(=[O:34])=[O:33]>ClCCl>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[S:32]([CH3:35])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)S(C)(=O)=O
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 μL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of mesyl chloride (56 μL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (175 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, 2H), 6.92-6.90 (d, 2H), 4.03 (t, 2H), 3.83-3.78 (m, 2H), 3.52 (t, 2H), 3.16 (s, 2H), 2.68 (s, 3H), 2.64 (t, 2H), 2.54 (m, 4H), 2.19-2.15 (m, 5H), 2.05-1.91 (m, 4H), 1.81-1.78 (m, 4H).
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1>CCO>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[N:11]=1
Reactant: O=C(O)CCCS
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCCSc1cccc(Br)n1
Yield: 85.8 %

Procedure:
A mixture of sodium (1.84 g.), EtOH (100 ml.) and 4-mercaptobutyric acid (5.28 g.) was heated to reflux and then treated with 2,6-dibromopyridine (9.5 g.), and the mixture heated under reflux for 18 hours and then evaporated to dryness. The residue was partitioned between water and ether and the aqueous phase was acidified with HOAc and extracted with ether. The ether extract was dried and evaporated to dryness to give 4-(2-bromopyrid-6-ylthio)butyric acid (9.5 g.), m.p. 72°-74°.