Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:28]=[CH:27][C:12]([CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>CO>[N:30](=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:28]=[CH:27][C:12]([CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:11][CH:10]=1)[NH2:31]
Reactant: O=C(NCCOCc1ccc(C(=O)c2ccccc2)cc1)Nc1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NN=C(c1ccccc1)c1ccc(COCCNC(=O)Nc2ccccc2)cc1
Yield: 94.8 %

Procedure:
A solution of (XI) (0.7 g, 1.9 mmol) in methanol (10 ml) was treated with hydrazine hydrate (1.9 g, 38 mmol). The resulting solution was heated to a gentle reflux for 16 h., cooled and concentrated in vacuo. The residue was partitioned between DCM and water and the organic layer was collected, washed with water and dried over MgSO4. Concentration in vacuo yielded (XII) (0.7 g, 99%) as a thick cloudy white oil; δH (CDCl3, 200 MHz) 3.47 (m, 2H, N(H)CH2CH2), 3.61 (m, 2H, OCH2CH2), 4.43, 4.52 (s, 2H, ArCH2O), 5.49 (s, 2H, NNH2), 6.55 (m, 1H, CH2NHC(O)), 6.99 (m, 1H, 4″-H), 7.22 (m, 7H, 3-, 3′-, 3″-, 4′-, 5-, 5′-, 5″-H), 7.46 (m, 6H, 2-, 2′-, 2″-, 6-, 6′-, 6″-H), 7.80 (m, 1H, ArNHC(O)) ppm; υmax 3435 (N—Hstr), 1734 ((R(H)N)2C═Ostr) cm−1; m/z 389 [M+H]+ (15%), 447 [M+MeCN+NH4]+ (100%); found 389.1973, C23H25N4O2 requires 389.1978.
Reaction SMILES: C(O[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5][C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F.C1(N)CCCCC1.C1(C(NC2CCCCC2)=[CH:37][C:38]2CC[CH2:41][CH2:40][N:39]=2)C=CC=CC=1.CS([O-])(=O)=O>C(NCC)C>[C:12]1([C:4]([N:39]([CH2:40][CH3:41])[CH2:38][CH3:37])=[CH:5][C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=CC1=NCCCC1)c1ccccc1
Reactant: C(=C(NC1CCCCC1)c1ccccc1)C1=NCCCC1
Agent: CS(=O)(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: NC1CCCCC1
Solvent: CCNCC
Product: CCN(CC)C(=CC1=NCCCC1)c1ccccc1

Procedure:
Analogously to Example 1, there is obtained, starting with 9.5 of 2-(2-ethoxy-2-phenyl-ethenyl)-3,4,5,6-tetrahydropyridine-tetrafluoroborate and 30 ml of cyclohexylamine, 2-[(2-phenyl-2-(cyclohexylamino)-ethenyl]-3,4,5,6-tetrahydropyridine, and from this its (1:1)-methanesulphonate, m.p. 172°-173°; and starting with 9.5 g of 2-(2-ethoxy-2-phenyl-ethenyl)-3,4,5,6-tetrahydropyridine-tetrafluoroborate and 30 ml of diethylamine, is obtained 2-[2-phenyl-2-(diethylamino)-ethenyl]-3,4,5,6-tetrahydropyridine, and from this its (1:1)-fumarate, m.p. 169°-170° (from isopropanol).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[Cl:29][C:30]1[CH:35]=[C:34]([O:36][Si](C(C)(C)C)(C)C)[CH:33]=[CH:32][C:31]=1B(O)O>COCCOC.O.CCOC(C)=O.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>[Cl:29][C:30]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)c(Cl)c1
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2cc(-c3ccc(O)cc3Cl)ccc12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of methyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthoate (0.97 g, 2.91 mmol), tetrakis(triphenylphosphine)palladium (0) (0.13 g, 0.116 mmol), 2 M Na2CO3 (13.6 mL) and 2-chloro-4-[((1,1-dimethylethyl)dimethylsilyl)oxy]phenylboronic acid (1 g, 3.49 mmol) in ethylene glycol dimethyl ether (15.5 mL) was heated at 80° C. for 40 minutes. The reaction mixture was cooled to room temperature, diluted with water and EtOAc, and transferred to a separatory funnel. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as an oil. The crude material was purified by flash chromatography over SiO2 with a Hex:EtOAc (0 to 20% EtOAc) gradient to afford 0.74 g (82%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1 H), 8.75 (d, J=9 Hz, 1 H), 8.22 (d, J=8 Hz, 1 H), 8.13 (d, J=7 Hz, 1 H), 8.01 (s, 1 H), 7.68 (m, 1 H), 7.61 (t, J=8 Hz, 1 H), 7.34 (d, J=9 Hz, 1 H), 6.96 (m, 1H), 6.86 (m, 1 H), 3.93 (s, 3 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([N:11]([C:20]1[C:25]([O:26][CH3:27])=[N:24][C:23]([CH3:28])=[CH:22][N:21]=1)[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:10])=[O:9].[CH2:29]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH:30]([CH3:32])[CH3:31].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CCOCC.C(O)C>[CH2:29]([C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8]([N:11]([C:20]2[C:25]([O:26][CH3:27])=[N:24][C:23]([CH3:28])=[CH:22][N:21]=2)[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:10])=[O:9])=[CH:35][CH:34]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Reactant: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cnccc1Cl
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: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cnccc1-c1ccc(CC(C)C)cc1
Yield: 77.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.018 g) was added to a deoxygenated mixture of 4-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.225 g), 4-isobutylphenylboronic acid (0.109 g), toluene (4 ml), ethanol (2 ml) and 2M sodium carbonate solution (6 ml) and the mixture was stirred and heated under reflux for 18 hours. Ether (25 ml) was added and the mixture was washed with water (2×25 ml) and saturated sodium chloride solution. Aqueous layers were back-extracted with ether (25 ml). The organic extracts were combined and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 25-50% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 4-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]-pyridine-3-sulphonamide (0.213 g) as an oil; 1H NMR (d6-DMSO): −0.1 (s, 9H), 0.7 (t, 2H), 0.9 (d, 6H), 1.9 (m, 1H), 2.45 (s, 3H), 2.5 (d, 2H), 3.5 (t, 2H), 3.8 (s, 3H), 4.7 (s, 2H), 7.2 (d, 2H), 7.3 (d, 2H), 7.4 (d, 1H), 8.0 (s, 1H), 8.8 (d, 1H), 9.2 (s, 1H); mass spectrum (+VE esp): 543 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Li]CCCC.[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#N.C([O:25]CC)C>>[Br:9][C:4]1[CH:3]=[C:2]([C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:25])[CH:7]=[C:6]([Br:8])[CH:5]=1
Reactant: N#Cc1cccnc1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: CCOCC
Agent: [Li]CCCC
Product: O=C(c1cccnc1)c1cc(Br)cc(Br)c1
Temperature: -72 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
1,3,5-Tribromo-benzene (31.4 g, 100 mmol) was dissolved under argon in a flame dried three-neck flask in 1000 mL diethylether and the solution was cooled to −72° C. A solution of 62 mL nBuLi (1.6 M in hexane, 100 mmol) was added to the resulting suspension in such a fashion that temperature did not rise above −70° C. The mixture was stirred for 30 min at −75° C. and the reaction was monitored by HPLC. A solution of 10.4 g (100 mmol) 3-cyanopyridine in 100 mL diethylether was added in such a fashion that temperature did not rise above −71° C. The mixture was stirred at −75° C. for 60 min and the reaction was monitored by HPLC. The cooling bath was removed and warmed to −25° C. 2 N HCl (250 mL) was added and the mixture was stirred for 20 min at room temperature. The mixture was made alkaline by addition of 1 N NaOH. The product was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4. The product was purified by chromatography (700 g silica agel, CH2Cl2, then CH2Cl2/ethyl acetate 1:1, UV) to yield 27.7 g (81%) of (3,5-dibromo-phenyl)-pyridin-3-yl-methanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:16][CH2:12][CH2:13][C:14]#[CH:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C#CCCO
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCOc1ccc(Br)cc1[N+](=O)[O-]
Yield: 71.4 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (20.0 g, 90 mmol), 3-butyn-1-ol (7.0 g, 99.8 mmol) and potassium carbonate (13.8 g, 99.8 mmol) in dry DMF (20 mL) was heated with 4 Å molecular sieves for 43 h. The mixture was cooled, diluted with water to approximately 500 mL and extracted three times with ethyl acetate. The combined organic extracts were washed with water and then brine, dried and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 5 to 10% ethyl acetate in cyclohexane) to give 4-Bromo-1-but-3-ynyloxy-2-nitro-benzene as a yellow solid (17.35 g, 71%). NMR showed an impurity (19%) which was not removed at this stage. LCMS: RT=4.41 min, [M+Na]+=292/294.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl-:10].[Na+].S(=O)(=O)(O)O.I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[Cl:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: [Cl-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C(CCl)c1ccccc1
Temperature: 80 °C
Yield: 55 %

Procedure:
Acetophenone (1 mmol) was treated with sodium chloride (1.2 mmol) in acetonitrile: water (2:1, 6 ml). 20% Sulfuric acid (5 ml) and sodium periodate (20 mol %) was added to the reaction mixture. The mixture was heated at 80° C. under inert atmosphere for 6 h. The product was purified by column chromatography to give α-chloroacetophenone (55%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1.[H-].[Na+].I[CH3:17]>CN(C)C=O>[OH:1][CH2:2][C:3]1[N:13]([CH3:17])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1
Reactant: CI
Reactant: Cc1cc(C)c2nc(CO)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2nc(CO)n(C)c2n1
Yield: 53.5 %

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 2.6 g of 2-hydroxymethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 85), 0.64 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.2 g of iodomethane and 80 ml of dimethylformamide were used. After working up the product as described in Preparation 15, the resulting crude product was purified by column chromatography through silica gel, using a 1:6 by volume mixture of ethanol and ethyl acetate as the eluent, followed by recrystallization from ethyl acetate, to give 1.5 g of the title compound, melting at 178°-179° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.N1C=CC=CC=1.Cl[C:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])=[O:20]>ClCCl>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])=[O:20])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Yield: 60.8 %

Procedure:
5-Amino-1,3-dihydro-indol-2-one 30c (500 mg, 3.38 mmol) was dissolved in 10 ml of dichloromethane under stirring at room temperature, and pyridine (470 μl, 5 mmol) was added to the solution at −40° C. in a dry ice-acetone bath. Acetic acid chlorocarbonylmethyl ester (473 mg, 3.48 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above reaction solution. Upon completion of the addition, the dry ice-acetone was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was washed with water (10 ml×3) and recrystallized to obtain the title compound acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-methyl ester 44a (510 mg, yield 60.7%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:16][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2ncnc(C)c2cc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2ncnc(CBr)c2cc1OC
Temperature: 25 °C

Procedure:
4-Methyl-6,7-dimethoxyquinazoline (D-1) (3.43 g, 14.7 mMol), N-bromosuccinimide (NBS) (2.64 g, 14.7 mMol) and benzoyl peroxide (BPO) (500 mg) were heated under reflux in 200 mL of carbon tetrachloride with irradiation by a 200 W sun lamp for 5 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and extracted twice with water. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. Flash chromatography on silica gel, eluting with hexanes/ethyl acetate gave 4-bromomethyl-6,7-dimethoxyquinazoline (E-1) as a pinkish solid, 1.39 g; 1H NMR (CDCl3, 300 MHz) 9.07 (s, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 4.85 (s, 2H), 4.06 (s, 6H) ppm; 13C NMR (CDCl3, 75 MHz) 161.22, 156.32, 153.45, 150.72, 149.22, 118.85, 107.47, 101.78, 56.84, 56.70, 30.13; MS (ES) 283/285 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:15][CH3:16])[C:7](=[O:14])[CH:8]([N:11]([CH3:13])[CH3:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:19][CH3:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[N:6]([CH2:15][CH3:16])[C:7](=[O:14])[CH:8]([N:11]([CH3:12])[CH3:13])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:19][CH3:20])=[N:23][CH:24]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)C(N(C)C)CCc2c1ccc(N)c2OC
Product: CCN1C(=O)C(N(C)C)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC
Yield: 15.9 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-3-dimethylamino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (78 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (89 mgs) were converted to the title compound as a tan solid (24 mgs). 1H-NMR (CDCl3, 400 MHz): 9.49 (s, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.27 (d, J=8.9 Hz, 1H), 8.20 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 7.31-7.28 (m, 1H), 6.94 (d, J=9.1 Hz, 1H), 4.32-4.26 (m, 1H), 3.83 (s, 3H), 3.54-3.48 (m, 2H), 3.15-3.08 (m, 1H), 3.00-2.95 (m, 1H), 2.78 (s, 6H), 2.65-2.10 (m, 8H), 1.27-1.24 (m, 2H), 1.15 (t, J=7.1 Hz, 3H). LC/MS found (M+H)+=588.21
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH:29]=O)=[N:24]2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:29][CH2:28][S:27][C:23]2[CH:22]=[N:21][C:20]3[C:25](=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[N:24]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ncc(SCC=O)nc2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.2 %

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (2.82 g, 14.09 mmol, 1.5 eq) is added at room temperature to a stirred solution of (7-methoxy-quinoxalin-2-ylsulfanyl)-acetaldehyde (2.2 g, 9.39 mmol, 1.0 eq) in 1,2-dichloroethane (80 mL), followed by sodium triacetoxyborohydride (3.98 g, 18.78 mmol, 2.0 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×60 mL) and a saturated sodium hydrogen carbonate aqueous solution (60 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: ethyl acetate:hexane, 1:1, v/v) to give a yellow solid that is further recrystallized with ethyl acetate:hexane (1:6, v/v) to afford {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as light yellow needles (2.6 g, 66% yield).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][N:20]=[C:19]([CH2:24][N:25]2[N:53]=[C:29]3[CH2:30][C:31](=O)[C:32]4[CH2:33][S:34][N:35]=[C:36]([N:37](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:27]([C:28]=43)=[N:26]2)[C:18]=1[CH3:54].ClC(Cl)C.[CH:59]1([NH2:63])[CH2:62][CH2:61][CH2:60]1.[OH-].[Na+]>CO.C(O)(=O)C>[CH:59]1([NH:63][CH:31]2[C:32]3[CH2:33][S:34][N:35]=[C:36]([NH2:37])[C:27]4=[N:26][N:25]([CH2:24][C:19]5[C:18]([CH3:54])=[C:17]([O:16][CH3:15])[C:22]([CH3:23])=[CH:21][N:20]=5)[N:53]=[C:29]([C:28]=34)[CH2:30]2)[CH2:62][CH2:61][CH2:60]1
Reactant: NC1CCC1
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(Cl)Cl
Product: COc1c(C)cnc(CN2N=C3CC(NC4CCC4)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
Sodium triacetoxyborohydride (16 mg) was added to a mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (34 mg), dichloroethane (0.7 ml), cyclobutylamine (15 μl) and acetic acid (10 μl), and the mixture was stirred at room temperature overnight. Methanol (three drops) was added dropwise to the reaction mixture, and then a 1 N sodium hydroxide solution was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography. The resulting oil was dissolved in dioxane, followed by lyophilization to obtain the title compound (6.3 mg, 25%) as a colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:5]([Cl:17])=[CH:4][CH:3]=1.Br[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>COCCOC.CCO>[Cl:17][C:5]1[CH:4]=[CH:3][C:2]2[N:7]([CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:1]=2)[C:6]=1[CH2:8][P:9]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:16]
Reactant: CCOP(=O)(Cc1nc(N)ccc1Cl)OCC
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(CP(=O)(OCC)OCC)c(Cl)ccc2n1
Yield: 13 %

Procedure:
Following the procedure for Example 17, the residue from Example 28 was combined with ethyl bromopyruvate (0.468 g, 2.4 mmol) in DME (25 mL). After the resulting salt was refluxed in abs EtOH (30 mL) for 6 h, workup and puricication produced 0./114 g (13% of title compound).
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4]CSC.[P:8]([O-])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].IN1C(=O)CCC1=O>C1COCC1.C(OCC)(=O)C>[P:8]([O:4][CH2:3][S:2][CH3:1])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:9]
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: CSCOCSC
Agent: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSCOP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of bis(methylthiomethyl)ether (30 mg, 2.34 mmol) and molecular sieves (300 mg) in THF (100 ml) at room temperature was added dibenzyl phosphate (2.74 g, 9.85 mmol) followed by N-iodosuccinimide (608 mg, 2.71 mmol) and the solution was stirred for 4 h. The reaction mixture was then diluted with ethyl acetate and filtered through a pad of celite. The filtrate was treated with a 1:1 (v:v) solution of saturated aqueous sodium bicarbonate and 5% aqueous sodium thiosulfate. The colorless organic extract was then washed with brine, dried over sodium sulfate and concentrated in vacuo to provide 600 mg (69%) of the title compound:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[OH:31])[C:21]([Cl:32])=[CH:20][N:19]=1.Cl.O1CCOCC1>CC(O)C>[Cl:32][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[OH:31])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4O)n3)cc2CC1
Temperature: 140 °C
Yield: 27.7 %

Procedure:
3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (76 mg, 0.34 mmol) and trans-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanol (100 mg, 0.38& mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (95 μL, 0.38 mmol, 1.1 eq) was added and the reaction was heated at 140° C. in a microwave for 2.5 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain trans-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexanol as a pink foam (42 mg, 28%). LCMS (m/e) 446 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.35-7.22 (m, 2H), 7.04 (d, 1H, J=8.1 Hz), 6.78 (s, 1H), 5.17 (d, 1H, J=7.1 Hz), 3.96-3.85 (m, 1H), 3.60-3.54 (m, 2H), 3.38 (s, 3H), 3.00-2.85 (m, 4H), 2.81-2.65 (m, 6H), 2.20-2.10 (m, 2H), 1.85-1.77 (m, 2H), 1.45-1.10 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[O:16]([CH2:23][CH2:24]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:24][CH2:23][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrCCOc1ccccc1
Product: Cc1cc(C#Cc2cn(CCOc3ccccc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=318.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-phenoxyethyl bromide.