Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][OH:11])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl-].Cl[C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1>O>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:20]2[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(CO)n1
Reactant: COC(=O)c1cccc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
A mixture of 4-tert-butyl-2-(hydroxymethyl)thiazole (441 mg, 2.57 mmol), potassium-tert-butoxide (580 mg, 5.17 mmol), tricaprylmethylamminium chloride (100 mg) and methyl 6-chloropyridine-2-carboxylate (660 mg, 3.85 mmol) was stirred at 120° C. for 2 hours. Water was added to the reaction solution and the product formed was extracted with ethyl acetate. The extract was washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent =hexane:ethyl acetate=20:1 to 10:1) to give methyl 6-(4-tert-butyl-2-thiazolylmethoxy)pyridine-2-carboxylate (198 mg, 0.65 mmol, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:27])[C:10](=[CH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:11](=O)[CH3:12])[CH:6]=[CH:7][CH:8]=1.[NH2:28]/[C:29](/[CH3:36])=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([CH3:36])[NH:28][C:11]=1[CH3:12])=[O:27]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: COc1cccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)c1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)c2cccc(OC)c2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
245 mg (0.67 mmol) of 1-(3-methoxyphenyl)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-butane-1,3-dione are heated with 87 mg (0.67 mmol) of ethyl 3-aminocrotonate in 5 ml of 2-propanol under reflux overnight. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 102 mg (32% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)[N:7]=1.[C:16]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[CH3:30])=[CH:24][CH:23]=1)([O:18][CH3:19])=[O:17]>>[C:16]([CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH:29]([N:10]2[CH2:11][CH2:12][O:13][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:14])([F:1])[F:15])[S:4][CH:5]=3)[CH2:9]2)[CH3:30])=[CH:26][CH:27]=1)([O:18][CH3:19])=[O:17]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: FC(F)(F)c1nc(C2CNCCO2)cs1
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-(2-trifluoromethyl-thiazol-4-yl)morpholine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification of the base on a silica gel column using toluene/ethyl acetate=8:2 as eluant.
Reaction SMILES: Cl.[NH2:2]O.[OH-].[Na+].C1CO[C:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:9][C:10](OCC)=[O:11])[O:7]1.Cl>O.C(O)C>[OH:11][C:10]1[CH:9]=[C:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O:7][N:2]=1
Reactant: NO
Reactant: CCCCCCCCCCCCCCCC1(CC(=O)OCC)OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCc1cc(O)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.12 g of hydroxylamine hydrochloride were added to a solution of 12.60 g of sodium hydroxide in a mixture of 80 ml of water and 100 ml of ethanol, whilst ice-cooling. A solution of the whole of the crude ethyl 3,3-ethylenedioxystearate prepared as described above in 200 ml of ethanol was added all at once, whilst ice-cooling, to the resulting mixture. The reaction mixture was then stirred at room temperature for 2 hours. At the end of this time, 100 ml of concentrated hydrochloric acid were added, and the mixture was heated under reflux for 1.5 hours. The mixture was allowed to cool, and the precipitated solid was collected by filtration and dissolved in methylene chloride. The methylene chloride solution was washed with a saturated aqueous solution of sodium bicarbonate and with water, dried and concentrated by evaporation under reduced pressure. The residue was filtered with the aid of suction to give 7.19 g of the title compound as crystals. An oily material (19 g) separated from the filtration was subjected to column chromatography through 250 g of alumina (grade III). From the fractions eluted with a 20:1 by volume mixture of methanol and acetic acid, an additional 0.82 g of crystals was obtained. These crystals melted at 81.5°-82.5° C. (from cold methylene chloride).
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]([C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]([C:30]1[CH:35]=[C:34](/[CH:36]=[CH:37]/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:33]=[C:32]([CH3:44])[CH:31]=1)=[C:28]=[O:29]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:8]([CH3:26])[C:9]([C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][NH:19][C:28]([NH:27][C:30]2[CH:35]=[C:34](/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:33]=[C:32]([CH3:44])[CH:31]=2)=[O:29])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N=C=O)cc(/C=C/c2ccccc2)n1
Reactant: CN(Cc1ccccc1)C(=O)C1(c2ccccc2)CCN(CCN)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NCCN2CCC(C(=O)N(C)Cc3ccccc3)(c3ccccc3)CC2)cc(/C=C/c2ccccc2)n1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 1-(2-amino-ethyl)-4-phenyl-piperidine-4-carboxylic acid benzyl-methyl-amide (Example B8., 0.25 mmol) in CH2Cl2 is added a freshly prepared solution of 4-isocyanato-2-methyl-6-(E)-styryl-pyridine (Example C2., 0.3 mmol) in toluene (2 mL). The mixture is stirred for 15 h at 20° C. Evaporation of the solvent and purification by HPLC provides the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([S:14][CH3:15])[C:5](=[O:13])[N:6]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:7]=1.[CH3:16][Al](C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([CH:8]([N:6]1[CH:7]=[C:2]([CH3:16])[N:3]=[C:4]([S:14][CH3:15])[C:5]1=[O:13])[CH2:11][CH3:12])[CH3:10]
Reactant: CCC(CC)n1cc(Br)nc(SC)c1=O
Reactant: C[Al](C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCC(CC)n1cc(C)nc(SC)c1=O
Temperature: 0 °C
Yield: 73 %

Procedure:
A solution of XXXI (2.0 g, 6.9 mmol) and dichlorobis(triphenylphosphine)palladium(II) (484 mg, 0.7 mmol) in THF (40 mL) was treated with trimethylaluminum (6.2 mL, 12.4 mmol, 2M/toluene) dropwise at 0° C. The reaction was refluxed for 4 h, cooled to 0° C. quenched with water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to give crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexane 1:1) gave the product XXXII (1.14 g, 73%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:10]=[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3]1.C([O-])([O-])=[O:26].[K+].[K+]>CO.OO>[NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:10]=[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:12]([C:15]([NH2:16])=[O:26])=[N:13][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3N)cnc2C#N)cc1
Agent: OO
Agent: [K+]
Solvent: CO
Product: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3N)cnc2C(N)=O)cc1

Procedure:
To a solution of 5-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-3-(p-tolylamino)pyrazine-2-carbonitrile in methanol (1 ml) was added K2CO3 (excess) and H2O2 (50%, a few drops). After completion, it was concentrated and purified by preparative HPLC to give 5-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-3-(p-tolylamino)pyrazine-2-carboxamide. MS found for C17H22N6O2 as (M+H)+343.3, UV: λ=251.2, 302.9.
Reaction SMILES: [C:1]1([C@:7]23[NH:14][C@H:11]([CH2:12][CH2:13]2)[CH2:10][CH2:9][C@H:8]3[O:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[CH2:23]([N:14]1[C@@H:11]2[CH2:12][CH2:13][C@@:7]1([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:8]([O:15][Si:16]([CH2:19][CH3:20])([CH2:21][CH3:22])[CH2:17][CH3:18])[CH2:9][CH2:10]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC[Si](CC)(CC)O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of (1R,2R,5R)-1-phenyl-2-triethylsilyloxy-8-azabicyclo[3.2.1]octane (Description 51; 100 mg, 0.315 mmol), benzyl bromide (0.5 ml), potassium carbonate (380 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 30 minutes. The reaction mixture was treated with diethyl ether, washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel to give the title compound (107 mg, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:20]([CH3:37])[NH:21][C:22](=[O:36])[CH2:23][CH2:24][NH:25][C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:38]([O:40][CH:41]([O:55][CH2:56][CH3:57])[CH2:42][NH:43][CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)[CH3:39].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>ClCCl.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([N:20]([CH3:37])[NH:21][C:22](=[O:36])[CH2:23][CH2:24][NH:25][C:26]([NH:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C:17]([N:43]([CH2:42][CH:41]([O:40][CH2:38][CH3:39])[O:55][CH2:56][CH3:57])[CH2:44][C:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH:48]=[CH:47][CH:46]=2)=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CNCc1cccc2ccccc12)OCC
Reactant: CN(NC(=O)CCNC(=O)NCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(C)NC(=O)CCNC(=O)NCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
To a solution of (S)-3-(4-(benzyloxy)phenyl)-2-(2-(3-(3-benzylureido)propanoyl)-1-methylhydrazinyl)propanoic acid (Compound VII-1) 126 mg (0.25 mmol) in dichloromethane 1.5 ml, 2,2-diethoxy-N-(naphthalen-1-ylmethyl)ethanamine (Compound IV-2) 85 mg (0.31 mmol) and DMT-MM 173 mg (0.63 mmol) were added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with chloroform 50 ml and washed with water 50 ml twice and brine 50 ml twice and dried over magnesium sulfate and filtered. The mother solution was concentrated in vacuo and the residue was purified on silica gel column chromatography (Merck 60N spherical, neutral 10 ml elution by chloroform:methanol=100:0 to 90:10, each elution 50 ml) to give the desired product as pale yellow oil 85.0 mg (35.8%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2.S(=O)(=O)(O)O.[C:20](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:20])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cnc2ccc(O)cc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2ccc(O)cc2c1
Temperature: 70 °C

Procedure:
6-Hydroxyquinoline-3-carboxylic acid (Int-15, 1 g, 5.29 mmol) was suspended in methanol (25 mL) to which sulfuric acid (0.3 mL, 5 mmol) was carefully added. The reaction was heated at 70° C. under an atmosphere of nitrogen for 48 h. The reaction was cooled to room temperature and saturated sodium bicarbonate solution (2 mL) was added. The solvent was removed under reduced pressure and the crude residue was co-evaporated with toluene twice. The dried residue was purified by silica gel chromatography (methylene chloride to 95/5 methylene chloride/methanol gradient) to afford Int-16 (0.89 g, 83%). LC-MS: (FA) ES+ 204; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.23 (d, J=1.7 Hz, 1H), 9.09 (s, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.59 (dd, J=9.1, 2.5 Hz, 1H), 7.50 (d, J=2.5 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: FC(F)(F)C(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=O.[Br-:23].[Li+]>C1COCC1.C(#N)C>[Si:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][Br:23])=[CH:8][CH:9]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: [Br-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(COC(=O)C(F)(F)F)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CBr)cc1
Yield: 88 %

Procedure:
The benzyl trifluoroacetate 8 (17.9 g) was dissolved in dry THF, and dry lithium bromide (5.06 g) was added with stirring. The mixture was refluxed overnight, cooled, diluted with acetonitrile, and extracted three times with hexane. The hexane layers were combined, dried, filtered, and concentrated, thereby leaving the product 10 as a white oil in 88% yield.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]2[OH:9])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OC[C@H]1CCCC[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCC[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of (1S,2R)-2-(hydroxymethyl)cyclohexanol (0.44 g, 3.85 mmol) and N,N-dimethylaminopyridine (DMAP) (0.485 g, 3.97 mmol) in anhydrous CH2Cl2 (10 mL) was added a solution of p-toluenesulfonyl chloride (0.767 g, 4.02 mmol) in anhydrous CH2Cl2 (5 mL) under argon at room temperature. The reaction mixture was stirred at room temperature for 22 hrs and triethylamine (0.5 mL) was added. The mixture was stirred for additional 100 min, concentrated under reduced pressure, water was added and the product was extracted with EtOAc twice. Combined organic layers were washed with brine, concentrated under reduced pressure and purified by flash chromatography (20% to 70% EtOAc/hexanes gradient) to give ((1R,2S)-2-hydroxycyclohexyl)methyl 4-methylbenzenesulfonate as a colorless oil. Yield (0.732 g, 71%). 1H NMR (400 MHz, DMSO-d6) δ 7.72-7.76 (m, 2H), 7.42-7.47 (m, 2H), 4.60 (d, J=5.5 Hz, 1H), 4.12 (dd, J=3.1, 9.2 Hz, 1H), 3.90 (dd, J=7.2, 9.2 Hz, 1H), 3.00-3.10 (m, 1H), 2.40 (s, 3H), 1.73-1.80 (m, 1H), 1.46-1.65 (m, 3H), 1.34-1.42 (m, 1H), 0.85-1.16 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[CH2:14]([N:16]([CH2:27][CH3:28])[CH2:17][CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH3:15]>C1COCC1.CC(O)C>[CH2:27]([N:16]([CH2:14][CH3:15])[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)=[CH:25][CH:26]=1)[CH3:28]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CCNc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCNc1nc(Nc2ccc(OCCN(CC)CC)cc2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a solution of 1.013 g (5 mmol) of 2-chloro-4-(ethylamino)-5-nitropyrimidine in 50 mL THF at −78° C. is added a solution of 2.48 g (12 mmol) of 4-[2-(diethylamino)ethoxy]aniline in 50 mL of 2-propanol, and the resulting mixture is allowed to warm slowly to room temperature. After removal of the solvent, the residue is dissolved in aqueous acetic acid and filtered through celite. The aqueous solution is then basified with aqueous ammonia, and the resulting precipitate is collected, washed with water, and dried to give 1.65 g (95%) of the title compound: mp (MeOH) 134–136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.Br[CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][N:7]([CH2:8][CH3:9])[CH2:6][CH3:5])[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: O=C(Cl)CCCBr
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Product: CCN(CC)CCCC(=O)N1c2ccc(Cl)cc2NC(=O)c2ccccc21

Procedure:
The 5-(5-bromobutyryl)-8-chloro-5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one, used as starting material, is synthesized similarly to the starting material described in Example 1 from 8-chloro-5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one and 4-bromobutyryl chloride. The yield is 83.1% of the theoretical yield and the melting point is 176°-177° C.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[C:12]([NH:11][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)(=[O:14])[CH3:13]
Reactant: Nc1ccc(O)c2c1CCC2
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(O)c2c1CCC2

Procedure:
A mixture of 25 g of 7-hydroxy-4-amino indane and of 8 ml of acetic anhydride in 400 ml of iced water was stirred for 30 minutes. After filtering, the precipitate was washed with water and ethyl ether and was recrystallized in isopropanol.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:25][O:26][CH2:27][C:28](O)=[O:29]>ClCCl>[C:3]1([CH2:2][CH2:1][NH:9][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: COCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COCC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Phenethylamine(11.6 ml, 92.1 mmol) was added dropwise to a solution of dicyclohexylcarbodiimide(19 g, 92.1 mmol), methoxyacetic acid(8.3 g, 92.1 mmol) in dichloromethane(50 ml) at room temperature. After addition was completed, the reaction mixture was stirred for 1 hour at room temperature and the resulting solid was filtered. The filtrate was washed with aqueous hydrochloric acid solution, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford 8.15 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23][OH:24])[N:22]=2)[CH2:14][C@H:13]1[O:30][CH3:31])=[O:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:30][CH3:31])=[O:10]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (0.63 g, 1.3 mmol, Example 143) in methylene chloride was added Dess-Martin periodinane (0.61 g, 1.4 mmol). After 1 hr stirring at room temperature the reaction was complete. The crude reaction mixture was washed with water (×2) and brine, followed by drying with MgSO4 and concentrating to a minimal volume of methylene chloride after which it was directly deposited on a silica gel flash column (gradient elution to 1:1 EtOAc in CH2 Cl2). Pure fractions concentrated to clean, yellow solid (0.56 g). NMR: 1.29 (t, 3 H) 1.75 (s, 2 H) 2.18 (s, 3 H) 3.38 (s, 4 H) 3.44 (s, 1 H) 3.57 (s, 1 H) 4.03 (d, 1H) 4.22-4.35 (m, 4 H) 7.15 (d, 1 H) 10.31 (s, 1 H) 12.16 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: N[C@@H]1CCc2ccccc21
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NC3CCc4ccccc43)c2CC1)C(F)(F)F
Yield: 63.1 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.5 mmol) with (R)-1-aminoindan (188 mg, 1.4 mmol) in toluene (5 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to give 7-chloro-6-(indan-1-ylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (129 mg, 67%). GC-MS m/z: 408 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:26][O:27][CH3:28])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and chloromethyl methyl ether (0.056 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (2% methanol/chloroform) to give the subject compound (107 mg, yield 69%).