Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([N+:15]([O-])=O)[CH:12]=2)[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=C(C=CC=1Cl)C[O:50][C:51](=O)[CH:52]([C:54]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=2)=[CH:56][CH:55]=1)O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl.C1COCC1.[Fe].CCOC(C)=O>[C:22]([O:21][C:19]([N:6]1[C@H:5]([C:3]([OH:2])=[O:4])[CH2:14][C:13]2[CH:12]=[C:11]3[C:10]([O:18][CH:52]([C:54]4[CH:59]=[CH:58][C:57]([O:60][CH2:61][C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=5)=[CH:56][CH:55]=4)[C:51](=[O:50])[NH:15]3)=[CH:9][C:8]=2[CH2:7]1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: COC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)(C)C
Reactant: O=C(OCc1ccc(Cl)c(Cl)c1)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Fe]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)NC(=O)C(c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of (S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (3.0 g, 8.5 mmol), resin-bound triphenylphosphine (17 mmol), [4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid 3,4-dichloro-benzyl ester (13.0 mmol) in DCM-THF (1-1, 80 mL) was cooled to 0° C. To this solution was added DIAD (13.0 mmol) and the mixture was agitated for 10 min at 0° C. and the mixture was slowly allowed to warm up to r.t. and agitated for 16 h. The reaction mixture was filtered, concentrated and the residue passed over a plug of silica-gel hexanes-ethyl acetate (9:1). The resulting residue was dissolved in glacial acetic acid (65 mL) and iron powder (170 mmol) added. The resulting mixture was heated at 100° C. for 1 h. The mixture was poured onto water and EtOAc. The organic layer was washed with water, brine, saturated sodium bicarbonate solution and dried over sodium sulfate. The solution was concentrated under reduced pressure to give the desired product. This crude product was purified by silica gel column chromatography using hexanes-ethyl acetate (7:3) to afford (7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (1.6 g). LC-MS (m/z) 614.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32](O)=[O:33])[CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:32]([C:28]5[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][N:29]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1ccnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccnc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)c1
Yield: 24.4 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (120 mg, 0.371 mmol), 4-methylpyridine-2-carboxylic acid (76 mg, 0.557 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (114 mg, 0.594 mmol), 1-hydroxybenzotriazole (81 mg, 0.600 mmol), triethylamine (0.09 mL, 0.631 mmol) and N,N-dimethylformamide (6.0 mL), and by a reaction in the same manner as in Example 187, the title compound (40 mg, 24%) was obtained as pale-yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11](=[O:22])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH:30]([CH:32]=O)=O>O>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11](=[O:22])[CH:12]([C:14]2[CH:15]=[C:16]3[C:17](=[CH:18][CH:19]=2)[N:20]=[CH:32][CH:30]=[N:21]3)[CH3:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=CC=O
Reactant: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(N)c(N)c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc2nccnc2c1
Temperature: 25 °C

Procedure:
To the flask of N-(4-tert-butyl-benzyl)-2-(3,4-diamino-phenyl)-propionamide (81 mg, 0.249 mmol) was added glyoxal (4 mL, 40% in water soln.) at room temperature, and additionally added DMF (4 mL) because SM was not soluble in glyoxal sufficiently. The reaction mixture was refluxed for 2 hrs then cooled to room temperature. The mixture was diluted with H2O (25 mL) and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:1) as eluant.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[S:8].[CH3:15]I.CO>[OH-].[Na+]>[CH3:15][S:8][CH:7]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])[NH:6][C:2]1[S:1][CH:5]=[N:4][N:3]=1
Reactant: CCOC(=O)NC(=S)Nc1nncs1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)NC(Nc1nncs1)SC
Temperature: 40 °C

Procedure:
A mixture of 6.96 g (30 mM) of [(1,3,4-thiadiazol-2-ylamino)thioxomethyl]carbamic acid, ethyl ester (prepared as described in Preparation 1) in 45 ml of 1N sodium hydroxide containing 9.0 g (4 ml) of methyl iodide and 15 ml of methanol was heated at 40° C. for ten minutes. The reaction mixture was cooled to 5' C. and filtered. The filter cake was washed with water and air dried to provide 4.72 g of [(methylthio)(1,3,4-thiadiazol-2-ylamino)methyl]carbamic acid, ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[Br:23][CH2:24][C:25](Cl)=[O:26]>ClCCl.CN(C)C1C=CN=CC=1.[Cl-].[NH4+]>[Br:23][CH2:24][C:25]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:26]
Reactant: O=C(Cl)CBr
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCCC2
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CCC2
Reaction time: 8 h

Procedure:
A mixture of 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (0.19 g, 0.91 mmol) and triethylamine (0.5 mL, 3.7 mmol, Aldrich) in dichloromethane was treated with dropwise addition of bromoacetyl chloride (0.33 mL, 4.0 mmol, Fluka). A catalytic amount of 4-dimethylaminopyridine was added and the reaction stirred overnight. The mixture was diluted with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1-(bromoacetyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline which was taken directly to the next step without determination of yield. RF=0.3 (50% EtOAc/hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([OH:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: CCO
Product: CCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and ethanol. Light brown solid. MS (m/e): 208.1 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.N1([C:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)CCCC1.[OH2:24]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:17]2=[O:24])=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C1=C(N2CCCC2)CCCCC1
Solvent: CN(C)C=O
Product: O=C(CC1CCCCCC1=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 80 g (0.28 mole) of p-bromophenacyl bromide in dry dimethylformamide is added dropwise to a cooled solution of 40.2 g (0.28 mole) of 1-pyrrolidino-1-cycloheptene in dry dimethylformamide. After stirring at ambient temperature for 24 hours, and at 100° C. for 5 hours, water is added and the mixture is stirred for an additional 4 hours. The reaction mixture is poured into 1500 ml. of water and extracted with chloroform. The chloroform solution is washed with water, dried, and evaporated to a red oil which is stirred at 100° for 1 hour under a high vacuum. Upon cooling the oil converts to a semi-solid. The semi-solid is crystallized from an ethanol - cyclohexane mixture to give 2-(p-bromophenacyl)cycloheptanone, m.p. 124°-127° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([NH:22]C(=O)OC(C)(C)C)[CH:20]=5)[NH:15][C:14]4=[O:30])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:30])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)=[CH:43][CH:42]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C1(CC1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3n[nH]c4cc([C@@H]5C[C@@]56C(=O)Nc5ccc(N)cc56)ccc34)cc2)CC1
Reaction time: 1 h
Yield: 5.1 %

Procedure:
The Suzuki coupling was executed according to the method in Example A45, except substituting tert-butyl 2-(3-iodo-1H-indazol-6-yl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-ylcarbamate (70 mg, 0.136 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (57 mg, 0.190 mmol). The resulting product was was dissolved into CH2Cl2 (1.0 mL) and TFA (50 uL) was added. After 1 h the reaction was complete, the solvent was removed and the residue purified by prep-HPLC to give a white powder (3.2 mg, 15%); 1H NMR (400 MHz, CD3OD) δ 7.94 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.53 (s, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.05-7.02 (m, 3H), 6.04 (s, 1H), 4.01-3.97 (bs, 2H), 3.75-3.65 (bs, 2H), 3.46 (t, J=8.4 Hz, 1H), 3.32-3.28 (bs, 2H), 3.18-3.08 (bs, 2H), 3.00 (s, 3H), 2.35-2.31 (m, 1H), 2.29-2.25 (m, 1H); MS ESI [M+H]+ 465.1, calcd for [C28H28N6O+H]+ 465.24.
Reaction SMILES: [Br-].[CH3:2][CH:3]([CH3:7])[CH2:4][CH2:5][Zn+].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH:32][C:33](=[O:35])[CH3:34])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26](Br)[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C@@H:16]1[CH3:43])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH:32][C:33](=[O:35])[CH3:34])[CH2:23][C:24]2[CH:25]=[C:26]([CH2:5][CH2:4][CH:3]([CH3:7])[CH3:2])[CH:27]=[C:28]([F:30])[CH:29]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C@@H:16]1[CH3:43])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(Br)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Reactant: CC(C)CC[Zn+]
Agent: [Br-]
Product: CC(=O)N[C@@H](Cc1cc(F)cc(CCC(C)C)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Yield: 78 %

Procedure:
Beginning with 3-methylbutyl zinc bromide and (2R,3S,5R)-5-[(1S,2S)-1-hydroxy-2-acetylamino-3-(3-bromo-5-fluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (0.165 g, 0.287 mmol), the title compound (0.127 g, 78%) may be prepared essentially as described in Preparation 409.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[N:18]=[C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]4[CH:26]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([NH:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[N:18]=[C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]4[CH:26]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccn2cc(CCc3ccc4nc(N)oc4c3)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(CCc3cn4ccc(C)cc4n3)cc2o1
Temperature: 0 °C
Yield: 58.3 %

Procedure:
A solution of acetyl chloride (1.94 g) in dichloromethane (6 ml) was added dropwise to a solution of 2-amino-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (6.00 g) and pyridine (4.92 ml) in dichloromethane (60 ml) with stirring at 0° C. The mixture was stirred for two hours at the same temperature and further 22 hours at ambient temperature. Saturated aqueous sodium hydrogen carbonate solution (100 ml) was added thereto and that was stirred for 2.5 hours at 0° C. The resulting precipitate was collected by filtration and washed with water. Recrystallization from a mixture of ethanol and diethyl ether gave 2-acetylamino-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (4.00 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[N:9]([CH2:10][CH2:11]O)[CH2:8][CH2:7][O:6][CH2:5]1.S(Cl)([Cl:15])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[ClH:15].[Cl:15][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][O:6][CH2:5][C@H:4]1[CH2:3][O:2][CH3:1]
Reactant: COC[C@@H]1COCCN1CCO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC[C@@H]1COCCN1CCCl
Product: Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 149.4 %

Procedure:
To an ice-cooled solution of 2-[(3R)-3-(methoxy-methyl)morpholino]ethanol (505 mg) in toluene (2.5 ml) was added dropwise a solution of thionyl chloride (429 mg) in toluene (1.5 ml) at 5° C. or below under a nitrogen atmosphere. The mixture was stirred at 70° C. for 1.5 hours. After cooling the mixture to room temperature, ethyl acetate was added to the mixture and the solvent was evaporated from the produced suspension under reduced pressure. Diisopropyl ether was added to the residue. After stirring the mixture at room temperature for 15 minutes, the produced precipitates were filtered, washed with diisopropyl ether and dried at 40° C. under reduced pressure to give (3R)-4-(2-chloroethyl)-3-(methoxymethyl)morpholine hydrochloride (620 mg) in the form of pale yellow powders.
Reaction SMILES: [C:1](#[N:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([OH:8])[CH3:7].[ClH:9]>C(OC(C)C)(C)C>[ClH:9].[C:1](=[NH:5])([O:8][CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCO
Reactant: CCCC#N
Agent: Cl
Solvent: CC(C)OC(C)C
Product: CCCC(=N)OCC
Temperature: -20 °C
Reaction time: 96 h

Procedure:
Butyronitrile (85 ml, 839 mmol) is dissolved in absolute ethanol (65 ml, 961 mmol) and cooled to 0° C. to 5° C. While cooling further, gaseous hydrogen chloride (about 40 g, about 1.1 mol, differential weighing of the pressure cylinder) is passed into the solution. The reaction mixture is left at about 4° C. for 96 hours and then, while stirring, 260 ml of diisopropyl ether are added, and the mixture is cooled to −20° C. and filtered with suction at 0° C. through a sintered funnel. The crystals are rapidly (the product is hygroscopic) washed twice with 50 ml of cold diisopropyl ether each time and stored, sealed air-tight, in a refrigerator.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:14]1[O:15][C:7]2([CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH2:8]2)[O:12][CH2:13]1
Reactant: OCCO
Reactant: O=C1CCc2cc(Br)ccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)CCC1(C2)OCCO1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
6-bromo-2-tetralone (2.0 g, 8.89 mmol) was dissolved in toluene (50 mL) and treated with excess ethylene glycol (4.88 mL, 88.9 mmol) and catalytic p-toluenesulfonic acid (15 mg). The solution was stirred at reflux 16 hours, and water was removed from the reaction mixture using a Dean-Stark condenser. After cooling to ambient temperature, the toluene solution was washed 2×1N NaOH, 1×water, 1×brine, dried over Na2SO4 and concentrated in vacuo to give 2.23 g (93%) of 6-bromo-2-tetralone ethylene ketal as a brown oil which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: c1ccc(COc2ccc(N3CCN(Cc4nc5ccccc5[nH]4)CC3)nc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1

Procedure:
The product from Example 29D (800 mg) in ethyl acetate (35 mL) was treated with 10% palladium on carbon (85 mg) under a blanket of hydrogen gas at 23° C. until TLC indicated consumption of starting material. The mixture was filtered and the filter cake washed with with methanol and CH2Cl2. The filtrates were combined and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 90:10:0.1 CH2Cl2:methanol:NH40H) to provide the title compound pure as a white solid (566 mg, 92%). mp 144–145° C.; Rf=0.08; (95:5 CH2Cl2:methanol:0.1% NH40H); MS 310 (M+H)+; 1H NMR (300 MHz, MeOD) δ 7.72 (d, 1H, J=2.7 Hz), 7.53 (m, 2H), 7.21 (m, 2H), 7.12 (dd, 1H, J=9, 3 Hz), 6.75 (d, 1H, J=9 Hz), 3.85 (s, 2H), 3.40 (t, 4H, J=5.1 Hz), 2.69 (t, 4H, J=5.1 Hz); Analysis calculated for C17H19N5O (1.0 equivalent methanol, 0.1 equivalent dichloromethane): C 62.13; H 6.68; N 20.01. Found: C 62.04; H 6.57; N 19.67.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.I[CH:43]([CH3:49])[CH2:44][C:45]([F:48])([F:47])[F:46]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:49][CH2:43][CH2:44][C:45]([F:48])([F:47])[F:46])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: CC(I)CC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(CCCC(F)(F)F)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 72.3 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol), 3-iodo-1,1,1-trifluorobutane (0.127 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.172 g (72%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[N+:6]([O-])[C:7]([CH3:13])=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:18]>ClCCl>[CH2:11]([O:10][C:9]1[CH:8]=[C:7]([CH2:13][OH:18])[N:6]=[N:5][C:4]=1[O:3][CH2:1][CH3:2])[CH3:12]
Reactant: CCOc1cc(C)[n+]([O-])nc1OCC
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(CO)nnc1OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3,4-Diethoxy-6-methylpyridazine 1-oxide (1.44 g) was initially charged in dichloromethane (50 ml) and admixed dropwise at RT with trifluoroacetic anhydride (2.5 ml). After 2.5 h, the mixture was concentrated to dryness and the residue was taken up with ethanol and saturated potassium carbonate solution. After stirring at RT for 4 h, the mixture was concentrated to dryness again and the residue was admixed with water and dichloromethane. Removal of the organic phase was followed by extraction twice more with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified twice using silica gel with dichloromethane/methanol as the eluent. The product-containing fractions were combined and dried. 716 mg of the desired product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][C@@H:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])=[C:18]([CH3:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: C[C@@H](N)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(F)cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(4-fluorophenyl)ethylamine (35 mg) in is chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (26 mg, yield 58%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[F:18][C:19]([F:30])([F:29])[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21]>C(O)CCC>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([NH:22][C:20](=[O:21])[C:19]([F:18])([F:29])[F:30])[CH2:24]2)[CH:3]=1
Reactant: O=C(NC1CCCNC1)C(F)(F)F
Reactant: Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCCC(NC(=O)C(F)(F)F)C2)ncn1
Temperature: 170 °C
Reaction time: 24 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.149 g, 1.15 mmol) and diisopropylethylamine (0.446 g, 3.45 mmol) were suspended in n-butanol. 2,2,2-Trifluoro-N-piperidin-3-ylacetamide 9-3 (0.226 g, 1.15 mmol) was then added. The reaction was stirred at 170° C. for 24 hours. The butanol was then removed under reduced pressure and the product was purified on a silica column eluted with DCM:MeOH:NH4OH (95:5:0.5). 1H-NMR (CD3OD): 8.06 ppm (s, 1H); 5.82 ppm (s, 1H); 4.27 ppm (d, 1H); 4.15 ppm (d, 1H); 3.85 ppm (m, 1H); 3.73 ppm (p, 3H); 3.23 ppm (q, 3H); 3.08 ppm (dd, 2H); 2.13 ppm (m, 1H); 1.85 ppm (m, 1H); 1.71 ppm (m, 1H); 1.62 ppm (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([C:12]([NH2:15])([CH3:14])[CH3:13])(I)[CH2:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)O1>>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:5]4[S:10][C:9]([C:12]([NH2:15])([CH3:14])[CH3:13])=[CH:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CC(C)(N)C1(I)Cc2nc(Cl)nc(N3CCOCC3)c2S1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(C)(N)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)propan-2-amine (30 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 11.5 mg of 310. MS (Q1) 395.0 (M)+