Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[C:8]([OH:10])([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].N1C=CC=CC=1.ClCCl.[C:21](Cl)(=[O:23])[CH3:22]>O>[C:21]([O:10][C:8]1([CH3:9])[CH:7]=[CH:6][C:5](=[O:11])[CH:4]1[CH2:1][CH:2]=[CH2:3])(=[O:23])[CH3:22]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CCC1C(=O)C=CC1(C)OC(C)=O
Reaction time: 2 h
Yield: 94.1 %

Procedure:
Into a flask equipped with a stirrer and a thermometer, dl-2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (30.4 g), pyridine (30 g) and dichloromethane (300 g) were charged, and acetyl chloride (30 g) was dropwise added thereto at a temperature from 10° to 20° C. in 2 hours. Then, stirring was continued at a room temperature for 24 hours. To the reaction mixture kept below 10° C., water (100 ml) was added to decompose excess of acetyl chloride. From the resultant mixture, the organic layer was separated and washed with 1% hydrochloric acid, 1% sodium bicarbonate solution and water in order. Removal of the solvent by distillation gave dl-3-acetoxy-2-allyl-3-methyl-4-cyclopentenone (36.5 g). Yield, 94%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:10]=3)[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2nc3ccccc3o2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 90 %

Procedure:
To a suspension of amide 1 (9.6 g, 26 mmol) in anhydrous 1,4-dioxane (100 mL) was added phosphorous oxychloride (POCl3) (9.2 mL, 100 mmol) slowly. The whole was then heated at 100° C. overnight. After cooling to r.t., the mixture was poured into ice (200 g) with stirring. Filtration, followed by recrystallization in DCM/hexanes gave a pale grey solid (Compound 5) (8.2 g, in 90% yield).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[N:18]=[C:19]([NH:21][C:22]([O:24]C3C=CC=CC=3)=O)[S:20][C:14]=2[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C.O>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[N:18]=[C:19]([NH:21][C:22]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:24])[S:20][C:14]=2[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)Oc3ccccc3)sc2C1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.3 %

Procedure:
45 mg allylamin was added to 200 mg 2-phenoxycarbonylamino-6,7-dihydro-4H-thiazolo (5,4-c) pyridine-5-carboxylic acid tert-butyl ester in 25 mL DMF. The reaction was stirred for 12 h at RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution and concentrated. The residue was purified by column chromatographie (silica gel, eluent: 40% ethylacetate in hexane) to give 179 mg of desired product. (M+H)+: 339
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6](=[O:41])[CH2:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])[N:11]=[N:10][CH:9]=1)C>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:11]=[N:10][CH:9]=[C:8]([CH2:7][C:6]([O-:41])=[O:5])[CH:13]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22].[Na+:2]
Reactant: CCOC(=O)Cc1cnnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(CC(=O)[O-])cnn2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A 0.25 N sodium hydroxide aqueous solution (0.060 mL) was added to a solution of [6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridazin-4-yl]acetic acid ethyl ester (Example 183-(4); 6.5 mg, 0.012 mmol) in methanol (0.20 mL) at room temperature, and the mixture was stirred at room temperature for four hours. The reaction mixture was concentrated under reduced pressure to give the title compound (6.5 mg, 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:34]2)=CC=1.C1(C)C=CC=CC=1>[Cl-].[Na+].O>[CH2:1]([N:8]1[C:13](=[S:34])[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cccnc2c(-c2ccccn2)nn1Cc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: S=c1c2cccnc2c(-c2ccccn2)nn1Cc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one RL-10 (45 mg, 0.143 mmol), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (57 mg, 0.143 mmol), and 4 mL of toluene were heated to 115° C. for 2 h. Another 35 mg aliquot of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide was added and the heating was continued for 2 h. Still another 35 mg aliquot of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide was added and heating continued for an additional 2 h. After cooling, the reaction mixture was poured into 15 mL of saturated brine and then extracted with 4×20 mL of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried overnight at 60° C. under vacuum to give 6-benzyl-8-(pyridine-2-yl)pyrido[2,3-d]pyridazine-5(6H)-thione RL-11 (31 mg, 0.94 mmol). 1H NMR (400 MHz, Chloroform-d) δ 9.25 (dd, J=8.4, 1.7 Hz, 1H), 9.19-9.12 (m, 1H), 9.03 (s, 1H), 8.13 (bd, J=57.3 Hz, 1H), 7.72 (dd, J=8.4, 4.4 Hz, 1H), 7.64-7.52 (m, 3H), 7.40-7.25 (m, 4H), 6.17 (s, 2H). LCMS: (M+H)+, 331.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([O:33]C)[C:5]2[NH:6][C:7](=[O:30])[CH:8]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:9]=[C:10]([C:11]3[CH:21]=[CH:20][C:14]4[NH:15][C:16](=[O:19])[N:17]([CH3:18])[C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:32]=[C:31]([OH:33])[C:5]2[NH:6][C:7](=[O:30])[CH:8]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:9]=[C:10]([C:11]3[CH:21]=[CH:20][C:14]4[NH:15][C:16](=[O:19])[N:17]([CH3:18])[C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1cc(Cl)cc2c1NC(=O)C(Cc1ccccc1Cl)N=C2c1ccc2[nH]c(=O)n(C)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(=O)[nH]c2ccc(C3=NC(Cc4ccccc4Cl)C(=O)Nc4c(O)cc(Cl)cc43)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7-chloro-3-(2-chlorobenzyl)-9-methoxy-5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (25 mg, 0.05 mmol) under a nitrogen atmosphere was added 1M boron tribromide solution in dichloromethane (3 mL). This mixture was stirred at ambient temperature for 1 hour, then quenched with water (30 mL). Ethyl acetate (30 mL) was added and the mixture was slurried overnight. The layers were separated and the organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography eluting with a gradient of 0-20% methanol in dichloromethane to yield 7-chloro-3-(2-chlorobenzyl)-9-hydroxy-5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one. HRMS [M+H]+ predicted: 481.0834. found: 481.0828.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:59][C:57]2[S:56][C:46]3[C:47]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=3[N:58]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(-c2ccccc2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a stirred solution of 44 mg (0.31 mmol) 4-fluoro-benzoic acid in 4 ml THF were added 130 mg (0.34 mmol) HATU and 0.068 ml (0.62 mmol) N-methylmorpholine and stirring continued at 50° C. for 16 h. 40 mg (0.16 mmol) 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 7 mg (12%) 4-fluoro-N-(7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-yl)-benzamide as a white crystalline solid. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:17](N(C)C)N(C)C>>[N:1]12[P:17]3[N:11]([CH2:10][CH2:9][CH2:8][N:7]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14]2
Reactant: C1CNCCCNCCNCCNC1
Reactant: CN(C)P(N(C)C)N(C)C
Product: C1CN2CCCN3CCNCCN(C1)P23

Procedure:
A stirred mixture of 6.00 g (30 mmol) of 1,4,7,11-tetraazacyclotetradecane and 4.90 g of hexamethylphosphorous triamide is heated under nitrogen for 3 hr at 120° and then distilled in a short-path apparatus to give 5.50 g (80%) of clear, colorless liquid 1,5,9,12-tetraaza-15-phosphatricyclo[7.5.1.05,15 ]pentadecane, bp 106°-110° (0.30 mm), which solidifies on storing below 0°.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.O=P(Cl)(Cl)Cl.CN([CH:22]=[O:23])C.CC([O-])=O.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH:22]([C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C=O)c12
Temperature: 50 °C

Procedure:
A solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in dichloroethane (2 mL) was treated with a solution of POCl3-DMF (1.5 equivalent (eq)) at room temperature (rt). The orange solution was heated at 50° C. for 1 hour. The reaction solution was poured into ice-cold aqueous (aq.) NaOAc (1 g in 2 mL), the aqueous solution was adjusted to pH=8 with 1 M NaOH, and extracted with EtOAc (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl 3-formyl-indole-4-carboxylate as an oil, 271 mg (93%). 1H NMR (300 MHz, d6-DMSO) δ3.68 (s, 3H), 7.16 (t, 1H, J=7.8 Hz), 7.40 (dd, 1H, J=7.8, 0.8 Hz), 7.56 (d, 1H, J=7.8, 0.8 Hz), 8.16 (d, 1H, J=3.2 Hz), 10.00 (s, 1H), 12.30 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[OH2:10]>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: Cc1cc(Cl)ccc1Br
Reactant: O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Product: O=Cc1cc(Cl)ccc1Br
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To the solution of 2-bromo-5-chlorotoluene (25 g) in acetic anhydride (100 ml) and sulfuric acid (20 ml) was added dropwise chromium(VI) oxide (36.5 g) in acetic anhydride (200 ml) for 3 hours at -15° C. The mixture was stirred for 1 hour at -5° C. and then poured into ice-cooled water, and extracted with ether. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was suspended in ethanol (100 ml) and 3N-HCl (200 ml) and refluxed for 1 hour. After removal of the solvent, water was added to the residue, and extracted with ether.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH3:17])[C:10]=1[CH2:18][C:19]([N:21]([CH3:32])[N:22]=[C:23]([N:29]([CH3:31])[CH3:30])[C:24](OCC)=[O:25])=[O:20])[CH3:8]>C1COCC1.O>[CH2:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH3:17])[C:10]=1[C:18]1[C:19](=[O:20])[N:21]([CH3:32])[N:22]=[C:23]([N:29]([CH3:31])[CH3:30])[C:24]=1[OH:25])[CH3:8]
Reactant: CCOC(=O)C(=NN(C)C(=O)Cc1c(CC)cc(C)cc1CC)N(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(N(C)C)nn(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
To a solution of potassium t-butoxide (380 mg, 3.38 mmol) in dry THF (10 ml) was slowly added a solution of ethyl 2-[2-(2,6-diethyl-4-methylphenyl)acetyl-2-methylhydrazono]-2-dimethylaminoacetate (Compound (II-2)) (280 mg, 0.840 mmol) in dry THF (3 ml) dropwise. The mixture was stirred at room temperature for 15 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was washed with hexane, filtered, and dried to give 230 mg of Compound (I-1-2).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]2[CH:7]=[CH:8][C:9](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:10][C:11]=2[C:12]([CH3:16])([CH3:15])[CH2:13][CH:14]=1)(=[O:3])[CH3:2].CC1(C)C2C=CC([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=3)=CC=2C(=O)CC1>>[C:1]([O:4][C:5]1[C:6]2[CH:7]=[C:8]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=3)[CH:9]=[CH:10][C:11]=2[C:12]([CH3:16])([CH3:15])[CH2:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OC(C)=O)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OC(C)=O)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105), 90.0 mg (0.26 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (light yellow powder) using 0.06 ml (0.78 mmol) of acetic anhydride and 5 mg (0.03 mmol) of p-toluenesulfonic acid.
Reaction SMILES: [CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][CH:43]=[C:42]2[CH:48]=O>>[CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:48][C:42]2[C:41]3[C:45](=[CH:46][CH:47]=[C:39]([F:38])[CH:40]=3)[NH:44][CH:43]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3ccc(F)cc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Yield: 71.5 %

Procedure:
Following the procedure described for Example 1 (A), Step A, N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide (Preparation 9) (100 mg, 0.198 mmol) was condensed with 5-fluoro-1H-indole-3-carbaldehyde (38.8 mg, 0.238 mmol). Purification by medium pressure chromatography eluting with 50% EtOAc in CH2Cl2 provided 91.5 mg of N-benzyl-2-[8,9-difluoro-4-(5-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 7.92 (d, 1H), 7.10-7.67 (m, 13H), 6.84 (m, 1H), 6.64 (m, 1H), 4.37-4.97 (m, 5H), 4.20 (m, 1H), 1.20 (m, 6H); MS 647.4 (M+1), 645.3 (M−1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=O)[CH2:2]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]([NH2:24])([CH3:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]([NH:24][C:10](=[O:12])[CH2:9][CH:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)([CH3:22])[CH3:23])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(C(C)(C)N)c1
Reactant: O=C(O)CC1CN2CCC1CC2
Product: COc1cccc(C(C)(C)NC(=O)CC2CN3CCC2CC3)c1
Yield: 39.8 %

Procedure:
Using general procedure I, 2-(quinuclidin-3-yl)acetic acid (169 mg, 1.00 mmol) and 2-(3-methoxyphenyl)propan-2-amine (182 mg, 1.10 mmol) gave the title compound as a white solid (126 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.71 (dd, J=8.0, 2.0 Hz, 1H), 3.75 (s, 3H), 3.31-3.42 (m, 2H), 3.00-3.19 (m, 4H), 2.47-2.60 (m, 2H), 2.27 (dd, J=14.0, 6.0 Hz, 1H), 1.83-2.06 (m, 4H), 1.64-1.74 (m, 1H), 1.61 (d, J=12.4 Hz, 6H) ppm. 13C NMR (400 MHz, CDCl3) δ 170.0, 159.7, 149.3, 129.5, 117.5, 111.8, 111.0, 55.9, 55.4, 52.0, 50.6, 46.6, 46.0, 39.7, 30.9, 29.7, 29.1, 24.3, 18.8 ppm. Purity: 93.7% HPLCMS (210 nm); retention time 0.76 min; (M+1) 317.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:43][C:44]([NH2:46])=[O:45]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:43][C:44]([NH2:46])=[O:45])[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)CCl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC(N)=O)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (19 mg, 0.04 mmol) in dry DMF (1 mL) was added potassium carbonate (12 mg, 0.08 mmol) and 2-chloroacetamide (12 mg, 0.12 mmol) at room temperature under nitrogen. The reaction mixture was stirred overnight at room temperature and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient 0 to 80% AcOEt in hexane) to give the title compound (14 mg, 67%). 1H NMR (500 MHz, CDCl3): 7.32 (1H, s), 7.28-7.23 (7H,m), 7.16-7.14 (2H,m), 6.22 (1H, br s), 5.65 (1H, br s), 5.09 (1H, br s), 4.94 (2H, s), 4.52 (2H,s), 2.55-2.25 (4H, m), 2.09-2.01 (1H, m), 1.85-1.76 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH4+].[OH-]>C(Cl)Cl.[Cl-].[Na+].O.[Zn]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Clc1nc(Cl)c2c(n1)CCCC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ncc2c(n1)CCCC2

Procedure:
2, 4-Dichloro-5,6,7,8-tetrahydroquinazoline (4 g) is dissolved in 50 mL of methylene chloride and the resulting solution covered with 9% NH4OH in saturated brine. Zinc (4 g) is added and the resulting mixture gently refluxed overnight. After filtration through celite, the organic layer is washed with water, dried and concentrated.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14]([C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([C:18]1[N:23]=[C:22]([NH:24][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:21]=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CC(C)(C)c1cccc(N)n1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C)n1
Temperature: 130 °C
Yield: 48.7 %

Procedure:
A mixture of ethyl 4,6-dichloropyridazine-3-carboxylate (0.73 g, 3.3 mmol) and 6-tert-butylpyridin-2-amine (992 mg, 6.61 mmol, available commercially from J&W PharmLab, LLC) was dissolved in acetonitrile (3.00 mL) and heated at 130° C. for 20 h. After cooling to room temperature, the mixture was concentrated and the residue purified by flash chromatography (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 20% acetone in dichloromethane over 20 min to give ethyl 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (539 mg, 48.7% yield) as a light brown residue. 1H NMR (CHLOROFORM-d) δ: 10.59 (s, 1H), 9.32 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 4.48 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H), 1.28-1.35 (m, 9H); LC-MS 335.0, 337.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:36]1[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(Cl)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 4-chlorophenylboronic acid. Colorless crystals (55 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]>FC(F)(F)C(O)=O.[Pt](=O)=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NC(C)C
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3c(c2n1NC(C)C)CCCC3
Reaction time: 15 h
Yield: 53 %

Procedure:
A solution of 2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.700 g, 2.34 mmol) in 25 mL of trifluroacetic acid was treated with platinum(IV) oxide (0.27 g, 1.2 mmol) and the mixture was shaken under an atmosphere of hydrogen (3.8×105 Pa). After 15 h, the reaction mixture was filtered through a pad of CELITE filter agent, rinsed with 9:1:0.5 CHCl3:MeOH:trifluoroacetic acid (TFA) and concentrated under reduced pressure to yield a creamy white solid. The solid was triturated with concentrated NH4OH solution for 2 h and then extracted with CHCl3 (3×). The organic portion was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a white foam. The foam was triturated with diethyl ether, filtered and dried under reduced pressure to yield 2-ethoxymethyl-N1-isopropyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.376 g) as a fine white solid. mp 144–146° C.; 1H NMR (300 MHz, CDCl3) δ 5.08 (d, J=2.7 Hz, 1H), 4.92 (s, 2H), 4.78 (s, 2H), 3.61 (q, J=7.0 Hz, 2H), 3.53–3.43 (m, 1H), 3.07–3.03 (m, 2H), 2.85–2.81 (m, 2H), 1.92–1.79 (m, 4H), 1.25 (t, J=7.0 Hz, 3H), 1.08 (d, J=6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 149.4, 148.9, 148.1, 138.8, 122.9, 107.4, 66.6, 65.4, 53.0, 32.5, 23.7, 23.2, 22.8, 20.5, 15.1; MS (APCI) m/z 304 (M+H)+; Anal. Calcd for C16H25N5O: C, 63.34; H, 8.31; N, 23.08; Found: C, 63.32; H, 8.31; N, 22.97.