Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1C=CC=[CH:3][CH:2]=1.C(CC(O)=O)#N.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+]>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1/[CH:17]=[CH:3]/[C:2]#[N:1]
Reactant: c1ccncc1
Reactant: COc1cccc(OC)c1C=O
Agent: CC(=O)[O-]
Agent: N#CCC(=O)O
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1/C=C/C#N
Yield: 89.3 %

Procedure:
Add, one after another, 1.13 g (14.7 mmol) of ammonium acetate, 40.4 mL (500 mmol) of pyridine and 31.2 g (367 mmol) of 2-cyanoacetic acid to a solution of 61 g (367 mmol) of 2,6-dimethoxybenzaldehyde in 360 mL of toluene. Reflux the reaction mixture for 15 h, distilling the toluene-water azeotrope in Dean-Stark apparatus. Take up the solution in 500 mL toluene and 40 mL pyridine and reflux again for 48 h in the Dean-Stark apparatus. After concentration under reduced pressure, take up the residue in 800 mL of dichloromethane (DCM) and wash successively with 1 L of 1N HCl aqueous solution, 500 mL of saturated aqueous solution of sodium carbonate (Na2CO3) and 1 L of water. After drying over sodium sulphate (Na2SO4) and concentration under reduced pressure, we obtain 62 g of (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile in the form of brown oil, which is used “as is” in the next stage.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]Cl.C(=O)=O.CC(C)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:11])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(F)cc1
Reactant: ClCl
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: ON=C(Cl)c1ccc(F)cc1
Reaction time: 1 h
Yield: 48.1 %

Procedure:
A solution of 25 g of 4-fluorobenzaldoxime in 200 ml of chloroform was cooled to 0° to -10°. From a pressure bottle, 14.2 g of chlorine was run into a flask cooled by dry ice-acetone and allowed to distill into the aldoxime solution, the solution being maintained at 0° ± 5°. The reaction mixture was stirred for one hour in an ice bath while nitrogen was bubbled through the solution. The chloroform was evaporated to leave an oil to which hexane was added quickly. The solid which separated was recrystallized from hexane to give 15.0 g of 4-fluorobenzohydroximoyl chloride, m.p. 74.5°-75°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[NH:5][C:6]2[N:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[OH:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=O)=[CH:21][CH:20]=1.C(N(CC)CC)C>CC(N(C)C)=O>[N:26]1[N:25]=[C:23]([C:22]2[CH:27]=[CH:28][C:19]([CH2:18][OH:17])=[CH:20][CH:21]=2)[N:8]2[C:2]=1[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[NH:5][C:6]1[N:12]=[CH:11][CH:10]=[CH:9][C:7]2=1
Reactant: ClC1=Nc2cccnc2Nc2ccccc21
Reactant: NNC(=O)c1ccc(CO)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: OCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1

Procedure:
A solution of 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine (4.3 g, 19 mmol), 4-(hydroxymethyl)benzohydrazide (3.2 g, 20 mmol) and triethylamine (2.8 mL, 20 mmol) in dimethylacetamide (100 mL) was stirred at 85° C. until the starting material is all consumed (as followed by LC/MS). The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with water (3×100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate (20 mL) and the solid was collected by filtration. The (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)methanol was obtained as a yellow solid (4.8 g, 74%). M.p.=276-278° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.78 (s, 1H), 8.21 (dd, J=4.8, 1.6 Hz, 1H), 7.96 (dd, J=7.2, 1.6 Hz, 1H), 7.50-7.33 (m, 6H), 7.17-7.12 (m, 2H), 6.91 (dd, J=8.0, 4.8 Hz, 1H), 5.33 (t, J=5.6 Hz, 1H), 4.55 (d, J=6.0 Hz, 2H); LCMS [M+H]: 342.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15]CC)=O)=[CH:9]2)([O-:3])=[O:2].[NH3:18]>>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:18])=[O:15])=[CH:9]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: N
Product: NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 50 °C

Procedure:
A suspension of 133 mg (0.57 mmol) of ethyl 7-nitroindole-2-carboxylate in 3.84 ml of 28% aqueous ammonia is heated at 50° C. for 18 h in a stoppered glass tube. The reaction medium is filtered over sintered glass. The yellow solid obtained is washed with water and with cyclohexane and then dried under vacuum. 70 mg of 7-nitro-1H-indole-2-carboxamide are obtained in the form of a yellow solid.
Reaction SMILES: COC([C:5]1[C:6]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=[CH:9][N:10]=1)=O.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:6]3[CH:5]=[N:10][CH:9]=[CH:8][N:7]3[CH:11]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-c2cn3ccncc3n2)cc1
Temperature: 105 °C
Yield: 93 %

Procedure:
A mixture of 2-(4-fluorophenyl)imidazo[1,2-a]pyrazine-8-carboxylic acid methyl ester (Preparation #1, 6.30 g, 23.2 mmol) in DCM (66 mL) was treated with 1.0 M HCl in water (200 mL). The mixture was heated at about 105° C. open to the air for about 16 h. The solution was allowed to cool and was treated with saturated aqueous NaHCO3 and DCM. The mixture was sonicated to dissolve all solids and the layers were separated. The aqueous layer was washed with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound (4.60 g, 93%): LC/MS (Table 1, Method b) Rt=1.6 min; MS m/z: 214.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:4]=[N:3]1.[Li]CCCC.CN([CH:21]=[O:22])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][N:2]1[C:6]([CH:21]=[O:22])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:4]=[N:3]1
Reactant: Cn1cc(-c2ccccn2)nn1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccn2)c1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of 2-(1-methyl-1H-[1,2,3]triazol-4-yl)-pyridine (3.52 g, 22 mmol) in THF (112 mL) was added n-BuLi (1.6 M in hexane, 16.5 mL, 4.96 mmol) dropwise at −75° C. and under Ar. The resulted light brown suspension was stirred at −75° C. for 1 h. Then DMF (2.20 mL, 29 mmol) was added dropwise at −75° C. and the yellow solution was allowed to warm up to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (3.75 g, 91%) as a white solid. MS: m/e=188.0 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Br[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:25][C:20]2=[N:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:25][C:20]3=[N:19][CH:18]=2)=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-n2cncn2)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-n4cncn4)c3)cnc2n1

Procedure:
4-Fluoro-3-([1,2,4]triazol-1-yl)phenylboronic acid (100 mg, 0.48 mmol) was coupled to 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (113 mg, 0.44 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 5% methanol then trituration with diethyl ether gave 2-[3-(4-fluoro-3-([1,2,4]triazol-1-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a pink solid: δH (400 MHz, CDCl3) 1.63 (6H, s), 4.31 (1H, s), 7.12 (1H, d, J 7), 7.47-7.57 (2H, m), 7.91 (1H, s), 8.14-8.18 (2H, m), 8.61 (1H, d, J 7), 8.79 (1H, d, J 3); m/z (ES+) 339 (M++H).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([C:26]([F:35])([F:36])[F:25])=[CH:28][CH:29]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: Cl
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [4-(trifluoromethyl)benzyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12-1.21 (m, 5H), 1.44-1.59 (m, 5H), 1.86 (s, 3H), 2.24 (s, 3H), 3.71 (d, J=10.74 Hz, 1H), 4.62 (d, J=4.82 Hz, 2H), 7.50-7.58 (m, 3H), 7.67 (d, J=8.11 Hz, 2H), 8.20 (t, J=5.15 Hz, 1H), 12.99 (bs, 1H); MS (ESI) m/z 379.1 (M+1)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:4][CH2:5][CH3:6]>C(O)C>[CH2:3]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
Aqueous sodium hydroxide (6M, 4 mL, 24 mmol, 2 eq) was added to a solution of ethyl 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyrate (4.1 g, 12.0 mmol, 1.0 eq) in ethanol (50 mL) and stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure, dissolved in water (15 mL) and adjusted to a pH of 4. The precipitate was filtered and dried at 65° C. under vacuum to afford 3.53 g of 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyric acid as a tan powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH2:16][C:17](OC(C)(C)C)=O)=[CH:11][CH:10]=2.[C:24]1([C:30]2[N:35]=[N:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH2:16][C:17]1[N:34]3[N:35]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:31]=[CH:32][C:33]3=[N:36][N:37]=1)=[CH:11][CH:10]=2
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COCCOc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate (0.080 g, 0.25 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.094 g, 0.50 mmol), HYDROCHLORIC ACID (0.063 ml, 0.76 mmol), and water (0.2 mL) as solvent. The vial was sealed and first heated at 90° C. for 30 min then placed into CEM microwave for 15 min. at 140° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and the precipitate was collected via filtration. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removed solvent in vacuo. The crude product was purified using SiO2 chromatography (TELEDYNE ISCO REDISEP®, P/N 68-2203-026, 12 g SiO2, DCM:EtOAc:MeOH=60%:37%:3%, Flow=30 mL/min) to afford the desired product as light yellowish solid. MS m/z: 412.3 (M+H). Calc'd. for C24H21N5O2−411.45.
Reaction SMILES: [NH2:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][C:25]=1[F:36])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[CH2:19][C:20]([O:22]C)=[O:21].[OH-].[Na+].O1CCOCC1>O>[NH2:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][C:25]=1[F:36])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: COC(=O)CC1CN(CCSc2cccs2)CCC1CCC(N)c1c(F)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ncc(F)c(C(N)CCC3CCN(CCSc4cccs4)CC3CC(=O)O)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of 0.355 g of methyl (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate in 1.66-cm3 of a 1 N aqueous sodium hydroxide solution and 5-cm of dioxane was heated at a temperature in the region of 60° C., with stirring, for 2 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. The evaporation residue obtained was taken up in 30-cm3 of water and 30-cm3 of diethyl ether, the aqueous phase was separated after settling out and neutralized with 1.66-cm3 of a 1 N aqueous hydrochloric acid solution and was then extracted twice with 100-cm3 of ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness according to the same conditions above. 0.238 g of (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid were obtained in the form of a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][C:46]([OH:48])=[O:47])[CH2:41][CH2:40]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:39]3[CH2:44][CH2:43][CH:42]([CH2:45][C:46]([OH:48])=[O:47])[CH2:41][CH2:40]3)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: O=C(O)CC1CCNCC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(N3CCC(CC(=O)O)CC3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, Piperidin-4-yl-acetic acid was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give {1-[4-((S)-1-Methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-yl]-piperidin-4-yl}-acetic acid. MS: (ES+): 515
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([NH:34][CH2:33][CH2:31][OH:32])=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Product: O=C(NCCO)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2

Procedure:
2-[4-(2,4-Difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and ethanolamine were reacted in the general amide coupling procedure to give 375. NMR: (CDCl3): 2.72 (1H, s, OH), 3.01-3.04 (2H, m), 3.57-3.61 (2H, m), 3.72-3.81 (2H, m), 4.20-4.23 (2H, m), 6.68-6.72 (1H, m, NH), 6.79 (1H, s, Ar), 6.94 (1H, d, J 8.4, Ar), 7.02-7.06 (2H, m, Ar), 7.33-7.40 (1H, m, Ar), 7.50-7.53 (1H, m, Ar), 7.89-7.90 (1H, m, Ar) and 8.16 (1H, s, Ar). MS: (ESI+) MH+=469.04
Reaction SMILES: CC1C=CC(S([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=4)[N:23]=3)[CH:15]=[CH:16][CH:17]=2)(=O)=O)=CC=1.ClC1C=CC2N(C=C(NC(=O)C)N=2)N=1.NC1C=C(B(O)O)C=CC=1>>[NH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=3)[N:23]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Agent: CC(=O)Nc1cn2nc(Cl)ccc2n1
Agent: Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cn2nc(-c3cccc(N)c3)ccc2n1

Procedure:
Following the procedure described for compound N-(6-(3-(4-methylphenylsulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1, Step 4) (0.071 g, 0.34 mmol) was reacted with 3-aminobenzeneboronic acid (0.094 g, 0.60 mmol, Alfa Aesar, Avocado Organics, Ward Hill, Mass.) to afford the title compound as a yellow solid. MS (ESI positive ion) m/z: 268 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.87 (s, 1H), 8.24 (s, 1H), 8.00 (d, J=9.4 Hz, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.25 (t, J=1.9 Hz, 1H), 7.12-7.19 (m, 2H), 6.69-6.71 (m, 1H), 5.30 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([C:30](Cl)=[O:31])[CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:22]3[CH:21]=[N:20][C:29]4[C:24]([CH:23]=3)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cnc2ccccc2c1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cnc2ccccc2c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-quinolinecarboxamide as a white crystalline solid, m.p. 116.0-118.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 9.24 (d, J=2.1 Hz, 1H), 8.86 (t, J=5.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.25 (s, 1H), 8.09-8.05 (m, 3H), 7.86 (dt, J=7.5, 1.0 Hz, 1H), 7.69 (t, J=7.5 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.5 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 6.68 (s, 2H), 4.67 (t, J=6.9 Hz, 2H), 1.97 (quintet, J=7.2 Hz, 2H), 1.65 (quintet, J=7.2 Hz, 2H); MS (EI) m/e 410.1864 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][C:19](Cl)=[O:20].CN(C)C=O.[H-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:18][C:19]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1CNCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2ccccc2CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 19.0 g of 2-(benzylamino-methyl)-phenol and 75 mL of toluene was cooled to 0° C., and a solution of chloroacetyl chloride (7.8 mL) in 75 mL of toluene was slowly added while stirring. Stirring was continued for 16 h. Dry N,N-dimethylformamide (60 mL) was added and the solution was cooled to 0° C. In a nitrogen atmosphere 3:4 g of sodium hydride (95%; dispersion in mineral oil) were added in small portions and the mixture was allowed to stir at room temperature for 2 h. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent was removed in vacuo yielding 12.4 g of 4-benzyl-4,5-dihydro-benzo[f][1,4]oxazepin-3-one. M.p. 95-97° C.,
Reaction SMILES: [F:1][C:2]1([F:19])[O:7][C:6]2[CH:8]=[CH:9][C:10](C(C(C)C)=O)=[CH:11][C:5]=2[C:4]([F:18])([F:17])[O:3]1.[Cl:20]C(Cl)(Cl)C1C=C(Cl)C=CC=1OC(F)=O.F>>[F:1][C:2]1([F:19])[O:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:20])=[CH:11][C:5]=2[C:4]([F:18])([F:17])[O:3]1
Reactant: CC(C)C(=O)c1ccc2c(c1)C(F)(F)OC(F)(F)O2
Reactant: O=C(F)Oc1ccc(Cl)cc1C(Cl)(Cl)Cl
Agent: F
Product: FC1(F)Oc2ccc(Cl)cc2C(F)(F)O1

Procedure:
For the preparation of a ketone such as isopropyl 2,2,4,4-tetrafluoro-1,3-benzodioxan-6-yl ketone, the procedure disclosed in U.S. Pat. No. 3,632,820 (Jan. 4, 1972), Example 6, is used to prepare the intermediate halobenzodioxane. According to that reference, fluoroformic acid 2-trichloromethyl-4-chlorophenyl ester is allowed to react with anhydrous hydrofluoric acid to yield 2,2,4,4-tetrafluoro-6-chloro-1,3-benzodioxane. This compound can then be utilized to prepare the isopropyl 2,2,4,4-tetrafluoro-1,3-benzodioxan-6-yl or related alkyl or aryl ketones by any of the methods set forth above for the other ketones.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])=[CH:5][C:4]=1[CH:21]=[CH2:22].[H][H]>O1CCCC1.[Pd]>[CH2:21]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:3]=1[O:2][CH3:1])[CH2:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])[CH3:22]
Reactant: C=Cc1cc(CN2C(=O)c3ccccc3C2=O)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cc(CN2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 92.1 %

Procedure:
2.75 g of N-(4-methoxy-3-vinylbenzyl)phthalimide was dissolved in 50 ml tetrahydrofuran, 0.1 g of 10% Pd—C was added thereto, and the mixture was stirred for 40 min in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography to give 2.55 g of N-(3-ethyl-4-methoxybenzyl)phthalimide.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH2:7]([OH:11])[CH2:8][C:9]#[CH:10].[OH:12][CH2:13][C:14]1([CH2:18][CH2:19][CH3:20])[CH2:17][O:16][CH2:15]1.N1C=CC=CC=1>ClCCl.O>[C:1]([O:11][CH2:7][CH2:8][C:9]#[CH:10])(=[O:5])[C:2]([O:12][CH2:13][C:14]1([CH2:18][CH2:19][CH3:20])[CH2:17][O:16][CH2:15]1)=[O:3]
Reactant: C#CCCO
Reactant: CCCC1(CO)COC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: C#CCCOC(=O)C(=O)OCC1(CCC)COC1
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (4.3 ml) was added to a stirred solution of but-3-yn-1-ol (3.5 g) in dry dichloromethane (75 ml), at 0°. The solution was stirred at 0° for 30 minutes and was then added, dropwise to a stirred solution of 3-hydroxymethyl-3-n-propyloxetane (6.4 g) and dry pyridine (30 ml) in dry dichloromethane (75 ml). The mixture was stirred at 20° for 24 hours. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with 5% hydrochloric acid solution, saturated sodium hydrogen carbonate solution and finally water. The ethereal extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. The resulting oil was chromatographed on silica (pre-eluted with 1% triethylamine in hexane), and eluting with 1:1 diethyl ether:hexane. But-3-ynyl (3-n-propyloxetan-3-yl)methyl oxalate was obtained as a colourless oil (7.0 g).