Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[C:16]([F:25])[C:17]([F:24])=[C:18]([F:23])[CH:19]=2)[NH:14][CH:13]=1)=[O:11])C.Br[CH2:27][CH2:28][F:29].[I-].[Na+]>CN(C=O)C>[F:23][C:18]1[CH:19]=[C:20]2[C:15](=[C:16]([F:25])[C:17]=1[F:24])[N:14]([CH2:27][CH2:28][F:29])[CH:13]=[C:12]([C:10]([OH:9])=[O:11])[C:21]2=[O:22]
Reactant: FCCBr
Reactant: CCOC(=O)c1c[nH]c2c(F)c(F)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 10 h
Yield: 39.9 %

Procedure:
Anhydrous potassium carbonate (2.2 g), 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (0.8 g), 1-bromo-2-fluoroethane (3.8 g), sodium iodide (4.5 g), and DMF (30 ml) were combined and heated with stirring at 90°-100° C. for 10 hours. After the solvent evaporated and cooled, water was added to the residue and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. To the residual solid was added a mixture of 18% hydrochloric acid (14 ml) and ethanol (7 ml) and the acidic mixture was refluxed for 2.5 hours. Water (14 ml) and ethanol (14 ml) were added to the reaction mixture and cooled. The precipitate was collected by filtration and recrystallized from a mixture of DMF and ethanol to give 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.34 g), mp 208°-210° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([OH:8])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:3]=1.CCN(CC)CC.[O:23](S(C(F)(F)F)(=O)=O)[S:24]([C:27]([F:30])([F:29])[F:28])(=O)=[O:25]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[S:24]([O:8][C:5]1[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])(=[O:25])=[O:23]
Reactant: Cc1cccc(-n2nc(C)c(C)c2O)n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-n2nc(C)c(C)c2OS(=O)(=O)C(F)(F)F)n1
Temperature: -78 °C
Yield: 74.8 %

Procedure:
To the 500 mL round-bottomed flask with 3,4-dimethyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-ol (6.68 g, 33 mmol) were added Et3N (5.5 mL, 39 mmol) and 35 mL CH2Cl2. the solution was cooled in dry ice acetone bath. Tf2O (6.1 mL, 36 mmol) was added slowly. The mixture was stirred at −78° C. and allowed to warm to room temperature. The mixture was then concentrated in vacuo. The crude product was purified using a Biotage Horizon System (0 to 25% EtOAc/hexane) to afford a colorless oil (8.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:7](=[O:21])[CH:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[NH:9][C:10](=O)[C:4]=2[CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:44])=O>C1(C)C=CC=CC=1>[Cl:44][C:10]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:32]=[CH:31][C:5]=2[N:6]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:7](=[O:21])[CH:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)NC(=O)c3cc(Cl)ccc32)cc1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
7-Chloro-3-(2-chlorophenethyl)-1-(4-methoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (950 mg) was dissolved in toluene (20 mL) and then N,N-dimethylaniline (564 mg, 2.3 eq) was added followed by phosphorous-oxychloride (403 mg, 1.3 eq). The reaction was heated to 90° C. overnight, then cooled to room temperature and washed with ice cold water, then cold 0.5 M HCl, then cold sodium bicarbonate, then cold water, then brine, and then it was dried over sodium sulfate, and filtered through a plug of silica gel (eluting with 1:1 hexanes:EtOAc), and concentrated, and held under vacuum for 24 h. Crude product was a viscous purple oil. 1H-NMR (300 MHz, CDCl3) δ 7.70 (d, 1H), 7.40 (dd, 1H), 7.30-7.22 (m, 2H), 7.20-7.07 (m, 2H), 7.00 (d, 2H), 6.81-6.70 (m, 3H), 5.28 (d, 1H), 4.82 (d, 1H), 3.75 (s, 3H), 3.55 (t, 1H), 2.95 (s, 2H), 2.90-2.79 (m, 2H), 2.55-2.45 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C:15]1[N:19]([CH2:20][CH3:21])[N:18]=[CH:17][CH:16]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH2:20]([N:19]1[C:15]([NH:14][C:2]2[C:3](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:16][CH:17]=[N:18]1)[CH3:21]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCn1nccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCn1nccc1Nc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A mixture of 2-chloro-5-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2CO3 (2.76 g, 0.02 mol) and Cu(OAc)2H2O (0.5 g) is refluxed for 24 hours. The reaction mixture is cooled to room temperature, poured into ice waterl and acidified with acetic acid to a pH of 5. A solid forms which is collected by filtration and dried to afford 3.8 g (68%) of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[C:24]([OH:26])=O)[C:5]([N+:27]([O-])=O)=[CH:4][CH:3]=1>[Fe].C(O)(=O)C>[C:14]([N:11]1[CH2:12][CH2:13][N:8]2[C:6]3[N:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[NH:27][C:24](=[O:26])[CH:9]2[CH2:10]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1nc(F)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2ccc(F)nc2N2CCN(C(=O)OCc3ccccc3)CC12

Procedure:
To a solution of 14.0 g. of 1-(6-fluoro-3-nitro-2-pyridinyl)-4-carbobenzoxypiperazine-2-carboxylic acid in 300 ml. of acetic acid is added, while stirring, 7.0 g. of iron powder. The mixture is warmed to 55° for 3 hours then concentrated. The residue is treated with water and extracted with methylene chloride, dried (MgSO4) and concentrated. The residue is placed on a dry column of alumina and eluted with chloroform. The product band in the column is cut out and the product is washed from the alumina with methanol. Concentration of the methanol wash gives 5.0 g. of the light green-colored title product. Recrystallization from ethanol gives 2.2 g. of pure product, m.p. 210°-214°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][S:12](=[O:15])(=[O:14])[N:11]=[C:10](SC)[NH:9]2)=[CH:4][CH:3]=1.[OH-:18].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][S:12](=[O:15])(=[O:14])[NH:11][C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CSC1=NS(=O)(=O)CC(c2ccc(Cl)cc2)N1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1NC(c2ccc(Cl)cc2)CS(=O)(=O)N1

Procedure:
Using a method similar to that described by K. Hasegawa and S. Hirooka (Bull. Chem. Soc. Jap., 1972, 45, 1893), 5-(4-chlorophenyl)-3-methylsulfanyl-5,6-dihydro-4H-[1,2,4]thiadiazine 1,1-dioxide DE2 in acetone is treated with 1N NaOH and the mixture is refluxed for 2 h. The acetone is evaporated and the mixture is acidified with conc. HCl to afford the title compound DE3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[C:18]([Cl:26])[C:17]=1[CH2:27]OS(C)(=O)=O.O>CN(C)C=O>[Cl:15][C:16]1[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[C:18]([Cl:26])[C:17]=1[CH2:27][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: COCOc1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Reaction time: 1 h

Procedure:
A solution of 8-hydroxy-2-methylquinoline (737 mg) in dimethylformamide was dropwise added to a solution of sodium hydride (60% in oil, 185 mg) in dimethylformamide under ice-bath cooling, and the mixture was stirred for 1 hour at the same temperature. To the mixture was added 2,6-dichloro-1-methylsulfonyloxymethyl-3-(methoxymethoxy)benzene (1.46 g) under ice-bath cooling, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to give 8-[2,6-dichloro-3-(methoxymethoxy)-benzyloxy]-2-methylquinoline as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][NH:11][N:10]=2)[CH:8]=1)#[N:2].Cl.Cl[CH2:30][C:31]1[N:35]=[CH:34][N:33]([CH3:36])[N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:30][C:31]3[N:35]=[CH:34][N:33]([CH3:36])[N:32]=3)[N:10]=2)[CH:8]=1)#[N:2]
Reactant: COc1ccc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Reactant: Cn1cnc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1-c1nn(Cc2ncn(C)n2)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.5 %

Procedure:
N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.15 g, 0.42 mmol) was dissolved in 10 mL of DMF, then 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (82 mg, 0.63 mmol) and Cs2CO3 (0.41 g, 1.26 mmol) were added. The mixture was stirred at room temperature for 2 hours, then filtered through celite and purified by reverse phase HPLC to give 44.8 mg (23%) of N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=455.1; 1H NMR (400 MHz, CDCl3) δ: 9.64 (s, 1H), 9.34 (d, 1H), 8.75 (d, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.95 (d, 1H), 7.73 (d, 1H), 7.47 (d, 1H), 7.28 (dd, 1H), 5.39 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH3:9])(=[O:7])=[O:6].[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:10]([CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH3:9])(=[O:7])=[O:6])=[N+:11]=[N-:12]
Reactant: CNS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)CCCN=[N+]=[N-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 3-chloro-N-methylpropane-1-sulfonamide (29 mmol), NaN3 (29 mmol) in DMF (50 ml) was stirred at 100° C. for 2 h. The mixture was poured into 40 ml of brine. The mixture was extracted with ether (3×30 ml). The organic layers were combined and washed with 20 ml of brine. The organic layer was dried with Na2SO4, filtered and the filtrate was evaporated. Yield: 4.2 g (90% purity, 81% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:2]=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)=[N:5][CH:6]=1)#[N:9]
Reactant: CCCCCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
5.7 G. of 4-chloro-5-cyano-2-(4-n-hexylphenyl)-pyrimidine are reacted in 250 ml. of 50% dioxane with 21.9 g. of pre-treated zinc dust and worked up after the reaction in a manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-n-hexylphenyl)-pyrimidine as colorless crystals having a melting point of 86.3°-87.8° C. (smectic); nematic at 101.3° C; clearing point 102.6°-103.2° C. The substance is identical with the compound obtained according to Example 10.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)C#N)=[CH:4][CH:3]=1.OS(O)(=O)=O.O.[C:25]([O-:28])([O-])=[O:26].[Na+].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[C:25]([OH:28])=[O:26])=[CH:4][CH:3]=1
Reactant: CN1CCC(CC(C#N)c2ccc(Br)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCC(CC(C(=O)O)c2ccc(Br)cc2)CC1

Procedure:
The oily residue of 2-(4-bromo-phenyl)-3-(1-methyl-piperidin-4-yl)-propionitrile was hydrolyzed by refluxing for 2 h with 4 mL of concentrated H2SO4 and water (38:28). The mixture was neutralized with Na2CO3, then MeOH (20 mL) was added. The solid was filtered and washed with MeOH (3×10 mL). The combined methanol solution was evaporated to give an oil. MS: calc'd 326 (MH+), exp 326 (MH+).
Reaction SMILES: N1C2C=CC=CC=2N=C1.[OH-].[Na+].C1(C)C=CC=CC=1.[Na:19].[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:29]=[C:28]([S:30]([CH2:32][C:33]3[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=3)=[O:31])[NH:27][C:26]=2[CH:43]=1>C(C(C)=O)C>[Na:19].[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:29]=[C:28]([S@:30]([CH2:32][C:33]3[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=3)=[O:31])[NH:27][C:26]=2[CH:43]=1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of 650 mg (1.89 mmol) of (+)-(5)6-methoxy-2-[1(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole in 6.5 mL of methyl ethyl ketone (MEK) in a 50 mL flask was added at ambient temperature 0.39 mL of a 5M aqueous sodium hydroxide solution. To that mixture was added 13 mL of toluene. The resulting mixture was turbid, so an additional 6.5 mL of MEK was added and the mixture became a clear, yellow solution. This mixture was allowed to stir at ambient temperature overnight. The following morning, several crystals of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole sodium salt were added to act as seed crystals, but no product crystals formed. A stream of dry nitrogen gas was blown over the mixture to begin removing the solvent. After approximately 10 minutes, the product precipitated. The solids were isolated by vacuum filtration and washed with a small amount of diethyl ether. The solids were then placed into a vacuum desiccator to remove the last traces of ether, to yield approximately 500 mg of the desired product as an off-white powder.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[ClH:34].[NH2:35][C:36]1[CH:37]=[C:38]([C:42]2[C:50]3[S:49][C:48]([C:51]([NH:53][C@@H:54]4[CH:59]5[CH2:60][CH2:61][N:56]([CH2:57][CH2:58]5)[CH2:55]4)=[O:52])=[CH:47][C:46]=3[CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:40][CH:41]=1.[CH3:62][O:63][CH2:64][C:65](O)=[O:66]>CN(C=O)C>[ClH:34].[N:56]12[CH2:57][CH2:58][CH:59]([CH2:60][CH2:61]1)[C@@H:54]([NH:53][C:51]([C:48]1[S:49][C:50]3[C:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][C:65](=[O:66])[CH2:64][O:63][CH3:62])[CH:37]=4)=[CH:43][CH:44]=[CH:45][C:46]=3[CH:47]=1)=[O:52])[CH2:55]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
96.4 mg (0.25 mmol) of HATU and 71.5 μl (0.41 mmol) of N,N-diisopropylethylamine are added to a solution of 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 81) and 18.5 μl (0.24 mmol) of methoxyacetic acid in 0.5 ml of DMF at 0° C. The mixture is stirred at room temperature for 3 h. Purification by preparative HPLC is followed by concentration of the product fractions and, after addition of a 3:1 mixture of acetonitrile and 1N hydrochloric acid, concentration again. Drying under high vacuum results in 7 mg (11% of theory) of the title compound.
Reaction SMILES: N1CCCNCC1.O1C=CC=C1C(Cl)=O.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[O:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]([N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]
Reactant: O=C(c1ccco1)N1CCCNCC1
Agent: C1CNCCNC1
Agent: O=C(Cl)c1ccco1
Product: O=C(C1CCCO1)N1CCCNCC1

Procedure:
In the illustrated reactions, the compound of Formula II is prepared by reacting hexahydro-1,4-diazepine with furoyl chloride in an acid solution. The resultant 1-(2-furoyl)-hexahydro-1,4-diazepine is hydrogenated to produce 1-(tetrahydro-2-furoyl)-hexahydro-1,4-diazepine which is reacted with 2-chloro-4-amino-6,7-dimethoxyquinazoline in the presence of methoxy ethanol to give the compound 2-[4-(tetrahydro-2-furoyl)-hexahydro-1,4-diazepinyl-1]-4-amino-6,7-dimethoxy quinazoline. The hydrochloride salt is prepared by acidifying with hydrogen chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:32][C:33]1[N:37]([CH2:38][C:39](O)=[O:40])[N:36]=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][N:37]3[C:33]([CH3:32])=[CH:34][C:35]([C:42]([F:45])([F:44])[F:43])=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)Nc1cncc(C(=O)c2cn(C(C)(C)CO[Si](C)(C)C(C)(C)C)c3c(F)cncc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79.1 μmol), (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (22 mg, 106.9 μmol) and DIPEA (48 μL, 276.8 μmol) in THF (3 mL), T3P (166 μL, 276.8 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (70%, 37 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:8]3[C:9]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[N:26][OH:27])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl.Cl.COC1C=CC2C3C(N4CCNCC4)=NC4C(C=3C(=O)C=2C=1)=CC=CC=4.C(C1OC1)Cl>>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:27][N:26]=[C:6]1[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:8]=2[C:23]2[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]1=2
Reactant: COc1ccc2c(c1)C(=NO)c1c-2c(N2CCNCC2)nc2ccccc12
Reactant: CN(C)CCCl
Agent: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Agent: Cl
Solvent: ClCC1CO1
Product: COc1ccc2c(c1)C(=NOCCN(C)C)c1c-2c(N2CCNCC2)nc2ccccc12

Procedure:
9-Methoxy-6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one O-2-(dimethylamino)ethyl oxime (6r) was prepared substantially according to the procedures as set forth in the above Synthesis Example 18, except that compound 6p and 2-dimethylaminoethyl chloride·HCl were used in place of compound 5x and epichlorohydrin, respectively, giving the title compound at a yield of 45%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[S:17][C:10]=12.[OH:25][C:26]([CH3:45])([CH3:44])[CH2:27][N:28]1[C:32]([CH3:33])=[C:31]([C:34](O)=[O:35])[C:30](=[O:37])[N:29]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:34]([C:31]2[C:30](=[O:37])[N:29]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:28]([CH2:27][C:26]([OH:25])([CH3:45])[CH3:44])[C:32]=2[CH3:33])=[O:35])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[S:17][C:10]=12
Reactant: Cc1noc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2cc3nccc(Oc4ccc(NC(=O)c5c(C)n(CC(C)(C)O)n(-c6ccccc6)c5=O)cc4F)c3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
A 16 mm sealed tube was charged with 3-fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine (0.0740 g, 0.22 mmol), 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (0.094 g, 0.32 mmol), EDC (0.062 g, 0.32 mmol), HOBT (0.033 g, 0.22 mmol), Hunig's Base (0.13 ml, 0.76 mmol), and DMF (1.00 ml), sealed, and stirred at room temperature for 18 hours. LC/MS analysis indicated the presence of remaining 3-fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine, so additional 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (0.031 g, 0.11 mmol) was added and the reaction mixture was stirred at 50° C. for 8 hours. The flask was allowed to cool to room temperature, the mixture was diluted with chloroform (25 mL), then washed with water (25 mL), sat. aq. NaHCO3 (25 mL), and brine (25 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield a tan oil. The product was purified by silica gel chromatography eluting with 3% methanol in methylene chloride. The isolated yellow solid was triturated with EtOAc to yield N-(3-fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.035 g, 26% yield). MS (ESI pos. ion) m/z: 615 (MH+). Calc'd exact mass for C8H4ClNO2S: 614. 1H NMR (400 MHz, DMSO-d6) 11.00 (s, 1 H), 8.68 (d, J=5.31 Hz, 1 H), 8.49 (s, 1 H), 7.96-8.04 (m, 1H), 7.43-7.60 (m, 4 H), 7.35 (d, J=8.21 Hz, 3 H), 6.89 (d, J=5.31 Hz, 1 H), 4.84 (s, 1 H), 3.87 (s, 2 H), 2.80 (s, 3 H), 2.46 (s, 3 H), 0.96 (s, 6 H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[C:8](Cl)(=[O:10])[CH3:9].C([O-])([O-])=O.[K+].[K+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([O:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: O=C1OCCC1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A mixture of racemic α-hydroxy-γ-butyrolactone (25 g; 0.25 mol), DMAP (1.5 g), acetylchloride (25.5 ml; 0.37 mol) in CH2Cl2 (325 mL) was added solid K2CO3 (50 g) in portions (slightly exothermic). The reaction mixture was stirred at room temperature overnight, filtered and evaporated to dryness. Column chromatography (Petrol ether 80-100:EtOAc=2:1) gave 26.4 g (75%) racemic α-acetoxy-γ-butyrolactone.