Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH:3]1[C:13]([O:15][CH3:16])=[O:14].Br[CH2:18][CH2:19][CH2:20][Cl:21].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:21][CH2:20][CH2:19][CH2:18][C:3]1([C:13]([O:15][CH3:16])=[O:14])[C:2](=[O:1])[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4]1
Reactant: ClCCCBr
Reactant: COC(=O)C1Oc2ccccc2CCC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1(CCCCl)Oc2ccccc2CCC1=O
Yield: 81.6 %

Procedure:
A mixture of 5.0 g of methyl 3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate, 7.1 g of 1-bromo-3-chloropropane, 1.5 g of potassium iodide, 6.3 g of potassium carbonate and 60 ml of acetonitrile is heated under refluxing for 4 hours. After cooling, the inorganic substances are filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with water and then extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=8:1→2:1), to give 5.5 g of methyl 2-(3-chloropropyl)-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as a colorless oil. Recrystallization from ethanol gives 4.4 g of colorless prisms: m.p. 75°-77° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9](SC)[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[NH:28])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSC(=Nc1cccc(F)c1)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Reactant: N
Product: CC(C)C(c1ccc(NC(=N)Nc2cccc(F)c2)cc1)n1ccnc1
Temperature: 40 °C
Yield: 46 %

Procedure:
A solution of methyl N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-phenyl]carbamimidothioate (0.0094 mol) in NH3/CH30H (60 ml) was stirred and heated in autoclave at 40° C. for 3 days. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.2 to 90.10/0.5). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanone and (C2H5)2O and filtered off, yielding 0.89 g (46%) N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]guanidine (compound 744).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[OH:13])([O-])=O.[H][H]>O>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[OH:13]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: O
Product: Nc1ccc(O)c(N)c1
Reaction time: 2.5 h
Yield: 103.8 %

Procedure:
The process of hydrogenation is conducted in the reactor described in the foregoing Example 10. Into this reactor there are charged 4 g of 2,4-dinitrophenol, poured 100 ml of water and the resulting solution is stirred. Into the tube (membrane catalyst) hydrogen is continuously fed under the pressure of 40 atm at the rate of 10 l/min. The hydrogenation is conducted at the temperature in the reactor of 100° C. for 2.5 hours. After cooling the solution is partially evaporated in vacuum and the precipitated crystals of 2,4-diaminophenol are separated. After recrystallization from acetone there are obtained 2.8 g of 2,4-diaminophenol with the melting point of 79° C. The product yield is 91.5% based on the starting 2,4-dinitrophenol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:28][CH:29]1[CH2:31][CH2:30]1>O>[CH:29]1([CH2:28][N:12]2[CH2:13][CH2:14][CH:15]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=3)[CH2:11]2)[CH2:31][CH2:30]1
Reactant: COc1cccc(C2=CCCNC2)c1
Reactant: ClCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C2=CCCN(CC3CC3)C2)c1
Temperature: 75 °C

Procedure:
A mixture of 10 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine hydrochloride, 100 ml of dimethylformamide, 14 g of sodium carbonate and 4.4 ml of chloromethyl cyclopropane was heated at 75° C. for 24 hours and was then cooled and diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-1-1 cyclohexane-chloroform-triethylamine mixture to obtain 9.25 g of 1-cyclopropylmethyl-3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15](/[N:17]=[CH:18]\[N:19](C)C)=O)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.C(O)(=O)C.O.[NH2:27]N>>[Br:1][C:2]1[S:3][C:4]([C:15]2[NH:17][CH:18]=[N:19][N:27]=2)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1
Reactant: NN
Reactant: CN(C)/C=N\C(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(Cc2nc(Br)sc2-c2nnc[nH]2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In a 250 mL round bottomed flask were placed 2-bromo-4-(4-chlorobenzyl)-N-[(1Z)-(dimethylamino)methylene]-1,3-thiazole-5-carboxamide and acetic acid (50 mL, 900 mmol). Hydrazine hydrate (490 uL, 10 mmol) was added and the mixture was stirred for 1 h at 50° C. The mixture was allowed to cool to rt, then was concentrated under reduced pressure to obtain 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-4H-1,2,4-triazole as a yellowish off-white crystalline solid. The crude material was used in the next step without further purification. LC/MS (FA) ES+ 357.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].O.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[N:24]=[CH:25][N:26]([C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH:27]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(COc1noc2ccc(Cl)cc12)Cc1c[nH]cn1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)n1cnc(CC(COc2noc3ccc(Cl)cc23)NC(=O)OC(C)(C)C)c1
Yield: 141.1 %

Procedure:
To a solution of 0.12 g of 3-[2-tert-butoxycarbonylamino-3-(4-imidazolyl)propoxy]-5-chloro-1,2-benzoisoxazole in 3 ml of pyridine is added 0.05 g of dimethylcarbamoyl chloride at room temperature, and they are subjected to reaction at 50° C. for two hours. After cooling, water and ethyl acetate are added and shaken, and the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and the solvent is removed by distillation under reduced pressure, to obtain 0.2 g of oily 3-[2-tert-butoxycarbonylamino-3-(1-dimethylcarbamoyl-4-imidazolyl)propoxy]-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:22])=[C:12]([NH:14]C(=O)OC(C)(C)C)[CH:13]=2)[N:4]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[F:43][C:44]1([F:51])[C:47]([F:49])([F:48])[CH2:46][CH:45]1O>ClCCl.O>[CH3:22][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[N:4]=[C:3]([CH2:2][O:1][CH:46]3[CH2:45][C:44]([F:51])([F:43])[C:47]3([F:49])[F:48])[O:7][N:6]=2)=[CH:13][C:12]=1[NH2:14]
Reactant: OC1CC(F)(F)C1(F)F
Reactant: Cc1ccc(-c2noc(CO)n2)cc1NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(COC3CC(F)(F)C3(F)F)n2)cc1N
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl (5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)carbamate (137) (0.35 g, 1.15 mmol) was dissovled in dichloromethane (5 mL) and followed by addition of DIEA (0.6 mL, 3.45 mmol) and MsCl (197 mg, 1.72 mmol). The reaction was stirred for 10 minutes. The mixture was diluted with dichloromethane (10 mL) and washed with water. The organic layers were combined, dried over Na2SO4, filtered and concentrated to give a residue which was dissolved in 2,2,3,3-tetrafluorocyclobutanol (2 mL) and followed by addition of K2CO3(476 mg, 3.45 mmol). The reaction mixture was heated at 90° C. for 2-3 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. To this residue was added TFA (1 mL) and stirred for 15 minutes. Then aqueous Na2CO3(2M, 20 mL) was added and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel gave 2-methyl-5-(5-((2,2,3,3-tetrafluorocyclobutoxy)methyl)-1,2,4-oxadiazol-3-yl)aniline (138). 1H NMR (400 MHz, CDCl3) δ 9.36 (bs, 2H), 8.12 (d, J=1.2 Hz, 1H), 7.91 (dd, J=1.2, 8.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 4.95 (dd, J=14.4, 68.4 Hz, 2H), 4.51 (m, 1H), 2.95 (m, 1H), 2.51-2.68 (m, 4H). MS m/z 332.0 (M+1)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.Cl([O-])(=O)(=O)=O.[CH2:22]1[C:29]2[CH2:28][CH2:27][CH2:26][N+:25]=2[CH2:24][CH2:23]1.Cl>C1COCC1.CCOC(C)=O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:29]23[CH2:28][CH2:27][CH2:26][N:25]2[CH2:24][CH2:23][CH2:22]3)[CH:8]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Brc1cnc2ccccc2c1
Agent: Cl
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc2ncc(C34CCCN3CCC4)cc2c1
Temperature: -100 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A solution of 2.5M nBuLi (1.2 mL, 2.8 mmol) in hexanes was added to 3-bromoquinoline (386 μL, 2.8 mmol) in THF (10 mL) at -100° C. followed immediately by 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (200 mg, 0.9 mmol). The reaction mixture was allowed to stir for 2 hours at -100° C. and then 2N HCl was added at 0° C. After warming to ambient temperature, the mixture was poured over EtOAc and the phases were separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (3×). The organic fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; EtOAc) to afford a pale solid (104 mg, 46%). mp 80°-83° C. MS (CI/NH3) m/e: 239 (M+H)+. 1 H NMR (CDCl3, 300 MHz) δ1.61-1.75 (m, 2H), 1.83-1.94 (m, 2H), 2.03-2.17 (m, 4H), 2.71-2.80 (m, 2H), 3.20-3.27 (m, 2H), 7.52 (ddd, J=7.0, 7.0, 1.1 Hz, 1H), 7.65 (ddd, J=7.0, 7.0, 1.5 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 8.32 (d, J=2.2, Hz, 1H), 8.97 (d, J=2.2 Hz, 1H).
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH3:12][Si:13]([CH3:17])([O:15][CH3:16])Cl>C1(C)C=CC=CC=1.C1COCC1>[C:1]([Si:13]([CH3:17])([CH3:12])[O:15][CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[Si](C)(C)Cl
Reactant: CC(C)(C)[Mg]Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CO[Si](C)(C)C(C)(C)C
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To the silane mixture comprising dimethylmethoxychlorosilane as produced by the disproportionation reaction in (a) above, was added 150 ml of toluene to dissolve the silanes in toluene, and to give a toluene solution of said silane mixture. To the toluene solution was added dropwise the THF solution of tert-butyl magnesium chloride as produced in Example 20, through a dropping funnel, at 40° C.-50° C. over 1 hour. Then, the resulting mixture was stirred at 70° C. for 4 hours. The Grignard reagent could react with dimethylmethoxychlorosilane contained in the said toluene solution, to produce tert-butyldimethylmethoxysilane.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2([C:17](OCC)=[O:18])[CH2:12][CH2:11][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:8]2)=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([CH2:12][CH2:11][CH:10]([C:13]([F:15])([F:14])[F:16])[CH2:9][CH2:8]3)[C:17]2=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(Cc2ccc(Br)cc2I)CCC(C(F)(F)F)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCC(C(F)(F)F)CC2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
Ethyl 1-(4-bromo-2-iodobenzyl)-4-(trifluoromethyl)cyclohexanecarboxylate (Intermediate 77, 2.41 g, 4.64 mmol) was dissolved in THF (40 mL). The atmosphere was exchanged to argon, and the solution was cooled to −78° C. Isopropylmagnesium chloride—lithium chloride (1.3 M in THF) (2.86 mL, 3.71 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. The reaction mixture left to warm up to r.t., while stirred for 30 min. The reaction mixture was quenched with sat. NH4Cl. Brine was added, and the phases were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative chromatography (XBridge C18 (10 μm, 50×250 mm) column with a gradient of 50-100% MeCN) in (95% 0.05M NH4OAc in MilliQ water and 5% MeCN) over 15 min at a flow rate of 100 mL/min). The purification provided the title compound (0.849 g, 52% yield): 1H NMR (400 MHz, CDCl3) δ ppm 1.51-1.61 (m, 3H) 1.75-1.84 (m, 2H) 1.97 (m, 2H) 2.18 (m, 2H) 2.90 (s, 2H) 7.29 (dd, 1H) 7.69 (dd, 1H) 7.84 (d, 1H); MS (ES+) 346 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[C:12]([CH3:16])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]([CH3:16])[C:13]=2[CH2:14][OH:15])=[C:4]([F:17])[CH:3]=1
Reactant: Cc1nccc(-c2ccc(Cl)cc2F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nccc(-c2ccc(Cl)cc2F)c1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 248.3 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)-2-methylnicotinaldehyde (60 mg, 0.240 mmol) in MeOH (2 mL) at 0° C., was added NaBH4 (27.3 mg, 0.721 mmol) and the solution stirred for 3 h at RT. The mixture was concentrated and diluted with EtOAc (15 mL) and water (10 mL). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford (4-(4-chloro-2-fluorophenyl)-2-methylpyridin-3-yl)methanol (0.15 g, 0.596 mmol, 89% yield) as a brown solid. LCMS (ESI) m/e 252.03 [(M+H)+, calcd for C13H12ClFNO 252.1]; LC/MS retention time (Method G): tR=0.80 min.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].O>CN(C=O)C>[F:7][C:6]([F:9])([F:8])[C:5]([N:4]([CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12])[CH3:3])=[O:10]
Reactant: C=CCCCCBr
Reactant: CNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCCN(C)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 31.5 g, 1.28 eq.) was slowly added under nitrogen atmosphere to a solution of N-methyl-2,2,2-trifluoroacetamide (100 g, 1.28 eq.) in DMF (500 mL) at 0° C. The reaction mixture was stirred for 90 min at 0° C., and then 6-bromo-1-hexene (100 g, 1 eq.) was added dropwise over 45 min. The reaction mixture was allowed to warm up to room temperature, and stirred for 3 days at room temperature. The reaction mixture was then poured into water and extracted tree time with EtOAc. The combined organics layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to produce compound 31a as colorless oil in 56% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.27-1.38 (m, 2H), 1.48-1.60 (m, 2H), 2.00-2.06 (m, 2H), 2.93-3.07 (2m, 3H), 3.35-3.40 (m, 2H), 4.92-5.04 (m, 2H), 5.73-5.83 (m, 1H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:67])[CH:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:66][CH:63]5[CH2:64][CH2:65][CH:60]([N:59]([CH3:67])[CH3:58])[CH2:61][CH2:62]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCC(N(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N1,N1-dimethylcyclohexane 1,4-diamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.96 (m, 18 H) 2.17 (s, 6 H) 3.31 (s, 3 H) 3.73 (m, 1 H) 3.92 9m, 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.52 Hz, 2 H) 4.46 (m, 1 H) 7.42-7.59 (m, 2 H) 7.89 (s, 1 H) 8.11 (m, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.34 Hz, 1 H). Melting point: 208-214° C. [M+H] calculated for C30H41F2N7O3, 586; found 586.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.[C:15]([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4][C:9](=[CH:23][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[CH:26][CH:25]=2)[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C=C2NC(=O)CN(C(C)=O)C2=O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
1,4-Diacetyl-2,5-piperazinedione (10.0 g, 50 mmol), prepared by the published procedure mentioned in Reference Example 1, was stirred in DMF (40 ml) with 4-acetamidobenzaldehyde (8.24 g, 50 mmol) and triethylamine (7 ml, 50 mmol) and heated to 120° C. After 2% h the mixture was cooled to room temperature, diluted with EtOAc (100 ml) and stirred overnight. The solid formed was collected, washed with EtOAc and dried to give 8.46 g (56%) of a yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([CH2:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:33]([C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:34]
Reactant: C1CCNC1
Reactant: CCc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Product: CCc1cc(Nc2ncnc3[nH]nc(OCCN4CCCC4)c23)ccc1OCc1ccccn1
Yield: 57 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-ethyl-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 19) and pyrrolidine to give the title compound in 57% yield; NMR Spectrum: 1.29 (t, 3H), 1.64-1.67 (m, 4H), 2.52-2.54 (m, 4H), 2.65 (q, 2H), 2.86 (t, 2H), 4.40 (t, 2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.36 (m, 2H), 7.48-7.54 (m, 2H), 7.85 (td, 1H), 8.23 (s, 1H), 8.38 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 460 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])(=[O:3])[CH3:2].[C-]#N.[Na+].[C:16](#[N:20])/[CH:17]=[CH:18]/[CH3:19]>CN(C)C=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]([CH:18]([CH3:19])[CH2:17][C:16]#[N:20])=[O:9])(=[O:3])[CH3:2]
Reactant: C/C=C/C#N
Reactant: CC(=O)Oc1cccc(C=O)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(C(=O)C(C)CC#N)c1

Procedure:
3-Acetoxybenzaldehyde was treated with sodium cyanide and crotononitrile in dimethylformamide in a similar manner to that described in Example 14(i) to give 3-(3-acetoxybenzoyl)-butyronitrile.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[NH:7]1[C:3]([CH2:2][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][N:5]=[N:6]1
Reactant: C1COCCN1
Reactant: ClCc1nnn[nH]1
Product: C1CN(Cc2nnn[nH]2)CCO1
Yield: 80.6 %

Procedure:
A solution of 5-(chloromethyl)-1H-tetrazole (260 mg, 2.2 mmol) in morpholine (1.5 mL, 17.2 mmol) was stirred at 25° C. for 20 minutes. The crude reaction mixture was purified by preparative LCMS using pH 2 buffer to yield the desired product (300 mg, 82%). MF═C6H11N5O; LCMS calculated for C6H12N5O(M+H)+: m/z=170.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=O)[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:30]>C1(C)C=CC=CC=1>[Cl:30][C:9]1[N:10]=[N:11][CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=c1[nH]ncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cnnc(Cl)c2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
4,5-Bis(4-chlorophenyl)pyridazin-3(2H)-one (16.5 g, 52.2 mmol) was suspended in toluene (50 mL). To the resultant solution was added pyridine (8.3 mL, 104.4 mmol), followed by the addition of POCl3 (14.3 mL, 156.6 mmol). The reaction mixture was placed in an oil bath preheated at 110° C. After 4 h, the reaction mixture was cooled to RT, then poured over 500 g ice to quench the excess POCl3. The dark mixture was extracted with EtOAc (2×300 mL). The combined organic layers were washed with water (500 mL), and filtered through a silica gel pad (˜50 g). The filtrate was concentrated under reduced pressure to give the title compound, 3-chloro-4,5-bis(4-chlorophenyl)pyridazine as a pale colored solid (16.0 g, 92%). MS: M+H=335. 1H NMR (CDCl3, 500 MHz): δ 9.24(1H, s), 7.35 (2H, d, J=10 Hz), 7.26 (2H, d, J=10.0 Hz), 7.08–7.16 (4H, m).