Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:35])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[N:25](COCC[Si](C)(C)C)[CH:24]=[N:23][C:22]=3[Cl:34])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:35])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:34])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (120 mg, 0.192 mmol) in DCM (5 ml) was added TFA (1.0 mL) and the mixture was stirred at room temperature for 3 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (78 mg, 0.158 mmol, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (d, 1H), 8.02-8.42 (m, 1H), 7.73 (s, 1H), 7.41-7.54 (m, 1H), 7.32 (t, 1H), 7.08-7.15 (m, 1H), 6.95-7.06 (m, 1H), 4.49 (d, 2H). LC-MS (ES+) m/z 491.87, [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15]Br)[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S-:21].[Na+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][S:21][CH3:20])[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (1.0 g, 3.1 mmol) in 20 mL DMF is added sodium thiomethoxide (228 mg, 3.26 mmol). The solution is stirred at RT for 2 h then water is added and the mixture is extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as a yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.C[C:24]#[N:25].O>CN(C)C=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:16]1[C:12]2([CH2:17][CH2:18][CH:9]([O:8][C:6]3[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=[C:2]([C:24]#[N:25])[CH:7]=3)[CH2:10][CH2:11]2)[O:13][CH2:14][CH2:15]1
Reactant: FC(F)(F)c1nc(Cl)cc(OC2CCC3(CC2)OCCO3)n1
Reactant: CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 140 °C

Procedure:
4-Chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine (described in Example 1, Step 1) (27.1 mg, 0.0800 mmol) was stirred in N,N-dimethylformamide (1.3 mL). Zinc cyanide (23 mg, 0.20 mmol) was adde, followed by tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0096 mmol). The solution was flushed with nitrogen (subsurface). The vial was sealed, and the solution was heated at 140° C. for 10 minutes in a microwave reactor. LCMS showed no remaining starting material and showed a new peak that did not ionize. The product was isolated by preparative LC using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column; 62% CH3CN—H2O (0.1% TFA), 0.5 min, 4.5 min gradient to 82%; 60 mL/min; detector set at 254 nm; retention time=3.8 min. The solvent was removed by rotary evaporation to give 21 mg. 1H NMR (400 MHz, acetone-d6): δ 7.78 (s, 1H); 5.41 (m, 1H, OCH); 3.94 (s, 4H, OCH2); 1.9-2.1 (m, 4H); 1.83 (m, 2H); 1.67 (m, 2H). 13C NMR (100 MHz, acetone-d6): δ 171.6 (s, OC); 142.1 (s, C—N); 117.8 (s, CH); 115.8 (s, CN); 108.2 (s, O2C); 76.1 (s, OCH); 65.0 (s, OCH2); 31.7 (s, CH2); 28.6 (s, CH2); two quartets were not resolved due to insufficient number of scans. The compound of Example 54 was then obtained by following the steps described for Example 45.
Reaction SMILES: [O:1]([CH:9]([C:39]([F:47])([F:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17]C2CCCCO2)[CH2:15][C:14](=[O:24])[CH:13]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[Si](C(C)(C)C)(C)C.F>C(#N)C>[F:46][C:39]([F:47])([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@H:9]([OH:1])[CH2:10][CH2:11][C@H:12]1[C@H:16]([OH:17])[CH2:15][C:14](=[O:24])[CH:13]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34]
Reactant: CCCCCCC(F)(F)C(CC[C@@H]1C(CCCCCCCCC(=O)OC(C)C)C(=O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Product: CCCCCCC(F)(F)[C@H](O)CC[C@@H]1C(CCCCCCCCC(=O)OC(C)C)C(=O)C[C@H]1O

Procedure:
The compound (12-11) (0.93 g) was hydrolyzed in acetonitrile (30 ml) with 46% hydrofluoric acid (1.55 ml). The crude product obtained by the conventional treatment was purified by silica gel chromatography (n-hexane/ethyl acetate=7/3-1/1), and the compound obtained was further fractionated by HPLC to give isopropyl 9-{2(R)-4,4-difluoro-3(R)-hydroxydecyl]-3(R)-hydroxy-5-oxocyclopentyl}nonanoate (12-12).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH3:2].[OH-].[Na+]>CO.O>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH3:20]
Reactant: CCOC(OCC)c1cc2ccc(C(=O)OC)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1cc2ccc(C(=O)O)cc2o1
Reaction time: 96 h
Yield: 103.4 %

Procedure:
Methyl 2-(diethoxymethyl)-1-benzofuran-6-carboxylate (417 mg, 1.5 mmol) is dissolved in MeOH (8 ml) and H2O (2 ml). 2N NaOH (0.9 ml, 1.8 mmol) is added drop-wise, and the reaction is stirred for 4 days. The volatiles are removed in vacuo and the residue is dissolved in H2O (2 ml). Concentrated HCl is used to adjust the pH to 3, and the resulting precipitate is isolated via filtration and dried overnight to afford 410 mg (>100%, water present) of 2-(diethoxymethyl)-1-benzofuran-6-carboxylic acid as a brown solid. 1H NMR (400 MHz, CDCl3): δ 1.29, 3.72, 6.9, 7.66, 8.04, 8.29 ppm.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[OH:15][CH2:16][CH2:17][S:18][S:19][CH2:20][CH2:21][OH:22]>ClCCl>[CH3:10][S:11]([O:15][CH2:16][CH2:17][S:18][S:19][CH2:20][CH2:21][O:22][S:11]([CH3:10])(=[O:13])=[O:12])(=[O:13])=[O:12]
Reactant: OCCSSCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCSSCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
N,N-Diisopropylethylamine (4.35 ml) and 1.70 ml of methanesulfonyl chloride were added to a suspension of 1.22 ml of 2-hydroxyethyl disulfide in 30 ml of dichloromethane at −40° C. under an argon atmosphere. The mixture was stirred at that temperature for 30 min. The reaction solution was then diluted with dichloromethane, and the diluted solution was washed with an dilute aqueous hydrochloric acid solution, an aqueous sodium hydrogencarbonate solution, and water in that order, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure to prepare 3.08 g of 2-methanesulfonyloxyethyl disulfide.
Reaction SMILES: [CH3:1][CH2:2][N:3](C(C)C)[CH:4](C)[CH3:5].[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=O)[C:14]=1[OH:22])([O-:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C.Cl>CN(C=O)C>[CH2:2]([N:3]([CH2:4][CH3:5])[C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([N+:10]([O-:12])=[O:11])[C:14]=1[OH:22])[CH3:1]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cccc([N+](=O)[O-])c1O
Reaction time: 0.02 h

Procedure:
1.19 ml of DIPEA are added to a stirring dispersion of 0.5 g 3-nitrosalicyclic acid and 1.14 g of HATU in 4 ml of DMF at rt under an inert atmosphere of nitrogen. After stirring at it for 1 minute, 0.31 ml of diethylamine in 1 ml of dry DMF are added. After stirring at it for 1 hour, a reaction mixture obtained is added to 50 ml of 1M HCl and extracted with 50 ml EtOAc. Solvent is evaporated and a residue obtained is purified by chromatography on silca eluting with 2:1 iso-hexane/EtOAc. The title compound is obtained. MH+ 239.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[C:14]1([C:20]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:21]2[C:25]([C:26]3[C:31]([C:32]4[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=4)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:23]=[N:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:38][C:35]3[CH:34]=[CH:33][C:32]([C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:25]4[N:21]([C:20]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:22]=[N:23][N:24]=4)=[CH:37][CH:36]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
5,7-Dimethyl-2-ethyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Example 7, Part A from 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (1.51 g, 8.62 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (5.29 g, 9.48 mmol), and NaH (17.2 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:35]=[CH:34][C:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:35]=[CH:34][C:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(c3)CCN(CCCC(=O)O)CC4)no2)cc1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
A suspension of ethyl 4-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]butanoate (Preparation 97) (185 mg, 0.371 mmol) in ethanol (3 ml), was treated with 2M sodium hydroxide (0.556 ml, 1.11 mmol) at room temperature overnight to give a colourless precipitate. A further 1-2 mls of ethanol was added and the temperature was raised to 50° C. to complete the reaction. Acetic acid (0.07 ml, 1.22 mmol) was added to the solution and the mixture concentrated. The resultant oily residue was treated with water (ca 3 ml) then stirred at room temperature for 1-2 hr and filtered. The solid was washed with water, then dissolved in methanol and the solvent evaporated. The resultant solid was dried overnight in vacuo at ca 60° C. to give the title compound (153 mgs).
Reaction SMILES: N12CCN(CC1)CC2.[CH3:9][N:10]([CH3:15])[S:11](Cl)(=[O:13])=[O:12].[CH2:16]([O:18][C:19]([C:21]1[NH:22][N:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)=[O:20])[CH3:17]>CC#N.O>[CH2:16]([O:18][C:19]([C:21]1[N:22]([S:11](=[O:13])(=[O:12])[N:10]([CH3:15])[CH3:9])[N:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)=[O:20])[CH3:17]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
1,4-Diazabicylo[2.2.2]octane (1.0 g, 8.93 mmol) and dimethylsulfamoyl chloride (0.88 mL, 8.2 mmol) were sequentially added to a solution of 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (2.0 g, 8.12 mmol) in CH3CN (10 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with H2O and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents concentrated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 40/60). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (2.42 g, 84% yield) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: N#Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccccc2C#N)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 36.5 %

Procedure:
To a solution of 1-Boc-homopiperazine(2.18 g, 11.0 mmol) in DMSO (20 mL) was added 2-fluorobenzonitrile (1.21 g, 1.08 mL, 10 mmol) and potassium carbonate (1.52 g, 11 mmol). The mixture was stirred at 80° C. for about 48 hours. The mixture was cooled to r.t. and diluted with diethyl ether (200 mL). The solution was washed with 1N HCl (2×20 mL), H2O (3×20 mL) and brine (20 mL), dried over sodium sulfate and concentrated to a yellow oil. Purification by flash chromatography (3:1 hexanes/ethyl acetate) gave the title compound (1.1 g, 36%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(C)(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.038 g, 44%). MP: 85-93° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.45 (s, 1H), 8.08-8.06 (m, 1H), 7.72 (s, 1H), 7.45 (s, 1H), 7.36-7.31 (m, 1H), 7.30-7.25 (m, 2H), 6.57 (s, 1H), 6.14-6.06 (m, 1H), 3.82 (s, 3H), 3.41-3.33 (m, 2H), 2.89-2.76 (m, 6H), 2.75-2.70 (m, 2H), 2.57-2.50 (m, 2H), 1.69 (t, 3H, J=18.7 Hz), 1.13-1.06 (m, 3H). MS: 563.18 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH:9]([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:13]([CH3:12])(=[O:15])=[O:14])[CH:6]=[C:7]([CH:9]([F:10])[F:11])[CH:8]=1
Reactant: Nc1cc(Br)cc(C(F)F)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cc(Br)cc(C(F)F)c1
Yield: 104.6 %

Procedure:
3-Bromo-5-(difluoromethyl)aniline (876 mg, 3.95 mmol) was treated with methanesulfonyl chloride (458 μl, 5.92 mmol) according to the method described in Preparation 15b to give 1.24 g (100% yield) of the title compound. Purity 95%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:24]([C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccccc1Cl
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccccc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 23 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 2-Chlorobenzaldehyde (39.4 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 24.35 mg (23%) of the title compound. (300 MHz, DMSO-d6) 13.15 (s, 1H), 7.99 (s, 1H), 7.84 (m, 1H), 7.74 (s, 1H), 7.64 (m, 1H), 7.53 (m, 2H), 7.20 (m, 2H), 6.29 (s, 2H), 5.14 (t, J=17 Hz, 8.5 Hz, 1H), 2.86 (s, 1H), 2.79 (s, 1H), 2.58 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=414 (M+H), HPLC: 2.49 min. (G Method)
Reaction SMILES: [Na].Cl[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[CH:32][CH:33]=1)[N:8]=[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3[N:26]=[C:25]([NH2:27])[C:24]4[C:19](=[CH:20][C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[CH:23]=4)[N:18]=3)[CH2:13][CH2:12]1)[N:10]=2.O.[CH2:35]([OH:37])[CH3:36]>>[CH2:35]([O:37][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[CH:32][CH:33]=1)[N:8]=[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3[N:26]=[C:25]([NH2:27])[C:24]4[C:19](=[CH:20][C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[CH:23]=4)[N:18]=3)[CH2:13][CH2:12]1)[N:10]=2)[CH3:36]
Reactant: CCO
Reactant: COc1cc2nc(N3CCN(c4nc5ccc(Cl)ccc-5n4)CC3)nc(N)c2cc1OC
Agent: [Na]
Solvent: O
Product: CCOc1ccc2nc(N3CCN(c4nc(N)c5cc(OC)c(OC)cc5n4)CC3)nc-2cc1
Reaction time: 2 h

Procedure:
A solution of sodium (0.53 g) in ethanol (22 ml) was added over a period of 1 hr to a suspension of 2-[4-(6-chloro-2-cycloheptimidazolyl)-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine (2.6 g, described in Example 2). The resulting mixture was stirred at 20°-25° C. for 2 hr, refluxed for 1 hr, cooled and poured into water at 0° to 5° C. The precipitate was collected, washed with water, dried and chromatographed through silica gel using methanoldichloromethane (1:9). The eluates were evaporated to give the title compound (1.18 g): mp>250° C.; ir (nujol) 3430, 3300 and 3170 cm-1 ; uv max (MeOH) 214 (ε=27685), 253 (ε=70380), 275 (ε=38560), 370 (ε=38560) and 390 nm (ε=21950); nmr (DMSO-d6) δ 1.4 (t, 3H), 3.9 (m, 14H), 6.75 (s, 1H), 7.17 (s, 2H), 7.4 (s, 1H), and 7.5-8 (m, 4H); and Anal. Calcd for C24H27N7O3 : C, 62.46% H, 5.90% N, 21.24% and Found: C, 62.13% H, 6.01% N, 20.95%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]2[N:25]([CH2:33][CH3:34])[C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=2[CH:22]=1.Cl>O1CCOCC1.COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:36]=[CH:35][C:24]3[N:25]([CH2:33][CH3:34])[C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:30])([CH3:31])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc21
Yield: 26.2 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (82 mg, 0.276 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (61 mg, 0.263 mmol), 4 N HCl in dioxane (80 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 3.5 hours. Filtered off solid, then purified the solid with normal phase chromatography eluting with 9/1 methylene chloride/methanol. Washed product with saturated sodium bicarbonate solution and extracted into methylene chloride. Washed organic phase with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield an off-white solid, 2-[5-Chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (34 mg, 25%). LCMS: m/z=493.37 (M+H+), 1H NMR (400 MHz, CDCl3) δ 11.11 (s, 1H), 8.60 (d, 1H, J=8.3 Hz), 8.09 (s, 1H), 7.68 (dd, 1H, J=8.3, 2.3 Hz), 7.52 (d, 1H, J=7.3 Hz), 7.39 (m, 1H), 7.33 (d, 1H, J=2.3 Hz), 7.16 (d, 1H, J=8.8 Hz), 7.08 (m, 1H), 6.70 (br s, 1H), 3.79 (m, 2H), 3.40 (s, 1H), 3.01 (d, 3H, J=4.5 Hz), 2.38 (s, 2H), 2.27 (m, 2H), 1.29 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][O:25][CH3:26]>>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:23][CH2:24][O:25][CH3:26])[C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: COc1ccc(C)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C)ccc(OC)c21

Procedure:
The title compound is prepared starting from 4-methyl-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole and (2-bromoethyl)-methyl ether using the same reaction conditions as described in Example 1. The title compound is obtained as a colorless oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:22](Br)[CH3:23])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]21[O:21][CH2:20][CH2:19][O:18]2>O.CS(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:22]([CH3:23])[C:1]#[N:2])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]21[O:21][CH2:20][CH2:19][O:18]2
Reactant: [C-]#N
Reactant: CC(Br)c1ccc(CC2CCCCC23OCCO3)c(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C#N)c1ccc(CC2CCCCC23OCCO3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
7.35 g of sodium cyanide were dissolved in 10 ml of water under heat, incorporated with 60 ml of dimethylsulfoxide, cooled to room temperature and then incorporated with a solution of 51 g of 1-[3-chloro-4-(2,2-ethylenedioxycyclohexane-1-yl methyl)phenyl]ethyl bromide in 90 ml of dimethylsulfoxide. The reaction mixture obtained was agitated at 70° C. for one hour, thereafter incorporated with water and extracted with ethyl acetate. The extract was washed with water, dried and then freed of the solvent at a reduced pressure to obtain a residue. The thus obtained residue was adhered to a silica gel-packed column and then eluted with isopropyl ether hexane (2/1). The eluate obtained was freed of the solvent thereby to obtain 32.7 g of 2-[3-chloro-4-(2,2-ethylenedioxycyclohexane-1-yl methyl)phenyl]propionitrile.