Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].CS(O[CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[C:12]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH2:3][C:2](=[O:1])[N:7]([CH2:21][CH2:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27][CH2:28]3)[C:6]=2[CH:8]=1)#[N:13]
Reactant: N#Cc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2C(=O)COc3ccc(C#N)cc32)CC1

Procedure:
3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60) (350 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{trans-4-[(tert butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate (Intermediate 76) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) afforded the product as a solid (50%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:20]=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25]>CS(C)=O>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:1][C:19]2[CH:20]=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:4]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 85 %

Procedure:
p-Hydroxybenzotrifluoride (0.22 g, 1.36 mmol), powdered potassium carbonate (0.185 g, 1.34 mmol), and methyl 5-chloro-2-nitrobenzoate (0.288 g, 1.34 mmol) were heated at 70° C. under a nitrogen atmosphere in 3 ml of dimethyl sulfoxide. After 50 minutes, an aliquot was quenched in methanolic HCl. (By gas chromatography, the reaction is 45% complete.) After 18 hours (overnight), the reaction mixture was cooled to room temperature, diluted with water, and extracted with ether. The organic extracts are shaken with brine, dried (MgSO4) and concentrated to afford methyl 5-(4-trifluoromethylphenoxy)-2-nitrobenzoate in 85% yield. Gas chromatography showed no starting phenol remained. Step B--Methyl 5-(2-chloro-4-trifluoromethylphenoxy) -2-nitrobenzoate
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[F:60][CH:61]([F:78])[CH2:62][NH:63][CH:64]1[CH2:70][CH2:69][C:68]2=[C:71]([NH2:77])[C:72]([O:75][CH3:76])=[CH:73][CH:74]=[C:67]2[CH2:66][CH2:65]1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:77][C:71]2[C:68]3[CH2:69][CH2:70][CH:64]([NH:63][CH2:62][CH:61]([F:78])[F:60])[CH2:65][CH2:66][C:67]=3[CH:74]=[CH:73][C:72]=2[O:75][CH3:76])=[N:22][CH:23]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc2c(c1N)CCC(NCC(F)F)CC2
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1ccc2c(c1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCC(NCC(F)F)CC2

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with N*7*-(2,2-Difluoro-ethyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,7-diamine to afford N-((1R,2R)-2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (Single Diasteromer B). 2nd peak elution from HPLC purification. LC/MS (ESI): 573.25. 1H NMR (400 MHz, DMSO, d6) δ 9.14 (m, 2H), 7.15 (m, 2H), 6.87 (m, 1H), 6.41 (td, 1H), 3.70 (s, 3H), 3.56 (m, 3H), 3.42 (m, 2H), 3.16 (s, 3H), 2.91 (m, 4H), 2.74 (m, 1H), 2.54 (m, 2H), 1.67 (m, 1H), 1.34 (m, 4H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=2)[N:11]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:18]1[C:17]2[C:12](=[CH:13][C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=2)[N:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCSc1ccccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1.29 g of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one, 0.38 ml of phosphorus oxychloride, 523 mg of N,N-diisopropylethylamine and 20 ml of toluene was stirred at 90° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain 1.23 g of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 4).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:20]=O.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CCO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[C:14]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([CH3:20])[CH2:25][CH2:24]4)=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Oc1cccc(Nc2ccnc3cc(Cl)ccc23)c1
Reactant: C=O
Solvent: CCO
Product: CN1CCN(Cc2c(O)cccc2Nc2ccnc3cc(Cl)ccc23)CC1
Yield: 15 %

Procedure:
3-[(7-chloroquinolin-4-yl)amino]phenol (0.20 g, 0.74 mmol), formaldehyde 37% (62 μL, 1.1 eq), and N-methylpiperazine (90 μL, 1.1 eq) was dissolved in 1 mL of EtOH. The mixture was refluxed overnight, evaporated and purified by flash chromatography (DCM/MeOH/NH4OH 7.5:2.5:0.2) to yield expected compound as a pale yellow oil (42 mg, 15% yield). LC-MS: m/z (ESI) 383.3-385.3 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:42]([C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=1)=[O:43].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([C:44]2[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 100 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.038 mL of triethylamine in 3 mL of THF was added 46.9 mg of methyl 4-(chlorocarbonyl)benzoate, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 56.0 mg of methyl 4-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoate as a colorless foamy substance. FAB+: 607
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[OH-:10].[Na+].[Mn]([O-])(=O)(=O)=[O:13].[K+]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])=[O:10])=[CH:4][C:3]=1[F:9]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc(Br)c(F)c1
Yield: 52.4 %

Procedure:
A solution of 4-bromo-3-fluorotoluene (35 g) and sodium hydroxide (7.7 g) in pyridine and water was stirred and heated to reflux. Potassium permanganate (123 g) was added to the mixture over 2 hours. The resulting suspension was heated at reflux for a further 3 hours. The mixture was filtered hot through hyflo. The hyflo was washed with boiling water, followed by ethyl acetate. The cooled aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue triturated with petroleum spirit (bp 60°-80° C.) to give 4-bromo-3-fluorobenzoic acid as a white solid (21.25 g), m.p. 213°-215° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(Cl)cc3)ccc2n1-c1ccc(N(CC)CC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (150 mg, 0.35 mmol, see step (b) Example 1) and 4-chlorophenylboronic acid (83 mg, 0.53 mmol). Yield 107 mg (57%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[C:29]4[CH2:33][CH2:34][NH2:35])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[C:29]4[CH2:33][CH2:34][NH:35][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:17])[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN)c[nH]c34)no2)cc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Product: CCOC(=O)CCNCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
Ethyl acrylate (100 mg) and Sc(OTf)3 (5 mg) were added to the solution of 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethanamine (D84) (530 mg) in dichloromethane (3 mL). The resulting reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was purified by Mass Directed Auto Prep to afford ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}-β-alaninate (D85) (186 mg) as a yellow solid. MS (ES): C26H29ClN4O4 requires 496; found 497.2 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:19]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:20])=[CH:14][CH:13]=1.CCOCC>CCOC(C)=O>[Cl-:1].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[C:19]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N+:24]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:25][CH2:26]3)[CH2:23]2)=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccc(F)cc1)N1CCCCC1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccc(F)cc1)N1CCCCC1)C2)c1ccccc1
Product: [Cl-]
Yield: 58.6 %

Procedure:
2-Chloro-1-phenylethanone (29.5 mg, 0.19 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (60 mg, 0.17 mmol) in EtOAc (3 ml). 2-Chloro-1-phenylethanone (8.85 mg, 0.06 mmol) were added and stirring was kept for 4 additional hours. Et2O was added and the precipitate was collected by suction filtration to obtain (3R)-3-(2-(4-fluorophenyl)-2-(piperidin-1-yl)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (49.9 mg, 57.5% yield) as a gummy yellow solid.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:11]=23)=[CH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>O>[C:1]([C:5]1[N:9]([CH3:27])[CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:11]=23)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ncc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)nc1C(C)(C)C
Yield: 51 %

Procedure:
To a mixture of 4-(2-tert-butyl-1H-imidazol-5-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.019 g, 0.000051 mol) and potassium carbonate (0.15 g, 0.0011 mol) in DMF (3 mL, 0.04 mol) was added methyl iodide (0.01 mL, 0.00015 mol) in two portions over 48 hours. Water was then added and the product was extracted with MTBE. The combined extracts were dried with sodium sulfate, filtered, and concentrated in vacuo, then purified by silica gel chromatography (20% ethyl acetate/hexanes) to afford 4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (10 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([CH3:19])[NH:12][C:11]3[CH2:20][O:21][CH:22]([CH3:25])[C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:10]3[C:23](=[O:24])[C@@H:22]([CH3:25])[O:21][CH2:20][C:11]=3[NH:12][C:13]3[CH2:19][O:17][C:15](=[O:16])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)C(C)OC2)C1c1ccc(F)c(Br)c1
Agent: Cl
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C[C@H]1OCC2=C(C1=O)[C@@H](c1ccc(F)c(Br)c1)C1=C(COC1=O)N2
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
The product from Example 84D (1.0 g, 2.5 mmol) was dissolved in chloroform (15 mL) under a nitrogen atmosphere, cooled to −10° C., treated with pyridine (0.24 mL, 3.0 mmol) and pyridinium tribromide (0.97 g, 3.0 mmol), stirred at −10° C. for 20 minutes, diluted with dichloromethane (100 mL) and treated with 1M HCl (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, heated to 130° C. under nitrogen for 15 minutes and cooled to ambient temperature. The residue was purified by chromatography on silica gel eluting with 38:1:1:40 ethyl acetate:formic acid:water:hexane to provide the title compound as the faster moving diasteriomer which was crystallized from dichloromethane. 1H NMR (DMSO-d6) δ 1.22 (d, 3H), 4.12 (q, 1H), 4.48 (d, 1H), 4.65 (d, 1H), 4.68 (s, 1H), 4.86 (dd, 1H), 4.99 (d, 1H), 7.24-7.28 (m, 2H), 7.48 (dd, 1H), 10.42 (bs, 1H);
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[F:8][C:9]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O>[F:8][C:9]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:10]=1[CH2:11][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:2](=[O:4])(=[O:3])[NH:5][C:6]1=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Fc1cc(F)c(CNc2ccccc2)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: O=C1NS(=O)(=O)c2ccccc2N1Cc1c(F)cc(F)cc1F
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 42.9 %

Procedure:
A solution of chlorosulfonylisocyanate (4.72 mL, 54.2 mmol) in nitroethane (75 mL) was cooled to approximately −40° C. and a solution of N-(2,4,6-trifluorobenzyl)aniline (9.90 g, 41.7 mmol) in nitroethane (75 mL) added dropwise over approximately 10 min. The mixture was stirred at −40° C. for 10 min, then at 0° C. for 30 min. Aluminium chloride (5.56 g, 41.7 mmol) was added and the mixture heated at reflux for 30 min, before cooling to rt and cautious addition to stirred ice-H2O (approximately 250 mL). The title compound (6.12 g, 17.9 mmol) was isolated by filtration.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1>CN(C)C=O>[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccnc2)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 47.6 parts of 1H-imidazole, 33.6 parts of sodium hydride dispersion 50% and 750 parts of N,N-dimethylformamide was stirred at room temperature for 15 minutes. The resulting solution was added to 106 parts of 3,6-dichloropyridazine in 750 parts of N,N-dimethylformamide and the whole was further stirred for 2 days at room temperature. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from methanol. The product was filtered off, washed with petroleumether and dried, yielding 48.5 parts of 3-chloro-6-(1H-imidazol-1-yl)pyridazine: mp. 182.9° C. (compound 1).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][OH:7])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)Cn1c(CO)c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-Bromo-2,5-pyrrolidinedione (0.26 g) was added to a solution of the product from Example 27 step b) (0.5 g) in DMF (5 ml) and the solution stirred at room temperature for 20 mins. Water (5 ml) was added and the mixture stirred for a further 30 mins. The reaction was diluted with further water (50 ml), extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid Filtered off and dried to yield the title compound as a white solid (48 mg).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: CN1CCN(c2nn(N)c(=O)c3ccccc23)CC1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CN1CCN(c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)CC1

Procedure:
The product from Example 107B and (4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.77 (s, 1H), 8.32 (d, J=7.9, 1H), 8.03-7.97 (m, 2H), 7.96-7.89 (m, 1H), 7.45-7.36 (m, 4H), 3.68 (s, 2H), 3.65-3.50 (m, 4H), 3.08-2.98 (m, 2H), 2.91 (s, 3H), 2.49-2.44 (buried m, 2H); MS (APCI+) M/Z 412 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(OCC)C)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]=O)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:45]([SH:48])[CH2:46][SH:47].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]3[S:48][CH2:45][CH2:46][S:47]3)=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: SCCS
Reactant: CCCCc1nc2cc(-c3ccccc3)c(C=O)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCc1nc2cc(-c3ccccc3)c(C3SCCS3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 80.3 %

Procedure:
0.1 g(0.000169 mole) of the aldehyde compound obtained in step 11 of Example 1 and 0.024 g(0.00025 mole) of 1,2-ethanedithiol were dissolved in 5 ml of benzene and to the resulting solution was added 0.01 mg of p-toluenesulfonic acid. The resultant was refluxed for 6 hours, neutralized with aqueous NaHCO3 solution and extracted with ethyl acetate(5 ml×3). The organic layer was dried over Na2SO4, concentrated under reduced pressure and evaporated under reduced pressure (1 mmHg, 80° C.) for 5 hours to remove the residual 1,2-ethanedithiol. The resultant was recrystallized from hexane-methylene chloride to obtain 80 mg of the title compound(yield 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)#[N:25].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
230 mg (0.77 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 37 mg (0.92 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 196 mg (1.00 mmol) of 4-cyanobenzyl bromide was added to the obtained mixture, and they were stirred at room temperature for 4 hours. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.