Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:35](=[O:36])[N:34]([CH3:37])[C:12]2[N:13]([CH3:33])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH2:21][C:22](=O)[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)=[CH:16][CH:15]=3.O.[NH2:39][NH2:40]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:35](=[O:36])[N:34]([CH3:37])[C:12]2[N:13]([CH3:33])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:39][N:40]=[C:22]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=1)=[CH:16][CH:15]=3
Reactant: NN
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CC(=O)COC4CCCCO4)ccc3n(C)c21
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc(COC5CCCCO5)n[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 80 above, with compound A, 1-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-4-(tetrahydropyran-2-yloxy)butane-1,3-dione and hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]2[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][CH:10]2[OH:16])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C@@H:9]2[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][C@H:10]2[OH:16])=[O:7])=[CH:23][CH:24]=1
Reactant: CCN1CC(O)C(N(C(=O)c2ccc(Cl)cc2)C2CCCCC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN1C[C@@H](O)[C@H](N(C(=O)c2ccc(Cl)cc2)C2CCCCC2)C1

Procedure:
A mixture of 6.9 g (0.014 mole) of trans-4-chlorobenzoic acid ester with 4-[(4-chlorobenzoyl)(cyclohexyl)amino]-1-ethyl-3-pyrrolidinol, 0.9 g (0.016 mole) of potassium hydroxide, 10 ml of water and 40 ml of methanol was heated on a steam bath for 1 hr. then concentrated to 10 ml volume under reduced pressure. The residue was partitioned between water and methylene chloride and the organic layer was dried and conentrated under reduced pressure. After recrystallization from 60% aqueous methanol, 3.5 g (72%) of white powder, m.p. 111°-116° C. was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:17][C:18](=[O:27])[C:19]1[C:24](Cl)=[CH:23][CH:22]=[CH:21][C:20]=1Cl.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C(=O)([O-])[O-].[K+].[K+]>[Cu-]=O.CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:17][C:18](=[O:27])[C:19]1[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:23][CH:22]=[CH:21][C:20]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(Nc1cccc2c(-n3ccnc3)c(Br)cnc12)c1c(Cl)cccc1Cl
Reactant: c1c[nH]cn1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc2c(-n3ccnc3)c(Br)cnc12)c1c(-n2ccnc2)cccc1-n1ccnc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a mixture of 3-bromo-8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)quinoline (50 mg) and N-methylpyrrolidone were added imidazole (11 mg), potassium carbonate (22.4 mg) and copper(I) oxide (7.74 mg), and the mixture was stirred for 1.5 hours at 60° C. and for 1 hour at 80° C. The mixture was partitioned between dichloromethane and water, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography and crystallized from diisopropyl ether to give 3-bromo-8-[2,6-bis(imidazol-1-yl)benzoylamino]-4-(imidazol-1-yl)quinoline (17 mg).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:19]=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:41])[C@:34]([OH:40])([CH3:39])[C:35]([F:38])([F:37])[F:36].[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:30])=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:41])[C@:34]([OH:40])([CH3:39])[C:35]([F:38])([F:37])[F:36]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)Nc3ccccc3)cc2)cc1Cl)C(F)(F)F
Reaction time: 144 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.195 g) was added to a solution of 4-(dimethylamino)pyridine (0.25 g), (R)-N-[2-chloro-4-(4-carboxyphenyl-sulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 121) (0.317 g) and aniline (0.075 ml) in DCM (30 ml) and the mixture was stirred for 6 days. Solvent was then removed by evaporation and the residue was partitioned between ethyl acetate (50 ml) and dilute aqueous hydrochloric acid (25 ml). The aqueous layer was further extracted with ethyl acetate (50 ml). The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography eluting with 40% ethyl acetate/hexane to give the title compound (0.179 g) as a solid. NMR (CDCl3+DMSO-δ6): 1.59 (s, 3H), 7.03 (t, 1H), 7.25 (t, 2H), 7.48 (brs, 1H), 7.64 (d, 2H), 7.78 (dd, 1H), 7.92 (m, 3H), 8.06 (d, 2H), 8.56 (d, 1H), 9.72 (s, 1H), 9.9 (s, 1H); MS (ESP−): 525.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)([OH:10])[CH3:9])=[CH:4][C:3]=1[C:24]([NH:26][CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)=[O:25].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])([CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH3:9])=[CH:4][C:3]=1[C:24]([NH:26][CH2:27][C:28]12[CH2:29][CH:30]3[CH2:31][CH:32]([CH2:33][CH:34]([CH2:36]3)[CH2:35]1)[CH2:37]2)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(O)(c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C1CCNCC1
Yield: 123.4 %

Procedure:
To a solution of 4-[1-[4chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-1-hydroxyethyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.07 g, Example 77a) in methanol (3 ml) was added 4N hydrochloric acid solution in dioxane (1 ml). After 14 h the solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.038 g).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([CH3:7])[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:15]([O:17]CC)=[O:16])[CH2:3]1.CO.[OH-].[Li+].Cl>C1COCC1.O>[C:11]([O:10][C:8]([N:5]1[C@@H:6]([CH3:7])[C@@H:2]([CH3:1])[CH2:3][C@H:4]1[C:15]([OH:17])=[O:16])=[O:9])([CH3:12])([CH3:14])[CH3:13]
Reactant: CCOC(=O)[C@@H]1C[C@H](C)[C@H](C)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)[C@H]1C
Temperature: 45 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of rel-(2S,4S,5S)-1-tert-butyl 2-ethyl 4,5-dimethylpyrrolidine-1,2-dicarboxylate in a mixture of THF (70 mL), MeOH (25 mL), and H2O (25 mL) was added lithium hydroxide (1.53 g, 63.7 mmol). The slurry was stirred at room temperature for 2.5 h and at 45° C. for 2 h. The solution was cooled to room temperature and HCl (aqueous, 1N, 70 mL) was added. The organics were concentrated and the resulting aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated to provide rel-(2S,4S,5S)-1-(tert-butoxycarbonyl)-4,5-dimethylpyrrolidine-2-carboxylic acid (3.08 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].C(O)(=O)C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[N+:41]([O-])([OH:43])=[O:42]>>[N+:41]([C:11]1[CH:12]=[CH:13][C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([C:18]([F:23])([F:24])[C:19]([F:22])([F:21])[F:20])=[CH:17][C:2]=2[Cl:1])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])([O-:43])=[O:42]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 83.9 %

Procedure:
A 50 ml 3-neck round bottom flash was charged with 2.5 gm (6.83 mmol) of 3-(2-chloro-4-pentafluoroethylphenoxy)benzoic acid, 2.18 gm (2.08 ml, 36.19 mmol) of glacial acetic acid, 2.1 gm (20.49 mmol) of acetic anhydride and 70 mg (683 mmol) of concentrated sulfuric acid. The resulting slurry was stirred vigorously while cooling to 0°-5° C. with the aid of an icewater bath. To the cooled slurry was added dropwise a mixture 280 mg (2.73 mmol) of concentrated sulfuric acid and 620 mg (9.56 mmol) to 97% nitric acid (red fuming). The yellow solution was maintained at 0°-5° C. for about 1.5 hours at which time the reaction mixture was poured into stirred ice water. The gummy residue that formed in the bottom of the flask was extracted with 100 ml of ether, the ether layer separated, and the aqueous acid layer reextracted with a second portion of ether. The combined ether layers were washed with brine, dried and evaporated in vacuo leaving a yellow oil. Much of the yellow color was removed by dissolving the oil in 300 ml of chloroform and eluting through a pad of silica gel. Evaporation of the eluent yielded 2.36 gm (83.9%) of a light yellow oil which crystallized on standing. The product had the following elemental analysis, calculated (found): C: 43.76 (44.43); H: 1.71 (2.24); Cl: 8.61 (8.83); F: 23.07 (18.90); N: 3.40 (2.47); O: 19.43.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[C:7]([N+:21]([O-])=O)=[C:8]([CH:18]=[CH:19][CH:20]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10].[H][H]>[Ni].CO>[NH2:21][C:7]1[C:6]([O:5][CH3:4])=[CH:20][CH:19]=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10]
Reactant: COc1cccc(C(=O)N2CCCC2CO)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cccc(C(=O)N2CCCC2CO)c1N
Reaction time: 2 h
Yield: 96 %

Procedure:
Hydrazine hydrate (4.37 g, 136.4 mmol) was added dropwise to a solution of 92 (6.37 g, 22.7 mmol) in gently refluxing methanol (100 mL) over Raney nickel (2.4 g, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded a brown glass (5.49 g, 21.8 mmol) as a single spot by TLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10](Cl)=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:20])[CH3:19].C1COCC1>C1COCC1>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([NH:20][CH2:18][CH3:19])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 100.4 %

Procedure:
4-Chloro-3-nitrobenzoic acid tert-butyl ester (3.0 g, 11.6 mmol), prepared according to a published procedure [WO 9707101], was cautiously added to a solution of 2.0 M EtNH2/THF (20 mL, 40 mmol) and TEA (2.0 mL, 14 mmol) in anhydrous THF (30 mL). The resulting mixture was heated at 65° C. for 3 h, cooled, concentrated under reduced pressure, diluted with DCM (200 mL), washed with water (2×100 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated to give the title compound (3.1 g, 99%) as a yellow solid, which was used without further purification. 1H-NMR (CDCl3): δ 8.80 (1H, d), 8.24 (1H, br s), 8.02 (1H, dd), 6.84 (1H, d), 3.41 (2H, m), 1.59 (9H, s), 1.40 (3H, t).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH2:31][CH2:32]OS(C)(=O)=O)=[O:17])[CH:13]=[CH2:14].O>CN(C)C=O.C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:20][C@H:19]1[CH2:31][CH2:32][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:17])[CH:13]=[CH2:14]
Reactant: c1c[nH]cn1
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1ccnc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of imidazole (1.52 in N,N-dimethylformamide (70 ml) were added potassium t-butoxide (2.51 g) and a solution of (2R,4R)-1-allyloxycarbonyl-2-(2-methanesulfonyloxyethyl)-4-(t-butyldimethylsilyloxy)pyrrolidine (8.3 g) in N,N-dimethylformamide (13 ml) at ambient temperature with stirring, and the mixture was stirred at about 60° C. for 1 hour. The reaction mixture was cooled with ice-cooling, and water and ethyl acetate were added thereto. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a mixture of chloroform and methanol (10:0.3, V/V) to give (2R,4R)-1-allyloxycarbonyl-2-[2-(imidazol-1-yl)ethyl]-4-(t-butyldimethylsilyloxy)pyrrolidine (11.11 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[CH:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:12]2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14]([OH:16])[CH:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:12]2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(=O)C2CCCCC21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(O)C2CCCCC21

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2,5-dione (2.7 g) and sodium borohydride (0.2 g) in ethanol (100 ml) is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure, and the residue dissolved in dichloromethane (100 ml). The solution is extracted with ice-cold 2N HCl (2×50 ml) and saturated brine (50 ml) and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue triturated with ether to give 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[S:7][CH:8]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:25]=[O:26].C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:16][C:15]1[C:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:25]([NH:24][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[N:5]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCc1csc(Nc2ncccc2OCc2ccccc2)n1
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCc1csc(Nc2ncccc2OCc2ccccc2)n1)Nc1ccccc1
Reaction time: 2 h
Yield: 35.7 %

Procedure:
Crude 4-(2-aminoethyl)-N-(3-(benzyloxy)pyridin-2-yl)thiazol-2-amine (Example 134, Step A; 0.25 g, 0.766 mmol) was dissolved in DMF (10 mL), and 1-isocyanatobenzene (0.182 g, 1.53 mmol) was added. The reaction mixture was stirred for 2 hours, then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with 2:3 hexane:ethyl acetate to afford the title compound (0.122 g, 35.8% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 2.75 (t, 2H), 3.42 (q, 2H), 5.27 (s, 2H), 6.19 (t, 1H), 6.70 (s, 1H), 6.86-6.91 (m, 2H), 7.20 (t, 2H), 7.34-7.43 (m, 6H), 7.58 (d, 2H), 7.87 (d, 1H), 8.48 (s, 1H), 9.94 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH:10]([O:12]CCCC)=[CH2:11].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)C>[C:10]([C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:12])[CH3:11]
Reactant: Cn1cc(Br)ccc1=O
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC(=O)c1ccc(=O)n(C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 106.1 %

Procedure:
5-Bromo-1-methyl-2(1H)-pyridone (150 g) was dissolved in DMF (1500 ml). To the solution were added 1,3-bis(diphenylphosphino)propane (21.7 g), n-butyl vinyl ether (400 g), and 3M aq. potassium carbonate (262.5 ml) and Pd(OAc)2 (10.2 g). The mixture was heated at 80° C. and stirred for 3 hours at the same temperature. The reaction mixture was cooled to 25-30° C. and poured to 1N HCl (1485 ml). The mixture was stirred for 2 hours at 30-40° C. The solution was extracted with EtOAc (1500 ml, three times). The aqueous layer was extracted with CH2Cl2 (1000 ml, three times). The collected organic solution was dried over MgSO4. Evaporation of solvent gave solidly residue, which was pulverized with IPA (150 ml) and IPE (1500 ml). The suspension was stood in the refrigerator overnight. The precipitate was collected by filtration, dried in vacuo, to give 5-acetyl-1-methyl-2(1H)-pyridone as white powder (128 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[F:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1>>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][C:25]([CH2:24][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:33][CH:32]=3)([OH:31])[CH2:30][CH2:29]2)=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Product: OC1(Cc2ccc(F)cc2)CCN(CCOc2ccc(OCc3ccccc3)cc2)CC1

Procedure:
The title compound, MS: m/e=436.5 (M+H+), was prepared from 1-(2-bromoethoxy)-4-(benzyloxy)-benzene and 4-(4-fluoro-benzyl)-piperidin-4-ol.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:9][CH:8]2[C:4]1([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH2:5][NH:6][CH2:7]2.[OH-].[Na+]>Cl>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]([C:4]23[C:3](=[O:2])[CH2:9][CH:8]2[CH2:7][NH:6][CH2:5]3)=[CH:15][CH:14]=1
Reactant: COC1(OC)CC2CNCC21c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C23CNCC2CC3=O)cc1
Yield: 83.9 %

Procedure:
A stirred mixture of about 4.1 g of 6,6-dimethoxy-5-(p-methyl-phenyl)-3-azabicyclo[3.2.0]heptane and about 50 ml of approximately 10% hydrochloric acid was heated under reflux for about 30 minutes. The solution was made basic with 5N sodium hydroxide and then was extracted with dichloromethane. The extract was dried over sodium sulfate, filtered, and evaporated under reduced pressure to give about 2.8 g of 5-(p-methylphenyl)-3-azabicyclo[3.2.0]heptane-6-one, b.p. 125°-130° C. (0.2 mm), as a yellow liquid. The fumarate salt had m.p. 130°-133° C. A mixture of about 3.8 g of the ketone, about 5 ml of 1,2-ethanedithiol and about 5 ml of freshly distilled boron trifluoride etherate in about 40 ml of acetic acid was stirred at room temperature for approximately 4 days, and then was evaporated under reduced pressure to give a tarry residue. This residue was slurried with ether and about 10% hydrochloric acid, and then the aqueous phase was made basic with approximately 5N sodium hydroxide and extracted with dichloromethane. The extract was dried over sodium sulfate and evaporated to give about 4.1 g of a solid. Recrystallization from acetonitrile gave 5-(p-methylphenyl)-3-methyl-spiro[3-azabicyclo[3.2.0]heptane-6,2'-[1,3]-dithiolane] as a tan solid, m.p. 81°-86° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[NH:9][C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:65][N:66]([CH3:71])[CH2:67][CH2:68][CH2:69][NH2:70]>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[NH:9][C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:70][CH2:69][CH2:68][CH2:67][N:66]([CH3:71])[CH3:65])=[O:27])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Reactant: CN(C)CCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a mixture of 0.06 g (0.14 mmole) of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-151), 0.08 g (0.21 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.07 mL (0.41 mmole) diisopropylethylamine. After stirring at room temperature for 30 minutes, 0.05 mL (0.41 mmole) of 3-(dimethylamino)-propylamine was then added. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient 0:100-25:75) to give 0.020 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-154).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].Br[CH2:28][CH:29]([OH:33])[CH2:30][CH2:31]Br>>[OH:33][CH:29]1[CH2:30][CH2:31][N:1]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:28]1
Reactant: OC(CBr)CCBr
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1N1CCC(O)C1

Procedure:
The title compounds, both light yellow solids, MS: m/e=455.3 [(M+H)+], were prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 1,4-dibromo-2-butanol. The 2 diastereomers could be separated by column chromatography however the relative configuration was not assigned.