Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[CH:8][C:7]([OH:18])=[CH:6][CH:5]=2.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28].C(Cl)(=O)C>C1COCC1.[OH-].[Na+].O.C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[CH:8][C:7]([O:18][S:27]([C:21]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=1[F:19])(=[O:29])=[O:28])=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccc(O)cc2c1C1CCN(C)CC1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(OS(=O)(=O)c3c(F)cccc3F)cc2c1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A solution of 2-methyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (4.05 mmol, 0.989 g) in THF (12 mL) and 1M sodium hydroxide (4.09 mL) was treated with 2,6-difluorobenzenesulfonyl chloride (4.46 mmol, 0.948 g). After stirring one hour at room temperature the reaction was diluted with water (25 mL) and extracted with ethyl acetate (3×25 mL). The organic phases were combined, concentrated in vacuo to afford foam. The free amine was converted to the hydrochloride salt. Acetyl chloride (approximately 1.2 eq) was added to a cooled solution of ethanol (0° C.). After stirring approximately five minutes, this solution was added to a solution of the free amine in ethanol. The biphasic solution was concentrated in vacuo to foam. The foam was dissolved in acetone, crystals formed, collected by filtration to afford 1.12 g (60%) of the title compound: mp=138° C. (decomposes); mass spectrum (ion spray): m/z=420 (M−1); Calculated for C21H22F2N2O3S-HCl-0.2H20-0.6C3H6O: C, 55.28; H, 5.49; N, 5.66. Found: C, 55.42; H, 5.46; N, 5.30
Reaction SMILES: C([O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[C:14]3=[N:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[CH3:23])=[C:7]([Cl:26])[CH:6]=1)(=O)C.CO.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[Cl:26][C:7]1[CH:6]=[C:5]([OH:4])[CH:25]=[CH:24][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH3:23]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(OC(C)=O)cc3Cl)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(O)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.2 %

Procedure:
To a mixture of methyl 3-(4-acetoxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (2.87 g), methanol (29 ml), 1,4-dioxane (29 ml) and water (2.9 ml) was added sodium hydrogencarbonate (968 mg), and the mixture was stirred at room temperature for 2.5 hr. 1,4-Dioxane (29 ml) was added to dissolve the insoluble matter, and the mixture was stirred for 2 hr. Sodium hydrogencarbonate (968 mg) was added and the mixture was stirred at room temperature for 2 days and at 60° C. for 3 hr and stood overnight. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was again extracted with ethyl acetate. The organic layers were combined and concentrated to dryness under reduced pressure. The residue was pulverized in ether to give the objective compound (1.94 g) as a pale-yellow powder.
Reaction SMILES: [AlH4-].[Li+].O1CCCC1.C[O:9][C:10](=O)[C:11]1[C:12](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:13](OC)=[O:14]>>[OH:14][CH2:13][C:12]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:11]=1[CH2:10][OH:9]
Reactant: COC(=O)c1ccc(OC)cc1C(=O)OC
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CO)c(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred suspension of Lithium tetrahydroaluminate (16.6 g, 0.436 mol) in Tetrahydrofuran (300 mL, 4 mol) at 0° C. under nitrogen was added dropwise a solution of 4-Methoxy-phthalic acid dimethyl ester (24.46 g, 0.1091 mol) in Tetrahydrofuran (100 mL, 1 mol). The reaction was stirred at 0° C. for 1 h then warmed to room temperature overnight. HPLC indicated no starting material present. Reaction was recooled at 0° C. and quenched with addition of water (125 mL) carefully dropwise, 1 N NaOH (100 mL) and water (125 mL). Evolution of gas was observed upon initial quenching with water. A white solid precipitated out of solution (aluminum salts). Following complete quenching of the reaction mixture, the aluminum salts were removed by filtration. The filtrate was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 17.80 grams (97%) of (2-Hydroxymethyl-4-methoxy-phenyl)-methanol as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-])=O)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)(=O)C.[Fe]>[Si:1]([O:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH2:22])=[CH:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O[Si](C)(C)C(C)(C)C)C1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1CC(c2ccncc2N)=CC(O[Si](C)(C)C(C)(C)C)C1
Yield: 78 %

Procedure:
A heterogeneous solution of 4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)-3-nitropyridine (1.0 eq.) and iron (6.0 eq) in acetic acid, at a concentration of 0.4 M, was stirred vigorously for 2 hours. The mixture was then passed through a celite pad, eluting with MeOH. Upon removal of the volatiles in vacuo, the residue was dissolved in EtOAc, washed with Na2CO3(sat.), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding 4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)pyridin-3-amine (78%). LCMS (m/z): 319.3 (MH+); LC Rt=3.77 min.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][CH:11]([CH2:13][CH:14]=[O:15])[CH3:12])[CH3:7]>CN(C)C=O>[CH3:12][C:11]([CH:10]=[CH:9][CH2:8][CH:6]([CH3:5])[CH2:7][CH2:9][CH2:8][CH:6]([CH3:7])[CH3:5])=[CH:13][C:14]([O:1][CH2:2][CH3:3])=[O:15]
Reactant: CC[O-]
Reactant: CC(C)CCCC(C)CC=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)C
Reaction time: 8 h

Procedure:
Sodium ethoxide (9 g. sodium in 600 ml. of ethanol) is added slowly to a mixture of 42 g. of dihydrocitronellal and 75 g. of diethyl 3-ethoxycarbonyl-2-methylprop-2-enyl phosphonate (about 49% trans) in one liter of dimethylformamide, under nitrogen and at 0°, with stirring. The mixture is allowed to stand overnight at about 5° and the reaction worked up by extraction with ether, washing with water and brine and filtering through Florisil to yield ethyl 3,7,11-trimethyldodeca-2,4-dienoate as a cis/trans mixture, mostly trans,trans.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8](=O)[CH2:9][CH2:10][CH3:11].O>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:8](=[N:7][S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CCCC=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Product: CCCC=N[S@@](=O)C(C)(C)C
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinamide (6.7 g, 55 mmol) in dichloromethane (125 mL) is added butyraldehyde (4.0 g, 55 mmol) followed by titanium isopropoxide (32 g, 110 mmol). The reaction is then heated at reflux (bath temperature=60° C.) for 4 hours. The resultant mixture is cooled to room temperature and poured into a stirred mixture of diatomaceous earth (10 g) and water (100 mL). The slurry is stirred for 10 min and then filtered. The organic layer from the filtrate is concentrated in vacuo to afford a crude yellow oil which is purified by flash chromatography on silica gel (eluted with 5 to 30% dioxane/hexanes) to afford (S)-2-methyl-propane-2-sulfinic acid butylideneamide as a colorless oil (7.4 g, 77%).
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:33]1[CH2:37][C@@H:36]([CH2:38][CH3:39])[C:35](=[O:40])[O:34]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:19][C:18]1([CH3:32])[CH3:31])([CH3:11])([CH3:10])[CH3:9].[CH3:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH2:45]>>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:19][C:18]1([CH3:31])[CH3:32])[C@@H:33]([OH:34])[CH2:37][C@H:36]([C:35](=[O:40])[NH:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH3:42])[CH2:38][CH3:39])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3C)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC(C)(C)CN
Agent: Oc1ccccn1
Product: CC[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2C)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
10 mg of 2-hydroxypyridine (0.11 mmol) was added to a solution of 100 mg of {(S)-2-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (110b) (0.21 mmol) in (2,2-dimethylpropyl)amine (0.5 ml), and the mixture was stirred at 80° C. for four hours. The reaction mixture was cooled and then concentrated under reduced pressure and further stirred at 80° C. for 14 hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate) to obtain 105 mg of the title compound (yield: 89%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1>CO.C(Cl)Cl.[Pd]>[CH3:22][C:15]1[CH:14]=[C:13]([N:10]2[CH2:11][CH2:12][C@H:8]([CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])[CH2:9]2)[CH:18]=[CH:17][C:16]=1[NH2:19]
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2S,3R)-2-methyl-1-[1-(3-methyl-4-nitro-phenyl)-pyrrolidin-3-yl-methyl]-pyrrolidine (0.3 g, 1 mmol) in MeOH (15 mL) was deaerated and nitrogen was introduced. To this solution was added Pd—C (10%, 30 mg). This mixture was stirred under H2 atmosphere at r.t. overnight. TLC (10% MeOH in DCM) and LC/MS showed the reaction was complete, product peak was observed at t=1.458 min, m/z: 274 (M). The mixture was passed through a Celite pad, rinsed with methanol. The filtrate was concentrated to dryness, and further dried under high vacuum to yield the title compound as a reddish brown liquid after drying under high vacuum.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@@H:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[CH:4][CH:3]=[N:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[CH:4][CH:3]=[N:2]1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3ccno3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4ccno4)c(c23)C1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
A mixture of (-)(2aR,4S)-6-(5-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (253 mg, 0.8 mmol) and 1 g of MnO2 in 100 ml of CH2Cl2 was sonicated at 50-55 KHz for four hours. The reaction mixture was warmed to reflux during the time period. After four hours, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The resulting residue was chromatographed (flash column, silica gel, EtOAc) to provide 130 mg of title product. Recrystallization from hexane gave 60 mg of purified title product.
Reaction SMILES: [Li].[F:2][C:3]([F:22])([F:21])[O:4][C:5]1[CH:6]=[C:7]([C:11]([O-])=[CH:12][C:13](=O)[C:14]([O:16]CC)=[O:15])[CH:8]=[N:9][CH:10]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:46][C:47]1[CH:48]=[C:49]([NH:54][NH2:55])[CH:50]=[CH:51][C:52]=1[F:53]>>[Cl:46][C:47]1[CH:48]=[C:49]([N:54]2[C:11]([C:7]3[CH:8]=[N:9][CH:10]=[C:5]([O:4][C:3]([F:2])([F:21])[F:22])[CH:6]=3)=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[N:55]2)[CH:50]=[CH:51][C:52]=1[F:53]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cncc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
1.13 g (3.25 mmol) of the compound of Example 18A is reacted analogously to the synthesis of the compound of Example 20A with 961 mg (4.88 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 576 mg (44% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:26])=[CH:3][CH2:4][N:5]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH3:27][C:28]([CH3:33])([CH3:32])[CH2:29][CH:30]=O>>[CH3:27][C:28]([CH3:33])([CH3:32])[CH2:29][CH2:30][N:9]1[CH2:8][CH2:7][CH:6]([N:5]([CH2:4][CH:3]=[C:2]([CH3:26])[CH3:1])[C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)CC=O
Reactant: CC(C)=CCN(c1ccc(CCc2ccccc2)cc1)C1CCNCC1
Product: CC(C)=CCN(c1ccc(CCc2ccccc2)cc1)C1CCN(CCC(C)(C)C)CC1

Procedure:
The preparation of Example 48: [1-(3,3-Dimethyl-butyl)-piperidin4-yl]-(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amine was prepared in accordance with the methods of Step 8 in Example 37 except that (3-Methyl-but-2-enyl)-(4-phenethyl-phenyl)-piperidin-4-yl-amine (48g) was used instead of [4-(3,3-Dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-pipendin-4-yl-amine (37g) and 3,3-dimethylbutyraldehyde was used instead of isovaleraldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([O:39]C)=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([OH:39])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)OC)c3ccccc3n2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
Alternatively, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (200 mg, 0.359 mmol) was treated with LiOH (2 eq.) in a solution of THF:H2O (3:1, 8 mL). The reaction mixturre was stirred at ambient temperature for 5 hours. The pH value was adjusted to between pH 3 and pH 4 with 1 N HCl solution. Evaporation of the solvents, extraction with ethyl acetate, washing with H2O and brine, followed by evaporation and flash column chromatography with 100% ethyl acetate, 1-5% MeOH in ethyl acetate gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-carboxyquinoline (106 mg). To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-carboxyquinoline (500 mg (two batches combined), 0.922 mmol) in THF (10 mL) was added 1-methyl 5-t-butyl ester glutamic acid (300 mg, 1.5 eq), EDCI (216 mg, 1.2 eq.), HOBt (140 mg, 1.1 eq.), and the resulting mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1 M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%-3% MeOH in CH2Cl2 afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-[(1-(methoxycarbonyl)-3-(1,1-dimethylethoxycarbonyl)propyl)aminocarbonyl]quinoline (387 mg); NMR (CDCl3) 1.28 (t, 3), 1.40 (s, 9), 1.47 (s, 9), 1.83 (m, 1), 2.16 (m, 2), 2.35-2.50 (m, 5), 3.5-3.76 (m, 8), 3.8 (s, 3), 4.18 (q, 2), 4.85 (m, 1), 5.35 (m, 1), 7.15 (d, 1), 7.65 (m, 1), 7.80 (m, 1), 8.20 (d, 1), 8.30 (d, 1), 8.35 (s, 1), 8.70 (d, 1) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)[CH:5]=[C:4]([NH2:24])[N:3]=1.[N:25]([O-])=[O:26].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])=[CH:12][CH:11]=2)[C:5]([N:25]=[O:26])=[C:4]([NH2:24])[N:3]=1
Reactant: Nc1cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 70 °C
Yield: 76.9 %

Procedure:
Pyrimidine 37 (Example 20, 4.72 g, 13.7 mmol) is dissolved in 60 mL acetic acid (30%) and heated to 70° C. NaNO2 (1.4 g, 20.03 mmol) dissolved in 5 mL water is added drop wise until KJ-starch paper remains black. After cooling to 0° C. in an ice-bath, the purple precipitate is collected by filtration and recrystallized from acetone to yield 3.9 g (10.54 mmol, 77%) of a purple solid. 1H-NMR (400 MHz, DMSO-d6) δ=10.03 (d, J=4.0, 1H, 5-NHa), 10.00 (t, J=5.8, 1H, CF3CONH), 8.01 (d, J=4.0, 1H, 5-NHb), 7.86 (s, 1H, 1-NHa), 7.81 (s, 1H, 1-NHb), 7.51 (d, J=8.1, 2H, ArH), 7.30 (d, J=8.1, 2H, ArH), 5.54 (s, 2H, OCH2), 4.38 (d, J=5.8, 2H, CH2N) ppm.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1.[CH3:14]I>CS(C)=O>[CH3:14][O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1
Reactant: OCc1ccc2sccc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCc1ccc2sccc2c1
Yield: 69.9 %

Procedure:
To a stirred mixture of powdered KOH (18.9 g, 0.336 mol) in dimethylsulfoxide (100 ml) was added 5-hydroxymethylbenzo[b]thiophene (13.8 g, 0.084 mol) in 25 ml of dimethylsulfoxide. Then methyl iodide (23.9 g, 0.168 mol) was added dropwise at ambient temperature over several minutes. Stirring was continued for 11/2 hours. The mixture was filtered, diluted with water (150 ml) and extracted with methylene chloride (200 ml) in three portions. The combined extracts were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. This gave 14.1 g of amber liquid. Distillation gave 10.47 g of colorless liquid, b.p. 2.2 mm Hg 110°-111° C. (Yield 70%).
Reaction SMILES: [CH:1](=[C:8]1[C:16]2[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[N:24]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=5)[N:27]=4)[CH2:19][CH2:18]3)=[N:14][CH:13]=[N:12][C:11]=2[NH:10][C:9]1=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O=[Pt]=O>[CH2:1]([CH:8]1[C:16]2[C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[N:24]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[C:30]([C:35]([F:36])([F:38])[F:37])[CH:29]=5)[N:27]=4)[CH2:21][CH2:22]3)=[N:14][CH:13]=[N:12][C:11]=2[NH:10][C:9]1=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3c2C(=Cc2ccccc2)C(=O)N3)CC1
Agent: O=[Pt]=O
Solvent: CCO
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3c2C(Cc2ccccc2)C(=O)N3)CC1
Yield: 34.6 %

Procedure:
Combine 5-benzylidene-4-(4-(1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl)-piperidin-1-yl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.3 g; 0.00050 mol), PtO2/C (0.15 g; 0.00055 mol) in ethanol (5 mL) and stir under a hydrogen balloon atmosphere at 80° C. for 16 h. Cool the reaction to RT, filter through Celite® and concentrate. Purify over silica gel column using methanol in DCM as eluent to give the title compound (105 mg; 35%). MS (ES+): m/z=608 (M+1).
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.CC1C=C(N2CCOCC2)C=CC=1N.[CH3:55][C:56]1[CH:61]=[C:60]([N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)[CH:59]=[CH:58][C:57]=1[NH:68][C:69]([N:71]1[C:75]2[N:76]=[C:77]([N:105]3[CH2:110][CH2:109][O:108][CH2:107][CH2:106]3)[N:78]=[C:79]([C:80]3[CH:81]=[N:82][C:83]([N:86](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[N:84][CH:85]=3)[C:74]=2[CH2:73][CH2:72]1)=[O:70]>>[CH3:55][C:56]1[CH:61]=[C:60]([N:62]2[CH2:63][CH2:64][O:65][CH2:66][CH2:67]2)[CH:59]=[CH:58][C:57]=1[NH:68][C:69]([N:71]1[C:75]2[N:76]=[C:77]([N:105]3[CH2:110][CH2:109][O:108][CH2:107][CH2:106]3)[N:78]=[C:79]([C:80]3[CH:81]=[N:82][C:83]([NH2:86])=[N:84][CH:85]=3)[C:74]=2[CH2:73][CH2:72]1)=[O:70]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3ccc(N4CCOCC4)cc3C)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: Cc1cc(N2CCOCC2)ccc1N
Product: Cc1cc(N2CCOCC2)ccc1NC(=O)N1CCc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Yield: 63 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 2-methyl-4-morpholin-4-yl-phenylamine (39 mg) obtained in Step B instead of 2-methyl-5-morpholin-4-yl-phenylamine, in the same manner as Step C in Example 1-D-237, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (2-methyl-4-morpholin-4-yl-phenyl)-amide was obtained as a crude product. Using 195 mg of this compound, PMB group was removed according to Deprotection method 2, to obtain the desired compound (D-240) (90 mg, 63%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]([N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH3:22])=[O:20])=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:30]=1)=[O:4].[CH3:31][NH:32][CH3:33]>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:21]([CH3:22])[C:19]([C:17]1[S:16][C:15]2[C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:32]([CH3:33])[CH3:31])=[CH:30][C:10]=3[O:11][CH2:12][CH2:13][C:14]=2[CH:18]=1)=[O:20]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CCl)cc1OCC2)c1ccccc1Cl
Reactant: CNC
Product: CN(C)CC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedure in Example 147 for the synthesis of 237, 8-(2-chloroacetamido)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was reacted with dimethylamine to give 210. MS: (ESI+) 470.2
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=O>CO.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:14]([CH3:16])[C:13]([OH:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CC(=O)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 40 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
2,3,4-Trifluoronitrobenzene (1.01 g) and pyruvic acid (0.75 g) were dissolved in methanol (8 ml). After adding 5% Pd—C (0.11 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 4.9 MPa (converted from 50 kgf/cm2) for 5 hours. After filtering off Pd—C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (1.20 g) was obtained as colorless crystals. Various spectral data of this product was identical with those of a specimen synthesized separately.