Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](Cl)=[O:25]>>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: O=C(Cl)c1ccccn1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccn4)nc23)CC1
Yield: 22.5 %

Procedure:
Beginning with 0.30 gm (1.30 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.34 gm (1.56 mMol) 2-pyridinecarbonyl chloride, 0.098 gm (26%) of the title compound were prepared as a crystalline solid essentially by the procedure described in Example 4.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH:7]1([NH:10][C:11](=O)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.O.[OH-].[Na+]>O1CCCC1>[CH:7]1([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8]1
Reactant: O=C(Cc1ccc(F)cc1)NC1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(CCNC2CC2)cc1
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
To a suspension of aluminum lithium hydride (0.86 g) in tetrahydrofuran (46 mL) was slowly added dropwise N-cyclopropyl-2-(4-fluorophenyl)acetamide (the compound of Preparation Example 22) (2.17 g) on an iceth. After steirring at room temperature for 8.5 hours, water (0.85 mL), an aqueous solution of 5N sodium hydroxide (0.85 mL) and water (2.5 mL) were poured sequentially, and the solution was stirred at room temperature for 15 hours. The resulting insoluble matter was removed by filtration, the residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (dichloromethane/methanol), and a crude purifcation product (424 mg) of cyclopropyl-[2-(4-fluorophenyl)ethyl]amine (pale yellow solids) was obtained. From 5-bromothiophene-2-sulfonyl chloride (243 mg) and the above-mentioned amine (354 mg), the title compound (85 mg) was obtained as a colorless oily matter in two steps, which were the same as Preparation Example 41 and Preparation Example 67.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.446 g, 2.15 mmol) and 6-chloro-3-(piperidin-4-yl)-1H-indole 0.500 g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate (0.593 g, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.330 g (37%) of a colorless foam. FDMS m/e=407 (M+ of free base).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4=CC=CC=C4C3=O)[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cccc(-c2nccn2CCCCCCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(-c2nccn2CCCCCCN)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-methyl-2-pyridyl)-1-(6-(phthalimido)hexyl)imidazole (4.2 g) in 50 mL EtOH was added 1.5 mL hydrazine hydrate. The resulting solution was stirred at 80° C. overnight. The solution was cooled to room temperature and suction filtered to remove the precipitate. The filtrate was evaporated to give the crude product, which was purified by a silica gel column using 5% conc. NH3H2O/CH3CN as the eluent. Yield: about 2.5 g.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH2:21].C(Cl)Cl.CO.[NH4+].[OH-]>>[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and Nε-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=119-121° C.). The reaction was monitored by tlc (Rf=0.46 in 90:10:1 CH2Cl2\MeOH\NH4OH).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.N>>[F:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]([CH2:6][NH2:7])=[CH:8][CH:9]=1
Reactant: Cc1nc(F)ccc1C#N
Agent: N
Product: Cc1nc(F)ccc1CN

Procedure:
The title compound was prepared using the procedure as described in Example 78B, substituting 6-fluoro-2-methyl-nicotinonitrile for the product of Example 78A. MS (DCI/NH3) m/z 141 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9]([S:24][CH3:25])[N:8]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]2)[N:10]=[C:9]([S:24]([CH3:25])=[O:39])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SC)nc1N1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(S(C)=O)nc1N1CCC(O)CC1
Reaction time: 1 h

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-methylthiopyrimidine (prepared in the above (4)) 121 mg in chloroform 3 ml is dropped a solution of m-chloroperbenzoic acid 54 mg in chloroform 4 ml on an ice bath over a period of 15 minutes, and the mixture is stirred for 1 hour. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1 yl)-2-methylsulfinylpyrimidine as a colorless caramel.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>C([O-])(=O)C>[C:25]1([CH2:31][C:32]([NH:1][CH:2]2[C:23](=[O:24])[N:4]3[C:5]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=4)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]23)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: O=C(Cl)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12

Procedure:
For example, p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate is reacted with phenylacetyl chloride in cold aqueous acetate containing sodium bicarbonate to provide p-nitrobenzyl 7-phenylacetamido-3-chloro-3-cephem-4-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:18][C:19]([C:21]3[C:22]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH:15]=2)[CH2:10]1.[CH2:38](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH3:38])[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:18][C:19]([C:21]3[C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=4)=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH:15]=2)[CH2:10]1
Reactant: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(NCc2ccccn2)C3)c1-c1ccc(C(F)(F)F)cc1
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(N(C)Cc2ccccn2)C3)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a solution of 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-pyridylmethylamino)-indan-5-yl] amide (the compound of Example 20f, 0.4 g, 0.8 mmol) in methylene chloride (5 mL) is added triethylamine (0.12 g, 1.15 mmol) and paraformaldehyde (0.024 g, 0.8 mmol). The mixture is stirred for two hours and then sodium triacetoxyborohydride (0.24 g, 1.12 mmol) is added. The mixture is stirred overnight and then washed with dilute sodium bicarbonate, dried over sodium sulfate, and evaporated. The residue is purified by flash chromatography (SiO2; ethyl acetate) to afford 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid [2[(2-pyridylmethyl)(methyl)amino]-indan-5-yl] amide as a white solid, mp 105-115°.
Reaction SMILES: COC(=O)C([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[C@@H:8]([O:14][C:15](=O)COC2C=CC=CC=2)[C:7]1=[O:25])=O.[Cl:27][C:28]([Cl:38])([Cl:37])[CH2:29][O:30][C:31](=[O:36])[CH:32]=[C:33]([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1>C(OC(=O)C)(=O)C.C(O)(=O)C>[Cl:27][C:28]([Cl:37])([Cl:38])[CH2:29][O:30][C:31](=[O:36])[C:32]([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[C@@H:8]([O:14][CH3:15])[C:7]1=[O:25])=[C:33]([CH3:35])[CH3:34]
Reactant: COC(=O)C(=O)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SC(C)=O
Reactant: CC(C)=CC(=O)OCC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CO[C@H]1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C)[C@@H]1SC(C)=O
Reaction time: 1.25 h

Procedure:
A solution of 3.26 g of 2- (3S,4R)-4-(benzthiazol-2-yldithio]-3-methoxy-2-oxoazetidin-1-yl]-3-methyl-crotonic acid 2,2,2-trichloroethyl ester in 36.3 ml of acetic anhydride and 12.4 ml of acetic acid is cooled to -15° and 1.7 g of triphenylphosphine are added. After stirring under nitrogen at the same temperature for 75 minutes, 24.8 ml of pyridine are added to the mixture. After stirring for a further 3 hours at 0°, the reaction mixture is concentrated by evaporation under reduced pressure and the resulting residue is purified by chromatography over silica gel with toluene and toluene/ethyl acetate (19:1). IR spectrum (in methylene chloride): characteristic absorption bands at 3.40, 5.63, 5.77, 5.80, 6.13, 7.25, 7.35, 8.26, 9.0, 9.52 and 11.90 μ.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[OH-].[Na+].C=O.C[CH2:18][OH:19]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:18][OH:19])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: CCO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCc1ccc2cc(F)ccc2n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
6-Fluoro-2-methylquinoline (1.00 g, 6.20 mmol) and sodium hydroxide were each added sequentially to the mixture of HCHO in water. Then 2 mL of EtOH were added to the mixture. The resulting solution was stirred at about 85° C. overnight. The organic layer was extracted with EA (3×10 mL), collected and dried with anhydrous Na2SO4, filtered and concentrated to afford a pink oil. The crude material was purified by chromatography on silica-gel (eluent: PE/EA=6/1) and then further purified by combi-flash chromatography (NH4HCO3/H2O, MeOH/H2O=40%-60%) to give 360 mg of the title product (yield: 30.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[C:13]4[O:18][CH2:17][O:16][C:14]4=[CH:15][C:8]=3[C:7](=[O:19])[C:6]=2[CH:20]=1.[CH3:21][N:22](C)C=O.C(Cl)(Cl)Cl.[C-]#N.[Na+]>O>[CH2:17]1[O:18][C:13]2[C:14](=[CH:15][C:8]3[C:7](=[O:19])[C:6]4[CH:20]=[C:2]([C:21]#[N:22])[CH:3]=[CH:4][C:5]=4[CH2:11][O:10][C:9]=3[CH:12]=2)[O:16]1
Reactant: O=C1c2cc(Br)ccc2COc2cc3c(cc21)OCO3
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)C(=O)c1cc3c(cc1OC2)OCO3

Procedure:
Heat a mixture of 9.26 gm. (0.0278 mole) of 9-bromo-6,11-dihydro-2,3-methylenedioxy-11-oxodibenz[b,e]oxepin, 5.23 (0.0584 mole) of cuprous cyanide and 33 ml. of dimethylformamide under reflux for 9 hours with vigorous stirring. Cool the reaction mixture and shake with a mixture of 45 ml. of chloroform, 32 ml. of saturated sodium cyanide solution and 32 ml. of water until all solids have dissolved. Separate the organic layer, wash with aqueous sodium cyanide solution and water and dry over anhydrous magnesium sulfate. Remove the solvent under vacuum to obtain the title product (yield 7.76 gm., m.p. 217°-220° C.). Recrystallize from acetic acid to obtain pure product as tan prisms [m.p. 224°-225° C., pmr (CDCl3) 5.03 (2H,s, CH2O), 617(2H,s,OCH2O--)].
Reaction SMILES: [C:1]([C:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[CH:4][C:5]([O-:7])=[O:6])#N.[K+].S(=O)(=O)(O)[OH:18].O>C(O)=O>[Cl:15][C:10]1[CH:9]=[C:8]([C:3]2[C:1](=[O:18])[O:6][C:5](=[O:7])[CH:4]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: N#CC(=CC(=O)[O-])c1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(O)O
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: O=C1C=C(c2ccc(Cl)c(Cl)c2)C(=O)O1
Reaction time: 1 h

Procedure:
25.8 g (92 mmol) of potassium 3-cyano-3-(3,4-dichlorophenyl)acrylate were dissolved in 200 ml of 88% strength formic acid and admixed dropwise with 15 ml of concentrated sulfuric acid. The mixed was then heated under reflux for 3 h, poured at 90° C. into 2.5 l of water and stirred for 1 h, and the product was filtered off, washed with water and dried. Yield: 18.9 g, m.p. 112° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][CH3:22])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][C:37]1[O:41][N:40]=[C:39]([C:42](Cl)=[O:43])[CH:38]=1.CNC>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([N:21]([CH3:22])[C:42]([C:39]5[CH:38]=[C:37]([CH3:36])[O:41][N:40]=5)=[O:43])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:27][CH:28]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CNC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: CNC
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N(C)C23CCC(CC2)Cn2c3nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)no1
Temperature: 25 °C
Yield: 16.5 %

Procedure:
To a solution of N-(4-fluorobenzyl)-3-hydroxy-10-(methylamino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.061 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.051 mL, 0.365 mmol) followed by 5-methylisoxazole-3-carbonyl chloride (17.69 mg, 0.122 mmol) and the resulting mixture was stirred at room temperature. After 16 at room temperature the reaction mixture was concentrated to give crude product which was dissolved in methanol (2 mL) and treated with 2M dimethylamine in methanol (0.5 mL). The resulting reaction mixture was stirred at 60° C. for 2 h, then cooled and purified by preparative HPLC to afford the title compound (5 mg, 17% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 11.81 (1 H, brs), 8.70 (1 H, d, J=5.19 Hz), 7.31 (2 H, dd, J=8.55, 5.49 Hz), 6.92-7.01 (2 H, m), 6.09 (1 H, s), 4.75-4.86 (1 H, m), 4.58-4.67 (1 H, m), 4.38-4.47 (1 H, m), 3.67 (1 H, d, J=15.56 Hz), 3.35-3.46 (1 H, m), 3.13 (3 H, s), 2.50 (1 H, brs), 2.41 (3 H, s), 2.07-2.16 (3 H, m), 1.95-2.05 (1 H, m), 1.72-1.86 (2 H, m), 1.37-1.50 (1 H, m). LCMS (M+H)=496.66. HPLC purity: >95%.
Reaction SMILES: Cl[C:2]1[C:3]([O:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:19]([C:2]1[C:3]([O:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:20]
Reactant: COC(=O)c1cnc(OC(C)C(F)(F)F)c(Cl)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Product: COC(=O)c1cnc(OC(C)C(F)(F)F)c(C#N)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 627 mg (2.21 mmol) of methyl 5-chloro-6-(2,2,2-trifluoro-1-methylethoxy)nicotinate (from Step B), 123 mg (0.22 mmol), 156 mg (1.33 mmol) of zinc cyanide, and 29 mg (0.44 mmol) of zinc dust in 5.0 ml of DMF was added 101 mg (0.11 mmol) of tris(dibenzylideneacetone)dipalladium(0). After stirring at 120° C. overnight, the mixture was filtered through a cake of Celite and washed with EtOAc. The filtrate was washed with brine (10 mL), H2O (3×10 mL), and brine (10 mL). The organic layer was dried over MgSO4 and concentrated. Chromatography on a Biotage 40M cartridge using 1:9 v/v EtOAc/hexanes as the eluant gave 498 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.59 (d, J=6.6, 3H), 3.97 (s, 3H), 5.93 (m, 1H), 8.54 (d, J=2.2, 1H), 8.96 (d, J=2.3, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]1[N:17]([CH2:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:16](=[O:24])[CH:15]([CH2:25][C:26](O)=[O:27])[S:14]1.[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:42][CH2:41][C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[NH:38][C:37]2=[O:47])[CH2:32][CH2:31]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]1[N:17]([CH2:18][CH2:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:16](=[O:24])[C@H:15]([CH2:25][C:26]([N:30]2[CH2:31][CH2:32][CH:33]([N:36]3[CH2:42][CH2:41][C:40]4[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=4[NH:38][C:37]3=[O:47])[CH2:34][CH2:35]2)=[O:27])[S:14]1
Reactant: CN(C)CCNc1c(F)cccc1C1SC(CC(=O)O)C(=O)N1CCC(C)(C)C
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCNc1c(F)cccc1C1S[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N1CCC(C)(C)C
Yield: 22.8 %

Procedure:
2-(2-(2-(2-(dimethylamino)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (125.5 mg, 0.295 mmol), 4,5-dihydro-3-(piperidin-4-yl)-1H-benzo[d][1,3]diazepin-2(3H)-one (144.7 mg, 0.5900 mmol), EDC (113.1 mg, 0.5900 mmol), and HOBt (90.35 mg, 0.5900 mmol) in DMF (6 mL) were stirred at RT overnight. The mixture was transferred to a separatory funnel with water, extracted with EtOAc (3×), the organic layers were combined, dried over Na2SO4 and concentrated to a brown oil. Crude product was purified by ISCO flash chromatography on a 12 g Redisep column eluting with 5-15% MeOH in CH2Cl2. Obtained 44 mg of desired 3-(1-(2-((5S)-2-(2-(2-(dimethylamino)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetyl)piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:33])[NH:27]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:32][C:31]1[C:23]([F:22])=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:33])=[CH:25]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OCc1ccccc1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCc1ccccc1
Yield: 38.2 %

Procedure:
A solution of 6-benzyloxy-4-chloro-7-methoxyquinazoline (0.39 g, 1.3 mmol), (EP1153920 production examples 28-30), 4-fluoro-5-hydroxy-2-methylindole (0.24 g, 1.43 mmol) and cesium carbonate (1.2 g, 4 mmol) in DMF (4 ml) was stirred at 95° C. for 45 minutes. After cooling, the mixture was filtered and the filtrate was evaporated under vacuum The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and ethyl acetate to give 6-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline (0.213 g, 37%).
Reaction SMILES: O1CCOCC1.C[O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19]C)=[C:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][C:30]#[C:31][CH2:32][OH:33])[C:10]=1[CH3:34].[N+]([O-])(O)=O>[Ag]=O.O>[CH3:34][C:10]1[C:9](=[O:8])[C:18]2[C:13]([C:12](=[O:19])[C:11]=1[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][C:30]#[C:31][CH2:32][OH:33])=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: COc1c(C)c(CCCCC#CCCCC#CCO)c(OC)c2ccccc12
Agent: O=[Ag]
Solvent: O
Solvent: C1COCCO1
Solvent: O=[N+]([O-])O
Product: CC1=C(CCCCC#CCCCC#CCO)C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 89.9 %

Procedure:
Dioxane (15 ml) was added to 1,4-dimethoxy-2-methyl-3-[(12-hydroxy-5,10-dodecadiynyl)]naphthalene (II, 0.57 g, 1.5 mmole) and silver oxide (0.74 g, 6.0 mmole), and the mixture was stirred under cooling with ice. 6 N nitric acid (1.5 ml) was added to the mixture over a 5-minute period and, 5 minutes later, the ice bath was taken off, followed by stirring at room temperature for 30 minutes. Water (20 ml) was added to the reaction solution, and the dioxane was distilled off under reduced pressure. Ethyl acetate (50 ml) was added to the residue, and the insolubles were filtered out. The organic layer was separated out, washed with water and dried (over MgSO4), followed by distilling off the solvent under reduced pressure. The crystals precipitated were recrystallized from isopropyl ether, thereby yielding the desired 2-methyl-3-(12-hydroxy-5,10-dodecadiynyl)-1,4-naphthoquinone (I, 0.47 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccccc1-c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(-c2ccccc2C(=O)O)c1

Procedure:
To a stirred solution of ethyl 2-(3-methoxyphenyl)benzoate from Step A (7.33 g, 28.6 mmol) in MeOH (200 mL) and water (30 mL) was added 1.0 N aq. NaOH (63 mL, 63 mmol) dropwise. The mixture was heated to reflux for 3 hours, then allowed to cool overnight. The solution was concentrated to remove most of the MeOH, cooled on ice, and 10% aq. citric acid (300 mL) was added. The resulting mixture was extracted with CH2Cl2 (3×250 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the titled product as a white solid.