Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=3[CH:26]=2)[O:3]1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:27])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]=[CH:14][C:13]=3[CH:26]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OB(c2ccc3c(c2)C=NCCO3)OC1(C)C
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (3.0 g, 8.00 mmol) in dichloromethane (90 mL) and trifluoroacetic acid (10 mL) was heated to reflux for 1 h, and then cooled to room temperature. The reaction mixture was concentrated and the residue was azeotroped with toluene (100 mL) to give 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazepine trifluoroacetate salt (2.9 g, quantitative yield). MS (EI) for C15H22BNO3: 276 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[N:16]([CH3:24])[N:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=2)=[O:13])=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[C:20]([C:18]1[CH:19]=[C:15]([NH:14][C:12](=[O:13])[NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:25])=[O:3])=[CH:10][CH:9]=2)[N:16]([CH3:24])[N:17]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 80 °C

Procedure:
To a suspension of 4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]benzoic acid ethyl ester (0.24 g, 0.71 mmol) in ethanol (4 mL) is added 1 N aq. NaOH solution (2 mL) and the mixture is heated at 80° C. for 2 hours. Then, 1 N HCl is added until pH 6 and the mixture is diluted with ethyl acetate. The organic phase is washed once with aqueous sodium chloride solution and dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 0.19 g (0.59 mmol), 83% as white solid. ES+(m/z) 317 [M+H].
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:20]#[N:21])=[CH:15][CH:14]=1>CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:20]#[N:21])=[CH:15][CH:14]=1
Reactant: BrCCc1ccccc1
Reactant: N#CC(c1ccc(F)cc1)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCc1ccccc1)(c1ccc(F)cc1)c1cccnc1
Reaction time: 0.25 h
Yield: 78 %

Procedure:
In a 300 ml. 3 neck round bottomed flask under N2 was charged 0.9 g. of 60% NaH (1.5 eq., 0.0225 moles), washed 2 times with 15 ml hexanes, in 40 ml. DMF and 5.5 g. of 2-bromoethylbenzene (2.0 eq., 0.030 moles). This was followed by the addition of 3.18 g. of alpha-4-fluorophenyl-3-pyridylacetonitrile (1.0 eq., 0.015 moles) in 10 ml. DMF which resulted in an exotherm to 46° C. After 15 min. GLC analysis showed no unreacted nitrile. The reaction was quenched by the addition of 100 ml. water and then extracted with 250 ml. ether. The organic phase was washed twice with 100 mi. water, dried over MgSO4 and concentrated to give 5.0 g. of oil. The crude product was purified by flash chromatography with 2:3 EtOAc/hexane to give 3.7 g. of an oil (78.0 % yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[CH2:10]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[N+:1]([O-:4])=[O:2])[CH3:11]
Reactant: CCOC(=O)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
10.0 mL of conc. HNO3 at 0° C. was slowly treated with 20.0 mL of conc. H2SO4, then 7.6 g (40 mmol) of 3,5-difluoro-benzoic acid ethyl ester. The reaction mixture was warmed up to room temperature and stirred overnight. This mixture was poured into a beaker containing ice. The resulting mixture was extracted with ethyl acetate, washed with cold water and evaporated to produce 7.4 g (32 mmol, 80%) of 3,5-difluoro-2-nitro-benzoic acid ethyl ester. LCMS: 232 (M+1)+.
Reaction SMILES: Cl.C([S:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[CH2:28][CH2:27]2)=[O:25])[CH2:7]1)(=O)C>O1CCOCC1>[SH:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@@H:8]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:36])[CH2:30][CH2:31]2)=[O:25])[CH2:7]1
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCCN1CCN(C(=O)[C@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 60.5 %

Procedure:
40 ml of a 10% w/v methanolic solution of hydrogen chloride were added to a solution of 1.0 g of (2S,4S)-4-acetylthio-2-(4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine [prepared as described in step (ii) above] in 10 ml of 1,4-dioxane, and the resulting mixture was stirred at 50° C. to 52° C. for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with 100 ml of ethyl acetate. The dilute solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and washed, in turn, with 30 ml of water and with 30 ml of an aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by colorful chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 566 mg of the title compound, as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:4]2[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]2)=[CH:10][CH:9]=1
Reactant: Nc1cc[nH]n1
Reactant: Fc1ccc(CBr)cc1
Product: Nc1ccn(Cc2ccc(F)cc2)n1

Procedure:
Prepared in analogy to example 10a) starting with 3-amino-1H-pyrazole and 4-fluorobenzylbromide. The title compound was obtained as a colorless solid (Yield=34%). MS ISP (m/e): 192.2 (100) [(M+H)+].
Reaction SMILES: [CH:1]([O:4][C:5](=[O:24])[C:6]1[CH:7]=[C:8]([CH:14]=[C:15]([C:17](=[O:23])[N:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[CH:16]=1)[C:9]([O:11]CC)=[O:10])([CH3:3])[CH3:2].C(O)(C)C.[OH-].[Li+]>[OH-].[Na+].O>[CH:1]([O:4][C:5](=[O:24])[C:6]1[CH:16]=[C:15]([C:17](=[O:23])[N:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[CH:14]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=1)([CH3:2])[CH3:3]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)OC(C)C)c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
Stir a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid 1-ethyl ester 3-isopropyl ester (149 mg, 0.4 mmol) in 0.2 N NaOH in 1:10 water:isopropanol (2.2 mL) overnight. Add 1 N lithium hydroxide (0.44 mL) and stir for 1 h at room temperature. Dilute with water and extract with dichloromethane. Acidify the aqueous with 5 N HCl, extract the aqueous with dichloromethane, dry (magnesium sulfate) and concentrate to give the title compound (79 mg, 56%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(-c3ccccc3)cc2)[nH]c1N
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere, 1.65 g (1 0 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride (for preparation see: Liebigs Ann. Chem., 1895 (1977)) are introduced into 10 ml of ethanol and, at 0-5° C., 0.73 g (10 mmol) of sodium ethanolate is added thereto. The bright yellow suspension is stirred for 20 min and then 1.4 g (5 mmol) of 2-bromo-1-(biphen-4-yl)-ethan-1-one (2-bromo-4'-phenyl-acetophenone; Aldrich; Milwaukee/USA) are added thereto. After 48 hours' stirring at RT, the reaction mixture is concentrated by evaporation and the residue is taken up in ethyl acetate and washed with 3 portions of water and brine. The aqueous phases are extracted twice with ethyl acetate and the organic phases are dried over MgSO4 and concentrated by evaporation. Column chromatography (SiO2 ; ethyl acetate/hexane [1:1]) and stirring in diisopropyl ether/hexane yield the title compound; m.p. 186-188° C.; TLC-Rf =0.17 (ethyl acetate/hexane [1:1]); FAB-MS: (M+H)+ =306.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:29])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccnc2)CC1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with nicotinoyl chloride hydrochloride (0.028 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (39 mg, 95%). LCMS calculated for C21H20ClN4O2 (M+H)+: m/z=395.1; Found: 395.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-n2cnnn2)c1
Solvent: CO
Product: Nc1cccc(-n2cnnn2)c1
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a 2 L pressure vessel was added 1-(3-nitrophenyl)-1H-tetrazole 10 (10.0 g, 52.3 mmol, 1.0 eq.) and methanol (500 mL). The resulting solution was purged with N2 for 5 min. 10% Pd/C (500 mg) was added to the solution and the vessel was placed on a Parr hydrogenator at 50 psi for 3 h. The Pd/C was removed by filtration and the filtrate was concentrated to yield a light gray solid (7.66 g, 91%). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 162.1 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d) δ 9.96 (s, 1H), 7.23-7.19 (m, 1H), 7.01-7.00 (m, 1H), 6.93-6.91 (m, 1H), 6.70-6.67 (m, 1H), 5.64 (m, 2H) ppm.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[CH:12]=[C:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18])([CH3:8])([CH3:7])[CH3:6]>>[CH3:1][NH:2][C:3]([N:15]1[CH2:16][CH2:17][C:13](=[CH:12][C:11]2[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]([OH:22])=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH:10]=2)[C:14]1=[O:18])=[O:4]
Reactant: CN=C=O
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Product: CNC(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 70.3 %

Procedure:
Methyl isocyanate (5.0 ml) was added to 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (277 mg, 0.75 mmole) (J. Med. Chem., p1995, 30, 1987) and the mixture was heated under reflux for 15 hours. The reaction mixture was evaporated under reduced pressure to obtain a residue, which was purified by using silica gel chromatography (n-hexane:ethyl acetate=4:1) and recrystallized from dichloromethane-ether, whereby 189 mg of the objective compound was obtained as white crystal in 70.3% yield. The physical constants are described on Table 1.
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O>ClCCl>[CH3:1][CH:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: OCCBr
Reactant: CC(N)c1ccccc1
Solvent: ClCCl
Product: CC1NCCc2ccccc21
Temperature: 52 °C
Reaction time: 50 h
Yield: 86.1 %

Procedure:
103.08 g(0.86 mole) of α-methylbenzylamine was dissolved in 110 ml of dichloromethane and 127.56 g(1.02 mole) of 2-bromoethanol was added thereto. This mixture was stirred at 52° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 109 g of the title compound, which had a pale yellow color.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][N:25]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)[N:26]=3)[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:37][O:38][CH2:39][CH2:40][NH2:41].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][N:25]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:34])=[CH:30][CH:29]=4)[N:26]=3)[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COCCN
Reactant: O=C(O)c1ccc(Cn2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNC(=O)c1ccc(Cn2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3n2)cc1
Yield: 229.5 %

Procedure:
A solution of 4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoic acid (45 mg), 2-methoxyethylamine (9 mg), 1-hydroxybenzotriazole (18 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (26 mg) and triethylamine (0.08 mL) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 30 hrs. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (basic silica gel; ethyl acetate) to give the title compound (115 mg) as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[C:34](#[N:37])[CH:35]=[CH2:36]>>[CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:36][CH2:35][C:34]#[N:37])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: C=CC#N
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(CCC#N)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and acrylonitrile were reacted to give 568. LCMS m/z: 250.7 (2M+H+)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([OH:14])=[CH:6][CH:5]=1.[O:15]([CH2:22][CH2:23][CH2:24]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([O:14][CH2:24][CH2:23][CH2:22][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1
Reactant: BrCCCOc1ccccc1
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1nc(Br)ccc1OCCCOc1ccccc1
Temperature: 100 °C
Yield: 85.5 %

Procedure:
Sodium hydride (60% in mineral oil, 172 mg, 4.53 mmol) was added to a mixture of methyl 6-bromo-3-hydroxypicolinate (26B) (1.0 g, 4.31 mmol) and 3-phenoxypropyl bromide (927 mg, 4.31 mmol) in DMA (20 mL) at it. The mixture was heated to 100° C. for 1.75 hours, cooled, diluted with 10% citric acid and extracted with EtOAc. The organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE:EtOAc 100:0-75:25, to provide 1.35 g (86%) of the desired product methyl 6-bromo-3-(3-phenoxypropoxy)picolinate (26C): 1H NMR (300 MHz, CDCl3) δ 7.52 (1H, d), 7.27 (2H, m), 6.92 (2H, m), 4.25 (2H, t), 4.19 (2H, t), 3.92 (3H, s), 2.30 (2H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[C:10]3[C:15]([N:16]=[C:17]4[C:22]=2[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:10]3[C:15]([N:16]=[C:17]4[C:22]=2[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:24][CH:25]=1
Reactant: COc1ccc(CNc2c3c(nc4ccccc24)CCCC3=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2c3c(nc4ccccc24)CCCC3O)cc1
Temperature: 0 °C

Procedure:
3,4-Dihydro-9-(4-methoxybenzylamino)acridin-1(2H)-one (4.25 g) was dissolved in 75 ml of dry THF and chilled with ice-water. 1M lithium aluminum hydride in THF (7.0 ml) was then added dropwise. After 15 minutes the reaction was quenched by the sequential dropwise addition of 0.4 ml of water, 0.4 ml of 15sodium hydride and 1.2 ml of water. The inorganic salts were filtered off, the solvents were evaporated, and the residue recrystallized from dichloromrthane-ether to give 3.0 g of analytically pure product, mp 163°-165° C.
Reaction SMILES: [CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18][NH2:19])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[CH2:28]([O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][C:37]([CH:41]=O)=[N:38]2)=[CH:33][C:32]=1[F:43])[CH3:29]>C(O)C>[CH2:28]([O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][C:37](/[CH:41]=[N:19]/[NH:18][C:15]3[N:14]=[CH:13][C:12]([C@H:7]([N:4]4[CH2:5][CH2:6][C@@:2]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:1])[CH2:3]4)[C:8]([F:9])([F:10])[F:11])=[CH:17][CH:16]=3)=[N:38]2)=[CH:33][C:32]=1[F:43])[CH3:29]
Reactant: CCOc1cc2nc(C=O)ccc2cc1F
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN([C@@H](c2ccc(NN)nc2)C(F)(F)F)C1
Solvent: CCO
Product: CCOc1cc2nc(/C=N/Nc3ccc([C@H](N4CC[C@](C)(NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 122, Steps A and B; 5.113 g, 13.13 mmol) in ethanol (25 mL) was added 7-ethoxy-6-fluoroquinoline-2-carbaldehyde (2.878 g, 13.13 mmol) and stirred overnight at ambient temperature. The precipitate was filtered to give desired product as a pale yellow solid (5.276 g). The filtrate was subjected to chromatography (C18, 300 g, 75 mL/min, 10% MeCN/H2O to 95% MeCN over 25 column volumes) and combined with the filtered product to give tert-butyl (S)-1-((S)-1-(6-((E)-2-((7-ethoxy-6-fluoro quinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ylcarbamate (6.322 g, 10.70 mmol, 81.53% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.[I-].[Na+].C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH:19]1([CH2:22][N:10]2[CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]=3[N:7]([CH3:13])[C:8](=[O:12])[CH2:9]2)[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CNC2
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CN(CC1CC1)C2

Procedure:
A mixture of 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0020 mol), [B] Cyclopropylmethyl bromide (0.55 mL, 0.0057 mol), Sodium iodide (0.003 g, 0.00002 mol) and N,N-Diisopropylethylamine (0.87 mL, 0.0050 mol) in N,N-Dimethylformamide (4 mL, 0.05 mol) was reacted in an analogous manner to example 743-C to give 4-Cyclopropylmethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a red oil. (0.56 g, 92%). LCMS (m/e) 306 (M+1); 1H-NMR (DMSO, 400 MHz) δ 7.92 (s, 1H), 7.44 (s, 1H), 3.95 (s, 3H), 3.66 (s, 2H), 3.26 (s, 2H), 3.13 (s, 2H), 2.89 (s, 1H), 2.73 s, 1H), 2.44-2.42 (d, 2H, J=6.57 Hz), 1.30-1.20 (br, 1H), 0.95-0.87 (br, 2H), 0.50 (d, 2H, J=7.83 Hz), 0.18-0.16 (d, 2H, J=4.80 Hz).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[N:22]=[CH:21]3)=[C:14]2[C:13]([C:31]([F:34])([F:33])[F:32])=[N:12]1)[C:5]([NH2:7])=[O:6].[NH2:35]C1C=C(C=CC=1N1C2=NC=CC(I)=C2C(C(F)(F)F)=N1)C(N)=O>>[NH2:35][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[N:22]=[CH:21]3)=[C:14]2[C:13]([C:31]([F:33])([F:34])[F:32])=[N:12]1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Reactant: Cc1cc(C(N)=O)ccc1-n1nc(C(F)(F)F)c2c(-n3cnc(-c4cnn(C)c4)c3)ccnc21
Product: Cn1cc(-c2cn(-c3ccnc4c3c(C(F)(F)F)nn4-c3ccc(C(N)=O)cc3N)cn2)cn1

Procedure:
According to Example 99(2), compound (155) (0.040 g, 36%) was prepared using compound (158b) (0.090 g) instead of compound (99a).