Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].F[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: COCCN
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCO
Product: COCCNc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-methoxyethaneamine (3 mL) is added to a solution of 1-fluoro-2-nitrobenzene (400 mg, 2.84 mmol) in ethanol. The reaction may be stirred at room temperature for an appropriate time period (such as overnight) and concentrated. The residue may be purified by any appropriate method including Biotage column chromatography to give N-(2-methoxyethyl)-2-nitroaniline (477 mg).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>CC(C)=O.O>[C:5]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([N:1]=[N+:2]=[N-:3])(=[O:17])=[O:16])=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Sodium azide (7.8 g, 120 mmol) was charged in a 1 L round bottom flask with water. 4-Acetamidobenzene-1-sulfonyl chloride (23.4 g, 100 mmol) was dissolved in acetone, and this solution was slowly added to the solution of sodium azide. The reaction was then stirred for 16 hours at room temperature and diluted with water. The acetone was then removed. The solid was filtered to give 4-acetamidobenzenesulfonyl azide (21 g, 87%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19]O.C=O>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[CH2:19])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CO
Agent: C=O
Solvent: O
Product: C=NN(C)C(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.5 %

Procedure:
To a test tube (outside diameter 21 mmφ×overall length 160 mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 380 mg of methanol and 130 μl of 37 wt % formalin aqueous solution were added and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture and the resultant was extracted with chloroform three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 97 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-methylidenehydrazine ((40-b)-(15)-1).
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][C:13]=2[N+:22]([O-])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4]>[Pt].C(#N)C>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][C:13]=2[NH2:22])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(CNc2c([N+](=O)[O-])cnc3ccccc23)no1
Agent: [Pt]
Solvent: CC#N
Product: CCCCc1cc(CNc2c(N)cnc3ccccc23)no1
Yield: 98.4 %

Procedure:
Catalytic 5% platinum on carbon (150 mg) was added to a suspension of N-[(5-butylisoxazol-3-yl)methyl]-3-nitroquinolin-4-amine (1.33 g, 4.08 mmol) in acetonitrile (50 mL), and the mixture was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for six hours. The mixture was filtered through a layer of CELITE filter agent, and the filtrate was concentrated under reduced pressure to provide 1.19 g of N4-[(5-butylisoxazol-3-yl)methyl]quinoline-3,4-diamine.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([CH3:14])=[C:8]([O:12]C)[CH:9]=2)[CH2:4][O:3]1.[H-]>CN(C=O)C>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([CH3:14])=[C:8]([OH:12])[CH:9]=2)[CH2:4][O:3]1
Reactant: COc1cc2c(c(OC)c1C)COC(C)C2
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1c(C)c(O)cc2c1COC(C)C2

Procedure:
A method for synthesizing isochromans comprising reacting 3,7-dimethyl-6,8-dimethoxyisochroman with sodium ethyl thiolate or hydride reagents in DMF to produce 3,7-dimethyl-6-hydroxy-8-methoxyisochroman.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][C:27](OCC)=[O:28])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][OH:28])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C

Procedure:
Ethyl 3-(1-trityl-4-imidazolyl)propionate (93.0 g, 223 mmol) in tetrahydrofuran/diethyl ether (1:1, 100 mL) was added dropwise to a suspension of lithium aluminium hydride (17.0 g, 446 mmol) during 1 hr. The mixture was refluxed for 3 hrs, then treated with water (100 mL), 20% sodium hydroxide (100 mL) and water (100 mL) under cooling with ice/water, filtered and the solid washed with tetrahydrofuran. The organic phase was dried over anhydrous potassium carbonate, filtered and evaporated to give 3-(1-trityl-4-imidazolyl)propanol as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37].[Cl-].[NH4+]>CN(C)C=O>[F:28][C:3]1[CH:4]=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=[CH2:32]
Reactant: C=CCCCCBr
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
512 mg (1.31 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 15 ml of dimethylformamide under argon atmosphere, 160 mg of sodium hydride (60% oil disperison) and 0.35 ml of 6-bromo-1-hexene were added under ice-cooling and the mixture was stirred at room temperature for 2 hours. An aqueous saturated solution of ammonium chloride was added to the reaction solution and the mixture was extracted three times with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to give 409 mg (66%) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(5-hexenylamino)-4H-1-benzopyran-4-one.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:12]([O-:17])(=[O:16])[CH:13]([CH3:15])[OH:14].C[N+](C)(C)C>CN(C)C=O>[C:12]([O:17][CH2:2][C:3](=[O:4])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:16])[CH:13]([CH3:15])[OH:14]
Reactant: O=C(CBr)Oc1ccccc1
Reactant: CC(O)C(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: CN(C)C=O
Product: CC(O)C(=O)OCC(=O)Oc1ccccc1
Yield: 31 %

Procedure:
Phenyl bromoacetate (45.0 g, 0.209 mol) was added to a stirring solution of tetramethylammonium lactate (40.7 g of an 88% aq soln, 1.05 eq) in 50 mL of dimethylformamide at room temperature. The resulting tetramethylammonium bromide which separated from the reaction mixture as a solid was removed by filtration and washed with ethyl acetate. The dimethylformamide and ethyl acetate solutions were combined and washed with a NaHCO3 /brine solution, the separated aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgSO4. The solvent was removed and the resulting residue was chromatographed on silica gel (ethyl acetate/hexane) to give the title compound (14.7 g, 31%): 1H NMR δ 1.50 (d, 3H, J=7.0), δ 3.12 (d, 1H, J=5.3), δ 4.40-4.49 (m, 1H), δ 4.87 (d, 1H, J=16.1), δ 4.99 (d, 1H, J=16.2), d 7.09-7.40 (5H, phenyl); HRMS calcd for C10H8O5TMS (M--CH3) 281.0845, obsd 281.0856.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11]N(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][O:8][C:6]=2[N:7]=1.[CH:26]1[C:36]2[C:30](=[N:31][C:32]3[CH:40]=[CH:39][CH2:38][CH2:37][C:33]=3[CH2:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=1.[H-].[Na+].NC1N=C(N)C2C(CCl)=COC=2N=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][CH:37]3[C:33]4[CH2:34][CH:35]=[C:36]5[CH:26]=[CH:27][CH:28]=[CH:29][C:30]5=[N:31][C:32]=4[CH:40]=[CH:39][CH2:38]3)=[CH:9][O:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)coc2n1
Reactant: C1=CC2=C(CC=c3ccccc3=N2)CC1
Agent: Nc1nc(N)c2c(CCl)coc2n1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(N)c2c(CC3CC=CC4=C3CC=c3ccccc3=N4)coc2n1

Procedure:
9-[(2,4-Diaminofuro[2,3-d]pyrimidin-5-yl)methyl]-9,10-dihydrodibenz-[b,f]azepine (Formula I: Ar=2,4-diaminofuro[2,3-d]pyrimidin-5-yl; W=CH2; X=N; Z=CH2CH2; m=n=0) is prepared similarly to N-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed above by using 9,10-dihydrodibenz[b,f]azepine (158 mg, 0.8 mmol), sodium hydride (50 mg, 2.1 mmol), and 2,4-diamino-5-chloromethylfuro[2,3-d]pyrimidine (60 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:13]2[CH:18]=[C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][C:14]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])[CH2:12][CH2:11][CH2:10][CH:9]=1.[CH3:35][N:36]1[CH:40]=[CH:39][N:38]=[C:37]1[CH:41]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:13]2[CH:18]=[C:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:41][C:37]4[N:36]([CH3:35])[CH:40]=[CH:39][N:38]=4)[CH2:21][CH2:20]3)[CH:16]=[CH:15][C:14]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCC2)n1
Reactant: Cn1ccnc1C=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccnc1CN1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCC3)c2)CC1

Procedure:
This compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 18) and 1-methyl-1H-imidazole-2-carbaldehyde according to the procedure in Example 21. 1H-NMR (400 MHz, CD3OD): δ 8.03 (m, 2H), 7.50 (d, 1H), 7.42 (s, 1H), 7.20 (m, 2H), 6.02 (m, 1H), 4.22 (s, 2H), 3.96 (s, 3H), 3.30 (m, 2H), 2.82-2.40 (m, 7H), 2.13-1.84 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H29N7O, 456.2 (M+H), found 456.2.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:26]4[C@H:25]([CH3:24])[CH2:29][O:28][C:27]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)nc3)CC2)c(C)c1
Yield: 47.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (187.6 mg) described in Preparation Example 73 and (R)-4-methyloxazolidin-2-one (50.6 mg) described in Preparation Example 25, the title compound (94.5 mg) was obtained.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:17])([F:16])[C:5]([C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([OH:7])[CH3:6].C([O-])(=O)C.[K+].[OH-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[Br:1][C:12]1[CH:13]=[C:8]([C:5]([OH:7])([CH3:6])[C:4]([F:3])([F:16])[F:17])[CH:9]=[N:10][C:11]=1[O:14][CH3:15]
Reactant: BrBr
Reactant: COc1ccc(C(C)(O)C(F)(F)F)cn1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ncc(C(C)(O)C(F)(F)F)cc1Br
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Bromine (0.734 mL, 14.24 mmol) was added under nitrogen atmosphere to an acetic acid (20 mL, 349 mmol) mixture of (RS)-1,1,1-trifluoro-2-(6-methoxypyridin-3-yl)propan-2-ol (Step A, 2.1 g, 9.49 mmol) and potassium acetate (4.66 g, 47.5 mmol), which was then stirred for 30 minutes at 80° C. in oil bath. LCMS showed 30% conversion to product with a clean profile. The reaction was allowed to stir for 1.5 hours total at 80° C. and LCMS showed 40% conversion. Two additional bromine additions (0.734 mL, 14.24 mmol each) were added 30 minutes apart. The reaction was then allowed to stir at 25° C. for 48 hours. The reaction was 80% complete by LCMS. It was diluted with ethyl acetate and poured slowly into 5N NaOH (70.1 mL, 350 mmol) to neutralize the acetic acid. The organic layer was washed with brine (100 mL) and concentrated. Silica gel chromatography using a linear gradient of 0-100% ethyl acetate/hexanes gave the title compound as a pale yellow solid. LCMS (M+H)+: 302.2. 1H NMR (CDCl3, 500 MHz): δ 8.29 (d, J=1.8 Hz, 1H), 8.07 (d, J=1.8 Hz, 1H), 4.06 (s, 3H), 2.53 (s, 1H), 1.81 (s, 3H).
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[C:8]([NH:10][C@@H:11]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)[C@H:12]([OH:26])[CH2:13][NH:14][C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[CH:19]=2)[CH2:17][CH2:16]1)=[O:9])[CH:2]=[CH2:3].CC(O)=[O:41].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.CCOCC>[CH2:1]([S:4]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[C:8]([NH:10][C@@H:11]([CH2:27][C:28]1[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=1)[C@H:12]([OH:26])[CH2:13][NH:14][C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[CH:19]=2)[CH2:17][CH2:16]1)=[O:9])=[O:41])[CH:2]=[CH2:3]
Reactant: CC(=O)O
Reactant: C=CCSc1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2(c3cccc(CC)c3)CC2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCS(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2(c3cccc(CC)c3)CC2)c1
Reaction time: 0.5 h

Procedure:
3-(allylthio)-N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)benzamide (325 mg, 0.606 mmol) was dissolved in CH2Cl2 (10 mL) and AcOH (1 mL)and treated with mCPBA (104 mg, 0.606 mmol). The reaction mixture was stirred for 2.5 h, at which time more mCPBA (20 mg, 0.11 mmol) was added and stirring continued for 30 min. more. The organic layer was diluted with Et2O and washed with 15% sodium thiosulfite solution. The organic was washed with brine, then dried (MgSO4) and concentrated to give an oil, which was chromatographed with 25% to 50% EtOAc in hexanes to give the title compound. (LRMS (M+H) m/z 553.8)
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([NH:28][C:29](=[NH:33])[S:30][CH2:31][CH3:32])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:34]>>[ClH:34].[ClH:34].[NH2:8][CH2:16][C:17]1[CH:18]=[C:19]([NH:28][C:29](=[NH:33])[S:30][CH2:31][CH3:32])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27]1
Reactant: CCSC(=N)Nc1ccc(-n2cccc2)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: Cl
Product: CCSC(=N)Nc1ccc(-n2cccc2)c(CN)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of the compound (40 mg) obtained in Example 1g and 4 N HCl (10 ml) was stirred at room temperature for 1 hour and then concentrated at reduced pressure to give the titled compound (28 mg; yield, 96%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[CH:12]=[C:13]([C:16]([Cl:19])=[CH:17][N:18]=1)[C:14]#[N:15].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[Cl:19][C:16]1[C:13]([C:14]#[N:15])=[CH:12][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:18][CH:17]=1
Reactant: N#Cc1cc(Cl)ncc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: N#Cc1cc(-c2ccccc2)ncc1Cl

Procedure:
Tetralds(triphenylphosphine)palladium(0) (167 mg, 0.14 mmol) was added to a stirred solution of phenylboronic acid (423 mg, 3.47 mmol), 2,5-dichloro-isonicotinonitrile (550 mg, 2.89 mmol) and sodium carbonate (3.5 mL of 2M aqueous solution) in dimethoxyethane (7 mL) and ethanol (3.5 mL). The resulting suspension was stirred at reflux for 3 hours, concentrated in vacuo and water (25 mL) added. The aqueous solution was extracted with ethyl acetate (×3) and the combined organic extracts were washed with brine, dried and concentrated. Purification by column chromatography using 2% v/v ethyl acetate in hexane as eluent afforded the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][C@@:9]1([CH3:30])[C:10](O)=[O:11])=[O:7])([CH3:4])[CH3:3].C([N:34](C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C[Si](N[Si](C)(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:34][C:10]([C@:9]1([CH3:30])[CH2:13][CH2:14][C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])=[O:11]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A solution of (5R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methyl-5-{4-[(phenylmethyl)oxy]phenyl}-L-proline (D8, 870 mg, 2.11 mmol), diisopropylethyl amine (0.74 ml, 4.22 mmol) and TBTU (814 mg, 2.53 mmol) in dry DMF (8 ml) was stirred for 15 min at room temperature. HMDS (0.70 ml, 3.17 mmol) was added and stirring was continued at room temperature overnight. The mixture was cooled to 0° C. and saturated aqueous NaHCO3 solution was added. The mixture was extracted with ethyl acetate and washed three times with ice cold brine. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane and ethyl acetate (7:3) to afford the title compound (857 mg, 99%); Rt (HPLC): 5.85 min; MS: (ES/+) m/z: 433 [M+Na+]; C24H30N2O4 requires 410; Rf (cyclohexane:ethyl acetate=6:4): 0.32.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH:19]([CH2:21][C:22]([O:24]CC)=[O:23])[C:18]4[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=4[CH2:16][C:15]=3[CH:31]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH:19]([CH2:21][C:22]([OH:24])=[O:23])[C:18]4[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=4[CH2:16][C:15]=3[CH:31]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCc3cccc(N)n3)cc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cccc(CCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)O)C3)n1
Yield: 46.5 %

Procedure:
A solution of ethyl (±)-10,11-dihydro-3-[2-(6-aminopyridin-2-yl)-1-ethoxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (0.030 g, 0.072 mmole) and 1.0 N NaOH (0.14 mL, 0.14 mmole) in MeOH (2 mL) was stirred at RT overnight, then was concentrated. The residue was dissolved in H2O and the pH of the solution was adjusted to 7 with 1.0 N HCl. Concentration and chromatography on a C-18 Bond Elute column (10:9:1 CH3CN/H2O/TFA) gave the title compound (0.013 g): MS (ES) m/e 389 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1cc2c(N3CCOCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C25H25ClN6O3, 492.9
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][C@H:15]([C:17]([C:19]1([NH2:40])[C:25](=[O:26])[N:24]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[N:21]([CH2:35][CH:36]2[CH2:38][CH2:37]2)[C:20]1=[O:39])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][C@H:15]([C:17]([C:19]2([NH2:40])[C:25](=[O:26])[N:24]([CH2:27][CH:28]3[CH2:29][CH2:30]3)[C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[N:21]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[C:20]2=[O:39])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white solid (melting point=211-212° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.44 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=[O:11])[CH3:10])[C:3]=1[NH2:4].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:4][C:3]1[C:5]([C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)c1cccc(C)c1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc(C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-6-acetylaniline (25 g) and pyridine (26.5 g) in 1 liter methylene chloride were cooled in an ice-acetone bath. A solution of chloroacetyl chloride (37.9 g) in 100 ml methylene chloride was dripped in slowly. The solution was stirred at room temperature for 2 hours, washed with 10% HCl, 10% NaOH, dried (MgSO4) and stripped. Yield: the title product as a white solid, MP 88°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=2[C:12]1=[O:21]>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=2[C:12]1=[O:21]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])ccc1F
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Yield: 78.1 %

Procedure:
To a suspension of electrolytic iron powders (9 g) in 5% acetic acid (200 g) under reflux, a solution of N-(2-fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide (VII) (15 g) in acetic acid (50 g) was added dropwise. After completion of the addition, the resultant mixture was heated under reflux for 30 minutes, cooled and filtered. The filtrate was diluted with water and extracted with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration to give 10.5 g of N-(2-fluoro-5-aminophenyl)-3,4,5,6-tetrahydrophthalimide (VIII). M.P., 117°-119° C.