Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([S:20][CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[S:45](Cl)(=[O:47])=[O:46].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[S:45]([NH:23][C@H:22]([C:24]([OH:26])=[O:25])[CH2:21][S:20][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=1)(=[O:46])=[O:47]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COc1ccc(C(SC[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C(SC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a stirred mixture of commercially available S-4-monomethoxytrityl-(L)-cysteine (11) (0.34 g, 1 mmol), dioxane (5 mL) and 10% aqueous sodium carbonate (5 mL) was added 2-naphtalenesulfonyl chloride (0.25 g, 1.1 mmol). After stirring for 1 h, the reaction mixture was acidified by addition of 5% aqueous citric acid (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (magnesium sulfate) and concentrated under reduced pressure. The crude product was chromatographed on silica gel (methanol/dichloromethane/triethylamine, 0/99/1 to 4/95/1, v/v/v) to yield 12 (76% yield, 0.44 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:41])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:31][CH2:32][O:33][Si](C(C)(C)C)(C)C)[CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[CH:14][CH:13]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CO>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:41])[CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH2:31][CH2:32][OH:33])[CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(C=CC(=O)Nc2ccccc2N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccccc1NC(=O)C=Cc1ccc(CN(CCO)CCc2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.2 %

Procedure:
To a stirred solution at −20° C. of 5 (1.49 g, 2.62 mmol) in anhydrous THF (30 mL) under nitrogen was slowly added a solution of TBAF (2.88 mL, 2.88 mmol, 1.0M in THF). The reaction mixture was allowed to warm-up to the room temperature over 1 h and was stirred for additional 22 hours. MeOH was added and the reaction mixture was concentrated, diluted with AcOEt, and successively washed with saturated aqueous solution of NaHCO3, H2O, a saturated aqueous solution of NH4Cl and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2, 5/95→10/90 plus several drops of NH4OH) and triturated with a mixture of AcOEt/CH2Cl2/hexane to afford the title compound 6 (956 mg, 2.10 mmol, 80% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.76 (s, 1H), 9.39 (s, 1H), AB system (δA=7.58, δB=7.44, JAB=8.0 Hz, 4H), 7.56 (d, J=15.7 Hz, 1H), 7.42-7.34 (m, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.05 (td, J=7.2, 1.2 Hz, 1H), 6.98-6.90 (m, 2H), 6.90 (d, J=15.8 Hz, 1H), 6.77 (dd, J=8.0, 1.4 Hz, 1H), 6.60 (ddd, J=7.5, 7.5, 1.4 Hz, 1H), 4.98 (bs, 2H), 4.43 (t, J=5.4 Hz, 1H), 3.78 (s, 2H), 3.56 (td, J=6.3, 5.6 Hz, 2H), 2.94-2.84 (m, 2H), 2.82-2.74 (m, 2H), 2.68 (t, J=6.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[N:5]=[C:4]2[NH:12][C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Si:34]([O:41][CH2:42][CH2:43][C:44]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>C1COCC1>[Si:34]([O:41][CH2:42][CH2:43][C:44]1([S:47]([N:12]2[C:4]3=[N:5][CH:6]4[N:10]([CH3:11])[CH:9]=[N:8][CH:7]4[C:2]([Cl:1])=[C:3]3[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:13]2=[O:23])(=[O:48])=[O:49])[CH2:46][CH2:45]1)([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCCC1(S(=O)(=O)Cl)CC1
Reactant: Cn1cnc2c(Cl)c3c(nc21)[nH]c(=O)n3-c1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C=NC2C(Cl)=c3c(n(S(=O)(=O)C4(CCO[Si](C)(C)C(C)(C)C)CC4)c(=O)n3-c3ccc(I)cc3F)=NC21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-chloro-1-(2-fluoro-4-iodophenyl)-5-methyl-3,5-dihydrodiimidazo[4,5-b:4′,5′-e]pyridin-2(1H)-one (example 16, step B) (150 mg, 0.35 mmol) in THF (5 ml) at −78° C. is added LiHMDS (0.39 ml, 1 M in THF, 0.39 mmol). The reaction mixture is stirred at −78° C. for 30 min and 1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropane-1-sulfonyl chloride (144 mg, 0.48 mmol) is added to the mixture. The reaction is slowly warmed to room temperature and stirred at the temperature for 16 h. The reaction is quenched with saturated aqueous NH4Cl solution (20 ml) and extracted with EtOAc (2×30 ml). The combined organic solution is washed with brine (30 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the desired product.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29]OC1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.CC1C=CC(S([O-])(=O)=[O:45])=CC=1.C1C=C[NH+]=CC=1>>[Si:1]([O:18][CH:19]([OH:45])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCCCCCC#CCCCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCCCC#CCCCC(O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 72 %

Procedure:
Following the procedure reported to prepare analog 25, 1-(tert-butyldiphenylsilyloxy)-11-(tetrahydro-2H-pyran-2-yloxy)undec-6-yne was cleaved with a catalytic amount of PPTS to give the title compound (72%) as a colorless liquid. TLC: EtOAc/hexanes (3:7), Rf˜0.43; 1H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 3.62 (t, J=5.6 Hz, 4H), 2.06-2.22 (m, 4H), 1.64-1.50 (m, 10H), 1.04 (s, 9H); 13C NMR (100 MHz) δ 135.82, 134.33, 129.77, 127.84, 80.77, 80.11, 64.06, 62.69, 32.35, 32.10, 29.10, 27.12, 25.60, 25.33, 18.97, 18.78. HRMS calcd for C27H39O2Si [M+1]+ 423.2719. found 423.2718.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[CH2:11][O:10][C@H:9]([CH2:12][O:13]C(=O)C)[CH2:8][O:7]1)(=O)C.O1CCOCC1.Cl>CO>[OH:4][CH2:5][C@H:6]1[CH2:11][O:10][C@H:9]([CH2:12][OH:13])[CH2:8][O:7]1
Reactant: CC(=O)OC[C@@H]1CO[C@@H](COC(C)=O)CO1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: OC[C@@H]1CO[C@@H](CO)CO1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a stirred suspension of trans-2,5-bis-(acetoxymethyl)-1,4-dioxane (14.5 g, 220 mmol, Preparation #11: Step a) in MeOH (40 mL) was added 4N.dioxane.HCl (20 mL, 220 mmol) and heated to reflux for 1 h. Then reaction mixture was cooled to RT and the solvents were evaporated under reduced pressure. The resulting oily residue was triturated with 10% EtOAc in hexane (3×50 mL) to afford trans-2,5-bis-(hydroxymethyl)-1,4-dioxane 9.0 g (97%) as brown solid; 1H NMR (400 MHz, CDCl3): δ 3.85-3.82 (m, 2H), 3.67-3.52 (m, 10H), 2.05 (bs, 1H); MS: m/z 149.1 (m+H)+.
Reaction SMILES: [C:1]1(=O)[C:5]2=[CH:6][CH2:7][CH2:8][CH2:9][N:4]2[CH:3]=[N:2]1.I[C:12]1[CH:19]=[C:18]([CH3:20])[C:15]([C:16]#[N:17])=[C:14]([CH3:21])[CH:13]=1>>[CH3:21][C:14]1[CH:13]=[C:12]([CH:6]2[CH2:7][CH2:8][CH2:9][N:4]3[CH:3]=[N:2][CH:1]=[C:5]23)[CH:19]=[C:18]([CH3:20])[C:15]=1[C:16]#[N:17]
Reactant: O=C1N=CN2CCCC=C12
Reactant: Cc1cc(I)cc(C)c1C#N
Product: Cc1cc(C2CCCn3cncc32)cc(C)c1C#N

Procedure:
starting from 6,7-dihydro-5H-imidazo[1,5-a]pyridin-one [426219-51-4] and 4-iodo-2,6-dimethylbenzonitrile [160682-00-8]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]=2[CH:15]=1.[N+:16]([O-])([OH:18])=[O:17]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]=2[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1coc2ccc(Br)cc12
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1coc2cc([N+](=O)[O-])c(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of ethyl 5-bromobenzofuran-3-carboxylate (95 g, 353 mmol) in CHCl3 (1000 mL), fuming HNO3 (192 mL, 95%) was added dropwise at −20° C. over 90 min and stirred at 0° C. for 1 hour. The reaction mixture was added to ice water and extracted with CH2Cl2. The organic layer was washed with NaHCO3 and brine. The solvent was removed by distillation to provide the crude product of ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, yield: 85%). It was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:11]2[C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:10]2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>[Pd].O>[C:15]1([N:13]2[C:12](=[O:21])[N:11]3[CH2:2][NH:3][C:4]4[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=4[C:10]3=[N:14]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1n(-c2ccccc2)nc2c3c(nc(Cl)n12)CCCC3
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=c1n(-c2ccccc2)nc2n1CNC1=C2CCCC1

Procedure:
A mixture of 5-chloro-2-phenyl-7,8,9,10-tetrahydro-1,2,4-triazolo[4,3-c]quinazolin-3-one (150 mg, 0.5 mmol), diisopropylethylamine (130 ml, 0.74 mmol) and 10% Pd-C (30 mg) was hydrogenated under H2 balloon for 1 hour. The reaction was filtered through Celite. NaBH4 (30 mg, 0.79 mmol) was added to the filtrate and the mixture was heated to reflux temperature. The reaction was poured into water and extracted with CH2Cl2 (3×50 ml). The combined organic layers were dried over Na2 SO4 and evaporated under reduced pressure. The residue was triturated with ethanol and filtered to afford 2-phenyl-5,6,7,8,9,10-hexahydro-1,2,4-triazolo[4,3-c]-quinazolin-3-one (Compound 31), m.p. 158°-159° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C1COCC1.CCO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:16]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(F)cc3)nc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2ccc(-c3ccc(F)cc3)nc2-c2ccc(O)cc2)cc1
Reaction time: 4 h
Yield: 89.1 %

Procedure:
The 2-(4-benzyloxyphenyl)-3-(4-methoxyphenyl)-6-(4-fluorophenyl)pyridine (1.2 g, 2.6 mmol) was dissolved in 50 mL of THF/ EtOH (1:1), 5% Pd/ C (0.3 g, 0.14 mmol Pd) added, and the reaction mixture hydrogenated at 40 psi for 4 h at rt. The reaction mixture was filtered and concentrated to give 0.86 g (90% yield) of white foam: mp 143°-145° C.; 1H NMR (CDCl3) d 3.83 (s, 3H, OCH3), 4.78 (s, 1H, ArOH), 6.72-6.75 (d, 2H, J=8 Hz, ArH), 6.84-6.87 (d, 2H, J=8 Hz, ArH), 7.14-7.27 (m, 4H, ArH), 7.37-7.40 (d, 2H, J=8 Hz, ArH), 7.69-7.73 (m, 2H, ArH), 8.10-8.15 (m, 2H, ArH); MS(FD) 371(M+). Anal. Calcd for C24H18 NO2F: C, 77.61; H, 4.89; N, 3.77. Found: C, 77.88; H, 5.12; N, 3.51.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([CH3:11])[CH:3]=1.[N+:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[CH:15]([N+:12]([O-:14])=[O:13])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N=C=O
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)Nc1ccc(Br)cc1C)[N+](=O)[O-]
Yield: 25 %

Procedure:
A mixture of 9.22 grams (0.04 mole) of 4-bromo-2-methylphenyl isocyanate, 5.78 grams (0.04 mole) of ethyl nitroacetate, 6.01 grams (0.04 mole) of anhydrous potassium carbonate and 90 milliliters of benzene was stirred and heated under reflux for 3 hours then cooled and stirred at room temperature for a period of about 16 hours. The precipitated material was filtered off and thoroughly triturated with 200 milliliters of ice water, filtering to remove a precipitate which was discarded. Chilling and acidification of the filtrate with concentrated HCl caused precipitation of a yellow-white solid which was collected, water-washed and air-dried. Recrystallization from benzene-cyclohexane (3:1) gave 3.38 grams (0.01 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-2-nitro-3-oxopropanoate as white crystals having a melting point of 126° C.-129° C.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[O:25]([CH2:32][C:33]1([NH2:36])[CH2:35][CH2:34]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:36][C:33]2([CH2:32][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:35][CH2:34]2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: NC1(COc2ccccc2)CC1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(COc4ccccc4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 163 mg (1 mmol) 1-phenoxymethyl-cyclopropylamine. Yield: 26 mg (5%, trifluoroacetate); mass spectroscopy: [M+H]+=371.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH:28]1([CH2:31]Br)[CH2:30][CH2:29]1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][CH2:31][CH:28]1[CH2:30][CH2:29]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(OCC2CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
A solution of ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (4.1 g, 11.26 mmol) was taken in 50 ml of DMSO and to it added Cs2CO3 (3.02 g, 12.39 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then added cyclopropylmethyl bromide (1.67 g, 12.39 mmol) dropwise. After completion of addition, the reaction mixture was stirred at 70° C. for 4 h. After completion of the reaction, it was poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:3) as eluent provided 3 g of ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.20 (s, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45(d,2H),1.95-2.00(m,1H), 1.75-1.80(m,1H), 1.45-1.50(m,1H), 1.20 (t,3H), 1.00 (m, 6H), 0.35-0.25 (m,5H). Mass: (414, M+1, 100%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[NH2:10][C@H:11]([C:19]([NH2:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[OH:20][C:19]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[N:21]=1
Reactant: O=C1CCCCC1=O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1nc2c(nc1Cc1ccccc1)CCCC2
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A methanol (30 ml) solution of 1,2-cyclohexanedione (13.44 g, 0.12M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1M) dissolved in methanol (200 ml) under cooling below -30° C., and aqueous 12.5N NaOH (20 ml) was added dropwise thereto. The reaction mixture was stirred under -30° C. for 30 mins., whereafter cooling was removed and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (15 g) was added after 10 mins. stirring the methanol then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was washed with water, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product (19.7 g, yield: 82.1%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:22])=[C:5]([C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].[Br-:23].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[Br:23][C:10]1[C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])=[C:5]([C:4]([CH3:22])=[C:3]([CH2:1][CH3:2])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CCc1ccc(NS(=O)(=O)c2ccccn2)c(C(=O)O)c1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(Br)c(NS(=O)(=O)c2ccccn2)c(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 130B (50 mg, 0.16 mmole) in DMF (5 mL) was added tetra-n-butylammonium tribromide (85 mg, 0.176 mmole), then water (5 mL). After stirring overnight at ambient temperature, the solvents were evaporated and the residue was partitioned between water and ethyl acetate (20 mL each). The two phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column eluting with 5% methanol in dichloromethane with 1% acetic acid to provide the desired product, 70 mg (95%). 1H NMR (DMSO-d6) δ 1.2 (t, 3H), 2.04 (s, 3H), 2.55 (q, 2H), 7.15 (s, 1H), 7.25 (t, 1H), 7.68 (d, 1H0, 7.86 (t, 1H), 8.58 (d, 1H), 10.05-13.00 (br s, 2H). MS (ESI(−)) m/e 397, 399 (M−H)−.
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:13][C:6]1[CH:5]=[C:4]([B:1]([OH:2])[OH:3])[CH:12]=[CH:11][C:7]=1[C:8]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:10]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccc(B(O)O)cc1F)N1CCOCC1
Yield: 90 %

Procedure:
A solution of 4-borono-2-fluorobenzoic acid (1.000 g, 5.44 mmol), morpholine (0.951 mL, 10.87 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.103 g, 5.53 mmol) in DMF (10 mL) was stirred at room temperature for 16 h and quenched with 1 N HCl (20 mL). Attempted extraction with EtOAc did not remove all of the product from aqueous phase. The two phases were combined, concentrated and purified by reverse phase HPLC (Sunfire S10 30×250 mm column, 30-45% solvent B gradient) to give the expected product as white solid (1.2385 g, 90% yield). MS (ES+) m/z: 254 (M+H); LC retention time: 2.06 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([O:11]CC2C=CC=CC=2)[C:8]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:7][N:6]=1.C1(C)C=CC=CC=1>CO>[CH3:1][O:2][C:5]1[NH:6][CH:7]=[C:8]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:9](=[O:11])[N:10]=1
Reactant: Cc1ccc(Cc2cnc(Cl)nc2OCc2ccccc2)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1nc(=O)c(Cc2ccc(C)nc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A solution of 13.25 ml (0.0581 m) of 25% sodium methoxide in methanol was added dropwise to a mixture of 20 g (0.063 m) of 2-chloro-4-benzyloxy-5-[(6-methyl-3-pyridinyl)-methyl]-pyrimidine prepared as in Example 3 and 250 ml of toluene. The mixture is allowed to stir overnight at room temperature then washed with water and evaporated. The residual oil which was 2-methoxy-4-benzyloxy-5-[(6-methyl-3-pyridinyl)-methyl]-pyrimidine was dissolved in ethanol and hydrogenated over 0.6 g of 10% palladium on charcoal. After hydrogen absorption, the reaction mixture was filtered, concentrated to an oil which was taken up in methylene dichloride. Ether was added to give 8.4 g (59%) of 2-methoxy-5-[(6-methyl-3-pyridinyl)-methyl]-4-(1H)-pyrimidinone, m.p. 145°-147°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[S:10][C:11]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[O:16])=[C:12]([CH3:14])[N:13]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(CC)CC>C(O)C>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[S:10][C:11]=1[C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccccc1C(=O)c1sc(NCCCCCN)nc1C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1sc(NCCCCCNS(=O)(=O)c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
A solution of 18 mg (0.05 mmol) [2-(5-Amino-pentylamino)-4-methyl-thiazol-5-yl]-o-tolyl-methanone hydrochloride in 1 ml ethanol was treated with 10.6 mg (0.06 mmol) benzenesulfonylchloride and 21 ml NEt3. The mixture was allowed to stir for 15 h at room temperature and afterwards subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 12.6 mg (55%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:4]=1[C:5]#[N:6].[Cl-].[NH4+]>CO>[C:5]([C:4]1[CH:7]=[C:8]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[NH2:11])#[N:6]
Reactant: COc1ccc([N+](=O)[O-])cc1C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(N)cc1C#N
Yield: 66.1 %

Procedure:
A mixture of 2-methoxy-5-nitrobenzonitrile (14 g), ammonium chloride (5 g), the powder of reduced iron (9 g) in methanol was refluxed for 4 hours and cooled. The reaction mixture was filtered and the filtrate was poured into water. The resultant precipitates were filtered and washed with water to give 3-cyano-4-methoxyaniline (7.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:37])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([Cl:37])=[O:26])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of step A (0.33 mmol) in dichloromethane (3 mL) was added a drop of N,N-dimethylformamide followed by oxalyl chloride (0.532 mmol). After stirring for 0.5 hour at room temperature, the solution was heated to reflux for three hours. The solvent and excess oxalyl chloride were evaporated to yield the crude product, which was used without further purification.