Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][C:8](=O)[CH2:9][CH3:10].[NH2:13][NH2:14]>CC#N.O>[CH2:9]([C:8]1[CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:14]2[N:13]=1)[CH3:10]
Reactant: CCC(=O)CC(=O)CCCCCl
Reactant: NN
Solvent: O
Solvent: CC#N
Product: CCc1cc2n(n1)CCCC2

Procedure:
To a solution of 1-chloro-5,7-nonanedione (14.74 g, from Step 1) in a mixture of CH3CN (100 mL) and H2O (33 mL) was added 4.87 mL of hydrazine. After refluxing for 18 h, the reaction mixture was partitioned between EtOAc and aqueous NaHCO3 (saturated). Aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. After concentration, the residue was purified by flash chromatography with 20% EtOAc in hexanes followed by 50% EtOAc in hexanes to give the title compound as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 1.24 (t, 3H, J=7.5 Hz), 1.79-1.85 (m, 2H), 1.95-2.05 (m, 2H), 2.62 (q, 2H, J=7.8 Hz), 2.75 (t, 2H, J=6.4Hz), 4.08 (t, 2H, J=6.1 Hz), 5.78 (s, 1H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:27][C@@H:28]([CH3:29])[C:30]([OH:32])=[O:31])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)=[CH:21][CH:22]=1
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(Cl)cc3)ccc2c1O
Product: C[C@H](NC(=O)c1ncc2cc(Oc3ccc(Cl)cc3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-50 by reacting 7-(4-Chloro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (compound of example A-60 a) with L-alanine in a microwave reactor for 20 min at 130 C. MS-(−)-ion: M−1=385.1.
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[C:22][Si](C)(C)C)[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:2][CH2:3]1
Reactant: CN(Cc1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
A solution of 8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-6-trimethylsilanylethynyl chroman (Intermediate 10, 0.729 g, 1.97 mmol) in methanol (30 mL) was treated with potassium carbonate (1.4 g, 10.2 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown oil (0.571 g, 98%).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:24]>CN(C)C=O>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH3:10])[C:8]([NH2:9])=[S:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S
Reactant: CC(C#N)(c1ccccc1)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C(N)=S)(c1ccccc1)c1ccccn1

Procedure:
With continuous stirring, subject a mixture containing 6 g. of α-phenyl-α-(2-pyridyl) propionitrile and 5 ml. of triethylamine in 60 ml. of dimethylformamide to a stream of hydrogen sulfide for 24 hours. Pour the resulting solution into 200 ml. of ice water, filter, wash and dry the solids which are formed. Recrystallize the solids from acetonitrile to obtain the intermediate α-phenyl-α-(2-pyridyl) thiopropionamide, m.p. 186°-183° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][CH:9]([N:11]([CH2:13][C@@H:14]2[C@@H:21]3[C@@H:17]([O:18][C:19]([CH3:23])([CH3:22])[O:20]3)[C@H:16]([N:24]3[CH:32]=[N:31][C:30]4[C:25]3=[N:26][CH:27]=[N:28][C:29]=4[NH2:33])[O:15]2)[CH3:12])[CH2:8]1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].O>CN(C=O)C>[N:34]([CH2:6][CH:7]1[CH2:8][CH:9]([N:11]([CH2:13][C@@H:14]2[C@H:21]3[O:20][C:19]([CH3:22])([CH3:23])[O:18][C@H:17]3[C@H:16]([N:24]3[CH:32]=[N:31][C:30]4[C:25]3=[N:26][CH:27]=[N:28][C:29]=4[NH2:33])[O:15]2)[CH3:12])[CH2:10]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CN=[N+]=[N-])C1
Temperature: 70 °C
Yield: 67.6 %

Procedure:
To a solution of (3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)methyl methane sulfonate (150 mg, 0.31 mmol) in DMF (3 ml) was added NaN3 (81 mg, 1.24 mmol). The mixture was heated at 70° C. for 3 h. Water (30 ml) was added and the mixture was extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by Prep-TLC (DCM:MeOH=30:1) to obtain the title compound (90 mg, Yield 67%). ESI-MS (m/z): 430.2 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:56][C@H:57]([C:59]([O:61][CH2:62][CH2:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[C:76]([C:77]#[N:78])=[C:75]([N:79]3[CH2:83][CH2:82][CH2:81][CH2:80]3)[N:74]=[C:73]([S:84][CH2:85][C:86]3[N:87]=[C:88]([C:91]4[CH:96]=[CH:95][C:94]([Cl:97])=[CH:93][CH:92]=4)[S:89][CH:90]=3)[C:72]=2[C:98]#[N:99])=[CH:67][CH:66]=1)=[O:60])[CH3:58]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:56][C@H:57]([C:59]([O:61][CH2:62][CH2:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[C:76]([C:77]#[N:78])=[C:75]([N:79]3[CH2:80][CH2:81][CH2:82][CH2:83]3)[N:74]=[C:73]([S:84][CH2:85][C:86]3[N:87]=[C:88]([C:91]4[CH:92]=[CH:93][C:94]([Cl:97])=[CH:95][CH:96]=4)[S:89][CH:90]=3)[C:72]=2[C:98]#[N:99])=[CH:67][CH:66]=1)=[O:60])[CH3:58])=[O:16])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
217 mg (0.942 mmol) of N-(tert-butoxycarbonyl)-L-isoleucine together with 246 mg (1.284 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 157 mg (1.027 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 0.746 ml (4.281 mmol) of N,N-diisopropylethylamine were dissolved in 7.5 ml of DMF, after which 650 mg (0.856 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl L-alaninate trifluoroacetate were added. After stirring at room temperature overnight, the reaction mixture was purified by preparative HPLC (acetonitrile/water). This gave 414 mg (56% of theory) of the target compound.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29]CC)=O)=[N:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[NH3:32].CO>>[NH2:24][C:21]1[CH:22]=[CH:23][C:17]2=[CH:16][CH:15]=[C:14]3[C:19]([N:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:6]=4)[N:12]=[C:13]3[C:27]([NH2:32])=[O:29])=[C:18]2[CH:20]=1
Reactant: N
Reactant: CCOC(=O)c1nn(-c2cccc(S(N)(=O)=O)c2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Solvent: CO
Product: NC(=O)c1nn(-c2cccc(S(N)(=O)=O)c2)c2c1ccc1ccc(N)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sealed solution of ethyl 1-[3-(aminosulfonyl)phenyl]-8-nitro-4,5-dihydro-1H-benzo[g]indazole-3-carboxylat from step 1 (2.20 g, 4.98 mmol) in excess NH3/MeOH was heated at 110° C. for 10 h. The mixture was then concentrated to 10 mL, cooled to RT and the solid product collected by filtration. The solid was dissolved in HOAc, exposed to H2 (5 psi) at RT in the presence of Pd—C (5%) for 2 h. The mixture was filtered through celite pad, concentrated, taken into MeOH, filtered again through celite. The clear solution was concentrated, recrystallized in EtOH to give a grey solid (450 mg). Its structure was confirmed by 1H NMR and MS (382, M+1). C18H15N5O3S.H2O.(Et2O)0.2, Calc.: C: 54.51, H: 4.62, N: 16.91; Found, C: 54.79, H: 4.06, N: 16.72.
Reaction SMILES: C[C@@H]([C@@H]1[C@@:12]2(C)[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@]4(C)C[CH2:22][C@@H:23](O)[CH2:24][C@H:19]4[CH2:18][CH2:17][C@@:16]3(C)[C@@H:11]2[CH2:10][CH2:9]1)CCC([O-])=O.[Na+].[OH:31][CH2:32]C(CO)O>>[CH3:12][C:13]([CH2:14][CH2:15][C:16]1[CH:11]=[CH:10][C:9]2[CH:22]=[C:23]([O:31][CH3:32])[CH:24]=[CH:19][C:18]=2[CH:17]=1)=[O:28]
Reactant: C[C@H](CCC(=O)[O-])[C@H]1CC[C@H]2[C@]3(C)CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: OCC(O)CO
Agent: [Na+]
Product: COc1ccc2cc(CCC(C)=O)ccc2c1

Procedure:
A weighed quantity of the drug material and a volume of a solution containing 2.2% Poloxamer 188, 0.1% sodium deoxycholate, and 2.2% glycerin adjusted to pH 8.7 were combined and mixed under high shear to form a pre-suspension. The pre-suspension was homogenized for 20 discrete passes at a pressure of 25,000 psi.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:35])[CH2:17][CH2:18][C:19]([C:21]3[CH:34]=[CH:33][C:24]4[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29][C:23]=4[CH:22]=3)=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:35])[CH2:17][CH2:18][CH:19]([C:21]3[CH:34]=[CH:33][C:24]4[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29][C:23]=4[CH:22]=3)[OH:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)N1CCc2ccc(C(=O)CCC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CCc2ccc(C(O)CCC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (81 mg, 2.14 mmol) was added to a suspension of 4-[4-(4-chlorophenyl)-1-piperidinyl]-1-(3-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4-oxo-1-butanone (0.50 g, 1.07 mmol) obtained in Example 30 in methanol (20 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residues were partitioned into ethyl acetate and water. The ethyl acetate layer was washed with a saturated saline solution and dried over magnesium sulfate. The solvent was distilled away under reduced pressure, whereby the title compound was obtained as amorphous powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[C:4]([C:8]2(O)[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([F:18])=[C:4]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:15])[CH3:16])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1CCC(O)(c2cccc(Br)c2F)CC1
Solvent: Cc1ccccc1
Product: CN(C)C1CC=C(c2cccc(Br)c2F)CC1
Yield: 88.4 %

Procedure:
Heat 1-(3-bromo-2-fluoro-phenyl)-4-dimethylamino-cyclohexanol (preparation 6, 2.04 g, 6.45 mmol) and p-TsOH monohydrate (3.07 g, 16 mmol) in toluene (50 mL) at reflux for 2 hr. Partition the reaction mixture between saturated aqueous NaCl and ethyl acetate, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by chromatography on a silica gel column (DCM: 2M NH3 in MeOH, gradient) to give the title product (1.70 g): MS (ES): m/z=300 (M+H)+ and 298 (M−H)−. 1HNMR (CDCl3): δ 7.39 (m, 1H), 7.14 (m, 1H), 6.94 (m, 1H), 5.88 (m, 1H), 2.60-2.38 (m, 4H), 2.35 (s, 6H), 2.20 (m, 1H), 2.08 (m, 1H), 1.56 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28](OC)=[O:29])[C:15](=[O:27])[N:16]3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:29])[C:15](=[O:27])[N:16]3[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(OC)cc2)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(OC)cc2)c1=O
Yield: 89 %

Procedure:
In a similar manner to that described in example 196, from methyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.115 mmol) and [2-(methyloxy)ethyl]amine was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (47 mg, 89% yield) as a white solid. 1H NMR (CDCl3) δ 10.14 (s, 1 H), 8.47 (s, 1 H), 7.12-7.04 (m, 4 H), 7.00-6.96 (m, 2 H), 6.93-6.89 (m, 2 H), 6.74 (s, 1 H), 3.91 (s, 2 H), 3.86 (s, 3 H), 3.59 (m, 2 H), 3.51 (m, 2 H), 3.31 (s, 3 H); HRMS m/z calcd for C26H25FN3O5: 478.1773. Found: 478.1773.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 48 %

Procedure:
Solid N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester, 15.5 g (0.04 mole) was heated in glass at 210°-20° C. in a Wood's metal bath for 8 minutes. The residue was dissolved in methylene chloride, treated with charcoal, and filtered through a Celite pad. The filtrate (red) was treated with Florisil® to give a colorless filtrate. The filtrate was evaporated to give a solid, which was recrystallized from tetrahydrofuran-petroleum ether. The solid was collected, washed with petroleum ether (along with a small amount of tetrahydrofuran), and dried under high vacuum at 50° C. overnight to give 7.0 g (48%) of title compound, mp 123°-24° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:41]1([CH2:47][CH2:48][N:49]([CH2:61][CH2:62][CH3:63])[CH:50]2[CH2:59][C:58]3[CH:57]=[C:56]([OH:60])[CH:55]=[CH:54][C:53]=3[CH2:52][CH2:51]2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:60][C:56]1[CH:57]=[C:58]2[C:53]([CH2:52][CH2:51][CH:50]([N:49]([CH2:61][CH2:62][CH3:63])[CH2:48][CH2:47][N:41]3[CH2:42][CH2:43][N:44]([C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[NH:1][CH:2]=[CH:3]5)=[O:12])[CH2:45][CH2:46]3)[CH2:59]2)=[CH:54][CH:55]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCN1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
Indole-5-carboxylic acid (30 mg, 0.19 mmol), EDCI (45 mg, 0.24 mmol), HOBT (31 mg, 0.24 mmol), triethylamine (31 mg, 0.32 mmol), and compound 39a (50 mg, 0.16 mmol) were dissolved in dry CH2Cl2 (10 ml) and stirred at ambient temperature overnight. The mixture was poured into sat. NaHCO3 and extracted with dichloromethane. The organic extract was dried (Na2SO4), filtered and concentrated to yield the crude product. Column chromatography afforded 40a (26 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 0.87 (t, 3H, J=7.2 Hz), 1.40-1.54 (m, 3H), 1.93 (d, 1H, J=10.0 Hz), 2.45-2.78 (m, 14H), 2.86-2.91 (m, 1H), 3.70 (m, 4H), 6.45 (d, 1H, J=2.0 Hz), 6.55-6.58 (m, 2H), 6.87 (d, 1H, J=8.0 Hz), 7.21-7.24 (m, 2H), 7.33 (d, 1H, J=8.4 Hz), 7.71 (s, 1H), 8.79 (1H, bs). The free base of 40a was converted into oxalate salt. m.p. 194-199° C. Anal. [C28H38N4O.2.0(COOH)2] C, H, N.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19]([S:22][CH3:23])[N:20]=[CH:21][C:10]=3[C:9]2=[O:24])[CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[Cl:48][C:49]1[CH:54]=[C:53](I)[CH:52]=[CH:51][N:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[Cl:48][C:49]1[CH:54]=[C:53]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:17][CH:16]4[N:12]([CH2:13][CH2:14][CH2:15]4)[C:11]4[N:18]=[C:19]([S:22][CH3:23])[N:20]=[CH:21][C:10]=4[C:9]3=[O:24])[CH:5]=[CH:6][CH:7]=2)[CH:52]=[CH:51][N:50]=1
Reactant: Clc1cc(I)ccn1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(Br)c1)C2=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CSc1ncc2c(n1)N1CCCC1CN(c1cccc(-c3ccnc(Cl)c3)c1)C2=O
Temperature: 100 °C
Yield: 43.1 %

Procedure:
(S)-5-(3-Bromophenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (243 mg, 0.599 mmol) obtained in Step 1 of Example 13 was dissolved in 1,4-dioxane (7 mL), and the mixture was stirred at 100° C. for hours after adding bis(pinacolato)diboron (0.380 g, 1.50 mol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf); 98.0 mg, 0.120 mmol), and potassium acetate (0.295 g, 3.00 mmol). The reaction mixture was filtered through sellite, and the filtrate was diluted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography. The resulting crude product was dissolved in 1,4-dioxane/water=4/1 (12.5 mL), and the mixture was stirred at 100° C. for 3 hours after adding 2-chloro-4-iodopyridine (216 mg, 0.902 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf); 49.0 mg, 0.060 mmol), and sodium carbonate (191 mg, 1.80 mmol). The reaction mixture was then filtered through sellite, and the filtrate was extracted with ethyl acetate. The organic layer was then washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by silica gel column chromatography to give 5-[3-(2-chloropyridin-4-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro5,8,10,10b-tetraazabenzo[e]azulen-6-one (113 mg, 43% (2 steps)).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]1[CH2:13][O:12]1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:13][O:12]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCC1CO1
Product: Ic1ccc(OCC2CO2)cc1
Yield: 89 %

Procedure:
Alkylation of 4-iodophenol with 2-(bromomethyl)oxirane (76) as in Example 2A for 52 h, followed by chromatography of the product on silica gel, eluting with 0-10% CH2Cl2/petroleum ether (foreruns) and then with 20-25% CH2Cl2/petroleum ether, gave 2-[(4-iodophenoxy)methyl]oxirane (79) (reported by Apparu et al., 2000 using glycidyl tosylate) (89%) as a white solid: mp (CH2Cl2/petroleum ether) 67-68° C.; 1H NMR (CDCl3) δ 7.56 (dt, J=9.0, 2.7 Hz, 2H), 6.70 (dt, J=9.0, 2.7 Hz, 2H), 4.20 (dd, J=11.1, 3.1 Hz, 1H), 3.92 (dd, J=11.1, 5.7 Hz, 1H), 3.33 (m, 1H), 2.90 (dd, J=4.8, 4.3 Hz, 1H), 2.74 (dd, J=4.9, 2.6 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1.[CH3:22][S:23][C:24]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>C(#N)C>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([F:32])([F:33])[F:34])[C:24]=3[S:23][CH3:22])=[N:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(NCC1CCOCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: CSc1c(N)cccc1C(F)(F)F
Solvent: CC#N
Product: CSc1c(Nc2ncc(C(=O)NCC3CCOCC3)c(C(F)(F)F)n2)cccc1C(F)(F)F
Yield: 14.4 %

Procedure:
2-Chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (50 mg), 2-methylthio-3-(trifluoromethyl)aniline (125 mg, ex Maybridge) and acetonitrile (0.5 ml) were heated at 190° under microwave irradiation for 30 minutes. The solvent was evaporated in vacuo and the residue purified by mass-directed autopreparation technique, to give the title compound (11 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([F:35])[CH:10]=2)[CH2:4]1.C([SiH](C(C)C)C(C)C)(C)C.F[C:47](F)(F)[C:48](O)=[O:49]>ClCCl>[C:48]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:11]([F:35])[CH:10]=2)[CH2:4]1)(=[O:49])[CH3:47]
Reactant: NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BAL resin immobilized 5-(S)-Aminomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]-oxazolidine-2-one (5.00 g, 2.05 mmol) was suspended in 5% trifluoroacetic acid and 2.5% triisopropylsilane in dichloromethane (50 mL), and the mixture was agitated for 1 h. The resin was filtered and the procedure repeated with fresh 5% trifluoroacetic acid and 2.5% triisopropylsilane in dichloromethane (50 mL) for another 30 minutes. The resin was filtered and washed liberally with dichloromethane. Resulted thiol resin was immediately suspended in a mixture of acetic anhydride (20 mL) and pyridine (30 mL) in DCM (50 mL), and the mixture was agitated overnight at r.t. The resin was filtered, washed liberally with dichloromethane and dried under vacuum.
Reaction SMILES: O1CCCCC1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C@H:17]([C:18](=[O:27])[CH2:19][CH2:20][CH2:21]1)[CH2:16][CH2:15]3.Cl>C(O)C>[OH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C@H:17]([C:18](=[O:27])[CH2:19][CH2:20][CH2:21]1)[CH2:16][CH2:15]3
Reactant: C[C@]12CCCC(=O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Agent: Cl
Solvent: CCO
Product: C[C@]12CCCC(=O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Yield: 116.7 %

Procedure:
To 75 ml of ethanol is added 2.32 g of the product of Step E to form a solution which is then treated with 5 ml of 2.5 N hydrochloric acid and warmed on a steam bath for 40 min. to yield 2.1 g of a crystalline product having a m.p. of 123°-126° C.