Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:11]=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.I[CH3:24]>C1COCC1.C(C1C=CC=CC=1)C.C1COCC1>[CH3:24][CH:13]1[C:12](=[O:11])[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(=O)C(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
Lithium hexamethyldisilazanide in THF/ethylbenzene (1M, 117.5 mL) was added dropwise to a stirred solution of ethyl 4-oxocyclohexane-1-carboxylate (20 g, 0.12 mol) in THF (100 mL) at −78° C. The mixture was stirred for 30 minutes. Iodomethane (7.32 mL, 0.12 mol) was added dropwise, then the mixture was gradually warmed to room temperature over 1 h and stirred for 4 h. The mixture was quenched with water (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified twice by FCC, eluting with 20-70% ethyl acetate in cyclohexane, to afford the title compound (3.3 g, 15%) as a colourless oil. δH (500 MHz, CDCl3) 4.15 (q, J 7.1 Hz, 2H), 2.82 (tt, J 12.2, 3.5 Hz, 1H), 2.50-2.40 (m, 2H), 2.40-2.27 (m, 3H), 1.91-1.78 (m, 1H), 1.59 (q, J 13.0 Hz, 1H), 1.27 (t, J 7.1 Hz, 3H), 1.05 (d, J 6.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.[CH2:29]([NH2:32])[CH2:30][NH2:31]>>[NH2:31][CH2:30][CH2:29][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24]([N:26]([CH3:27])[CH3:28])=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1
Reactant: NCCN
Reactant: CN(C)C(=O)c1ccc2c(c1)CCCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Product: CN(C)C(=O)c1ccc2c(c1)CCCN(c1cc(NCCN)c3cc(Cl)ccc3n1)C2
Temperature: 180 °C
Reaction time: 3 h

Procedure:
The mixture of 2-(4,6-dichloroquinolin-2-yl)-N,N-dimethyl-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxamide (133 mg, 0.32 mmol) and ethane-1,2-diamine (2 mL) was heated with stirring in a 5 mL microwave process vial for 3 hours at 180° C. under microwave irradiation. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 11 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 438. 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (s, 1 H), 7.60 (d, J=8.0 Hz, 1 H), 7.49 (d, J=8.8 Hz, 1 H), 7.38 (m, 1 H), 7.22 (m, 2 H), 6.01 (s, 1 H), 4.80 (s, 2 H), 4.16 (m, 2 H), 3.44 (t, J=6.4 Hz, 2 H), 3.11-2.97 (m, 10 H), 1.93 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:7]2[C:6]3[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1cccc2cc[nH]c12
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3c(F)cccc23)CC1
Yield: 65.3 %

Procedure:
A stirred solution of 7-fluoroindole (400 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (620 mg, 66%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][N:23]4[N:32]=[C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:34](Br)=[C:22]4[N:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:43]B(O)O>O1CCOCC1.C(Cl)Cl.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]>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][N:23]4[N:32]=[C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:34]([CH3:43])=[C:22]4[N:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(-c3nc4c(Br)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)C1
Reactant: CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)nn2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CC(C)(O)C4)cc3)nc12
Temperature: 100 °C
Yield: 41 %

Procedure:
A mixture of compound 10-3 (62 mg, 0.1 mmol), Methyl boronic acid (60 mg, 1 mmol), aq.Na2 CO3 (2M, 0.25 mmol, 0.12 mL) and Pd(DPPF)Cl2 (10 mg) in dioxane (2 mL) was heated at 100° C. in microwave system under N2 atmosphere for 30 min. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 23 mg of 10-5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C@H:11]2[C@@H:20](O)[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[O:13][CH2:12]2)[CH:5]=1.[H][H].CO>C(O)(=O)C.ClCCl.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[O:13][CH2:12]2)[CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1cccc(C[C@@H]2COc3ccc(O)cc3[C@@H]2O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CC2COc3ccc(O)cc3C2)c1
Yield: 81 %

Procedure:
A mixture of 5.0 g (0.017 mole) of (3R-cis)-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid methyl ester (prepared by esterification of the corresponding carboxylic acid (prepared according to the method of co-pending U.S. Pat. Application of Murtiashaw, et al., U.S. Ser. No. 07/964,336 filed Oct. 21, 1992) and 1.0 g palladium hydroxide in 100 mL glacial acetic acid was shaken in a Parr hydrogenator under 50 psi hydrogen at room temperature for 3 hours. The mixture was filtered through Celite and the filtrate concentrated to give an oil. Flash chromatography on silica gel eluting with 5% methanol in dichloromethane yielded 4.3 g (81% of the title product as an oil). NMR (CDCl3): δ2.30 (m, 1H); 2.50 (dd, 1 ,H) ; 2.75 (m, 3H); 3.80 (dd, 1H); 3.92 (s, 3H); 4.15 (dd, 1H). MS (Cl, NH3) m/e: 316 (100).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:40][CH2:41][CH3:42])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][CH2:41][CH3:42])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: CCCn1cc(C(=O)CCCCCBr)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: CCCn1cc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c2ccccc21

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.50 g) as starting compound and 6-bromo-1-(1-propyl-1 H-indol-3-yl)-1-hexanone were reacted and treated in the same manner as in Example 172 to give 0.83 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-propyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Br[C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1)=[N+:21]=[N-:22]
Reactant: Nc1ncnc2c1nc(Br)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nc2c(N)ncnc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of 8-bromo-2'-deoxyadenosine (0.403 g, 1.22 mmol) in DMF (25 ml) was added sodium azide (0.278 g, 4.27 mmol), and the mixture stirred at 90° C. for 2 h. The solvent was removed and the residue was purified on silica gel (10% methanol/chloroform) to give 0.325 g (91%) of 8-azido-2'-deoxyadenosine: 1H NMR (Me2SO-d6)δ2.17 (m, 2H), 3.59 (m, 2H), 3.82 (m, 1H), 4.42 (m, 1H), 5.25 (m, 2H), 6.11 (m, 1H), 7.24 (br.s, 2H), 8.07 (s, 1H); UV (H2O) λmax 282.5 nm; FTIF (KBr) 2155 cm-1. 8-Azido-2'-deoxyadenosine was silylated by Procedure A (77% yield) and then reduced, dideoxygenated, and converted to 8-amino-2',3'-dideoxyadenosine (VIII) using in sequence Procedure D (79%), Procedure E (77%), and Procedure F (81%): mp 177°-179° C., 13C NMR (Me2SO-d6) δ26.0, 29.0, 63.1, 79.5, 83.9, 117.1, 148.4, 148.9, 151.4, 152.3; 1H NMR (Me2SO-d6) 2.16 (m, 4H), 3.61 (m, 2H), 4.11 (m, 1H), 5.54 (m, 1H), 6.10 (m, 1H), 6.40 (br.s, 2H), 6.52 (br.s, 2H), 7.89 (s, 1H); UV (H2O) λmax 273.5 nm (λ13950); FAB HRMS obsd (M+ +H) 251.1266, calcd for C10H14N6O2 251.1257.
Reaction SMILES: [K].[NH2:2][C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5](F)[N:4]=1.[CH:11]([OH:14])([CH3:13])[CH3:12]>>[NH2:2][C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([O:14][CH:11]([CH3:13])[CH3:12])[N:4]=1
Reactant: Nc1nc(F)cc(F)n1
Reactant: CC(C)O
Agent: [K]
Product: CC(C)Oc1cc(F)nc(N)n1

Procedure:
29.4 g (0.3 mol) of potassium isopropylate were reacted as in 1.2 with 39.3 g (0.3 mol) of 2-amino-4,6-difluoropyrimidine (A.1a) in a total of 400 ml of isopropanol. After the working up, washing with petroleum ether and water in the usual manner, 38.5 g (75% of theory) of the title compound of melting point 66°-68° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O-:14])=O.[CH2:15]([N:22]=[C:23]=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(O)(=O)C>[CH2:15]([N:22]1[C:12](=[O:14])[C:3]2[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[NH:1][C:23]1=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=NCc1ccccc1
Reactant: COC(=O)c1ccc(N)c(C(=O)[O-])c1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]c(=S)n(Cc3ccccc3)c(=O)c2c1

Procedure:
This process is illustrated in Scheme 2 below: Methyl 4-aminoisophthalate (2a) is treated with benzyl isothiocyanate, in a solvent such as pyridine or acetic acid, to give 3-benzyl-6-(methoxycarbonyl)-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-one (2b). This compound is heated, in a refluxing alcohol, in the presence of hydrazine hydrate to give the corresponding hydrazine which is in turn cyclized by reaction with a carboxylic acid derivative R1COOH (such as an acid chloride or an orthoester). The 4-benzyl-7-(methoxycarbonyl)-4,5-dihydrotriazolo[4,3-a]quinazolin-5-one (2d) obtained is N4-debenzylated using aluminium chloride in benzene, and the intermediate secondary lactam is then substituted with a halide, in the presence of a base such as cesium carbonate, in a solvent such as dimethylformamide. The N-substituted analogue obtained (2f) is then hydrolysed, preferably in acidic medium, to give the corresponding acid (2g) which may be subsequently subjected to a coupling reaction of peptide type.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=2)[CH2:4]1.O.[NH2:21][NH2:22]>C(O)C>[CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([NH:21][NH2:22])=[O:13])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: NN
Reactant: CCOC(=O)c1ccc(N2CCC(N(C)C)C2)cc1
Solvent: O
Solvent: CCO
Product: CN(C)C1CCN(c2ccc(C(=O)NN)cc2)C1
Temperature: 5 °C

Procedure:
A mixture of ethyl 4-(3-dimethylaminopyrrolidin-1-yl)benzoate (2.0 g), hydrazine hydrate (3.8 g) and ethanol (7 ml) was boiled under reflux for 15 hours. After cooling to 5° C., the resulting precipitate was filtered off with suction. The product with the molecular weight of 248.33 (C13H20N4O) was obtained in this way; MS (ESI): 249 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(Cl)cc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (2,4-dichlorophenyl)methanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 557/559 [M+H]+.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[C@@H:16]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:26]([CH3:34])[CH:25]=2)[CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(#N)C>[OH:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[C@@H:16]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[C:26]([CH3:34])[CH:25]=2)[CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)=[N:10]1
Reactant: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)ccc1S(C)(=O)=O
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCO)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.5 %

Procedure:
In a flask containing (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (100 mg, 0.18 mmol) was added ethanol (3 mL) and concentrated hydrochloric acid (three drops) and it was stirred at 25° C. for 45 min. It was then diluted with acetonitrile and absorbed onto silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)—N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (55 mg, 69%) as a yellow foam: [α]32589=−73.6° (c=0.14, methanol); ES-HRMS m/e calcd for C21H27N3O5S (M+H)+ 434.1745, observed 434.1745; 1H NMR (400 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.77-2.28 (m, 8H, 4×CH2), 2.63 (s, 3H, ArCH3), 3.18 (s, 3H, SO2CH3), 3.67 (q, J=5.5 Hz, 2H, OCH2), 3.91 (m, 1H, ArCHCO), 3.99 (t, J=5.5 Hz, 2 H, NCH2), 4.82 (t, J=5.5 Hz, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.46 (brs, 1H, Ar), 7.47 (brd, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.86 (d, Jo=8.5 Hz, 1H, Ar), 10.77 (s, 1H, NH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:33]([O:35]C)=[O:34])#[N:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:18][CH:19]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:33]([OH:35])=[O:34])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(C(F)(F)F)c4)cc3)c(C#N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of methyl 6-cyano-7-(4-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylate (0.019 g, 0.0383 mmol) in 3:1 THF/methanol (2 ml) was added 1M sodium hydroxide (0.0459 ml, 0.0459 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was concentrated and partitioned between EtOAc and diluted HCl in water. The aqueous was extracted once with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by preparative thin layer chromatography eluting with 95:5:1 dichloromethane/methanol/acetic acid to yield 10 mg of the title compound (54.2% yield). MS (apci) m/z=480.8 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][C:21]1[C:25]([C:26]2[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[C:30]([CH:33]=2)[CH:31]=O)=[C:24]([CH3:36])[O:23][N:22]=1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:31][C:30]2[CH:33]=[C:26]([C:25]3[C:21]([CH3:20])=[N:22][O:23][C:24]=3[CH3:36])[CH:27]=[CH:28][C:29]=2[O:34][CH3:35])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Reactant: COc1ccc(-c2c(C)noc2C)cc1C=O
Product: COC(=O)C1CCC(NCc2cc(-c3c(C)noc3C)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Example 89, Step A) and the known 5-(3,5-dimethylisoxazol-4-yl)-2-methoxybenzaldehyde (P. J. Ward, et al., J. Med. Chem. 1995, 38, 4985-92).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Cl[C:27]1[CH:32]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]3[CH:46]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:44]=[C:43]([NH2:53])[N:42]=3)=[CH:36][CH:35]=2)[CH:30]=[CH:29][N:28]=1.[Li+].C[Si]([N-:59][Si](C)(C)C)(C)C.Cl.[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:59][C:27]1[CH:32]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]3[CH:46]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:44]=[C:43]([NH2:53])[N:42]=3)=[CH:36][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccccc2)n1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Nc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Temperature: 65 °C
Reaction time: 12 h
Yield: 18.5 %

Procedure:
To a 8-mL vial was added Pd2(dba)3 (0.028 g, 0.03 mmol), 2-dicyclohexylphosphinobiphenyl (0.025 g, 0.070 mmol), and N4-{4-[(2-chloropyridin-4-yl)oxy]phenyl}&phenylpyrimidine-2,4-diamine (0.20 g, 0.51 mmol, Example 48). The vial was sealed, evacuated, and back filled with nitrogen. THF was then added via syringe, followed by addition of LiHMDS (1M in THF, 0.72 mL, 0.72 mmol). The mixture was heated at 65° C. overnight. The mixture was then cooled to rt, treated with 1N HCl, and stirred for 12 h at rt. The mixture was then neutralized using 1N NaOH and extracted with methylene chloride (10 mL×3). The organic extracts were combined, washed with brine, dried over magnesium sulfate, and purified by preparative HPLC to furnish 0.035 g of the desired product (18%). 1H NMR (CD3OD) δ 7.96 (d, 2H), 7.79 (m, 3H), 7.60 (m, 3H), 7.22 (m, 2H), 6.61 (d, 1H), 6.58 (s, 1H), 6.20 (s, 1H); MS ES 371 (M+H)+ calcd 371.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10](Cl)[N:9]=[C:8]([Cl:13])[N:7]=1)=[O:5]>CS(C)=O>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10]([NH2:1])[N:9]=[C:8]([Cl:13])[N:7]=1)=[O:5]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: N
Solvent: CS(C)=O
Product: COC(=O)c1cc(N)nc(Cl)n1
Yield: 79 %

Procedure:
Ammonia was slowly bubbled through a solution of 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (20.0 g, 97 mmol, see H. Gershon, J. Org. Chem. 1962, 27, 3507-3510 for preparation) in DMSO (100 mL) cooled with an ice bath to maintain the temperature below 70° C. When the temperature of the reaction solution began to decline, no additional ammonia was added. When the temperature of the reaction solution reached 44° C., the ice bath was removed. When the temperature of the reaction solution reached 32° C., the reaction mixture was diluted with 200 mL of water and filtered. The filtered product was washed with water, washed with ethyl acetate, and dried under vacuum to provide the title compound (14.4 g, 79% yield) that was used without further purification. Flash chromatography on silica gel yielded an analytically pure sample of the title compound: 1H NMR (DMSO-d6) δ 7.7 (br s, 2H), 7.00 (s, 1H), 3.84 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:21][C:20]2[N:16]([N:17]=[N:18][C:19]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[CH2:13]1)=[O:11])(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[NH2:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:21][C:20]2[N:16]([N:17]=[N:18][C:19]=2[C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccccc2-n2nnc(-c3ccc(F)cc3)c2C1)Cc1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CC(=O)N1Cc2ccccc2-n2nnc(-c3ccc(F)cc3)c2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of [3-[3-(4-fluoro-phenyl)-4H,6H-1,2,5,10b-tetraaza-benzo[e]azulen-5-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]carbamic acid tert-butyl ester (28.0 mg, 0.047 mmol) in DCM (2 mL), was added trifluoroacetic acid (0.18 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford a gummy solid which was crystallized from hexane to afford trifluoroacetic acid salt of (R)-3-amino-1-[3-(4-fluoro-phenyl)-4H,6H-1,2,5,10b-tetraaza-benzo[e]azulen-5-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one (25 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([O:10][CH3:11])[CH:3]=1.[C-:12]#[N:13].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]#[N:13])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: [C-]#N
Reactant: COc1cc(Cl)ccc1CCl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(Cl)ccc1CC#N
Yield: 36.7 %

Procedure:
Step B In a manner similar to the method described in Example 57 Step B, 4-chloro-2-methoxybenzyl chloride (5.1 g, 27 mmol) was reacted with NaCN (3 g, 61 mmol) in ethanol (40 mL) and water (20 mL) at 100° C. for 8 h to give 4-chloro-2-methoxybenzyl cyanide as a colorless oil (1.8 g, 36%)