Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH3:33])[CH:9]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]2[C:23](=[O:32])[C:24]([OH:31])=[C:25]([C:27](OC)=[O:28])[N:26]=[C:10]12)C1C=CC=CC=1.Cl.[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[CH3:44])[CH2:39][NH2:40]>CO.[Pd]>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[CH3:44])[CH2:39][NH:40][C:27]([C:25]1[N:26]=[C:10]2[CH:9]([NH:8][CH3:33])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:13][CH2:12][N:11]2[C:23](=[O:32])[C:24]=1[OH:31])=[O:28]
Reactant: Cc1ccc(CN)cc1Cl
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCN(C(=O)OC(C)(C)C)CC2N(C)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC1CN(C(=O)OC(C)(C)C)CCn2c1nc(C(=O)NCc1ccc(C)c(Cl)c1)c(O)c2=O
Temperature: 25 °C

Procedure:
8-tert-butyl 2-methyl 10-[benzyl(methyl)amino]-3-hydroxy-4-oxo-6,7,9,10-tetrahydropyrimido[1,2-d][1,4]diazepine-2,8(4H)-dicarboxylate (see Example 11, Steps 1-4) was dissolved in MeOH, treated with 1 N HCl (1 eq.) and stirred overnight under an H2 atmosphere in the presence of 10% Pd/C. The catalyst was then filtered off through celite, and the filtrate was concentrated under reduced pressure. MS (ES) C16H24N4O6 requires 368. Found: 369 (M+H+). The crude organic product was taken in methanol and treated with 1.2 eq. of 3-chloro-4-methyl-benzylamine and resulting mixture was refluxed overnight. After cooling to room temperature, evaporation of volatiles under reduced pressure yielded title product which was directly taken in the next step. MS (ES) C23H30ClN5O5 requires 491. Found: 492 (M+H+).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[CH:18]=[C:19]2[C:22](=[CH:23][CH:24]=1)[CH:21]([C:25]#[N:26])[CH2:20]2.C(N(CC)CC)C.O>ClCCl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[CH:18]=[C:19]2[C:22](=[CH:23][CH:24]=1)[CH:21]([C:25]#[N:26])[CH2:20]2)(=[O:3])=[O:2]
Reactant: N#CC1Cc2cc(O)ccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reaction time: 72 h

Procedure:
2.4 mL of triflic anhydride (1.2 equivalents) are poured at 0° C., over 1 hour, into a solution of 2 g (13.8 mmoles) of 3-hydroxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile in 40 mL of dichloromethane and 3.9 mL (2 equivalents) of triethylamine. Stirring is carried out for 3 days at 25° C. The reaction mixture is poured into water, extracted with dichloromethane, dried over MgSO4, filtered and evaporated to obtain 3.8 g of an oil. This residue is purified by flash chromatography over 150 g of silica; eluant=100% toluene. The expected product is obtained in the form of an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[C:12]([F:14])[C:9]([CH2:10][OH:11])=[C:8]([F:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[C@H:25]([CH2:32][CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([F:15])[C:9]([CH2:10][O:11][C:29]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][C@H:25]2[CH2:32][CH3:33])=[O:30])=[C:12]([F:14])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(F)c(CO)c(F)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CCCCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(F)c1
Yield: 80 %

Procedure:
This compound was prepared from 4-butoxy-2,6-difluoro-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (454 mg; 80%); MS (ISP): 479.4 (M+Na)+.
Reaction SMILES: C([O:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[O:14]1[CH2:13][CH2:12][CH:11]([O:10][C:9]2[CH:17]=[CH:18][C:6]([OH:5])=[CH:7][CH:8]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)Oc1ccc(OC2CCOCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(OC2CCOCC2)cc1
Yield: 94.2 %

Procedure:
4-(4-Tert-butoxyphenoxy)tetrahydro-2H-pyran (257 mg, 1.027 mmole) was taken up in TFA (5 mL) at RT. After 90 min the mixture was concentrated. The residue was taken up in saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound (188 mg, 94%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 6.82 (m, 2 H); 6.77-6.73 (m, 2 H); 4.71 (s, 1 H); 4.37-4.29 (m, 1 H); 4.03-3.95 (m, 2 H); 3.55 (m, 2 H); 2.03-1.95 (m, 2 H); 1.81-1.70 (m, 2 H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([O:31][C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1)[CH3:30]>>[CH2:29]([O:31][C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:30]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCOc1nc2ccccc2[nH]1
Product: CCOc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-ethoxy-1H-benzo[d]imidazole were reacted to give 337. LCMS: M+H+=535.3
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].C[Si](Cl)(C)C.Cl>O1CCCC1>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8]/[C:7](=[C:14](/[C:13]3[CH:12]=[CH:1][C:2]([CH3:11])=[CH:3][CH:4]=3)\[CH3:15])/[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1CCCC2
Reactant: [Li]CCCC
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Product: C/C(=C1\CCCc2c(C)ccnc21)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
5,6,7,8-Tetrahydro-4-methylquinoline (7.5 g) in tetrahydrofuran (THF) (25 ml) was added to a solution of n-butyl lithium (1.37M, 37 ml) in THF (40 ml) maintained at 0° C. After 30 minutes the solution was blown over with nitrogen onto a solution of trimethylsilyl chloride (5.6 g) in THF (25 ml) at 0° C. Further n-butyl lithium (1.37M, 37 ml) was added and after 30 minutes the reaction mixture was blown over with nitrogen onto 4-methylacetophenone (15 g) in THF (25 ml) at 0° C. After 10 minutes 2M HCl (150 ml) was added.
Reaction SMILES: C1(COC([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:16][CH:15]=2)=O)C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[CH:18][CH:19]=1
Reactant: O=C(NCCc1ccc(NS(=O)(=O)c2ccccc2)cc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCCc1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 89.2 %

Procedure:
A solution of 600 mg (1.46 mmol) of Cbz amine from Example 5 in 18 mL of methanol was stirred over 20% palladium hydroxide on carbon under an atmosphere of hydrogen for 2.5 h. The reaction mixture was filtered through a Celite pad and concentrated to give 360 mg (89%) of a white solid: 1H NMR (400 MHz, CD3OD) δ7.73 (d, 2H, J=7.1 Hz), 7.52 (t, 1H, J=7.4 Hz), 7.44 (t, 2H, J=7.5 Hz), 7.04 (d, 2H, J=8.7 Hz), 6.99 (d, 2H, J=8.6 Hz), 2.82 (t, 2H, J=7.3 Hz), 2.66 (t, 2H, J=7.3 Hz).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:13]([O:14]C(=O)C)[C@H:12]([O:18][C@@H:19]2[O:56][C@H:55]([CH2:57][O:58]C(=O)C)[C@H:30]([O:31][C@H:32]3[O:49][C@H:48]([CH2:50][O:51]C(=O)C)[C@H:43]([O:44]C(=O)C)[C@H:38]([O:39]C(=O)C)[C@H:33]3[O:34]C(=O)C)[C@H:25]([O:26]C(=O)C)[C@H:20]2[O:21]C(=O)C)[C@@H:11]([CH2:62][O:63]C(=O)C)[O:10][C@H:6]1[O:7][CH2:8][CH3:9])(=[O:3])[CH3:2]>C[O-].[Na+]>[C:1]([NH:4][C@@H:5]1[C@@H:13]([OH:14])[C@H:12]([O:18][C@@H:19]2[O:56][C@H:55]([CH2:57][OH:58])[C@H:30]([O:31][C@H:32]3[O:49][C@H:48]([CH2:50][OH:51])[C@H:43]([OH:44])[C@H:38]([OH:39])[C@H:33]3[OH:34])[C@H:25]([OH:26])[C@H:20]2[OH:21])[C@@H:11]([CH2:62][OH:63])[O:10][C@H:6]1[O:7][CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CCO[C@@H]1O[C@H](COC(C)=O)[C@@H](O[C@@H]2O[C@H](COC(C)=O)[C@H](O[C@H]3O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: CCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1NC(C)=O
Yield: 61 %

Procedure:
Compound 87 (58 mg, 0.06 mmol) was O-deacetylated in methanolic sodium methoxide (0.036M, 5.5 ml) at room temperature for 21 h. The mixture was neutralized with Duolite C-26 (H) resin, filtered and concentrated. The residue was dissolved in water and lyophilized to give 88 (21 mg, 60%) with [α]D22 +25° (c 0.7, water). 1H-NMR [(CD3)2SO+D2O, 50°, Me4Si] δ inter alia 4.80 (d, 1H, J=3.5 Hz, H1"), 4.37 (d, 1H, J=8 Hz, H1 or H1'), 4.29 (d, 1H, J=7.5 Hz, H1 or H1'), 4.07 (bt, 1H, J~6.5 Hz), 1.81 (s, 3H, MeCON), 1.08 (t, 3H, J=7 Hz, CH3CH 2). 13C-NMR (D2O, TSP) δ 177.4, 106.1, 103.4, 103.1, 81.6, 80.1, 78.2, 77.7, 75.4, 75.0, 73.7, 73.6, 72.0, 71.7, 71.4, 69.1 (CH2), 63.3 (CH2), 63.2 (CH2), 62.9 (CH2), 58.1, 25.0, 17.1. b: Compound 86 (15 mg, 0.017 mmol) was O-deacetylated and worked-up as above to give 88 (8.0 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14](=O)[CH2:15]Br>O1CCOCC1>[Cl:8][C:7]1[C:2]2[N:3]([CH:15]=[C:14]([C:13]3[CH:18]=[CH:19][CH:20]=[C:11]([O:10][CH3:9])[CH:12]=3)[N:1]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Nc1nccnc1Cl
Reactant: COc1cccc(C(=O)CBr)c1
Solvent: C1COCCO1
Product: COc1cccc(-c2cn3ccnc(Cl)c3n2)c1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
To a solution of 2-amino-3-chloropyrazine (0.20 g, 1.5 mmol, 1.00 equiv) and 3-methoxyphenacyl bromide (0.71 g, 3.1 mmol, 2.0 equiv) in dioxane (10 mL) was heated at 90° C. for 3 hr. The resulting mixture was cooled to rt and filtered. The filtrate was partitioned between 10% IPA/DCM and 1 N NaOH. The aqueous extract was washed with 10% IPA/DCM (2×) and the combined organic extracts were washed with brine and dried with sodium sulfate. Concentration afforded 8-chloro-2-(3-methoxy-phenyl)-imidazo[1,2-a]pyrazine (76 mg, 19%). MH+ (LCMS) 260.1 (m/z).
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:8](=[O:14])[C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[C:6]#[N:7])C.[N+:15]([O-])(O)=O.NNC(N)=N.[OH-].[Na+]>C(O)C>[NH2:2][C:4]1[C:5]([C:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[O:14])=[CH:6][NH:7][N:15]=1
Reactant: O=[N+]([O-])O
Reactant: CN(C)C=C(C#N)C(=O)c1ccco1
Agent: N=C(N)NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1n[nH]cc1C(=O)c1ccco1
Yield: 96.1 %

Procedure:
A reaction mixture comprising 19.0 g of α-[(dimethylamino)methylene]-β-oxo-2-furanepropanenitrile, 16.1 g of aminoguanidine nitrate, 250 ml of ethanol and 11.0 ml of 10N sodium hydroxide was refluxed for 6 hours and then evaporated to dryness. Water was added to the crude residue and the precipitated solid was collected, giving 17.0 g of the desired product, mp 153°-155° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20](OC)=[O:21].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21]
Reactant: COC(=O)c1nc(C)c2ccc(Oc3ccccc3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3ccccc3)ccc12
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 2e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 2e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-(4-hydroxy-1-methyl-6-phenoxyisoquinoline-3-carboxamido)acetic acid.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[CH:14]=[N:13]2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH:41][C:9](=[O:10])[CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:21]([F:27])=[CH:22][CH:23]=[CH:24][C:25]=3[F:26])[CH:14]=[N:13]2)[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCCCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 65 %

Procedure:
Using the method described in Example 49, 3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 33) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (1.42 g, 65%); ES+-HRMS m/e calcd for C30H41N5O4SiF2 [M+H+] 602.2969 found 602.2971. 1H NMR (300 MHz, DMSO-d6) δ ppm −0.07 (s, 6H) 0.80 (s, 9H) 0.84-1.30 (m, 6H) 1.63 (br s, 5H) 1.75-1.92 (m, 1H) 2.04-2.21 (m, 1H) 3.85 (t, J=5.1 Hz, 2H) 4.06 (t, J=5.1 Hz, 2H) 5.54 (dd, J=10.7, 4.1 Hz, 1H) 6.03 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.33-7.52 (m, 3H) 7.53 (d, J=2.1 Hz, 1H) 8.28 (d, J=2.7 Hz, 1H) 10.73-10.91 (m, 1H).
Reaction SMILES: C1C2C(=CC=CC=2)CC1C(O)=O.C[O:14][C:15]([CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[S:26]([N:29]2[CH:34]3[CH2:35][CH2:36][CH2:37][CH:30]2[CH2:31][N:32]([C:38]2[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=2)[CH2:33]3)(=[O:28])=[O:27])[CH2:18]1)=[O:16].[Li+].[OH-].FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1>CO.O1CCCC1>[F:48][C:45]([F:46])([F:47])[O:44][C:41]1[CH:40]=[CH:39][C:38]([N:32]2[CH2:33][CH:34]3[N:29]([S:26]([C:23]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:24]=4[CH2:25][CH:17]([C:15]([OH:16])=[O:14])[CH2:18]5)(=[O:28])=[O:27])[CH:30]([CH2:37][CH2:36][CH2:35]3)[CH2:31]2)=[CH:43][CH:42]=1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: O=C(O)C1Cc2ccccc2C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-|3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo|3.3.1|nonane-9-sulfonyl|-indan-2-carboxylic acid: A mixture of 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid methyl ester (13 mg, 0.025 mmol), 1N LiOH (2 mL), tetrahydrofuran (8 mL), and methanol (2 mL) was stirred at rt for 3 h. The reaction was poured into 1N HCl (40 mL) and extracted with ethyl acetate (40 mL×2). The combined organic extracts were dried, filtered, and concentrated to give 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid: 1H NMR (400 MHz, DMSO-d6): δ7.69 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 7.19 (d, 2H), 6.92 (d, 2H), 4.04-3.97 (m, 2H), 3.74-3.67 (m, 2H), 3.44-3.30 (m, 3H), 3.26-3.10 (m, 2H), 2.96-2.86 (m, 2H), 2.26-2.15 (m, 1H), 1.86-1.72 (m, 4H), 1.51-1.43 (m, 1H); MS (ESI): 511.4 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[N:13][CH:14]=2)O1.Br[C:24]1[C:25]([Cl:34])=[C:26]2[C:31](=[N:32][CH:33]=1)[NH:30][CH2:29][CH2:28][CH2:27]2>>[Cl:34][C:25]1[C:26]2[CH2:27][CH2:28][CH2:29][NH:30][C:31]=2[N:32]=[CH:33][C:24]=1[C:9]1[CH:10]=[C:11]([C:15]2([OH:21])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:12]=[N:13][CH:14]=1
Reactant: CC1(C)OB(c2cncc(C3(O)CCOCC3)c2)OC1(C)C
Reactant: Clc1c(Br)cnc2c1CCCN2
Product: OC1(c2cncc(-c3cnc4c(c3Cl)CCCN4)c2)CCOCC1

Procedure:
4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-tetrahydro-pyran-4-ol is coupled with 6-bromo-5-chloro-1,2,3,4-tetrahydro-[1,8]naphthyridine to give 4-[5-(4-chloro-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-tetrahydro-pyran-4-ol using Suzuki Coupling Method VI.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=1>>[CH3:7][C:8]1[CH:13]=[C:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Brc1cccs1
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2cccs2)c1

Procedure:
2-Bromothiophene and 3-methylphenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(3-methylphenyl)thiophene as colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[O:3]1.[CH3:17][C:18]1[CH:22]=[C:21]([NH2:23])[N:20]([C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[N:29]3)[N:19]=1.ClCCl>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:23][C:21]3[N:20]([C:24]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:25]=4[CH:26]=[CH:27][CH:28]=[N:29]5)[N:19]=[C:18]([CH3:17])[CH:22]=3)(=[O:14])=[O:13])[CH:8]=2)[O:3]1
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc3c(c2)CCC(C)(C)O3)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 10 %

Procedure:
A stirring mixture of 2,2-dimethylchroman-6-sulfonyl chloride (0.050 g, 0.22 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.068 g, 0.26 mmol) in pyridine (1.0 mL) was heated at 80° C. for 15 h. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous saturated bisulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in hexanes), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.010 g, 0.022 mmol, 10%). 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J=4.8 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.66 (dd, J=4.8, 8.8 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.40-7.38 (m, 2H), 6.72 (d, J=9.2 Hz, 1H), 6.09 (s, 1H), 2.71 (t, J=6.4 Hz, 2H), 2.34 (s, 3H), 1.83 (t, J=6.4 Hz, 2H), 1.36 (s, 6H); MS: (ES) m/z calculated for C24H25N4O3S [M+H]+ 449.2. found 449.1
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12].C[Si](C)(C)N[Si](C)(C)C>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O1CCOCC1>[CH2:9]([NH:13][C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN
Reactant: O=C1CONC(=O)N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCCCNC1=NC(=O)NOC1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A solution of 1.16 g (0.010 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 5 mg of ammonium sulfate, 0.88 g (0.012 mole) of n-butylamine and 20 ml hexamethyldisilazane in 40 ml freshly distilled dry dioxane is refluxed for 17 hours. After cooling to room temperature, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield 1.02 g (87 percent) of 5-butylamino-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36]>>[ClH:36].[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:35]=[CH:34][C:17]=43)[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2

Procedure:
4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was treated with hydrochloric acid to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride. 1-H NMR 400 MHz (DMSO-d) δ: 9.08 (2H, s), 8.37 (1H, d, J=8.30 Hz), 8.18 (1H, s), 8.07 (1H, s), 7.06 (1H, dd, J=8.35, 1.80 Hz), 6.91 (1H, d, J=1.80 Hz), 5.85 (1H, m), 4.53 (4H, m), 3.35 (2H, d, J=12.46 Hz), 2.98 (2H, m), 2.87 (1H, m), 1.93 (4H, m), 1.50 (6H, d, J=6.57 Hz)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[S:16][CH2:17]C(O)=O)(=O)[CH3:2].C(=O)=O>C(O)(=O)CC>[CH3:2][C:1]1[C:4]2[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=2[S:16][CH:17]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1SCC(=O)O
Agent: O=C=O
Solvent: CCC(=O)O
Product: Cc1csc2c([N+](=O)[O-])cc([N+](=O)[O-])cc12

Procedure:
A solution of 0.8 mole of (2-acetyl-4,6-dinitrophenylthio)acetic acid in 1 liter of propionic acid is heated at the boiling point until the evolution of CO2 has ended (about 4 hours).