Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][NH:7][C:8]([NH:10][CH3:11])=[S:9])=O.Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+].Cl>>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]1[N:10]([CH3:11])[C:8](=[S:9])[NH:7][N:6]=1
Reactant: CNC(=S)NNC(=O)c1ccccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cn1c(-c2ccccc2F)n[nH]c1=S

Procedure:
1-(2-Fluorobenzoyl)-4-methylthiosemicarbazide (11.3 g, 4.97×10-2 mole) or the aforementioned mixture of the above and pyridine hydrochloride and 1 molar aqueous NaHCO3 (480 ml, 4.80×10-1 mole) were stirred and heated to reflux. After refluxing overnight, the reaction was cooled in an ice bath before being acidified by the dropwise addition of concentrated hydrochloric acid (40 ml, 4.8×10-1 mole). The resulting precipitate was collected by filtration, washed with a little H2O, and dried by suction. This afforded a colorless powder. This material was of sufficient purity to go on to the next step. If desired this material could be crystallized from EtOAc/hexane affording colorless needles, Mp 137°-139° C.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].Br[CH2:37][CH2:38][O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:37][CH2:38][O:39][CH:40]6[CH2:45][CH2:44][CH2:43][CH2:42][O:41]6)[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CCOC4CCCCO4)CC3)ccc1-2
Temperature: 60 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 375 (310 mg, 0.61 mmol) in DMF (3.5 mL) was added 2(2-bromoethoxy)tetrahydro-2H-pyran (0.1 mL, 0.67 mmol) and potassium carbonate (290 mg, 2.10 mmol) and the reaction mixture stirred at 60° C. for 16 h. The reaction mixture was diluted with DCM and washed with sodium bicarbonate (sat aq.) then water followed by brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% MeOH in DCM) to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (106 mg, 33%). LCMS: RT=3.71 min, [M+H]+=524 1H NMR 400 MHz (DMSO-d6) δ: 8.27 (1H, d, J=8.19 Hz), 8.09 (1H, d, J=0.58 Hz), 7.09 (1H, dd, J=8.26, 1.82 Hz), 6.92 (1H, d, J=1.78 Hz), 5.82-5.82 (1H, m), 4.58 (1H, t, J=3.52 Hz), 4.35 (2H, t, J=5.02 Hz), 3.75-3.74 (2H, m), 3.44-3.42 (4H, m), 2.99 (2H, t, J=10.97 Hz), 2.54 (2H, t, J=6.17 Hz), 2.47 (1H, s), 2.09 (2H, t, J=11.61 Hz), 1.79-1.55 (6H, m), 1.55 (6H, d, J=6.59 Hz), 1.52-1.43 (4H, m).
Reaction SMILES: O.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:12]1[O:17][C@H:16]([C:18]([OH:20])=[O:19])[C@@H:15]([NH2:21])[C@H:13]1[OH:14].[CH:22]([NH:24][C@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23]>>[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:12]1[O:17][C@H:16]([C:18]([OH:20])=[O:19])[C@@H:15]([NH:21][C:33](=[O:34])[C@H:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:24][CH:22]=[O:23])[C@H:13]1[OH:14]
Reactant: O=CN[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](N)[C@H]1O
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)[C@H](Cc2ccccc2)NC=O)[C@H]1O
Yield: 27.1 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-1,3-dideoxy-3-(N-formyl-L-phenylalanylamino)-β-D-ribofuranuronic acid (58 mg) was prepared by reacting 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid monohydrate (140 mg) prepared in Example 99 with N-hydroxysuccinimide ester of N-formyl-L-phenylalanine (130 mg) according to a similar manner to that of Example 5, mp. 169°-181° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 1-benzyl-piperidin-4-ol (25 g, 130.7 mmol) and triethylamine (36.1 ml, 261.4 mmol) in 250 ml of THF is treated with 2,2-dimethyl-propionyl chloride (32.2 ml, 261.4 mmol). The suspension is heated under reflux over night. The solvent is evaporated, the residue taken up in DCM and washed with saturated sodium bicarbonate solution and brine. Drying and evaporation gave an orange oil.
Reaction SMILES: [C:1]1([NH:7]/[N:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[N+]([C:24]([CH2:51][CH2:52][CH2:53][CH3:54])=[CH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][C:27]=1[C:39]([N:41]1[CH2:50][CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40])([O-])=O.C(O)(C(F)(F)F)=O>C1COCC1>[C:33]([O:32][C:30]([C:29]1[CH:37]=[CH:38][C:26]([C:25]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:24]=2[CH2:51][CH2:52][CH2:53][CH3:54])=[C:27]([C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[CH:28]=1)=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a solution of (E)-ethyl 2-(2-phenylhydrazono)acetate (31 mg, 0.16 mmol) in THF (1 mL) at −78° C. was added potassium tert-butoxide (0.161 mL, 0.161 mmol). After stirring at −78° C. for 15 min, a solution of tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (75 mg, 0.161 mmol) in THF (1.0 mL) was added. After stirring at −78° C. for 15 min, TFA (0.024 mL, 0.323 mmol) was added and the reaction mixture became colorless. The reaction mixture was stirred at −78° C. for 2 h and was then allowed to warm to room temperature and stirred at room temperature for 30 min. The reaction mixture was quenched with sat. aq. sodium bicarbonate solution and then extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 40 g column eluting with 0-40% EtOAc/hexanes) to give the title compound (33 mg, 34%) as a colorless oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.09 (dd, J=8, 2 Hz, 1H), 8.05-8.03 (m, 1H), 7.49-7.37 (m, 6H), 7.26-6.81 (m, 4H), 5.02-4.98 (m, 1H), 4.47-4.38 (m, 1H), 4.32-4.27 (m, 2H), 4.16-3.98 (m, 1H), 3.58-3.40 (m, 1H), 2.82-2.51 (m, 4H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.20 (t, J=8 Hz, 1.5H), 1.47-0.91 (m, 4H), 0.60-0.56 (m, 3H); MS(ESI+) m/z 608.3 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](C2C=C3C(C(C4C=CC5C(=CC=CC=5)C=4)=NN3S(C3C(C)=CC(C)=CC=3C)(=O)=O)=CC=2)=[CH:11][C:10]=1[O:46][CH3:47])C1C=CC=CC=1.C(OC1C=CC([C:62]2[CH:70]=[C:69]3[C:65]([C:66]([C:71]4[CH:80]=[CH:79][C:78]5[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=5)[CH:72]=4)=[N:67][NH:68]3)=[CH:64][CH:63]=2)=CC=1OC)C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:72]1[C:73]2[C:78](=[CH:77][CH:76]=[CH:75][CH:74]=2)[CH:79]=[CH:80][C:71]=1[C:66]1[C:65]2[C:69](=[CH:70][CH:62]=[CH:63][CH:64]=2)[N:68]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:46][CH3:47])[CH:11]=2)[N:67]=1
Reactant: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1OCc1ccccc1
Reactant: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)ccc1OCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(-n2nc(-c3ccc4ccccc4c3)c3ccccc32)ccc1O

Procedure:
6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole was converted to 6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole as described in Example 1(a), step (ix). Rf sm 0.40, p 0.17 (ethyl acetate-hexane 3:7); 1H NMR (CDCl3) δ 8.40 (s, 1H), 8.12 (d, 1H, J=8.5 Hz), 8.10 (dd, 1H, J=1.6, 8.4 Hz), 7.93 (d, 1H, J=8.3 Hz), 7.88 (m, 2H), 7.61 (m, 1H) 7.56 (s, 1H), 7.43 (m, 5H), 7.30 (m 3H), 7.15 (d, 1H, J=2.0 Hz), 7.08 (dd, 1H, J=2.1, 8.3 Hz), 6.91 (d, 1H, J=8.3 Hz), 5.16 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2cccnc2c1NCC1(O)CCOCC1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cnc2cccnc2c1NCC1(O)CCOCC1
Yield: 115.1 %

Procedure:
A mixture of 4-[(3-nitro[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol (12.2 g), 5% platinum on carbon (1.22 g), and ethyl acetate (160 mL) was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for 3 hours. The reaction mixture was filtered through a layer of CELITE filter aid and the filter cake was rinsed with 1:1 ethyl acetate:methanol (150 mL). The filtrate was concentrated under reduced pressure to provide 12.66 g of 4-[(3-amino[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol as a thick semi-solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8](=[O:17])[N:7]([CH2:18][C:19]([OH:21])=[O:20])[C:6]2=[O:22].[Cl:23][C:24]1[CH:25]=[N+:26]([O-:49])[CH:27]=[C:28]([Cl:48])[C:29]=1[CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[N+:26]([O-:49])[CH:27]=[C:28]([Cl:48])[C:29]=1[CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1)[O:20][C:19](=[O:21])[CH2:18][N:7]1[C:6](=[O:22])[C:5]2[C:9](=[CH:10][C:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:17]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1cc2c(cc1NS(C)(=O)=O)C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc2c(cc1NS(C)(=O)=O)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
A mixture of 2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid (0.183 g, 0.557 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.234 g, 0.557 mmol), EDC (0.321 g, 1.672 mmol) and DMAP (0.034 g, 0.279 mmol) in DCM (20 ml) was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with 1N HCl, 5% NaHCO3 and brine. The organic phase was dried over sodium sulfate, the solvent was removed, and the crude was purified by flash chromatography on silica gel cartridge (DCM:ethyl acetate from 1:1 to 4:1) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a pale orange solid (0.097 g, 0.133 mmol, 24% yield). MS/ESI+ 730.13 [MH]+; [αD]=−33.40, c=0.43, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.54 (br. s., 1H), 8.44 (s, 2H), 7.77 (s, 1H), 7.55 (s, 1H), 7.19 (d, 1H), 7.08 (d, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.39 (s, 2H), 4.04 (s, 3H), 3.93 (d, 2H), 3.39 (dd, 1H), 3.23 (dd, 1H), 3.15 (s, 3H), 1.01-1.37 (m, 1H), 0.50-0.72 (m, 2H), 0.25-0.45 (m, 2H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30]CC)=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17](/[CH:26]=[C:27](\[CH3:33])/[C:28]([OH:30])=[O:29])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(C)=C/c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C/C(=C\c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.8 %

Procedure:
A mixture of methyl ester 4.1 (50 mg, 0.112 mmol) and 1N LiOH (2 ml) in 3 ml of MeOH/THF (1:2) was stirred at rt for 18 h, concentrated, and partitioned between Et2O and H2O. The organic phase was extracted with 0.1 N NaOH (2×), and the combined aqueous extracts were acidified with conc. HCl, and extracted with EtOAc (3×). The combined organic extracts were washed with H2O, brine, and dried (Na2SO4) before being concentrated to afford 47 mg (100%) of 4.2. HRMS (ESI) calc'd for C26H29N2O3 417.2178, found 417.2174 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=1.1, 1H), 7.49–7.36 (m, 5H), 7.30 (d, J=8.7, 2H), 7.07 (d, J=8.7, 2H), 6.45 (s, 1H), 5.14 (s, 2H), 4.14–4.07 (m, 1H), 2.26 (d, J=1.5, 3H), 2.07–2.00 (m, 2H), 1.95–1.84 (m, 4H), 1.36–1.22 (m, 4H).
Reaction SMILES: CC1C=CC2NC(=O)[C@@H](NC(=O)OC(C)(C)C)COC=2C=1.CCN=C=NCCCN(C)C.[NH2:33][C:34]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:35]=1[O:36][C@@H:37]([CH3:50])[C@H:38]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:39](O)=[O:40]>>[CH3:50][C@@H:37]1[O:36][C:35]2[CH:51]=[C:52]([CH3:55])[CH:53]=[CH:54][C:34]=2[NH:33][C:39](=[O:40])[C@H:38]1[NH:42][C:43](=[O:44])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47]
Reactant: Cc1ccc(N)c(O[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc2c(c1)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N2
Product: Cc1ccc2c(c1)O[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2
Yield: 55.5 %

Procedure:
In a similar manner to that described for the preparation of (S)-tert-butyl 8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate, except 1.5 eq. of EDCI was used, (2S,3S)-3-(2-amino-5-methyl-phenoxy)-2-tert-butoxycarbonylamino-butyric acid (290 mg, 894 μmol) was converted to tert-butyl (2S,3S)-2,8-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (152 mg, 55.5% yield) as a solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([C:13]1([C:44]([O:46]CC2C=CC=CC=2)=[O:45])[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[C:33]([F:43])[CH:32]=4)[O:28][N:27]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH2:3]([O:10][C:11]([C:13]1([C:44]([OH:46])=[O:45])[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)=[C:33]([F:43])[CH:32]=4)[O:28][N:27]=3)=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution (50 mL) of sodium hydroxide (1.7 g, 0.043 mol) is added to a stirred solution of 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}piperidine-4,4-dicarboxylic acid dibenzyl ester (18.3 g, 0.027 mol) in tetrahydrofuran (150 mL). The reaction mixture is stirred overnight at room temperature and then concentrated under reduced pressure. The residue is acidified to pH ˜6 with diluted hydrochloric acid to give a solid which is filtered and washed with diethylether (100 mL) to furnish 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}piperidine-4,4-dicarboxylic acid mono benzyl ester.
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[N:17]2[CH3:20])=[CH:13][CH:12]=1>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:16]([C:21]([O:23][CH3:24])=[O:22])[N:17]2[CH3:20])=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc2ccc(Cl)cc2n1C
Reactant: CCOC(=O)CC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)CC(=O)c1c(C(=O)OC)n(C)c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.2 ml (48.4 mmol) of ethyl 3-chloro-3-oxopropanoate in 70 ml of 1,2-dichloroethane is cooled to 0° C. In small portions 5.3 ml (48.3 mmol) of titanium tetrachloride are added and the mixture is stirred at 0° C. for 30 minutes. A solution of 4.3 g (19.2 mmol) of methyl 6-chloro-1-methyl-1H-indole-2-carboxylate in 35 ml of 1,2-dichloroethane is added and the mixture is stirred at ambient temperature for 12 h. It is poured into ice water and extracted with dichloromethane. The organic phase is separated off, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent: cyclohexane/ethyl acetate: 90/10 to 80/20). This gives a yellow solid, which is triturated in heptane and then in diisopropyl ether.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:31]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=3)[C:30]#[N:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C#N)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (Intermediate 1) and 3-cyanophenylboronic acid. The title compound was obtained in 46% yield as yellow foam. MS (m/e): 507.3 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][C:14](=[O:16])[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([Cl:11])[C:6]=12.[CH3:17][Mg]Cl>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:13][C:14]([CH3:17])([OH:16])[CH2:15]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([Cl:11])[C:6]=12
Reactant: O=C1CC(c2nc(Br)c3c(Cl)nccn23)C1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)CC(c2nc(Br)c3c(Cl)nccn23)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (51.988 g, 0.17 mot) in anhydrous THF (550 g, 620 mL) under nitrogen at −78° C. was treated with a 3.0 M solution of methyl magnesium chloride in THF (130 mL, 0.38 mol) over 30 min. The mixture was stirred at −78° C. for 30 min and then the cooling bath was removed and the mixture quenched with 14% NH4Cl (132 g). EtOAc was added to the aqueous phase and the pH was adjusted to ˜5 with 20% HCl and the layers separated. The combined organic phases were concentrated in vacuo to a slurry and 0.5 L of toluene was added and the mixture concentrated in vacuo until the EtOAc was removed. The slurry was heated at reflux until homogeneous then allowed to coot to provide desired product, which was isolated by filtration and dried in vacuo. 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (s, 3H), 2.35-2.49 (m, 4H), 3.52 (dddd, 1H, J=9.6, 9.6, 9.6, 9.6 Hz), 5.18 (bs, 1H), 7.37 (d, 1H, J=5.2 Hz) and 8.26 (d, 1H, J=5.2 Hz).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@H:17]([OH:27])[CH2:18][CH2:19]2)/[C:14](=[CH:28]/[CH3:29])/[C:13]3=[O:30])[CH2:10][CH2:9]1)[CH3:7].[OH-].[Na+]>>[OH:27][C@@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15](/[C:14](=[CH:28]/[CH3:29])/[C:13](=[O:30])[C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:31])=[O:2])[CH2:16]1
Reactant: C/C=C1\C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: [Na+]
Agent: [OH-]
Product: C/C=C1\C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
reacting E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester (4A) with NaOH to form E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid (5A),
Reaction SMILES: Cl.C(OC([N:9]([CH2:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][NH:22][C:23]2[C:33]3[CH2:32][CH2:31][N:30](C(=O)C(F)(F)F)[CH2:29][CH2:28][C:27]=3[CH:26]=[CH:25][C:24]=2[Cl:40])=[CH:19][CH:18]=1)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=O)(C)(C)C.O.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Cl:40][C:24]1[CH:25]=[CH:26][C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32][C:33]=2[C:23]=1[NH:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc2c(c1NCc1ccc(CNC3CCCCC3)cc1)CCNCC2
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Bubble hydrogen chloride into a solution of 6-{-4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (355 mg, 0.6 mmol) in EtOAc (5 mL) at room temperature. Stir the mixture for 1 h, and concentrate in vacuo. Dissolve the residue in methanol (5 mL) and add water (2 mL) and K2CO3 (1 g, 7.2 mmol). Stir the mixture at room temperature overnight. Concentrate the mixture in vacuo and partition the residue between water (20 mL) and DCM (20 mL). Extract the aqueous phase with DCM (2×20 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate in vacuo. Purify by reverse phase chromatography [Phenomonex C18(2) column (5×25 cm) eluting with a gradient of water:acetonitrile (0.1% TFA in each) 9:1 through 2:3 over 50 min, 118 mL/min]. Concentrate pure fractions and apply to a SCX column (3.5 g) eluting with methanol and 3N ammonia in methanol to obtain 7-chloro-6-{4-[N-(cyclohexyl)-aminomethyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (204 mg, 86%).