Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:39])/[C:11](/[CH2:27][O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][O:20]C2CCCCO2)=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1.FC(F)(F)C(O)=O.CO.ClCCl>CO>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:39])/[C:11](/[CH2:27][O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][OH:20])=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCCC/C=C(\COc1cccc2ccccc12)C(=O)NCCCn1ccnc1)NOC1CCCCO1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCC/C=C(\COc1cccc2ccccc12)C(=O)NCCCn1ccnc1)NO
Temperature: 25 °C
Yield: 36.8 %

Procedure:
(E)-N1-(3-(1H-imidazol-1-yl)propyl)-2-((naphthalen-1-yloxy)-methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide (203 mg, 0.38 mM) obtained in Example (2-1-3) was dissolved in methanol (2 ml), and trifluoroacetic acid (146 μl, 1.90 mM) was slowly added thereto at 0° C. Then, the resulting mixture was heated to room temperature and reacted for 18 hrs. After the completion of reaction, the solvent was removed under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: methanol/dichloromethane=1/9) to obtain 63 mg of the title compound (yield 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C>>[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:36]
Reactant: O=C(O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(F)cc4Cl)c3)c2c1
Yield: 16 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-chloro-4-fluorophenylacetic acid (0.13 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 38 mg (14% yield) of the title compound. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.65 (d, 1H), 7.52–7.4 (m, 3H), 7.35 (s, 1H), 7.2 (m, 1H), 3.9 (s, 2H); ES-MS (m/z) 423 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([NH:8][NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH:20]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
A solution of 9H-fluoren-9-ylmethyl 4-[(t-butoxycarbonyl)hydrazono]piperidine-1-carboxylate (10.0 g, 22.9 mmol) in acetic acid (150 mL) was shaken with platinum oxide (1.0 g) under 45 psi hydrogen on a Parr apparatus for 2 h. The solution was filtered and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][C:15]=1I>>[Br:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][C:15]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(Sc2ccc(C(F)(F)F)cc2Br)cc1

Procedure:
Prepared from 4-methyl-benzenethiol and 3-bromo-4-iodo-benzotrifluoride.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 78.9 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 846 mg (4.96 mmol) of 4-anisoyl chloride under ice-cooling with stirring and the mixture was stirred for at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with ether and dried to obtain 990 mg of the desired compound (78.9% colorless powder), mp: 121.0°-122.0° C.
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](=[O:28])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)=[CH:14][CH:13]=2)[CH2:7]1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH3:36]>CN(C=O)C>[CH3:1][S:2]([O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](=[O:28])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:20]([CH2:35][CH3:36])[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:14][CH:13]=2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OC1CCN(C(=O)c2ccc(Cc3nc4ccccc4[nH]3)cc2)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(Cc2ccc(C(=O)N3CCC(OS(C)(=O)=O)C3)cc2)nc2ccccc21
Temperature: -5 °C
Yield: 19 %

Procedure:
A stirred solution of 1-{4-[(1H-benzo[d]imidazol-2-yl)methyl]benzoyl}-pyrrolidin-3-yl methanesulfonate (0.250 g, 0.6 mmol) in DMF was treated with potassium carbonate (0.260 g, 1.9 mmol), cooled to −5° C., treated dropwise with ethyl iodide (0.24 g, 1.5 mmol) at 0° C. over 20 min, warmed to room temperature, heated at 50° C. for 3 h, cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The resultant residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated in vacuo. Purification of this residue by column chromatography (neutral alumina, chloroform:methanol 100:0→98:2) afforded 1-{4-[(1-ethyl-1H-benzo[d]imidazol-2-yl)methyl]benzoyl}pyrrolidin-3-yl methanesulfonate (19%). 1H NMR (400 MHz, CDCl3): 7.79-7.77 (m, 1H), 7.44-7.51 (m, 3H), 7.32-7.25 (m, 4H), 5.37 & 5.23 (bs, 1H), 4.36 (s, 2H), 4.05-4.10 (q, J=8 Hz, 2H), 3.93 (bs, 1H), 3.82 (m, 1H), 3.57-3.71 (bs, 2H), 3.08 & 3.00 (s, 3H), 2.33-2.36 (m, 1H), 2.17-2.21 (m, 1H), 1.18-1.22 (t, J=8 Hz, 3H). [M+H] 428.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH:14]1[CH:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([CH:24]=O)[C:17]2=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[C:23]1(/[CH:24]=[C:2]2\[N:3]=[C:4]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:13][C:1]\2=[O:12])[C:17]2[C:18](=[CH:19][CH:14]=[CH:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccccc2)=N/C1=C\c1cccc2ccccc12
Temperature: 80 °C

Procedure:
A solution of hippuric acid (4.0 g, 1.0 eq.) was added to a solution acetic anhydride (10 mL), 1-naphthylaldehyde (3.84 g, 1.1 eq.) and sodium acetate (2.21 g, 1.2 eq.). The reaction mixture was then heated at 80° C. for 2 hours, then cooled to room temperature, filtered, and washed with acetic anhydride. After air drying, the solid was washed back with water and air-dried overnight to give the desired compound.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C2C(=NC=CC=2)N(CC2C=CC3N=C(S(C)(=O)=O)SC=3C=2)C=1.[NH2:46][C@@H:47]([CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)[CH2:48][OH:49].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:46][C@@H:47]([CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)[CH2:48][OH:49])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: N[C@H](CO)C1CCCCC1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Agent: CS(=O)(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@@H](Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1)C1CCCCC1
Temperature: 150 °C

Procedure:
A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (60 mg) from Step 2 of this Example was dissolved in anhydrous DMA (1.5 mL) and to this solution were added (S)-2-amino-2-cyclohexylethanol (52 mg, 0.366 mmol) from Step 3 of this Example and DIEA (94 mg, 0.732 mmol). The reaction vessel was sealed and the mixture was heated in a Biotage microwave synthesizer at 150° C. for 30 min. LCMS analysis indicated that the reaction was not complete. To the reaction mixture was added additional (S)-2-amino-2-cyclohexylethanol (52 mg, 0.366 mmol). The reaction vessel was sealed and the mixture was heated in a Biotage microwave synthesizer at 150° C. for 40 min. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (S)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol (4 mg) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.37 (m, 1H), 8.08 (m, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.66 (s, 1H), 7.18-7.31 (m, 3H), 5.48 (s, 2H), 3.71 (m, 1H), 3.50 (m, 1H), 1.54-1.77 (m, 7H), 0.95-1.24 (m, 6H). LCMS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[NH2:14][N:15]1[C:19]([NH2:20])=[N:18][N:17]=[C:16]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:20][C:19]2=[N:18][N:17]=[C:16]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[N:14]=1
Reactant: Cc1ccc(Cl)c2c1NC(=O)C2=O
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Product: Cc1ccc(Cl)c2c1[nH]c1nc3nnc(Cc4ccc(O)cc4)n3nc12

Procedure:
According to the general cyclization procedure (for Example 27), 0.60 mmol of 4-chloro-7-methyl-1H-indole-2,3-dione (117.5 mg) and 0.70 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (144 mg) was used for the preparation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:7][C:6]=2[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>C(O)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:7][C:6]=2[C:17]=1[O:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Brc1ccc2c(c1Oc1ccccc1)N=C(c1ccccc1)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc2c(c1Oc1ccccc1)NC(c1ccccc1)CO2
Temperature: 90 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A suspension of 6-bromo-5-phenoxy-3-phenyl-2H-1,4-benzoxazine (0.0692 g, 0.182 mmol) in ethanol (1.20 mL) and water (0.240 mL) was treated with sodium tetrahydroborate (13.8 mg, 0.364 mmol) and stirred at 90° C. for 2 h. The reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (67.3 mg, 97%) as a colorless oil. LCMS calculated for C20H17BrNO2 (M+H)+: m/z=382.0, 384.0. found: 382.0, 384.0.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][N:29]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:25][CH3:26])[C:12]=2[N:13]=1)=[O:7].COCCNC.COCCN(CC1C=C(C=CN=1)C(NC1S[C:51]2[C:57]([N:58]3[CH2:63][CH2:62]OCC3)=CC=C(OC)C=2N=1)=O)C>>[O:23]1[CH2:24][CH:18]([C:17]2[C:11]3[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:27]=[CH:28][N:29]=[C:3]([CH2:2][N:58]5[CH2:57][CH2:51][CH2:62][CH2:63]5)[CH:4]=4)=[N:13][C:12]=3[C:14]([O:25][CH3:26])=[CH:15][CH:16]=2)[CH2:19][O:20][CH2:21][CH2:22]1
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Reactant: COCCN(C)Cc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Agent: CNCCOC
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccnc(CN4CCCC4)c3)nc12
Yield: 48 %

Procedure:
2-Chloromethyl-N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide and N-(2-methoxyethyl)-methylamine were reacted as described for 2-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in WO03/043636. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the tide compound as light yellow solid (48% yield). Mp 108-111° C., MS: m/e=469(M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[Si:27]([O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].CCN(CC)CC.N1C=CC=CC=1.CC1C=CC(S(OCC23CCC(C4SC(C)=NC=4C4C=CC=CC=4)(CC2)OC3)(=O)=O)=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Si:27]([O:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:13][CH2:12][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][CH2:15]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Oc4cccc(O[Si](C)(C)C(C)(C)C)c4)c3)(CC1)OC2
Yield: 69 %

Procedure:
A mixture of Example 7F compound [tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate] (350 mg, 0.97 mmol), (3-((tert-butyldimethylsilyl)oxy)phenyl)boronic acid (244 mg, 0.97 mmol), Cu(OAc)2 (144 mg, 0.97 mmol), Et3N (98 mg, 0.97 mmol) and pyridine (76 mg, 0.97 mmol) with 4A molecular sieves (1 g) in DCM (10 mL) was stirred at rt for 4 days. The reaction was then filtered, and the filtrate was concentrated in vacuo. The crude product was dissolved in EtOAc (5 mL) and washed with 1N aq. HCl and water, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo and chromatographed (SiO2; continuous gradient of EtOAc/hexanes from 0-40%) to afford the title compound as a light yellow oil (380 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 7.08-7.05 (m, 1H), 7.01-6.93 (m, 2H), 6.93-6.89 (m, 1H), 6.66 (ddd, J=8.1, 2.5, 1.1 Hz, 1H), 6.43-6.37 (m, 2H), 6.31 (t, J=2.3 Hz, 1H), 3.76 (s, 2H), 3.67 (s, 2H), 3.38 (t, J=7.0 Hz, 2H), 1.87 (s, 2H), 1.83 (dd, J=10.7, 5.4 Hz, 4H), 1.62-1.49 (m, 4H), 1.31 (s, 9H), 0.81-0.77 (m, 9H), 0.02-−0.02 (m, 6H).
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][C@@H:7]1[C:12](=O)[O:11][C:9](=[O:10])[CH2:8]1)(=[O:5])[CH3:4].O>O1CCCC1>[O:10]=[C:9]1[O:11][CH2:12][C@@H:7]([NH:6][C:3](=[O:5])[CH3:4])[CH2:8]1
Reactant: CC(=O)N[C@H]1CC(=O)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1COC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a stirred suspension of sodium borohydride (1.264 g, 33.41 mmol) in tetrahydrofuran (100 mL), N-acetyl-L-aspartic anhydride (5.0 g, 31.82 mmol, prepared as described in example A) was added in five portions at 0° C. over 1 h. The white suspension was warmed to room temperature, stirred for 3 h and cooled again to 0° C. Cold water (˜50 mL) was slowly added to the stirred mixture while the temperature was allowed to reach 15° C. After stirring overnight at room temperature, tetrahydrofuran was evaporated in vacuo. The residual aqueous solution was diluted with water to a volume of 100 mL and passed through a Dowex 50X8 ion exchange column (100 g). The ion exchange column was rinsed with water (3×100 mL). The resulting aqueous solution was concentrated in vacuo and the residue was taken up in a mixture of toluene (30 mL) and methanol (70 mL). The solvent was evaporated in vacuo. This procedure was repeated, i.e. the residue was taken up in toluene-methanol and concentrated again another three times. The remaining colorless oil (5.4 g) which consisted of a mixture of hydroxy-acid and lactone was dissolved in acetic acid (54 mL). Toluene (54 mL) was added and the solution was stirred at 110° C. for 2.5 h. After this time, all hydroxy-acid was cyclized to the desired lactone according to GC analysis of a reaction sample which had been concentrated and silylated. The reaction mixture was concentrated in vacuo. Three times the residue was taken up in toluene and concentrated again to give the crude product (4.2 g) as a white solid. For purification, the crude product was dissolved in acetonitrile (30 mL). Toluene (60 mL) was added to the solution and acetonitrile was partly removed from the mixture in vacuo, until the product started to crystallize. The product was collected by filtration, washed with toluene and tert-butyl methyl ether and dried in vacuo to afford (S)-N-(5-oxo-tetrahydro-furan-3-yl)-acetamide (3.8 g, 83% based on N-acetyl-L-aspartic anhydride) as white crystals. The structure of the compound was confirmed by 1H-NMR, MS, IR. and elemental analysis.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.N([O:15][CH2:16][CH3:17])=O.[CH2:18]([OH:20])[CH3:19]>>[CH2:16]([O:15][C:2]1([O:20][CH2:18][CH3:19])[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[CH3:17]
Reactant: CCON=O
Reactant: O=C1CCCc2ccccc21
Reactant: CCO
Agent: Cl
Product: CCOC1(OCC)CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2-Diethoxy-1-tetralone (compound Ib) was prepared by charging 48.9 g of 1-tetralone, 105 g of absolute ethanol, 5.2 g of gaseous hydrogen chloride to a reactor flask. To another flask (feeder flask) was added 62.6 g of ethyl nitrite. The feeder flask was connected to the reaction flask by a hose ending with a gas dispersion tube which would allow subsurface addition of the ethyl nitrite. The feeder flask was maintained at room temperature to facilitate ethyl nitrite evaporation. The ethyl nitrite was added to the reaction, with stirring, over about 60 minutes at a reaction temperature of 40-42° C. When the addition was complete, the mixture was neutralized to pH 8 and then ethanol was vacuum stripped on a rotary evaporator. The residue was held for 2 hours at about 50° C. to complete the saponification. The product was extracted into hexane and the hexane removed under vacuum. The residue was distilled under vacuum (0.2-0.5 mm Hg) to give 1.9 g of product. NMR, IR and MS were consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[S:4][N:3]=1.[Li+].C[Si]([N-:26][Si](C)(C)C)(C)C>C1COCC1.O.[NH4+].[Cl-].CCOC(C)=O>[NH2:26][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[S:4][N:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nc(Br)ns2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nc(N)ns2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(3-bromo-1,2,4-thiadiazol-5-yl)phenylcarbamate (3.22 g, 9.04 mmol) in THF (35 mL) at 0° C. was added LiHMDS (1 M in PhMe, 23 mL, 23.0 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. Water (20 mL) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water, saturated NH4Cl, and EtOAc. The aqueous phase was extracted with EtOAc (2×), and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. The concentrate was dissolved in 10% MeOH in DCM (200 mL), filtered through a pad of silica (2 cm), and diluted with hexanes (150 mL). The precipitate that formed was collected by filtration, washed with hexanes, and dried under high vacuum to give tert-butyl 4-(3-amino-1,2,4-thiadiazol-5-yl)phenylcarbamate.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=1.[O:16]=[C:17]1[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:35][C:36](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:29]1([C:22]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:20][CH2:19][N:18]([CH2:35][C:36]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=4)[N:14]=3)[C:17]2=[O:16])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(C(F)(F)F)nc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)—N-hydroxy-6-(trifluoromethyl)nicotinimidamide (0.146 g, 0.711 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.200 g, 0.646 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.161 g, 0.840 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 3 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF15-12 column (Analogix®) and the product eluted using a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate over 30 minutes (Flow=30 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 9.44 (d, J=1.9, 1H), 8.56 (ddd, J=0.5, 2.0, 8.1, 1H), 7.95-7.75 (m, 1H), 7.43-7.08 (m, 10H), 4.94 (s, 2H), 3.65 (t, J=6.5, 2H), 2.84-2.57 (m, 2H), 1.93 (dtd, J=3.1, 6.4, 9.4, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24]([O:26]C)=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:30])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cc(C)cc(C)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 47 %

Procedure:
A solution of the 9-[(3,5-dimethylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (200 mg, 0.55 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 4 days at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 2.5 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 90 mg (47%) of the 9-[(3,5-dimethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 7.75 (d, 1H, J=8 Hz), 7.45 (m, 2H), 7.3 (t, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.85 (s, 1H), 6.7 (s, 2H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H), and 2.2 (s, 6H). IR (KBr, cm−1) 3417, 3198, 3113, 3063, 1631, 1601, 1562, 1438, 1332, 1263, 1217, 781, and 773. MS (ES) m/e 343, 345.