Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:34]=O)[CH:27]=[N:28][C:29]=1[C:30]([F:33])([F:32])[F:31].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:23][C:24]1[CH:25]=[C:26]([CH2:34][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]3[N:19]4[C:20]5[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=5[CH:16]=[CH:17][C:18]4=[O:21])[CH2:10]3)[CH2:6][CH2:7]2)[CH:27]=[N:28][C:29]=1[C:30]([F:33])([F:31])[F:32]
Reactant: Cc1cc(C=O)cnc1C(F)(F)F
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Cc1cc(CNC2CCN(C[C@@H]3Cn4c(=O)ccc5ccc(=O)n3c54)CC2)cnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (Example 1 step (j): 70.5 mg, 0.235 mmol), 5-methyl-6-(trifluoromethyl)-3-pyridinecarbaldehyde (Preparation 12: 37 mg, 0.196 mmol) and magnesium sulphate (anhydrous) (58.9 mg, 0.489 mmol) in DCM (7 ml) was stirred overnight at RT. LCMS on the crude product showed imine and not starting material was present. Rt of the desired compound was 2.59 [M+H] 472.2. Then sodium triacetoxyborohydride (124 mg, 0.587 mmol) was added and the mixture was stirred for 3 hours. LCMS showed imine so 1 eq. sodium triacetoxyborohydride (41.5 mg, 0.196 mmol) was added. Saturated aqueous sodium bicarbonate solution was added to the organic phase until pH9 was achieved. The organic phase was extracted with DCM and isolated, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by Flash-Master chromatography on a 2 g silica gel cartridge using DCM/MeOH 5% to obtain three batches (9.3 mg). 1H NMR was consistent with the desired compound, and LCMS was consistent with the desired compound [M+H]+ 474, Rt=1.81 purity 95%.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=O)=[CH:18][CH:17]=1>>[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[N:7][CH:6]=2)/[CH2:9][CH3:10])=[CH:18][CH:17]=1
Reactant: CCC(=O)c1ccc(O)nc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)nc1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(6-hydroxypyridin-3-yl)propan-1-one (0.3 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.37 g, 2.5 eq) to give the desired Z-product (Z and E isomer can be separated via column chromatography).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:12]S([O-])(=O)=O)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH:10]([CH3:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N+:18]=[N-:19]
Reactant: CC(CNC(=O)OC(C)(C)C)CS(=O)(=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CNC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 85 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)propan-2-ylmethanesulfonate (10.0 g, 39.5 mmol) in DMF (100 mL) at RT was added NaN3 (7.7 g, 118.5 mmol). The reaction mixture was stirred at 85° C. for 24 h, cooled to RT, diluted with cold water (300 mL) and extracted with diethyl ether (3×300 mL). The combined organic layers were washed with saturated NaHCO3 (2×200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-azidopropylcarbamate (7.0 g, 88.6%) as a light yellow oil. 1HNMR (CDCl3): δ3.6 (m, 1H, CH), 3.25 (m, 1H, CH2), 2.9 (m, 1H, CH2), 1.49 (s, 9H, CH3), 1.2 (d, 3H, CH3).
Reaction SMILES: CCN(CC)CC.[CH:8]([O:11][C:12]1[CH:17]=[C:16]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:15]([CH3:24])=[CH:14][C:13]=1[NH:25][C:26]1[N:27]=[C:28]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[S:43]([CH:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])[C:29]2[C:34]([CH3:35])=[CH:33][NH:32][C:30]=2[N:31]=1)([CH3:10])[CH3:9].Br[CH2:50][C:51]([NH2:53])=[O:52]>CN(C=O)C>[CH:8]([O:11][C:12]1[C:13]([NH:25][C:26]2[N:27]=[C:28]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S:43]([CH:46]([CH3:48])[CH3:47])(=[O:44])=[O:45])[C:29]3[C:34]([CH3:35])=[CH:33][NH:32][C:30]=3[N:31]=2)=[CH:14][C:15]([CH3:24])=[C:16]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:50][C:51]([NH2:53])=[O:52])[CH2:20][CH2:19]2)[CH:17]=1)([CH3:10])[CH3:9]
Reactant: NC(=O)CBr
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)c[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)c[nH]c3n2)c(OC(C)C)cc1C1CCN(CC(N)=O)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
82 uL of Et3N (0.69 mmol) was added into a solution of 40 mg N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (11) (0.069 mmol) and 28.5 mg 2-bromoacetamide (0.207 mmol) in 1 mL of DMF. The reaction mixture was heated to 100° C. and stirred for 10 minutes under microwave irradiation. After cooling to room temperature, the solvent was removed under vacuum and the residue was redissolved in 1 mL of DMSO and purified by mass-triggered HPLC to give the title compound.
Reaction SMILES: [F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1.O.NN>CO.[Ni]>[F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)C(F)C1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(N)cc23)C(F)C1
Yield: 44.9 %

Procedure:
A solution of compound 132 (0.175 g, 0.635 mmol) in dry methanol (5 mL) was treated with hydrazine hydrate (0.198 mL, 6.357 mmol) followed by Ra—Ni (˜0.05 g) at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 2 min. The reaction was brought to room temperature, filtered through celite bed, washed with methanol (3 10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 133 (0.07 g, 45%) as a solid. mp 176-178° C.; 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 2.40-2.56 (m, 1H), 2.73-2.83 (m, 1H), 2.99-3.08 (m, 1H), 3.30-3.42 (m, 1H), 4.51 (s, 2H), 5.37 (d, 1H, J=48.9 Hz), 6.22-6.26 (m, 1H), 6.51 (dd, 1H, J=1.8, 8.5 Hz), 6.97 (d, 1H, J=1.8 Hz), 7.08 (d, 1H, J=8.4 Hz), 7.27 (t, 1H, J=1.8 Hz), 10.72 (s, 1H); ESI-MS m/z (%): 246 (MH+, 12), 203 (100).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl.[NH2:27][O:28][CH2:29][CH2:30][OH:31].C(N(CC)CC)C>CO>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([CH:12]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[F:1])[N:8]([CH3:11])[N:7]=[CH:6]4)[CH3:13])=[CH:15][N:16]=2)[N:19]=1)\[CH3:24]
Reactant: CC(=O)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Reactant: NOCCO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=N\OCCO)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Temperature: 30 °C
Reaction time: 20 h
Yield: 18 %

Procedure:
To a solution of 1-(3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (100 mg, 0.267 mmol) in methanol (10 mL) was added 2-(aminooxy)ethanol hydrochloride (30.3 mg, 0.267 mmol). Triethyl amine was added dropwise to adjust the pH to 5˜6. The reaction mixture was stirred at 30° C. for 20 h. The solvent was removed in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (aq) and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product which was purified by chromatography on silica gel to afford 19 mg (17%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.58 (d, 1H), 7.50 (s, 1H), 7.49 (d, 1H), 4.91 (q, 1H), 4.76 (t, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.65 (m, 2H), 2.13 (s, 3H), 1.76 (d, 3H). LCMS (method B): [MH]+=397, tR=2.50 min. Chiral separation (method K) provided enantiomeric pure compounds example 39-R and example 39-S.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:56])C(=O)C1.O.O[Li].O>CC#N.C1COCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:56])[N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Temperature: 70 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (20 mg, 0.031 mmol, 1 equiv) in MeCN (1 mL) was added NCS (4 mg, 0.031 mmol, 1 equiv). After 1 h, the reaction was concentrated in vacuo. The crude chloride was taken up in 9:1 MeOH:water (1.1 mL) and LiOH.H2O (39 mg, 0.918 mmol, 30 equiv) was added. A few drops of THF were added to aid solubility. The reaction was heated to 70° C. for 1.5 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 60-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (10 mg, 48%). 1H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.36 (s, 1H), 7.16-7.08 (m, 3H), 6.02-5.67 (m, 1H), 4.60 (d, J=3.3 Hz, 1H), 3.96 (d, J=10.6 Hz, 2H), 3.52 (d, J=8.4 Hz, 1H), 3.42-3.30 (m, 1H), 2.44 (s, 3H), 2.40-2.31 (m, 2H), 2.29 (s, 3H), 2.05-1.51 (m, 10H), 1.20 (br. s., 3H), 1.19 (s, 9H), 1.03 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 673.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][C@@H:38]([CH3:41])[CH2:39][OH:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][C@@H:38]([CH3:41])[CH2:39][OH:40])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-2-amino-1-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.53 Hz, 3 H), 1.47-1.58 (m, 4 H), 1.61-1.74 (m, 4 H), 2.41 (d, J=11.58 Hz, 2 H), 3.38 (t, J=6.95 Hz, 4 H), 3.48 (t, J=5.05 Hz, 2 H), 3.97-4.12 (m, 1 H), 4.15-4.27 (m, 4 H), 4.98-5.02 (m, 1 H), 7.14 (t, J=8.95 Hz, 2 H), 7.41 (dd, J=8.84, 5.69 Hz, 2 H), 7.99 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.37 (d, J=8.00 Hz, 1 H), 17.24 (s, 1 H); ES+ MS: 525 (M+H+).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(O[C:21](=[O:33])[CH2:22][C:23]1[N:27]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:26]2=[N:25][CH:24]=1)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1COCC1.CO>[Br:32][C:29]1[CH:30]=[CH:31][C:26]2[N:27]([C:23]([CH2:22][C:21]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])=[CH:24][N:25]=2)[CH:28]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)Cc1cnc2ccc(Br)cn12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cc1cnc2ccc(Br)cn12)N1CCOCC1
Yield: 32 %

Procedure:
Add 0.5M diisobutylaluminum hydride in toluene (4.6 mL, 2.29 mmol) to a solution of (6-bromo-imidazo[1,2-a]pyridin-3-yl)-acetic acid ethyl ester (0.65 g, 2.29 mmol) and morpholine (5 mL) in THF (40 mL) at −78° C. Gently warm the reaction to room temperature and dilute carefully with methanol. Filter and concentrate the filtrate. Flash chromatography gives the subtitled compound (0.24 g, 32%) as a white solid. MS ES+ m/e 324.0, 326.0 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[C:21]#[N:22]>>[C:21]([C:8]1[CH:9]=[C:10]([C:13]2[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])#[N:22]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)c(C#N)c1
Reactant: CS(=O)(=O)Cl
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)c(C#N)c1
Yield: 74 %

Procedure:
This compound was prepared according to the procedure of Example 48 using methane-sulfonyl chloride (0.044 mL, 0.6 mmol) and 5-(4-amino-3-cyanophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.100 g, 0.45 mmol) to afford the title compound (0.100 g, 50%).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][N:12]([CH:28]3[C:37]4[N:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH2:31][CH2:30][CH2:29]3)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C.C(OCC)C>[F:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][N:12]([CH:28]3[C:37]4[N:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH2:31][CH2:30][CH2:29]3)[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2c(F)cccc2[nH]1)C1CCCc2cccnc21
Agent: NN
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: NCCCCN(Cc1nc2c(F)cccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.6 %

Procedure:
To a stirred solution of 2-{4-[(4-fluoro-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (86 mg, 0.173 mmol) in ethanol (2.0 mL) was added hydrazine hydrate (0.05 mL, 1.03 mmol) and the mixture stirred at room temperature for 20 hours. The mixture was then diluted with diethyl ether, dried (MgSO4), filtered and concentrated under reduced pressure to give a crude yellow oil. The oil was purified by flash chromatography (1.75 cm ID, 12 g silica, 25:1:1 CH2Cl2: MeOH: NH4OH) to give pure N1-(4-fluoro-1H-benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (29 mg, 46%). 1H NMR (CDCl3) δ 1.28-1.47 (m, 4H), 1.63-1.77 (m, 1H), 1.85-2.09 (m, 2H), 2.15-2.25 (m, 1H), 2.46-2.60 (m, 3H), 2.65-2.76 (m, 2H), 2.79-2.91 (m, 1H), 4.01-4.18 (m, 3H), 6.89 (dd, 1H, J=10.3, 8.0 Hz), 7.05-7.11 (m, 1H), 7.12-7.18 (m, 1H), 7.35 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=7.9 Hz), 8.59 (d, 1H, J=4.4 Hz).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].Cl>CN(C)C1C=CN=CC=1.C(#N)C.C(N(CC)CC)C>[CH3:54][S:55]([NH:58][C:18](=[O:19])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:16][CH2:15]1)(=[O:57])=[O:56]
Reactant: CS(N)(=O)=O
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(c1cccc2cc(C3=NCC(CC(=O)NS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 32.3 %

Procedure:
A solution of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 2-methyl-6-nitrobenzoic acid anhydride (190 mg), 4-dimethylaminopyridine (56 mg), triethylamine (200 μL) and methanesulfonamide (46 mg) in acetonitrile (5 mL) was stirred at room temperature for 18 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (76 mg, yield 33%) as white crystals from a fraction eluted with ethyl acetate. melting point 141° C.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([O:8][NH2:9])[CH2:4]1.[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][C:18](=[O:30])[CH:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21](=O)[CH2:20]4)[C@@H:15]1[CH2:14][CH2:13][C:12]2=[O:31].O.[Na+].[Cl-]>C1COCC1>[ClH:1].[NH:3]1[CH2:7][CH2:6][CH:5]([O:8][N:9]=[C:21]2[CH2:22][CH2:23][C@@:24]3([CH3:25])[CH:19]([C:18](=[O:30])[CH2:17][C@@H:16]4[C@@H:26]3[CH2:27][CH2:28][C@@:11]3([CH3:10])[C@H:15]4[CH2:14][CH2:13][C:12]3=[O:31])[CH2:20]2)[CH2:4]1
Reactant: NOC1CCNC1
Reactant: C[C@]12CCC(=O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=NOC3CCNC3)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of 3-(RS)-pyrrolidinyloxyamine dihydrochloride (III-c, Prepn. 3, 227 mg) and androstane-3,6,17-trione (495 mg) in THF: water (2/1, 27 mL) was stirred for 30 min. NaCl was added and stirred till the two phases separated. After extraction of the aqueous layer with THF, the combined organic phases were washed with brine, dried and evaporated. The crude was purified by flash chromatography (SiO2, CH2Cl2:MeOH:NH3 9:1:0.1). To the concentrated fractions 5M HCl in EtOAc was added. After dilution with Et2O, the solid was collected by filtration to give the title compound I-ac (464 mg, 60%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 9.59 (1H, bb), 9.41 (1H, bb), 4.74 (1H, m), 3.80-2.90 (5H, m), 2.60-1.20 (21H, m), 0.78 (6H, s).
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[C:13]([O:23][CH3:24])[CH:12]=[CH:11][C:10]=1[C:25]([C:27]1[C:33]2[CH:34]=[C:35]([O:42][CH3:43])[C:36]([O:40][CH3:41])=[C:37]([O:38][CH3:39])[C:32]=2[CH2:31][CH2:30][CH2:29][CH:28]=1)=[O:26])C1C=CC=CC=1.C1CC=CCC=1.CC(=O)OCC>CCO.[Pd]>[OH:8][C:9]1[C:14]([OH:15])=[C:13]([O:23][CH3:24])[CH:12]=[CH:11][C:10]=1[C:25]([C:27]1[C:33]2[CH:34]=[C:35]([O:42][CH3:43])[C:36]([O:40][CH3:41])=[C:37]([O:38][CH3:39])[C:32]=2[CH2:31][CH2:30][CH2:29][CH:28]=1)=[O:26]
Reactant: COc1ccc(C(=O)C2=CCCCc3c2cc(OC)c(OC)c3OC)c(OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1=CCC=CC1
Product: COc1ccc(C(=O)C2=CCCCc3c2cc(OC)c(OC)c3OC)c(O)c1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 63 %

Procedure:
95 (0.69 g, 1.19 mmol) was dissolved in 20 mL of anhydrous EtOH under nitrogen and the reaction mixture was immersed in a water bath to maintain a temperature of 25° C. 1.2 g of Pd—C was added followed by 1,4-cyclohexadiene (1.13 mL, 11.90 mmol) and the reaction mixture was stirred for 7 h. The reaction mixture was monitored for completion by TLC (Rf: 0.32, 60:40 Hex:EA). The reaction mixture was filtered through celite, washed with ethylacetate, rotavaped and purified by column chromatography (20:80 EtOAc:Hexanes) to obtain 0.3 g (63%) of 23 as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]=[O:22])=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]([OH:22])[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:38])[F:39])=[CH:35][CH:34]=3)=[C:19]([CH:23]([CH3:24])[CH3:25])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc([Mg]Br)cc1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC1(CCC1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under argon, 0.60 g (1.70 mmol) of 5-(4-fluorophenyl)-7-isopropyl-4-oxo-3,4-dihydrospiro-[chromen-2,1′-cyclobutane]-6-carbaldehyde (Example 51A) is suspended in 15 ml of tetrahydrofuran and cooled to −70° C. 4.3 ml (2.13 mmol) of a freshly prepared 0.5 M solution of [4-(trifluoromethoxy)phenyl]magnesium bromide in tetrahydrofuran are added slowly. The mixture is stirred briefly at −78° C. and then warmed to 0° C. After 1 h, the mixture is hydrolyzed with sodium bicarbonate solution, diluted with water and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 25:1→10:1). This gives 710 mg (81% of theory) of the title compound in a purity of 70%.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1>N1C=CC=CC=1.[Cu]>[CH3:32][O:31][C:5]1[CH:4]=[N:3][C:2]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])[C:6]=12
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Reactant: c1nc[nH]n1
Agent: [Cu]
Solvent: c1ccncc1
Product: COc1cnc(-n2cncn2)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Temperature: 145 °C

Procedure:
A mixture of 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (80 mg, 0.163 mmol), 1H-1,2,4-triazole (45.0 mg, 0.651 mmol) and copper (20.69 mg, 0.326 mmol) in pyridine (1 mL) was heated at 145° C. for 10 hours, LCMS indicated the formation of desired product. The reaction mixture was filtered and the clear solution purified by prep. HPLC to give 1-(4-methoxy-7-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione as pale yellow solid (28 mg, 35%). LCMS: m/e 480.11 (M+H)+, 1.52 min (method 9). 1H NMR (500 MHz, MeOD) δ ppm 2.81-3.10 (m, 2H) 3.70-4.04 (m, 5H) 4.76-5.10 (m, 2H) 7.37-7.72 (m, 3H) 7.80-7.93 (m, 1H) 8.00-8.22 (m, 2H) 8.30-8.42 (m, 2H) 8.55-8.75 (m, 1H) 8.83-8.99 (m, 1H) 9.39 (s, 1H).