Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CCC)=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1.[OH-].[Li+].CO.Cl>C1COCC1>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1
Reactant: CCCOC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](O)C[C@H]1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)CCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@H](Cl)C[C@H]1O
Yield: 90.8 %

Procedure:
A solution of 137 mg (0.31 mmol) of ester 16 in 2 mL of THF was hydrolyzed with 800 uL (0.40 mmol) of aqueous lithium hydroxide (0.5M) and 1 mL of methanol at 25° C. for 6 h. The mixture was acidified to pH 5-6 by addition of 400 uL of 1.0M hydrochloric acid and the residual water was removed in vacuo. The residual products were purified by FCC on 10 g of silica gel eluted with 8% methanol:92% EtOAc, then 10% methanol:90% ethyl acetate. Isolated from appropriate fractions was 110 mg of free acid 17 as an oil (88% yield); 1H NMR (acetone-d6): 1.13 (d, J=6.3 Hz, 3H), 1.16-1.68 (m, 13H), 1.86 (m, 1H), 2.0-2.24 (m, 3H), 2.29 (t, J=7.5 Hz, 2H), 3.73 (m, 1H), 4.09 (m, 3H), 5.56 (m, 2H). LC-MS 373.3 [M++1-H2O].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6](=[O:20])[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:21][CH:23]4[CH2:24][O:25]4)=[CH:3][CH:4]=3)[O:9][CH:8]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 7-hydroxy-3-(4-methoxyphenyl)chromen-4-one (0.86 g, 3.21 mmol), epichlorohydrin (1.25 ml, 16 mmol) and potassium carbonate (0.89 g, 6.42 mmol) in dimethylformamide (20 ml) was stirred at 80° C. for 3 hours. After removing solvent under reduced pressure, water was added to the residue, and the precipitate filtered off and washed with water. The crude product was purified by chromatography on silica gel, eluting with ethyl acetate/hexanes. (1:4 to 2:3), to afford 3-(4-methoxyphenyl)-7-(oxiran-2-ylmethoxy)chromen-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[CH:5]=[CH:6][CH:7]=1.C(O[C:15](=O)[CH2:16][CH2:17][C:18]1[N:19]([CH:31]2[CH2:33][CH2:32]2)[C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:21][CH:22]=1)C.CC(C)([O-])C.[Na+].CCO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:15]([CH2:16][CH2:17][C:18]3[N:19]([CH:31]4[CH2:33][CH2:32]4)[C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[O:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cnc(-c2ccc(OC)cc2)n1C1CC1
Reactant: NC(=NO)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ncc(CCc3nc(-c4cccc(Cl)c4)no3)n2C2CC2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
3-chloro-N′-hydroxybenzenecarboximidamide (54.3 mg, 0.32 mmol), 3-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-propionic acidethyl ester (100 mg, 0.32 mmol) and sodium-tert-butoxide (30.6 mg, 0.32 mmol) were mixed with EtOH (1 ml) and toluene (1 ml), followed by stirring at 100° C. for 24 h. The mixture was then concentrated, in-vacuo, and the residue was purified via column chromatography using 50% EA in hex. and then triturated with Et2O to isolate the title compound (27 mg). 1H-NMR: 8.1 (m, 1H), 7.97 (dd, 1H), 7.64 (d, 2H), 7.47 (m, 2H), 6.96 (d, 2H), 6.88 (s, 1H), 3.87 (s, 3H), 3.37 (m, 4H), 3.24 (m, 1H), 1.06 (m 2H), 0.68 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][Cl:19])[CH:11]=1.[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][NH:25]2.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][CH2:18][CH2:17][O:16][C:12]1[CH:11]=[C:10]([C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:2]=2[NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[CH:24][NH:25]3)[C:8]#[N:9])[CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cncc(-c2cccc(OCCCl)c2)c1Cl
Reactant: Nc1cccc2[nH]ccc12
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: N#Cc1cncc(-c2cccc(OCCCl)c2)c1Nc1cccc2[nH]ccc12
Temperature: 90 °C
Yield: 58.6 %

Procedure:
To a stirred solution of 4-chloro-5-[3-(2-chloroethoxy)phenyl]-nicotinonitrile (200 mg, 0.68 mmol), 4-aminoindole (135 mg, 1 mmol), DavePhos (80 mg, 0.20 mmol), and K3PO4 (216 mg, 1 mmol) in 4 mL anhydrous ethylene glycol dimethyl ether was added Pd2(dba)3 (62 mg, 0.07 mmol). The mixture was heated at 90° C. for 2 h then cooled, filtered through celite, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 5-50% MeOH in CH2Cl2 to yield 155 mg (59% yield) of 5-[3-(2-chloroethoxy)phenyl]-4-(1H-indol-4-ylamino)-nicotinonitrile 165 as a tan solid. MS: 389.1 (M+H), HPLC retention time: 9.60 min.(a).
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)N=1)(C)CO.C(O)(C(F)(F)F)=O.C([O:36][C:37](=O)[C:38]([NH2:65])([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:54][C@H:55]3[CH2:60][CH2:59][C@H:58]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:57][CH2:56]3)[C:46]=2[C:50]([F:53])([F:52])[F:51])[N:41]=1)[CH3:39])C>>[NH2:65][C:38]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:54][C@H:55]3[CH2:56][CH2:57][C@H:58]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:59][CH2:60]3)[C:46]=2[C:50]([F:51])([F:52])[F:53])[N:41]=1)([CH3:39])[CH2:37][OH:36]
Reactant: CCOC(=O)C(C)(N)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: CC(N)(CO)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
2-Amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2- yl]-propan-1-ol was synthesized as per 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-propan-1-ol (Example 18) in 49% yield (TFA salt) using 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propionic acid ethyl ester as starting material (TFA salt). MS: m/z=425.20 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.70 (d, J=8.8 Hz, 1H), 8.15 (d, J=9.5 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H), 7.50 (d, J=9.3 Hz, 1H), 4.33-4.45 (m, 1H), 4.08-4.25 (m, 2H), 2.15-2.27 (m, 2H), 1.85-1.98 (m, 2H), 1.78 (s, 3H), 1.48-1.64 (m, 2H), 1.04-1.24 (m, 3H), 0.90 (s, 9H).
Reaction SMILES: C(O)(C)(C)C.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]/[C@@H:21]([OH:26])[C@@H:22]([NH2:25])[CH2:23][OH:24].Cl.[CH:28]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1.CN1CCOCC1>O1CCCC1>[OH:24][CH2:23][C@H:22]([NH:25][C:34]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:35])[C@H:21]([OH:26])/[CH:20]=[CH:19]/[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: O=C(O)C1CCCCC1
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO)NC(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.5 %

Procedure:
N-((2S,3R,E)-1,3-dihydroxyoctadec-4-en-2-yl)cyclohexanecarboxamide (Compound I-1) was synthesized by adding 40 mg (0.29 mmol) of tert-butyl alcohol (HOBt) and 100 mg (0.29 mmol) of D-sphingosine/HCl at 0° C. to the solution of 38 mg (0.29 mmol) of cyclohexanecarboxylic acid in 25 mL of anhydrous tetrahydrofuran (THF). After 5 min, 67 mg (0.33 mmol) of dicyclohexylcarbodiimide (DCC) was added, and the pH of the solution was adjusted to 8 with 4-methylmorpholine. The reaction mixture was stirred at 0° C. for 2 h and at room temperature overnight. On evaporation the residue was dissolved in 100 mL of ethyl acetate. The solution was washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, and saturated sodium chloride, and the organic phase was separated and dried over anhydrous magnesium sulfate for 2 h. After filtration and evaporation under reduced pressure, the crude product was recrystallized in ethyl ether to obtain 60 mg (51%) of N-((2S,3R,E)-1,3-dihydroxyoctadec-4-en-2-yl)cyclohexanecarboxamide as colorless powder. GC/MS (m/e): 391 [M+H2O]+. 1H NMR (d6-DMSO, 300 MHz) δ/ppm=7.224 (d, J=8.4 Hz, 1H), 5.513 (dt, J=15.3 Hz, J=6.6 Hz, 1H), 5.345 (dd, J=15.3 Hz, J=6.6 Hz, 1H), 4.789 (d, J=5.1 Hz, 1H), 4.422 (t, J=5.4 Hz, 1H), 3.872 (q, J=6.0 Hz, 1H), 3.636 (m, 1H), 3.446 (m, 2H), 2.088 (m, 1H), 1.917 (m, 2H), 1.652 (m, 6H), 1.225-1.157 (m, 26H), 0.843 (t, J=6.6 Hz, 3H). 13C NMR (d6-DMSO, 75 MHz) δ/ppm=132.083, 131.506, 72.063, 61.298, 55.665, 44.657, 32.358, 31.979, 30.172, 29.732, 29.656, 29.382, 29.246, 26.194, 26.042, 22.778, 14.624. Anal. Calcd for C25H47NO3: C, 73.30; H, 11.56; N, 3.42; O, 11.72. Found: C, 72.99; H, 11.64; N, 3.74; O, 11.91.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]([OH:10])[CH2:3][NH:2]1.[H-].[Na+].[CH2:15]([O:17][CH2:18][CH2:19][CH2:20]Br)[CH3:16]>CN(C=O)C.O>[CH2:15]([O:17][CH2:18][CH2:19][CH2:20][N:2]1[CH2:3][CH:4]([OH:10])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[S:1]1(=[O:12])=[O:11])[CH3:16]
Reactant: CCOCCCBr
Reactant: O=S1(=O)NCC(O)c2ccsc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCCN1CC(O)c2ccsc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
A solution of the product from Example 1, Step C (13.0 g, 63.3 mmol) in DMF (50 mL) was added to a suspension of sodium hydride (2.5 g of a 60% slurry in mineral oil, washed with hexane, 63.3 mmol) in DMF (300 mL) at 0° C. After stirring for 45 min, the product from Step A (10.6 g, 63.3 mmol) was added and the mixture was stirred for 18 hr, during this time the temperature slowly increased to room temperature. The reaction mixture was diluted with cold water (300 mL) and extracted with ethyl acetate (5×10 mL). The combined extracts were washed with water (3×10 mL), saturated aqueous sodium chloride (20 mL), dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, gradient, 3:1 hexane/ethyl acetate to 7:3 methylene chloride/methanol) to provide a clear oil (13.1 g, 71%) which was used in the next step.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:16][C:17]([CH3:19])=[CH2:18].O>C1COCC1.C(OCC)C>[CH3:18][C:17](=[CH2:16])[CH2:19][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C=C(C)COc1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
Suspend 40 g (0.25 mol) of 4-(1H-imidazol-1-yl)phenol in 280 mL of THF and treat with 15 9 (0.375 mol) of a 60% dispersion of sodium hydride in mineral oil. Stir this suspension for 20 min and then add 27.1 mL (0.25 mol) of 3-chloro-2-methylpropene. Heat this mixture to 100° C. for 3 h. After this time, add 250 mL of water and 250 mL of diethyl ether and separate the layers. Re-extract the aqueous layer with 2×250 mL of diethyl ether. Evaporate the combined ether extracts on a rotary evaporator. Triturate with 300 mL of hexanes and filter off the resulting solid to provide the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]3[N:19]4[C:20](=[N:25][CH:26]=[C:18]4[C:17]2=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>C(O)C>[ClH:28].[ClH:28].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]3[N:19]4[C:20](=[N:25][CH:26]=[C:18]4[C:17]2=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2c(=O)c3cnc4cccc2n43)CC1
Agent: Cl
Solvent: CCO
Product: O=c1c2cnc3cccc(n1CCC1CCNCC1)n32
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a solution prepared by dissolving 5.30 g (14.13 mM) of 1,2-dihydro-1-[2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 50 ml of ethanol was added 5.88 ml (71.53 mM) of 12N-hydrochloric acid and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crystals that formed were collected by filtration and rinsed with small amounts of ethanol and ether to provide 3.51 g (yield of 71.5%) of the title compound as white crystals.
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[NH2:26][C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=[S:28].CN(C=O)C>C([O-])([O-])=O.[Na+].[Na+]>[C:22]([C:19]1[N:17]2[N:18]=[C:13]([C:2]3[S:28][C:27]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[N:26][C:3]=3[C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=3[F:12])[CH:14]=[CH:15][C:16]2=[N:21][N:20]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: CC(C)(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)cc3F)c(-c3ccc4nnc(C(C)(C)C)n4n3)s2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.3 %

Procedure:
A mixture of 2-bromo-2-(3-tert-butyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-(2,4-difluorophenyl)ethanone (3.78 g, 9.24 mmol; prepared using General Procedure A.2 from Preparation #K.1.1), tert-butyl 4-(aminocarbothioyl)tetrahydropyridine-1-(2H)-carboxylate (3.08 g, 12.6 mmol, Maybridge) and DMF (60 mL) was stirred at ambient temperature for about 2 d. The reaction was diluted with saturated aqueous Na2CO3 and extracted with Et2O (2×200 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The crude material was loaded onto a silica gel column and eluted with a gradient of 30-100% EtOAc in heptane to give the title compound (3.5 g, 68%): LC/MS (Table 1, Method a) Rt=2.64 min; MS m/z: 555.4 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:3][CH2:2]1.[CH:18]12[NH:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]([OH:26])[CH2:19]2>>[OH:26][CH:20]1[CH2:19][CH:18]2[N:25]([C:12]([C:11]3[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:10]=3)=[O:14])[CH:22]([CH2:23][CH2:24]2)[CH2:21]1
Reactant: OC1CC2CCC(C1)N2
Reactant: O=C(O)c1cccc(OCC2CCOCC2)c1
Product: O=C(c1cccc(OCC2CCOCC2)c1)N1C2CCC1CC(O)C2

Procedure:
Prepared from 3-(tetrahydro-pyran-4-yl-methoxy)-benzoic acid and 8-aza-bicyclo[3.2.1]octan-3-ol. LC-MS (m/z): 346 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:6]=[C:5]([CH:7]2[CH:13]3[CH:8]2[CH2:9][CH:10]2[CH:12]3[O:11]2)[N:4]([CH:14]([CH3:16])[CH3:15])[N:3]=1.[Li+].[B-](CC)(CC)CC>O1CCCC1.[Cl-].[NH4+]>[I:1][C:2]1[CH:6]=[C:5]([CH:7]2[CH:13]3[CH:8]2[CH2:9][CH2:10][CH:12]3[OH:11])[N:4]([CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: CC(C)n1nc(I)cc1C1C2CC3OC3C21
Agent: CC[B-](CC)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1nc(I)cc1C1C2CCC(O)C21
Temperature: 20 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To an ice-cooled solution of 3-iodo-1-isopropyl-5-(3-oxatricyclo[4.1.0.02,4]heptan-7-yl)-1H-pyrazole (0.500 g, 1.52 mmol) in anhydrous tetrahydrofuran (5 mL) was added lithium triethylhydroborate (10 mL, 1 M in THF) dropwise. The reaction mixture was warmed to 20° C. After 1 h, the reaction mixture was cooled to 0° C. and diluted with saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was extracted with ethyl acetate (2×10 mL). The collected organic was concentrated in vacuo. Purification by flash column chromatography (17% ethyl acetate in petroleum ether) afforded product as a colorless oil (460 mg, 91% yield).
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]2[C:15]([NH:28][C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:41][CH2:40][CH2:39][C:38]4=[O:42])[CH2:33][CH2:32]3)=[O:30])=[C:16]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)=[O:19])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[C:14]2[C:15]([NH:28][C:29]([C@H:31]3[CH2:32][CH2:33][C@H:34]([N:37]4[CH2:41][CH2:40][CH2:39][C:38]4=[O:42])[CH2:35][CH2:36]3)=[O:30])=[C:16]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)=[O:19])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c12
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans-4-t-butoxycarbonylamino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (108 mg) obtained in Example 425 is dissolved in trifluoroacetic acid (2 ml), and the mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, and the resulting residue is neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then ethyl acetate) to give the title compound (85.4 mg).
Reaction SMILES: OC(C(F)(F)F)=O.C1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:32]([O:34]C)=[O:33])=[CH:19][C:20]=3[N:21]3[C:27]=2[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][CH2:23][CH2:22]3)CCCCC1.C1(N=C=O)CCCC1>C(N(CC)CC)C.C(Cl)Cl>[CH:28]1[C:26]2[C:27]3[N:21]([C:20]4[CH:19]=[C:18]([C:32]([OH:34])=[O:33])[CH:17]=[CH:16][C:15]=4[CH:14]=3)[CH:22]=[CH:23][NH:24][C:25]=2[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Agent: O=C=NC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2cc3n(c2c1)C=CNc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)-carboxylate TFA (80 mg, 0.17 mmol) in triethylamine (0.20 mL) and CH2Cl2 (5 mL) which had been stirred for 5 min. was added cyclopentyl isocyanate (0.20 mL, 1.77 mmol). The reaction solution was stirred overnight at rt, concentrated to dryness, dissolved into MeOH/THF (1:1, 3 mL) and treated with 1M aqueous NaOH (0.80 mL). The reaction mixture was stirred and heated at 80° C. with microwave irradiation for 15 min in a sealed tube. The clear solution was diluted with H2O (3 mL), neutralized with 1M aqueous HCl (0.80 mL) and concentrated to remove organic solvents. The solids were collected by filtration, washed with water and purified by preparative HPLC (MeOH/H2O with NH4OAc buffer) to yield 5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid, 13-cyclohexyl-5-[(cyclopentylamino)carbonyl]-6,7-dihydro (8 mg, 0.02 mmol, 10%) as an off-white solid. 1HNMR (300 MHz, CD3OD) δ 8.14 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.72 (dd, J=8.4, 1.1 Hz, 1H), 7.68-7.59 (m, 3H), 7.52-7.46 (m, 1H), 4.79-4.60 (m, 2H), 4.05-3.46 (m, 3H), 3.06-2.92 (m, 1H), 2.14-1.25 (m, 18H). LCMS: m/e 472 (M+H)+, ret time 2.66 min, column A, 3 minute gradient.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OC)=O.[CH2:15]([N:22]1[CH2:26][CH2:25][C@@H:24]([NH:27][C:28]2[C:35]([F:36])=[CH:34][C:31]([CH:32]=O)=[CH:30][N:29]=2)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[CH2:15]([N:22]1[CH2:26][CH2:25][C@@H:24]([NH:27][C:28]2[N:29]=[CH:30][C:31](/[CH:32]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:34][C:35]=2[F:36])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(F)c1
Reactant: CCOC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(F)c1
Temperature: 24 °C
Reaction time: 0.67 h
Yield: 36 %

Procedure:
To an ice-cooled suspension of sodium hydride (38.5 mg) in THF (10 ml) was added ethyl (dimethoxyphosphoryl)acetate (206 mg), and the mixture was stirred at 24° C. for 40 minutes. To the mixture was added 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinaldehyde (250 mg) at 24° C., the reaction mixture was stirred at same temperature for 30 minutes. The reaction mixture was poured into a mixture of AcOEt and 5% aqueous NaCl. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (8.2 g) using a mixed solvent of CH2Cl2 and MeOH(100:1 to 35:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (111 mg, 36%) was obtained as oil.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][O:20]C1C=CC=CC=1C(C1C=CC=CC=1)=O>>[CH3:17][O:18][CH2:19][O:20][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][NH2:9]
Reactant: Cc1ccccc1C(CN)c1ccccc1
Reactant: COCOc1ccccc1C(=O)c1ccccc1
Product: COCOc1ccccc1C(CN)c1ccccc1

Procedure:
The title material was prepared as described for the synthesis of 2-phenyl-2-o-tolylethanamine (Example FF) in using (2-(methoxymethoxy)phenyl)(phenyl)methanone. 1H NMR (400 MHz, DMSO-d6) δ ppm: 6.88-7.44 (9H, m), 5.16-5.18 (1H, m), 5.09-5.15 (2H, m), 3.41-3.46 (2H, m), 3.21-3.23 (3H, m).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][C:41]([CH3:60])([OH:59])[CH2:40]2)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:58][C:45]1[CH:44]=[C:43]2[O:42][C:41]([CH3:60])([OH:59])[CH2:40][C@@:10]3([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:48]2=[CH:47][C:46]=1[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(O)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 34.4 %

Procedure:
To a solution of 45 (30 mg, 36.3 μmol) in a mixture of MeOH (3.0 mL) and THF (1 mL) was added Pd(OH)2/C (30 mg). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The aromatic chloride was partially cleaved. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory HPLC to give 53 (5.8 mg, 34%). 1H NMR (300 MHz, CD3OD) δ 7.50 (s, 1H), 7.00-7.07 (m, 4H), 6.77 (s, 1H), 3.98 (s, 2H), 3.93 (dd, J=2.1, 11.7 Hz, 1H), 3.65-3.82 (m, 3H), 3.55 (dd, J=8.1, 9.6 Hz, 1H), 3.27 (t, J=9.6 Hz, 1H), 2.80 (d, J=11.1 Hz, 1H), 2.57 (q, J=7.5 Hz, 2H), 1.96 (d, J=11.4 Hz, 1H), 1.68 (s, 3H), 1.19 (t, J=7.5 Hz, 3H). LC/MS m/z 447 (M−OH).