Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65](=[O:73])[NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:69])=[O:68])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:52][CH2:51]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56](O)=[O:57])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.[CH:75]12[NH:82][CH:79]([CH2:80][CH2:81]1)[CH2:78][O:77][CH2:76]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65]([NH:66][S:67]([CH:70]([CH3:71])[CH3:72])(=[O:68])=[O:69])=[O:73])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:51][CH2:52]5)[N:48]=[C:47]([CH:53]([CH3:54])[CH3:55])[C:46]=4[C:56]([N:82]4[CH:75]5[CH2:81][CH2:80][CH:79]4[CH2:78][O:77][CH2:76]5)=[O:57])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CC2COCC1N2
Reactant: COc1ccc2c(c1)C=C(c1c(C(=O)O)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C=C(c1c(C(=O)N3C4CCC3COC4)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reaction time: 2 h
Yield: 33.3 %

Procedure:
HATU (65.0 mg, 0.171 mmol) was added to a stirring solution of 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.114 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (34 mg, 0.23 mmol), DIEA (80 μL, 0.456 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to stir for 2 hours. The reaction was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/MeOH gradient, and concentrated to give the titled compound (30 mg, 0.038 mmol, 34% yield) consistent by LCMS and NMR, with sufficient purity by HPLC.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:19][C:2]2[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=23)=[CH:16][CH:15]=1
Reactant: Cc1[nH]c2c(Cl)nncc2c1C
Reactant: OCc1ccc(F)cc1
Product: Cc1[nH]c2c(OCc3ccc(F)cc3)nncc2c1C
Yield: 29.8 %

Procedure:
The title compound was prepared as pale yellow crystals in 29.8% yield in a similar procedure to that described in Referential Example 79 by using 7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine and 4-fluorobenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: Cc1ccccc1CBr
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1ccccc1Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 1-(bromomethyl)-2-methylbenzene using DBU as a base in DMF at 80° C., Mass: 514.11 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]([C:15]([O:17][CH3:18])=[O:16])[NH:3]1.[H-].[Na+].C1(P(C2C=CC=CC=2)(O[NH2:30])=O)C=CC=CC=1>CN(C=O)C>[NH2:30][N:3]1[C:2](=[O:1])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC(=O)N1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CC(=O)N1N
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(tert-Butyl) 3-methyl 5-oxo-1,3-piperazinedicarboxylate (4.5 g) was dissolved in DMF (90 ml) and combined with sodium hydride (0.84 g, in oil) with cooling on ice. After stirring at 50° C. for 1 hour, O-diphenylphosphinyl hydroxylamine (4.5 g) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was combined with aqueous sodium bicarbonate and extracted with dichloromethane. The extract was dried and concentrated to obtain 1-(tert-butyl) 3-methyl 4-amino-5-oxo-1,3-piperazinedicarboxylate as a yellow oil. A solution of this material and 1-(4-pyridinyl)-4-piperidone (3.1 g) in ethanol (90 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 15 hours. The reaction mixture was concentrated to obtain a residue, which was dissolved in methanol (90 ml) and combined with acetic acid (2.1 ml) with cooling on ice,followed by sodium cycanoborohydride (2.2 g) and then stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried, concentrated and purified by a column chromatography on a basic silica gel (ethyl acetate:methanol=20:1) to obtain the title compound (3.8 g) as a pale yellow non-crystalline powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:24]([CH3:26])[CH3:25])[C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[C@H:10]([CH2:27][OH:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:24]([CH3:25])[CH3:26])[C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[C@H:10]([CH:27]=[O:28])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CO)C(=O)OCC[Si](C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C=O)C(=O)OCC[Si](C)(C)C
Reaction time: 8 h

Procedure:
To a well stirred mixture of (3S,4S)-3-hydroxymethyl-4-{[isopropyl-(2-trimethylsilanyl-ethoxycarbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (16.6 g, 39.8 mmol) and Dess-Martin periodinane (16.9 g, 39.8 mmol) in CH2Cl2 (110 mL), slowly wet CH2Cl2 (0.79 mL of water in 110 mL of CH2Cl2) is added. The clear solution becomes cloudy toward the end of wet CH2Cl2 addition and is further stirred overnight. Then concentrated to a few mL of solvent by rotary evaporation and taken up in Et2O. A solution of 1:1 10% Na2S2O3 saturated aqueous NaHCO3 is added. The layers are separated and the organic extract is washed successively with H2O and brine. The aqueous washings are back-extracted with Et2O, and this organic layer is washed with H2O and brine. The combined organic layers are dried with Na2SO4, filtered and concentrated. The crude mixture is used in the next step without further purification. TLC, Rf (CH2Cl2/MeOH 9:1)=0.48. MS (LC-MS): 437.0 [M+Na]+.
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[Br:10].OS(O)(=O)=O.[N+:19]([O-])([O-:21])=[O:20].[K+]>>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[C:7]([N+:19]([O-:21])=[O:20])[C:6]([F:9])=[CH:5][C:4]=1[Br:10]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
(2-Bromo-4-fluoro-phenyl) methyl carbonate (8.25 g, 33.13 mmol) was added portionwise to conc. H2SO4 (45 mL) to generate a colorless homogeneous solution. This solution was then cooled to 0° C. and KNO3 (3.7 g, 36.44 mmol) was added portionwise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice-water and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was then purified by silica gel column chromatography using 15% EtOAc/hexane gradient to yield 2-bromo-4-fluoro-5-nitrophenyl methyl carbonate (8.93 g, 92%) 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=6.7 Hz, 1H), 7.65 (d, J=9.6 Hz, 1H), 4.01 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:25]=[C:24]([CH3:26])[CH:23]=2)=[C:7]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([C:31]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:32])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:8]=1)#[N:11]
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCN(C(=O)NC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.4 %

Procedure:
To a solution of compound 24 (0.100 g, 0.27 mmol) in CH2Cl2 (3 mL) was added isopropyl isocyanate (0.032 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). Reaction was stirred for 20 hrs at room temperature, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was then concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with CH2Cl2/hexanes and vacuum filtered to yield a powder. The powder was redissolved in CH2Cl2 and chromatographed for a second time over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with hexanes and vacuum filtered to afford compound 58 as a white powder (0.014 g, 11.3% yield, 99.1% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.27 (d, J=2 Hz, 1H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H) 6.93 (s, 1H), 6.89 (s, J=9 Hz, 1H), 6.69 (s, 2H), 4.17 (m, 1H), 3.95 (m, 1H), 3.44 (m, 4H), 3.35 (m, 4H), 2.34 (s, 6H), 1.14 (d, J=7 Hz, 6H); MS (ESI, EI+): m/z=457 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[C:31](B(O)O)[CH:30]=[N:29]2)=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH:32]=[C:31]([C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]4)=[CH:4][CH:3]=3)[CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Br)cc2)C1
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cnn(-c4ccc(F)cc4)c3)cc2)C1
Temperature: 150 °C
Yield: 36.6 %

Procedure:
A mixture of (S)-tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate (100 mg, 0.29 mmol), 1-(4-fluorophenyl)-1H-pyrazole-4-ylboronic acid (60 mg, 0.29 mmol), tribasic potassium phosphate (124 mg, 0.585 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.5 mg, 0.0117 mmol) in dimethylacetamide (2 ml) was placed in a microwave tube, closed and heated at 150° C. for 10 min using a microwave synthesizer (Personal Chemistry Emrys Optimizer). After cooling water (10 ml) was added, and the reaction mixture was extracted with ethyl acetate. The aqueous phase was re-extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography (12 g silica gel, 10 to 50% ethyl acetate in heptane) to yield a light brown solid (45 mg, 36%). MS (ISP): 424.1 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>O1CCCC1>[Br:1][C:2]1[N:3]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:4](=[O:13])[C:5]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Oc1nc(Br)cnc1NC1CCC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(Br)cnc(NC2CCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a suspension of CaH2 (1.7246 g, 40.96 mmol) in 80.0 mL tetrahydrofuran (0.50 M) was added 5-bromo-2-(N-cyclobutylamino)-3-hydroxypyrazine (EX-115C) (5.0477 g, 20.68 mmol) in 50.0 mL tetrahydrofuran (0.41 M) dropwise via an addition funnel. The resulting suspension was heated to reflux for 30 minutes. To the mixture was then added a solution of tert-butyl bromoacetate (3.40 mL, 23.03 mmol) in tetrahydrofuran (23 M). Refluxing of the mixture was continued for 18 hours. The reaction mixture was allowed to cool to room temperature and cautiously poured in to a stirred ice water mixture (600.0 mL). The aqueous layer was extracted with ethyl acetate (4×250 mL). The combined organic solutions were washed with saturated NaHCO3 (1×250 mL) and brine (2×250 mL). The organic solution was dried (MgSO4), filtered, and concentrated. Purification of the crude product by MPLC (20% ethyl acetate/hexanes) afforded pure 6-Bromo-1-t-butoxycarbonylmethyl-3-(N-cyclobutylamino)pyrazinone (EX-115D) in 72% yield as an off white solid 1H NMR (400 MHz, CDCl3) δ 6.97 (s, 1H), 6.18 (br d, J=7.5 Hz, 1H), 4.79 (s, 2H), 4.39–4.29 (m, 1H), 2.41–234 (m, 2H), 1.96–1.86 (m, 2H), 1.79–1.68 (m, 2H) 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 165.8, 152.5, 149.0, 124.6, 105.1, 83.3, 49.7, 46.3, 31.3, 28.2, 15.6; HRMS (EI) calcd for C14H21N3O3 358.0766, found 358.0746.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[N+:10]([CH3:13])([O-:12])=[O:11].[O-]CC.[Na+].C(O)C.C(O)(=O)C>C(O)C>[N+:10]([CH2:13][C:3]1([OH:9])[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)([O-:12])=[O:11]
Reactant: O=C1CN2CCC1CC2
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
A mixture of 3-quinuclidinone (24.4 g, 0.195 mole) and nitromethane (15.9 g, 0.260 mole) in absolute ethanol (100 ml) was added to a cooled (0° C.) mechanically stirred solution of 21% sodium ethoxide/ethanol (64.8 g, 200 mole) in absolute ethanol (300 ml) under nitrogen. The mixture was stirred at room temperature for one hour, then at 55°(±5°) C. for 18 hours. The cooled suspension was treated dropwise with acetic acid (13.2 g, 0.220 mole), filtered through Celite®, washed with methanol, and concentrated in vacuo. The residue was filtered through alumina (eluted with 1:2 methylene chloride/methanol), concentrated in vacuo, and triturated from acetonitrile to afford 8.44 g (23%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[N:13]1[C:21]2[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:2]1([CH2:1][NH:8][C:9](=[O:10])[O:22][C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[N:13]([N:12]([CH3:11])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:14]=[CH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: CN(c1ccncc1)n1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(c1ccncc1)n1ccc2cc(OC(=O)NCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
Benzyl isocyanate (1.7 g) was added to a solution of 1-(methyl-4-pyridinylamino)-1H-indol-5-ol (2.5 g) in 75 mL tetrahydrofuran containing potassium carbonate (milled, 3 g). After stirring three hours at ambient temperature the mixture was filtered and concentrated. The residue was eluted through silica with ethyl acetate via flash column chromatography to yield 3.8 g solid. This was recrystallized from acetonitrile to yield 3.2 g crystals, m.p. 179°-181° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]([CH2:19][C:20]3[CH:39]=[CH:38][C:23]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OCc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)cc1
Temperature: 0 °C
Yield: 45.8 %

Procedure:
To a solution of 2-phenylindole (0.17 g, 0.86 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 35 mg, 0.86 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (0.25 g, 0.78 mmol) was added to the obtained mixture and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) to give the title compound (0.17 g, yield 46%) as a colorless oil. 1H NMR (CDCl3) δ: 2.59 (2H, t, J=7.8 Hz), 2.89 (2H, t, J=7.8 Hz), 3.66 (3H, s), 4.98 (2H, s), 5.38 (2H, s), 6.66 (1H, s), 6.88 (2H, d, J=8.7 Hz), 7.00-7.20 (7H, m), 7.29-7.47 (7H, m), 7.67 (1H, m).
Reaction SMILES: CN1[CH2:6][CH2:5][N:4]([CH3:7])C1=O.[CH3:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18]>C1COCC1>[NH:4]1[C:5]2[C:6](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:11]([C:16]([O:20][CH:16]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[CH3:9])[CH:17]([CH3:18])[CH3:19])=[O:20])=[CH:7]1
Reactant: CN1CCN(C)C1=O
Reactant: CC(C)C(O)C1CCCCN1C
Solvent: C1CCOC1
Product: CC(C)C(OC(=O)c1c[nH]c2ccccc12)C1CCCCN1C

Procedure:
The title compound was prepared by the procedures of Example 1 wherein the reaction solvent is changed to THF: 1,3-dimethyl-2-imidazolidinone using 1-(1-methyl-2-piperidyl)-2-methyl-1-propanol prepared in Reference Examples 5 and 6.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[C:26]2[CH:32]=[C:33]([CH2:40][CH3:41])[C:34]([C:36]([F:39])([F:38])[F:37])=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=2)[C:26]2[CH:32]=[C:33]([CH2:40][CH3:41])[C:34]([C:36]([F:39])([F:37])[F:38])=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Add 3,5-bistrifluoromethylbenzaldehyde (4.30 g, 24.22 mmol) to a solution of (S)-5-amino-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (4.91 g, 13.70 mmol) in dichloromethane (100 mL) and glacial acetic acid (6 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxyborohydride (6.01 g, 28.35 mmol) and stir the mixture for 2 h. Remove the solvents under reduced pressure and dilute the residue with dichloromethane (50 mL) and water (50 mL). Collect the organic layer and extract the aqueous layer with dichloromethane (3×30 mL). Wash the combined organic extracts with water (20 mL) and brine (20 mL) and dry over anhydrous sodium sulfate. Filter and remove the solvents under reduced pressure to provide the title compound as an amber oil (6.58 g, 75%), which is used in the next step without purification. 1H NMR (CDCl3, 300 MHz) δ 1.21-2.30 (m, 19H), 2.83-2.89 (m, 2H), 4.78-4.80 (m, 3H), 6.89-7.60 (m, 3H), 7.70-7.91 (m, 2H); APCI MS m/z 585 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH3:56])([CH3:55])[C@H:16]3[C@:29]([CH3:32])([CH2:30][CH:31]=2)[C@@H:28]2[C@:19]([CH3:54])([C@@:20]4([CH3:53])[C@H:25]([CH2:26][CH2:27]2)[C@H:24]2[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]2([CH2:39][N:40]([CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:44]([CH2:43][CH2:42][C:41]([N:40]([CH2:39][C@:23]12[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:24]1[C@@H:25]1[C@@:20]([CH3:53])([CH2:21][CH2:22]2)[C@@:19]2([CH3:54])[C@@H:28]([C@:29]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:56])([CH3:55])[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:13][CH:12]=2)=[CH:31][CH2:30]3)[CH2:27][CH2:26]1)[CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])=[O:47])([OH:46])=[O:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 57.4 %

Procedure:
To a solution of 4-((((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(tert-butoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl)(2-(dimethylamino)ethyl)amino)-4-oxobutanoic acid (47 mg, 0.061 mmol) in DCM (1 ml) was added TFA (0.25 ml, 3.24 mmol). The mixture was stirred at rt. After 1.75 h, The mixture was concentrated under reduced pressure, was diluted with dioxane and MeOH and was purified by prep HPLC to afford 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-carboxy-N-(2-(dimethylamino)ethyl)propanamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid as a white solid (25 mg, 0.035 mmol, 57.4% yield. LCMS: m/e 715.4 (M+H)+, 2.16 min (method 6).