Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:41])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Clc1ccccc1-c1cc(Br)ccn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccnc(-c5ccccc5Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-(2-chloro-phenyl)-pyridine.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[C:20]([NH:19][CH2:18][C@@H:16]1[O:15][C:14](=[O:23])[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:1]34[CH2:6][CH:5]3[CH2:4][N:3]([C:32]([O:34][CH3:35])=[O:33])[CH2:2]4)=[CH:12][CH:11]=2)[CH2:17]1)(=[O:22])[CH3:21]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC2CC2(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)C1
Temperature: 0 °C
Yield: 75.2 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (200 mg, 0.57 mmol) in DCM (25 mL), was added triethyl amine (0.3 mL, 2.27 mmol). The resulting solution was cooled to 0° C. and methyl chloroformate (0.07 mL, 0.86 mmol) was added dropwise. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with DCM (100 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.2:9.8 MeOH:CHCl3) to provide the title compound (160 mg, 74%) as white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]([CH3:30])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].O.Cl>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]([CH3:30])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(CN(C)c3ccc(F)c(C(=O)O)c3)cc2)cc1
Temperature: 100 °C
Reaction time: 0.97 h
Yield: 59.4 %

Procedure:
To a solution of methyl 5-[{4-[(4-butylphenyl)ethynyl]benzyl}(methyl)amino]-2-fluorobenzoate (66 mg; 0.15 mmol) in 3 mL of anhydrous THF were added. Lithium Hydroxide monohydrate (65 mg; 1.54 mmol) and water (1 mL). The reaction mixture was stirred under micro waves at 100° C. for 3500 s. Then an aqueous solution of HCl was added; the residue was extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated to give 37 mg of the title compound as a white solid. HPLC, Rt: 5.66 min (purity=93.20%). LC/MS, M−(ESI): 414.5. 1H NMR (CDCl3) δ: 7.40 (m, 4H), 7.31 (s, 1H), 7.20 (m, 4H), 6.92 (t, 1H), 6.75 (m, 1H), 4.42 (s, 2H), 2.92 (s, 3H), 2.54 (t, J=7.7 Hz, 2H), 1.50 (m, 2H), 1.25 (m, 2H), 0.82 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH:16]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[NH2:18][CH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH2:16][NH:18][CH2:19][C@@H:20]3[CH2:24][N:23]([C:25]4[CH:26]=[CH:27][C:28]5[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=5[N:34]=4)[C:22](=[O:36])[CH2:21]3)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1
Reactant: COc1cnc2ccc(=O)n(CCC=O)c2n1
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cnc2ccc(=O)n(CCCNC[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
To a solution of 3-(3-methoxy-6-oxopyrido[2,3-b]pyrazin-5 (6H)-yl)propanal (Reference Example 24, 120 mg, 0.515 mmol) in N,N-dimethylformamide (1.6 ml) were added 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 54, 175 mg, 0.66 mmol) and acetic acid (0.04 ml, 0.66 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled on ice, sodium triacetoxyborohydride (141 mg, 0.66 mmol) was added thereto and stirred overnight at room temperature. Two equivalents of sodium triacetoxyborohydride (282 mg, 1.32 mmol) were further added thereto and the reaction solution was stirred for 2 days. A sodium hydrogen carbonate aqueous solution was added to the reaction solution, which was then extracted with ethyl acetate and the obtained organic layer was washed with water and saturated sodium chloride solution. Subsequently, the organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained crude product was purified by thin layer chromatography (dichloromethane/methanol) to yield 27 mg (11%) of the title compound.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:19]([C:20](O)=[O:21])=[C:18]3[C:13]([CH2:14][CH2:15][CH:16]([CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[CH3:37][NH2:38]>C(Cl)Cl.C(#N)C>[C:29]([O:28][C:26](=[O:27])[N:24]([CH2:23][CH:16]1[CH2:15][CH2:14][C:13]2[C:18](=[C:19]([C:20](=[O:21])[NH:38][CH3:37])[C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])=[CH:11][CH:12]=2)[O:17]1)[CH3:25])([CH3:31])([CH3:30])[CH3:32]
Reactant: CN(CC1CCc2ccc(S(=O)(=O)c3ccccc3)c(C(=O)O)c2O1)C(=O)OC(C)(C)C
Reactant: CN
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CNC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1OC(CN(C)C(=O)OC(C)(C)C)CC2
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 7-benzenesulfonyl-2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-chroman-8-carboxylic acid (52 mg, 0.113 mmol) in DCM (10 mL) was added SOCl2 (25 μL, 0.339 mmol). The reaction was heated to reflux for 2 hours, then a solution of MeNH2 (40% in water, 0.5 mL) in acetonitrile (5 mL) was added and the mixture was allowed to stir for 1 hour. The reaction was concentrated in vacuo and the residue was purified via flash chromatography (DCM/MeOH, 98/2) to give (7-benzenesulfonyl-8-methylcarbamoyl-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (52 mg, 98% yield) as clear oil.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)=[O:11])[CH2:5][CH2:4]1.[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1>CN(C=O)C>[ClH:22].[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH2:36][CH2:37][O:38][CH3:39])[N:26]=[CH:25][N:24]=[C:23]2[CH:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([C:10](=[O:11])[CH2:9][N:6]3[CH2:7][CH2:8][O:3][CH2:4][CH2:5]3)[CH:13]=2)[NH:17][C:16]1=[O:21]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C1Cc2cc(C(=O)CN3CCOCC3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ccc(C(=O)CN5CCOCC5)cc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.8 %

Procedure:
Sodium hydride (58 mg, 2.4 mmol) was added to solution of 5-(2-morpholinoacetyl)oxindole (312 mg, 1.2 mmol) and 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (160 mg, 0.6 mmol), (prepared as described for the starting material in Example 2), in DMF (15 ml). The mixture was stirred for 1.5 hours at ambient temperature and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (96/4 followed by 94/6). The purified solid product was triturated with ether, collected by filtration, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride (10 ml) and methanol (10 ml) and 1M methanolic hydrogen chloride (2 ml) was added. The volatiles were removed by evaporation and the solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(2-methoxyethoxy)-4-(5-(2-morpholinoacetyl)oxindol-3-yl)quinazoline hydrochloride (136 mg, 39%).
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([O-:5])=[O:4]>S(=O)(=O)(O)O>[I:1][C:13]1[CH:12]=[C:8]([CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: II
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 97987.5 %

Procedure:
To a stirred solution of iodine (137.95 g, 0.5436 mmol) in fuming sulfuric acid (250 ml) was added m-nitrobenzoic acid (64.6 g, 0.3866 mmol) at room temperature. The reaction mixture was slowly heated to 85° C. overs 2 hours and stirred at the same temperature for another 12 hours. The reaction mixture was cooled to room temperature and poured into ice, and the aqueous solution was extracted with dichloromethane. The organic phase was separated and washed with water, 2.0 M solution of Na2S2O3 and brine, and then dried over Na2SO4. Solvent was removed under reduced pressure to yield 3-iodo-5-nitrobenzoic acid as slight yellow solid 111 g, yield 98%. MS (M+H)=294.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].CI.[C:13]([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(Br)ccc1O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(Br)cc1C#N

Procedure:
A mixture of 5-bromo-2-hydroxybenzonitrile (1 g, 5 mmol), MeI (0.85 g, 6 mmol) and K2CO3 (2 g, 15 mmol) in 25 mL of dry CH3CN were heated to refluxed over night. The solvent was evaporated off and the residue was added water. Extracted the mixture with DCM and the organic layer was washed with saturated chloride, dried over Na2SO4. The residue was purified with fast column chromatograph to afford compound 5-bromo-2-methoxybenzonitrile.
Reaction SMILES: C([O:4][CH2:5][CH:6]([O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([NH2:24])=[N:18][C:19]=2[Cl:23])[CH2:7][O:8]C(=O)C)(=O)C.C[O-].[Na+]>CO>[OH:4][CH2:5][CH:6]([O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([NH2:24])=[N:18][C:19]=2[Cl:23])[CH2:7][OH:8]
Reactant: CC(=O)OCC(COC(C)=O)OCn1cnc2c(Cl)nc(N)nc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc(Cl)c2ncn(COC(CO)CO)c2n1

Procedure:
A solution of 781 mg (2.18 mmoles) of 9-(1,3-diacetoxy-2-propoxymethyl)-2-amino-6-chloropurine in 22 ml of methanol was treated with 109 mmoles (5 mole percent) of freshly prepared sodium methoxide. Within ten minutes the stirred solution became cloudy and the product precipitated gradually in the course of forty-five minutes. The product was isolated by filtration, washed with 10 ml of water and dried in vacuo over P2O5 yielding 507 mg of pure product. A 200 MHz nmr spectrum in d6DMSO was fully in accord with the structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:6]([N:8]1[CH2:12][C:11](F)(F)[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:48]6[CH2:53][CH2:52][O:51][CH2:50][CH2:49]6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7].[C:67](OC(N1CC(F)(F)CC1C1NC(C2C=CC(C3C=CC4C(=CC=C(C5NC(C6CCCN6C(OCC6C=CC=CC=6)=O)=NC=5)C=4)C=3)=CC=2)=CN=1)=O)(C)(C)[CH3:68]>>[CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:6]([N:8]1[CH:9]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:36]6[NH:37][C:38]([CH:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:48]7[CH2:53][CH2:52][O:51][CH2:50][CH2:49]7)=[N:39][CH:40]=6)[CH:32]=5)[CH:27]=4)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:10][C:11]2([CH2:68][CH2:67]2)[CH2:12]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc4c3)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Yield: 33 %

Procedure:
{2-[6-(5-{4-[6-(2-{-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-5-aza-spiro[2.4]hept-5-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester (0.09 g, 33%) was prepared following the procedure for {2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester, substituting 6-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester for 2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS-ESI+: calc'd for C51H54N8O7: 890.41 (M+); Found: 891.96 (M+H+).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]2[C:14](SC)=[N:15][C:16]3[S:20][CH:19]=[CH:18][C:17]=3[C:12]2=[N:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](OC)(=[O:26])C=C.C[O-].[Na+].C(O)(=O)C>CO.ClCCl>[CH2:1]([S:8][C:9]1[N:13]=[C:12]2[N:11]([C:14]([O:26][CH3:23])=[N:15][C:16]3[S:20][CH:19]=[CH:18][C:17]=32)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: CSc1nc2sccc2c2nnc(SCc3ccccc3)n12
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COc1nc2sccc2c2nc(SCc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Benzylthio-5-methylthiothieno[3,2-e][1,2,4]-triazolo[4,3-c]pyrimidine (19.2 g (57.2 mmol)was mixed with 100 mL of methanol and to this was added with stirring 7.7 mL (86 mmol) of methyl acrylate and 3.3 mL of 25 percent sodium methoxide in methanol. After 2 hours at ambient temperature, the mixture was heated to reflux for about 2.5 hours during which time another 10 mL of 25 percent sodium methoxide in methanol was added. The mixture was stirred at ambient temperature overnight and then another 5 mL of the 25 percent sodium methoxide in methanol was added and the mixture heated to reflux again for 2 hours. The resulting mixture was acidified with acetic acid and was then concentrated by evaporation under reduced pressure to obtain a tan solid. This was dissolved in 600 mL of dichloromethane and the solution obtained was washed 3×100 mL with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The tan, solid residue was flash chromatographed on silica gel (240-400 mesh, 5×20 cm (centimeter) column) eluting with mixtures of hexane and ethyl acetate ranging from 90:10 to 50:50. The second compound to elute was collected to obtain 12.6 g of the title compound as a nearly white solid melting at 160°-162° C. The proton NMR spectra of this was consistent with the assigned structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCn1c(C(=O)OCC)cc2ccccc21
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of 18.9 g of ethyl indole-2-carboxylate in 100 ml of dimethylformamide was added to a suspension of 2.64 g of sodium hydride in 50 ml of dimethylformamide. After 1 hour, a solution of 20.9 g of ethyl 5-bromovalerate in 100 ml of dimethylformamide was added dropwise. After 48 hours, the mixture was poured into water, extracted with dichloromethane and the combined dichloromethane extracts were washed with water, dried and concentrated to give 26.2 g of ethyl 1-(4-ethoxycarbonylbutyl)indole-2-carboxylate.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH:27]=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
Sodium triacetoxyborohydride (35.7 g, 0.168 mol) was added to a mixture of crude (S)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (11.2 g, 0.056 mol), pyrrolidine (5.16 ml, 0.062 mol) and mol sieves (10 g) in dichloromethane (100 ml). Acetic acid (6.42 g, 0.112 mol) was added. The reaction mixture was stirred for 16 hours at room temperature. The precipitation was removed by filtration. The filtrate was diluted with a 1 N aqueous solution of sodium hydroxide (100 ml) and tert-butyl methyl ether (100 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×80 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane/triethylamine (1:1, 5%) as eluent, to give 9.23 g of (S)-2-((pyrrolidin-1-yl)methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[S:13][C:12]([NH2:14])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:8].[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[S:13][C:9]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8]
Reactant: O=C(O)c1ccncc1
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1)c1ccncc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
Compound 186 (209 mg, 0.770 mmol) was dissolved in DMF (4 mL), and isonicotinic acid (190 mg, 1.54 mmol), EDC hydrochloride (296 mg, 1.54 mmol) and 1-hydroxybenzotriazole monohydrate (236 mg, 1.54 mmol) were added thereto, followed by stirring at 50° C. for 3 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, followed by reslurrying with ethanol to afford the entitled Compound 187 (211 mg, 72%) as a yellow solid.
Reaction SMILES: Cl[C:2]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[O:3].CCN(C(C)C)C(C)C.[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH2:56]>ClCCCl.CN(C1C=CN=CC=1)C>[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH:56][C:2]([C@:4]12[CH2:39][CH2:38][C@@H:37]([CH:40]([CH3:42])[CH3:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C@@H:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)=[O:3]
Reactant: CN(C)CCN
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)NCCN(C)C)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a flask containing methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(chlorocarbonyl)-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)benzoate (77 mg, 0.13 mmol) in DCE (2 mL) was added Hunig's base (0.068 mL, 0.390 mmol), DMAP (1 mg, 8.19 mmol), and N,N-dimethylethylenediamine (0.029 mL, 0.260 mmol). The mixture was stirred for two hours at rt. The reaction was quenched with 5 mL of water and was extracted with dichloromethane (3×5 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure and was purified by Biotage flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a white foam (37 mg, 44% yield). LCMS: m/e 647.7 (M+H)+, 3.09 min (method 3).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Br:17])[CH:8]=1.[N+](C1C=C[C:24]([C:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=2)=C(C(F)(F)F)C=1)([O-])=O.CC[O:46]C(C)=O>C1COCC1>[C:36]([O:35][C:33]([N:30]1[CH2:31][CH2:32][CH:27]([C:24](=[O:46])[C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Br:17])[CH:8]=2)[CH2:28][CH2:29]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Reactant: FC(F)(F)c1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)cc(C(F)(F)F)c2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
Add n-butyllithium (2.5 N, 1.44 mL) to the solution of 1,3-dibromo-5-(trifluoromethyl)benzene (1 g, 3.28 mmol) in THF (15 mL) at −78° C. and stir the mixture at −78° C. for 1 hr. Then add tert-butyl 4-(methoxy(methyl)carbamoyl) piperidine-1-carboxylate (1.4 g, 4.92 mmol) obtained in Step 1 to the mixture and continue stirring. TLC (PE:EtOAc=5:1) shows the reaction is complete. Quench the reaction mixture with saturated ammonium chloride solution. Partition between EtOAc and water, separate the organic layer, and wash with brine, dry over anhydrous sodium sulfate, concentrate to give the crude product. Purify by flash chromatography (silica gel, DCM:MeOH=20:1) to afford the product (387 mg, 27%). MS: (M+1): 436.