Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[CH2:35][CH2:34][CH2:33]2.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)=O>C1COCC1.CCOC(C)=O>[C:7]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[CH2:35][CH2:34][CH2:33]3)[N:10]=[CH:9]1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCCc2cc(OCCCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc21

Procedure:
According to the method of Example 32, Step 1, 3-[1-(triphenylmethyl)-1H-imidazole-4-yl]propanol (see for example, J. Med. Chem., 1996;39: 1220-1226) (2.58 g, 7 mmol) was coupled to 6-hydroxy tetralone (1.30 g, 7 mmol) with diethylazodicarboxylate (1.26 mL, 8 mmol) and triphenylphosphine (2.10 g, 8 mmol) in 10 mL of dry THF to afford, after chromatography (SiO2, 50% EtOAc in hexanes), 2.73 g of a 1:1 mixture of the title compound and Ph3PO as determined by HPLC analysis (C18, 0.1% TFA in H2O:0.1% TFA in AcCN gradient 80:20 to 20:80): title compound, retention time=15.87 minutes (48.2%); Ph3PO, retention time=13.12 minutes (50.1%). CI-MS m/e 279 (Ph3PO), 513 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1.[CH:37]1([N:40]2[CH:45]=[CH:44][C:43](I)=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1>>[CH:37]1([N:40]2[CH:45]=[CH:44][C:43]([C:20]3[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]4[CH2:10][CH2:9][C@@:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12]4=[O:14])[CH3:16])=[CH:22][CH:21]=3)=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O
Reactant: O=c1cc(I)ccn1C1CC1
Product: C[C@@H](c1ccc(-c2ccn(C3CC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 1-cyclopropyl-4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 23 Step 9. LC-MS Method 2 tR=1.05 min, m/z=505; 1H NMR (CDCl3) δ 0.88 (m, 2H), 1.12 (s, 3H), 1.15 (s, 1H), 1.17 (s, 1H), 1.21 (s, 3H), 2.18-2.29 (m, 2H), 2.30-2.34 (m, 1H), 2.42 (d, 1H), 2.54 (d, 1H), 2.90 (m,1H), 3.35 (m, 1H), 5.70 (m, 1H), 6.32 (m, 1H), 6.68 (m, 1H), 6.98 (m, 1H), 7.09 (d, 2H), 7.18 (t, 1H),7.25-7.36 (m, 4H),7.50 (t,1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:15]=[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]3=[N:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCn1nc2ccccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 37.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (111 mg, 0.58 mmol, Example 190(E)) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 61 mg (0.22 mmol, 37%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a grey solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([OH:15])[C@@H:5]([NH2:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@@H:4]1[O:15][C:27](=[O:29])[NH:14][C@H:5]1[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)[C@H](O)[C@@H](N)c1ccc(F)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1OC(=O)N[C@H]1c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2R, 3S)-3-amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester (5.8 g, 25 mmol) in 250 mL tetrahydrofuran at 0° C. was added N,N-diisopropylethylamine (8.75 mL, 50 mmol) and triphosgene (2.48 g, 8.4 mmol). The reaction was stirred at 0° C. for 30 min when it was poured over ethyl acetate (200 mL) and saturated sodium carbonate solution (100 mL). The layers were separated, the organic layer washed with saturated sodium carbonate solution (1×100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide a pale yellow oil. The material was triturated with 25% ethyl acetate/hexane from dichloromethane to provide (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester. The recovered mother liqour was passed through silica (50% ethyl acetate/hexane) to give an additional 1.1 g (4.8 g total, 18 mmol, 75%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>>[F:16][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:2]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)=[N:3][CH:4]=1
Reactant: Fc1cnc(Cl)nc1NCc1cccnc1
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(NCc3cccnc3)n2)c1
Yield: 43 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 3-pyridylmethylamine (162 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) were reacted to give 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine. Then 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) reacted to give 5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 43%). 1H NMR (CD3OD): δ 4.71 (s, 2H), 6.38 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 6.88 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 7.00 (t, J=8.1 Hz, 1H), 7.14 (t, J=2.4 Hz, 1H), 7.37 (dd, J=4.8 and 7.8 Hz, 1H), 7.73 (d, J=3.6 Hz, 1H), 7.87 (dt, J=2.1 and 7.5 Hz, 1H), 8.39 (dd, J=1.2 and 7.8 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −170.99; LCMS: ret. time: 8.82 min.; purity: 92.90%; MS (m/e): 312.05 (MH+).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13]([CH2:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([CH2:20][NH:21][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1NCCc1ccccc1
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A mixture of 300 mg (1.62 mmol) of 2-chloro-5-nitrobenzaldehyde, 196 mg (1.62 mmol) of N-benzylmethylamine and 268 mg (1.94 mmol) of potassium carbonate in dimethylformamide was heated at 80° C. for 5 hour. The solvent was removed and the residue was partitioned between water and ethyl acetate (×2). The combined organic phases were evaporated and the residue was purified by column chromatography eluting with 25% ethyl acetate/petroleum ether (40-60° C.) to give 290 mg of 2-(benzylmethylamino)-5-nitrobenzaldehyde as a yellow oil which solidified on standing; MS: m/e 270.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[C:15](B(O)O)=[C:14]([O:19][CH3:20])[CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[C:14]([O:19][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[F:9])=[CH:4][CH:3]=1
Reactant: COc1cccc(F)c1B(O)O
Reactant: Oc1ccc(Br)cc1
Solvent: ClCCl
Product: COc1cccc(F)c1Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a 100 mL round bottom flask was added 4-bromophenol (2.04 g, 11.8 mmol), 6-fluoro-2-methoxyphenylboronic acid (1.00 g, 5.88 mmol), cupric acetate (1.4 g, 7.70 mmol) and DCM (50 mL). TEA (4.0 mL, 29.0 mmol) was then added followed by 4 A° molecular sieves and the reaction mixture was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N(CC)CC)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.[CH3:71][O:72][C:73]1[CH:78]=[CH:77]C(S(Cl)(=O)=O)=[CH:75][CH:74]=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([C:32]4[CH:77]=[CH:78][C:73]([O:72][CH3:71])=[CH:74][CH:75]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Product: COc1ccc(S(=O)(=O)Nc2cnc3n(c2=O)[C@H](C(=O)NCc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)CC3)cc1
Yield: 46.2 %

Procedure:
Following a procedure similar to that for the preparation of 16a, intermediate 3a (50 mg, 0.117 mmol) and 4-methoxybenzene sulfonyl chloride (31.4 mg, 0.152 mmol) yielded 32.2 mg (46.2%) of 31a. MS (ESI) 597.0 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:39])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]=[C:14]([CH:16]3[CH2:18][CH:17]3[C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25](COCC[Si](C)(C)C)[C:24](=[O:37])[CH:23]=[CH:22]4)[O:13][N:12]=2)=[CH:6][C:5]=1[CH3:38].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].[F:39][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]=[C:14]([C@@H:16]3[CH2:18][C@H:17]3[C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:37])[CH:23]=[CH:22]4)[O:13][N:12]=2)=[CH:6][C:5]=1[CH3:38]
Reactant: Cc1cc(Nc2noc(C3CC3c3ccc4c(ccc(=O)n4COCC[Si](C)(C)C)c3)n2)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2noc([C@@H]3C[C@H]3c3ccc4[nH]c(=O)ccc4c3)n2)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-(2-(3-((4-(difluoromethoxy)-3-methylphenyl)amino)-1,2,4-oxadiazol-5-yl)cyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (60 mg, 0.108 mmol) in DCM (2 mL) was added TFA (0.042 mL, 0.541 mmol) at 0° C. and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with DCM and washed with sat. NaHCO3 solution. The organic layer was dried Na2SO4, and concentrated. The crude product which was purified by preparative HPLC on a Sunfire C18 column (150×19, 5μ) using a buffer of mobile phase A: 0.1% TFA/Mobile Phase-B: ACN to give trans-6-(2-(3-((4-(difluoromethoxy)-3-methylphenyl)amino)-1,2,4-oxadiazol-5-yl)cyclopropyl)quinolin-2(1H)-one as an off white solid (12 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.83 (m, 2H) 2.22 (s, 3H) 2.56-2.64 (m, 1H) 2.72-2.78 (m, 1H) 6.51 (dd, J=9.54, 2.01 Hz, 1H) 6.84-7.15 (m, 2H) 7.24 (d, J=3.01 Hz, 1H) 7.29-7.35 (m, 2H) 7.43 (dd, J=8.66, 1.88 Hz, 1H) 7.58 (d, J=1.76 Hz, 1H) 7.84 (d, J=9.54 Hz, 1H) 9.83 (s, 1H) 11.72 (s, 1H). LCMS, RT 2.23 min; LCMS (ES-API), m/z 425.2.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[CH2:8][CH2:9][NH:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1.C(N(CC)CC)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl>[CH3:29][C@:26]12[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:43])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C:20]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:44]([C:47]([CH3:49])=[CH2:48])[CH2:45][CH2:46][C@:11]1([NH:10][CH2:9][CH2:8][N:2]1[CH2:3][C@@H:4]3[CH2:7][C@H:1]1[CH2:6][N:5]3[S:58]([CH3:57])(=[O:60])=[O:59])[CH2:28][CH2:27]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CN4)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
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CN4S(C)(=O)=O)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
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-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 (75.2 mg, 0.113 mmol) and triethyl amine (0.078 mL, 0.563 mmol) in DCM (3 mL) was added methanesulfonyl chloride (10.67 μl, 0.135 mmol). The reaction mixture was stirred at rt. After 1.5 h, the reaction mixture was diluted with DCM (25 mL) and washed with H2O (2 mL). The aqueous layer was extracted with DCM (15 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give methyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-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 as a light brown solid (69.0 mg, 78% yield). LC/MS: m/e 746.8 (M+H)+, 246 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.88 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 5.25 (d, J=4.6 Hz, 1H), 4.71 (s, 1H), 4.57 (s, 1H), 4.26 (s, 1H), 3.86 (s, 3H), 3.69 (br. s., 1H), 3.58 (d, J=9.5 Hz, 1H), 3.19 (dd, J=9.4, 1.8 Hz, 1H), 2.97 (dd, J=9.8, 2.0 Hz, 1H), 2.85 (s, 3H), 2.80 (dd, J=8.3, 4.2 Hz, 2H), 2.65 (d, J=9.8 Hz, 1H), 2.61-2.44 (m, 2H), 2.07 (dd, J=17.1, 6.4 Hz, 2H), 1.95-1.68 (m, 6H), 1.66 (s, 3H), 1.65-1.37 (m, 9H), 1.31-1.06 (m, 7H), 1.04 (s, 3H), 0.96 (s, 3H), 0.94 (s, 3H), 0.89 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[C:20]([O:22][CH3:23])=[O:21].[C:24](Cl)(=[O:26])[CH3:25].Cl>O1CCOCC1.N1C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[C:20]([O:22][CH3:23])=[O:21])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 315 mg(1 mmole) of 4-(2-aminophenyl)-2,6-dimethyl-3,5-bis(methoxycarbonyl)-1,4-dihydropyridine [J. Am. Chem. Soc., 71, 4003 (1949)] in 1 ml of dioxane and 1 ml of pyridine a solution of 0.18 g of acetylchloride in 1 ml of dioxane was added drop-wise during 20 minutes in a temperature range of 0° to 10° C., then the mixture was stirred for 40 minutes at this temperature and for 3 hours at room temperature, thereafter it was poured into 10 ml of aqueous 10% hydrochloric acid. The precipitate formed was filtered, washed with water and dried. Yield 350 g (97.5%), m.p. 284° to 285° C. (ethanol).
Reaction SMILES: CB(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:13]N(C)C=O.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([C:29]2[C:34]([Cl:35])=[CH:33][C:32](Br)=[CH:31][N:30]=2)[C:27]=1[CH3:28])=[O:22])[CH3:19]>O>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([C:29]2[C:34]([Cl:35])=[CH:33][C:32]([CH3:13])=[CH:31][N:30]=2)[C:27]=1[CH3:28])=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Reactant: CN(C)C=O
Agent: CB(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2ncc(C)cc2Cl)c1C
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Methylboronic acid (457 mg), tripotassium phosphate (3.40 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (296 mg) were added to a N,N-dimethylformamide solution (36 ml) of 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.50 g) described in Reference Example 44(2), and the mixture was stirred at 100° C. for three hours. Methylboronic acid (154 mg) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (103 mg) were subsequently added and the mixture was further stirred for three hours. The reaction solution was cooled to room temperature and left stand for 16 hours, and methylboronic acid (153 mg) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (114 mg) were further added and the mixture was stirred again at 100° C. for five hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water and extracted with ethyl acetate three times. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(3-chloro-5-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.03 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.CN.[CH3:18][N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:19][CH3:18])=[O:14])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N)c2c1OCCO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 117.1 %

Procedure:
A 50-mL round bottom flash was charged with 8-amino-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (200 mg, 1.025 mmol), methylamine hydrochloride (138 mg, 2.05 mmol), HATU (467 mg, 1.23 mmol), TEA (0.5 mL), and DMF (5.0 mL). The reaction mixture was stirred at room temperature for 15 h. It was then purified by reverse-phase Combi-Flash eluting with 0.1% NH4HCO3 in water/CH3CN to afford the title compound as red oil (250 mg, 88%). LCMS: ESI (3 minute run), m/z=209.1 [M+1]+; Retention time: 1.53 minute.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31].[H-].[Li+].[Cl:38][CH2:39][CH2:40][CH2:41]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:41][CH2:40][CH2:39][Cl:38])[CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31]
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: ClCCCI
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=C(C)C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.57 g, 2.95 mmol) prepared in example 116a was reacted with LiH (2.3 g, 29.5 mmol) and 1-chloro-3-iodo-propane (6.04 g, 29.5 mmol) in N,N-dimethyl-formamide (100 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.6 g, 33.5%).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])([OH:7])=[O:5]
Reactant: CCOC(=O)c1cc2c(C)cccc2n1CCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(C)cccc2n1CCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
A mixture of ethyl 1-(2-tert-butoxycarbonylethyl)-4-methyl-1H-indole-2-carboxylate (3.76 g, 11.4 mmol), trifluoroacetic acid (14.8 g, 130 mmol) and dichloromethane (50 ml) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue, followed by extraction with diethyl ether (three times). The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 1-(2-carboxyethyl)-4-methyl-1H-indole-2-carboxylate (3.12 g).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][NH:7][C:8](=[O:30])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][O:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](Br)=[C:23]([CH3:29])[CH:22]=2)[CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)C.[C:32]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:36]1[CH:41]=[CH:40][C:39]([C:24]2[C:23]([CH3:29])=[CH:22][C:21]([O:20][CH2:19][CH:15]([C:12]3[CH:11]=[CH:10][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])=[O:30])=[CH:14][CH:13]=3)[CH:16]([CH3:18])[CH3:17])=[CH:26][C:25]=2[CH3:27])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(COc2cc(C)c(Br)c(C)c2)C(C)C)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1cc(OCC(c2ccc(C(=O)NCCC(=O)O)cc2)C(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound is prepared by essentially following the procedures as described in Example 21, using 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxymethyl)-2-methyl-propyl]-benzoylamino}-propionic acid ethyl ester and 4-tert-butyl phenyl boronic acid as starting materials. MS (ES): 514.2 [M+H]−.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]#[N:26].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1/C=C/C=C/C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1C=CC=Cc1nnn[nH]1

Procedure:
According to the method described for Example 1, (E,E)-5-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile was allowed to react with sodium azide-ammonium chloride to give 5-[4-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-1,3-butadien-1-yl]tetrazole. Recrystallization from dichloromethane-methanol gave colorless prisms, m.p.192°-193° C.