Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:12]3[S:16][C:15]([CH:17]4[O:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:14][CH:13]=3)OCC[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.Cl>C(OCC)(=O)C>[C:7]([C:12]1[S:16][C:15]([CH:17]2[O:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:14][CH:13]=1)(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(c2ccc(C3(c4ccccc4)OCCO3)s2)O1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2ccc(C(=O)c3ccccc3)s2)O1

Procedure:
5-[5-(2-Phenyl-1,3-dioxolan-2-yl)-2-thienyl]-oxazolidine-2,4-dione (0.40 g.) was dissolved in 30 ml. of ether and stirred with 10 ml. of 6 N hydrochloric acid at room temperature for 1 hour. Ethyl acetate (10 ml.) was added, and the organic layer was separated and evaporated in vacuo to dryness (0.388 g.). Chromatography on 50 ml. of silica gel, eluted with 1:1 hexane:ethyl acetate/5% acetic acid and monitored by tlc, gave in early fractions purified 5-(5-benzoyl-2-thienyl)oxazolidine-2,4-dione (0.22 g., m.p. 153°-155° C., m/e 287).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:16]([O:18]CC)=[O:17])[CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]=[CH:10]2>C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:16]([OH:18])=[O:17])[CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]=[CH:10]2
Reactant: CCOC(=O)c1cc(OC)c2[nH]c(=O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)O)cc2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 91.4 %

Procedure:
8.09 ml of a 5N aqueous sodium hydroxide solution was added to a suspension of 2.00 g of 8-methoxy-6-ethoxycarbonylcarbostyril in ethanol. The mixture became uniform in about 1 minute. The mixture was stirred at room temperature for 4 days. The resulting precipitate was collected by filtration and dissolved in water. The solution was washed with ethyl acetate, and then was made acidic with concentrated hydrochloric acid with ice-cooling. The resulting precipitate was collected by filtration to obtain 1.62 g of 8-methoxy-6-carboxycarbostyril as a white powder.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:29]2[C:33]([CH3:34])=[N:32][NH:31][C:30]=2[NH2:35])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:29]2[C:33]([CH3:34])=[N:32][NH:31][C:30]=2[NH:35][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: COc1ccc(-c2c(C)n[nH]c2N)cc1OC
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C)n[nH]c2NC=C2C(=O)Nc3ccccc32)cc1OC

Procedure:
The named compound is prepared by substituting 4-(3,4-dimethoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2085 gms. of 4-(3,4-dimethoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:29])([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([CH3:29])([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Agent: [Pd]
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Yield: 100.7 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-methyl-2-phenoxypropionate (4.97 g), which is the product of Reference example 8(a), and palladium on carbon (5%, 0.75 g) and the reaction mixture was treated to afford the desired compound (3.85 g) as a syrup.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH:27]([O:40][C:41]([NH:43][C:44]1[CH:49]=[CH:48][N:47]([CH2:50][C:51](O)=[O:52])[C:46](=[O:54])[N:45]=1)=[O:42])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:51](=[O:52])[CH2:50][N:47]2[CH:48]=[CH:49][C:44]([NH:43][C:41]([O:40][CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])=[N:45][C:46]2=[O:54])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.00 (brs, 1H), 8.34 (m, 1H), 8.26 (m, 1H), 7.90 (d, 0.6H), 7.84 (d, 0.4H), 7.72 (m, 2H), 7.44 (d, 4H), 7.37 (t, 4H), 7.29 (t, 2H), 6.94 (t, 1H), 6.79 (s, 1H), 4.82 (s, 1.2H), 4.72 (s, 0.8H), 4.45 (s, 0.8H), 4.28 (s, 1.2H), 4.22 (t, 1.2H), 4.07 (t, 0.8H), 3.99 (t, 1.2H), 3.86 (t, 0.8H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]2[CH2:13][C:14]([CH2:16][C@H:9]1[CH2:10][CH2:11]2)=O)=[O:7])([CH3:4])[CH3:3].[BH3-]C#[N:19].[Na+]>CO>[NH2:19][CH:14]1[CH2:16][CH:9]2[N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH:12]([CH2:11][CH2:10]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(N)C2
Yield: 98.9 %

Procedure:
A stirred mixture of Boc-nortropinone (287 mg, 1.3 mmol), NH4OAc (1.96 g, 25.5 mmol), NaCNBH3 (800 mg, 12.7 mmol) and MeOH (20 mL) was heated at reflux for 2 h. The mixture was concentrated, the residue was diluted with 0.5 M aq NaOH (30 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated to afford tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (291 mg, quant) as a mixture of isomers. LC-MS Method 1 tR=0.88 min, m/z=227.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:26]1[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]1>>[OH:32][CH:29]1[CH2:30][CH2:31][N:26]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)=[O:24])[CH2:27][CH2:28]1
Reactant: OC1CCNCC1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)N3CCC(O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and piperidin-4-ol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30](Br)=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:35]([Sn](CCCC)(CCCC)C=C)[CH2:36]CC>[N+](CC)(CC)(CC)CC.[Cl-].C1COCC1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([CH:35]=[CH2:36])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(Br)n4cc3-c3ccccc3)cc2)CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=Cc1cnc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn12
Temperature: 100 °C
Yield: 86.6 %

Procedure:
A mixture of compound 4-3 (100 mg 0.193 mmol), Tributyl-vinyl-stannane (92 mg, 0.58 mmol), K2 CO3 (27 mg, 0.193 mmol), Et4NCl (31.8 mg 0.193 mmol) and Pd(PPh3)2Cl2 (10 mg) in THF (5 mL) was heated at 100° C. in microwave system under N2 atmosphere for 45 min. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 78 mg of 4-5.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][N:8]([CH3:41])[C:9]([C:11]1[CH:12]=[C:13]([S:17]([C:19]2[CH:28]=[C:27]3[C:22]([C:23]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)=[C:24]([C:29]([NH2:31])=[O:30])[CH:25]=[N:26]3)=[CH:21][CH:20]=2)=[O:18])[CH:14]=[CH:15][CH:16]=1)=[O:10]>CN(C)C=O>[CH3:7][N:8]([CH3:41])[C:9]([C:11]1[CH:12]=[C:13]([S:17]([C:19]2[CH:28]=[C:27]3[C:22]([C:23]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)=[C:24]([C:29]([NH2:31])=[O:30])[CH:25]=[N:26]3)=[CH:21][CH:20]=2)(=[O:1])=[O:18])[CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: O=S([O-])OO
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3cc(S(=O)c4cccc(C(=O)N(C)C)c4)ccc23)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3cc(S(=O)(=O)c4cccc(C(=O)N(C)C)c4)ccc23)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Oxone (0.22 g) was added portionwise to a stirred solution of Example 575 (0.035 g) in N,N-dimethylformamide (4 ml). The mixture was stirred at room temperature under nitrogen for 24 h, a further portion of oxone (0.17 g) was added, and the mixture stirred for a further 5 h. The reaction was quenched with a solution of sodium sulphite (1.2 g) in water (15 ml), diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a buff solid (0.035 g).
Reaction SMILES: I[C:2]1[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([CH:20]=1)[C@@H:7]1[O:19][C@H:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:8]1.[CH:23]1[C:40]2=[C:41]3[C:30]([C:31]4[C:42]5[C:35](=[CH:36][CH:37]=[CH:38][C:39]2=5)[CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:28]=[CH:27][C:26]3=[C:25]([C:43]#[CH:44])[CH:24]=1.CCN(CC)CC>CN(C=O)C.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.[Cu]I>[CH:23]1[C:40]2=[C:41]3[C:30]([C:31]4[C:42]5[C:35](=[CH:36][CH:37]=[CH:38][C:39]2=5)[CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:28]=[CH:27][C:26]3=[C:25]([C:43]#[C:44][C:2]2[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([CH:20]=2)[C@@H:7]2[O:19][C@H:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:8]2)[CH:24]=1
Reactant: C#Cc1ccc2c3cccc4cccc(c5cccc1c52)c43
Reactant: CC(C)(C)C(=O)OC[C@@H]1CC[C@H](n2cc(I)c(=O)[nH]c2=O)O1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC[C@@H]1CC[C@H](n2cc(C#Cc3ccc4c5cccc6cccc(c7cccc3c74)c65)c(=O)[nH]c2=O)O1
Temperature: 25 °C
Reaction time: 43 h
Yield: 95.5 %

Procedure:
A solution of 5-iodo-5′-O-pivaloyl-2′,3′-dideoxyuridine (442 mg, 1 mmol) and 3-perylenylacetylene (345 mg, 1.25 mmol) in 10 mL of DMF was degassed three times by alternation between vacuum and argon. Then Pd(PPh3)4 (115 mg, 0.1 mmol), CuI (38 mg, 0.2 mmol) and Et3N (0.278 mL, 2 mmol) were added and the flask was degassed once again, filled with argon, and the mixture was stirred for 43 hours at ambient temperature. The mixture was diluted with 300 mL of EtOAc, washed 3×200 mL of water, dried with Na2SO4, and evaporated. Chromatography on a silica gel column using a 0 to 2% of EtOH/CHCl3 gradient gave rise to a chromatographically homogeneous (Rf 0.28, 5% EtOH/CHCl3) product as orange foam (545 mg, 96%). 1H-NMR (DMSO-d6): 11.85 (s, 1H, NH), 8.44 (d, 1H, J 7.8), 8.39-8.35 (m, 3H), 8.32 (d, 1H, J 8.2) (perylenyl), 8.06 (s, 1H, H-6), 7.83-7.81 (m, 2H), 7.69-7.60 (m, 2H), 7.58-7.53 (m, 2H) (perylenyl), 6.00 (dd, 1H, J1′,2′α 6.9 J1′,2′β 4.6, H-1′), 4.37-4.34 (m, 1H, H-4′), 4.32-4.26 (m, 2H, H-5′), 2.42-2.36 (m, 1H, H-2′), 2.17-2.12 (m, 1H, H-2′), 2.06-2.00 (m, 1H, H-3′), 1.90-1.83 (m, 1H, H-3′), 1.17 (s, 9H, tBu).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=O)=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1>Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:9][N:11]2[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=CCc1ccc(Br)cc1NC1CCOCC1
Agent: Cl
Solvent: CO
Product: Brc1ccc2ccn(C3CCOCC3)c2c1
Yield: 96 %

Procedure:
4-Bromo-2-[(tetrahydropyran4-yl)amino]-phenylacetaldehyde, dimethyl acetal (522 mg, 1.516 mmol) was dissolved in 20 ml of 1M HCl in methanol. The solution was refluxed for 2 hrs and the solvent evaporated to give the title compound (407 mg, 96%) as an off-white solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7](=[NH:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:26][C:27]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C1COCC1>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)/[C:7](=[N:18]/[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:27]=2[F:26])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(C)(C)C)cc(=N)n1CC1CCOCC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2F)n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a solution of Example 95E (0.53 g, 2.1 mmol) and Et3N (0.88 mL, 6.3 mmol) in THF (10 mL) was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.320 mL, 2.108 mmol). The mixture was stirred at ambient temperature for 4 h then was quenched with saturated aqueous NaHCO3 (10 mL) and diluted with EtOAc (10 mL). The layers were separated and the aqueous phase was extracted EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes in EtOAc) afforded the title compound (0.48 g, 1.1 mmol, 52% yield). MS (DCI/NH3) m/z 442 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[CH:19]([C:20](O)=[O:21])[NH:18][CH:17]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]32[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[NH:29][C:28]3=[O:37])[CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:20]([CH:19]2[NH:18][CH:17]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:16]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:15]2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[C:10]=2[F:38])=[O:21])=[CH:65][CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 44.7 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 97 (0.4 g, 0.66 mmol), was reacted with diisopropylethylamine (0.77 g, 5.9 mmol), diphenylphosphinic chloride (0.62 g, 2.6 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.31 g, 2.6 mmol) to give rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white foam (Yield 0.18 g, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[C:11]([C:21](O)=[O:22])[CH:10]=1.Cl.Cl.[NH:26]1[CH:30]=[N:29][C:28]([C@H:31]([NH2:33])[CH3:32])=[N:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:12]=[C:11]([C:21]([NH:33][C@@H:31]([C:28]2[N:29]=[CH:30][NH:26][N:27]=2)[CH3:32])=[O:22])[CH:10]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCOCC3)c2)c(F)c1
Reactant: C[C@@H](N)c1nc[nH]n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3nc[nH]n3)cc(N3CCOCC3)c2)c(F)c1
Reaction time: 16 h

Procedure:
To a solution of 2′-fluoro-4′methyl-5-morpholin-4-ylbiphenyl-3-carboxylic acid (52.0 mg, 0.15 mmol) in N,N-dimethylformamide (1.0 mL) was added (1R)-1-(1H-1,2,4-triazol-3-yl)ethanamine dihydrochloride (30.1 mg, 0.16 mmol), EDC (36.8 mg, 0.19 mmol), HOBT (22.6 mg, 0.15 mmol) and diisopropylethylamine (0.10 mL, 0.59 mmol). After 16 h, the mixture was purified by reverse phase HPLC (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound. HRMS 410.1990 (M+1).). 1H NMR (500 MHz, CD3OD): δ 9.37 (s, 1H); 7.86 (d, J=7.6 Hz, 2H); 7.67 (s, 1H); 7.45 (t, J=8.1 Hz, 1H); 7.13 (d, J=7.9 Hz, 1H); 7.07 (d, J=12.0 Hz, 1H); 5.52-5.47 (m, 1H); 4.00 (t, J=4.6 Hz, 4H); 3.52 (t, J=4.5 Hz, 4H); 2.40 (s, 3H); 1.79 (d, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:21])=[CH:8][C:9]=1[CH2:10][CH2:11]2.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([O:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:8][C:9]=1[CH2:10][CH2:11]2
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(OS(C)(=O)=O)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
28.84 g of 11β-fluoro-1,3,5(10)-estratrien-3-ol-17-one (100 mmol) is dissolved in 200 ml of pyridine, cooled in an ice bath, 20 ml of methanesulfonic acid chloride is added in drops, and it is stirred for 2 hours at room temperature. Then, it is stirred into 2.5 liters of ice water, and after two hours of stirring, it is filtered off. The solid residue is dissolved in dichloromethane, the solution is shaken out with 1N hydrochloric acid, water and saturated common salt solution and dried with Na2SO4. After the solvent is drawn off, the residue is 37 g, and after crystallization from methanol, 33.6 g of 11β-fluoro-3-mesyloxy-estra-1,3,5(10)-trien-17-one (91% of theory), flash point, is obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19](OCC)=[O:20])=[CH:17][N:16]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O1CCCC1.O>[C:7]([O:11][C:12]([NH:14][C:15]1[N:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:24][CH:25]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To 4.6 mL (4.6 mmol) of a 1M solution of lithium aluminum hydride in diethyl ether at −40° C. under a nitrogen atmosphere, was added a slution of 618 mg (2.3 mmol) of ethyl 6-(tert-butyloxycarbonylamino)nicotinate from part B in 40 mL of anhydrous tetrahydrofuran. After the addition, this was warmed to room temperature, stirred for 3 hours, cooled to 0° C., and 145 μL of water, 145 μL of 20% sodium hydroxide solution and 290 μL of water were successively added. To the resulting mixture was added 50 mL of tetrahydrofuran and stirring continued for 30 minutes. Anhydrous magnesium sulfate was added, the solids removed via filtration and the filtrate concentrated under reduced pressure to afford 460 mg of the desired product, m/e=224(M+), which was used directly in the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:17]([O:19]CC)=[O:18])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]([CH3:16])[CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:17]([OH:19])=[O:18])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]([CH3:16])[CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)C)c2nc(C3CC3)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-cyclopropyl-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.696 mmol) in ethanol (5 mL) was added sodium hydroxide (2.088 mL, 2.088 mmol), and the mixture stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo. The residue was diluted with water (30 mL) and then acidified with acetic acid. The contents were extracted with DCM (3×30 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The final product was obtained as 0.17 g (94%). LCMS E-S (M+H)=260.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.12 (m, 4H) 1.44 (d, J=6.57 Hz, 6H) 2.27-2.38 (m, 1H) 2.55 (s, 3H) 5.07 (quin, J=6.69 Hz, 1H) 7.43 (s, 1H) 13.30-14.08 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+]>O1CCCC1.O>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=2)[C:4]([OH:26])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid ethyl ester (707 mg, 1.80 mmol in tetrahydrofuran/water (24 mL, 3:1) was treated with lithium hydroxide (166 mg, 3.97 mmol). The reaction was stirred at 25° C. for 24 h. At this time, the reaction concentrated in vacuo. The residue was diluted with water (25 mL) and extracted with diethyl ether (1×15 mL). The aqueous layer was acidified to pH=1 with a 2N aqueous hydrochloric acid solution, and extracted with chloroform (3×25 mL). The organics were washed with water (1×25 mL), a saturated aqueous sodium chloride solution (3×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (426.7 mg, 65%) as a white solid: mp 122-123° C.; EI-HRMS m/e calcd for C16H19O4S (M+) 364.0956 found 364.0956.