Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1)#[N:2].C(OC([N:19]1[CH2:24][CH2:23][O:22][C@H:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20]1)=O)(C)(C)C>>[ClH:32].[Cl:32][C:27]1[CH:26]=[C:25]([C@H:21]2[O:22][CH2:23][CH2:24][NH:19][CH2:20]2)[CH:30]=[CH:29][C:28]=1[NH:31][C:9](=[O:11])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[N:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)c(Cl)c2)C1
Reactant: N#Cc1ccc(C(=O)O)cn1
Product: Cl
Product: N#Cc1ccc(C(=O)Nc2ccc([C@@H]3CNCCO3)cc2Cl)cn1

Procedure:
In analogy to example 79, step a) using 6-cyano-3-pyridinecarboxylic acid (CAS 70165-31-0) instead of 4-cyanopicolinic acid (CAS 640296-19-1) and (+)-(R)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. White solid. MS (ISP): 341.1 ([M+H]+)
Reaction SMILES: [NH2:1][CH:2]([CH3:50])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]5[CH2:35][O:34][C:33]([C:42]6[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=6[F:49])([CH2:36][N:37]6[CH:41]=[N:40][CH:39]=[N:38]6)[O:32]5)=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH3:4].[CH:51](=O)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.S1C=CC=C1>CO.[Pd]>[F:49][C:43]1[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:42]=1[C:33]1([CH2:36][N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[O:32][CH:31]([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14]4[CH:13]=[CH:12][C:11]([N:8]5[CH:7]=[N:6][N:5]([CH:3]([CH3:4])[CH:2]([NH:1][CH2:51][C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)[CH3:50])[C:9]5=[O:10])=[CH:16][CH:15]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)[CH2:35][O:34]1
Reactant: O=Cc1ccccc1
Reactant: CC(N)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CC(NCc1ccccc1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O

Procedure:
A mixture of compound 37 (0.0029 mol) and benzaldehyde (0.0029 mol) in methanol (250 ml) was hydrogenated at 50° C. overnight with Pd on activated carbon 10% (2 g) as a catalyst in the presence of thiophene solution (2 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE and 2-propanol, filtered off and dried, yielding 1.1 g (48%) of [2S-[2α,4α(S*,R*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(phenylmethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (compound 106; mp. 154.3° C.).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[N:41]=[C:42](Cl)[S:43][CH:44]=2)=[O:39])[CH3:36])[CH:26]=[C:27]([F:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:34][C:27]1[CH:26]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[N:41]=[C:42]([C:6]3[CH:7]=[C:8]([CH:10]4[CH2:11][CH2:12]4)[CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)[S:43][CH:44]=2)=[O:39])[CH3:36])[CH:24]=[C:23]([F:22])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC1(C)OB(c2cc(C3CC3)cc(C3CC3)c2)OC1(C)C
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1csc(-c2cc(C3CC3)cc(C3CC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 16.3 %

Procedure:
2-(3,5-Dicyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (74 mg, 0.26 mmol) and 2-chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (110 mg, 0.26 mmol) was reacted using Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (254 mg, 0.78 mmol) as described above to give the title compound (22 mg, 16%) after purification by flash chromatography on silica gel (% EtOAc′ in hexane=30%˜70%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17](=[S:19])[NH:16][C:15]2=[O:20])=[CH:9][C:8]=1[O:21][CH3:22].COCCOC.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O.C(O)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]2[S:18][C:17](=[S:19])[NH:16][C:15]2=[O:20])=[CH:9][C:8]=1[O:21][CH3:22]
Reactant: COc1cc(C=C2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(CC2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 368 %

Procedure:
To a N2-purged flask was added ′5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-thioxo-thiazolidin-4-one (42 mg, 85 μmol) and DME (4 mL). To the solution was added NaBH3CN (20 mg, 255 μmol) followed by acetic acid (2 mL). The reaction was stirred at rt for 2 h. The reaction solution was then diluted with EtOAc (100 mL), neutralized by successive washings of sat NaHCO3 (100 mL×3), washed with sat. NaCl (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was chromatographed (SiO2, DCM/MeOH 100:0 to 98:2) to provide intermediate compound (155 mg, 50% yield). 1H NMR (CDCl3) δ 9.29 (1H, br s), 7.99 (1H, d, J=8.1 Hz), 7.94 (1H, s), 7.83 (1H, d, J=8.1 Hz), 6.72-6.81 (3H, m), 5.38 (2H, s), 4.60 (1H, dd, J1=3.9 Hz, J2=9.8 Hz), 3.92 (3H, s), 3.48 (1H, dd, J=3.9 Hz, J2=14.2 Hz), 3.14 (1H, m); MS (ESI) 496 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].N.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:13]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:22]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Agent: N
Product: CC(=O)N[C@@H]1c2ccccc2C[C@H]1O
Product: O=C(N[C@@H]1c2ccccc2C[C@H]1O)c1ccccc1

Procedure:
The trans amide can be made from the epoxide either (1) by treating the indene oxide with ammonia or a primary amine to produce a trans-1-amino-2-indanol and reacting the trans-1-amino-2-indanol with an acylating agent, or (2) by treating the epoxide with an amide anion to produce the trans hydroxy amide directly. In one embodiment the indene is oxidized with aqueous hypochlorite in the presence of a chiral salen catalyst to produce a partially resolved epoxide, which is converted to the partially resolved trans-1-amino-2-indanol by treating with ammonia or a primary amine followed by acylating with benzoyl chloride or acetic anhydride. The resulting benzamide or acetamide is recrystallized to yield substantially optically pure trans-1-benzamido-2-indanol or trans-1-acetamido-2-indanol. In two preferred embodiments, the cis-1-amino-2-indanols are (1S,2R)-1-amino-2-indanol and (1R,2S)-1-amino-2-indanol, produced by oxidation of indene in the presence of an R,R or S,S-salen catalyst respectively.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]([NH:7][CH:8]1[CH2:13][CH:12]2[C:14]([CH3:16])([CH3:15])[C:9]1([CH3:17])[CH2:10][CH2:11]2)=[O:6].[CH3:19][O-].[Na+].[N:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=1.Cl.[N:31]1[CH:36]=[CH:35][C:34](CCl)=[CH:33][CH:32]=1>CO.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:34]1[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=1)([C:5](=[O:6])[NH:7][CH:8]1[CH2:13][CH:12]2[C:14]([CH3:15])([CH3:16])[C:9]1([CH3:17])[CH2:10][CH2:11]2)[CH:28]([CH3:19])[C:25]1[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=1
Reactant: ClCc1ccncc1
Reactant: COC(=O)CC(=O)NC1CC2CCC1(C)C2(C)C
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)NC1CC2CCC1(C)C2(C)C)(c1ccncc1)C(C)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-malonamic acid methyl ester (0.95 g, 3.7 mmol) in methanol (7 ml), sodium methoxide (0.20 g, 3.7 mmol) was added, and the mixture was stirred for 1 hour at ambient temperature. 4-Picolylchloride (0.53 g, 4.1 mmol of freshly liberated free base from 4-picolyl chloride hydrochloride; Aldrich Chemical Co.) was added, and the reaction was then stirred for 18 hours at ambient temperature. Ethyl acetate and water (15 ml of each) were added, and the mixture was well shaken. The separated aqueous extracted was then extracted with an equal volume portion of fresh ethyl acetate. The combined organic extracts were dried (anhydrous sodium sulfate), and concentrated in vacuo to an orange oil (1.16 g). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with initially ethyl acetate and subsequently with methanol/ethyl acetate up to a 1:4 ratio, respectively, in volume) afforded the title compound (12 mg) as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C([O-])([O-])=O.[K+].[K+]>CCO>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:10][C:8]1[CH:7]=[CH:6][C:5]2[S:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Oc1ccc2scnc2c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: BrCCCCOc1ccc2scnc2c1
Reaction time: 8 h
Yield: 27 %

Procedure:
A mixture of intermediate 25 (206 mg, 1.4 mmol), 1,4-dibromobutane (0.5 mL, 4.2 mmol) and anhydrous K2CO3 (193 mg, 1.4 mmol) in EtOH (20 mL) was heated to reflux and stirred overnight. The yellow solid was filtered and purified by column chromatography (elution with PE/EtOAc=4:1) to afford 5-(4-bromobutoxy)benzo[d]thiazole (intermediate 26) (108 mg, 39%) as a yellow oil. HPLC: 99%, RT 3.426 min. MS (ESI) m/z 288.0 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:21]=[CH:20][C:10]2[C:11]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[N:12][O:13][C:9]=2[C:8]=1[Cl:22])C.[OH-].[Na+].Cl>C(O)C>[Cl:22][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:10]=2[CH:20]=[CH:21][C:7]=1[O:6][CH2:5][C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccc(C)s3)noc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2noc3c(Cl)c(OCC(=O)O)ccc23)s1

Procedure:
A mixture of 15.0 g of ethyl{[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazole-6-yl]oxy}acetate of Example 9b and 10 ml of 50% NaOH in 800 ml of ethanol is refluxed for 30 minutes and then 100 ml of the 5% HCl is added, making the solution homogeneous. A product begins to crystallize as the solution cools and additional water is added. The product is filtered off and recrystallized form isopropanol giving {[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 235°-238° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:18][C@@H:17]3O[C@@:16]3([CH2:20]O)[C@@H:7]2[C@H:8]([O:11][C:12](=[O:15])[NH:13][CH3:14])[O:9][CH:10]=1)=[O:4].C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:18][CH:17]=[C:16]([CH2:20][Cl:33])[C@@H:7]2[C@H:8]([O:11][C:12](=[O:15])[NH:13][CH3:14])[O:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@@]3(CO)[C@H]12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CCl)[C@H]12
Yield: 24 %

Procedure:
2.0 g of (1S,4aS,6S,7R,7aR)-6,7-epoxy-7 -(hydroxymethyl)-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydrocyclopenta [c] pyrane-4-carboxylic acid methylester described in Example 19 were dissolved in dichloromethane followed by addition of 2.5 ml of triethylamine and 1.4 ml of methanesulfonylchloride while stirring and cooling with ice. After stirring for 12 hours at the same temperature, the reaction mixture was extracted with ethyl-acetate. After washing the organic phase with saturated aqueous sodium bicarbonate and brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a pale yellow oil from the hexane-ether eluate in the form of (1S,4aS,7aR)-7-(chloromethyl)-1-(methylcarbamoyloxy )-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (770 mg, yield: 24%). The physicochemical properties of this compound are described below.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>C(Cl)(Cl)Cl>[ClH:3].[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccccn1
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCc1ccccn1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Thionyl chloride (SOCl2, 6.2 ml) in chloroform (15 ml) was added dropwise to an ice chilled solution of 2-(2-hydroxyethyl)pyridine (Aldrich, 10 g, 81 mmol in chloroform (10 ml . After addition was complete, the reaction mixture was stirred for 15 hours. The solvent and excess thionyl chloride were removed on a vacuum rotary evaporator followed by exposure to high vacuum (90 minutes, 0.5 mm Hg, 80° C.) Recrystallization of the crude brown solid from isopropanol-isopropyl ether yielded 10.8 g of pure 2-(2-pyridinyl)ethyl chloride hydrochloride (mp. 124°-125° C., lit. mp., about 120° C., Gump et al., U.S. Pat. No. 2,533,243; Chem. Abstr., 1950, 45, p. 4271c) as light tan beads.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)[CH3:35])=[CH:4][N:3]=1.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[N:51][CH:52]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:9]=[C:8]([C:7]3[C:2]([NH:46][C:47]4[CH:52]=[N:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)=[N:3][CH:4]=[C:5]([CH:34]([C:36]4[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:43])=[O:44])=[CH:38][CH:37]=4)[CH3:35])[CH:6]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51.5 %

Procedure:
4-(2-Fluoro-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (764.7 mg, 1.218 mmol) and 5-amino-2-methoxypyridine (162.9 mg, 1.312 mmol) were dissolved in THF (12 mL) and the flask was cooled in an ice water bath while being stirred under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran/ethyl benzene, 3.6 mL, 3.6 mmol) was added via syringe, and the reaction was stirred at 0° C. After 40 min, the reaction was treated with ice water (1.5 mL), diluted with DCM, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted funnel with about 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 75:1 DCM/MeOH to 40:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum in a water bath (about 40° C.) to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (459.4 mg). 1H NMR (CDCl3, 400 MHz) δ 11.57 (s, 1H), 8.65 (d, J=2.35 Hz, 1H), 8.25 (d, J=2.35 Hz, 1H), 8.14 (d, J=2.35 Hz, 1H), 7.89 (dd, J=8.71 Hz, 2.45 Hz, 1H), 7.81 (d, J=8.22 Hz, 2H), 7.40 (d, J=8.02 Hz, 2H), 7.24-7.14 (m, 4H), 6.90-6.81 (m, 4H), 6.70 (d, J=8.80 Hz, 1H), 4.87 (d, J=4.89 Hz, 2H), 4.77 (d, J=5.09 Hz, 2H), 4.23-4.16 (m, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 2.98 (s, 3H), 2.57 (s, 3H), 1.66 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 732 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)O1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
A solution of commercial 1-(benzyloxy)-4-bromobenzene (104 g, 395 mmol) and commercial tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (147 g, 474 mmol) in 1100 mL of acetonitrile was purged with nitrogen for 2 min. Water (1100 mL) was added, followed by sodium carbonate (126 g, 1186 mmol) and tetrakis(triphenylphosphine)palladium (27.4 g, 23.7 mmol). The reaction mixture was purged with nitrogen for 5 min, and then heated to 90° C. and stirred for 16 h. The reaction mixture was then allowed to cool to rt and diluted with 1 L of ethyl acetate. The layers were separated, and the aqueous layer was extracted with two additional 250 mL portions of ethyl acetate. The organic layers were combined, washed with 200 mL of brine, dried over sodium sulfate, and evaporated in vacuo to provide an off-white solid. The product was purified by silica gel chromatography eluting with 6% ethyl acetate in petroleum ether to provide 129 g (88%) of the desired product. LC/MS RT (conditions A)=2.732 min, (M−H)+=364.0. 1H NMR (300 MHz, chloroform-d) δ 7.49-7.30 (m, 5H), 7.27 (d, J=10.7 Hz, 2H), 6.99-6.87 (m, 2H), 6.03-5.87 (m, 1H), 5.07 (s, 2H), 4.05 (d, J=2.6 Hz, 2H), 3.62 (t, J=5.7 Hz, 2H), 2.49 (br. s., 2H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[OH:29])=[CH:24][C:23]=1[OH:31].C([O-])(O)=O.[Na+]>CC#N>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[OH:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(O)c1ccc(OCCCCl)c(O)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1
Yield: 106.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.3 g, 19.5 mmol), 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzenemethanol (4.5 g, 19.5 mmol), KI (200 mg), NaHCO3 (1.8 g, 21.5 mmol) and CH3CN (125 ml) was stirred at reflux under nitrogen for 24 hours. The cooled reaction was filtered and the filter cake was washed with CH3CN. The filtrate was concentrated to afford an oily residue, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 8.6 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates prep LC/system 500) to is yield 5.0 g. The compound was recrystallized twice from ethanol to provide 3.9 g (49%) of 4-[3-4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-hydroxy-α-methyl-benzene methanol as a light beige solid, m.p.=142-144° C.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[CH2:15][CH2:14][C@@:12]4([CH3:13])[C@@H:8]([CH2:9][CH2:10][C:11]4=[O:20])[C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1.C1(C)C=CC(S(O)(=O)=[O:28])=CC=1.N1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.O1C=CCCC1.C(OCC)(=O)C>[O:28]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:1][C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[CH2:15][CH2:14][C@@:12]4([CH3:13])[C@@H:8]([CH2:9][CH2:10][C:11]4=[O:20])[C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CCC2=O
Reactant: c1ccncc1
Agent: C1=COCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]12CCC3=C(CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=O

Procedure:
A suspension of 2.0 g of 3-hydroxy-estra-1,3,5(10),8-tetraen-17-one in 20 ml of tetrahydrofuran and 2.0 ml of dihydropyran is stirred with 9.4 mg of para-toluenesulfonic acid for 3 hours at room temperature. Then, 0.3 ml of pyridine is added, diluted with ethyl acetate, washed with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone/triethylamine. 2.4 g of 3-tetrahydropyranyloxy-estra -1,3,5(10),8-tetraen-17-one is obtained as colorless crystals with a melting point of 122-125° C., [α]D22 =+0.00° (c=0.515% in pyridine).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[OH-].[Li+]>O1CCCC1.CO>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccc(F)cc1)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccc(F)cc1)CCC3
Yield: 50.7 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(4-fluorobenzyl)-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (0.34 g, 0.78 mmol) in tetrahydrofuran (15 mL) and methanol (15 mL) was treated with 1 M aqueous lithium hydroxide solution (20 mL) at room temperature for 66 h. The mixture was concentrated in vacuo and the residue acidified with concentrated hydrochloric acid. The resulting precipitate was collected via vacuum filtration, washed with water, and air-dried to provide 168 mg (51%) of the title compound as a green solid: mp 199-201° C. (dec). 1H NMR (DMSO-d6) δ 13.10 (bs, 1H), 7.18 (m, 2H), 6.95 (m, 2H), 6.50 (s, 1H), 5.55 (s, 2H), 4.62 (s, 2H), 2.95 (t, J=6.6 Hz, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.50 (s, 3H), 1.98 (quintet, J=7.3 Hz, 2H).