Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:26]2[CH:27]=[C:22]([Cl:21])[N:23]=[CH:24][N:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 15.5 mmol) and potassium tert-butoxide (1.74 g, 1 eq) in 20 mL THF at 0° C., was added 4,6-dichloropyrimidine (2.3 g, 1 eq). The reaction mixture was stirred for 1 h then a solution of saturated sodium bicarbonate was added. The aqueous layer was extracted with ethyl acetate twice and the combined extracts were washed with a solution of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue was purified on silica gel (eluent: 20% ethyl acetate in hexane) to give 2.49 g (51% yield) of 3a.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[CH:15][C:14]=1[CH3:22])(=[O:12])=[O:11].[CH3:27][C:28]1([NH2:32])[CH2:31][O:30][CH2:29]1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:20])[CH2:21][NH:32][C:28]2([CH3:27])[CH2:31][O:30][CH2:29]2)=[CH:15][C:14]=1[CH3:22])(=[O:11])=[O:12]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)cc2C)c(C)c1
Reactant: CC1(N)COC1
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CNC3(C)COC3)cc2C)c(C)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-(2,4-dimethylphenyl)-N-isobutyl-2-methyl-4-(oxiran-2-yl)benzenesulfonamide (20 mg, 0.054 mmol) in ethanol at 25° C. was added 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50° C. for 18 hours. Another portion of 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50° C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 5.2 mg. LCMS [LCMS2] Rt 1.23 min, m/z (ES+) 461 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]2[N:9]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:10][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:3]=12.[CH3:34][N:35](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.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>[Cl:8][C:7]1[C:2]([C:34]#[N:35])=[C:3]2[C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH2:10][N:9]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[C:4]2=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4Br)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4C#N)c21
Temperature: 95 °C
Yield: 33 %

Procedure:
To a solution (R)-tert-butyl 4-bromo-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.200 g, 0.375 mmol) in DMF (2 mL) was added zinc cyanide (0.088 g, 0.75 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.022 g, 0.019 mmol). The mixture was heated at about 95° C. for 2 days. After cooling, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc hexanes, 1:1) to give (R)-tert-butyl 5-chloro-4-cyano-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.060 g, 33%) as a oil. LCMS (APCI+) m/z 480, 482 [M+H]+; Rt=4.51 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Yield: 85.8 %

Procedure:
According to the method of Preparation 25(a), 2-bromo-5-nitrotoluene (15 gm, 69.4 mmol) was treated with phenyl boronic acid (12.7 gm, 104.1 mmol) under palladium catalysis, using 2M aqueous sodium carbonate as base at reflux in dimethoxyethane for 16 h. After being cooled, the mixture was separated the organic layer was diluted with diethyl ether and washed with water (twice). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane to hexane:ethyl acetate 95:5) to give 2-methyl-4-nitro-1-phenylbenzene as a yellow solid (12.7gm, 86%).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:25]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[N:25]=[C:21]([CH3:20])[S:22][CH:23]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 423.01 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]>[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Product: CC(=O)c1cc(N)ccc1Cl

Procedure:
Procedure A was performed with 2′-chloro-5′-nitro-acetophenone (0.22 g, 1.1 mmol) and iron powder (0.64 g, 11 mmol). The crude product was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (0:1 to 1:0) to afford the desired 2′-chloro-5′-amino-acetophenone.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:22]([Sn](CCCC)(CCCC)C#CC)[CH2:23][CH2:24]C>O1CCOCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:22]([C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1)#[C:23][CH3:24]
Reactant: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: CC#Cc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Temperature: 100 °C
Yield: 63.2 %

Procedure:
A mixture of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.200 g, 0.674 mmol), tributyl(prop-1-yn-1-yl)stannane (0.266 g, 0.809 mmol), and bis(tri-t-butylphosphine) palladium (o) (0.017 g, 0.034 mmol) in p-dioxane (4 mL) was heated at 100° C. in 16 h. The reaction mixture was cooled, concentrated, and purified by ISCO (0-60% EtOAc/Hexanes) to give the title compound (128 mg, 68%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].Cl.O[NH:27]/[C:28](=[N:37]\[H])/[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:37]=[C:28]([CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:27]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: [H]/N=C(/COc1ccccc1)NO
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(COc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C

Procedure:
To ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (26 mg, 0.073 mmol) and (1Z)—N-hydroxy-2-(phenyloxy)ethanimidamide hydrochloride (16 mg, 0.079 mmol) in EtOH (1 ml) was added 21% wt. ethanolic sodium ethoxide solution (0.068 ml, 0.183 mmol) and the mixture was heated under microwave irradiation at 140° C. for 10 min. The mixture was partitioned between EtOAc and 2M HCl, the organic phase dried (Na2SO4) evaporated and purified by MDAP to give title compound as a gum which solidified upon trituration with ether (5.9 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(Br)cc1
Yield: 81.1 %

Procedure:
1.79 g (0.00931 mol) of 1-benzyl-4-hydroxy-piperidine and 2.3 ml (0.0164 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 1.63 g (0.00745 mol) of 4-bromobenzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 2.26 g (81%) of 1-benzyl-piperidin-4-yl 4-bromo-benzoate were obtained as white crystals; m.p. 71°-72°.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][CH3:10].[B:11]1(B2OC(C)(C)C(C)(C)O2)[O:15]C(C)(C)C(C)(C)[O:12]1.C([O-])(=O)C.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:10][O:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[B:11]([OH:15])[OH:12]
Reactant: COc1cnccc1Br
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1cnccc1B(O)O
Temperature: 90 °C
Reaction time: 19 h

Procedure:
A mixture of 4-bromo-3-methoxypyridine hydrochloride (0.34 g, 1.5 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.13 g, 0.16 mmol), bis(pinacolato)diboron (0.47 g, 1.85 mmol), and potassium acetate (0.75 g, 7.7 mmol) in dry 1,4-dioxane (6.0 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 19 h, the reaction was cooled to rt then filtered. After concentration, the residue was identified as 3-methoxypyridin-4-ylboronic acid that was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=1.[CH2:18]([NH2:22])[CH2:19][CH2:20][NH2:21]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:21][CH2:20][CH2:19][CH2:18][NH2:22])=[N:12][CH:11]=1
Reactant: NCCCN
Reactant: Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Product: NCCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Yield: 59 %

Procedure:
N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 6 ml of 1,3-propanediamine were heated to 80° C. for 3 hours. The excess 1,3-propanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (168 mg, 59% yield) as a brown solid. LC-MS (m/z) 286 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[N:19]=[CH:18][C:17]2[NH:16][C:15]3[N:20]=[CH:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:26][CH:25]=4)=[CH:23][C:14]=3[C:13]=2[CH:12]=1)=O.[Cl-].[NH4+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.O.C(Cl)Cl.CO>[N:31]1([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:22]3[CH:21]=[N:20][C:15]4[NH:16][C:17]5[CH:18]=[N:19][C:11]([CH2:9][OH:8])=[CH:12][C:13]=5[C:14]=4[CH:23]=3)=[CH:25][CH:26]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
A 1M solution of lithium aluminum hydride in THF (1.2 mL, 1.2 mmol) was slowly added to a suspension of 3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (48.0 mg, 0.120 mmol) in THF at 0° C. The mixture was slowly warmed to ambient temperature. A further portion of 1M solution of lithium aluminum hydride in THF (1.2 mL, 1.2 mmol) was added slowly to the bright orange-yellow, homogeneous mixture at ambient temperature. After 1 h, the mixture was treated with aqueous ammonium chloride, and diluted with water and 50% DCM/methanol. The resulting mixture was treated with Rochelle's salt and allowed to stir vigorously for 2 h. The solids were removed by filtration, and the filtrate layers were separated. The aqueous phase was extracted with 20% methanol in DCM and the combined organic phase concentrated in vacuo. The residue was dissolved in DMSO and purified by preparative HPLC (2-60% MeCN/water modified with 0.1% ammonium hydroxide) to provide a light-yellow solid (7.1 mg, 16%). 1H NMR (DMSO-D6, 400 MHz): 12.10 (s, 1H), 9.02 (m, 1H), 8.90 (m, 1H), 8.82 (m, 1H), 8.28 (m, 1H), 7.79 (m, 2H), 7.46 (m, 2H), 5.40 (t, J=5.7 Hz, 1H), 4.74 (d, J=5.6 Hz, 2H), 3.59-3.41 (m, 2H), 2.38 (m, 4H), 1.54 (m, 4H), 1.42 (m, 2H). LCMS (Method D): RT=4.48 min, M+H+=373.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][CH:7]=1)(=[O:5])=[O:4].[NH2:17]OS(O)(=O)=O>CN(C=O)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]([NH2:17])[CH:7]=1)(=[O:4])=[O:5]
Reactant: NOS(=O)(=O)O
Reactant: CN(C)S(=O)(=O)c1c[nH]c2ccc(F)cc12
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1cn(N)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A solution of 5-fluoro-1H-indole-3-sulfonic acid dimethylamide (1.24 g) in dry DMF (50 mL) is cooled to 0° C. and treated portion wise with 60% MaH oil dispersion (3.07 g). The mixture is stirred at 0° C. for 30 min. Hydroxylamine-O-sulfonic acid (2.9 g) is added portion wise and the mixture is warmed to rt and stirred for 5 h. The reaction mixture is poured onto ice/water and extracted with EtOAc. The organic layer is separated, washed water and brine, dried (MgSO4) filtered and concentrated in vacuo. The residue is triturated with ether. The solid is collected by filteration to afford 1-amino-5-fluoro-1H-indole-3-sulfonic acid dimethylamide (0.53 g, 41%). MS: 258 (M+H).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[F:6][C:7]([F:18])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]([F:10])[F:9].[OH-].[Na+:20]>>[F:6][C:7]([F:18])([O:11][C:12]1[CH:13]=[CH:14][C:15]([S:1]([O-:3])(=[O:5])=[O:2])=[CH:16][CH:17]=1)[CH:8]([F:9])[F:10].[Na+:20]
Reactant: FC(F)C(F)(F)Oc1ccccc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)([O-])c1ccc(OC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.9 %

Procedure:
A 50 mL flask equipped with a stir-bar and a nitrogen bubbler was charged with concentrated sulfuric acid (14.55 g) and 4-(1,1,2,2-tetrafluoroethoxy)benzene (4.9 g) at room temperature. The reaction mixture was stirred at room temperature for 17 h. A sodium hydroxide solution (12.25 g, in 40.02 g water) was slowly added to the reaction mixture while the reaction mixture was cooled with an ice-water bath. The resulting solid was filtered off. The filtrate was neutralized with concentrated hydrochloric acid (˜3 mL) and used to wash the solid. This wash solution was neutralized with sodium bicarbonate to pH˜7, and used to wash the solid again. The solid was extracted with refluxing ethanol. The ethanol solution was dried to give sodium 4-(1,1,2,2-tetrafluoroethoxy)benzenesulfonate (4FEBSNa) 4.4 g (yield 59%): 1H NMR (D2O) 6.34 (tt, 52, 3 Hz, 1H), 7.45 (d, J=9 Hz, 2H), 7.88 (m, 2H) ppm; 19F NMR (D2O) −88.7 (m, 2F), −138.0 (dt, J=52, 5 Hz, 2F) ppm.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([CH2:13][O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]3[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH2:13][O:14][CH2:15][C:16]4([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C3CC3)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2(COCc3cc(C4CC4)cc4cn[nH]c34)CCNCC2)cc1

Procedure:
tert-Butyl 4-(((5-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (34 mg, 0.06 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 4 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated and the product purified by reverse phase HPLC to afford 10 mg (48%) as a clear oil. 1H-NMR (CD3OD, 500 MHz) δ 7.96 (s, 1H), 7.42-7.47 (m, 5H), 7.31-7.34 (m, 1H), 7.01 (m, 1H), 4.71 (s, 2H), 3.51 (s, 2H), 3.24-3.28 (m, 2H), 2.89-2.95 (m, 2H), 2.46-2.49 (m, 2H), 2.16-2.21 (m, 2H), 1.98-2.02 (m, 2H); 13C-NMR (126 MHz, CD3OD) δ ppm 141.1, 138.1, 136.8, 133.5, 129.1, 127.2, 127.0, 125.6, 124.1, 120.1, 116.5, 78.9, 70.4, 41.1, 41.0, 28.9, 15.1, 8.1. Mass spec.: 362.22 (MH)+. Accurate mass spec.: m/z 362.2217 [MH]+, Δ=4.2 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH2:17][CH2:18]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][N:24]2[C:23](=[O:25])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:30])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(COCCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(COCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 0.344 g (1.26 mmol) of 1-t-butoxycarbonyl-4-(3-hydroxypropyloxymethyl)piperidine (Example 17, Step 3), 0.926 g (6.3 mmol) of phthalimide, and 0.661 g (2.52 mmol) of triphenylphosphine in 10 mL of THF at 0° C. was added dropwise 0.4 mL of diethylazodicarboxylate (DEAD). The reaction mixture was allowed to warm to rt and was stirred for 36 h. To the reaction mixture was added 20 mL of ether and it was filtered through a thin pad of celite. The filtrate was washed with sat'd NaHCO3 solution and sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 2:1) to give 1-t-butoxycarbonyl-4-(3-phthalimidopropyloxymethyl)piperidine. Removal of the BOC protecting group was achieved as described in Example 4, Step 2 to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]4[OH:21])[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1.N.[Li+].CC[O-].[Al]>[Pt].C(O)C>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]1[OH:21]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: [Pt]
Agent: CC[O-]
Agent: N
Solvent: CCO
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1

Procedure:
2.0 g. of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol is electrolyzed in 200 ml. of liquid ammonia and 20 ml. of ethanol in the presence of 2 g. of lithium ethylate and 0.5 g. of lithium anilide for 3 hours in an undivided cell between an aluminum cathode and a platinum anode, with a current density of 2.5 A/cm2. After the reaction mixture has been worked up, 1.8 g. of 3-methoxy-2,5(10)-estradien-17β-ol is isolated, m.p. 110° C.
Reaction SMILES: F[C:2](F)(F)C(O)=O.ClCCl.CS(C1C=[C:17]2[C:21](=[CH:22]C=1)[N:20]([C:24]1N=CN=C(OC3CCN(C(OC(C)(C)C)=O)CC3)[CH:25]=1)[CH2:19][CH2:18]2)(=O)=O>C1COCC1>[CH:21]([N:20]([CH:24]([CH3:25])[CH3:2])[CH2:19][CH3:18])([CH3:17])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.35 mL) was added at 0° C. to a dichloromethane (9.38 mL) solution of the tert-butyl 4-({6-[5-(methylsulfonyl)indolin-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (469 mg, 0.988 mmol) produced in Example 1, and the mixture was stirred at room temperature for 1 hour. From the reaction solution, the solvent was then distilled off. To a THF (450 μL) solution of a portion (150 mg) of the obtained residue and diisopropylethylamine (431 μL, 2.48 mmol), a THF (3.0 mL) solution of the preceding produced acid chloride compound was added at 0° C., and the mixture was stirred at room temperature for 3 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride and water were added, followed by extraction with ethyl acetate three times. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin-layer silica gel chromatography (hexane:ethyl acetate=1:2, V/V) to obtain the title compound as white foam (13 mg, yield: 11%).