Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:19]2[C:6](=[C:7]3[C:16](=[CH:17][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9](=[O:21])(=[O:20])[NH:8]3)[N:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26].CCN(C(C)C)C(C)C>CCCCO>[O:20]=[S:9]1(=[O:21])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[C:7](=[C:6]3[C:19](=[CH:18][CH:17]=2)[C:2]([NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])=[CH:3][CH:4]=[N:5]3)[NH:8]1
Reactant: O=S1(=O)Nc2c(ccc3c(Cl)ccnc23)-c2ccccc21
Reactant: CN(C)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(C)CCNc1ccnc2c3c(ccc12)-c1ccccc1S(=O)(=O)N3
Yield: 27.1 %

Procedure:
In a similar fashion using route 48 general procedure 114, 1-chloro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 305 (75 mg, 0.23 mmol), N,N-dimethylethylenediamine (0.08 ml, 0.71 mmol), DIPEA (0.09 ml, 0.53 mmol) and n-BuOH (1 ml) gave the title compound (23 mg, 26%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccccc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.062 mMol) benzoyl chloride, the title compound was prepared.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:11]([CH2:12][P:13]([OH:16])([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[O-:17][Mn](=O)(=O)=O.[K+].[OH-].[Na+]>O>[C:2]([C:3]1[NH:4][C:5]2[C:11]([CH2:12][P:13]([OH:16])([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)([OH:17])=[O:1]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=P(O)(O)Cc1cccc2nc(CO)[nH]c12
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1nc2cccc(CP(=O)(O)O)c2[nH]1
Temperature: 80 °C

Procedure:
2-Hydroxymethyl-4-phosphonomethylbenzimidazole (411 mg) and KMnO4 (70 mg) in water (7 mL) containing 3 equivalents of NaOH were warmed to 80° C. KMnO4 (636 mg) was divided into 9 equal portions and added over 3.5 hours. The reaction was stirred at 80° C. for one additional hour then cooled and filtered through diatomaceous earth. The pale yellow solution was concentrated to a yellow solid. The solid was taken up in water and applied to a column of Amberlite CG 400 (0.5×16 cm). The column was eluted with water (50 mL), then 1N HOAc, 2N HOAc, 4N HOAc, and finally 1N HCl (50 mL each). The HCl fractions were pooled and concentrated to a yellow solid. The solid was triturated with water, then collected by suction filtration and washed with a small amount of ethanol and ether to obtain a white solid. H NMR data: D2O (HDO at 4.64 ppm) 3.06 (d, 2H), 7.15 (m, 2H), 7.41 (d, 1H). E.A. Cal'd for C9H9N2O5P.0.6 H2O; C, 40.49, H, 3.85, N, 10.49. Found; C, 40.10, N, 3.57, N, 10.30.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:17][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(CCCCC(=O)O)nc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=C(O)CCCCc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cn1
Reaction time: 18 h
Yield: 63.7 %

Procedure:
4-Chlorobenzenesulphonyl chloride (1.09 g, 5.15 mmole) was added portionwise over 10 minutes to a solution of 5-(5-aminopyrid-2-yl)pentanoic acid (1.00 g, 5.15 mmole) in pyridine (15 ml). The resulting solution was stirred for 18 hours when the solvent was removed and the residue was dissolved in dilute sodium hydroxide solution (30 ml). This solution was extracted with ethyl acetate (4×50 ml) the extracts being discarded. The aqueous layer was acidified (pH 3) and extracted with ethyl acetate (4×100 ml). The combined ethyl acetate extracts were dried over magnesium sulphate, evaporated to dryness and the residue was recrystallised from acetonitrile to give the title compound (1.21 g) as a pale yellow solid. m.p. 145°-147° C.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([CH3:34])[C:25]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:48]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([CH3:34])[C:25]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)cc(C)c2-c2cc(C(C)C)ccc2OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1c(C)cc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (20 mg) is dissolved in ethanol (2 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (21 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 1N-aqueous sodium hydroxide solution (28 μl) and the reaction solution is concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (19 mg). MS (m/z): 742 [M−Na]−
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[C:3]=1[CH:12]([CH3:14])[CH3:13].[H-].[Na+].[CH3:17][O:18][CH2:19]Cl>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:17][O:18][CH3:19])[C:4](=[O:11])[C:3]=1[CH:12]([CH3:13])[CH3:14]
Reactant: CCn1c(Cl)c(C(C)C)c(=O)[nH]c1=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(Cl)c(C(C)C)c(=O)n(COC)c1=O
Reaction time: 0.67 h
Yield: 91.2 %

Procedure:
To a stirred solution of 6-chloro-1-ethyl-5-isopropyl-1H-pyrimidine-2,4-dione (11.5 g, 53 mmol) in DMF (100 mL) in a water bath, was added 60% NaH (3.18 g, 79.6 mmol). After stirring for 40 min., technical grade chloromethyl methyl ether (7.6 mL, 80 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:5)) to give 12.6 g (91%) of 6-chloro-1-ethyl-5-isopropyl-3-methoxymethyl-1H-pyrimidine-2,4-dione as a colorless oil. H-NMR (200 MHz, CDCl3) δ 1.26-1.34 (9H, m), 3.24 (1H, m), 3.44 (3H, s), 4.16 (2H, q, J=7.0 Hz), 5.35 (2H, s); m/z (EI) 260 (M+).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2]([Cl:4])=[O:3].ClC(=[CH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:23]([Cl:24])=[C:22]([O:25][CH:26]([F:28])[F:27])[N:21]([CH3:29])[N:20]=2)[C:16]([Cl:30])=[CH:15][C:14]=1[Cl:31])C(O)=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:6][C:1](=[CH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:23]([Cl:24])=[C:22]([O:25][CH:26]([F:27])[F:28])[N:21]([CH3:29])[N:20]=2)[C:16]([Cl:30])=[CH:15][C:14]=1[Cl:31])[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F

Procedure:
3 drops of dimethylformamide and then 11.1 g (87 mmol) of oxalyl chloride were added dropwise to a solution of 12.5 g (29 mmol) of 2-chloro-3-(2,4-dichloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)phenyl)propenoic acid in 300 ml of toluene. The reaction mixture was stirred at reflux temperature for 5 hours and then concentrated. Yield: quantitative.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B2OCCCO2)=[C:23]([F:33])[C:22]=1[O:34][CH3:35].[F-].[Cs+].C(#N)C>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.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:34][CH3:35])[C:23]=2[F:33])[N:5]=[C:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)cc(Cl)c2Cl)c1F
Temperature: 25 °C

Procedure:
A 250 mL three-neck flask equipped with a reflux condenser and nitrogen inlet was charged with benzyl 4,5,6-trichloropicolinate (17.77 g, 56.10 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (19.20 g, 79.0 mmol) and CsF (17.04 g, 112.0 mmol). Acetonitrile (100 mL) and water (30 mL) were added. The reaction mixture was evacuated/backfilled with nitrogen (5×). Solid Pd(PPh3)2Cl2 (1.724 g, 2.456 mmol) was added. The solution was evacuated/backfilled with nitrogen (5×) and then stirred at reflux for 90 min. A white solid precipitated upon cooling to room temperature. The solid was filtered, washed with water and dried in air (18.66 g, 75%): 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H, pyridine H), 7.52-7.32 (m, 5H, phenyl), 7.27 (dd, JH-H=8.4 Hz, JF-H=1.7 Hz, 1H, aromatic), 7.10 (dd, JH-H=8.4 Hz, JF-H=6.8 Hz, 1H, aromatic), 5.44 (s, 2H, CH2Ph), 3.98 (d, J JF-H=1.3 Hz, 3H, OMe); 13C{1H} NMR (101 MHz, CDCl3) δ 163.0, 153.7, 153.5 (d, JF-C=253 Hz, C2′), 146.0, 144.5 (d, JF-C=13 Hz), 144.1, 135.0, 134.2, 129.9 (d, JF-C=3 Hz), 128.5, 126.1, 125.8 (d, JF-C=14 Hz), 125.3 (d, JF-C=3 Hz), 124.9 (d, JF-C=2 Hz), 67.9 (CH2), 61.5 (d, JF-C=4 Hz, OMe). Anal. Calcd for C20H13Cl3FNO3: C, 54.51; H, 2.97; N, 3.18. Found: C, 54.60; H, 3.08; N, 3.16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: CC(O)c1cc(Cl)ncc1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 1-(2-chloro-5-nitropyridin-4-yl)ethanol (1.0 equiv.) in dichloromethane (0.1 M) was added Dess-Martin periodinane (1.8 eq.) and the solution was stirred for 16 hours. The solution was poured into ethyl acetate (800 mL), was washed with 1:1 10% Na2S2O3/NaHCO3(sat.) (4×), with NaCl(sat.), dried over MgSO4, filtered and concentrated yielding 1-(2-chloro-5-nitropyridin-4-yl)ethanone (96%) as a yellow solid. LCMS (m/z): 201.0 (MH+); LC Rt=2.80 min. 1H NMR (CDCl3): δ 9.18 (s, 1H), 7.36 (s, 1H), 2.60 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([NH:12][NH2:13])=[O:11].Cl.[N:15]([O-])=O.[Na+]>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]=[N+:13]=[N-:15])=[O:11]
Reactant: O=N[O-]
Reactant: NNC(=O)c1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1nc2ccccc2s1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a suspension of benzo[d]thiazole-2-carbohydrazide (9.3 g, 48.2 mmol) in aqueous HCl (1 N, 75 mL, 75 mmol) and water (200 mL) was added a solution of NaNO2 (6.9 g, 100 mmol) in water (50 mL) dropwise at 0-5° C. The mixture was stirred at 0-5° C. for 2 h and RT for 2 h. The precipitate was filtered, washed with cold water, and dried under high vacuum to give benzo[d]thiazole-2-carbonyl azide (9.0 g, 92%). LRMS (M+H+) m/z 205.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]([N:14]1[CH2:18][C@H:17]([S:19]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][C@H:15]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=1[F:50])=[O:13])=[O:4].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]([N:14]1[CH2:18][C@H:17]([SH:19])[CH2:16][C@H:15]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=1[F:50])=[O:13])=[O:4]
Reactant: COC(=O)c1ccccc1OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1OC(=O)N1C[C@H](S)C[C@H]1COCc1cc(F)c(F)cc1F

Procedure:
(Method 3): A solution of 0.4 g (0.58 mmol) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid 2-methoxycarbonyl-phenyl ester in 5.8 ml TFA was treated at 0° C. with 0.92 ml (5.78 mmol) triethylsilane and after 10 min at room temperature evaporated and purified by flash chromatography on silica gel (Hexane/EtOAc 4:1) to give 0.22 (82%) (2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-methoxycarbonyl-phenyl ester, MS: 456 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[C:11]1[N:16]=[C:15]([NH2:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1>CO.[Pd]>[CH3:18][C:13]1[CH:12]=[C:11]([CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[N:16]=[C:15]([NH2:17])[CH:14]=1
Reactant: Cc1cc(N)nc(C2=Cc3ccccc3CC2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)nc(C2CCc3ccccc3C2)c1
Yield: 53.4 %

Procedure:
6-(3,4-Dihydro-naphthalen-2-yl)-4-methyl-pyridin-2-ylamine (CAS 521917-11-3) (1.8 g) is dissolved in methanol (30 mL) under an Ar atmosphere. To the obtained solution Pd/C (10%; 250 mg) was added. After that hydrogen was flushed through the reaction mixture (1 bar) for 2 h at 25° C. After that the catalyst was removed by filtration, the filtrate was evaporated to dryness and the crude product was purified by flash chromatography (200 g SiO2, CH2Cl2/1% MeOH) to yield 4-methyl-6-(1,2,3,4-tetrahydro-naphthalen-2-yl)-pyridin-2-ylamine (970 mg) as an oil.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([O:8][NH2:9])[CH2:4]1.[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][C:18](=[O:30])[CH:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21](=O)[CH2:20]4)[C@@H:15]1[CH2:14][CH2:13][C:12]2=[O:31].O.[Na+].[Cl-]>C1COCC1>[ClH:1].[NH:3]1[CH2:7][CH2:6][CH:5]([O:8][N:9]=[C:21]2[CH2:22][CH2:23][C@@:24]3([CH3:25])[CH:19]([C:18](=[O:30])[CH2:17][C@@H:16]4[C@@H:26]3[CH2:27][CH2:28][C@@:11]3([CH3:10])[C@H:15]4[CH2:14][CH2:13][C:12]3=[O:31])[CH2:20]2)[CH2:4]1
Reactant: C[C@]12CCC(=O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NOC1CCNC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CCC(=NOC3CCNC3)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of 3-(RS)-pyrrolidinyloxyamine dihydrochloride (III-c, Prepn. 3, 227 mg) and androstane-3,6,17-trione (495 mg) in THF: water (2/1, 27 mL) was stirred for 30 min. NaCl was added and stirred till the two phases separated. After extraction of the aqueous layer with THF, the combined organic phases were washed with brine, dried and evaporated. The crude was purified by flash chromatography (SiO2, CH2Cl2:MeOH:NH3 9:1:0.1). To the concentrated fractions 5M HCl in EtOAc was added. After dilution with Et2O, the solid was collected by filtration to give the title compound I-ac (464 mg, 60%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 9.59 (1H, bb), 9.41 (1H, bb), 4.74 (1H, m), 3.80-2.90 (5H, m), 2.60-1.20 (21H, m), 0.78 (6H, s).
Reaction SMILES: [S:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])(=O)=O>C(Cl)Cl>[O:7]([C:4]1[CH:3]=[CH:2][S:1][CH2:6][CH:5]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1C=CSCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1=CCSC=C1
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
2,3-Dihydro-4H-thiopyran-4-one (1.50 g, 13.1 mmol, synthesized as described in Richards et al. J. Org. Chem. 46,4836–4842 (1981)) was dissolved in CH2Cl2 (130 mL) and triethylamine (5.47 mL, 39.4 mmol) was added. tert-Butyldimethylsilyl trifluoromethanesulfonate (3.62 mL, 15.8 mmol) was then added. After 10 minutes, the volatiles were removed in vacuo at 25° C. The resulting yellow oil was passed through a short column of SiO2 eluting with 3% TEA in hexanes to yield 1.82 g (7.97 mmol, 61%) of compound 1A as an orange oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:53]=[O:54].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:53][OH:54])[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 4j (7.6 g, 10.45 mmol) was dissolved in 80 mL 1,4-dioxane, followed by addition of 15.8 mL 37% formaldehyde solution and sodium hydroxide (31.35 mL, 31.35 mmol) in turn. The reaction mixture was stirred for 16 hours at 70° C. Thereafter, the reaction mixture was extracted with ethyl acetate (50 mL×4) after 50 mL saturated sodium chloride solution were added. The organic extract was washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 4k (7.9 g, colourless grease), which was used directly without purification in the next step.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])([CH3:4])[CH3:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>ClCCl>[CH3:4][C:2]([N:5]([CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[C:13](=[O:15])[CH3:14])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NCC(O)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N(CC(O)C(Cl)(Cl)Cl)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
To a stirred suspension of 5 grams of 3-(1,1-dimethylethylamino)-1,1,1-trichloro-2-propanol in 75 grams of dichloromethane at -60° C., 2.2 grams of acetic anhydride was added dropwise during 15 minutes. After the reaction mixture was allowed to warm to ambient temperature during 1 hour, the mixture was stirred for 2 hours. The solution was washed with 100 grams of saturated aqueous sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under a reduced pressure of 100 mm. Hg to 3.9 grams of an oil. The oil was crystallized from methylcyclohexane to yield 1.4 gram of white N-(1,1-dimethylethyl)-N-(3,3,3-trichloro-2-hydroxypropyl)acetamide melting 124°-126° C.
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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>[N:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
To a solution of 4-boronobenzoic acid (1.66 g, 10 mmol) and 4-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) was added. The mixture was degassed and purged withed nitrogen. The mixture was stirred at 100° C. for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.8 g of white solid of 4-(pyridin-4-yl)benzoic acid. Yield: 90%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:22][NH2:23])[CH2:3]1.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26]>CO>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([C:18]([CH3:19])([CH3:20])[CH3:21])[CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:22][NH:23][CH2:26][CH2:25][C:24]([O:28][CH3:29])=[O:27])[CH2:3]1
Reactant: C=CC(=O)OC
Reactant: CN1C[C@H](CN)C[C@@H]2c3cc(C(C)(C)C)cc4[nH]cc(c34)C[C@H]21
Solvent: CO
Product: COC(=O)CCNC[C@@H]1C[C@@H]2c3cc(C(C)(C)C)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
A mixture of 5.1 g of 6-methyl-8β-aminomethyl-13-t-butyl-ergoline and 1.8 ml methyl acrylate in 100 ml of methanol was refluxed for 4 hours. The solvent was evaporated off and the residue was crystallized from ethylacetate to afford 6 g of 6-methyl-8β-N-(2-methoxycarbonylethyl)aminomethyl-13-t-butyl-ergoline, melting at 153°-157° C., (I, R1 =R2 =H, R3 =CH3, A=NHC2H4CO2CH3, n=1).