Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[NH2:17][C:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:29][CH:28]=2)=[N:25][CH:26]=1)([CH3:20])[CH3:19].CCN(CC)CC>O=S(Cl)Cl.C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:29][CH:28]=3)=[N:25][CH:26]=2)([CH3:19])[CH3:20])=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(-c2ccc(C(C)(C)N)cn2)cc1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(-c2ccc(C(C)(C)NC(=O)c3cnc(-c4cccnn4)nc3O)cn2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (200 mg, 0.92 mmol) was dissolved in SOCl2 (5 ml). The mixture was stirred at 60° C. for 4 hours, then concentrated under vacuo. The residue was dissolved with 5 ml of DCM, and added dropwise to a solution of diethyl 4-(5-(2-aminopropan-2-yl)pyridin-2-yl)phenylphosphonate, 33-g, (353 mg, 0.92 mmol) and Et3N (371 mg, 3.7 mmol) in DCM (10 ml) at 0° C. The mixture was stirred at room temperature for 5 hours and then washed with brine, dried, and concentrated under vacuo to give diethyl 4-(5-(2-(4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido) propan-2-yl)pyridin-2-yl)phenylphosphonate (220 mg, 44%).
Reaction SMILES: C([O:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][N:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:11]1=[O:12])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][N:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]nnc2n(C)c1=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]nnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 11020.4 %

Procedure:
To a stirring solution of (R)-1-(5-acetoxyhexyl)-3-methyl-8-azaxanthine (150 mg, 0.49 mmol) in methanol (25 ml) was added an anhydrous solution of hydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol). After stirring at room temperature for 24 hours, the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-hydroxyhexyl)-3-methyl-8-azaxanthine (CT 12463) (70 mg, 54 mmol) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[O:12][CH:13]=1.C(N([CH2:26][CH3:27])CC)C>ClCCl>[CH2:15]([Si:14]([CH2:17][CH3:18])([CH2:19][CH3:20])[C:11]1[O:12][CH:13]=[C:9]([CH2:8][O:7][C:1](=[O:5])[C:2]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([Si:14]([CH2:26][CH3:27])([CH2:17][CH3:18])[CH2:15][CH3:16])[O:12][CH:13]=2)=[O:3])[CH:10]=1)[CH3:16]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC[Si](CC)(CC)c1cc(CO)co1
Solvent: ClCCl
Product: CC[Si](CC)(CC)c1cc(COC(=O)C(=O)OCc2coc([Si](CC)(CC)CC)c2)co1
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (0.59 ml, 6.79 mmol) was added dropwise to a solution of 4-hydroxymethyl-2-triethylsilylfuran (Compound 1, 1.2 g, 5.66 mmol) and triethylamine (0.95 ml, 6.79 mmol) in dichloromethane (10 ml) at 0°. After 10 minutes, the reaction mixture was quenched with ice. Extraction (dichloromethane) and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromotograhy on silica using 5% ethyl ether/hexane. Fractions with Rf of about 0.17 gave, after evaporation the title oxalate ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)oc3ccc(Cl)cc23)cc1
Reaction time: 1 h
Yield: 89.8 %

Procedure:
6-Chloro-4-hydroxycoumarin (25.4 mmol, 5.0 g) is suspended in DCM (50 mL) and pyridine (63.3 mmol, 5.1 mL) is added. The mixture is cooled in an ice bath and p-toluenesulfonyl chloride (26.8 mmol, 5.1 g) is added. The ice bath is removed and the compound slowly dissolves and a solid is deposited (pyridine HCl). After 1 hr the mixture is transferred to a separatory funnel, HCl (2 M) is added, and a solid is formed. The organic layer is removed and the solid-containing aqueous layer is filtered to remove the precipitate. The filtrate is washed with DCM and the combined organic layers are washed with H2O, NaHCO3 (sat.), H2O, and brine. The extract is then dried over MgSO4 and is evaporated. The residue is triturated with Et2O to give the title compound (8.0 g, 90%) as a cream solid. 1H NMR (CDCl3, 400 MHz) δ 7.91 (2H, d, J=8 Hz), 7.54 (1H, d, J=2 Hz), 7.51 (1H, dd, J=2, 9 Hz), 7.42 (2H, d, J=8 Hz), 7.26 (1H, d, J=9 Hz), 6.38 (1H, s), 2.49 (3H, s); LCMS (MeCN—H2O, Luna 3μC18(2) 30×4.6 mm; MS (ESI, Pos.) calcd for C16H11ClO5S m/z [M+H]=351 found [no mass ion detected].
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[C:10]1([CH3:20])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17](O)=[O:18].O=P(Cl)(Cl)Cl>[Cl-].[Cl-].[Zn+2]>[OH:3][C:2]1[CH:4]=[CH:5][C:6]([C:17](=[O:18])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:20])=[CH:7][C:1]=1[O:8][CH3:9]
Reactant: Cc1ccccc1CC(=O)O
Reactant: COc1ccccc1O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C(=O)Cc2ccccc2C)ccc1O
Temperature: 80 °C

Procedure:
To a mixture of guaiacol (1.24 g, 10 mmol), o-tolylacetic acid (1.50 9, 10 mmol), and ZnCl2 (5 g, 36.7 mmol) there was added POCl3 (15 mL, 161 mmol) and the resulting suspension was stirred and heated to 80° C. for 1.5 h. The reaction mixture was cooled and poured onto ice/water and the resulting suspension was stirred at room temperature for 1 h and then extracted with ethyl acetate. The organic layer was separated, washed with brine and dried with sodium sulphate. Volatiles were evaporated under reduced pressure and the residue was dissolved in diethylether. The solution was extracted twice with 50 mL of 2N aqueous solution of NaOH and the combined aqueous layers were combined and acidified with hydrochloric acid to pH=2. The emulsion formed was extracted by ethyl acetate, and the organic layer was washed with brine, dried, and the solvent was evaporated under diminished pressure. The residue was chromatographed on a column of silica gel with a mixture of petroleum ether and ethyl acetate to give 1-(4-hydroxy-3-methoxyphenyl)-2-(2-methylphenyl)-1-ethanone as off white crystals, m.p. 79 to 81° C.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(Cl)=[O:13].Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[C:28]([C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][NH:36][CH2:37]4)=[CH:32][CH:31]=3)[N:27]=[C:26]([NH2:40])[N:25]=2)[CH2:20][CH2:19]1>>[NH2:40][C:26]1[N:27]=[C:28]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][N:36]([C:12]([NH:11][C@@H:9]4[CH2:10][C@H:8]4[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:13])[CH2:37]3)=[CH:32][CH:31]=2)[CH:29]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)[N:25]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N[C@@H]3C[C@H]3c3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from trans-2-phenylcyclopropanamine hydrochloride (Aldrich, Cat. #P2237-0), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=484.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:16][S:15][C:14](=[O:17])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][CH2:19][N:13]1[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:16][S:15][C:14]1=[O:17]
Reactant: COc1ccc(C2=NNC(=O)SC2)cc1OC
Reactant: CN(C)CCCCl
Product: COc1ccc(C2=NN(CCCN(C)C)C(=O)SC2)cc1OC

Procedure:
In analogy to Example 1, by reacting 5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one with 3-chloropropyldimethylamine, 3-dimethylaminopropyl-5(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained; m.p. 195°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[CH2:30]OC(=O)C)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:30]/[CH:29]=[CH:28]/[C:25]4[CH:26]=[N:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[CH2:15][C:14]3=[O:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(/C=C/COC(C)=O)cn1
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COc1ccc(/C=C/CN2CCN(Cc3ccc4c(N)ncnc4c3)C(=O)C2)cn1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Nitrogen (g) is bubbled through a solution of 1-(4-amino-quinazolin-7-ylmethyl)-piperazin-2-one (100 mg, 0.39 mmol), EXAMPLE 72, in 2 mL of CH3CN. After 5 min, acetic acid 3-(6-methoxy-pyridin-3-yl)-(E)-allyl ester (75 mg, 0.36 mmol, prepared as described in EXAMPLE 19 in 2 mL of CH3CN, palladium(II) acetate (catalytic amount), triphenylphosphine (catalytic amount), 2 mL of H2O and 0.5 mL of triethylamine are added to the solution. The mixture is heated at 80° C. for 1 hours. At this time, the mixture is cooled, filtered and concentrated in vacuo. The crude material is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are combined and lyopholized to give the title compound (44 mg, 0.07 mmol) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ9.86 (s, 1H), 9.79 (s, 1H), 8.83 (s, 1H), 8.40 (d, 1H), 8.25 (s, 1H), 7.95 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 6.86 (d, 1H), 6.82 (d, 1H), 6.32 (dt, 1H), 4.78 (s, 2H), 3.98 (s, 2H), 3.93 (m, 2H), 3.85 (s, 3H), 3.53 (m, 4H). ESI MS, [M+H]+=405.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1ccccc1)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (60 mg, 0.19 mmol, 1.0 eq.) and pyridine (0.3 mL, 3.8 mmol, 20 eq.) in dichloro methane (5 mL) was added benzenesulfonyl chloride (51 mg, 0.29 mmol, 1.5 eq.) under nitrogen. Then the reaction mixture was stirred at room temperature for two hours. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated and the residue was purified by silica gel (petroleum ether/ethyl acetate=2:1) to afford 70 mg of methyl 3,3-dimethyl-2-(2-(phenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 85%; MS (ESI+APCI) M+1=451.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]#[C:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(OCC)(=O)C>CC#N.Cl[Pd]Cl>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:12]=[C:13]([C:14]([CH3:21])([CH3:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:1]2)=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)CC(C)(C)C#Cc1cc([N+](=O)[O-])c(F)cc1N
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a mixture of ethyl 5-(2-amino-4-fluoro-5-nitrophenyl)-3,3-dimethylpent-4-ynoate (34.5 g, 0.11 mol) and PdCl2(10.4 g, 58.6 nmol) in CH3CN (350 mL) was heated to reflux for 1.5 hours. The reaction mixture was cooled down to room temperature. Ethyl acetate (300 mL) was added, the precipitate was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 40:1) to give ethyl 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutanoate (34.0 g, 98%) as a deep yellow solid. 1H NMR (300 MHz, CDCl3) δ 10.11 (brs, 1 H), 8.30 (d, J=7.2 Hz, 1 H), 7.14 (d, J=11.7 Hz, 1 H), 6.35 (d, J=1.5 Hz, 1 H), 4.17 (q, J=7.2 Hz, 2 H), 2.69 (s, 2 H), 1.51 (s, 6 H), 1.25 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)([Cl:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:40]([Cl:42])=[O:41])[C:10]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C#N)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(C#N)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Yield: 94 %

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole (1.25 g, 2.88 mmol, example 25) was dissolved in methylene chloride and diisopropylethylamine (2.41 mL, 13.8 mmol) was added. The mixture was cooled in an ice bath and phosgene (6.09 mL, 11.52 mmol, 20% in toluene) was added. The reaction mixture was stirred for 30 mm at ice temperature and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (1.35 g, 94%).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([N:16]=[CH:17][C:18]=3[C:19](=[O:21])[CH3:20])[CH:15]=2)=[CH:6][CH:5]=1.Br.ClCCl>CC(O)=O>[Br:1][CH2:20][C:19]([C:18]1[CH:17]=[N:16][N:14]2[CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[CH:11]=[CH:12][C:13]=12)=[O:21]
Reactant: BrBr
Reactant: CC(=O)c1cnn2cc(-c3ccc(F)cc3)ccc12
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CBr)c1cnn2cc(-c3ccc(F)cc3)ccc12
Yield: 85.4 %

Procedure:
Bromine (57.9 μL, 1.13 mmol) was added to a solution of 1-[6-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-yl]ethanone (8, 197 mg, 0.775 mmol) in AcOH (1 mL) and hydrobromic acid (88 μL, 0.775 mmol). The reaction was heated to 50° C. for 2 hours after which an aqueous solution of 10% Na2S2SO3 (5 mL) and dichloromethane (10 mL) were added to the reaction. The organic was collected and washed with a saturated solution of sodium bicarbonate (10 mL), dried over sodium sulfate and concentrated. The reaction was purified by column chromatography (10% acetone in hexanes) to yield 2-bromo-1-[6-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-yl]ethanone (9, 220.4 mg, 0.662 mmol, 85% yield). MS APCI: [M+H]+ m/z 334.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@@:9]12[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:27])[CH2:20][CH2:19]4)[CH2:16][CH2:15][C:14]1=[CH:13][C:12](=[O:28])[CH2:11][CH2:10]2.[CH3:29][Si:30]([CH3:54])([CH3:53])[O:31][CH2:32][C@@:33]12[C@@H:50]3[C@H:41]([C@H:42]4[C@@:46]([CH2:48][CH2:49]3)([CH3:47])[C:45](=[O:51])[CH2:44][CH2:43]4)[CH2:40][CH2:39][C:38]1=[CH:37][C:36](=[O:52])[CH2:35][CH2:34]2>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@@:9]12[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:27])[CH2:20][CH2:19]4)[CH2:16][CH2:15][C@H:14]1[CH2:13][C:12](=[O:28])[CH2:11][CH2:10]2.[CH3:53][Si:30]([CH3:29])([CH3:54])[O:31][CH2:32][C@@:33]12[C@@H:50]3[C@H:41]([C@H:42]4[C@@:46]([CH2:48][CH2:49]3)([CH3:47])[C:45](=[O:51])[CH2:44][CH2:43]4)[CH2:40][CH2:39][C@H:38]1[CH2:37][C:36](=[O:52])[CH2:35][CH2:34]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43COC3CCCCO3)[C@@H]1CCC2=O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CCC2=O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)CC[C@@]43COC3CCCCO3)[C@@H]1CCC2=O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CCC2=O

Procedure:
Substituting 17β-hydroxy-4,6α,17α-trimethyl-4-androstene-3,19-dione, 17β-hydroxy-4,6α,17α-trimethyl-4-androstene-3,19-dione acetate, 19-tetrahydropyranyloxy-4-androstene-3,17-dione, 19-trimethylsiloxy-4-androstene-3,17-dione and 6α-methyl-19-(2'-tetrahydropyranyloxy)-4-androstene-3,17-dione for the 4,6α,17α-trimethyl-17β,19-di(2'-tetrahydropyranyloxy)-4-androsten-3-one above results in the preparation of 17β-hydroxy-4,6α,17α-trimethyl-5α-androstane-3,19-dione, 17β-hydroxy-4,6α,17α-trimethyl-5α-androstane-3,19-dione acetate, 19-tetrahydropyranyloxy-5α-androstane-3,17-dione, 19-trimethylsiloxy-5α-androstane-3,17-dione and 6α-methyl-19-(2'-tetrahydropyranyloxy)-5α-androstane-3,17-dione, respectively.
Reaction SMILES: [I:1][CH3:2].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH:14]([OH:23])[C:15]2[N:16]=[CH:17][N:18]3[CH:22]=[CH:21][S:20][C:19]=23)[CH2:12][C@H:11]([S:24][C:25]2[C@H:26]([CH3:42])[C@@H:27]3[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:28]3[C:29]=2[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]>>[I-:1].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH:14]([OH:23])[C:15]2[N:16]([CH3:2])[CH:17]=[N+:18]3[CH:22]=[CH:21][S:20][C:19]=23)[CH2:12][C@H:11]([S:24][C:25]2[C@H:26]([CH3:42])[C@@H:27]3[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:28]3[C:29]=2[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncn4ccsc34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3c4scc[n+]4cn3C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.8 %

Procedure:
Iodomethane (2.13 g) is added to 177 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-7-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate prepared in Example 14-b), and the mixture is stirred in an argon atmosphere in a light-shielded state at room temperature for 12 hr. The excess reagent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 206 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(6-methylimidazo[5,1-b]thiazolium-7-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide (a diastereomer mixture) as a light yellow amorphous material.
Reaction SMILES: [N:1]1(N)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:13]1[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>CCO>[CH:8]1[C:9]2[C:17]3[CH2:18][CH2:19][NH:13][CH2:14][CH2:15][C:16]=3[N:1]3[C:10]=2[C:5]([CH2:4][CH2:3][CH2:2]3)=[CH:6][CH:7]=1
Reactant: NN1CCCc2ccccc21
Reactant: O=C1CCCNCC1
Agent: Cl
Solvent: CCO
Product: c1cc2c3c(c1)c1c(n3CCC2)CCNCC1
Temperature: 20 °C
Yield: 25.2 %

Procedure:
To a solution of 3,4-dihydro-1(2H)-quinolinamine (1.0 g, 14 mmol) and hexahydro-4H-azepin-4-one hydrochloride (1.0 g, 14 mmol) in EtOH (13 mL) was added concentrated HCl (1.2 mL). The reaction was stirred at reflux for 14 h, then cooled to 20° C. A brown precipitate was filtered from the reaction mixture, affording the title compound (800 mg, 45%) as a brown solid. 1H NMR (CD3OD, 300 MHz) δ 2.14-2.23 (m, 2H), 2.91 (t, 2H, J=6.0 Hz), 3.16-3.21 (m, 2H), 3.27-3.33 (m, 2H), 3.39-3.50 (m, 4H), 4.04 (t, 2H, J=5.7 Hz), 6.70 (d, 1H, J=6.9 Hz), 6.87-6.93 (m, 1H), 7.22 (d, 1H, J=8.0 Hz) ppm. MS (ESI): 227.2 (base, M+H).
Reaction SMILES: C1COCC1.[BH4-].[Na+].[C:8]([NH:11][C@H:12]([C@H:18]([OH:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](OCC)=[O:14])(=[O:10])[CH3:9].C(OCC)(=O)C>O>[C:8]([NH:11][C@H:12]([C@H:18]([OH:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][OH:14])(=[O:10])[CH3:9]
Reactant: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](NC(C)=O)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 84 %

Procedure:
A THF suspension (0.3 mL) containing sodium borohydride (38.2 mg, 0.93 mmol) was heated to 60° C., and a THF solution (2.5 mL) of ethyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate (250.1 mg. 0.62 mmol) synthesized in the same manner as Example 14 was added thereto dropwise for 5.5 hours. After completion of the dropwise addition, the mixture was further stirred at 60° C. for 17 hours. After ethyl acetate and water were added thereto, the reaction mixture was stirred at 60° C. for 1 hour. After the organic layer was separated, the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was removed in reduced pressure. It was confirmed that 178.7 mg of the title compound was contained (yield: 84%). HPLC analysis was carried out to find that the optical purity of the anti-form was 99% ee.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:5][N:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:36][C:35]([CH3:38])([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([NH2:39])=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:36][C:35]([CH3:38])([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([NH:39][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][CH2:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=3)=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CNc1nccc(CNc2ccccc2C(=O)O)n1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(CNc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[(2-methylamino-pyrimidin-4-ylmethyl)-amino]-benzoic acid (Step C, 0.31 g, 1.20 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.33 g, 1.20 mmol), TBTU (0.43 g, 1.32 mmol), and DIEA (0.31 mL, 1.80 mmol) in 10 mL of DMF was stirred at RT for 2 h. The mixture was partitioned between EtOAc and Na2CO3 (aq). The organic layer was washed with water, brine, dried with MgSO4, filtered, condensed, and the residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2). The titled compound was obtained as a light yellowish solid. MS (ES+): 517.4 (M+H)+. Calc'd for C29H36N6O3-516.63