Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(N=NC(C#N)(C)C)([C:4]#[N:5])C.C1C(=O)N(Br)C(=O)C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:47]=[O:48])=[CH:24][CH:23]=1.CN>C(Cl)(Cl)(Cl)Cl.CO>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[C:47](=[O:48])[NH:5][CH3:4])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CN
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)OC)c3)cc12
Reaction time: 0.5 h
Yield: 210.7 %

Procedure:
AIBN (4.6 mg, 0.028 mmol) and NBS (21.6 mg, 0.121 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)benzoate (35 mg, 0.093 mmol) in CCl4 (5 mL) at 95° C. It was allowed to stir for 30 min and then allowed to cool and was then treated with methanamine (0.466 mL, 0.932 mmol, 2M in THF) and the reaction was allowed to stir for 10 min then diluted with MeOH. A ppt formed which was filtered away and the filtrate was concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=320 nm) to give to give the expected product methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (24 mg, 0.059 mmol, 64% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.60 (1H, d, J=2.14 Hz), 8.44 (1H, d, J=2.44 Hz), 8.32 (1H, s), 8.10 (1H, d, J=7.93 Hz), 7.95-8.00 (2H, m), 7.84 (1H, d, J=7.63 Hz), 7.59 (1H, t, J=7.78 Hz), 7.22-7.26 (2H, m), 5.91 (1H, br. s.), 3.98 (3H, s), 3.03 (3H, d, J=4.88 Hz). LC-MS retention time: 1.46 min; m/z (MH+): 405. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl>>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][S:23][C:21]1[O:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[N:11]=[CH:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:13]=3[CH:14]=2)=[N:19][N:20]=1
Reactant: Fc1cccc(CCl)c1
Reactant: COc1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Product: COc1ccc(-n2cnc3ccc(-c4nnc(SCc5cccc(F)c5)o4)cc32)cc1
Yield: 26 %

Procedure:
In the same manner as in Example 1 and using 5-[1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 26%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21](C)[N:20]=1>>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11]3([O:16][N:15]=[C:5]([C:4]#[C:3][C:22]4[CH:21]=[N:20][CH:19]=[CH:24][CH:23]=4)[CH2:14]3)[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1
Reactant: C=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Reactant: Cc1cccc(Br)n1
Product: Cc1ccc([N+](=O)[O-])c(N2CCC3(CC2)CC(C#Cc2cccnc2)=NO3)n1

Procedure:
The title compound was prepared following the procedure reported for the compound of Example 3, replacing 3-iodopyridine for 2-bromo-6-methylpyridine. After the usual work-up, the crude was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-EtOAc from 7:3 to 3:7) affording the title product as yellow solid. Yield: 66.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Li]CCCC.CCCCCC.CON(C)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]>C1COCC1>[Cl:1][C:2]1[C:3]([F:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]
Reactant: Fc1ccccc1Cl
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2F)C1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a stirred solution of 1-chloro-2-fluoro-benzene (13.0 g, 0.1 mol) in THF (250 mL) at −75° C. was added dropwise 2.5 M BuLi in hexane (40 mL, 0.1 mol) during 45 min. After additional stirring for 30 min at −75° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)-carbamoyl)piperidine-1-carboxylate (21.76 g, 0.08 mol) in THF (100 mL) was added dropwise over 30 min. The mixture was allowed to warm from −70° C. to 0° C. The mixture was quenched with sat'd aq NH4Cl, extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4. Solvent removal and flash column chromatography, eluting with 5% EtOAc/PE afforded (R)-tert-butyl 3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (19.2 g, 70%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.63 (m, 2H), 1.76 (m, 1 H), 2.06 (m, 1H), 2.87 (m, 1H), 3.15 (m, 1H), 3.25 (m, 1H), 3.9 (m, 1H), 4.2 (m, 1H), 7.18 (m, 1H), 7.60 (m, 2H). MS (E/Z): 342 (M+H+).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:5]=1)=[O:3].O1CCOCC1.Cl.[OH-].[NH4+]>C(#N)C>[NH:18]1[CH2:19][CH2:20][CH:15]([O:14][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:12])([F:11])[F:13])[N:7]=2)[C:2]([NH2:1])=[O:3])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(N)=O)cc(C(F)(F)F)n2)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1COCCO1
Product: NC(=O)c1cc(OC2CCNCC2)nc(C(F)(F)F)c1
Reaction time: 2.5 h
Yield: 60.7 %

Procedure:
tert-Butyl 4-{[4-(aminocarbonyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.20 g, 0.41 mmol, from Step B) was dissolved in 1,4-dioxane (3.0 mL, 38 mmol) and treated with 4.0M hydrogen chloride in dioxane (2.4 mL, 9.8 mmol). After 2.5 hours, the mixture was treated with ammonium hydroxide to achieve pH 11, and 15 mL of acetonitrile was added. The mixture was filtered and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product (72 mg, 60%). 1H NMR (400 MHz, dmso) δ 8.35 (s, 1H), 7.91 (s, 1H), 7.76 (d, J=1.2 Hz, 1H), 7.49 (s, 1H), 5.05 (tt, J=8.9, 4.1 Hz, 1H), 2.95 (dt, J=12.6, 4.2 Hz, 2H), 2.57 (ddd, J=12.7, 10.0, 2.9 Hz, 2H), 2.01-1.87 (m, 2H), 1.60-1.41 (m, 2H); 19F NMR (376 MHz, dmso) δ−67.49 (s); LCMS (M+H)+: 290.1.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f21) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[C:13]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=[O:22])=[CH:12]1)C)(C)(C)C.Cl>CO>[ClH:20].[Cl:20][C:17]1[CH:18]=[C:19]2[C:14]([C:13]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31][C:30]4=[O:38])[CH2:25][CH2:24]3)=[O:22])=[CH:12][N:11]2[CH2:10][CH2:9][NH:7][CH3:6])=[CH:15][CH:16]=1
Reactant: CN(CCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21
Yield: 191.5 %

Procedure:
A solution of 0.25 g (0.45 mmol) (2-{6-chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-ethyl)-methyl-carbamic acid tert-butyl ester in 3.6 ml (4.5 mmol) of a 1.25 M solution of hydrochloric acid in methanol was stirred for 20 min. at 50° C. The reaction mixture was concentrated to dryness to give 0.21 g of the title compound as an off-white solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:22])[C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:5])([CH3:4])[CH3:3].[CH2:23]([C@H:25]1[O:27][CH2:26]1)[Cl:24]>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].O>[C:2]([O:6][C:7](=[O:22])[C@@H:8]([NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:26][C@H:25]([OH:27])[CH2:23][Cl:24])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Reactant: ClC[C@@H]1CO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@H](O)CCl)C(=O)OC(C)(C)C
Yield: 39 %

Procedure:
A solution of 3 (4.83 g, 14.3 mmol) in chloroform (100 mL) was extracted with saturated NaHCO3 solution (2×100 mL) and water (100 mL). The organic layer was dried, concentrated, and further dried in vacuo. The resulting oil was dissolved in cyclohexane (26 mL), and (S)-(+)-epichlorohydrin (1.58 g, 17.1 mmol) was added under an Ar atmosphere. The precipitated product was filtered after 27 h, washed with cold cyclohexane, and dried in vacuo to give 12a (2.20 g, 39%) as a fine, white powder: mp 87-88° C.; 1H NMR δ 1.30-1.83 (m, 6H), 1.44 (s, 9H), 1.46 (s, 9H), 2.57-2.66 (m, 3H), 2.77 (dd, 1H, J=12.2, 3.9), 3.51 (dd, 1H, J=11.2, 5.7), 3.56 (dd, 1H, J=11.2, 5.2), 3.84-3.91 (m, 1H), 3.94 (dd, 1H, J=8.6, 5.3); 13C NMR 6 24.6, 28.3, 28.7, 30.0, 32.6, 48.2, 50.3, 53.5, 55.8, 71.1, 80.4, 82.5, 158.1, 173.8; HRMS m/z calcd for C18H36ClN2O5 395.2313, found 395.2303. Anal. calcd. for C18H35ClN2O5: C54.74, H 8.93, Cl 8.98, N 7.09. Found: C 54.80, H. 8.99, Cl 9.02, N 7.08 [α]22D−26.1° (c 1.00, CH3OH).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][OH:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH3:2].[C:39](Cl)(=[O:41])[CH3:40]>>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Product: CCOc1cc(CC(=O)NC(COC(C)=O)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1

Procedure:
Prepared analogously to Example 37 from benzyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate with acetyl chloride. Calculated: molecular peak m/e=558; Found: molecular peak m/e=558
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])[CH:13]=2)[CH:8]=[CH:7]1.O.CN([CH:30]=[O:31])C>>[CH:30]([C:8]1[C:9]2[C:14](=[CH:13][C:12]([CH2:15][C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)[NH:6][CH:7]=1)=[O:31]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc(Cc2ccc3cc[nH]c3c2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cc(Cc3cccc(C(=O)O)c3)ccc12
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
(I-8): 3 ml anhydrous DMF was cooled in ice-water bath, then 50 μl POCl3 was added, the solution was stirred about 15 minutes, then 32 mg of methyl 3-(1H-indol-6-ylmethyl)benzoate in 2 ml DMF was added. The mixture was heated to 40° C. for 3 hours. After cooling to room temperature, the mixture was treated by cold water, following the general procedure above, the target compound was purified as a brown solid. Mass calculated for C17H13NO3: 279; LCMS: 280.6 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.87 (1H, s), 8.24 (1H, d, J=3.0 Hz), 7.99 (1H, s), 7.80 (1H, d, J=7.3 Hz), 7.76 (1H, d, J=7.9 Hz), 7.52 (1H, d, J=7.9 Hz), 7.41 (1H, t, J=7.9 Hz), 7.34 (1H, s), 7.12 (1H, d, J=7.3 Hz), 4.12 (2H, s).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[NH:18][C:19]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=1.O>C(OCC)(=O)C>[C:6]([N:18]([C:19]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=1)[C:10]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:8])(=[O:7])[NH2:5]
Reactant: Cc1cccc([N+](=O)[O-])c1Nc1nc2c(c(C(F)(F)F)n1)CCCC2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc([N+](=O)[O-])c1N(C(N)=O)c1nc2c(c(C(F)(F)F)n1)CCCC2
Reaction time: 1 h

Procedure:
2.2 ml of chlorosulfonyl isocyanate are added at 3° C. to a solution of 7.0 g of 2-(2-methyl-6-nitrophenylamino)-5,6,7,8-tetrahydro-4-trifluoromethyl-quinazoline in 100 ml of ethyl acetate. The whole is stirred for one hour while cooling on an ice-bath, and subsequently 50 ml of ethyl acetate and 30 ml of water are added. The organic phase is separated off, washed with brine, dried and concentrated in vacuo. The residue is triturated with hexane, the product crystallising out. 7.8 g of the title compound of formula ##STR25## are isolated in the form of crystals having a melting point of 161°-162° C. (decomp.) (comp. No. 1.563).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO>[O:38]1[CH2:39][CH2:40][N:35]([C:32]2[N:33]=[CH:34][C:29]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=4)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)nc2)c2ccc(C=O)cc21
Temperature: 125 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
A mixture 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (25 mg, 0.62 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (22 mg, 0.75 mmol), PdCl2 (PPh3)2 (4 mg, 0.006 mmol) and 2M Na2CO3 (0.31 mL, 0.62 mmol) in DME/H2O/EtOH (2.8 mL/0.8 mL/0.4 mL) was sealed and heated with stirring under microwave irradiation at 125° C. for 4 h. Solvent was removed and the crude product was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to yield a bright yellow foam (266 mg, 97%). 1H NMR (400 MHz, CD3OD) δ 10.02 (s, 1H), 8.60 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 7.99 (dd, J=8.9, 2.5 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.64 (dd, J=8.7, 1.1 Hz, 1H), 6.80 (d, J=9.1 Hz, 1H), 5.78 (s, 2H), 3.76 (t, J=4.7 Hz, 4H), 3.61 (t, J=8.0 Hz, 2H), 3.49 (t, J=5.1 Hz, 4H), 0.84 (t, J=8.0 Hz, 2H), −0.12 (s, 9H); MS ESI 439.3 [M+H]+, calcd for [C23H30N4O3Si+H]+ 439.21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.CN(C=O)C.[NH2:30][C:31]1[C:32]([CH3:39])=[C:33]([OH:38])[CH:34]=[CH:35][C:36]=1[CH3:37]>C(Cl)Cl.C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[C:11]([NH:30][C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]([OH:38])[C:32]=2[CH3:39])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(C)c1N
Reactant: COc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2c(C)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
To a solution of 3-(3-fluorophenyl)-5-methoxy-benzoic acid (intermediate III(i)) (1.4 g, 5.7 mmol, 1.0 eq) in CH2Cl2 (15 mL) were added (COCl)2 (2.2 g, 17.3 mmol, 3.0 eq) and DMF (0.01 mL). The reaction mixture was stirred at room temperature for 1.5 h then the solvent and excess reagent removed under reduced pressure. The residue obtained was dissolved in THF (20 mL) and added dropwise to a solution of 3-amino-2,4-dimethylphenol (intermediate X(c)) (791 mg, 5.77 mmol, 1.0 eq) in THF (20 mL) at 0° C. The solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 1:1) to give the title compound as a white solid (1.2 g, 57%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>O1CCCC1>[Cl:18][CH2:19][CH2:20][C:21]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[O:22]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCl)Nc1ccc2[nH]ncc2c1
Yield: 44.4 %

Procedure:
Triethylamine (1.6 ml, 30.0 mmol) was added to a solution of 5-aminoindazole (2.0 g, 15.0 mmol) in tetrahydrofuran (50 ml) at room temperature, followed by adding thereto 3-chloropropionyl chloride (1.43 ml, 15.0 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 30 minutes. Then, the reaction solution was distilled under reduced pressure to remove the solvent, and the resulting residue was suspended in ethanol and stirred. Thereafter, the solid was collected by filtration and dried under reduced pressure to obtain 3-chloro-N-(1H-indazol-5-yl)propanamide (1.49 g, 44%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15](O)([CH2:16][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:18][C@@H:19]2[O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].ClCC(O)=O>C(=O)(OCC)OCC>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:18][C@@H:19]2[O:27][C:28](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Agent: O=C(O)CCl
Solvent: CCOC(=O)OCC
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)c2ccccc2)C1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
In 10 ml of diethyl carbonate was dissolved 350 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxy-1α-benzoyloxypregn-6-en-5α-ol, followed by addition of 0.1 ml of monochloroacetic acid. The mixture was stirred under heating at 100° C. in an atmosphere of argon gas for 10 hours. The reaction mixture was then worked up in the same manner as Example 124 to give 120 mg of 20-(1,3-dioxolan-2yl)-3β-acetoxy-1α-benzoyloxypregna-5,7-diene showing the following physical properties.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:22])[CH2:6][N:7]1[C:11]2[C:12]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=[O:21])([CH3:3])[CH3:2].[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].N(C(C)(C)C#N)=NC(C)(C)C#N>[CH:1]([O:4][C:5](=[O:22])[CH2:6][N:7]1[C:11]2[C:12]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:13][CH:14]=[C:15]([Cl:23])[C:10]=2[NH:9][C:8]1=[O:21])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(CC)c1cccc2[nH]c(=O)n(CC(=O)OC(C)C)c12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(CC)c1ccc(Cl)c2[nH]c(=O)n(CC(=O)OC(C)C)c12
Temperature: 70 °C
Reaction time: 72 h
Yield: 64.9 %

Procedure:
To a solution of isopropyl[7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate (5.29 g, 17.4 mmol) in carbon tetrachloride (350 mL) was added N-chlorosuccinimide (2.55 g, 19.1 mmol) and 2,2′-azobisisobutyronitrile (86 mg, 0.522 mmol), and the mixture was stirred at 70° C. for 3 days. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane (X2). The combined organic layer was washed with water (X1) and brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-50% ethyl acetate/hexane gradient mixture to give 3.83 g (11.3 mmol, 65.0%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([NH:12][C:13](=O)[CH2:14][N:15]3[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([NH:12][C:13](=[S:34])[CH2:14][N:15]3[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)OC(=O)N1CC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Product: CC(C)OC(=O)N1CC(=S)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared according to the procedure for Example 24 from isopropyl 7-(3-chlorophenyl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate and Lawesson's reagent. A yellowish solid: mp.208-212° C.; 1H-NMR (DMSO-d6) δ1.27(d, J=6.1 Hz, 6H), 4.62 (s, 2H), 4.94 (sep, J=6.1 Hz, 1H), 7.23 (m, 4H), 7.64 (t, J=1.8 Hz, 1H), 7.90 (s, 1H), 12.80 (s, 1H), MS (ESI) m/z 359/361 (M−H)−.