Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:11]2[NH:12][N:13]=[C:14]([NH:15][CH3:16])[C:10]=2[C:9](=[O:17])[N:8]([CH2:18][CH2:19][CH3:20])[C:7]1=[O:21].C(N(CC)CC)C.Cl[C:33]([O:35][CH3:36])=[O:34]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:11]2=[N:12][N:13]([C:33]([O:35][CH3:36])=[O:34])[C:14]([NH:15][CH3:16])=[C:10]2[C:9](=[O:17])[N:8]([CH2:18][CH2:19][CH3:20])[C:7]1=[O:21]
Reactant: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccc(Cl)c2)c1=O
Reactant: COC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c2c(NC)n(C(=O)OC)nc2n(Cc2cccc(Cl)c2)c1=O
Reaction time: 20 h
Yield: 86 %

Procedure:
To a mixture of 7-(3-chlorobenzyl)-3-methylamino-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.0 g, 2.9 mM) and triethylamine (1.2 ml, 8.6 mM) in dioxane (50 ml) was added dropwise methyl chloroformate (0.66 ml, 8.5 mM) at room temperature and the mixture was allowed to stir at the same temperature for 20 hours. The mixture was concentrated to dryness and the residue was triturated with water (10 ml). Recrystallization from chloroform/methanol gave colorless crystals (1.0 g, 86%), m.p. 164°-166° C.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:36])([C:33]([CH3:35])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH:37]CC2C=CC=CC=2)[C@@H:3]1[OH:45].Cl>>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:36])([C:33]([CH3:35])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:37])[C@@H:3]1[OH:45]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](NCc2ccccc2)[C@H](O)[C@H](C)O1
Agent: Cl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1

Procedure:
and 0.23 g (8%) of (I) and 0.07 g (2%) of (II), as HCl salts.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][C:20]([CH3:22])=[CH2:21])[C@H:15]([CH3:23])[O:14][C:13](=[O:24])[C@@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:15]([CH3:23])[O:14][C:13](=[O:24])[C@@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-9-methyl-8-((3-methylbut-3-en-1-yl)oxy)-2-oxo-1,5-dioxonan-3-yl)carbamate (100 mg, 0.223 mmol, 1.00 equiv) in EtOAc (3 mL) was added 10% Pd/C (12 mg, 0.011 mmol, 0.05 equiv). The resulting suspension was stirred under an atmosphere of H2 (balloon pressure) for 16 h and filtered through a plug of Celite®. The filtrate was concentrated to provide tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(isopentyloxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (97 mg, 97%) as a sticky oil: 1H NMR (400 MHz, CDCl3) δ 7.38-7.23 (m, 2H), 7.23-7.11 (m, 3H), 5.13 (d, J=7.7 Hz, 1H), 4.94 (dq, J=9.2, 6.4 Hz, 1H), 4.59 (q, J=7.3 Hz, 1H), 3.88 (dd, J=11.5, 7.3 Hz, 1H), 3.77-3.63 (m, 1H), 3.56 (dt, J=8.7, 6.9 Hz, 1H), 3.49-3.41 (m, 1H), 3.37 (dd, J=10.5, 6.4 Hz, 1H), 3.26 (dd, J=11.3, 7.3 Hz, 1H), 3.20-3.04 (m, 2H), 2.30 (t, J=12.6 Hz, 1H), 1.90 (s, 1H), 1.73 (dp, J=13.3, 6.7 Hz, 1H), 1.55-1.46 (m, 5H), 1.42 (s, 9H), 0.91 (dd, J=6.6, 0.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 172.25, 154.97, 139.96, 129.15, 128.43, 126.11, 85.13, 80.07, 75.58, 72.90, 72.45, 71.19, 52.97, 47.31, 39.17, 35.16, 28.27, 24.90, 22.70, 22.68, 18.77; ESIMS m/z 472.7 ([M+Na]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].CO[C:16](OC)([CH3:18])[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:16]1([CH3:18])[O:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[O:1]1
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)OC(C)(C)O2
Yield: 48.5 %

Procedure:
Ethyl 3,4-dihydroxybenzoate (910.9 mg, 5 mmol) was combined with 2,2-dimethoxypropane (1.23 mL, 10 mmol) and a catalytic amount of p-toluene sulfonic acid in toluene. The mixture was heated to reflux using a Dean-Stark trap for 20 hours. After solvent removal under reduced pressure, the crude was dissolved in ethyl acetate and washed successively with a saturated aqueous solution of sodium bicarbonate, water, and brine. The organic layer was dried over anhydrous sodium sulfate. Purification by chromatography on silica gel using a gradient hexane:ethyl acetate, 90:10 to 75:25, afforded a white powder (539.1 mg, 49%). 1H NMR (CDCl3): δ 1.36 (t, 3H, J=7.2 Hz), 1.69 (s, 6H), 4.32 (q, 2H, J=7.1 Hz, J=14.2 Hz), 6.74 (d, 1H, d, J=8.2 Hz), 7.38 (d, 1 h, J=1.7 Hz), 7.61 (dd, 1H, J=1.8 Hz, J=8.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][N:36]([CH3:41])[S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1.C(Cl)Cl>[CH3:35][N:36]([CH3:41])[S:37]([N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:25][CH2:24]1)(=[O:39])=[O:38]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)N(C)C)CC2)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (300 mg, 0.87 mmol, Example 59) and diisopropylethylamine (2 mL) in tetrahydrofuran (80 mL) was stirred at +5° C. To this was added dropwise dimethylsulfamoyl chloride (320 mg, 2.23 mmol, Aldrich) in methylene chloride (15 mL). The reaction was stirred at room temperature for 2 hours, poured into water and extracted into methylene chloride (2×50 mL). The combined organic extracts were washed with 5% aqueous sodium bicarbonate. The organic solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by silica gel chromatography to give 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonic acid dimethylamide as a white solid. HRMS, observed: 453.1720; Calcd for M+: 453.1715.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=O.CCCCCC>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:25][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc(CCCC=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cccc(CCCC=C(Br)Br)c1
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
To a solution of carbon tetrabromide (16.7 g) in methylene chloride (35 ml) was added triphenylphosphine (26.0 g) in methylene chloride (35 ml) at 0° C. and the mixture was stirred for 10 min. To the mixture was added a solution of 1-(3-formylpropyl)-3-methoxybenzene (3.00 g)in methylene chloride (20 ml) at 0° C. The mixture was stirred for 30 min at 0° C. To the mixture was added gradually n-hexane and the mixture was filtered to remove triphenylphosphineoxide. The filtrate was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=24:1) to give the title compound (5.33 g) having the following physical data.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[O:9][C:8](=[O:17])[CH:7]=1)=[CH2:5])C.[Br:18]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>C1COCC1.O>[Br:18][CH2:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[O:9][C:8](=[O:17])[CH:7]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1cc(=O)oc2cc(C)ccc12
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(C(=O)CBr)cc(=O)oc2c1
Temperature: 25 °C

Procedure:
To a solution of 4-(1-ethoxyvinyl)-7-methyl-2H-chromen-2-one (1.56 g, 6.77 mmol) in THF-water (27.5 mL, 10/1 mixture), N-bromosuccinimide (1.33 g, 7.45 mmol) was added. The reaction was then stirred at room temperature. After 3 hours stirring, toluene was added and the crude mixture was evaporated under reduced pressure. The crude residue obtained was purified by column chromatography (EtOAc/hexanes, 30:70) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.71 (d, 1H), 7.24 (s, 1H), 7.22 (d, 1H), 6.94 (s, 1H), 4.90 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:12]([F:14])([F:13])[F:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OC(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a stirred solution of 3,5-dichlorobenzaldehyde (10 g, 57 mmol) in THF (250 mL) were added trifluoromethyltrimethylsilane (9.79 g, 69.2 mmol) and a catalytic amount of tetrabutylammonium fluoride (TBAF). The reaction mixture was stirred at 25° C. for 8 h. After the reaction was deemed complete by TLC, the reaction mixture was diluted with 3 N hydrochloric acid (HCl) and then was stirred for 16 h. The reaction mixture was diluted with H2O and was extracted with ethyl acetate (EtOAc; 3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (8.41 g, 60%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][C:11]([CH2:17][NH2:18])=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH3:5].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][C:11]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCOc1ccc2c(c1)C=C(CN)CO2
Solvent: c1ccncc1
Product: CCCCCOc1ccc2c(c1)C=C(CNC(C)=O)CO2

Procedure:
0.34 g (1.38 mmol) of the amine obtained in Step F is acetylated with acetic anhydride in pyridine according to the usual procedure. The crude product of that reaction is purified on a silica column (eluant:ethyl acetate) to yield the title acetamide in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH:20]([C:22]([O:24]CC)=[O:23])[CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH:20]([C:22]([OH:24])=[O:23])[CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Yield: 86 %

Procedure:
In a 15 mL round-bottom flask were placed 100 mg (0.23 mmol, 1 equiv) of ethyl 4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate in 3 mL of methanol and 1.5 mL of THF. The mixture was stirred until all solids dissolved and then 0.93 mL (0.93 mmol, 4 equiv) of 1N NaOH was added. The reaction was allowed to stir at rt for 16 h and then organic solvents were concentrated in vacuo. The resulting residue was re-dissolved in H2O (10 mL) and the solution was acidified to pH 5 with 1N HCl. Once the solution was slightly acidic a white solid precipitated; the precipitate was filtered and washed with water (15 mL) and dried in a hi-vac oven overnight to provide 80 mg (87%) of the desired product, 1, as a pure white solid. 1H-NMR (DMSO-d6) δ 12.20 (s, 1H), 8.42 (s, 1H), 8.42 (s, 1H), 7.95 (t, 1H), 7.67–7.64 (m, 1H), 7.30–7.21 (m, 2H), 3.25–2.81 (m, 5H), 2.34–2.18 (m, 1H), 1.83–1.97 (m, 1H); LCMS RT=2.94 min; [M+H]+=406.2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)[C:12]1=[O:30])[C:2]1C=CC=CC=1.[O:32]=[C:33]1[N:39](CC(N[C@H]2CC(=O)OC2OCC2C=CC=CC=2)=O)[C:38]2[CH:58]=[CH:59][CH:60]=[CH:61][C:37]=2[N:36]([C:62](=[O:65])[CH2:63][OH:64])[CH2:35][C@@H:34]1[NH:66][C:67](=[O:77])[C:68]1C=[C:72](C)[C:71](O)=[C:70](C)[CH:69]=1>>[O:32]=[C:33]1[N:39]([C:12]([NH:11][C@H:10]2[CH2:34][C:33](=[O:32])[O:31][CH:9]2[O:8][CH2:1][CH3:2])=[O:30])[C:38]2[CH:58]=[CH:59][CH:60]=[CH:61][C:37]=2[N:36]([C:62](=[O:65])[CH2:63][OH:64])[CH2:35][C@@H:34]1[NH:66][C:67]([C:68]1[C:69]2[C:58](=[CH:59][CH:72]=[CH:71][CH:70]=2)[CH:38]=[CH:37][N:36]=1)=[O:77]
Reactant: Cc1cc(C(=O)N[C@H]2CN(C(=O)CO)c3ccccc3N(CC(=O)N[C@H]3CC(=O)OC3OCc3ccccc3)C2=O)cc(C)c1O
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Product: CCOC1OC(=O)C[C@@H]1NC(=O)N1C(=O)[C@@H](NC(=O)c2nccc3ccccc23)CN(C(=O)CO)c2ccccc21

Procedure:
(3S)-2-Oxo-3-(isoquinolin-1-oyl)amino-5-hydroxyacetyl-N-[(2RS,3S)-ethoxy-5-oxo-tetrahydrofuran-3-yl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carboxamide (696b) was synthesized from 600b via methods used to prepare 690a from 600b to afford 696b. 1H NMR (CDCl3) δ 0.9(m, 3H), 1.15(q, 3H), 1.15(m, 1H), 1.65(m, 1H), 2.5(m, 1H), 2.8(m, 1H), 2.95-3.0(m, 2H), 3.6(m, 2H), 3.7-3.85(m, 4H), 4.0(m, 2H), 4.3(m, 1H), 4.55(m, 1H), 4.65(m, 1H), 4.85-4.95(m, 1H), 5.05(m, 1H), 5.35(s, 1H), 5.45(d, 1H), 6.85(d, 1H), 7.25(d, 1H), 7.35-7.85(6H), 8.85(dd, 2H), 9.05(m, 1H), 9.35(dd, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[CH2:16]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccco1
Reactant: Nc1cccc(C2CN3CCSC3=N2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1cc(NCc2ccco2)cc(C2CN3CCSC3=N2)c1
Reaction time: 2 h

Procedure:
A mixture of 4.4 g. (0.020 mole) of 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole, 2.1 g. (0.022 mole) furfural, 3.5 ml. acetic acid and 50 ml. methanol are placed in a reaction flask along with some molecular sieves. To this 0.63 g. (0.01 mole) of sodium cyanoborohydride is added slowly and the mixture stirred two hours. The mixture is now acidified to pH 1 with hydrochloric acid. A solid material is removed by trituration and the solvent evaporated leaving an oily residue.
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].C(Cl)[C:8](=[CH2:10])[CH3:9]>>[CH3:5][C:4](=[CH:3][CH2:2][C:2]#[C:3][CH2:4][CH2:5][CH2:9][CH2:8][CH3:10])[CH3:6]
Reactant: CC(C)=CCCl
Reactant: C=C(C)CCl
Product: CCCCCC#CCC=C(C)C

Procedure:
Obtained in 77% yield from 1-heptyn using 1-chloro-3-methylbut-2-ene and using methallylchloride according to the procedure described under a).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1>C1(C)C(C)=CC=CC=1>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:2][CH:3]([OH:10])[CH2:4][O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(OCC(O)COc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
76.5 g (0.55 mole) of p-nitrophenol, 32.3 g (0.25 mole) of glycerol-αα′-dichlorohydrin, and 500 ml of xylene were added to a reaction solution, and the reaction mixtures were heated with stirring under a nitrogen current. After dissolving the solid, 345 g (2.5 moles) of potassium carbonate anhydride was added, and the reaction mixtures were refluxed with stirring for 12 hours. The reacted solution was separated by filtration while it was warm. After cooling, hexane was added to the filtrate. A yellow viscous liquid was obtained. After column purification and drying this liquid, a 55 g-yellow viscous liquid (1,3-bis (4-nitrophenoxy)-2-propyl alcohol) was obtained.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)[CH2:20][C@@:19]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@@H:17]([OH:31])[CH2:16][C@@:15]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Na].O>C(O)C>[OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)[CH2:20][C@@:19]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@H:17]([OH:31])[CH2:16][C@@:15]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3[C@H](O)C[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
A portion (4.0 g) of the solid (A) of Example 31 was dissolved in ethanol (140 ml) and sodium (8.5 g) was added portionwise over 4 h. The mixture was poured into water (1.4 l) and the precipitated solid was filtered off, washed with water and dissolved in methanol (40 ml). Methanesulfonic acid (1.6 ml) was added and the solution was stirred at room temperature for 1 h and then poured into water (400 ml). After extraction with ethyl acetate, sodium carbonate was added to the aqueous phase until the pH exceeded 9. The resulting mixture was extracted with dichloromethane and the organic phase was washed with water. After drying over sodium sulfate, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel. The purified product was crystallised from diethyl ether to give (2β,3α,5α,11α)-3,11-dihydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnan-20-one (750 mg). m.p. 182°-185° C.; [α]D +125.6° (c 0.25).
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.S(Cl)(Cl)=O.[F:21][C:22]1[CH:29]=[CH:28][C:25]([NH:26][CH3:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([N:26]([CH3:27])[C:4]([C:1]2([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:5])=[CH:24][CH:23]=1
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: CNc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(C(=O)C1(C(=O)O)CC1)c1ccc(F)cc1
Yield: 80.6 %

Procedure:
Using a procedure analogous to Example B1, 1,1-cyclopropanedicarboxylic acid (2 g, 15.37 mmol), Et3N (2.14 mL, 15.4 mmol), thionyl chloride (1.12 mL, 15.4 mmol), and 4-fluoro-N-methylaniline (1.83 g, 14.6 mmol) were combined to provide 1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropanecarboxylic acid (2.79 g, 72% yield). MS (ESI) m/z: 260.0 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH:22]1([O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)[CH2:26][CH2:25][CH2:24][CH2:23]1.[O-]CC.[Na+]>C(O)C>[CH:22]1([O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2/[CH:30]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:21][CH:20]=[CH:19][N:5]3[C:6](=[O:18])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OC1CCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)c1OC1CCCC1
Yield: 44.8 %

Procedure:
The title compound was prepared by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 2-cyclopentyloxy-3-methoxybenzaldehyde (398 mg, 1.813 mmol) in presence of sodium ethoxide (163 mg, 2.411 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to afford 296 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.50-1.60 (m, 6H), 1.74-1.81 (m, 2H), 3.77 (s, 3H), 4.83 (s, 1H), 6.85-6.99 (m, 4H), 7.51 (d, J=5.1 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.83 (d, J=7.2 Hz, 2H), 8.00 (d, J=4.8 Hz, 1H), 8.12 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 529.30 (M+H)+.
Reaction SMILES: N[C:2]12[CH:18]([OH:19])[CH2:17][CH:9]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=31)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].N([O-])=O.NO>C(O)(=O)C.O.C(OCC)(=O)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:17][C:2]([CH:18]=[O:19])([C:3]4[C:8]3=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:15]=2[CH:14]=1
Reactant: NC12c3ccccc3C(CC1O)c1ccc(Cl)cc12
Agent: NO
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 10 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
(9RS,10RS,12RS)-9-Amino-2-chloro-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene prepared as in Example 1i (445.5 g, 1.64 moles) was dissolved in glacial acetic acid (4.0 L), and the resulting solution cooled to 10° C. A solution of sodium nitrite (340.0 g, 4.93 moles) in water (1.4 L) was added to the reaction mixture over a period of 1.75 h. The temperature of the mixture was maintained at 10° C. during the addition of the nitrite, and for 4 h thereafter. The mixture was then stirred overnight and allowed to warm to room temperature. TLC analysis [silica gel/toluene:ethyl acetate (4:1)] showed complete conversion of the amino alcohol (Rf =0.12) to the desired aldehyde (Rf =0.80). The reaction mixture was diluted with water (4 L) which caused precipitation of a reddish-brown tar. The aqueous supernatant was decanted away from the tar, diluted with an equal volume of crushed ice, then adjusted to pH=5-6 with solid sodium hydroxide. The resulting aqueous mixture was extracted with ethyl acetate (3×1.5 L). The combined ethyl acetate extracts were used to redissolve the tar, and the resulting solution washed with brine (2×1 L) then dried over magnesium sulfate. Filtration, followed by removal of the solvent in vacuo, gave the crude product as a thick brown oil. Purification of this material by column chromatography over silica gel, eluting with a solvent mixture of methylene chloride:hexane (1:1), afforded a thick yellow oil which crystallized on standing (311.7 g, 74.6%). Trituration with diethyl ether:hexane (1:6-700 ml) gave a first crop of pure title compound as an off-white crystalline solid (224.1 g, 53.6%), mp 91°-92° C.