Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH2:11][O:12]C(=O)C)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[OH-].[NH4+]>CO>[OH:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1
Reactant: CC(=O)Nc1cc(COC(C)=O)ccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1cc(CO)ccn1
Reaction time: 24 h
Yield: 101.1 %

Procedure:
Acetic acid 2-acetylamino-pyridin-4-ylmethyl ester (4.2 g, 20 mmol) was stirred with ammonium hydroxide (10 ml) in methanol (50 ml) at room temperature. After 24 hr., the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA) to afford 3.36 g (quantitative) of N-(4-hydroxymethyl-pyridin-2-yl)-acetamide as a pale yellow solid. m.p. 145° C.; 1H NMR (200 MHz, CDCl3/CD3OD) δ 2.19 (3H, s), 4.67 (2H, s), 7.08 (1H, d, J=5.0 Hz), 8.10 (1H, s), 8.17 (1H, d, J=5.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19]([C:21]1[S:22][C:23]([CH2:26]Br)=[CH:24][CH:25]=1)=[O:20]>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:26][C:23]2[S:22][C:21]([C:19]([OH:20])=[O:18])=[CH:25][CH:24]=2)=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: COC(=O)c1ccc(CBr)s1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Product: O=C(O)c1ccc(COc2ccc(-c3ccccc3[N+](=O)[O-])cc2)s1

Procedure:
5-(2′-Nitro-biphenyl-4-yloxymethyl)-thiophene-2-carboxylic acid was prepared using general procedure A from 4-hydroxy-2′-nitrobiphenyl (available from TCI America, Portland, Oreg.) and 5-bromomethyl-thiophene-2-carboxylic acid methyl ester (Intermediate 7). Yield: 80 mg. Mass spectrum (ES) MH+=356.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12].[I:22]I.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.OS([O-])=O.[Na+]>O1CCOCC1.[OH-].[Na+].II.C(OCC)(=O)C.CCCCCC>[I:22][C:17]1[C:16]2[C:20](=[CH:21][C:13]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:14][CH:15]=2)[NH:19][N:18]=1
Reactant: II
Reactant: COCOc1ccc(-c2ccc3cn[nH]c3c2)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COCOc1ccc(-c2ccc3c(I)n[nH]c3c2)cc1OC
Yield: 77.6 %

Procedure:
In a 100-mL round-bottom flask under argon, 6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (1.19 g, 4.18 mmol, 1 equiv) was dissolved in dioxane (25 mL) and 3N NaOH (14 mL). This mixture was treated with iodine (1.17 g, 14.60 mmol, 1.10 equiv) added in ˜5 portions (˜10 min). Several (−4) additional portions of iodine (50 mg each) were added until the reaction was complete as visualized by TLC (3:7 ethyl acetate/hexane). The mixture was acidified with 20% citric acid (25 mL) and 5% NaHSO3 (20 mL) was added. The mixture was partitioned between ethyl acetate (150 mL) and water (100 mL). The organic material was washed with saturated sodium bicarbonate (80 mL) and brine (50 mL) and were dried over sodium sulfate and concentrated under reduced pressure. Purification by crystallization from ethyl acetate (3 mL) then hexane (7 mL) gave pure 3-iodo-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole as a solid (1.33 g, 78%): 1H NMR (CDCl3) δ 10.48 (bs, 1H), 7.62 (s, 1H), 7.57 (d, 1H, J=8.5 Hz), 7.47 (dd, 1H, J=1.3, 8.5 Hz), 7.18 (m, 3H), 5.29 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH:37]([CH3:39])[CH3:38])=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1>CN(C=O)C>[CH2:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)=[CH:31][C:32]=1[C:40]([F:41])([F:42])[F:43])[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: CC(C)Cc1ccc(CCl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.04 g, 0.139 mmol) was dissolved in DMF (1.0 mL) and cesium carbonate (0.045 g, 0.139 mmol) and 4-(chloromethyl)-1-isobutyl-2-(trifluoromethyl)benzene (0.035 g, 0.139 mmol) was added. The reaction mixture was stirred at room temperature for 48 h and then filtered through Celite®. The filtrate was partitioned between EtOAc and water. The aqueous layer was extracted two additional times with EtOAc and the combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the title compound (58 mg). LCMS m/z=502.6 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9](OC(=O)NC)[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](OC(OC)=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][O:22]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CNC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Yield: 44.2 %

Procedure:
The procedure of Example 17 was repeated except that 43.5 mg (0.0798 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-methylcarbamoyloxy)pregn-5-en-3β-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate to give 16.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α, 2α-epoxypregna-5,7-dien-3β-yl acetate. In addition, 15.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-methylcarbamoyloxy)pregn-5-en-3β-yl acetate was recovered. The yield of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate was 68% based on consumed 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-methylcarbamoyloxy)pregn-5-en-3β-yl acetate. The 1H-NMR spectrum of the product 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate was in agreement with that of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate obtained in Example 17.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+].CO>>[C:30]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:7])[N:9]=1)#[N:31]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1ccc(Oc2ccc3c(C#N)nc(C(=O)NCC(=O)O)c(O)c3c2)cc1
Yield: 117.5 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-(4-propoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (200 mg, 0.422 mmol), glycine (633 mg, 8.43 mmol) and NaOMe/MeOH solution (12.7 mL, 6.33 mmol) was refluxed overnight. Then the mixture was concentrated in vacuo and the residue was dissolved in water. The solution was acidified with 2 M HCl to pH=3˜4. The resulting precipitate was collected by filtration, washed with water, and freeze-dried to give the title compound as a powder (209 mg); ESI MS (m/z): 422 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)([OH:9])[CH3:8])(=O)C.[OH-].[Na+].C(O)C>O>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([C:7]([OH:9])([CH3:8])[CH2:6][CH2:5][OH:4])=[CH:11][CH:12]=1
Reactant: CC(=O)OCCC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of 3.2 g. of 1-acetoxy-3-(2',4'-difluoro-4-biphenylyl)-3-butanol and 2 g. of NaOH in 30 ml. of 80% aqueous ethanol is heated under reflux for 3 hours. Water is added; the product is extracted with chloroform, and the extract is evaporated to give 3-(2',4'difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: S1C=C(C2C=CC(C(O)=O)=CC=2)N=N1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.NC[C:30]1[CH:31]=[C:32]([CH:52]=[CH:53][CH:54]=1)[C:33]([NH:35]C1SC2C[C@@H](NC(=O)C(F)(F)F)CCC=2N=1)=[O:34].CCN(CC)CC.FC(F)(F)C(N)=O.C(=O)([O-])[O-].[K+].[K+].C(O)(C(F)(F)F)=O>CN(C=O)C.CO.O>[C:33]([NH2:35])(=[O:34])[C:32]1[CH:52]=[CH:53][CH:54]=[CH:30][CH:31]=1
Reactant: NCc1cccc(C(=O)Nc2nc3c(s2)C[C@@H](NC(=O)C(F)(F)F)CC3)c1
Agent: Cl
Agent: NC(=O)C(F)(F)F
Agent: O=C(O)c1ccc(-c2csnn2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Stir a solution of 4-[1,2,3]thiadiazol-4-yl-benzoic acid (21 mg, 0.10 mmol) and CDI (19 mg, 0.11 mmol) in DMF (3 mL) at rt for 1.5 h. To the clear solution add 3-aminomethyl-N—[(S)-6-(2,2,2-trifluoro-acetylamino)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-benzamide hydrochloride (45 mg, 0.10 mmol) followed by Et3N (0.098 mL, 0.70 mmol). Stir the mixture at rt overnight. Concentrate and use the mixture in the next step without any purification. Dissolve the crude trifluoroacetamide (50 mg, 0.085 mmol) in 4:1 MeOH/H2O (10 mL). Add potassium carbonate (47 mg, 0.34 mmol) to the mixture and stir at 50° C. for 48 h. Add a small amount of TFA to the mixture and purify by prep-HPLC (10% to 100%, CH3CN/H2O) to give the desired product N—((S)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-3-(4-[1,2,3]thiadiazol-4-yl)-aminomethyl)-benzamide in 48% yield (20 mg, 0.041 mmol) MS, electrospray 491.1 (M+H), rt 0.55 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]#[CH:16])=[C:13]([CH3:17])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]#[C:16][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[C:13]([CH3:17])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C#Cc1c(-c2ccc(OC)c(Cl)c2)noc1C
Reactant: Brc1ccccn1
Product: COc1ccc(-c2noc(C)c2C#Cc2ccccn2)cc1Cl
Yield: 72 %

Procedure:
As described for example 11c, 3-(3-chloro-4-methoxy-phenyl)-4-ethynyl-5-methyl-isoxazole (134 mg, 0.50 mmol) instead of 4-ethynyl-5-methyl-3-phenyl-isoxazole was converted (using 2-bromopyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 117 mg, 72%) which was obtained as a white solid. MS: m/e=325.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11](N)=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.ClC1C=C(CC(=O)C)C=CC=1[S:26]([NH2:29])(=[O:28])=[O:27].NC1C=CC(CC(=O)C)=CC=1Cl>>[Cl:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Cl)sc1-c1ccc(N)cc1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)c(Cl)c1
Agent: CC(=O)Cc1ccc(N)c(Cl)c1
Product: Cc1nc(Cl)sc1-c1ccc(S(N)(=O)=O)cc1

Procedure:
Starting from 4-(2-chloro-4-methyl-thiazol-5-yl)-phenylamine (25c) and following the two step process described for the preparation of 2-chloro-4-(2-oxo-propyl)-benzenesulfonamide (Example 23c) from 1-(4-amino-3-chloro-phenyl)-propan-2-one (Example 23a) gave the title compound.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][NH:4]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[CH3:23].C(N(CC)C(C)C)(C)C.O.[Cl-].[Na+].O>CS(C)=O>[CH3:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:3][N:4]=[CH:5][CH:6]=2)[CH2:11]1
Reactant: c1cc2c(cn1)CNCC2
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])ccc1N1CCc2ccncc2C1
Temperature: 115 °C
Yield: 61.6 %

Procedure:
A mixture of commercially available 1,2,3,4-tetrahydro-2,7-naphthyridine dihydrochloride (456 mg, 2.2 mmol), 2-fluoro-5-nitrotoluene (512 mg, 3.3 mmol), and N,N-diisopropylethylamine (2.0 mL, 11.4 mmol) in 8.0 mL DMSO was heated at 115° C. for 20 hours. The reaction was added to a H2O/brine mixture, then extracted with EtOAc. The EtOAc portion was washed with a H2O/brine mixture, aqueous Na2CO3 solution, dried with anhydrous Na2SO4, and evaporated to an oil. An impure sample from a previous reaction (1.0 mmol scale) was combined, and then chromatographed eluting with CHCl3/EtOAc to give the title compound as a yellow solid (365 mg, 42% combined yield). 1H NMR (CDCl3) δ: 8.40-8.43 (m, 2H), 8.05-8.11 (m, 2H), 7.14 (d, J=5.0 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 4.27 (s, 2H), 3.36 (t, J=5.7 Hz, 2H), 3.04 (t, J=5.6 Hz, 2H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C@@:4]1([OH:29])[CH2:27][C@H:26]([OH:28])[C:7]2=[C:8]([OH:25])[C:9]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]=4[O:23][CH3:24])[C:13](=[O:14])[C:10]=3[C:11]([OH:12])=[C:6]2[CH2:5]1)=[O:3].BrBr.[OH-:32].[Na+]>C(Cl)(Cl)Cl>[CH3:24][O:23][C:19]1[C:20]2[C:21]([C:9]3[C:8]([OH:25])=[C:7]4[C:6]([CH2:5][C@@:4]([OH:29])([C:2]([CH2:1][OH:32])=[O:3])[CH2:27][C@@H:26]4[OH:28])=[C:11]([OH:12])[C:10]=3[C:13](=[O:14])[C:15]=2[CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O
Reaction time: 16 h
Yield: 86.9 %

Procedure:
Daunomycinone (IX) (10 mg, 0.025 mmole) was placed in CHCl3 (1 ml). Br2 (13.5 mg) in CHCl3 (0.25 ml) was added and the solution stirred at 23° for 16 hrs. The solvent was removed and the residue was dissolved in 80% aq acetone (5 ml). NaOH (1.1 mg. 0.028 mmole) was added and the blue solution was refluxed for 5 min when the red color returned. The solution was concentrated to approximately 2 ml, diluted with water (10 ml) and extracted with 50% CHCl3 /MeOH (3 × 10 ml). The extracts were combined, dried and evaporated. The residue was crystallized from CHCl3 -MeOH/pet. ether (30°-60°) to afford 9.0 mg (87%) of (XI): irnujol 2.85 (OH), 5.75 (C = O), 615, 628 μ (chelated quinone); pmr 100 MHz CDCl3 δ 2.0-2.5 (m, 2H, 8-H2), 2.8-3.2 (m, 2H, 10-H2), 3.43 (m, 1H, 9-OH), 4.09 (s, 3H, OMe), 4.70 (d, 2H, J = 16Hz, 14-H2), 5.34 (m, 1H, ∥1/2 = 8Hz, 7-H), 7.38 (dd, 1H, J = 8Hz and J = 1Hz, 3-H), 7.76 (t, 1H, J = 8Hz, 2-H), 8.00 (dd, 1H, J = 8Hz and J = 1Hz, 1-H), 13.24 (s, 1H, 6-OH), 13.99 (s, 1H, 11-OH).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11]C)(=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH2:13][C:14]1[C:15]([C:20](OC)=[O:21])=[N:16][CH:17]=[CH:18][N:19]=1>CO>[CH3:9][O:8][C:6]([C:5]1[C:4](=[O:11])[NH:13][C:14]2=[N:19][CH:18]=[CH:17][N:16]=[C:15]2[C:20]=1[OH:21])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)c1nccnc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(O)c2nccnc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methoxide (6.5 ml) (30% by weight in methanol) was dissolved in methanol (75 ml) at room temperature. Dimethyl malonate (3.7 ml) was added dropwise at ambient temperature over a period of 20 minutes and the reaction stirred at ambient temperature for 1 hour. Methyl 3-aminopyrazine-2-carboxylate (5.0 g) was added in portions at ambient temperature over a period of 40 minutes. The reaction mixture was heated to reflux for 3 days, and then allowed to cool. The solvent was concentrated. The residue was dissolved in water and acidified with concentrated hydrochloric acid (36% by weight in water). The precipitate was isolated, washed with water, methanol and ethyl acetate, and dried under high vacuum to give 8-hydroxy-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester as a beige solid (4.16 g). 1H-NMR (d6-DMSO): 3.80 (s, 3H), 8.59 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:13])O[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14].[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1C(O)=O>CN(C)C=O.C(O)(=O)C>[F:1][C:2]1[C:7]2[C:8](=[O:13])[N:15]3[CH2:22][CH2:21][CH2:20][C@H:16]3[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=c1[nH]c2ccc(F)c(F)c2c(=O)o1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)c(F)c2C(=O)N2CCC[C@@H]12
Yield: 82.3 %

Procedure:
A solution of 28.8 g (144.6 mmol) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione and 16.7 g (144.6 mmol) of L-proline in 110 ml of dimethylformamide and 20 ml of acetic acid was stirred at 120° for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 30 g (82%) of (S)-6,7-difluoro-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione as colourless crystals of m.p. >250°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15]CC)=O)[NH:7][C:6]2=[O:18])#[N:2].[NH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C1COCC1>[NH2:24][C:23]1[CH:22]=[C:21]([CH2:20][NH:19][C:13]([C:8]2[NH:7][C:6](=[O:18])[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[N:9]=2)=[O:15])[CH:27]=[CH:26][CH:25]=1
Reactant: NCc1cccc(N)c1
Reactant: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Solvent: C1CCOC1
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(N)c3)[nH]c(=O)c2c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
A suspension of ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate obtained in Reference Example 51 (1.00 g, 4.11 mmol) and 3-(aminomethyl)aniline (0.753 g, 6.17 mmol) in THF (15 mL) was stirred at 80° C. for 15 hr. The reaction mixture was cooled to room temperature, IPE was added, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-IPE to give the title compound as a white powder (899 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH2:14][C:15]3([CH3:20])[O:19][CH2:18][CH2:17][O:16]3)[C:10](=[O:21])[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:28]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:20][C:15]1([CH2:14][CH2:13][CH2:12][NH:11][C:10]([C:9]2[NH:8][C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:6]3[C:5]=2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28]3)=[O:21])[O:19][CH2:18][CH2:17][O:16]1
Reactant: CC1(CCCN2C(=O)CN=C(c3ccccc3)c3cc(Cl)ccc32)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CCCNC(=O)c2[nH]c(-c3ccccc3)c3cc(Cl)ccc23)OCCO1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 40.0 g. of 7-chloro-1,3-dihydro-1-[3-(2-methyl-1,3-dioxolan-2-yl)-propyl]-5-phenyl-2H-1,4-benzodiazepin-2-one in 500 ml. of dimethylformamide is treated under an atmosphere of argon at room temperature with 0.115 mol. of sodium hydride (5.1 g. of a 55% dispersion in mineral oil). The mixture is warmed to 60° C. over a period of about 30 minutes, then stirred at this temperature for 1 hour and thereafter at 70° C. for an additional hour. After cooling, 10 ml. of water are added dropwise and the mixture is poured on to 4 liters of ice-water. After the addition of 150 g. of sodium chloride, the separated product is removed by filtration, washed with water and dissolved in methylene chloride. The organic solution is dried over sodium sulfate and concentrated to dryness. The residue is chromatographed on 1000 g. of silica gel using methylene chloride/ethyl acetate (4:1) for the elution. The homogeneous fractions are combined and evaporated. The residual oil crystallizes upon trituration with hexane, and there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid [3-(2-methyl-1,3-dioxolan-2-yl)propyl]amide in the form of yellowish crystals having a melting point of 157°-159° C. Recrystallization from ethanol does not increase the melting point.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=[CH:10][C:2]=12>CCOC(C)=O.[Pd]>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:2]=12
Reactant: CCOC(=O)N1C=Cc2nccnc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCc2nccnc2C1

Procedure:
To a solution of ethyl pyrido[3,4-b]pyrazine-6(5H)-carboxylate (149 mg, 0.726 mmol) in EtOAc (25 mL) is added 10% Pd/C (100 mg). The mixture is hydrogenated at 30 psi. overnight. The mixture is filtered through Celite and the solvent removed under vacuum to yield the title compound. MS (+VE) m/z 208.16 (M++1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:35])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][C@@H:18]1[C@@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])[C@H:21]([OH:33])[CH2:20][C@@H:19]1[OH:34].C(Cl)(Cl)Cl.O1CCCC1>C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:35])[CH2:12][CH2:13][CH2:14][CH:15]([Br:1])[CH:16]1[O:34][C@H:19]2[CH2:20][C@@H:21]([OH:33])[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])[C@H:18]2[CH2:17]1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCCCl)[C@H](O)C[C@@H]1O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCC(Br)C1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCCCl)[C@H](O)C[C@@H]2O1
Yield: 78.8 %

Procedure:
Under an atmosphere of nitrogen, 85 mg of N-bromosuccinimide were added to a solution of 175 mg of (5Z,13E)-(9α,11α,15S)-9,11,15-trihydroxy-20-chloroprosta-5,13-dienoic acid methyl ester [prepared as described in Example 4 of British Patent Application No. 22090/75 and, e.g. the equivalent Belgian Specification No. 842113] in 3 ml of a mixture of chloroform and tetrahydrofuran (1:1) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:2) as eluent to give 165 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH:1]1[C:2]2[CH:22]=[CH:21][C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH:13]=[CH:12][C:11]=3[C:3]=2[O:4][C:5]=1[C:6](OCC)=[O:7].[BH4-].[Li+].C1COCC1.Cl>O>[CH:1]1[C:2]2[CH:22]=[CH:21][C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH:13]=[CH:12][C:11]=3[C:3]=2[O:4][C:5]=1[CH2:6][OH:7]
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2o1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2ccc3c4ccccc4ccc3c2o1
Yield: 90.3 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet tube with bubbler was added ethyl phenanthro(1,2-b]furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 7.9 g, 27.2 mmol), lithium borohydride (Aldrich, 0.65 g, 30 mmol) and dry THF (400 mL). The mixture was stirred at reflux for 6 h and then poured into H2O (1 L). The reaction mixture was acidified with 1N HCl and the resulting white solid was filtered, washed with additional H2O (1500 mL) then dissolved in CH2Cl2 (500 mL), dried (Na2SO4), filtered, concentrated to 200 mL and diluted to 500 mL with hexane. The resulting material was filtered, washed with hexane (100 mL) and placed in a vacuum oven overnight. A total of 6.1 g (90.1%) of phenanthro[1,2-b]furan-2-methanol, mp 125°-126° was obtained (C,H).