Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]([CH3:29])[C@:16]2([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:31])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O.Cl>N1C=CC=CC=1>[C:32]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([Cl:1])[CH2:22]2)[C@:4]2([CH3:31])[C:9](=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]2)[CH2:10][CH2:11]3)[CH2:14][C@@H:15]1[CH3:29])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)O[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C

Procedure:
A solution of 11β-chloro-21-hydroxy-16β-methyl-17-propionyloxypregna-1,4-diene-3,20-dione (75 mg) in pyridine (1 ml) was treated with acetic anhydride (0.2 ml) at room temperature. After 3 hours water (0.4 ml) was added and the solution was poured into dilute by hydrochloric acid. The precipitated solid was removed by filtration and after drying was recrystallized from methanol to give the title compound, m.p. 212°-213°(K), [α]D + 101.1° (c 0.6 chloroform). λmax 239 nm (ε 16,280) (Found: C, 65.7; H, 7.0; Cl, 6.8. C27H35ClO6 requires C, 66.0; H, 7.2, Cl, 7.2%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].Cl.[NH2:37][CH2:38][CH2:39][N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42].C[O-].[Na+]>CCO>[CH3:44][S:41]([N:40]([CH3:45])[CH2:39][CH2:38][NH:37][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[CH:8]2)=[O:4])(=[O:43])=[O:42]
Reactant: CN(CCN)S(C)(=O)=O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 53.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (38.5 mg, 0.083 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (78 mg, 0.42 mmol), and NaOMe (22 mg, 0.42 mmol) in EtOH (3 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 26 mg of the title compound. MS: (+) m/z 584.26 (M+1).
Reaction SMILES: [C:1]([CH2:5][C:6](OCC)=[O:7])(=O)[CH2:2][CH3:3].FC(F)(F)C(O)=O.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:28]=[C:27]([CH:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[NH:36])[NH2:35])[O:26][N:25]=1.C[O-].[Na+]>C(O)CCC>[CH2:2]([C:1]1[N:35]=[C:34]([N:30]2[CH2:31][CH2:32][CH2:33][CH:29]2[C:27]2[O:26][N:25]=[C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH:28]=2)[N:36]=[C:6]([OH:7])[CH:5]=1)[CH3:3]
Reactant: N=C(N)N1CCCC1c1cc(-c2ccccn2)no1
Reactant: CCOC(=O)CC(=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: CCc1cc(O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Yield: 44.5 %

Procedure:
A mixture of ethyl propionylacetate (350 mg, 2.4 mmol), 2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidine-1-carboximidamide trifluoroacetate salt (Method 38) (901 mg, 2.43 mmol), sodium methoxide (144 mg, 7.7 mmol), in butanol (10 ml) was heated at 120° C. for 18 hours. The mixture was allowed to cool and poured directly on to an isolute SCX2 ion exchange column. The column was eluted with DCM/methanol (4:1) to remove neutrals and then with 7M methanolic ammonia to elute the product. The solvent was evaporated and the residue purified by chromatography on silica gel eluting with DCM/methanol (98:2 increasing in polarity to 95:5) to give the title compound (360 mg, 46%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([CH2:23][C:24]#[N:25])[CH:16]=1)[CH3:2].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27](=[O:28])[N:3]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:16]=[C:17]([CH2:23][C:24]#[N:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:1][CH3:2])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetonitrile and benzyl chloroformate. M+H is 483.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.289g. of valeric acid chloride as in Example 1. The 0.590 g. of brownish colored turbid oil obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.518 g. of a colorless, turbid oil which crystallizes upon trituration. It is recrytallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl valerate obtained melts at 36.5°-36.9° and has a clearing point of 61.7°. UV (EtOH): ε 271 = 25800.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:35]=[CH:34][C:19]([CH2:20][N:21]5[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:38])[CH:3]=1.[C:39]1([CH2:45][C:46]([N:48]=[C:49]=[S:50])=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CCO.C1(C)C=CC=CC=1>[F:38][C:4]1[CH:3]=[C:2]([NH:1][C:49]([NH:48][C:46](=[O:47])[CH2:45][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[S:50])[CH:37]=[CH:36][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[CH:34][CH:35]=3)[S:15][C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cc2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cc4)sc23)c(F)c1
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
Compound 454 (0.3323 g, 0.62 mmol) was suspended in EtOH/toluene (3 mL/3 mL) at RT and stirred for 30 min. 2-Phenylacetyl isothiocyanate (0. 165 g, 0.93 mmol) was added and the reaction mixture was stirred at RT for 1 h, quenched with MeOH (2 mL) and concentrated to dryness. The residue was purified by flash chromatography (eluent 9/1/90 MeOH/NH4OH/DCM) to give compound 450 as a white solid (60 mg, 16% yield). 1H NMR δ(400 MHz, CD3CN): 8.51 (d, J=5.5 Hz, 1H), 7.99 (dd, J=2.5, 12.3 Hz, 1H), 7.84 (s, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.32-7.53 (m, 9H), 6.62 (d, J=4.5 Hz, 1H), 3.81 (s, 2H), 3.54 (s, 2H), 2.30-2.53 (bs, 8H), 2.22 (s, 3H). LCMS: 613 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:4]([CH3:21])[C:5](=O)[NH:6][C@H:7]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:43]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C@@H:3]([C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:4]([CH3:21])[C:5]([NH:6][C@H:7]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[S:43]
Reactant: CO[C@H]([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CO[C@H]([C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 33.2 %

Procedure:
A mixture of #16 (350 mg, 0.739 mmol, 1 eq.) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson's reagent) (324 mg, 0.776 mmol, 1.05 eq.) in toluene (6 mL, 0.1 M) was warmed to 100° C. After 10 minutes, the mixture was cooled to room temperature. Insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 12% to 80% ethyl acetate in heptane) and then by reverse phase chromatography (Method E2) to give #17 (120 mg, 33%); HPLC (Protocol J): m/z 490.2 [M+H+], retention time=10.069 minutes; [α]20D—110 (c 0.24, MeOH); 1H NMR (400 MHz, CD3OD), characteristic signals: δ 7.78 (d, J=3.3 Hz, 1H), 7.51 (d, J=3.3 Hz, 1H), 7.32-7.37 (m, 2H), 7.24-7.30 (m, 2H), 7.17-7.23 (m, 1H), 6.52-6.61 (br m, 1H), 3.62 (br dd, J=15, 4 Hz, 1H), 3.37 (s, 3H), 2.98-3.09 (br m, 1H), 2.53-2.64 (br m, 1H), 1.60-1.78 (m, 2H), 1.49 (s, 9H), 1.27 (d, J=6.5 Hz, 3H).
Reaction SMILES: C([S:4][CH:5]([CH3:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1)=[O:7])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH:5]([CH3:23])[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:13][CH:14]=1)=[O:7]
Reactant: CC(=O)SC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(S)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 85.8 %

Procedure:
In 20 ml of methanol was dissolved 1.0 g of the compound obtained in Example 31. To this solution was added in a stream of nitrogen 10 ml of 1N caustic soda solution, and the mixture was reacted for 90 minutes at room temperature. The mixture was made acidic by the addition of 6-N hydrochloric acid to precipitate crystals, which were then collected by filtration and washed with methanol to obtain 750 mg of the end product. M.P. 236°-237° C. (uncorrected).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:48])[CH:6]([O:18][P:19]([CH:22]([NH:26][C:27](=[O:47])[CH:28]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:23]([CH3:25])[CH3:24])([OH:21])=[O:20])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(OCC)(=O)C>C(#N)C>[CH2:40]([O:39][C:37]([NH:36][CH:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:27]([NH:26][CH:22]([P:19]([OH:21])([O:18][CH:6]([CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:5]([OH:48])=[O:4])=[O:20])[CH:23]([CH3:25])[CH3:24])=[O:47])=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)C(CCCNC(=O)OC(C)(C)C)OP(=O)(O)C(NC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)P(=O)(O)OC(CCCNC(=O)OC(C)(C)C)C(=O)O
Reaction time: 3 h
Yield: 100.1 %

Procedure:
1 M LiOH (3.5 mL) was added to a solution of 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphinoyloxy}-5-tert-butoxycarbonylamino-pentanoic acid methyl ester (211 mg, 0.32 mmol) in acetonitrile (3.5 mL) and the mixture was stirred for 3 h. Ethyl acetate was added and the mixture was washed with 1 M HCl, dried and concentrated to give crude 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphinoyloxy}-5-tert-butoxycarbonylamino-pentanoic acid (208 mg, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[C:25]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:26]=[CH:27][C:28]([C:31]([NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=2)=[O:32])=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(OCCN)cc1)Oc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)Oc1ccccc1
Yield: 27.2 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-phenoxypropionate (666 mg), which is the product of Reference example 4, biphenyl-4-carboxylic acid (400 mg) and carbonyldiimidazole (393 mg) and the reaction mixture was treated to give the title compound (280 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CN(C)C=O>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:39][CH2:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:3][CH:4]=3)=[CH:9][C:10]([C:23]([F:26])([F:25])[F:24])=[N:11]2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
To a mixture of 5-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole (670 mg, 1.5 mmol, from step 1), triethylamine (10 mL) and dimethylformamide (2 mL) was added copper(I) iodide (15 mg, 0.08 mmol), bis(triphenylphosphine)palladium(II)chloride (105 mg, 0.15 mmol) and (trimethylsilyl)acetylene (221 mg, 2.25 mmol) at room temperature. The mixture was stirred for 4 hours at room temperature and concentrated. The concentrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (353 mg, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:6][OH:7].[CH3:14][S:15]([N:18]([CH2:37][CH2:38][Cl:39])[N:19]([S:33]([CH3:36])(=[O:35])=[O:34])[C:20](OCC1C=CC=CC=1[N+]([O-])=O)=[O:21])(=[O:17])=[O:16]>>[CH3:14][S:15]([N:18]([CH2:37][CH2:38][Cl:39])[N:19]([S:33]([CH3:36])(=[O:34])=[O:35])[C:20]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:21])(=[O:16])=[O:17]
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccccc1[N+](=O)[O-])S(C)(=O)=O
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Product: COc1cc(COC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O)ccc1[N+](=O)[O-]

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(3-methoxy-4-nitrobenzyloxy)carbonyl]hydrazine (compound 13d) was prepared from 3-methoxy-4-nitrobenzyl alcohol using a procedure similar to that described for compound 13a. The Mp was determined to be about 56-57° C., and the yield was about 29.4% by weight after recrystallization from ethanol. 1H NMR (acetone d6): δ 7.8, 7.5 and 7.2 (3H, 2d, s, aromatic H), 5.8 (2H, d, ArCH2), 3.6-4.1 (4H, m, CH2CH2Cl), 4.0 (3H, S, OCH3), 3.6 and 3.3 (6H, 2s, 2 CH3SO2).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1.C(O)(=O)C.[CH3:28][C:29]1[N:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][N:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:2][C@@H:3]1[CH2:7][N:6]([CH2:35][C:32]2[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=2)[CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1
Reactant: Cc1ncc(C=O)cn1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Temperature: 50 °C
Yield: 24.6 %

Procedure:
To a solution of 6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrogen chloride (493 mg) in 1,2-dichloroethane (10 mL) was added acetic acid (174 mg), 2-methylpyrimidine-5-carbaldehyde (236 mg) and sodium triacetoxy borohydride (635 mg). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated onto silica gel and purified by CombiFlash chromatography to provide the title compound (146 mg). 400 MHz 1H NMR (CDCl3) δ 8.63 (s, 2H), 8.01 (s, 1H), 4.82-4.76 (m, 1H), 4.12-4.08 (m, 2H), 3.68 (d, J=5.0 Hz, 3H), 3.64-3.54 (m, 2H), 3.28 (t, J=8.3 Hz, 1H), 3.04 (d, J=9.9 Hz, 1H), 2.89-2.86 (m, 1H), 2.71 (s, 3H), 2.66-2.62 (m, 1H), 2.49-2.27 (m, 3H), 1.97 (t, J=7.9 Hz, 1H), 1.91-1.83 (m, 2H), 1.19 (d, J=7.05 Hz, 3H). MS: (M+H m/z 410.2).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.[CH2:26]([Si:28](Cl)([CH2:31][CH3:32])[CH2:29][CH3:30])[CH3:27]>ClCCl>[CH3:1][O:2][CH2:3][C:4]1([CH2:17][O:18][Si:28]([CH2:31][CH3:32])([CH2:29][CH3:30])[CH2:26][CH3:27])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CC[Si](Cl)(CC)CC
Reactant: COCC1(CO)c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[Si](CC)(CC)OCC1(COC)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
1 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (4.2 mmol) was dissolved in 20 ml of dichloromethane. The solution was cooled in ice-water bath, and 0.87 ml of triethyl amine (6.2 mmol) was added thereto. After stirring for 5 minutes, 0.91 ml of triethylsilyl chloride (5.4 mmol) was added drop-wise, and the mixture was stirred for further 2 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.24 g of concentrate (yield 84%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([CH:18]=[O:19])=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:26])[CH:14]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][Mg]Br.O>C1COCC1>[CH2:1]([N:8]1[C:17]([CH:18]([OH:19])[CH3:28])=[C:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:26])[CH:14]=2)[C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) in THF (5 ml) was added dropwise a solution of methyl magnesium bromide in THF (3M, 0.5 ml) at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate-hexane to give the title compound (470 mg).
Reaction SMILES: [C:1]1([S:7]([N:10](S(C2C=CC=CC=2)(=O)=O)[C:11]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)sc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2ccccc12
Temperature: 60 °C
Yield: 60.2 %

Procedure:
A mixture of ethyl 2-[bis-(benzenesulphonyl)amino]benzo[b]thiophene-3-carboxylate (Intermediate 4, 0.173 g) and lithium hydroxide mono hydrate (0.043 g) in dioxane (6 ml) and water (3 ml) was stirred and heated at 60° C. for 2.5 hours. After cooling, the mixture was diluted with water and acidified by addition of hydrochloric acid (1M). It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane (5-10%) to give ethyl 2-benzenesulphonylaminobenzo[b]thiophene-3-carboxylate (0.075 g) as a white solid.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B.[OH-:29].[Na+].OO>O1CCCC1.O>[CH2:1]([O:17][CH2:18][CH:19]([O:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [OH-]
Reactant: C=CCCCCC(COCCCCCCCCCCCCCCCC)OC
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(CCCCCCO)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8-(hexadecyloxy)-7-methoxy-1-octene in 100 ml of tetrahydrofuran was added a solution of 112.3 ml of 1.0M borane in tetrahydrofuran at 0° C. over a 1 hour period. The mixture was stirred on addition 3 hours at 25° C. The solution was recooled to 0° C. and a solution of 187.3 ml of 3M sodium hydroxide was slowly added followed by 216 ml of 30% hydrogen peroxide. After 30 minutes, the mixture was poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was purified by chromatography giving 20 g of the title compound as a solid.