Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[CH3:18][O:19][CH2:20][CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32]([C:34]3[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=3)=[O:33])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:42]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([C:32]([NH:31][C:27]4[CH:26]=[C:25]5[C:30](=[CH:29][CH:28]=4)[N:22]([CH2:21][CH2:20][O:19][CH3:18])[C:23]([CH3:42])=[CH:24]5)=[O:33])=[CH:41][CH:40]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: COCCn1c(C)cc2cc(NC(=O)c3ccc(C=O)cc3)ccc21
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5c(c4)cc(C)n5CCOC)cc3)[nH]c2c1

Procedure:
Compound 675 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(1-(2-methoxyethyl)-2-methyl-5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C29H30N4O4: 499.24; found: 499.06.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[N+:6]([O-:22])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(C3CC3)cncc2c1
Solvent: ClCCl
Product: [O-][n+]1cc(C2CC2)c2ccccc2c1
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of 4-cyclopropylisoquinoline (0.4 g, 2.364 mmol) in DCM (10 ml) was added m-CPBA (1.224 g, 7.09 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The reaction mass was diluted with DCM and washed with water and aqueous sodium bicarbonate solution. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get desired compound (0.35 g, 80%) as solid. The crude compound was taken further without purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:12])[CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[C:15]1[N:16]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:17]2[S:18][CH:19]=1.[N:25]([O-])=[O:26].[Na+].[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:12])[CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[C:15]1[N:16]2[N:22]=[C:21]([O:23][CH3:24])[C:20]([N:25]=[O:26])=[C:17]2[S:18][CH:19]=1
Reactant: COCc1cc(OC)c(-c2csc3cc(OC)nn23)c(OC)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cc(OC)c(-c2csc3c(N=O)c(OC)nn23)c(OC)c1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A mixture of water and 5N hydrochloric acid (1:4, 70 mL) was added to 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxypyrazolo[5,1-b][1,3]thiazole (2.17 g, 6.47 mmol), and then sodium nitrite (1.06 g, 15.3 mmol) was added at 0° C. and the mixture was stirred for 1 hour. Aqueous 5N sodium hydroxide and ethyl acetate were added to the mixture at room temperature. After thoroughly shaking the mixture, the organic layer was separated and dried over anhydrous magnesium sulfate. The mixture was then filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (2.34 g, 6.44 mmol).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH3:16])[CH:8]=1.C([O-])(=O)C.[NH4+].CC(C)=O>[Cl-].[Cl-].[Cl-].[Ti+3].O>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH3:16])[CH:8]=1
Reactant: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1N
Reaction time: 12 h
Yield: 54.5 %

Procedure:
A solution of 20% titanium trichloride (8.4 g) was added to a mixture of 4-(3,5-bis-trifluoromethyl-benzyl)-2-methyl-nitrobenzene (0.44 g), ammonium acetate (9.3 g), acetone (20 ml) and water (10 ml) at room temperature and stirred for 12 hours. After the reaction, the reaction solution was extracted with ethyl acetate and washed with a saturated sodium bicarbonate solution and a saturated salt solution and then dried over anhydrous magnesium sulfate. After distilling the solvent off, the resultant residue was purified by silica gel column chromatography to obtain 4-(3,5-bis-trifluoromethyl-benzyl)-2-methylaniline (0.22 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.B(O)(O)[C:17]1[CH:22]=[N:21][CH:20]=[N:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:19]1[CH:18]=[C:17]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:22]=[N:21][CH:20]=1
Reactant: OB(O)c1cncnc1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(Oc2ccnc(-c3cncnc3)c2)cn1
Temperature: 95 °C
Yield: 21.7 %

Procedure:
A solution of Example A9 (0.25 g, 1.128 mmol) and pyrimidinyl-5-boronic acid (0.196 g, 1.579 mmol) in dioxane (8 mL) was treated with a solution of K2CO3 (0.156 g, 1.128 mmol) in water (2 mL), Pd(PPh3)4 (0.130 g, 0.113 mmol) and heated at 95° C. for 20 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-((2-(pyrimidin-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (65 mg, 22%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 2H), 9.24 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 7.84 (d, J=3.0 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.32 (dd, J=8.9, 3.0 Hz, 1H), 6.83 (dd, J=5.7, 2.4 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.04 (s, 2H); MS (ESI) m/z: 266.1 (M+H+).
Reaction SMILES: [C:1]([C@@:3]12[CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([O:21][CH3:22])[CH:15]=[CH:14][C:13]=3[C@H:12]1[C:11](=[O:23])[CH2:10][C@@:8]1([CH3:9])[C@H:4]2[CH2:5][CH2:6][C@@H:7]1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)#[N:2].C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([C@@:3]12[CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([O:21][CH3:22])[CH:15]=[CH:14][C:13]=3[C@H:12]1[CH:11]([OH:23])[CH2:10][C@@:8]1([CH3:9])[C@H:4]2[CH2:5][CH2:6][C@@H:7]1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)#[N:2]
Reactant: COc1ccc2c(c1)CC[C@]1(C#N)[C@@H]2C(=O)C[C@]2(C)[C@@H](OC3CCCCO3)CC[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@]1(C#N)[C@@H]3CC[C@H](OC4CCCCO4)[C@@]3(C)CC(O)[C@H]21
Reaction time: 1 h

Procedure:
A solution of 33.1 g of steroid 3 in 400 ml of THF was cooled to 0° C., mixed in portions with 51.0 g of LTBAH, and the solution was stirred for 1 hour while cooling was continued and for 1 hour at room temperature. 25 ml of saturated sodium bicarbonate solution was added in drops to the reaction solution at 0° C., the precipitate that was produced was separated by filtration on Celite, and the filtrate was concentrated by evaporation to a very large extent. The residue was extracted several times with ethyl acetate, the collected organic phases were then washed with brine, dried on magnesium sulfate, and the solvent was removed in a vacuum. In this way, 27.6 g (97%) of foamy 4 was obtained, which was used without further purification in the next stage.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7](S(C2C=CC=CC=2)(=O)=O)[C:8]2[C:13]([C:14]=1[S:15]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:17])=[O:16])=[CH:12][C:11]([Br:30])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.O>[Br:30][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]2[S:15]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:16])=[O:17]
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCCCC(=O)OC(C)(C)C)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCCCNS(=O)(=O)c1c(C(=O)O)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl-5-bromo-3-{[(5-tert-butoxy-5-oxopentyl)amino]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate (63 mg, 0.98 mmol) in 2 mL of 3:1 THF/water was added NaOH (2 pellets). After stirring at room temperature for 6 hours, another portion of NaOH was added. After 16 hours, the reaction was partitioned between 3N HCl and dichloromethane. The aqueous phase was extracted three times with dichloromethane, and the combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo to give the titled product as a white foam. ESI+ MS: 419 [M-CH2═CMe2]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][CH2:26][CH2:27][S:28]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[CH3:37][N:34]1[CH2:33][CH2:32][N:31]([S:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][CH:3]=2)(=[O:30])=[O:29])[CH2:36][CH2:35]1
Reactant: CN1CCN(S(=O)(=O)CCCCl)CC1
Reactant: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Product: CN1CCN(S(=O)(=O)CCCOc2cccc3c2N=C(NC(=O)c2cccnc2)N2CCN=C32)CC1

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-(7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Intermediate C) and 1-[(3-chloropropyl)sulfonyl]-4-methylpiperazine (Intermediate D). High vacuum drying at 60° C. gave the title compound (72 mg, 57%): HPLC MS RT=1.22 min, MH+=512.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.26-2.31 (2H, m), 2.82 (3H, s), 3.11-3.21 (4H, m), 3.45-3.50 (4H, m), 3.83-3.87 (2H, m), 4.27-4.34 (2H, m), 4.42 (2H, t), 4.58-4.65 (2H, m), 7.60 (1H, t), 7.73 (1H, d), 7.85 (1H, d), 7.94 (1H, dd), 8.86 (1H, d), 9.00 (1H, dd), 9.48 (1H, d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:19]1([CH2:20][CH2:21][CH:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:17][CH2:18]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)C1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Temperature: 60 °C
Yield: 73.8 %

Procedure:
To a 50 mL round bottom flask is added 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol), followed by 4-tert-butylcyclohexanone (1.43 g, 9.3 mmol). MeOH (20 mL) is added to give a clear solution, followed by pyrrolidine (1 mL). A condenser is attached to the RB flask, and the resulting solution is heated at 60° C. for two hours. MeOH is removed and the residue is redissolved in EtOAc (30 mL), washed with 1 N NaOH (10 mL), and 1 N HCl (10 mL), and dried over Na2SO4. Solvent is removed in vacuo to give 6-bromo-4′-t-butylspiro[chroman-2,1′-cyclohexan]-4-one (2.41 g, 74%), which is used for the next step without purification.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[C:27]([OH:28])=[CH:26][C:20]4[O:21][CH2:22][CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:27]([OH:28])=[CH:26][C:20]4[O:21][CH2:22][CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCCCO2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc3c(cc2O)OCCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1,3-dihydro-2H-indol-2-one was obtained (91%) as an off-white powder: mp 193-195° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.65 (br s, 1H), 7.39-7.27 (m, 9H), 7.23-7.20 (m, 2H), 7.13-7.04 (m, 2H), 6.96 (s, 1H), 6.73 (s, 1H), 6.60 (s, 1H), 6.53-6.50 (m, 1H), 5.09 (s, 1H), 4.25-3.99 (m, 4H), 2.22-2.06 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.9, 151.7, 151.6, 145.3, 143.3, 137.4, 137.1, 128.9, 128.8, 128.6, 128.4, 128.2, 128.0, 126.5, 126.1, 123.1, 120.2, 118.2, 112.9, 112.0, 71.0, 70.8, 58.9, 47.2, 32.3; MS (ES+) m/z 464.0 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH3:31][N:32]([CH3:42])[C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[CH3:31][N:32]([CH3:42])[C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:9]([CH2:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH:24]4[S:28][C:27](=[O:29])[NH:26][C:25]4=[O:30])=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:8])=[O:38])=[CH:35][CH:34]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccc(N(C)C)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 500 mg (3 mmol) of 4-dimethylaminobenzoyl chloride, and after purification, 200 mg (20%) of 4-dimethylamino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methylbenzamide, with a melting point of 100° C., are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.Cl.[NH2:16][CH2:17][C:18]#[C:19][CH3:20].O1CCCC1>C(N(CC)CC)C>[CH3:20][C:19]1[C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:12][C:11]=2[N:16]=[CH:17][CH:18]=1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2ccncc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1C(=O)CC(c1ccncc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.9 %

Procedure:
To a mixture of 5-(4-pyridyl)cyclohexane-1,3-dione (0.90 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.48 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 15 hours and cooled, insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 3.5 hours at 220° C. and cooled, to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/MeOH) to give oil of 4-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.1 g).
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[CH3:35][CH:36]([CH3:75])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][C:68]5[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=5)=[CH:63][CH:62]=4)=[O:59])=[CH:53][CH:52]=3)=[CH:47][CH:48]=2)[C:43]1=[O:74])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:75])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][C:68]5[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=5)=[CH:63][CH:62]=4)=[O:59])=[CH:55][CH:56]=3)=[CH:47][CH:48]=2)[C:43]1=[O:74])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Oc5ccccc5)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Oc5ccccc5)cc4)cc3)cc2C1=O
Yield: 71.9 %

Procedure:
The compound of example 50 was prepared analogous to compound of example 8 by hydrolysis of compound of example 49.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:35])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH3:34])=[O:28])[C:23]([OH:25])=[O:24].[CH2:36]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:35])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH3:34])=[O:28])[C:23]([O:25][CH3:36])=[O:24]
Reactant: Cc1ccsc1C(=O)O[C@]1(C(=O)O)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Reactant: C1CCC2=NCCCN2CC1
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(OC(=O)c2sccc2C)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (11.1 g) is dissolved in ethyl acetate (200 mL). DBU (4.05 g) and dimethyl sulphate (3.36 g) are added sequentially and the reaction mixture is stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over magnesium sulphate and evaporated. Crystallisation from methanol affords 3-methylthiophene-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 0.90 (3H, d), 0.92 (3H, s), 1.40 (3H, s), 2.40 (3H, s), 3.65 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]=1[O:13][C:14]1[CH:31]=[CH:30][C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22][C:16]=2[CH:15]=1.[OH-].[Na+].Cl>C(O)C>[CH3:29][C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][C:17]2[CH:30]=[CH:31][C:14]([O:13][C:4]3[CH:5]=[CH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:3]=3[O:2][CH3:1])=[CH:15][C:16]=2[CH2:22][CH2:21]1)=[O:24])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Oc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
1,1-Dimethylethyl 7-({2-(methyloxy)-4-[(methyloxy)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E264, Step 3) (240 mg, 0.56 mmol) was dissolved in ethanol (2 ml), treated with 2M sodium hydroxide (1 ml) and the resulting mixture was stirred for 1.5 hours. The mixture was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated in vacuo to afford the title compound (0.15 g); MS (ES+) m/e 314 [(M+H)—CO2tBu]+.
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][N:2]=1.[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>S(Cl)(Cl)=O.N1C=CC=CC=1>[C:1]1([C:14]([O:16][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:12])=[CH:3][N:2]=1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=C(O)c1cnc(C(=O)O)c2ccccc12
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)c1cnc(C(=O)OCCCCCCCCCCCCCCCC)c2ccccc12
Reaction time: 19 h

Procedure:
Isoquinoline-1,4-dicarboxylic acid (1.8 g, 5 mmol) is refluxed in 10 ml of thionyl chloride for 2 h. The solution is evaporated to dryness and the residue dissolved in 20 ml of dichloromethane. The latter solution is added dropwise to a mixture of 1-hexadecanol (2.90 g, 12 mmol) in 1 ml of pyridine. After 19 h at room temperature, the precipitate is filtered off and the filtrate is evaporated to dryness. The resulting residue is crystallized in toluene/ethanol. The crystals obtained are purified by silica gel flash-column chromatography (dichloromethane). Thus the title compound, m.p. 80.7°-81.4°, is obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([C:14]([O:16]C)=[O:15])[CH:5]=1.O.Cl>CO>[CH3:3][C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(C)c2[nH]c(=O)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 mL 4N aqueous sodium hydroxide solution were added to 5.00 g (24.1 mmol) methyl 4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carboxylate in 50 mL MeOH and the mixture was stirred for 24 h at RT. Then 10 mL of 4N aqueous sodium hydroxide solution were added and the mixture was stirred for a further 8 h at RT. Then the MeOH was eliminated i.vac., water was added and while cooling with ice the mixture was acidified with conc. hydrochloric acid solution until a precipitate formed. This was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH3:1][N:2]1[CH:20]=[N:19][C:18]2[N:7]([C@@H:8]3[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:9]3[O:10][CH3:11])[CH:6]=[N:5][C:4]=2[C:3]1=N.CN1C=NC2N([C@@H]3O[C@H](CO)[C@@H](OC)[C@H]3O)C=NC=2C1=N.[S-2:43].[Na+].[Na+]>CN(C)C=O>[CH3:1][N:2]1[CH:20]=[N:19][C:18]2[N:7]([C@@H:8]3[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:9]3[O:10][CH3:11])[CH:6]=[N:5][C:4]=2[C:3]1=[S:43]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=N)n(C)cnc21
Reactant: [S-2]
Agent: CO[C@H]1[C@@H](O)[C@H](n2cnc3c(=N)n(C)cnc32)O[C@@H]1CO
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=S)n(C)cnc21

Procedure:
Reaction Scheme 2 discloses the presently preferred method for preparing 1-N-,2'-O-dimethyl-6-thioinosine (Compound 25). In accordance with this method, adenosine (Compound 20) is reacted with methylchloride in a polar aprotic solvent, such as dimethylformamide (DMF) or dimethylacetamide (DMA) in the presence of strong base, such as sodium hydride. The resulting 2'-O-methyl adenosine is reacted, without isolation, with iodomethane to introduce the methyl group to the 1-N-position. After the treatment with iodomethane a crude product is obtained which contains approximately 60% of the desired 1-N-,2'-O-dimethyladenosine intermediate, and also contains some 1-N-,3'-O-dimethyladenosine as well as monomethylated derivatives. The crude product is reacted at a moderately elevated temperature (approximately 45° C.) with anhydrous sodium sulfide in anhydrous dimethylformamide, and the resulting crude product is purified by chromatography to yield the desired 1-N-,2'-O-dimethyl-6-thioinosine (Compound 25). ##STR7##