Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.C[C@H](NC)[C@@H](O)C1C=CC=CC=1.O.Cl>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: CN[C@@H](C)[C@@H](O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)[C@@]12C[C@@H](c3ccccc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a solution of racemic 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (100 g; 0.37M) in ethyl acetate (1.5L) and methanol (75mL) was added solid (1S,2S)-(+)-pseudoephedrine (61.1 g; 0.37M). With efficient agitation the mixture was warmed to reflux, held for 30 minutes and slowly cooled to 25° C. After a minimum of 2 h the slurry was filtered and washed with ethyl acetate to yield enriched diastereomeric salt (88.6 g; 0.20M; 55%; diastereomeric ratio 80:20, as determined by HPLC). The enriched salt was slurried in 3% methanolic ethyl acetate (2.74 L),warmed to reflux,held 30 minutes,cooled to 25 C. slowly, held 2 h and then filtered and washed with ethyl acetate to provide further enriched salt (70 g; 0.16M; 79%; diastereomeric ratio 95:5, as determined by HPLC). Treatment of the further enriched salt with 5% methanolic ethyl acetate using the same procedure yielded highly enriched salt (60.0 g; 0.14M; 85%; diastereomeric ratio 99:1, as determined by HPLC). This salt (60 g; 0.14M) was added to water (1L) and the consequent suspension acidified to pH 2-3 with concentrated hydrochloric acid (15 mL) and then extracted with diethyl ether (3×500 mL). The combined organic extracts were washed with brine,dried (MgSO4) and evaporated to an oil. Hexane was added and evaporated to afford enantiomerically enriched acid (36 g; 0.13M; 98% recovery; enantiomeric ratio 99:1, as determined by HPLC) as a white solid. Crystallisation from a mixture of hexane (360 mL) and cyclohexane (720 mL) afforded enantiomerically pure (9S,10S)-2-chloro-9,10-dihydro-9,10-methano-9-anthracene-carboxylic acid as a white solid (30 g, 0.11 mol, 81%) mp 172°-173° C. αD =+101° (c=2.0,CHCl3).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[NH:20]2)=[CH:9]1)(C)(C)C.Br[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[O:28]=[S:21]1(=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:19]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[CH:9]=2)[N:20]1[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Product: COc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1CCc1ccccc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 4, step c) and 2-bromoethylbenzene. 1H NMR (DMSO-d6) 13.03 (bs, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.65-7.60 (m, 2H), 7.50 (s, 1H), 7.29 (d, J=9.0 Hz, 1H), 7.25-7.13 (m, 4H), 7.09 (d, J=8.1 Hz, 2H), 6.74 (dd, J=2.4, 9.0 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 5.95 (s, 1H), 5.00 (s, 2H), 3.51 (s, 3H), 3.42 (ddd, J=6.3, 10.2, 15.9 Hz, 1H), 3.14 (ddd, J=5.7, 9.9, 15.0 Hz, 1H), 3.00-2.70 (m, 2H); MS: ESI (negative): 475 (M−H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[O:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])[CH3:26].CCN=C=NCCCN(C)C>>[OH:24][C:13]1([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:14][CH2:15][CH:10]([N:8]2[CH2:9][CH:6]([NH:5][C:3]([CH2:2][NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([O:25][CH3:26])[CH:28]=3)=[O:4])[CH2:7]2)[CH2:11][CH2:12]1
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Agent: CCN=C=NCCCN(C)C
Product: COc1cccc(C(=O)NCC(=O)NC2CN(C3CCC(O)(c4ccc(OC)nc4)CC3)C2)c1

Procedure:
The title compound was prepared as yellow solid from 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and 3-methoxylbenzoic acid (Aldrich) by EDCI coupling using the procedure described in Step C of Example 16.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[C:11]([O:24]C)[CH:10]=3)[CH3:2].[H-].[Na+].C(S)CCC.Cl>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[C:11]([OH:24])[CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCc3ccccc3)c3ccc(OC)cc3nc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCS
Product: CCn1ncc2c(NCc3ccccc3)c3ccc(O)cc3nc21
Temperature: 0 °C
Yield: 37.7 %

Procedure:
1-Ethyl-7-methoxy-N-(phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (4 g, 0.012 mol) in DMF (70 ml) was treated with 60% NaH (2.4 g, 0.06 mol), followed by butane thiol (5.4 g, 0.06 mol). The reaction mixture was refluxed overnight and then was poured into ice-water. The mixture was acidified with 2N HCl and then was extracted with ethyl acetate (2×500 ml). The aqueous layer was treated with solid NaHCO3 to adjust the pH to about 8, then the mixture was extracted with ethyl acetate (2×500 ml). The ethyl acetate layers were combined, washed with water, filtered and evaporated. The solid residue was recrytstallized from ethyl acetate (2×) to afford 1.44 g of 1-ethyl-7-hydroxy-N-(phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 252°-254° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16]1)(C)(C)C.[Cl:28]CCl>>[ClH:28].[F:26][C:23]1[N:22]=[CH:21][C:20]([N:17]2[CH2:18][CH2:19][C@H:15]([NH2:14])[CH2:16]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(F)nc2)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@H]1CCN(c2ccc(F)nc2)C1
Reaction time: 1 h
Yield: 70 %

Procedure:
Add trifluoroacetic acid (5 mL) to a solution of [1-(6-fluoropyridin-3-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (840 mg, 3.0 mmol) in dichloromethane (5 mL). Stir for 1 h then concentrate to dryness. Dissolve the residue in methanol and pass through a column of Dowex® 1x2-200 (Cl− form). Concentrate the residue and crystallize from methanol and acetone to give (S)-1-(6-fluoropyridin-3-yl)-pyrrolidin-3-ylamine hydrochloride as a tan solid (453 mg, 70%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:10]([C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([N:25]([OH:27])[CH3:26])=[O:24])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(Cl)Cl>[CH3:8][C:9]1[N:10]([C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([N:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[O:24])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)N(C)O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ON(C)C(=O)/C=C/c1ccc(-n2c(C)ccc2C)cc1
Reaction time: 0.25 h

Procedure:
Triethylamine (2.06 g) is added to a mixture of 5.0 g of (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-N-hydroxy-N-methyl-2-propenamide in 100 ml of methylene chloride and the mixture is stirred for 15 minutes. Acetic anhydride (2.07 g) is added and the mixture is stirred at room temperature overnight. The reaction mixture is washed with water and sodium bicarbonate solution, the organic layer is separated, treated with charcoal, dried and evaporated to dryness. The residue is crystallized from ethanol, water (1:1) to yield (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-N-acetoxy-N-methyl-2-propenamide, m.p. 120°-121°.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22](N(OC)C)=[O:23])[CH2:16][CH2:15]2)[C:7](=[O:28])[C:6]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]#[N:43])=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4].[CH3:44][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:15][CH2:16][C@H:17]([O:20][CH2:21][CH:22]([OH:23])[CH3:44])[CH2:18][CH2:19]2)[C:7](=[O:28])[C:6]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]Br
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Reaction time: 1 h

Procedure:
To a solution of 2-[(trans-4-{7-butyl-6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.30 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 0.74 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (6 mL), and sodium borohydride (0.020 g) was added at 0° C. After stirring at 0° C. for 30 min, ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.27 g, 98%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(OCC)C>ClCCl>[CH3:1][N:2]([C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To an ice bath cooled solution of N-methylaniline (536 mg) in dichloromethane (30 ml) were added triethylamine (0.837 ml) and p-nitrobenzoyl chloride (982 mg) and the mixture was stirred at ambient temperature for 3 hours. The solution was washed successively in 1N hydrogen chloride, saturated aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oil and the oil was solidified with diethyl ether to give N-methyl-N-(4-nitrobenzoyl)aniline (1.11 g) as a pale yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])[CH:20]=[CH:21][C:22]=2[OH:24])[CH2:17][CH2:16][C:15]1=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.S([O-])(O)(=O)=O.[K+]>O.CS(C)=O>[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])[CH:20]=[CH:21][C:22]=2[O:24][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:17][CH2:16][C:15]1=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=O)C(Cc2ccc(O)c3c2CCC(=O)N3Cc2ccccc2)S1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccccc3)c3c2CCC(=O)N3Cc2ccccc2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
55.5 mg of potassium tert-butoxide was added to a DMSO solution (1 ml) of 90 mg of 5-(1-benzyl-8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione, followed by stirring at room temperature for 1 hour. 30 μl of benzyl bromide was added thereto, followed by stirring at room temperature for 1 hour. Water was added to the reaction liquid, potassium hydrogensulfate was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by preparative silica gel thin layer chromatography (dichloromethane:methanol=20:1), giving 84.5 mg (76% yield) of 5-(1-benzyl-8-benzyloxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione as a colorless amorphous solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:10][CH2:11][CH2:12][O:13]CCO)[CH3:9].[CH:17]1(N=C=NC2CCCCC2)CCCC[CH2:18]1>>[CH2:17]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[O:7][CH2:9][CH2:8][O:10][CH2:11][CH2:12][OH:13])[CH3:18]
Reactant: CCOCCOCCO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Oc1ccccc1
Product: CCc1ccccc1OCCOCCO

Procedure:
Phenol (13.1 g, 0.28 mol), 15 g (0.33 mol) diethylene glycol monoethyl ether and 31.g (0.31 mol) N,N'-dicyclohexylcarbodiimide are heated for 24 hours at 100°-110° C. After cooling, the mixture is extracted with ether and dried. Evaporation of the reaction mixture and flash chromatography of the residue yields 12.6 g (30%) of phenolic ether.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([CH:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)O)[CH:14]=1.[OH-].[Na+]>C(Cl)Cl.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([CH:14]=1)[CH2:15][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(Br)cc1C(O)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Br)cc1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.7 %

Procedure:
3.06 g (80.89 mmol, 10.48 eq.) NAB4 (granules) were added slowly to 50 ml Trifluoroacetic acid at 0° C. To this mixture a solution of 2.65 g (7.72 mmol) (5-Bromo-2-methoxy-phenyl)-napthalen-1-yl-methanol (62) in 30 ml dry CH2Cl2 was added which led to an brownish mixture. After stirring this mixture for 19 h at r.t. it was diluted with water and cooled again to 0° C. At this temperature NaOH-pellets were added carefully to adjust the pH to 10 before the solution was extracted with ether. The comb. org. fractions. were washed with brine, dried over Na2SO4 and evaporated. Column chromatography (CH2Cl2) yielded 2.42 g (7.39 mmol, 95.72%) 1-(5-Bromo-2-methoxy-benzyl)-naphthalene (63) as a pale yellow oil. Rf (CH2Cl2)=0.73. 1H-NMR (400 MHz, CDCl3): δ=3.84 (s, 3H, OMe), 4.35 (s, 2H), 6.76 (d, 1H, J=8.72 Hz), 6.91 (d, 1H, J=2.53 Hz), 7.20 (dm, 1H, J1=6.82 Hz), 7.26 (dd, 1H, J1=8.84 Hz, J2=2.53 Hz), 7.38 (m, 1H), 7.41-7.49 (m, 2H), 7.74 (d, 1H, J=8.34 Hz), 7.84 (m, 1H), 7.91 (m, 1H). MS (EI): m/z=329 (18), 328 (97), 327 (20), 326 (100), 248 (16), 247 (35), 232 (22), 231 (25), 216 (20), 215 (41), 203 (17), 202 (25), 142 (21), 141 (61), 115 (10), 101 (14). HR-MS (EI): Calcd. for C18H15BrO: 326.030626. Found: 326.030567.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3].I[CH3:20]>[Ag]=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([O:12][CH3:20])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](O)C[C@H]1C=C(C)C(C)=O
Reactant: CI
Agent: O=[Ag]
Product: C=CCOC(=O)N1C[C@@H](OC)C[C@H]1C=C(C)C(C)=O
Reaction time: 48 h

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (4.00 g) in iodomethane (20 ml) was added silver oxide (20 g), and the mixture was allowed to stand at ambient temperature for 2 days. The resulting precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel (50 ml) eluting with a mixture of n-hexane and ethyl acetate (6:4 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-methoxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (2.31 g).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:8][OH:9])[CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH:20]1[CH2:23][N:22]([C:24]([C:26]2[O:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:29][N:30]=2)=[O:25])[CH2:21]1)[CH:14]=O.[Na].[C:38]([O-])(O)=[O:39].[Na+]>ClCCl.C1COCC1>[OH:9][CH2:8][C:3]1([CH3:2])[CH2:7][CH2:6][N:5]([CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:19][CH:20]3[CH2:23][N:22]([C:24]([C:26]4[O:27][C:28]([C:31]5[CH:32]=[CH:33][C:34]([O:39][CH3:38])=[CH:35][CH:36]=5)=[N:29][N:30]=4)=[O:25])[CH2:21]3)=[C:11]([CH3:10])[CH:12]=2)[CH2:4]1
Reactant: Cc1cc(C=O)ccc1OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: CC1(CO)CCNC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC(C)(CO)C5)cc4C)C3)o2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Intermediate 84A (0.095 g, 0.63 mmol) was dissolved in dichloromethane (6 mL), THF (1 mL) and TEA (0.106 mL, 0.76 mmol). Intermediate 74A (0.120 g, 0.31 mmol) was added and the mixture stirred at RT for 5 min. and then sodium triacetoxyhydroborate (0.129 g, 0.61 mmol) was added. The mixture was stirred at RT for 21 h. Aqueous NaHCO3 (8%, 6 mL) was added and the mixture was filtered through a phase separator, dichloromethane (4 mL) was added and the solvent was removed by evaporation. The product was purified by preparative HPLC under basic conditions followed by lyophilisation to give (0.106 g, 71%). 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 3H), 1.57-1.71 (m, 1H), 1.95-2.42 (m, 6H), 2.8-3.09 (m, 2H), 3.3-3.41 (m, 1H), 3.44-3.59 (m, 3H), 3.89 (s, 3H), 4.27-4.38 (m, 1H), 4.59-4.83 (m, 2H), 5-5.22 (m, 2H), 6.44 (d, 1H), 6.96-7.17 (m, 4H), 8.10 (d, 2H), MS (APCI+) m/z 493 [M+H]+, LC Purity: 91%.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([OH:18])[C:5]([NH:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1C=CC=CC=1.[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]2[O:18][C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][C:5]2=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=1
Reactant: CC(C)(C)C(=O)Nc1c(C(=O)O)cc(Br)c([N+](=O)[O-])c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1nc2c(C(=O)O)cc(Br)c([N+](=O)[O-])c2o1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
5-Bromo-2-(2,2-dimethylpropionylamino)-3-hydroxy-4-nitrobenzoic acid (I-221) (1.90 g, 5.26 mmol) was dissolved in benzene (38 ml), then p-toluenesulfonic acid monohydrate (1.00 g, 5.26 mmol) was added at room temperature. Under nitrogen atmosphere, the reaction liquid was heated under reflux for 21 hours, then cooled to room temperature. The reaction liquid was fractionated with ethyl acetate and saturated brine. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was removed by filtration, the solvent was evaporated away and the resulting residue was purified by middle-pressure liquid chromatography (eluent, ethyl acetate:methanol=4:1) to obtain the entitled compound (1.80 g, 98%) as a brown solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:33])[CH2:17][N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]([CH3:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:12]=[CH:11][C:10]=2[OH:34])=[O:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CC(C)=O>[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:33])[CH2:17][N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]([CH3:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:12]=[CH:11][C:10]=2[O:34][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:6])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)CC(=O)OC)ccc(O)c2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)CC(=O)OC)ccc(OCc3ccccc3)c2[nH]1

Procedure:
48.8 g of 4-[N-benzyl-N-(2-methoxycarbonyl-1-methylethyl)aminoacetyl]-7-hydroxyindole-2-carboxylic acid ethyl ester hydrochloride, 41.4 g of potassium carbonate, and 25 ml of benzyl bromide are heated under reflux for 6 hours in 900 ml of acetone. After cooling, the reaction mixture is concentrated to dryness, the residue is taken up in ethyl acetate and saturated sodium bicarbonate solution, the organic phase is separated and extracted three times with saturated sodium bicarbonate solution. The organic phase is washed with water, dried, concentrated, and the residue is recrystallized from ethyl acetate/n-hexane, thus obtaining 42.5 g of 4-[N-benzyl-N-(2-methoxycarbonyl-1-methylethyl)aminoacetyl]-7-benzyloxyindole-2-carboxylic acid ethyl ester, mp 120°-123° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][NH2:17])=[NH:15])[CH:9]=2)[N:5]=[C:4]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[C:3]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37].C[N:39](C)C=O.Cl.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[NH:15][N:39]=[N:17][N:16]=3)[CH:9]=2)[N:5]=[C:4]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[C:3]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C(=N)NN)c2)nc1NS(=O)(=O)c1ccc(C)cn1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(-c3nnn[nH]3)c2)nc1NS(=O)(=O)c1ccc(C)cn1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
20 g (37 mmol) of 5-methyl-pyridine-2-sulfonic acid [6-chloro-2-[2-(hydrazino-imino-methyl)-pyridine-4-yl]-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide were added to 160 ml of N,N-dimethyl formamide. To this solution was added dropwise 23 ml of 6 N aqueous hydrochloric acid at a temperature of 15° C. Then a solution containing 5.1 g (74 mmol) of sodium nitrite in 20 ml de-ionized water was added slowly. The reaction mixture was allowed to warm up to 20° C. and was stirred for 1.5 hr. Then 160 ml of de-ionized water were added and the suspension was stirred for 1 hr. The solid was filtered off under suction, washed with 100 ml of de-ionized water and dried at 50° C., 2000 Pa for 17 hr. There were obtained 18.9 g (92% of theory) of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl]-amide with a HPLC purity of 89.6% (w/w).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[N:3]=1.[S:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][NH2:17].C(N(CC)CC)C.[NH2:25][NH2:26]>CS(C)=O>[F:8][C:7]1[C:2]([NH:25][NH2:26])=[N:3][C:4]([CH3:10])=[N:5][C:6]=1[NH:17][CH2:16][C:12]1[S:11][CH:15]=[CH:14][N:13]=1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: NN
Reactant: NCc1nccs1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(NN)c(F)c(NCc2nccs2)n1
Temperature: 25 °C
Yield: 38 %

Procedure:
4,6-Dichloro-5-fluoro-2-methylpyrimidine (180 mg, 1 mmol) was dissolved in 1 mL of DMSO and stirred at room temperature. (1,3-Thiazol-2-ylmethyl)amine (124 mg, 1.1 mmol) was added, followed by triethylamine (150 μL, 1.1 mmol). The resulting reaction mixture was stirred for 3 h, then hydrazine was added (1.0 mL), and the contents were heated to 60° C. for 1.5 h. The reaction mixture was then cooled to room temperature and purified by RP-HPLC to provide 5-fluoro-4-hydrazino-2-methyl-6-[(1,3-thiazol-2-ylmethyl)amino]pyrimidine (97 mg, 38%). LCMS: (M+H)+: 255.2.