Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:7]2=[O:24].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[N:8]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:7]2=[O:24]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)[Si](C)(C)OCCCn1c(Cl)nc2c(Br)cccc2c1=O
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CCCO[Si](C)(C)C(C)(C)C
Temperature: 130 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of 8-bromo-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloroquinazolin-4(3H)-one (500a; 0.080 g, 0.185 mmol) in tert-butylamine (Aldrich; 0.584 mL, 5.56 mmol) was sealed and heated in a biotage initiator microwave at 100° C. for 30 min, 130° C. for 30 min, and 150° C. for 60 min. The reaction was partitioned between satd aq sodium bicarbonate and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-(tert-butylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)quinazolin-4(3H)-one (0.077 g, 0.164 mmol, 89% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, dd, J=8.0, 1.4 Hz), 7.85 (1H, dd, J=7.6, 1.4 Hz), 6.97 (1H, t, J=7.8 Hz), 5.24 (1H, s), 4.10 (2H, t, J=7.1 Hz), 3.75 (2H, t, J=5.4 Hz), 1.85-1.99 (2H, m), 1.62 (9H, s), 0.95 (9H, s), 0.12 (6H, br. s.). m/z (ESI, +ve ion) 468.0/470.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCNCC
Reactant: ClCC=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCN(CC)CC=Cc1ccccc1
Yield: 63.5 %

Procedure:
175.4 g of diethylamine and 152.5 g of chloromethylstyrene (mixture of m- and p- compounds) were dissolved in 300 ml of toluene, and the resulting solution was heated to 60°-70° C. for 13 hours. Diethylamine hydrochloride was separated during the progress of the reaction. After the hydrochloride was filtered out, the filtrate was washed with water. The toluene phase was dried with anhydrous sodium sulfate and thereafter concentrated. After adding 1 g of di-tert-butylcatechol, reduced pressure distillation was carried out to obtain 120.2 g of diethylaminomethylstyrene. (b.p.: 60° C./2 mm Hg, colorless liquid)
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]#[N:13])[N:10]=1)=[O:4].[CH2:14]([C:16]1[CH:59]=[CH:58][C:19]2[CH:20]([C:30]3[C:31](=[O:57])[NH:32][C:33](=[O:56])[N:34]([C:36]4[CH:41]=[CH:40][N:39]=[C:38](NCC(NC5SC=C(CC(O)=O)N=5)=O)[N:37]=4)[CH:35]=3)[C:21]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:22]=3[CH:23]=[CH:24][C:18]=2[CH:17]=1)[CH3:15]>>[C:12]([CH2:11][C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:38]2[N:37]=[C:36]([N:34]3[CH:35]=[C:30]([CH:20]4[C:19]5[CH:58]=[CH:59][C:16]([CH2:14][CH3:15])=[CH:17][C:18]=5[CH:24]=[CH:23][C:22]5[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:21]4=5)[C:31](=[O:57])[NH:32][C:33]3=[O:56])[CH:41]=[CH:40][N:39]=2)[S:7][CH:8]=1)#[N:13]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Reactant: N#CCc1csc(NC(=O)CN)n1
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC#N)cs3)n2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of step (iii) (1.58 g) and the product of example 15 step (viii) (1.14 g) by the method of example 7 step (i). Yield 0.7 g.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:43]([O:46][C@H:47]1[CH2:51][C@H:50]([N:52]2[CH:60]=[N:59][C:58]3[C:53]2=[N:54][CH:55]=[N:56][C:57]=3Br)[O:49][C@@H:48]1[CH2:62][O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])(=[O:45])[CH3:44]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:43]([O:46][C@H:47]1[CH2:51][C@H:50]([N:52]2[CH:60]=[N:59][C:58]3[C:53]2=[N:54][CH:55]=[N:56][C:57]=3[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:49][C@@H:48]1[CH2:62][O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])(=[O:45])[CH3:44]
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(Br)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(-c4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A flame dried flask was charged with Pd(OAc)2 (0.0185 g, 0.0823 mmol), 2-(dicyclohexylphosphino)biphenyl (0.0433 g, 0.123 mmol), phenyl boronic acid (0.151 g, 1.23 mmol), and K3PO4 under an atmosphere of argon. A solution of (2R,3S,5R)-5-(6-bromo-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-yl acetate (0.388 g, 0.823 mmol) in dry dioxane (5.49 mL) was added to the mixture and the solution was stirred at 90° C. overnight. The reaction mixture was filtered through celite with CH2Cl2, concentrated and purified by flash chromatography (10 to 30% EtOAc/hexanes) to afford the title compound as a clear oil (0.247 g, 64%).
Reaction SMILES: C([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(=O)C.OO>C(O)(=O)C>[C:10]([O:12][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:16][CH:17]=1)(=[O:11])[CH3:9]
Reactant: CCOC(=O)C(C)Oc1ccc(C(C)=O)cc1
Agent: OO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)Oc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Yield: 178.2 %

Procedure:
Ethyl 2-(4-acetylphenoxy)propanoate (5.01 g, 21.0 mmol) is dissolved in acetic acid (10 ML) and Amberlyst-15(R) (0.24 g) added. Hydrogen peroxide (70%), 1.58 g, 33.0 mmol is then charged dropwise over 30 minutes to the reaction. The reaction is refluxed for 8 hours at 45°-60° C. and 57-60 mm HgA whereupon the reaction is analyzed by GLC. The reaction is cooled to room temperature and concentrated under reduced pressure to give ethyl 2-(4-acetoxyphenoxy)propanoate (4.72 g) (yield 88.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34]2)=[CH:30][C:29]=1[O:42][CH3:43]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:36]=[C:35]4[C:31]([CH:32]=[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34]4)=[CH:30][C:29]=3[O:42][CH3:43])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1cc2cc(OC)c(N)cc2[nH]1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCOC(=O)c1cc2cc(OC)c(NC(=O)C(CCOC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1

Procedure:
150 mg (398 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 103 mg (438 μmol, 1.1 eq.) of ethyl 6-amino-5-methoxy-1H-indole-2-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water and acetonitrile, gradient 10% acetonitrile to 90% acetonitrile). Yield: 87 mg (36% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([CH2:15][OH:16])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]([NH:12][C@H:13]([CH3:14])[CH2:15][OH:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
11.42 g of benzyloxycarbonyl chloride were added dropwise to a mixture of 5.00 g of D-alaninol, 18.49 g of potassium carbonate, 15 ml of ethyl acetate and 15 ml of water, and the mixture was stirred at room temperature for 1.5 hours. At the end of this time, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer and the extract were combined, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The crude crystals which precipitated were collected by filtration and washed with hexane, to give 13.68 g of the title compound, melting at 78° C. to 80° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([CH3:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[N:28][CH:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([CH3:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([CH:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[N:28][CH:29]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1C1(C(N)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A40 (0.240 g, 0.761 mmol), tert-butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate (0.422 g, 1.52 mmol), Pd(OAc)2 (0.003 g, 0.015 mmol), Xantphos (0.018 g, 0.030 mmol) and Cs2CO3 (0.744 g, 2.28 mmol) in dioxane (8 mL) was bubbled with N2 for 10 minutes and then stirred in the microwave at 120° C. for 20 minutes. The volatiles were removed in vacuo and the residue was adsorbed onto SiO2 and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) to give the title compound A45 as a white solid (0.212 g, 50%). LCMS-D: rt 3.20 min; m/z 557 [M+H]+.
Reaction SMILES: [F:1][CH:2]([C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:20][N:21]=1)[C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[S:9][C:5]=2[CH:4]=1.[OH-].[Na+]>C1COCC1>[F:1][CH:2]([C:17]1[O:18][C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:20][N:21]=1)[C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[S:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cc2ccc(C(F)c3nnc(-c4ccccc4)o3)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(C(F)c3nnc(-c4ccccc4)o3)cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dehydration/Saponification; 6-[Fluoro-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl]-benzo[b]thiophene-2-carboxylic acid. A solution of ethyl 6-[2-(2-benzoylhydrazino)-1-fluoro-2-oxoethyl]-1-benzothiophene-2-carboxylate (51 mg, 0.13 mmol) in THF (2.0 mL) was treated with Burgess reagent (45 mg, 0.19 mmol). The reaction vessel was sealed and heated to 120° C. in the microwave reactor for 20 minutes. The reaction was evaporated in vacuo and purified by flash chromatography (10-40% ethyl acetate/hexanes) to give ethyl 6-[fluoro(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1-benzothiophene-2-carboxylate as a white solid. ESIMS calcd 383.1 (M++H), found 383.0 (M++H). To a solution of ethyl 6-[fluoro(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1-benzothiophene-2-carboxylate in THF (2.5 mL) was added 1M sodium hydroxide (5.0 mL, 5.0 mmol) and the resulting solution was stirred at ambient temperature for 1 hour. The reaction was partitioned between ethyl acetate and 1M HCl solution. The organics were dried over sodium sulfate, filtered and evaporated to give 6-[fluoro(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1-benzothiophene-2-carboxylic acid as a white solid. ESIMS calcd 355.1 (M++H), found 355.0 (M++H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2.C(O)(=O)C.[OH-].[Na+]>CN(C=O)C.O>[NH:24]1[C:25]2[C:21](=[C:20]([NH:19][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]([NH2:18])=[O:17])[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Nc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc4[nH]ccc34)c2cc1OC
Temperature: 100 °C
Yield: 32.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.90 g, 0.34 mmol), 4-aminoindol (0.039 g, 0.23 mmol), sodium acetic (0.020 g, 0.23 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 4.5 h. After cooling the reaction mixture was diluted with water (20 ml) and made alkaline with 1 M NaOH. The precipitate was isolated by centrifugation, re-suspended in water and centrifuged again. The procedure was repeated twice and the solid material dried to give the title compound (27 mg, 43%).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]([OH:23])[C:10]#[C:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]1([C:7]#[C:8][C:9](=[O:23])[C:10]#[C:11][C:12]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(C#Cc1ccccc1)C#Cc1ccnn1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(C#Cc1ccccc1)C#Cc1ccnn1-c1ccccc1
Yield: 62.4 %

Procedure:
To a solution of 1-phenyl-5-(1-phenyl-1H-pyrazol-5-yl)penta-1,4-diyn-3-ol (0.50 g) in dichloromethane (20.0 mL) was added manganese dioxide (0.438 g), and the mixture was heated under reflux for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane) to give the title compound (0.310 g).
Reaction SMILES: S([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=2)[C:10]([CH3:21])=[N:9]1)(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[CH3:21][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)[NH:8][N:9]=1
Reactant: COC(=O)c1ccc2c(C)nn(S(=O)(=O)C(F)(F)F)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1n[nH]c2cc(C(=O)O)ccc12
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of methyl 1-triflyl-3-methyl-indazole-6-carboxylate(0.668 g, Reference Example 46) in a mixture of methanol and water (3:1, 80 ml) was treated with potassium carbonate (1.15 g). The mixture was heated at reflux for 5 hours then cooled to room temperature then poured into 1N hydrochloric acid (50 ml). The mixture was extracted three times with ethyl acetate (50 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was washed with a mixture of hexane and ether to give the title compound (0.360 g).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([OH:28])=O)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][NH:35][CH3:36].CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([N:35]([CH3:36])[CH3:34])=[O:28])[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 2-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-3-carboxylic acid (0.066 g) in N,N-dimethylformamide (5 mL) were added N,N-dimethylamine (0.038 mL), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (57 mg) and N,N-diisopropylethylamine (0.069 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=70:30-100:0, volume ratio), and recrystallized from hexane-ethyl acetate to give the title compound (0.058 g, yield 84%) as colorless crystals. MS: 514 (MH+). melting point 180-182° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[C:7]([Cl:9])[CH:8]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH:11][CH:13]([CH3:15])[C:12]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: NNc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)NNc1cc(Cl)cc(Cl)c1

Procedure:
A mixture of 3,5-dichlorophenylhydrazine hydrochloride (5.07 g) and ethyl pyruvate (3.96 ml) in ethyl alcohol (30 ml) was refluxed for 2 hours, and the solvent was evaporated under reduced pressure. The residual solid was triturated with hexane to give ethyl 2-(3,5-dichlorophenylhydrazino)propionate (5.60 g). APCI-Mass m/Z 275/277 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[N:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:22])[CH3:21])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (0.33 g) in a mixture of dichloromethane (20 ml) and acetic anhydride (1.5 ml) was allowed to stand overnight and then evaporated. The residue was triturated with 50 ml of 10% sodium carbonate solution, and then the mixture was diluted to 100 ml with water and extracted several times with chloroform. The combined extracts were dried over sodium sulphate, evaporated and the residue crystallised from ethanol to give the title compound (0.15 g), m.p. 244°-247° C. Found: C,68.82; H,6.67; N,18.69. C17H20N4O requires: C,68.89; H,6.80; N,18.91%.
Reaction SMILES: C([O:6][CH2:7][C@H:8]1[O:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([NH2:23])=[N:17][C:18]=3[NH2:22])[CH2:10][O:9]1)(=O)C(C)C.CC(O)C>N>[NH2:23][C:16]1[N:15]=[C:14]2[C:19]([N:20]=[CH:21][N:13]2[C@H:11]2[CH2:10][O:9][C@@H:8]([CH2:7][OH:6])[O:12]2)=[C:18]([NH2:22])[N:17]=1
Reactant: CC(C)C(=O)OC[C@@H]1OC[C@H](n2cnc3c(N)nc(N)nc32)O1
Agent: N
Solvent: CC(C)O
Product: Nc1nc(N)c2ncn([C@H]3CO[C@@H](CO)O3)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.4 %

Procedure:
31.05 g of (2R,4R)-2-isobutyryloxymethyl-4-(2,6-diaminopurin-9-yl)-1,3-dioxolane×2-propanol (cf. Example 4) were dissolved in 310 ml of NH3-saturated methanol. The solution was stirred at 25° C. for 15 h, and the solvent was distilled off in vacuo. The residue was recrystallized from ethanol/water. 17.10 g (83%) of (−)-DAPD were obtained as colorless crystals.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([O:23]CC)=O)([O-])=O>C(O)C.O.[Fe]>[O:23]=[C:21]1[CH2:20][C:7]2[C:6](=[C:11]([S:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)Cc1cccc(Sc2ccc(Cl)cc2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=C1Cc2cccc(Sc3ccc(Cl)cc3)c2N1
Yield: 88 %

Procedure:
A mixture of iron powder (21.6 g) and ammonium chloride (2.2 g) in ethanol (200 ml) and water (75 ml) and ethyl 2-[2-nitro-3-(4-chlorophenylthio)phenyl]acetate (21.6 g) were treated in a similar manner to that of Preparation 28-(1) to give 2-oxo-7-(4-chlorophenylthio)indoline (14.9 g). mp 186°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([C:14]([O:16]C)=[O:15])=[CH:6]2.[OH-].[Na+]>C1COCC1.CO>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][C:7]([C:14]([OH:16])=[O:15])=[CH:8]2
Reactant: COC(=O)C1=Cc2cc(OC)c(OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1OC)CC(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
To a stirred solution of methyl 5,6-dimethoxy-1H-indene-2-carboxylate (330 mg, 1.41 mmol) in THF (8 mL) and MeOH (4 mL) was added 2 N NaOH solution (3.5 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours and the reaction was quenched with 1N HCl solution. Then mixture was diluted with water and the resulting suspension was filtered and the solid was dried under vacuum to give 5,6-dimethoxy-1H-indene-2-carboxylic acid (150 mg, 48%). LC-MS (ES-API); rt 8.44 min; m/z calculated for C12H12O4 [M−H]− 219.1, found 219.1.
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:43]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[OH:43][C@H:10]([CH3:11])[C:9]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc2ccccc12
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](O)C(=O)c1cccc2ccccc12
Yield: 38.3 %

Procedure:
Compound 10h was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(naphthalen-1-yl)prop-1-enyloxy)dimethylsilane, (9h, 4.58 g, 0.015 mol), AD-mix-β (21.4 g), and CH3SO2NH2 (1.5 g, 0.0158 mol) in tert-butyl alcohol-water (60 mL:60 mL). The reaction was quenched with sodium sulfite (15.3 g). After purification by column chromatography on silica gel, 1.15 g (38%) of the title product was isolated plus 2.1 g of starting olefin was recovered, raising the effective yield to 70%: [α]20D +140.2° (c 3.2, CHCl3); 1H NMR (CDCl3) δ 8.51-8.46 (m, 1H), 8.04 (d, 1H, J=8.3 Hz), 7.93-7.87 (m, 1H), 7.80-7.75 (m, 1H), 7.66-7.48 (m, 3H), 5.30-5.17 (m, 1H), 3.96 (d, 111, J=5.8 Hz), 1.36 (d, 3H, J=7.1 Hz); 13C NMR (CDCl3) δ 205.7, 134.1, 133.5, 132.5, 130.7, 128.7, 128.4, 127.7, 126.9, 125.5, 124.4, 71.2, 21.3; LCMS (ESI) m/z 201.2 [(M+H)+, M=C13H12O2].