Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=[CH2:18].C(=O)(O)O.ClC(OCC)=O>>[C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: NCCCCCc1nc2ccccc2s1
Reactant: C=C(C)C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C(O)O
Product: C=C(C)C(=O)NCCCCCc1nc2ccccc2s1

Procedure:
2-(5-Aminopentyl)benzothiazole (synthesized from 2-aminobenzenethiol and ε-caprolactam) was reacted with a mixed acid anhydride of methacrylic acid and carbonic acid prepared through reaction of methacrylic acid and ethyl chloroformate under basic conditions to obtain 2-(5-methacryloylaminopentyl)benzothiazole. Copolymerization with acrylic acid afforded a Polymer [BP-3] which is used in the present invention. The weight average molecular weight measured by GPC was 11.0×104 (polystyrene standard)
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Na].[NH2:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([CH2:14][Cl:15])[N:8]=1>CO>[NH2:6][C:7]1[N:8]=[C:9]([CH2:14][Cl:15])[CH:10]=[C:11]([N:3]([CH3:4])[CH3:2])[N:12]=1
Reactant: Nc1nc(Cl)cc(CCl)n1
Reactant: CNC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN(C)c1cc(CCl)nc(N)n1

Procedure:
8.1 Parts of dimethylamine hydrochloride was added to a solution of 2.3 parts of sodium in 20 parts of methanol. The resulting mixture was added dropwise with stirring over about 10 minutes to a solution of 9.9 parts of 2-amino-4-chloro-6-chloromethylpyrimidine in 50 parts of methanol. The reaction was monitored by TLC and when reaction was complete the solvent was evaporated and the residue stirred with about 20 parts of water. The solid obtained was filtered and dried. The product was purified by chromatography on silica, eluted with ethyl acetate, followed by sublimation at 110° C./0.04 mb to give 2-amino-4-chloromethyl-6-dimethylaminopyrimidine m.p. 127°-129° C.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[N:13]=[CH:12][C:11]=2[NH2:26])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:28](N)=[O:29].O>CN1CCCC1=O>[C:1]1([C@H:7]([N:9]2[C:10]3[CH:15]=[C:14]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)[N:13]=[CH:12][C:11]=3[NH:26][C:28]2=[O:29])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](Nc1cc(-c2cccc3ncccc23)ncc1N)c1ccccc1
Reactant: NC(N)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(-c3cccc4ncccc34)cc21
Temperature: 185 °C
Yield: 32.4 %

Procedure:
1-((1R)-1-phenylethyl)-6-(5-quinolyl)-4-imidazolino[4,5-c]pyridine-2-one. ((1R)-1-Phenylethyl)(3-amino-6-(5-quinolyl)(4-pyridyl))amine (150 mg, 0.44 mmol) and urea (52.8 mg, 0.88 mmol) were combined in 1-methylpyrrolidin-2-one (4 mL) and heated at 185° C. for 2 h. Water (10 mL) was added and the crude product was collected by filtration. The product was purified by reverse-phase preparative HPLC (20-95% acetonitrile in water, over 30 min) to give the title compound (52.3 mg, 32.4%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H) 8.91 (dd, J=4.10, 1.56, 1H) 8.39 (d, J=0.78, 1H) 8.33 (ddd, J=8.74, 1.71, 0.88, 1H) 8.05 (d, J=8.49, 1H) 7.80 (dd, J=8.49, 7.13, 1H) 7.59 (dd, J=7.22, 1.37, 1H) 7.41-7.46 (m, 3H) 7.30-7.40 (m, 3H), 5.75 (d, J=7.22, 1H), 4.16 (d, J=0.98, 1H), 1.87 (d, J=7.22, 3H); MS (ESI) m/z 367.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH2:20])=[O:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C1(C)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([NH:20][C:34]([NH:33][S:30]([C:27]4[CH:28]=[CH:29][C:24]([CH3:36])=[CH:25][CH:26]=4)(=[O:32])=[O:31])=[O:35])=[O:19])=[CH:15][CH:16]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CC(N)=O)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CC(=O)NC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 6 h
Yield: 91.7 %

Procedure:
A mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetamide (step 5, 105 mg, 0.30 mmol), p-toluenesulfonyl isocyanate (0.07 mL, 0.45 mmol), toluene (10 mL) and THF (5 mL) was heated at reflux temperature. After 6 h, an additional 0.1 mL of p-toluenesulfonyl isocyanate was added and the mixture was heated for 3 h. The mixture was cooled and left at room temperature for 2 days. The mixture was concentrated and the residue was purified by preparative TLC (ethyl acetate) to afford 150 mg (92%) of the title compound as colorless amorphous solids: 1H-NMR (CDCl3) δ 9.78 (1H, s), 7.95 (2H, d, J=8.3 Hz), 7.84 (1H, s), 7.54 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.0 Hz), 7.32 (2H, d, J=8.4 Hz), 7.18 (1H, s), 3.78 (2H, s), 2.77 (2H, q, J=7.5 Hz), 2.41 (3H, s), 1.35 (3H, t, J=7.5 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[F:14][C:15]([F:31])([F:30])[C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:20]2[CH2:21][C@H:16]([C:15]([F:31])([F:30])[F:14])[CH2:17][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:19]2)=[C:3]2[CH2:13][CH2:12][CH2:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 150 °C
Reaction time: 6 h
Yield: 62.1 %

Procedure:
To a mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (144.2 mg, 0.7260 mmol) and tert-butyl [(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (from MolBridge, 179.9 mg, 0.6706 mmol) was added 1-butanol (3.0 mL) followed by DIPEA (493.7 mg, 3.820 mmol). The mixture was stirred at 150° C. for 6 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (179.2 mg, 62%). LCMS calc. for C19H26F3N4O4 (M+H)+: m/z=431.2. found 431.2.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:10]([NH:12][C@@H:13]1[C:16](=[O:17])[N:15]2[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24]([NH2:26])=[O:25])[CH2:20][S:21][C@H:14]12)=[O:11])/[C:5]1[O:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([O:39][C:40](=[O:46])[C:41]([O:44][CH3:45])([CH3:43])[CH3:42])[CH3:38]>CN(C)C=O>[C:24]([O:23][CH2:22][C:19]1[CH2:20][S:21][C@@H:14]2[C@H:13]([NH:12][C:10](=[O:11])/[C:4](=[N:3]\[O:2][CH3:1])/[C:5]3[O:9][CH:8]=[CH:7][CH:6]=3)[C:16](=[O:17])[N:15]2[C:18]=1[C:27]([O:29][CH:37]([O:39][C:40](=[O:46])[C:41]([O:44][CH3:45])([CH3:43])[CH3:42])[CH3:38])=[O:28])(=[O:25])[NH2:26]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reactant: COC(C)(C)C(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(=O)C(C)(C)OC)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 1 h
Yield: 38.7 %

Procedure:
Cefuroxime (4.24 g) and powdered potassium carbonate (0.690 g) were stirred in anhydrous N,N-dimethylformamide (40 ml) till a solution was obtained. The solution was cooled to -3°, 2-methoxy-2-methylpropanoic acid 1-bromoethyl ester (2.50 g) was added and the solution was stirred for 1 hour. It was then partitioned between 2N hydrochloric acid (100 ml) and ethyl acetate (200 ml and 100 ml) and the combined organic layers were washed sequentially with 100 ml each of 2N hydrochloric acid (2×), water, saturated aqueous sodium bicarbonate, water (2×) and saturated brine, dried over magnesium sulphate and concentrated under reduced pressure to ca 20 ml. The solution was added slowly to petroleum ether (200 ml) and the resulting precipitate was filtered off, washed with petroleum ether and dried under vacuum to give the title ester (2.20 g); λmax (ethanol) 277.5 nm E11 342; νmax (CHBr3) 3520 and 3400 (NH and NH2), 1788 (β-lactam C=O), 1750 (ester C=O), 1732 (αβ unsaturated ester and carbamate C=O), and 1688 and 1514 cm-1 (amide C=O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:27]([C:31]([O-:33])=[O:32])[C:28]([O-:30])=O.[CH2:34](O)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].[N-]=C=O>>[NH:27]([C:28]([O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)=[O:30])[C:31]([O:33][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH3:34])=[O:32]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C([O-])NC(=O)[O-]
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: [N-]=C=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 66 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the iminodicarboxylate with N-octadecanyloxycarbonyl isocyanate prepared from 1-octadecanol (297 mg, 1.1 mmol) and N-chloroarbonyl isocyanate (106 mg, 1 mmol) in the same manner as the example 82 to give the compound 100 (295 mg, 66%). Mp. 96-98° C. Rf 0.46 (EtOAc). 1H-NMR (CDCl3): δH0.88 (3 H, t like, CH3), 1.25-1.30 (30 H, m, --CH2 --), 1.31 (6 H, d, J 6.9 Hz, (CH3)2CH), 1.62 (2 H, m, --CH2 --), 3.18 (1 H, sep, J 6.9 Hz, (CH3)2CH), 4.14 (2 H, t, J 6.9 Hz, CH2O), 5.23 (2 H, s, NCH2), 5.31 (2 H, s, OCH2), 6.71 (2 H, d, J 1.8 Hz, arom 2- and 6-H), 6.77 (2 H, d-like, 4-pyridyl 2- and 6-H), 6.95 (1 H, bs, NH), 7.06 (1 H, t, J 1.8 Hz, arom 4-H), 8.45 (2 H, d-like, 4-pyridyl 3- and 5-H). IR(CHCl3)cm-1 : 3394 (NH), 1791 and 1764 (NCO), 1715 (NCOO). Elementary analysis (for C39H56N4O4SCl2) Calcd. : C, 62.64% H, 7.55% N, 7.49% S, 4.29% Cl, 9.48% Found: C, 62.86% H, 7.73% N, 7.43% S, 4.00% Cl, 9.07%
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.ClC(Cl)(Cl)[CH:24](O)[OH:25]>C(OCC)(=O)C>[CH:24]([N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:4][C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[Cl:1])=[O:25]
Reactant: COc1ccc(CCNCc2ccccc2Cl)cc1OC
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CCN(C=O)Cc2ccccc2Cl)cc1OC
Temperature: 120 °C

Procedure:
N-(2-chlorobenzyl)-2-(3,4-dimethoxy-phenyl)-ethylamine (88.4 g, 0.29 mol) is mixed with chloral hydrate (52.5 g, 0.34 mol) and heated (120° C.) for 30 minutes. After cooling, ethyl acetate is added and the mixture is washed with water, dried and evaporated. Yield: 103 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25](C)[CH:26]=[O:27].[H-].[Na+].CO.Cl[CH2:34]Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([N:25]([CH3:24])[C:26](=[O:27])[CH3:34])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: ClCCl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N(C)n1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.5 g, 1.6 mmol) and dimethylformamide (20 mL). Add sodium hydride (0.08 g, 3.2 mmol). After 12 hours, add N-methyl-1-chloroacetamide (0.34 g, 3.14 mmol). After 12 hours, add N-methyl-1-chloroacetamide (0.17 g, 1.6 mmol). After 12 hours, heat to 70° C. After 4 hours, cool to ambient temperature and partition the reaction mixture between water (10 mL) and dichloromethane (100 mL). Separate the layers, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1.2% methanol/dichloromethane/0.5% saturated aqueous ammonia solution to give 1-(t-butoxycarbonyl)-4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.24 (silica gel, 1.8% methanol/dichloromethane/0.5% saturated aqueous ammonia solution).
Reaction SMILES: NCC[CH:4]([S:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH:5]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([N:12]2[CH:20]=[N:19][C:18]3[C:13]2=[N:14][CH:15]=[N:16][C:17]=3[NH2:21])[O:6]1.C(=O)([O-])[O-].[K+].[K+].[NH2:35][C:36]1[NH:45][C:44](=[O:46])[C:43]2[C:38](=[N:39][CH:40]=[C:41]([CH2:47]Br)[N:42]=2)[N:37]=1.[CH3:49][C:50]([N:52](C)C)=O>>[NH2:35][C:36]1[NH:45][C:44](=[O:46])[C:43]2[C:38](=[N:39][CH:40]=[C:41]([CH2:47][NH:52][CH2:50][CH2:49][N:26]3[CH2:27][CH2:28][CH:23]([S:22][CH2:4][CH:5]4[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([N:12]5[CH:20]=[N:19][C:18]6[C:13]5=[N:14][CH:15]=[N:16][C:17]=6[NH2:21])[O:6]4)[CH2:24][CH2:25]3)[N:42]=2)[N:37]=1
Reactant: Nc1nc2ncc(CBr)nc2c(=O)[nH]1
Reactant: CC(=O)N(C)C
Reactant: NCCC(SC1CCNCC1)C1OC(n2cnc3c(N)ncnc32)C(O)C1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1nc2ncc(CNCCN3CCC(SCC4OC(n5cnc6c(N)ncnc65)C(O)C4O)CC3)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
To a solution of 2-[1-(2-Amino-ethyl)-piperidin-4-ylsulfanylmethyl]-5-(6-amino-purin-9-yl)-tetrahydro-furan-3,4-diol (100.0 mg, 0.244 mmol, 1 eq) (8) and potassium carbonate (337.9 mg, 2.44 mmol, 10 eq) in 20 mL dimethylacetamide, 2-amino-6-bromomethyl-3H-pteridin-4-one (87.0 mg, 0.244 mmol, 1 eq) (11) was added and then stirred at room temperature for 24 hours. It was evaporated in high vacuum and the residue dissolved in water methanol mixture and purified by HPLC to give compound 13 (71.0 mg, 0.122 mmol, 50%) of a yellowish powder. MS (ESI) calculated for C24H32N12O4S [M+H]+ 585.24, found 585.1
Reaction SMILES: C([O:8][C:9](=[O:36])[CH2:10][C@@H:11]([C:24]1[CH:28]=[CH:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:25]=1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.CC(OC)(C)C>CCO>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([C:24]1[CH:28]=[CH:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:25]=1)[CH2:10][C:9]([OH:36])=[O:8])[C:20](=[O:23])[NH:21][CH3:22]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(F)cc2)c1)C(C)(C)C
Solvent: CCO
Solvent: COC(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(F)cc2)c1)C(C)(C)C

Procedure:
As described in Example 1(a), N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3 (S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]succinamic acid benzyl ester was hydrogenolyzed in EtOH after 1.5 hours. Trituration with MTBE/hex gave in quantitative yield N-[2,2- dimethyl-1(S)-(methylcarbamoyl)propyl]-3(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]succinamic acid as a colorless amorphous solid. 1H NMR: δ7.27-7.23 (m, 2H), 7.07 (t, 2H, J=8.6 Hz), 6.90-6.89 (m, 2H), 6.21 (t, 1H, J=2.2 Hz), 6.13-6.10 (m, 1H), 4.24 (d, 1H, J =9.6 Hz), 4.03 (dd, 1H, J=5.2, 8.5 Hz), 3.14 (dd, 1H, J=8.5, 16.6 Hz), 2.80 (dd, 1H, J=5.7, 16.7 Hz), 2.72 (d, 3H, J=4.8 Hz), 0.94 (s, 9H). Anal. Calculated for C21H26N3O4F: C, 63.17; H, 6.80; N, 10.09. Found: C, 62.89; H, 6.93; N, 9.81.
Reaction SMILES: C([OH:5])(C)(C)C.[OH2:6].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(OC)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+].[CH2:71]([C:74]1[C:83]2[O:82][C:81](=[O:84])[N:80]([CH3:85])[CH2:79][C:78]=2[CH:77]=[CH:76][C:75]=1[O:86][CH3:87])[CH:72]=[CH2:73]>C(Cl)(Cl)Cl>[OH:6][CH:72]([CH2:73][OH:5])[CH2:71][C:74]1[C:83]2[O:82][C:81](=[O:84])[N:80]([CH3:85])[CH2:79][C:78]=2[CH:77]=[CH:76][C:75]=1[O:86][CH3:87]
Reactant: O
Reactant: CC(C)(C)O
Reactant: C=CCc1c(OC)ccc2c1OC(=O)N(C)C2
Agent: 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
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1CC(O)CO)OC(=O)N(C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12 ml of t-butanol and 10 ml of water were added to and dissolved in 0.58 g of 8-allyl-7-methoxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-one. 2.48 g of AD-mix-β was added to this solution, and the obtained mixture was stirred at room temperature overnight. After confirming the disappearance of raw material, 2.97 g of sodium sulfite was added to the reaction solution, and the obtained mixture was then stirred for approximately 45 minutes. Thereafter, water and chloroform were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), so as to obtain 0.55 g of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][Mg+].[Br-].[NH4+].[Cl-]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C@@H:10]([OH:11])[CH3:20])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C@H:10]([OH:11])[CH3:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Mg+]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)c1ccc(F)c(Cl)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)c(Cl)c1
Product: C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)c(Cl)c1
Temperature: -78 °C

Procedure:
To a stirred solution of freshly prepared 328 (1.2 g, 4.171 mmol) in Et2O (20 mL) cooled to −78° C. under nitrogen was added MeMgBr (2.781 mL, 8.342 mmol, 3M solution in Et2O) dropwise via syringe. The resulting suspension became viscous as the Grignard addition proceeded and eventually became unstirrable. Et2O (20 mL) was added to aid stirring and the reaction was warmed to 0° C. The reaction was stirred for 2 h at 0° C. and then poured into a stirred satd. aq. NH4Cl (50 mL) solution. The layers were separated and the aqueous phase was extracted with Et2O (1×50 mL). The combined organic extracts were washed brine (1×100 mL), dried (MgSO4), filtered and concentrated to a clear oil. The crude product was loaded onto a SiO2 column (Biotage 40M) and eluted with EtOAc/hexane (25/75). The higher Rf material was residual aldehyde. The lower Rf material was isolated and concentrated to afford 354 mg (28%) of a 5:1 mixture (330) of tert-butyl (1S,2S)-1-(3-chloro-4-fluorophenyl)-2-hydroxypropylcarbamate and tert-butyl (1S,2R)-1-(3-chloro-4-fluorophenyl)-2-hydroxypropylcarbamate as clear oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][CH:9]=[N:8][CH:7]=1.C([Li])CCC.C([Sn](Cl)(CCCC)CCCC)CCC.C1(C)C(C([O:38][C@@H:39]2[C@@H:43]([CH2:44][O:45]C(C3C(C)=CC=CC=3)=O)[O:42][C@@H:41]([N:55]3[C:59]4=[N:60][CH:61]=[CH:62][C:63](I)=[C:58]4[CH:57]=[CH:56]3)[CH2:40]2)=O)=CC=CC=1>C(OCC)C.CN(C=O)C>[C@@H:41]1([N:55]2[C:59]3=[N:60][CH:61]=[CH:62][C:63]([C:9]4[S:10][C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[CH:7][N:8]=4)=[C:58]3[CH:57]=[CH:56]2)[O:42][C@H:43]([CH2:44][OH:45])[C@@H:39]([OH:38])[CH2:40]1
Reactant: c1csc(-c2cncs2)c1
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](n2ccc3c(I)ccnc32)C[C@@H]1OC(=O)c1ccccc1C
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](n2ccc3c(-c4ncc(-c5cccs5)s4)ccnc32)C[C@@H]1O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(2-thienyl)thiazole (0.4 mmol) in diethyl ether was cooled to −78° C., and n-butyllithium (0.4 mmol, 1.57 M solution in hexane) was added thereto, followed by stirring at −78° C. for 30 min. Furthermore, tributylstannyl chloride was added thereto, followed by stirring at room temperature for 30 min. The reaction solution was separated between ethyl acetate and water. The organic layer was washed with saturated brine and concentrated, and 1-[2-deoxy-3,5-di-O-(toluoyl)-β-D-ribofuranosyl]-4-iodo-pyrrolo[2,3-b]pyridine (120 mg, 0.2 mmol), chlorobistriphenylphosphine palladium (5% mol), and DMF (2 mL) were added thereto, followed by stirring at 100° C. for 1 hr. The reaction solution was separated between ethyl acetate and water, and the organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, and concentrated. After purification with a silica gel column and addition of sodium methoxide (1.6 mL), the resulting mixture was stirred at room temperature for 30 min. dDvas nucleoside (34 mg) was purified with a silica gel column and by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1>[Pd]>[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCCCc1ccccc1
Agent: [Pd]
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1CCCCCc1ccccc1
Product: Cl
Reaction time: 5 h
Yield: 33.9 %

Procedure:
A solution of 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-5-(5-phenyl-pent-1-ynyl)-phthalazine (770 mg, 1.665 mmoles), prepared as described in example 66, in THE (50 ml). was hydrogenated in Parr in the presence of 10% Pd/C (100 mg) for 24 hours. The catalyst was filtered off and the hydrogenation was kept on for further 24 hours at room temperature and for 5 hours at 80° C. The solution was brought to dryness and flash chromatographed (eluent: petrolatum/ethyl acetate 1:1). The fractions corresponding to the starting compound were brought to dryness and hydrogenated again for 24 hours, then worked up as above. The fractions containing the desired product were joined to the previously obtained ones, dissolved in ethyl acetate and acidified with HCl/ethyl acetate. The precipitate was filtered and crystallised from ethanol (2 ml) and ethyl acetate (8 ml) by subsequent concentration. There were yielded 142 mg of the title compound (yield: 17%). m.p.: 170-173° C.