Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]([OH:15])=[O:14])=[CH:5]2.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([NH:18][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]([OH:15])=[O:14])=[CH:5]2)=[O:20])[CH3:17]
Reactant: CCN=C=O
Reactant: Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Yield: 93 %

Procedure:
A mixture of 4.08 g (20 mmol) of 6-amino-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, 2.37 ml (30 mmol) of ethyl isocyanate, 2.8 ml (20 mmol) of triethylamine and 50 ml of dimethylformamide is stirred with ice bath cooling for 4.5 hrs. The reaction solution is evaporated to dryness and is treated with 1 N hydrochloric acid and ethanol to yield 5.12 g of 6-[[(ethylamino)carbonyl]amino]-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: C[O-].[Na+].[C:4]([NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]([C:28]4[CH:33]=[CH:32][C:31]([O:34]S(C)(=O)=O)=[CH:30][CH:29]=4)[C:24](=[O:27])[NH:25][N:26]=3)=[C:17]([F:39])[CH:16]=2)[CH2:10]1)(=[O:6])[CH3:5].C(O)(=O)C>CO>[F:39][C:17]1[CH:16]=[C:15]([N:11]2[CH2:10][C@H:9]([CH2:8][NH:7][C:4](=[O:6])[CH3:5])[O:13][C:12]2=[O:14])[CH:20]=[CH:19][C:18]=1[C:21]1[S:22][CH:23]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)[C:24](=[O:27])[NH:25][N:26]=1
Reactant: CC(=O)NCC1CN(c2ccc(C3=NNC(=O)C(c4ccc(OS(C)(=O)=O)cc4)S3)c(F)c2)C(=O)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)C(c4ccc(O)cc4)S3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
25% Sodium methoxide solution in methanol (0.027 ml, 0.117 mmol) is added to methanesulfonic acid 4-(2-{4-[5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluorophenyl}-5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-6-yl)-phenyl ester (0.050 g, 0.0932 mmol) in methanol (2 ml) and the mixture is stirred at room temperature overnight. The reaction mixture is neutralized with acetic acid (0.020 ml), evaporated to dryness and the residue is purified by PTLC (10% MeOH/DCM) to give product as a white solid (0.039 g, 92%); 1H NMR (300 MHz, DMSO-d6) δ 1.80 (s, 3H), 3.40-3.45 (bs, 2H), 3.74 (dd, J=6.9, 10.5 Hz, 1H), 4.12 (t, J=9.3 Hz, 1H), 4.70-4.79 (m, 1H), 4.98 (s, 3H), 6.73 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.7 Hz, 1H), 7.37 (dd, J=1.8, 8.7 Hz, 1H), 7.55-7.60 (m, 2H), 8.25 (t, J=5.7 Hz, 1H); mp >200 (decomp.); MS (m/z): [M+H]+=459.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([NH2:26])=[O:25])=[N:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].N[C:28]1C(C(OCC)=O)=NC(C2C=CC=C(O)C=2)=NC=1NC1C=CC=CC=1OC.N>CO>[OH:23][C:19]1[CH:18]=[C:17]([C:5]2[N:6]=[C:7]3[C:2]([N:1]=[CH:28][N:8]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:3]([C:24]([NH2:26])=[O:25])[N:4]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc(Nc2ccccc2OC)c1N
Reactant: COc1ccccc1Nc1nc(-c2cccc(O)c2)nc(C(N)=O)c1N
Agent: N
Solvent: CO
Product: COc1ccccc1-n1cnc2c(C(N)=O)nc(-c3cccc(O)c3)nc21
Temperature: 25 °C
Yield: 99 %

Procedure:
5-Amino-2-(3-hydroxyphenyl)-6-(2-methoxyphenylamino)pyrimidine-4-carboxamide. A solution of ethyl 5-amino-2-(3-hydroxyphenyl)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. (57.8 mg, 0.152 mmol) in anhydrous methanol (5 mL) was chilled to −78° C. The solution was then saturated with ammonia gas. The reaction vessel was sealed at −78° C. and allowed to warm to room temperature. After 18 h the reaction was chilled to −78° C. and opened to atmosphere. The volatiles were evaporated and the resulting material was purified by column chromatography (SiO2, 2% to 5% methanol in methylene chloride) to provide the title compound in 98.3% purity (53 mg, 0.151 mmol, 99% yield). 1H NMR (400 MHz, CD3OD) δ 8.41 (m, 1H), 7.79 (dt, J=8.00, 1.20, 1H), 7.73 (m, 1H), 7.21 (t, J=8.00, 1H), 7.06 (m, 3H), 6.79 (ddd, J=8.00, 2.54, 0.98, 1H), 3.94 (s, 3H); MS (ESI) m/z 352.2 [M+1]+; mp: 230-231° C.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[OH:14][C@H:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[Si:10]([O:14][C@H:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: O=C1NCC[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reaction time: 24 h
Yield: 97.6 %

Procedure:
4-Dimethylaminopyridine (0.199 g, 1.63 mmol), imidazole (6.73 g, 99 mmol) and TBDMS-Cl (20.6 ml, 59.3 mmol) was added to a stirred solution of (S)-3-hydroxypyrrolidin-2-one (5.0 g, 49.5 mmol) in DCM (198 ml) at RT. The reaction mixture was stirred for 24 h and then diluted with water. The mixture was extracted with DCM. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using silica gel column chromatography (50-80% EtOAc/hexanes) to afford (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (10.4 g, 97% yield) as a white solid: 1H NMR (500 MHz, chloroform-d) δ 6.15 (br. s., 1H), 4.28 (t, J=7.6 Hz, 1H), 3.40 (dddd, J=9.7, 8.5, 3.1, 1.2 Hz, 1H), 3.28 (dt, J=9.6, 7.4 Hz, 1H), 2.39 (dtd, J=12.7, 7.3, 3.1 Hz, 1H), 2.10-2.02 (m, 1H), 0.97-0.92 (m, 9H), 0.20-0.14 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:10][N:8]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60% dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was added and the reaction was allowed to warm slowly to ambient temperature. After about 16 h, the reaction mixture was poured onto ice-cold water (120 mL) and the precipitate was collected by vacuum filtration. The crude solid was dissolved in DCM (15 mL) and purified by silica gel chromatography eluting with DCM. The product-containing fractions were concentrated under reduced pressure to give 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 2, Method d) Rt=1.58 min; MS m/z: 352/354 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[CH:24]=1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:31]4[CH2:32][CH2:33][CH:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][NH:21][CH3:20])[CH:24]=5)[CH2:30]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CNCc1cccc(C2CCNC2)c1
Product: CNCc1cccc(C2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)C2)c1
Yield: 91 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.93 g, 3.5 mmol) and N-methyl-3-(3-pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound (1.38 g, 91%) as a white solid, mp 239°-240° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21]3[N:22]4[CH:28]=[C:27]([NH:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:26]=[CH:25][C:23]4=[N:24][C:20]=3[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:37])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:38]I.O>CN(C=O)C>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:21]3[N:22]4[CH:28]=[C:27]([N:29]([CH3:38])[C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:26]=[CH:25][C:23]4=[N:24][C:20]=3[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:37])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CI
Reactant: CCCCCC(=O)Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(=O)N(C)c1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Sodium hydride (1.6 equiv., 1.029 mmol, 0.041 g (60%)) was added to a solution of 86 (1.0 equiv., 0.643 mmol, 0.302 g) in DMF (15 ml), the reaction mixture was stirred for 1 h at room temperature. Methyl iodide (1.2 equiv., 0.772 mmol, 0.110 g) was added and the mixture was stirred at room temperature for 24 h. Water was added to the reaction mixture, and the formed precipitate was filtered off and washed with water and isopropyl ether to give N-[5,6-dihydro-6-(4-nitrophenyl)-5-oxo-pyrido[2′,1′:2,3]-imidazo[4,5-c]isoquinolin-9-yl]-N-methyl-hexanamide (87) (0.296 g, yield=95%, purity (LC)=93%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([CH3:22])=[CH2:21]>CN(C=O)C.O>[CH3:21][C:20](=[CH2:19])[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C(C)CBr
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cccc(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Methyl 3-hydroxybenzoate (1 g, 6.57 mmol) was dissolved in DMF (10 ml) to give a colorless solution. To the solution potassium carbonate (1.089 g, 7.88 mmol) and 3-Bromo-2-methylpropene (0.729 ml, 7.23 mmol) were added. The reaction mixture was heated to 90° C. and stirred for 1 h. After cooling the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and evaporated under vacuum to afford the title compound (1.180 mg)
Reaction SMILES: IC1C=[CH:10][C:9]2[C:4](=CC=C[CH:8]=2)N=1.C([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)C>C(Cl)Cl.CCOC(C)=O>[C:16]([O:15][C:9]([CH3:8])([CH3:4])[CH3:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: Ic1ccc2ccccc2n1
Reactant: CC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
HClO4 (1.17 mL, 13.6 mmol) is added to a suspension of 48k (3.40 g, 9.06 mmol) in t-butyl acetate (100 mL) and DCM (150 mL). The reaction mixture is stirred at RT overnight then is diluted with EtOAc (150 mL). The solution is washed twice with aqueous 5% NaHCO3 solution, dried (MgSO4), filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (Combi-Flash; EtOAc/hexane) to give t-butylether 481 (2.76 g, 71% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3](=[O:35])[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:32])[CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([CH:33]=[CH2:34])[CH:6]=1.C(Br)(Br)(Br)[Br:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:36][N:2]([CH3:1])[C:3](=[O:35])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([Br:38])([OH:32])[CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([CH:33]=[CH2:34])[CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)(Br)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 4-[3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyl dimethylcarbamate (3.00 g, 5.95 mmol) synthesized in step (f) of Example 192 and carbon tetrabromide (3.98 g, 12.0 mmol) in dichloromethane (20 ml) was added triphenyl phosphine (3.14 g, 12.0 mmol) at room temperature, and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-2:1) as the eluent to afford the title compound (2.62 g, yield: 78%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Cl.[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[Na+]>>[Cl:6]([OH:10])(=[O:9])(=[O:8])=[O:7].[NH2:1][C:2]([NH2:4])=[O:3]
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Product: [O-][Cl+3]([O-])([O-])O
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
606 Grams of urea were added to 1040 g of 35% hydrochloric acid and dissolved therein under agitation. Then, 1405 g of sodium perchlorate were added to the solution and the mixture was stirred vigorously for 10 minutes at 40° C and cooled to 20° C. The precipitated crystals were separated by filtration. These crystals were sodium chloride. The filtrate contained about 65% of urea perchlorate but still contained a small amount of sodium chloride dissolved therein. Thus, the filtrate was concentrated under reduced pressure at a temperature below 80° C and filtered while hot, thereby removing the majority of the sodium chloride. By repeating this procedure comprising concentration and cooling for the aqueous solution of urea perchlorate thus obtained, crystals of urea perchlorate could be produced in a high yield.
Reaction SMILES: IC.[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1.[C:39]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([O:29][CH3:39])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(O)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1cc(C)c(OC)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
19 μL (0.30 mmol) iodomethane were added to a solution of 100 mg (0.20 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 2 mL DMF and the mixture was stirred for 15 min at RT. Then 131 mg (0.40 mmol) Cs2CO3 was added and the reaction solution was heated to 50° C. for 3 h. The precipitate was filtered, the filtrate was evaporated down to 1 mL down and combined with 3 mL water. The precipitate was suction filtered, dried and further reacted without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19]([O-])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.Cl.[OH-].[Na+]>C(OCC)(=O)C.O>[CH2:17]([O:16][C:14]([C:13]1[C:12](=[O:11])[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:8]=2)[NH:6][CH:19]=1)=[O:15])[CH3:18]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]c2ccc(Cl)cc2c1=O
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 4-chloroaniline (156.7 mmol) and ethyl ethoxymethylenemalonate (156.7 mmol) was stirred at room temperature until homogeneous. The homogeneous solution was heated in an oil bath at 165° C. for 6 hours. The reaction mixture was cooled to room temperature and 1 N HCl (3 mL) was added. The reaction mixture was stirred and heated to 115° C. for 3 hours. The mixture was cooled to room temperature and then treated with 20 mL of water. The resulting suspension treated with 10 N NaOH solutions to reach the pH about 8. It was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 9:1 v/v hexane: ethyl acetate as solvent to afford title compound (28 g, 71% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:26][C@H:27]([CH2:35][OH:36])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.N[C@@H](CC1C=CC=CC=1)C[OH:40]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:26][C@H:27]([CH2:35][OH:36])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([OH:40])=[CH:31][CH:30]=2)[N:3]=1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: N[C@H](CO)Cc1ccccc1
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccc(O)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (intermediate ZM), by substituting 4-((S)-2-amino-3-hydroxy-propyl)-phenol for (S)-2-amino-3-phenyl-propan-1-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:21][CH2:22]O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH2:21][CH3:22])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2ccccc12
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])cc2ccccc12

Procedure:
To a solution of 3-nitronaphthalene-1-carboxylic acid (4.34 g, 20 mmol) in EtOH (50 mL) was added SOCl2 (3.70 mL, 30 mmol) at 0° C. The mixture was heated at reflux for 2 h and then concentrated. The residue was recrystallized from EtOH to yield ethyl 3-nitronaphthalene-1-carboxylate (4.2 g). 1H NMR (300 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.77 (d, J=8.7 Hz, 1H), 8.62 (s, 1H), 8.34 (d, J=8.1 Hz, 1H), 7.87 (t, J=7.2 Hz, 1H), 7.75 (t, J=7.2 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4cccs4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 60. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, 1H, J=3.52 Hz), 7.46 (d, 1H, J=4.69 Hz), 7.17 (d, 2H, J=8.21 Hz), 7.16-7.10 (m, 2H), 6.87-6.86 (m, 1H), 6.81 (d, 2H, J=8.60 Hz), 6.72-6.69 (m, 2H), 4.21 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.12 (d, 1H, J=14.08 Hz), 3.01 (t, 2H, J=6.26 Hz), 2.38 (s, 3H), 2.30 (s, 3H), 1.41 (s, 3H); HRMS (ES+) m/z exact mass calcd for C27H28NO5S 478.1688, found 478.1692.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:16]1[CH:21]=[CH:20][C:19](Br)=[C:18]([F:23])[N:17]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[C:30]([O:34][C:35]([N:37]1[C:41]2=[N:42][CH:43]=[C:44]([Cl:46])[CH:45]=[C:40]2[C:39]([CH2:47]Cl)=[CH:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].N>O1CCCC1>[C:30]([O:34][C:35]([N:37]1[C:41]2=[N:42][CH:43]=[C:44]([Cl:46])[CH:45]=[C:40]2[C:39]([CH2:47][C:19]2[C:18]([F:23])=[N:17][C:16]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[CH2:8][C:9]3[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=3)=[CH:21][CH:20]=2)=[CH:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Br)c(F)n1
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cc(Cl)cnc21
Agent: CC(C)[Mg]Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Cc2cn(C(=O)OC(C)(C)C)c3ncc(Cl)cc23)c(F)n1
Temperature: -35 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (143, 0.600 g, 1.50 mmol) in 10.0 mL of tetrahydrofuran at −25° C. under nitrogen, isopropylmagnesium chloride (0.730 mL, 2.0 M in tetrahydrofuran, 1.46 mmol) was added and the reaction allowed to come to 5° C. over 1 hour. The reaction was then cooled to −35° C., and CuCN-2LiCl (2.0 mL, 0.75 M in tetrahydrofuran, 1.5 mmol) was added. After 5 minutes, 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (142, 0.300 g, 0.996 mmol) in 4.0 mL of tetrahydrofuran was added and the reaction allowed to come to room temperature over 1 hour. The reaction was poured into dilute ammonia solution and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound (144, 130 mg). MS (ESI) [M+H]+=586.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[CH2:9]([Mg]Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CCOCC>[CH2:9]([C:2]1[CH:7]=[CH:6][C:5]([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC[Mg]Br
Reactant: Clc1ccc(Cl)cc1
Solvent: CCOCC
Product: CCCCCCc1ccc(CCCCCC)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A 2 L round-bottomed flask is charged with 1,4-dichlorobenzene (118 g, 0.80 mol), [1,3 -bis(diphenylphosphino)propane]Ni(II) chloride (500 mg, 0.9 mmol), and dry ether (600 mL). The mixture is cooled to 0° C. and a 2 M solution of n-hexylmagnesium bromide in ether (1 L) is added dropwise. The cooling bath is removed, and the solution is slowly heated to reflux and allowed to boil for 24 h. The mixture is cooled to 0° C. and diluted with water (50 mL) and then with a 2 M aqueous hydrochloric acid solution (500 mL). The aqueous layer is separated, extracted with ether (2×200 mL), and the combined organic layers are washed with water (100 mL) and dried over magnesium sulfate. The solvent is removed in vacuo and the product is purified by distillation.