Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CCCCC.[Cl-].[C:17]([O:21][C:22](=[O:25])[CH2:23][Zn+])([CH3:20])([CH3:19])[CH3:18]>C1COCC1.CCOC(C)=O>[C:17]([O:21][C:22](=[O:25])[CH2:23][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Cc1ccc2cc[nH]c2c1

Procedure:
To a solution of 6-bromoindole (2 g, 10.2 mmol) in THF (20 mL) under nitrogen atmosphere was added KH (30% in mineral oil de-greased with pentane, 1.5 g, 11.22 mmol) and the mixture was stirred at RT for 30 min before addition of [P(t-Bu)3PdBr]2 (40 mg, 0.051 mmol) diluted in THF (20 mL). The resulting mixture was added to a solution of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in Et2O, 22.4 mL, 11.2 mmol) stirred under nitrogen atmosphere and the mixture was further stirred at RT for 24 h. The reaction mixture was diluted with EtOAc, and washed with a saturated aqueous solution of NaHCO3, then with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 94:6 to c-hexane/EtOAc 8:2) to give the desired material. TLC, Rf (c-hexane/EtOAc 4:1)=0.3; MS (UPLC): 232.2 [M+H]+, 176.1 [MH−tBu]+, 249.2 [M+NH4]+, 463.4 [2M+H]+, 273.3 [M+HCOO]−.
Reaction SMILES: [C:1]1(Cl)[C:7](=O)[C:6](Cl)=[C:5](Cl)[C:3](=O)[C:2]=1Cl.C[N:14]1[C:18](=O)CCC1.C[N:21](C=O)C>>[N:21]1[C:2]2[CH:3]=[CH:5][CH:6]=[CH:7][C:1]=2[NH:14][CH:18]=1
Reactant: CN(C)C=O
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CN1CCCC1=O
Product: c1ccc2[nH]cnc2c1
Reaction time: 18 h

Procedure:
Each resin was suspended in DMF (200 μL) and a 1 M solution of the aldehyde in DMF was added (0.20 mmol, 200 μL), followed by a 0.25 M solution of chloranil in NMP (0.20 mmol, 800 μL). The resins were shaken for 18 h, the liquid was drained and the resins were washed successively with 1.2-mL portions of NMP (3×), 1 M DIEA/NMP (2×), NMP (3×), MeOH (3×) and DCM (4×). The reaction block was placed in a vacuum chamber for 30 min in order to dry the resin.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].I[C:11]1[C:12](=[O:28])[N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:14]=[CH:15][C:16]=1[CH3:17].CC#N.C(N(CC)CC)C>CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[C:2][C:11]2[C:12](=[O:28])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])=[CH:4][N:5]=1
Reactant: Cc1ccn(-c2cccc(C(F)(F)F)c2)c(=O)c1I
Reactant: C#Cc1cnc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccn(-c2cccc(C(F)(F)F)c2)c(=O)c1C#Cc1cnc(N)nc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-ethynylpyrimidin-2-amine (0.023 g, 0.19 mmol), 3-iodo-4-methyl-1-(3-(trifluoromethyl)phenyl)pyridin-2(1H)-one (0.041 g, 0.11 mmol), copper(I) iodide (0.001 g, 0.0054 mmol), and Pd(PPh3)2Cl2 (0.004 g, 0.0054 mmol) was added MeCN (2 mL) and triethylamine (0.300 ml, 2.200 mmol). The mixture was heated to 80° C. in a resealable tube. After 16 hrs, the reaction mixture was diluted with EtOAc and washed with water and brine. After concentrating in vacuo, the crude residue was purified by silica gel chromatography using 30-100% hexanes:EtOAc to afford 3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-1-(3-(trifluoromethyl)phenyl)-2(1H)-pyridinone as a white solid. Found M+H+=371.2.
Reaction SMILES: CN(C)[CH:3]1[C:14]2[C:6](=[CH:7][CH:8]=[C:9]3[C:13]=2[S:12](=C)[CH:11]=[N:10]3)[NH:5][C:4]1=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29]([CH3:30])=[CH:28][C:27](=[O:31])[NH:26]2)=[CH:21][CH:20]=1.[CH2:32](O)C>C(OCC)C>[CH3:30][C:29]1[N:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18]/[CH:32]=[C:3]3\[C:4](=[O:16])[NH:5][C:6]4[C:14]\3=[C:13]3[S:12][CH:11]=[N:10][C:9]3=[CH:8][CH:7]=4)=[CH:24][CH:23]=2)[NH:26][C:27](=[O:31])[CH:28]=1
Reactant: CCO
Reactant: C=S1C=Nc2ccc3c(c21)C(N(C)C)C(=O)N3
Reactant: Cc1cc(=O)[nH]n1-c1ccc(N)cc1
Solvent: CCOCC
Product: Cc1cc(=O)[nH]n1-c1ccc(N/C=C2\C(=O)Nc3ccc4ncsc4c32)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 8-dimethylamino-methylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one (Procedure E, 0.040 g, 0.163 mmol), 2-(4-aminophenyl)-3-methyl-pyrazoline-5-one (0.047 g, 0.248 mmol) in absolute ethanol (5 ml) was heated with stirring at 90° C. for 16 h. The reaction was diluted with ethanol and diethyl ether and the product collected by filtration to yield 0.052 (83%) of the title compound. 1H NMR (DMSO-d6): δ11.08 (d,1H, J=12.3 Hz), 10.84 (s,1H), 9.85 (s,1H), 9.23 (s,1H), 8.05 (d,1H, J=12.1 Hz), 7.78 (d,1H, J=8.2 Hz), 7.51-7.45 (m,4H), 7.10 (d,1H, J=8.4 Hz), 5.55 (s,1H), 2.25 (s,3H); ES−MS m/z 388 (M−H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
27.2 g of 4-hydroxyacetophenone is mixed with 100 ml of dimethylformamide, 25.3 g of benzyl chloride and 30.4 g of potassium carbonate. The resulting mixture is stirred in a stream of nitrogen at 100°-110° C. for 3 hours and then cooled. The cooled mixture is added to about 2 l of ice water to deposit solid. The solid is separated therefrom by filtration and then washed with water until the solid becomes neutral. The washed solid is dried and then recrystallized from 500 ml of ethanol to obtain 38.8 g of 4-benzyloxyacetophenone. Thus obtained 4-benzyloxyacetophenone has a melting point of 92.5°-93° C.
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:10]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])[N:9]=2)[CH2:6]CCC[CH2:2]1.C([Li])CCC.[CH:38]([OH:41])([CH3:40])[CH3:39]>>[CH:1]([O:7][C:8]1[N:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:10]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:9]=1)([CH3:6])[CH3:2].[CH:38]([O:41][C:12]1[C:11]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:10]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:9]=[CH:8][N:13]=1)([CH3:40])[CH3:39]
Reactant: CC(C)O
Reactant: CS(=O)(=O)c1nc(OC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Product: CC(C)Oc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Product: CC(C)Oc1ncnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2-Cyclohexyloxy-4-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Higher Rf product) (Example 52, Step A), (26 mg, 0.05 mmol) was reacted with 1 equivalent each of n-butyl lithium and isopropanol by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 95/5 hexanes/ethyl acetate) afforded 2-isopropoxy-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine and 2-cyclohexyloxy)-4-isopropoxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (HRf product): HPLC/MS: m/e=493 (M++1); Rt=5.26 min. 1H-NMR 500 MHz (CDCl3): δ 0.9 (m, 1H), 1.30 (m, 1H), 1.35) d, J=6 Hz, 6H), 1.42 (m, 2H), 1.65 (m, 3H), 1.90 (m, 2H), 2.15 (m, 2H), 5.03 (m, J=4 Hz, 1H), 5.47 (qn, J=6 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 7.18 (m, 4H), 7.32 (d, J=2 Hz, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH3:36])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([NH:28][CH:29]([CH2:40][CH:37]2[CH2:39][CH2:38]2)[C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH3:36])[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=CC1CC1
Reactant: Cc1nc(C)c(CNC2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc(C)c(C(CC2CC2)NC2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 25 h
Yield: 99.4 %

Procedure:
Sodium triacetoxyborohydride (1.80 g, 8.49 mmol) is added to a stirred solution of 4-{[(2,4-dimethyl-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.71 g, 5.25 mmol), cyclopropanecarboxaldehyde (0.44 ml, 5.89 mmol), acetic acid (0.32 ml, 5.59 mmol), and 1,2-dichloroethane (35 ml). The reaction is stirred for 25 h at room temperature under nitrogen. The reaction is poured into 2N NaOH (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered off. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 40% ethyl acetate/hexanes to yield (1.98 g, 99%) of 4-{[cyclopropylmethyl-(2,4-dimethyl-thiazol-5-ylmethyl)]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=380.3 (M+1); 1H NMR (CDCl3): δ=4.18 (2H, brs), 3.74 (2H, s), 2.86-2.78 (1H, m), 2.70-2.60 (5H, m), 2.41 (2H, d), 2.32 (3H, s), 1.81-1.70 (2H, m), 1.50-1.39 (11H, m), 0.87-0.80 (1H, m), 0.53-0.46 (2H, m), 0.12-0.06 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[C:33]([O:37][C:38](=[O:46])[NH:39][CH2:40][CH:41]([OH:45])[CH2:42][NH:43][CH3:44])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:46])[NH:39][CH2:40][CH:41]([OH:45])[CH2:42][N:43]([C:20]1[S:21][C:17](=[CH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=2[C:29]([F:30])([F:31])[F:32])[N:8]=[CH:9]3)[C:18](=[O:26])[N:19]=1)[CH3:44])([CH3:36])([CH3:34])[CH3:35]
Reactant: CNCC(O)CNC(=O)OC(C)(C)C
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CC(O)CNC(=O)OC(C)(C)C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
[3-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and (2-Hydroxy-3-methylamino-propyl)-carbamic acid tert-butyl ester following General Procedure
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.N1C=CC=CC=1.[CH2:15]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)Cl.C(Cl)(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:37](=[O:38])[CH2:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=1
Reactant: NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)NCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a 0° C. solution of 4.64 g of 2-(aminomethyl)pyridine, 13.2 ml of pyridine and 50 ml of methylene chloride is added, dropwise, 15 g of product from Example 53 in 150 ml of methylene chloride. The reaction is stirred at 0° C. for 1 hour followed by 18 hours at room temperature. The reaction is diluted with chloroform, washed with sodium bicarbonate, water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica ge1:75-100% ethyl acetate/hexane) to give 11.0 g of the desired product as colorless prisms.
Reaction SMILES: F[C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.O>C(#N)C>[N:14]1([C:2]2[C:3]([C:10]([F:13])([F:12])[F:11])=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: C1CNCCN1
Reactant: N#Cc1cccc(F)c1C(F)(F)F
Solvent: CC#N
Solvent: O
Product: N#Cc1cccc(N2CCNCC2)c1C(F)(F)F

Procedure:
A solution of 3-fluoro-2-(trifluoromethyl)benzonitrile (1.2 g, 6.3 mmol) and piperazine (0.72 g, 8.4 mmol) in acetonitrile (6 ml) was heated under microwave radiation at 150° C. for 15 minutes. The reaction mixture was poured into water (50 ml) and the aqueous phase was extracted with ethylacetate (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. Purification by flash column chromatography (ethylacetate/methanol, 1:1) gave the title compound: 1.1 g. MS m/z (rel. intensity, 70 eV) 255 (M+, 16), 214 (11), 213 (bp), 171 (8), 151 (7).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cc(OC)c(OC)c(OC)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3,4,5-trimethoxy-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3,4,5-trimethoxybenzoyl chloride (204 mg, 0.89 mmol). The title compound was obtained as yellow powder (177 mg, 43%).
Reaction SMILES: [CH2:1](N(CC)CC)C.ClCCl.C(OC(NC(C)(C)CN(C(OC(C)(C)C)=O)CCCO)=O)C1C=CC=CC=1.[C:38]([O:42][C:43]([N:45]([CH2:63][CH2:64][CH2:65][OH:66])[CH2:46][C@@H:47]([NH:49][S:50]([C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[CH:59]=[N:58][CH:57]=[CH:56]2)(=[O:52])=[O:51])[CH3:48])=[O:44])([CH3:41])([CH3:40])[CH3:39]>O>[C:38]([O:42][C:43]([N:45]([CH2:63][CH2:64][CH2:65][OH:66])[CH2:46][C:47]([NH:49][S:50]([C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[CH:59]=[N:58][CH:57]=[CH:56]2)(=[O:52])=[O:51])([CH3:1])[CH3:48])=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@@H](CN(CCCO)C(=O)OC(C)(C)C)NS(=O)(=O)c1ccc2cnccc2c1
Reactant: CCN(CC)CC
Agent: CC(C)(CN(CCCO)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CN(CCCO)C(=O)OC(C)(C)C)NS(=O)(=O)c1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.7 mL of triethylamine was added to a dichloromethane (20 mL) solution of 550 mg of 2-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl-3-hydroxypropylamino)-2-methylpropane (Reference Compound 37). To this reaction solution, a dichloromethane solution (100 mL) of 6-chlorosulfonylisoquinoline (Reference Compound 2) synthesized according to Reference Example 2 was added, and the mixture was stirred at room temperature for 16 hours. After the completion of reaction, water was added, followed by extraction with dichloromethane (20 mL×3). The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel chromatography (acetone:hexane=1:1) to obtain 140 mg of the compound of interest as a brown oil (14%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=CC=C(C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:13]=[CH:14][CH:15]=[CH2:16]>CC1C=CC=CC=1C>[CH3:13][C:14]1[CH:6]=[CH:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][C:16]=2[CH:15]=1
Reactant: Cc1cccc2c(C)cccc12
Reactant: C=CC=C
Solvent: Cc1ccccc1C
Product: Cc1ccc2cc(C)ccc2c1

Procedure:
The present inventors synthesized 1,5-DMN from o-xylene and butadiene as the starting raw materials and isomerized the resultant 1,5-DMN to obtain the mixture of isomers consisting essentially of 1,5-, 1,6- and 2,6-DMNs, which was cooled as it is to precipitate 2,6-DMN crystal in the form of scale. The crystal thus obtained was poor in the efficiency of separation from the mother liquor at the time of filtration, whereby it was difficult to obtain highly pure 2,6-DMN. As is the case with the foregoing, 2,6-DMN crystal in the form of scale was obtained from the mixture of isomers containing 2,7-, 1,7-DMN, etc. other than 1,5-, 1,6- and 2,6-DMN as the starting raw material for crystallization, but it was extremely poor in filtration efficiency.
Reaction SMILES: [N:1]([CH2:4][C:5](Cl)=[O:6])=[N+:2]=[N-:3].[OH:8][CH2:9][CH2:10][O:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[N:1]([CH2:4][C:5]([O:8][CH2:9][CH2:10][O:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(=O)Cl
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 59.6 %

Procedure:
A solution of 0.84 ml (8.4 mmol) azidoacetyl chloride in 5 ml dry dimethylformamide was added dropwise over 10 minutes in an ice-cooled, thoroughly stirred suspension of 1.25 g (5.55 mmol) 9-(2-hydroxyethoxymethyl)guanine and 0.78 ml (5.55 mmol) triethylamine in 40 ml dry dimethylformamide. After 45 minutes of thorough stirring at 0° C., 0.11 ml (1.1 mmol) azidoacetylchloride in 1 ml dimethylformamide was added, and stirring was continued for 15 minutes. The reaction was stopped by the addition of 15 ml 7% NaHCO3 solution whereupon the mixture was evaporated to dryness in vacuo. The residue was triturated with 20 ml of a mixture of methylene chloride:diethyl ether:ethanol (volume ratio 5:5:1). The solid substance obtained was filtered off, thoroughly washed with cold water and recrystallised from hot water, after treatment with active carbon. 1.02 g (62%) of 9-(2-azidoacetoxyethoxy-methyl)guanine m.p. 175°-177° C. (decomposition) was obtained. MS m/e 308 (M30), 151 (base+H); IR (KBr) 2110 (N3), 1745 (COOR) cm-1 ; UV (phosphate buffer, pH=7) λmax 253 nm (ε 8.42× 103), 270 (sh); TLC Rf 0.27 (CHCl3 --MeOH, 8:2), Rf 0.60 (EtOH--HOAc, 8:2).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][NH2:19])=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30]3([CH:33]=O)[CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C.C(O)(=O)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:33]([C:30]4([C:26]5[CH:25]=[C:24]6[C:29](=[CH:28][CH:27]=5)[N:20]=[CH:21][CH:22]=[CH:23]6)[CH2:32][CH2:31]4)=[N:19][N:18]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=CC1(c2ccc3ncccc3c2)CC1
Reactant: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1F
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
A mixture of methyl 2-fluoro-4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate (0.17 g, 0.64 mmol) and 1-quinolin-6-ylcyclopropanecarbaldehyde (0.13 g, 0.64 mmol) in ethanol (10 mL) and acetic acid (1 mL) was stirred at RT for 2 h. The mixture was concentrated. The residue was dissolved in methylene chloride (5 mL). To the solution was added iodobenzene diacetate (230 mg, 0.71 mmol) with stirring. The mixture was stirred at RT for 2 h then concentrated. The residue was flash chromatographed on a silica gel column to give the desired product (150 mg). Analytical LCMS: (M+H)+=441.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Reactant: C1COCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)c1cccc(N2CCOCC2)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 153.6 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 3-(1-tert-butoxycarbonylaminoethyl)phenyl ester (1.5 g, 4.08 mmol), morpholine (8 mL) Pd2(dba)3 (187 mg, 5 mol %), di-t-butyl-biphenylphosphine (243 mg, 20 mol %), potassium phosphate (1.21 g, 5.71 mmol) was stirred at 80° C. in a sealed tube for 10 hours. After cooling down, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (10 mL). The aqueous layer was extracted with dichloromethane (2×15 mL) and the combined organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography of Biotage with 30% ethyl acetate/hexanes to provide the title compound as a pale yellow solid (1.01 g, 81% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[O:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>ClCCCl>[Cl:1][CH2:2][CH2:3][C:4]([C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: c1ccoc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCCl)c1ccco1
Temperature: 0 °C
Yield: 11 %

Procedure:
At 25°, 3-chloropropionyl chloride (25.4 g, 0.20 mole) was added to a suspension of anhydrous aluminum chloride (27.1 g, 0.20 mole) in 1,2-dichloroethane (DCE). The mixture was stirred until the aluminum chloride had nearly dissolved. This solution was added at 0°-5° during 15 minutes to a solution of furan (13.6 g, 0.2 mole) in 100 ml of DCE. The reaction mixture became very dark and a tan precipitate was deposited. The reaction mixture was then immediately poured into 1 of ice-water. An emulsion of some brown precipitate formed. This mixture was extracted with diethyl ether (five times, 150 ml), and the combined ether extract was filtered through a column of 150 g of silica gel. The column was then washed with 200 ml of ether and the combined eluants were concentrated at reduced pressure (40°) to 100 ml. The solution was then washed with 100 ml of saturated sodium hydrogen carbonate, dried over anhydrous sodium sulfate, treated with activated carbon, and evaporated at reduced pressure to give a liquid (3.5 g) which rapidly darkened at room temperature. It was stored at -10°. PMR spectroscopy indicated the product was about 75% desired copound. The mixture was used without further purification.