Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:24][CH2:25][CH:26]([OH:28])[CH3:27]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21][S:24][CH2:25][CH:26]([OH:28])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)CS
Reactant: O=C(CCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CC(O)CSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 1, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) and 1-mercapto-2-propanol as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 89% yield.
Reaction SMILES: C(OC(N1CCN([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)CC1)=O)(C)(C)C.Cl.[C@H:32]12[CH2:38][C@H:35]([NH:36][CH2:37]1)[CH2:34][N:33]2[C:39]([NH2:41])=[O:40]>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:36]3[CH2:37][C@@H:32]4[CH2:38][C@H:35]3[CH2:34][N:33]4[C:39]([NH2:41])=[O:40])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: NC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc([C@H]2COc3cccnc3O2)cc1

Procedure:
Compound 268 is synthesized from Intermediate C and Intermediate P according to General Method J. (LC/MS method 16: ES+ m/z 367.3 [M+H]+, Rt=0.27 min)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11]>C1COCC1>[Cl:6][CH2:7][CH2:8][NH:9][C:10]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:11]
Reactant: COCCN
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: COCCNC(=O)NCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of methoxyethylamine (0.40 mL, 4.60 mmol) in THF (15 mL) was treated with 2-chloroethylisocyanate (0.35 mL, 4.10 mmol), stirred at RT for 3 h and concentrated to dryness to afford 1-(2-chloroethyl)-3-(2-methoxyethyl)urea (100% yield assumed) as a white solid. MS (ESI) m/z: 181.1 (M+H+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([S:27]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:29])=[O:28])[CH3:26]
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCNCC3)n[nH]c12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 3-(4-piperidinyl)-5-(2-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 17) (0.117 mmol) was reacted with ethane sulfonyl chloride (0.02 mL, 0.234 mmol) in the presence of triethylamine (0.04 mL, 0.468 mmol) in methylene chloride (10 mL) to give the title compound (4.9 mg, 10% for the last two steps)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH:18]([OH:20])[CH3:19])[S:17][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH:18]([O:20][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:19])[S:17][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(C(C)O)cc1C(c1ccccc1Cl)=NC2
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: Cc1nnc2n1-c1sc(C(C)OC(=O)C(C)(C)C)cc1C(c1ccccc1Cl)=NC2
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 3 g of 4-(2-chlorophenyl)-2-(1-hydroxyethyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine dissolved in 30 ml of pyridine is added 1 g of pivaloyl chloride under ice-cooling and then stirred overnight. After completion of the reaction, the mixture is concentrated under reduced pressure and the residue is dissolved in 30 ml of ethyl acetate. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off, the filtrate is concentrated under reduced pressure and the residue is subjected to chromatography on silica gel and eluted with chloroform-methanol (100:1-100:3). The objective fraction is concentrated under reduced pressure followed by crystallization from ligroinethyl acetate to give 1.1 g of 4-(2-chlorophenyl)-9-methyl-2(1-pivaloyloxyethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine as crystals, melting at 148°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NCCN1CCOCC1
Solvent: c1ccccc1
Solvent: O
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1

Procedure:
26 G. of p-chlorobenzaldehyde and 24 g. of N-(2-aminoethyl)-morpholine are boiled in 150 ml. of benzene for 3 hours under reflux with water being separated. Then, the mixture is evaporated to dryness and the residue is distilled at 165° C./0.01 mmHg. 5 G. of the resulting 4-{2-[(p-chlorobenzylidene)-amino]-ethyl}-morpholine, 2.3 g. of sodium acetate and 3 ml. of 30% hydrogen peroxide are stirred in 60 ml. of methanol overnight at room temperature. Thereafter, the mixture is evaporated to dryness and the residue is taken up in 50 ml. of methylene chloride and 50 ml. of water. The phases are separated and the aqueous phase extracted with 50 ml. of methylene chloride. The methylene chloride extract is dried over sodium sulfate and evaporated. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The pure fractions are combined and evaporated. The residue is recrystallized from isopropanol, and 0.7 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:34][CH2:33]1>>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][NH:41][C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:34][CH2:33]1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CN1CCN(CCCN)CC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCI, m/z): 501 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1c(F)cccc1Cl
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3c(F)cccc3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-6-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([O:14]C)=[O:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]=[CH:7]2.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([OH:14])=[O:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]=[CH:7]2
Reactant: COC(=O)c1ccc(F)c2c1C=CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(F)c2c1C=CCO2

Procedure:
Methyl 8-fluoro-2H-1-benzopyran-5-carboxylate (7.36 g, 35.4 mmol) was dissolved in absolute ethanol (220 mL), NaOH (2.0 g, 49.6 mmol) in H2O (25 mL), was added thereto, and the reaction mixture was refluxed for 1.5 hour. The reaction mixture was cooled and the solvent was removed in vacuo. The yellow solid was dissolved in H2O (150 mL), active charcoal was added and then filtered off. The resulting light-coloured liquid was washed with diethyl ether, the aqueous solution was made acidic with 2 M HCl and the product was extracted twice with ethyl acetate. The combined organic portions were treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give 6.64 g (97% yield) of a yellowish solid (dried in a desiccator over P2O5) as the title compound (mp 224-226° C.). EIMS (70 eV) m/z (relative intensity) 194 (93, M+), 193 (100), 149 (56), 148 (68), 120 (13), 88 (25), 75 (28), 74 (21), 60 (12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([N:13]([CH2:17][CH2:18]Cl)[CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[N:29]1[CH2:30][CH2:31][N:32]([CH2:18][CH2:17][N:13]([CH:14]([CH3:15])[CH3:16])[S:10]([C:3]2[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:12])[CH2:33][CH2:34]1
Reactant: c1ccc2[nH]c(N3CCNCC3)nc2c1
Reactant: CC(C)N(CCCl)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Product: CC(C)N(CCN1CCN(c2nc3ccccc3[nH]2)CC1)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
The title compound was prepared using the procedure described in Example 1 using D7 and 1-(1H-benzimidazol-2-yl)piperazine. MH+ 530/532/534/536.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C@H:9]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:33]=[N:32][C:31]3[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=3[N:25]=2)=[CH:18][CH:17]=1)[CH2:10][C:11]([O:13]CC)=[O:12].Cl>CCO>[CH3:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C@H:9]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]2[CH:33]=[N:32][C:31]3[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=3[N:25]=2)=[CH:20][CH:21]=1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C[C@@H](c1ccc(OCc2cnc3c(n2)C(C)(C)CCC3(C)C)cc1)c1nccn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ccnc1[C@@H](CC(=O)O)c1ccc(OCc2cnc3c(n2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10% NaOH(aq) (1 mL) is added to a solution of compound 55 (47 mg, 0.1 mmol) in EtOH (2 mL). The reaction mixture is stirred at room temperature for 4 hours. 1N HCl is added to neutralize the mixture to pH 6-7. The mixture is extracted with EtOAc (2×20 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is flash chromatographed (silica gel, 0-10% MeOH in DCM) to afford compound 56.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN.[CH2:36]([NH:38][C:39]([NH:41][C:42]1[N:47]=[CH:46][C:45]([C:48]2[CH:49]=[N:50][CH:51]=[C:52]([C:54]([OH:56])=O)[CH:53]=2)=[C:44]([C:57]2[S:58][CH:59]=[C:60]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:61]=2)[CH:43]=1)=[O:40])[CH3:37]>CN(C=O)C>[CH2:36]([NH:38][C:39]([NH:41][C:42]1[N:47]=[CH:46][C:45]([C:48]2[CH:49]=[N:50][CH:51]=[C:52]([C:54]([NH:2][CH3:1])=[O:56])[CH:53]=2)=[C:44]([C:57]2[S:58][CH:59]=[C:60]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:61]=2)[CH:43]=1)=[O:40])[CH3:37]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)O)c2)cn1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)NC)c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (73.7 mg, 0.19 mmol), DIEA (78.6 mg, 0.45 mmol) and methylamine (2M soln in THF, 0.15 mL, 0.30 mmol) were added to a solution of 6′-{[(ethylamino)carbonyl]amino}-4′-(4-phenyl-1,3-thiazol-2-yl)-3,3′-bipyridine-5-carboxylic acid (Example 132, 66.4 mg, 0.15 mmol) in DMF (1.5 mL). The resulting light yellow solution was stirred at room temperature for three hours. The reaction mixture was partitioned between water and ethyl acetate and layers separated. The organic layer was washed with saturated NaHCO3, water, brine, then dried over magnesium sulfate. The solvent was removed and the resulting residue was washed with acetonitrile and filtered to yield 33 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21]OS(C)(=O)=O)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:36]([O:35][C:33]([N:27]1[CH2:32][CH2:31][N:30]([CH2:21][C:12]2[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[N:15]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=3)[CH:11]=2)[CH2:29][CH2:28]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC(C)C)n2)cc1Cl
Yield: 89 %

Procedure:
Following the procedure of Example 1(10), 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 89.0%).
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([OH:16])[C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7]1)(=O)C>CN>[C@@H:9]1([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([OH:16])[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:6]([CH2:5][OH:4])[CH:7]=[CH:8]1
Reactant: CC(=O)OC[C@@H]1C=C[C@H](n2cnc3c(O)ncnc32)O1
Agent: CN
Product: OC[C@@H]1C=C[C@H](n2cnc3c(O)ncnc32)O1
Temperature: 30 °C
Reaction time: 4.5 h
Yield: 73.7 %

Procedure:
5′-O-Acetyl-2′,3′-dideoxy-2′,3′-didehydroinosine (100 gm) is added to 25% monomethyl amine (360 ml) at 25-35° C. and stirred for 4-5 hours at 25-35° C. The mass is filtered on a celite bed, washed with methanol (50 ml) and the solvent is distilled off completely under reduced pressure at below 70° C. Methanol (25 ml) is added to the filtrate, the solvent is distilled off completely, and methanol (25 ml) is again added and co-distilled. To the mass, acetone (25 ml) is added, co-distilled, again co-distilled with 25 ml of acetone at below 70° C. and acetone (400 ml) is added. The contents are cooled to 25-35° C., stirred for 2 hours to 2 hours 30 minutes at 25-35° C. Then the reaction mass is cooled to 0-10° C. and stirred for 1 hour to 1 hour 30 minutes. material is filtered, washed with acetone (80 ml) and dried at 55-65° C. to give 62.5 gm of 2′,3′-dideoxy-2′,3′-didehydroinosine (HPLC Purity: 98.14%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:31]=[CH:30][C:18]([O:19][CH:20]([CH3:29])[C:21]([O:23][CH2:24][CH2:25]N(C)C)=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.[CH3:32][I:33]>ClCCl>[CH3:32][I:33].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:31]=[CH:30][C:18]([O:19][CH:20]([CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1
Reactant: CC(Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1)C(=O)OCCN(C)C
Solvent: ClCCl
Solvent: CI
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(dimethylamino)ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate in dichloromethane was added to a large excess of methyl iodide in dichloromethane. The mixture was stirred for 2 hrs at room temperature, then evaporated to give 2-dimethyl amino)ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate methyl iodide salt as yellow crystals mp 76° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]([F:20])([F:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:12]([F:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:3]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCC(F)(F)c2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCC(F)(F)c2ccccc2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reaction time: 6 h
Yield: 105.7 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,2-difluoro-2-phenyl-ethyl)-amine (0.19 g, 0.62 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [190 mg, 0.94 mmol, see Example 49(b), step 2], and Cs2CO3 (0.51 g, 1.6 mmol) in ethylene glycol dimethyl ether (10 mL) and water (2 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium (0) (36 mg, 0.03 mmol) at room temperature. After 6 h at 85° C., the mixture is diluted with water (15 mL), and extracted with EtOAc (2×20 mL). The extracts are dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 eluting with 70% EtOAc in heptane to afford 2-{3-[6-(2,2-difluoro-2-phenyl-ethylamino)-2-methoxy-pyrimidin-4-yl]-phenyl}-2-methyl-propionic acid [0.28 g Example 67]. LCMS: RT=2.82 minutes; MS: 428 (M+H); 1H NMR (300 MHz, CDCl3) 9.6 (1H, s), 8 (1H, s), 7.81 (1H, d, J=7.5 Hz), 7.5-7.4 (7H, m), 6.4 (1H, s), 4.2-4 (2H, m), 3.96 (3H, s), 1.65 (6H, s). IC50=38 nM
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11]#[N:12])=[CH:7][S:8][CH:9]=1.S(=O)(=O)(O)[OH:19]>>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11]([NH2:12])=[O:19])=[CH:7][S:8][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1cscc1Nc1c(Cl)cccc1Cl
Product: NC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
28.3 g (0.1 mole) of 4-(2,6-dichloroanilino)-3-thiophenacetonitrile are introduced into 150 ml of concentrated sulfuric acid and stirred for one hour at room temperature. It is poured onto ice, and the precipitate which has formed is filtered off. Recrystallization from ethyl acetate yields 4-(2,6-dichloroanilino)-3-thiophenacetamide (m. 172° to 173°).
Reaction SMILES: [C:1]([CH:4]([C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=1)C(OC(C)(C)C)=O)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12](=[O:22])[CH:4]=[C:1]([OH:3])[CH3:2])=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCc1ccc(CC(=O)C(C(C)=O)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(CC(=O)C=C(C)O)cc1

Procedure:
A solution of the above t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate in trifluoroacetic acid (60 ml) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (4.00 g) as yellow oil. APCI-Mass m/Z 205 (M+H).
Reaction SMILES: [C:1](=[O:19])([O:12][C@@H:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])OC1C=CC([N+]([O-])=O)=CC=1.[CH3:20][O:21][C@:22]12[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][C@H:23]1[NH:24][CH2:25][CH2:26]2>C(Cl)(Cl)Cl>[CH3:20][O:21][C@:22]12[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][C@H:23]1[N:24]([C:1]([O:12][C@@H:13]([CH3:18])[C:14]([F:15])([F:16])[F:17])=[O:19])[CH2:25][CH2:26]2
Reactant: CO[C@@]12CCN[C@@H]1CN(C(=O)OC(C)(C)C)C2
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CO[C@@]12CCN(C(=O)O[C@@H](C)C(F)(F)F)[C@@H]1CN(C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (15 mg) prepared in Referential Example 2 in CHCl3 (2 mL) was added tert-butyl (3aR,6aR)-3a-methoxyhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (11 mg) at room temperature. The resulting mixture was stirred at 100° C. in a sealed tube for 2 hours and then cooled to room temperature. The mixture was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜0/1) to give 5-tert-butyl 1-[(2S)-1,1,1-trifluoropropan-2-yl] (3aR,6aR)-3a-methoxyhexahydropyrrolo[3,4-b]pyrrole-1,5-dicarboxylate as a pale yellow foam.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(OC)cc2)oc1C
Yield: 88.9 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.6 g), 4-methoxy-phenylboronic acid (2.3 g), tetrakis(triphenylphosphine)palladium(0) (0.7 g), 2N aqueous sodium carbonate solution (15 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.6 g, 88%) as a white solid.