Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:24]=[C:23]2[C:18]([C@@H:19]([NH2:25])[CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.[N-:37]=[C:38]=[O:39].Cl.[C:41]([O:44][C@@H:45]1[CH2:49][C@H:48]([C:50]2[N:54]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=3)[C:53]([CH3:63])=[N:52][N:51]=2)N[CH2:46]1)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:44][C@@H:45]1[CH2:49][C@H:48]([C:50]2[N:54]([CH2:55][C:56]3[CH:57]=[CH:58][C:59]([Cl:62])=[CH:60][CH:61]=3)[C:53]([CH3:63])=[N:52][N:51]=2)[N:37]([C:38](=[O:39])[NH:25][C@@H:19]2[C:18]3[C:23](=[CH:24][C:15]([C:14]([F:13])([F:26])[F:27])=[CH:16][CH:17]=3)[O:22][CH2:21][CH2:20]2)[CH2:46]1)(=[O:43])[CH3:42]
Reactant: N[C@H]1CCOc2cc(C(F)(F)F)ccc21
Reactant: CC(=O)O[C@H]1CN[C@@H](c2nnc(C)n2Cc2ccc(Cl)cc2)C1
Reactant: [N-]=C=O
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)O[C@@H]1C[C@H](c2nnc(C)n2Cc2ccc(Cl)cc2)N(C(=O)N[C@H]2CCOc3cc(C(F)(F)F)ccc32)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirring solution of triphosgene (23 mg, 0.078 mmol) in dichloromethane (0.5 ml) was slowly added dropwise via syringe a premixed solution of (S)-7-(trifluoromethyl)chroman-4-amine (45 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.073 ml, 0.42 mmol) dissolved in dichloromethane (0.8 ml). The reaction mixture was stirred at room temperature for 15 minutes. The isocyanate thereby generated was then treated dropwise with a solution of (3R,5R)-5-(4-(4-chlorobenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)pyrrolidin-3-yl acetate hydrochloride from Step E (70 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.073 ml, 0.42 mmol) dissolved in dichloromethane (0.8 ml). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 10% aqueous KHSO4, 5% aqueous NaHCO3, and brine, dried (Na2SO4), filtered and concentrated to yield an oil (120 mg, 100%) which was used without further purification in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.OC1O[N:20]=[N+:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:23][C:22]=12>C1(C)C=C(C)C=C(C)C=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[N:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:23][C:22]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(OCc1ccccc1)N1CC[n+]2noc(O)c2C1
Reactant: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1
Solvent: Cc1cc(C)cc(C)c1
Product: O=C(OCc1ccccc1)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccnc(Cl)n3)c2C1
Temperature: 165 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-4-[2-(4-fluorophenyl)ethynyl]pyrimidine (i.e. the product of Example 2, Step A) (2.51 g, 10.8 mmol) and 4,5,6,7-tetrahydro-3-hydroxy-5-[(phenylmethoxy)carbonyl][1,2,3]oxadiazolo[3,4-a]pyrazin-8-ium inner salt (i.e. the product of Step B) (3.00 g, 10.8 mmol) in mesitylene (100 mL) was stirred at 165° C. for 18 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and treated with silica gel (10.0 g). The silica gel suspension was concentrated under reduced pressure to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (0:1 to 1:1) as eluant to give 1.5 g of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:16][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[N:4][CH:3]=1
Reactant: CCCCN
Reactant: Brc1cncc2ncc(Br)n12
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCNc1nccn2c(Br)cnc12
Temperature: 70 °C
Yield: 51.1 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (200 mg, 0.72 mmol) in THF (3.6 ml) was added butylamine (2.2 ml, 21.6 mmol). The mixture was heated at 70° C. for 3 hr. The mixture was then cooled to rt, and diluted with DCM. The organic layer was washed with water, brine, dried and concentrated. The residue was purified on a silica gel column to afford 99 mg (yield 51%) of (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-butyl-amine.
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[CH:6]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)([OH:3])=O.Cl.[C:23]1([N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:23]1([N:29]([NH:30][C:1]([CH2:4]/[CH:5]=[C:6]2\[CH2:7][CH2:8][CH2:9][C:10]3[C:15]\2=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:3])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)COc1cccc2c1CCCC2/C=C/C(=O)O
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1cccc2c1CCC/C2=C\CC(=O)NN(c1ccccc1)c1ccccc1
Yield: 70.8 %

Procedure:
A solution of the carboxylic acid (prepared in reference example 5, 150 mg), 2-chloro-N-methylpyridinum iodide (197 mg). 1,1-diphenylhydrazine hydrochloride (147 mg) and triethylamine (0.216 ml) in methylene chloride (6 ml) was stirred overnight at room temperature. The mixture was poured into 1N hydrochloric acid, and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue was crystallized from crystallized ethyl acetate to give the title compound (as pale yellow powder; 167 mg) having the following physical data.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([O:25]C2CCCCO2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([OH:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OCc3ccccc3)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a mixture of ethyl 2-(4-(benzyloxy)-1-hydroxy-6-(tetrahydro-2H-pyran-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.48 g, 3.1 mmol) in THF (10 mL) was slowly added conc. HCl (1.48 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and neutralized by addition of Et3N. The resulting mixture was extracted with EtOAc (3×25 mL), dried over anhydrous Na2SO4 and concentrated to give the title compound as a white powder (1.01 g, Yield: 95%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([OH:12])(=[O:11])[CH2:9][OH:10].[O-2:13].[La+3].[O-2].[O-2].[La+3].[OH-].[Na+:19]>O>[C:8]([CH2:9][O:10][CH:2]([CH2:3][C:4]([O-:13])=[O:5])[C:1]([O-:6])=[O:7])([OH:12])=[O:11].[Na+:19].[Na+:19].[Na+:19]
Reactant: [O-2]
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(O)CO
Agent: [La+3]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CC(OCC(=O)O)C(=O)[O-]
Temperature: 25 °C

Procedure:
An amount of 19.6 g of maleic anhydride was dissolved into 50 g of water. Then, 21.7 g of a 70 weight % aqueous glycolic acid solution and 1.6 g of lanthanum oxide (molar ratio to maleic anhydride: 0.025) were added thereto, and the resultant reaction liquid was stirred at room temperature until it became homogeneous. After this stirring, the pH of the reaction liquid was adjusted to 8.5 with sodium hydroxide to carry out a reaction at 80° C. for 10 hours. After the end of the reaction, the same operation as of Example 1 was carried out to obtain trisodium carboxymethoxysuccinate (CMOS-3Na) with a yield of 11.8 mol % (as based on the charged maleic anhydride) in the filtrate.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:27]([Si:30](Cl)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1cc(-c2ccc(I)cc2)nn1-c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](Oc1cc(-c2ccc(I)cc2)nn1-c1ccccn1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
3-(4-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol (0.5 mmol, 1 equivalent) was dissolved in CH2Cl2 (5 mL) to which 3 equivalents of triethylamine were then added. Under stream of nitrogen, 2 equivalents of triisopropylsilyl chloride (TIPSCl) were added thereto at 0° C., followed by stirring at room temperature. After 10 minutes, the solution was concentrated by distillation under reduced pressure and hexane was added thereto, followed by washing with a saturated NaHCO3 aqueous solution. After extraction with hexane twice, the organic layer was dried over anhydrous MgSO4, filtered, concentrated and then dried under vacuum to afford the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][CH:12]=[C:11]([C:14](O)=[O:15])[C:10](=[O:17])[C:9]=2[CH:18]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][CH:12]=[C:11]([C:14]([Cl:25])=[O:15])[C:10](=[O:17])[C:9]=2[CH:18]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2scc(C(=O)O)c(=O)c2cc1OC(C)=O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2scc(C(=O)Cl)c(=O)c2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-4-oxo-4H-1-benzothiopyran-3-carboxylic acid (50 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 2 hours in benzene (20 mL), and then the solvent was distilled off. To the residue was added benzene (20 mL). Benzene was evaporated again and the residue was vacuum dried to give 6,7-diacetoxy-4-oxo-4H-1-benzothiopyran-3-carbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].[BH4-].[Na+]>CO.CC#N.COC(OC)N(C)C>[F:10][C:6]1[CH:5]=[C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:12])=[O:13])[CH:3]=[C:2]([F:1])[C:7]=1[CH2:8][OH:9]
Reactant: CN(C)C=NS(=O)(=O)c1cc(F)c(C=O)c(F)c1
Agent: COC(OC)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc(F)c(CO)c(F)c1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a solution of N′-(3,5-difluoro-4-formylphenylsulfonyl)-N,N-dimethylformimidamide (171 g, 619 mmol) in MeOH (1 L) was added NaBH4 (23.4 g, 619 mmol) at 0° C. After 1 h, the reaction mixture was concentrated, neutralized to pH 6 with 1N HCl, and extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4 and evaporated in vacuo. To a solution of this residue in CH3CN (1 L) was added N,N-dimethylformamide dimethylacetal (166 mL, 1.24 mmol, 2 eq). The solution was evaporated in vacuo and then purified by chromatography (silica, DCM/EtOAc, 1:1) to give N′-(3,5-difluoro-4-(hydroxymethyl)phenylsulfonyl)-N,N-dimethylformimidamide (80 g). 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.45-7.40 (m, 2H), 4.8 (d, J=3.6 Hz), 3.17 (s, 3H), 3.05 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:26]([N:28]([CH2:31]C)[CH2:29][CH3:30])[CH3:27].ClC(OC1C=CC=CC=1)=[O:35].N1CCCC1>O1CCCC1.CN(C)C=O>[N:28]1([C:31]([NH:1][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:13][CH:14]=3)[CH:3]=2)=[O:35])[CH2:29][CH2:30][CH2:27][CH2:26]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Reactant: Nc1cc(Nc2ccc(NC(=O)OCc3ccccc3)cc2)ncn1
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Nc2cc(NC(=O)N3CCCC3)ncn2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
Benzyl N-[4-(6-aminopyrimidin-4-ylamino)phenyl]carbamate (313 mg) was dissolved in tetrahydrofuran (10 ml) under a nitrogen atmosphere, and then triethylamine (0.78 ml) and phenyl chloroformate (0.35 ml) were added dropwise thereto while cooling in an ice bath, followed by stirring at room temperature for 30 min. To the reaction mixture were added pyrrolidine (1.0 ml) and N,N-dimethylformamide (2 ml), followed by further stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (210 mg, 52%) as pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.[CH2:16]([C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]=1[CH2:27][N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH2:31])[CH3:17].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[C:7](=[O:13])[NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:31]=[CH:30]/[C:29]([N:28]([CH2:27][C:19]3[O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:18]=3[CH2:16][CH3:17])[CH3:33])=[O:32])=[CH:3][C:4]=2[CH2:10][NH:9]1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1CC
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)oc2ccccc12
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
To 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (400 mg, 1.48 mmol) in propionitrile (40 mL) and DMF (10 mL) was added N-(3-ethyl-benzofuran-2-ylmethyl)-N-methylacrylamide (410 mg, 1.62 mmol), (i-Pr)2EtN (0.51 mL, 2.96 mmol), Pd(OAc)2 (332 mg, 0.148 mmol) and P(o-tol)3 (90.1 mg, 0.296 mmol), and the mixture was de-oxygenated with argon for 15 min. The mixture was heated to reflux overnight, allowed to cool and then filtered. The filtrate was concentrated and the residue was dissolved in CH2Cl2 (150 mL). The organic solution was washed with water and brine, dried (Na2SO4) and the solvent was removed in vacuo. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 20:1) gave the title compound (130 mg, 20%) as an off-white solid: MS m/z 433 (M+H)+.
Reaction SMILES: [C:1]([O:5][NH:6][C:7](=[O:28])[C@H:8]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[C:26][CH3:27])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](Cl)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([NH:13][C@@H:8]([C:7]([NH:6][O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:28])[CH2:9][CH2:10][CH2:11][NH:12][C:41]([C:37]2[S:36][CH:40]=[CH:39][CH:38]=2)=[O:42])(=[O:16])=[O:15])=[CH:18][CH:19]=1)[C:25]#[C:26][CH3:27]
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@H](CCCN)C(=O)NOC(C)(C)C)cc1
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N[C@H](CCCNC(=O)c2cccs2)C(=O)NOC(C)(C)C)cc1
Reaction time: 16 h

Procedure:
The residue from Step B (102 mg, 0.25 mmol) was dissolved in DCM (2 mL). Triethylamine (104 uL, 0.75 mmol), DMAP (0.3 mg, 0.025 mmol) and thiophene-2-carbonyl chloride (55 mg, 0.37 mmol) were added. The reaction was shaken on an orbital shaker for 16 hours then concentrated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[CH:16](OCC)=[O:17].[H-].[Na+]>COCCOC>[CH:16]([CH:10]([CH2:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccc(OC)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccc(OC)nc1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A mixture of ethyl 3-(6-methoxy-3-pyridyl)propionate (32.74 g), and ethyl formate (17.22 g), was added dropwise over 1.5 hours to a stirred suspension of sodium hydride in oil (50%, 9.38 g), in 1,2-dimethoxyethane (50 ml) cooled to -2°, allowed to stand overnight at room temperature and then poured on to ice. The mixture was extracted with ether and the aqueous phase was adjusted to pH 5 with 2N sulphuric acid. An oil was precipitated and crystallised on standing to give ethyl 2-formyl-3-(6-methoxy-3-pyridyl)propionate (25.9 g, 70%), m.p. 91.5°-94°. A sample recrystallised from aqueous ethanol had m.p. 93°-4°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][NH2:14].C[Si]([N:29]=[C:30]=[O:31])(C)C>C(O)(C)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][NH:14][C:30]([NH2:29])=[O:31]
Reactant: NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: NC(=O)NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reaction time: 20 h

Procedure:
A solution of N-(1H-benzimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-ethane-1,2-diamine (0.10 g, 0.31 mmol) in isopropanol (2 mL) was treated with trimethylsilylisocyanate (60 μL, 0.44 mmol) at room temperature. The reaction was stirred 20 hours and concentrated under reduced pressure. This afforded, after column chromatography with silica gel (2:0.5:97.5 MeOH:NH4OH:CH2Cl2), {2-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-ethyl}-urea (67 mg, 59%). 1H NMR (CDCl3) δ 1.68 (m, 1H), 1.86 (m, 1H), 2.02 (br, 1H), 2.23 (br, 1H), 2.65 (m, 1H), 2.82 (m, 3H), 3.17 (m, 2H), 4.00 (m, 1H), 4.07 (d, 1H, J=15.0 Hz), 4.18 (d, 1H, J=15.0 Hz), 4.43 (br, 2H, NH2), 6.00 (br, 1H, NH), 7.18 (m, 3H), 7.46 (d, 1H, J=7.0 Hz), 7.45-7.70 (br, 2H), 8.55 (d, 1H, J=4.0 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:21])[C:19]=1[OH:20])[CH:15]=O>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:15][C:14]2[CH:17]=[C:18]([CH3:21])[C:19]([OH:20])=[C:12]([CH3:11])[CH:13]=2)=[CH:5][CH:6]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CC(=O)c1ccc(Cl)cc1
Product: Cc1cc(C=CC(=O)c2ccc(Cl)cc2)cc(C)c1O

Procedure:
This compound was synthesized from 4-chloroacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:26])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[C:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([O-:22])=[O:21])=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][C:6](=[O:25])[CH2:5]1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:35]([O-])(=O)[C:36]1C=CC=CC=1>CN(C=O)C>[CH3:3][C:4]1([CH3:26])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[C:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:35][CH3:36])=[O:21])=[CH:18][CH:17]=3)[CH:12]=2)[N:7]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6](=[O:25])[CH2:5]1
Reactant: CC1(C)CC(=O)Nc2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Reactant: O=C([O-])c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(=O)N3Cc2ccccc2)cc1

Procedure:
NaH (93.6 mg, 2.6 mmol), ethyl 4-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl) ethynyl benzoate (Compound 4, 604 mg, 1.7 mmol) and benzyl bromide (2.06 mL, 17 mmol) in 3 mL of DMF were reacted substantially in accordance with the procedure used for the preparation of ethyl 4-[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-(1-iso-propyl-6-quinolinyl)ethynyl]benzoate (Compound 5), to yield the title compound as white solids (744 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:43][C:44]1[CH:45]=[C:46]([CH:61]=[CH:62][CH:63]=1)[O:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]2[CH:54]=[C:55]([C:57]([O:59][CH3:60])=[O:58])[S:56][C:49]=12.Cl>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:43][C:44]1[CH:45]=[C:46]([CH:61]=[CH:62][CH:63]=1)[O:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]2[CH:54]=[C:55]([C:57]([O:59][CH3:60])=[O:58])[S:56][C:49]=12)=[O:9]
Reactant: Cc1ccoc1C(=O)O
Reactant: COC(=O)c1cc2nccc(Oc3cccc(N)c3)c2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nccc(Oc3cccc(NC(=O)c4occc4C)c3)c2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-methyl-2-furoic acid (166 mg, 1.32 mmol) in anhydrous DMF (10 ml) were added HATU (552 mg, 1.45 mmol) and DIPEA (341 mg, 2.64 mmol). The mixture was stirred at room temperature for 10 minutes, and 330 mg of crude methyl 7-(3-aminophenoxy)thieno[3,2-b]pyridine-2-carboxylate from step 1 was added. The mixture was then heated at 65° C. for 2 hours, cooled to room temperature, and poured into 100 ml of water. 2M HCl was added until pH=4. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 2˜3% of MeOH in chloroform to afford methyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate as off-white solid. Yield: 230 mg, 26% for 2 steps.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2].O.[C:19]([C@@:22]1([OH:37])[C@@H:26]([CH2:27][OH:28])[O:25][C:24](Cl)([C:29](=[O:31])[CH3:30])[C@:23]1([C:34](=[O:36])[CH3:35])[OH:33])(=[O:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@:24]2([C:29](=[O:31])[CH3:30])[O:25][C@H:26]([CH2:27][OH:28])[C@@:22]([C:19](=[O:21])[CH3:20])([OH:37])[C@@:23]2([C:34](=[O:36])[CH3:35])[OH:33])=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(NC(C)=O)c2[nH]cnc2n1
Reactant: CC(=O)C1(Cl)O[C@H](CO)[C@](O)(C(C)=O)[C@]1(O)C(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1nc(NC(C)=O)c2ncn([C@]3(C(C)=O)O[C@H](CO)[C@](O)(C(C)=O)[C@]3(O)C(C)=O)c2n1
Reaction time: 8 h

Procedure:
The dried chloromercuri derivative (24 g., 0.05 mole) of 2,6-diacetamidopurine was refluxed in xylene using a Dean-Stark water separator. Freshly prepared triacetyl-D ribofuranosyl chloride in xylene was added to the hot chloromercuri derivative and the mixture was refluxed, in an oil bath, with vigorous stirring. After 41/2 hours the reaction mixture was allowed to stand overnight at room temperature and then filtered. The precipitate was extracted (several times) with warm CHCl3. The CHCl3 extract was washed successively with 30% aqueous KI (thrice), water (thrice) dried, charcoaled and filtered. The filtrate was evaporated in vacuo, and the residue on trituration with ether gave 14.3 g. (58%; m.p. 87°-92°) of 2,6-diacetamido-9-triacetyl-β-D-ribofuranosyl purine.