Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:30])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 64.6 %

Procedure:
A solution of [(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.846 g, 1.83 mmol) in ethyl acetate (10 mL) was added to a suspension of platinum (IV) oxide (45 mg, 0.198 mmol) in absolute ethanol (30 mL) and the mixture hydrogenated at 10 psi of hydrogen for 100 minutes. The reaction mixture was then filtered through celite and the filtrate concentrated under reduced pressure to afford a brown syrup. Purification by flash chromatography using a solvent gradient of 5 to 20% ethyl acetate in hexane afforded 0.548 g (64%) of [(2R)-8-(2.6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. HRMS: calcd for C23H20Cl2O4S+H+, 463.0532 1. found (ESI, [M+H]+), 463.0555.
Reaction SMILES: C(O)C.[F:4][C:5]([F:41])([F:40])[C:6]1[CH:39]=[CH:38][C:9]([C:10]([NH:12][C:13]2[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)[C:16]3[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=3[N:14]=2)=[O:11])=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)(=O)C>[F:40][C:5]([F:4])([F:41])[C:6]1[CH:39]=[CH:38][C:9]([C:10]([NH:12][C:13]2[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:16]3[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=3[N:14]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: O=C(Nc1nc2ccccc2n1CCCN1CCN(Cc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(Nc1nc2ccccc2n1CCCN1CCNCC1)c1ccc(C(F)(F)F)cc1
Yield: 63.9 %

Procedure:
To a solution composed of 75 ml. ethanol and 1 ml. glacial acetic acid was added 2-(4-trifluoromethylbenzamido)-1-[3-(4-benzyl-1-piperazinyl)-propyl]benzimidazole (500 mg., 0.96 millimole) and 100 mg. of 10% Pd/C catalyst. The mixture was shaken on a Paar apparatus at about 2 atm. pressure of hydrogen and 40° C. for 2.5 hrs. at which time the reaction was complete. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to yield a white solid, which on trituration under acetone yielded 300 mg. (63.9% yield) of 2-(4-trifluoromethylbenzamido)-1-[3-(1-piperazinyl)propyl]benzimidazole, as a white crystalline solid, m.p. 184°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].B(F)(F)F.[CH3:18][CH2:19]OCC.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[CH2:5][CH2:6][C:7]([O:9][CH2:18][CH3:19])=[O:8]
Reactant: Nc1ccc(CCC(=O)O)cc1F
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)c(F)c1

Procedure:
A solution of 3-fluoro-4-aminohydrocinnamic acid in 100 ml. of absolute ethanol containing 16 ml. of boron trifluoride etherate is heated to reflux for 48 hours. The solution is then cooled, poured into 5% aqueous sodium carbonate and extracted with methylene chloride. Evaporation of the organic extracts yields ethyl 3-fluoro-4-aminohydrocinnamate. CL 176. 3-Fluoro-4-(hexadecylamino)hydrocinnamic acid
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:26])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[CH3:26][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([CH3:1])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:24])[CH3:25])[CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: COCOc1ccc(Cc2c(C)cc(C(=O)OC)cc2C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOc1ccc(Cc2c(C)cc(C(=O)O)cc2C)cc1C(C)C
Temperature: 50 °C
Yield: 98.3 %

Procedure:
To a stirring solution of methyl 3,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzoate (0.750 g, 2.11 mmol) in MeOH (20.0 mL) at 0° C. was added 1 M NaOH (12.64 mL, 12.64 mmol). The reaction mixture was heated at 50° C. for 16 h, cooled to 0° C. and acidified with 2 N HCl. The mixture was extracted with ethyl acetate (20 mL) and washed with H2O (10 mL×2.). The solvent was removed under reduced pressure to afford 3,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzoic acid as white solid (0.71 g, 98%): 1H NMR (300 MHz, DMSO-d6): δ 12.76 (s, 1 H), 7.65 (s, 2 H), 6.98 (m, 1 H), 6.91 (m, 1 H), 6.60 (m, 1 H), 5.17 (s, 2 H), 4.00 (s, 2 H), 3.37 (s, 3 H), 3.23 (m, 1 H), 2.27 (s, 6 H), 1.14 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethyl acetate (4:1); Rf=0.00.
Reaction SMILES: C1C=CC2N(O)N=[N:7][C:5]=2C=1.CCN=C=NCCCN(C)C.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C@@H:35]([CH3:36])[CH2:34][N:33]([C:37]([NH:39][C:40]3[CH:45]=[CH:44][N:43]=[C:42]([C:46]([OH:48])=O)[CH:41]=3)=[O:38])[C@H:32]([CH3:49])[CH2:31]2)=[CH:26][C:25]=1[C:50]([F:53])([F:52])[F:51])#[N:23].CN>CN(C=O)C.O>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C@@H:35]([CH3:36])[CH2:34][N:33]([C:37]([NH:39][C:40]3[CH:45]=[CH:44][N:43]=[C:42]([C:46](=[O:48])[NH:7][CH3:5])[CH:41]=3)=[O:38])[C@H:32]([CH3:49])[CH2:31]2)=[CH:26][C:25]=1[C:50]([F:52])([F:51])[F:53])#[N:23]
Reactant: On1nnc2ccccc21
Reactant: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1C(=O)Nc1ccnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(NC(=O)N2C[C@H](C)N(c3ccc(C#N)c(C(F)(F)F)c3)C[C@H]2C)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
Under ice-cooling, 332 mg of HOBT and 519 mg of WSC were added in that order to a suspension of 1.10 g of (2R,5S)-4-{[4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethylpiperazine-1-carbonyl]amino}pyridine-2-carboxylic acid synthesized in Example 12-1 in 30 ml of DMF, and then the mixture was warmed up to room temperature and stirred for 1.5 hours. This was again ice-cooled, 10 ml of 40% aqueous methylamine was added thereto in one portion and then the mixture was stirred overnight. This was mixed with purified water and extracted with ethyl acetate, and the thus obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to a silica gel column chromatography to obtain 674 mg of the title compound from methanol-ethyl acetate (1:9, v/v) eluate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[OH:21])[C:7]=2[C:6]=1[CH3:23])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:31]1[CH2:34][CH2:33][CH2:32]1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:7]=2[C:6]=1[CH3:23])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC3)c2c1C
Temperature: 60 °C

Procedure:
A mixture of 4-(4-fluoro-2-hydroxy-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (200 mg), potassium carbonate (166 mg) and bromocyclobutane (113 μl) in DMF (3 ml) was stirred at 60° C. over the weekend. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was concentrated and the residue was triturated with diethyl ether to give the desired compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[NH:23][C:22]([C:24](O)=[O:25])=[N:21][C:20]=1[CH3:27])[CH3:18].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[CH2:17]([C:19]1[NH:23][C:22]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])=[N:21][C:20]=1[CH3:27])[CH3:18]
Reactant: CCc1[nH]c(C(=O)O)nc1C
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1C

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.77 g, 3.32 mmol), 5-ethyl-4-methyl-1H-imidazole-2-carboxylic acid obtained in Example (15e) (0.26 g, 1.66 mmol), WSC hydrochloride (1.85 g, 9.65 mmol) and DMAP (0.2 g, 1.64 mmol), to obtain 0.43 g of the title compound as a white foamy substance (70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[CH3:47][O:48][C:49]([O:52][CH3:53])([CH3:51])C>ClCCl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:51][CH:49]([O:48][CH3:47])[O:52][CH3:53])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: O=CCCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-]
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: COC(CCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-])OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
In this example, 5 m moles of 4-benzyloxy-2-(10-formyldecyl) quinoline-N-oxide is dissolved in dichloromethane, and a catalytic amount of D-camphorsulfonic acid and a large excess of 2,2-dimethoxypropane are added thereto. The mixture is stirred at room temperature for 3 hours. After the reaction, the reaction solution is washed with an aqueous saturated sodium hydrogen carbonate solution, and then with water, and dried over anhydrous sodium sulfate. After removal of the solvent by distillation, the residue is purified by silica gel column procedure, whereby the captioned compound is obtained as a colorless oily substance (yield: 70.6%).
Reaction SMILES: [OH:1][CH:2]([CH:24](CC1C=CC=CC=1)[O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)=[CH:28][CH:27]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1)=[O:8].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:1][CH:2]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)=[CH:28][CH:27]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCC(O)C(Cc2ccccc2)Oc2ccc(CCOCC3CC3)cc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCC(O)COc2ccc(CCOCC3CC3)cc2)cc1
Yield: 79.9 %

Procedure:
In a manner similar to that of Example 1 (iv), 6-[4-[3-[2-hydroxy-3-[4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-N-benzylpropylamino]propionamido]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (22 g) in ethanol (350 ml) was agitated for 5 hours in a hydrogen atmosphere at 344 kPa (50 p.s.i.) in the presence of palladium hydroxide on charcoal (5 g). The catalyst was removed by filtration and solvent removed under reduced pressure to afford the title compound as a yellow foam (15 g). To a solution of this in dichloromethane (800 ml) was added a solution of methanesulphonic acid (8.60 g) in dichloromethane (100 ml) with stirring. The mixture was evaporated under reduced pressure to give a yellow solid which was crystallised from isopropanol/ethanol (50:50; 400 ml) to yield the title compound as the monomethanesulphonate salt (16 g), m.p. 185°-6° C. Conversion of this material (from another run) by base formation and retreatment with methanesulphonic acid afforded material with m.p. 186°-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:29][CH:30]1[CH2:32][CH2:31]1>>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:13]1[C:12]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=2[N:10]=[C:9]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[O:8][CH2:29][CH:30]1[CH2:32][CH2:31]1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1
Reactant: BrCC1CC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CC3)n(Cc3cccc(Cl)c3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-[1-(3-chloro-benzyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol (Example 53, intermediate a) and bromomethyl-cyclopropane (CAS Reg. No. 7051-34-5). Colorless powder (22%). MS (Turbo Spray): m/z=459.3 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][C:15]1=[O:25]>C(O)CCC>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=[C:2]([N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:14][C:15](=[O:25])[CH2:16]2)[CH:11]=1
Reactant: Cc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: O=C1CNCc2ccccc2N1
Solvent: CCCCO
Product: Cc1ccc2nc(N3CC(=O)Nc4ccccc4C3)cc(Cl)c2c1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
The mixture of 2,4-dichloro-6-methyl-quinoline (422 mg, 2 mmol), 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one (298 mg, 2 mmol) and n-butyl alcohol (15 mL) was heated with stirring in a 20 mL microwave process vial for 3 hours at 160° C. under microwave irradiation. After cooling, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (methanol/dichloromethane, 1:20) to give the product. MS obsd. (ESI+) [(M+H)+] 338.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11](/[CH:10]=[CH:9]/[C:8]([NH:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([CH:20]=[CH:19][CH:18]=2)[O:1][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:17])[CH:12]=1
Reactant: COC(=O)CCl
Reactant: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
(E)-N-(3-hydroxyphenethyl)-3-(3-pyridyl)-2-propenoic acid amide (1.07 g, 4.0 mmol) obtained in Example 81 and methyl chloroacetate (0.52 g, 4.8 mmol) were dissolved in dimethylformamide (12 ml) and potassium carbonate (1.66 g, 12 mmol) was added and stirred at 60° C. for 8 hours. After allowing to cool, ethyl acetate was added to the reaction mixture and insoluble materials were filtered out. The filtrate was washed with water and dried over magnesium sulfate. After the solvent was distilled out under reduced pressure, the residue was recrystallized to yield the titled compound (0.83 g, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([N:28]1[CH:31]([S:32][CH2:33][C:34]#[C:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH:30]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:29]1=[O:63])=[P:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.C(OCC)(=[O:72])C>>[C:1]([O:5][C:6]([C:8]([N:28]1[CH:31]([S:32][CH2:33][C:34](=[O:72])[CH2:35][C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH:30]([NH:43][C:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:29]1=[O:63])=[P:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC(=O)Cc1ccc(F)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1-(1-t-Butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one (370mg) was refluxed is piperidine (25ml) under nitrogen for 6 hours. The mixture was cooled, diluted with ethyl acetate and the organic layer washed with N-hydrochloric acid and brine, dried and evaporated to an amorphous solid. Chromatography on silica gave 1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenyl-2-oxopropylthio)azetidin-2-one as an amorphous solid (330mg).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1.C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:33]([C:30]4[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=4)(=[O:35])=[O:34])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1nc(-c2cccc(NS(=O)(=O)c3ccc(C)cc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 5-amino-2-methylthio-4-(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) was dissolved in dry pyridine (5 ml). p-Toluenesulfonyl chloride (70 mg) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with 0.1M aq. HCl. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/EtOAc=3/2 (v/v) as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:26]([O:25][C:23]([CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(C=Cc2cccc3cncn23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C=Cc2cccc3cncn23)cc1

Procedure:
A solution of 5-[2-(p-hydroxyphenyl)ethen-1-yl]imidazo[1,5-a]pyridine (2.36 g) in 10 ml of dimethylformamide is added to a slurry of 0.5 g of sodium hydride in 30 ml of dry dimethylformamide at 0° under nitrogen. After warming to room temperature ethyl bromoacetate (1.67 g) is added and the reaction is heated to 60° for 5 hours. Water (200 ml) is added and the solution is extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated to yield 5-[2-(p-[ethoxycarbonylmethoxy]phenyl)ethen-1-yl]imidazo[1,5-a]pyridine.
Reaction SMILES: COCCOC.Cl[C:8]1[S:12][N:11]=[C:10]([S:13][CH3:14])[N:9]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:14][S:13][C:10]1[N:9]=[C:8]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)[S:12][N:11]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1nsc(-c2cccc(Cl)c2)n1
Yield: 57.3 %

Procedure:
To 25 ml of 1,2-dimethoxyethane were added about 2.0 g of 5-chloro-3-methylthio-1,2,4-thiadiazole, 2.25 g of 2-chlorophenylboronic acid, 694 mg of tetrakistriphenylphosphine palladium and 25 ml of a 2 M aqueous sodium carbonate solution, and the mixture was heated under reflux for 3 hours in a nitrogen atmosphere. Then, the reaction mixture was poured into water, and the mixture was extracted with t-butyl methyl ether. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by concentration was subjected to silica gel column chromatography to obtain 1.67 g of 3-methylthio-5-(3-chlorophenyl)-1,2,4-thiadiazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]3[C:20](=[O:30])[NH:19][C:18](=[O:31])[N:17]([CH3:32])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21]3[C:20](=[O:30])[N:19]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:18](=[O:31])[N:17]([CH3:32])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[7-(Benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (182 mg) was dissolved in N,N-dimethylformamide (2 ml), and potassium carbonate (90 mg) and ethyl bromoacetate (0.06 ml) were added thereto. The reaction solution was stirred at room temperature overnight, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]([O:23][C:24](=[O:28])[CH:25]([F:27])Br)[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[F:27])[CH3:22]
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: CCOC(=O)C(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)Oc1cccc2c1cc(C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (50 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromofluoroacetate (0.2 mL, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (500 mL) and washed with H2O (5×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (6:1 Hexane:EtOAc) to afford 6 (0.14 g, 32%) as an yellow oil.