Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[O:18][C:17]([S:19][CH3:20])=[N:16][N:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl>C1COCC1>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[O:18][C:17]([S:19][CH3:20])=[N:16][N:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2oc(-c3nnc(SC)o3)cc12
Agent: Cl
Solvent: C1CCOC1
Product: CSc1nnc(-c2cc3c(O)cccc3o2)o1
Yield: 73 %

Procedure:
To a solution (20 ml) of 5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2-methylthio-1,3,4-oxadiazole (1.0 g) in THF was added 2N aqueous hydrochloric acid (3.0 ml), and the mixture was refluxed under heating for 7 hr. The solvent was evaporated under reduced pressure to give the title compound (0.62 g) as yellow crystals.
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[F:25])=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[F:25][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)=[CH:16][C:11]=1[NH:10][C:9]([NH2:26])=[NH:8]
Reactant: COc1ccnc(-c2ccc(F)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccnc(-c2ccc(F)c(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)guanidine (0.2 g) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the resultant precipitate was collected by filtration and dried under reduced pressure to give (2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)guanidine dihydrochloride (143 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:10]3[CH:17]=[N:18][N:19]([CH3:20])[C:9]=3[CH2:8][CH2:7][C:6]2=1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:6]2=[CH:7][CH:8]=[C:9]2[N:19]([CH3:20])[N:18]=[CH:17][C:10]2=1
Reactant: COc1ccc2c(c1)c1c(n2C)-c2cnn(C)c2CC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1ccc3c(cnn3C)c1n2C
Reaction time: 8 h

Procedure:
7-methoxy-3,10-dimethyl-3,4,5,10-tetrahydro-2,3,10-triaza-cyclopenta[a]fluorene (136 mg, 0.51 mmol) in DMF (2 mL) was treated with KO2 (5.0 eq.) at room temperature. The reaction mixture was stirred overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried, concentrated. The crude material was purified by silica gel column to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].Br[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1>C1COCC1>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[CH2:9][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: Cc1ccoc1C
Reactant: BrCc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccc3ccccc3c2)oc1C

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using 2,3-dimethylfuran, 2-(bromomethyl)naphthalene and 1.6M n-BuLi/hexanes in THF. 1H NMR (DMSO-d6) δ1.89 (s, 3H), 2.15 (s, 3H), 4.08 (s, 2H), 5.95 (s, 1H), 7.40 (d, 1H), 7.45-7.57 (m, 2H), 7.77 (s, 1H), 7.83-7.91 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[OH:22][CH2:23][CH2:24][CH2:25][NH:26][OH:27]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:26]([OH:27])[CH2:25][CH2:24][CH2:23][OH:22])=[O:18])[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Reactant: OCCCNO
Agent: Cl
Product: O=C(c1cc2ccn(Cc3ccc(F)cc3)c2cn1)N(O)CCCO

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-(3-hydroxypropyl)hydroxylamine hydrochloride in a manner similar to step 8 of example 1. 1H NMR (CD3OD) δ ppm 8.71 (s, 1H), 8.20 (s, 1H), 7.71 (d, 1H, J=3.0 Hz), 7.26 (m, 2H), 7.05 (d, 2H, J=8.9 Hz), 6.75 (d, 1H, J=3.0 Hz), 5.55 (s, 2H), 3.90 (m, 2H), 3.65 (t, 2H, J=6.0 Hz), 1.94-2.00 (m, 2H). LCMS (API-ES, M+H+): 344.1. HRMS calcd for C18H19FN3O3 (M+H) 344.1405, found 344.1402. HPLC: 99.1% purity.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]1[NH:19][CH2:18][CH2:17][N:16]2[CH2:20][CH2:21][CH2:22][C@H:15]12.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:14]1[N:19]([C:9]([C:8]2[CH:12]=[CH:13][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:10])[CH2:18][CH2:17][N:16]2[CH2:20][CH2:21][CH2:22][C@H:15]12
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(S(=O)(=O)Cl)cc1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-(chlorosulfonyl)benzoyl chloride (3 mmol) in anhydrous dichloromethane (100 mL) was slowly added over 10 minutes (R)-octahydropyrrolo[1,2-a]pyrazine (0.379 g, 3 mmol) at room temperature in dichloromethane (4 mL). Then sodium carbonate (0.954 g, 9 mmol) was added. The mixture was stirred at room temperature overnight. Then the reaction mixture was concentrated to provide 4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonyl chloride which was used without additional purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:26])[CH3:25])[CH:19]=2)=O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].[ClH:33]>CO.Cl.Cl.NNC(N)=N>[ClH:33].[ClH:33].[C:28]([NH:31][N:32]=[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:26])[CH3:25])[CH:19]=1)[CH2:14][CH2:13][CH2:12][C:11](=[N:32][NH:31][C:28](=[NH:29])[NH2:30])[NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)(=[NH:30])[NH2:29]
Reactant: N=C(N)NN
Reactant: CC(=O)c1cccc(NC(=O)CCCC(=O)Nc2cccc(C(C)=O)c2)c1
Agent: Cl
Solvent: CO
Product: CC(=O)c1cccc(NC(CCCC(=NNC(=N)N)Nc2cccc(C(C)=O)c2)=NNC(=N)N)c1
Yield: 98.2 %

Procedure:
N,N′-bis(3-acetylphenyl)pentanediamide (3.66 g), aminoguanidine hydrochloride (2.75 g), and aminoguanidine dihydrochloride (0.05 g) were heated in methanol (35 mL) for 18 hr. Cooling and filtration gave 5.412 g of N,N′-bis(3acetylphenyl)pentanediamide bis(amidinohydrazone) dihydrochloride, mp 187-191° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH:25]([CH3:27])[CH3:26])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:28]([O:32][CH2:33]Cl)[CH2:29][CH2:30][CH3:31].O>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][O:32][CH2:28][CH2:29][CH2:30][CH3:31])[C:19](=[O:24])[N:18]([CH:25]([CH3:27])[CH3:26])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)n1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CCCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(C(C)C)c1=O
Reaction time: 1 h

Procedure:
0.583 g (4.22 mmol) of potassium carbonate was added at 60° C. to a suspension of 0.75 g (2.64 mmol) of 7-benzyl-3-isopropylxanthine from stage a) in 20 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 0.42 g (3.43 mmol) of butoxymethyl chloride was then added dropwise and the mixture was stirred at 80° C. for 6 hours. A further 0.11 g (0.87 mmol) of butoxymethyl chloride was then added and the mixture was stirred again for 5 hours. 20 ml of water were then added, the mixture was extracted three times using 30 ml of methyl tert-butyl ether each time, and the combined organic phases were washed twice with 20 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, heptane/ethyl acetate (2/1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OC)=O.[NH2:28][CH:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[N:32]([CH:41]([CH3:43])[CH3:42])[N:31]([CH3:44])[C:30]1=[O:45]>ClCCl>[CH3:44][N:31]1[C:30](=[O:45])[CH:29]([NH:28][C:13](=[O:15])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[N:32]1[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)N1C(=O)c2ccccc2C(N)C(=O)N1C
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)N(C)N(C(C)C)C(=O)c2ccccc21
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of N-boc-(L)-valine (IV, 1.04 g, 4.8 mmol) in dichloromethane (100 mL) was added the N-methyl morpholine (0.56 g, 5.6 mmol) and methyl chloroformate (0.37 mL, 4.8 mmol) at 0° C. The resulting solution was stirred for 10 minutes before the addition of a solution of 5(R,S)-amino-2,3,4,5-tetrahydro-3-methyl-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione (IIIA, 1.0 g, 4.04 mmol) in dichloromethane (5 mL) and it was further stirred for another 1 h. The resulting mixture was washed with 1N hydrochloric acid (50 mL), sodium bicarbonate (50 mL), brine (50 mL) and dried over MgSO4, filtered and concentrated to afford the crude product. This product was purified further on flash (silica gel) chromatography (hexane/ethyl acetate, 3/2) to afford 2,3,4,5-tetrahydro-3-methyl-5(R,S)-[[(2S)-2-[(1,1-dimethylethoxycarbonyl)amino]-3-methyl-1-oxobutyl]amino]-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione(1.5 g, 83%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.Br.C1C=C[NH+]=CC=1.[Br:16][Br-]Br>CC(O)=O>[Br:16][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C(O)c1ccsc1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(O)c1csc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of thiophene-3-carboxylic acid (12.6 g, 0.1 mol) in AcOH (96 ml), being stirred at room temperature, HBr solution (8 ml) was added, and the stirring continued until the color of mixture turned to yellow. Pyridinium bromide perbromide (27 g) was then sequentially added. The mixture was poured into ice-water, stirred for about 30 minutes. A white precipitate was formed, which was filtered and dried to obtain 5-bromo-thiophene-3-carboxylic acid (10.8 g) as a white solid after crystallization in hot water. HPLC: 92%.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=1[F:24].C(=O)([O-])[O-].[Cs+].[Cs+].[F:32][C:33]([F:37])([F:36])[CH2:34]I>CN(C=O)C.O>[CH3:1][C:2]1([CH3:25])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([O:23][CH2:34][C:33]([F:37])([F:36])[F:32])[CH:20]=[CH:19][C:18]=1[F:24]
Reactant: COC(=O)c1ccc(-c2cc(O)ccc2F)c(C2CCCC2(C)C)c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OCC(F)(F)F)ccc2F)c(C2CCCC2(C)C)c1
Reaction time: 5 h
Yield: 91.8 %

Procedure:
To a flask containing 66.23A (0.100 g, 0.29 mmol) and cesium carbonate (0.29 g, 0.88 mmol) in DMF (2 mL) was added 1,1,1-trifluoro-2-iodoethane (0.12 g, 0.58 mmol) (commercially available from Aldrich), and stirring was continued for 5 hours. The reaction was diluted with water and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.23B as a colorless oil (0.113 g, 91% yield).
Reaction SMILES: [CH:1]1([C@@H:7]([NH:25][CH2:26][C:27]2[C:32]([N+:33]([O-])=O)=[CH:31][N:30]=[C:29]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:28]=2)[CH2:8][CH2:9][C:10]([N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:43]#[C:44]Br>C(O)C.C1COCC1.[Pd]>[NH2:43][C:44]1[N:25]([C@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9][C:10]([N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:11])[CH2:26][C:27]2[CH:28]=[C:29]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:30]=[CH:31][C:32]=2[N:33]=1
Reactant: N#CBr
Reactant: O=C(CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1)N(Cc1nnn[nH]1)C1CCCCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1=Nc2cnc(Oc3ccccc3)cc2CN1[C@@H](CCC(=O)N(Cc1nnn[nH]1)C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(S),N-dicyclohexy-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-N-(1H-tetrazol-5-ylmethyl)-butyramide (0.75 g, 1.3 mmole) in ethanol (30 mL) and THF (20 mL) was added palladium on carbon (10%, 0.48 g). The reaction mixture was hydrogenated for 1 hour at 20 psi. The reaction mixture was then filtered. Cyanogen bromide (3 M in dichloromethane, 0.65 ml, 1.9 mmole) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the resulting residue was purified by reverse phase HPLC to yield 4-{[4-(2-amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-4-(S),N-dicyclohexyl-N-(1H-tetrazol-5-ylmethyl)-butyramide as a white solid, as its corresponding TFA salt.
Reaction SMILES: O1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][C:11](=[O:13])[NH:10][CH2:9]3)[CH2:7][CH2:6]2)[O:4]CC1>Cl>[CH2:9]1[C:8]2([CH2:7][CH2:6][C:5](=[O:4])[CH2:15][CH2:14]2)[CH2:12][C:11](=[O:13])[NH:10]1
Reactant: O=C1CC2(CCC3(CC2)OCCO3)CN1
Agent: Cl
Product: O=C1CCC2(CC1)CNC(=O)C2
Yield: 90.1 %

Procedure:
A solution of 1,4-dioxa-10-azadispiro[4.2.4.2]tetradecan-11-one (10.5 g, 49.8 mmol) in aq.HCl (2N, 20 mL) was stirred at RT for 2 h. The reaction mixture was then concentrated under reduced pressure and diluted with water. It was extracted with ethyl acetate (Three times) and the combined organic phases were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica (Pet.Ether:EtOAc) afforded the title compound as a white solid (7.5 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 7.58 (m, 1H), 3.15-3.15 (s, 2H), 2.30 (s, 4H), 2.28-2.25 (m, 2H), 1.82-1.79 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[Cl:22]C1C=C(SSC2C=CC(Cl)=C(Cl)C=2)C=CC=1Cl>>[Cl:22][C:7]1[CH:6]=[C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:19]([OH:21])=[O:20])[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: Clc1ccc(SSc2ccc(Cl)c(Cl)c2)cc1Cl
Reactant: Cc1ccc2c(Sc3ccc(Cl)cc3)c(C(=O)O)[nH]c2c1
Product: Cc1ccc2c(Sc3ccc(Cl)c(Cl)c3)c(C(=O)O)[nH]c2c1
Yield: 43.4 %

Procedure:
Following the method used to prepare 1, product 1 (0.15 g, 0.85 mmol) and bis(3,4-dichlorophenyl)disulfide (66) (0.37 g, 1.03 mmol) provided 0.13 g of product 21 (43%) as an off white solid, mp 252-255° C. 1H NMR (300 MHz, DMSO-d6) δ 2.40 (s, 3H), 6.95 (dd, J=2, 9 Hz, 1H), 6.99 (d, J=9 Hz, 1H), 7.23 (d, J=2 Hz, 1H), 7.30-7.34 (m, 2H), 7.46 (d, J=9 Hz, 1H), 12.30 (s, 1H), 13.38 (s, 1H). LC-MS (CI): m/z 350.0, 352.0 [(M−H)− C16H11Cl2NO2S requires 350.99]. Purity (100%). Calcd for C16H11Cl2NO2S.0.04-CH2Cl2: C, 54.17; H, 3.14; N, 3.94; S, 9.02; Cl, 20.74. Found: C, 54.00; H, 2.95; N, 3.93; S, 9.02; Cl, 20.74.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl>[OH-].[Na+]>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(O)C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)COc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.8 g (14.7 mmoles)3-chlorolactic acid and 3.4 g p-chlorophenol in 15 ml 3.3 N sodium hydroxide was stirred under reflux for two hours. The mixture was cooled to room temperature and acidified to pH=3, with concentrated hydrochloric acid. The resulting white crystals were filtered and dissolved in hot water and the hot solution was adjusted to pH=1 with concentrated sulfuric acid. Upon cooling the product, 3-(p-chlorophenoxy)-lactic acid was collected as clear crystals, 0.7 g, m.p. 135° to 136° C.; Edelson, et al. Biochem Pharmacol 18, 2331 (1969) reported m.p. 137° to 138° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O>[O-]CC.[Na+]>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 58.5 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (8.3g.) in sodium ethoxide solution (1.15g. sodium in 70 ml. of absolute ethanol) was added p-chlorobenzylchloride (8.1g.) in one portion. The mixture was heated under reflux for 16 hours, allowed to cool and poured into water (500 mls.) and the product extracted into ether. The organic layer was separated and dried (anhydrous MgSO4) and filtered. Evaporation of the solvent under reduced pressure gave the crude product which on recrystallization from ethanol, yielded by 4-ethoxycarbonylphenoxy-4-chlorophenyl methane (8.5g.) m.pt. 83°-84° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.CC[N:36]([CH:40]([CH3:42])C)[CH:37]([CH3:39])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:36]6[CH2:37][CH2:39][CH2:42][CH2:40]6)=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)=[O:33])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
To a solution of acid 225 (70 mg, 0.151 mmol), DIPEA (0.105 mL, 0.603 mmol) and pyrrolidine (0.025 mL, 0.301 mmol) in DMF (4 mL) was added HATU reagent (143 mg, 0.377 mmol). The mixture was stirred for 16 h at RT then partitioned between ethyl acetate and water. The organic phase was collected, washed with water, 1M NaOH, and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-15%, SNAP 10 g cartridge), then using chromatotron (eluent MeOH/DCM, 5-10%) followed by trituration with a mixture Et2O/MeOH/Acetone to give title compound 226 (15 mg, 0.029 mmol, 19% yield) 1H NMR (400 MHz, DMSO-d6) δ (ppm): OH from carboxylic acid is missing, 9.66 (bs, 1H), 8.98 (dd, J=1.9, 0.9 Hz, 114), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.22 (dd, J=8.1, 1.9 Hz, 1H), 8.17 (dd, J=8.1, 0.9 Hz, 1H), 7.77 (dd, J=13.7, 2.5 Hz, 1H), 7.45 (bs, 1H), 7.37 (t, J=9.1 Hz, 1H), 7.26 (dd, J=8.9, 1.5 Hz, 1H), 6.62 (d, J=5.3, 0.8 Hz, 1H), 2.60-2.52 (m, 1H), 0.69-0.56 (m, 2H), 0.50-0.37 (m, 2H). MS (m/z): 465.3 (M+H)
Reaction SMILES: [C:1]([C:4]1[S:13][C:12]2[N:11]3[C:14]([CH3:17])=[N:15][N:16]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:5]=1)(=[O:3])C.Cl[O-].[Na+].S([O-])(O)=[O:29].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[C:6]2[CH:5]=[C:4]([C:1]([OH:29])=[O:3])[S:13][C:12]=2[N:11]2[C:14]([CH3:17])=[N:15][N:16]=[C:10]2[CH2:9][N:8]=1
Reactant: O=S([O-])O
Reactant: CC(=O)c1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [O-]Cl
Product: Cc1nnc2n1-c1sc(C(=O)O)cc1C(c1ccccc1Cl)=NC2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 49.7 %

Procedure:
2-Acetyl-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (1.0 g) synthesized by the method described in Artneim.-Forsch./Drug Res. 28 (II), Heft 7, 1153-1158 (1978) was added to a 10% aqueous sodium hypochlorite solution (21 ml), and the mixture was stirred at 60° C. for 1.5 hours. Sodium hydrogensulfite (2.9 g) was added to the reaction mixture. Then, an aqueous citric acid solution was added to adjust the reaction mixture to pH 3. The obtained crystals were collected by filtration, and washed with water to give 0.5 g of (4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-2-yl)carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>>[CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:51][C:52]6[S:53][CH:54]=[CH:55][N:56]=6)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: Nc1nccs1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)Nc4nccs4)cc3F)cn2)cc1
Yield: 147.2 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 2-aminothiazole (23.6 mg, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-N-thiazol-2-yl-benzamide as a yellow solid (132 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-270) as a yellow powder (37.8 mg, 62%).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH2:19][S:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.ClC1C=CC=C(C(OO)=[O:39])C=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH2:19][S:20]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)=[O:39])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(SCc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Product: COC(=O)c1ccc(S(=O)Cc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
In a manner analogous to that of Example 2(b), 2.96 g (7 mmol) of methyl 4-[3-(1-adamantyl)-4-methoxyphenylmethylthio]benzoate were reacted with 1.42 g (7 mmol) of meta-chloroperbenzoic acid and 2.33 g (76%) of the expected methyl ester, having a melting point of 151°-2° C., were recovered.