Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:11][N:10]=1>C1COCC1.O.[Pt]=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-c3ccccc3)c2c1
Agent: O=[Pt]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(c1ccccc1)NN=C2Cc1c(Cl)cncc1Cl
Temperature: 50 °C
Reaction time: 24 h
Yield: 31.9 %

Procedure:
1-(3,5-Dichloro-pyridin-4-ylmethyl)-4-phenyl-6-methoxy-phthalazine (0.5 g, 1.26 mmoles), prepared as described in example 47, in THF (40 ml) was added with platinum oxide hydrate (catalytic amount), then hydrogenated in a Parr at 4 atmospheres under stirring for 4 days and at 50° C. for 24 hours. The catalyst was filtered off and the mixture dried to give a solid which flash chromatographed (eluent: petrolatum/ethyl acetate 8:2) giving 0.16 g of the title compound (yield: 32%). m.p.: 175.3-177.3° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH:5]=[N:4][N:3]=[N:2]1.N1C=CC=CC=1.S.O[S:21](O)(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:11])=[S:21])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(Cl)CCCCn1cnnn1
Reactant: O=S(=O)(O)O
Agent: S
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: OC(=S)CCCCn1cnnn1
Reaction time: 1 h

Procedure:
5 g of 5-(tetrazol-1-yl)-valeric acid chloride are dissolved in 4.5 ml of absolute methylene chloride and, at 0°, this solution is added dropwise to 35.5 ml of a solution of pyridine and H2S in methylene chloride (30 ml of pyridine and 6 g of H2S in 100 ml of methylene chloride). The mixture is then stirred at 0° under a nitrogen atmosphere for 1 hour. The reaction mixture is taken up in chloroform, and the aqueous phase is acidified to pH 2 with 2N H2SO4 and extracted twice with chloroform. The combined organic phases are washed twice with 25 ml of 10% NaHCO3 solution. The pH is then adjusted to 3 with 2N H2SO4 and the title compound is obtained by repeated extraction with chloroform. It is dried over sodium sulphate and concentrated.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][O:44]S(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:49][O-].[Na+]>CN(C)C=O.CO.COC(C)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][O:44][CH3:49])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: COC(C)(C)C
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOC)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 5 h

Procedure:
To a solution of 0.10 g of (2S,4R,5R)-2-(2-methanesulfonyloxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester in 2.0 ml of N,N-dimethylformamide are added 0.060 ml of a 5M solution of sodium methoxide in methanol at room temperature. The reaction mixture is stirred for 5 hours, diluted with tert-butyl methyl ether, washed with 1N hydrochloric acid and the organic phase is dried over sodium sulfate. The organic phase is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a slightly brown oil. Rf=0.25 (EtOAc-heptane 1:1); Rt=5.47.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]#[C:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[H][H]>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: [H][H]
Reactant: CN(C)CC#Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Yield: 62.6 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-prop-1-ynyl)-pyrazin-2-yl]-propionamide (prepared as in Example 11, 190 mg, 0.389 mmol) in methanol (20 ml) was treated with 10% palladium on activated carbon (65 mg). The resulting reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) overnight. At this time, the catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 methylene chloride/methanol) afforded the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl)-pyrazin-2-yl]-propionamide (120 mg, 63%) as a solid: (ES)+-HRMS m/e calcd for C24H33ClN4O3S (M+H)+ 493.2035, found 493.2041.
Reaction SMILES: CN([C@@H:4]1CC2C(=CC=CC=2)[C@H:5]1[OH:13])N.[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18].CC[OH:24]>CCOCC>[CH2:5]([OH:13])[CH2:4][O:18][C:17]([CH2:16][CH:15]([OH:24])[C:14]([OH:21])=[O:20])=[O:19]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CCO
Reactant: CN(N)[C@@H]1Cc2ccccc2[C@H]1O
Solvent: CCOCC
Product: O=C(CC(O)C(=O)O)OCCO

Procedure:
(1R,2R)-2-(1-methylhydrazino)-1-indanol (1.45 g, 8.1 mmol, prepared from (1R,2R)-2-methylamino-1-indanol (1.63 g, 10 mmol) according to Example 1) was treated with an equivalent amount of maleic acid in a mixture of EtOH and Et2O to give crystalline hydrogenmaleate salt which was filtered off and recrystallized.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:39]>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:39])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(CCc1ccccc1O)NCCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.56 ml) and octadecyl isocyanate (1.26 ml) were added to a solution containing 3-(2-hydroxyphenyl)-N-(3-morpholinopropyl)propanamide (1.05 g) in methylene chloride (11 ml) and stirred for 3 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=60:1 to 50:1), thereby yielding the entitled compound (1.78 g) as white solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:26][CH:19]([CH3:18])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)c1ccccc1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: CC(OC(=N)N1Cc2ccccc2-c2ccccc2C1)c1ccccc1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6carbonitrile and α-methylbenzyl alcohol, there is obtained α-methylbenzyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate as a resin, mass spectrum m/e: [M+ 342 (5), 237 (60), 194 (100), 105 (63);
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[S:20](=[O:28])(=[O:27])[NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25].[C:29]1([OH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[O:35]([C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[S:20](=[O:28])(=[O:27])[NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)CCNS(=O)(=O)c1cc(C(=O)NC2CCc3ccccc32)ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CCNS(=O)(=O)c1cc(C(=O)NC2CCc3ccccc32)ccc1Oc1ccccc1
Yield: 69.3 %

Procedure:
A solution of 100 mg of 4-fluoro-N-indan-1-yl-3-(3-methyl-butylsulfamoyl)benzamide (Example 41), 26 mg of phenol, and 100 mg of potassium carbonate in 4 ml of N,N-dimethylacetamide was heated to 100° C. for 6 h. After water had been added and the precipitated product filtered off with suction, 82 mg of 4-phenoxy-N-indan-1-yl-3-(3-methyl-butylsulfamoyl)benzamide were obtained; m.p. 73° C.
Reaction SMILES: [C:1]([Cl:4])(=O)C.Cl.[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C@H:10]([C:17]([OH:19])=[O:18])[NH:11][CH2:12]2>CO>[ClH:4].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C@H:10]([C:17]([O:19][CH3:1])=[O:18])[NH:11][CH2:12]2
Reactant: O=C(O)[C@H]1Cc2c(Br)cccc2CN1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H]1Cc2c(Br)cccc2CN1
Temperature: 25 °C
Reaction time: 36 h
Yield: 100.4 %

Procedure:
Dissolve dimethyl (3R)-5-bromo-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylate (27.55 g, 84.0 mmol) in 5N hydrochloric acid (330.6 mL, 1.65 mol) and heat to reflux for three days. Concentrate under reduced pressure to give a white solid. Wash the solid with diethyl ether and dry under vacuum at 40° C. overnight to give (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1:1) (20.8 g, 71.1 mmol). Add acetyl chloride (50.6 mL, 711.0 mmol) to a 0° C. mixture of (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1:1) (20.8 g, 71.1 mmol) in methanol (474 mL). Warm to room temperature and stir for 36 hours. Concentrate under reduced pressure and dry to give the title compound (21.9 g, 71.4 mmol). MS (m/z): 270 (M+1).
Reaction SMILES: [S:1]([CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8])([OH:4])(=[O:3])=[O:2].[CH2:11]([NH2:17])[CH2:12][S:13]([O-:16])(=[O:15])=[O:14].[Na+:18]>>[NH2:17][CH2:11][CH2:12][S:13]([OH:16])(=[O:15])=[O:14].[S:1]([CH2:5][CH2:6][S:7]([O-:10])(=[O:9])=[O:8])([O-:4])(=[O:3])=[O:2].[Na+:18].[Na+:18]
Reactant: O=S(=O)(O)CCS(=O)(=O)O
Reactant: NCCS(=O)(=O)[O-]
Agent: [Na+]
Product: NCCS(=O)(=O)O
Product: O=S(=O)([O-])CCS(=O)(=O)[O-]

Procedure:
It has been found that ethionic acid can also be used to neutralize the sodium taurinate to yield taurine and sodium ethionate. After the separation of taurine, sodium ethionate is combined with equimolar ethionic acid and then treated with calcium oxide/calcium hydroxide to obtain sodium vinyl sulfate. In this variation of the cyclic process, sulfuric acid is eliminated from the process and production cost is further reduced.
Reaction SMILES: [PH2](=O)O.C(N(CC)CC)C.C[Si](Cl)(C)C.[Cl-].[CH2:17]([O:24][C:25]([CH:27]([CH2:41][CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[CH2:28][P:29](CCCC1C=CC=CC=1)(=[O:31])[OH:30])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH2:17]([O:24][C:25]([CH:27]([CH2:41][CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:44])[CH2:28][PH:29](=[O:30])[OH:31])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=[PH2]O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
Dry phosphinic acid (100 g, 1.52 mol) was dissolved in 100 ml of chloroform and treated with triethylamine (155 g, 1.52mol). The mixture was evaporated and transferred to a three liter flask, containing 750 mL of chloroform. The solution was stirred by means of a mechanical stirrer and the flask cooled to 0° C. The clear solution was treated with triethylamine (277 g, 2.72 mol) followed by trimethylsilyl chloride (281 g, 2.58 mol). Once addition of trimethylsiyl chloride was complete dibenzyl 2-methylenepentanedioate (2) in 150 mL of chloroform was added dropwise over 20 minutes. The low temperature bath was removed and the mixture warmed to room temperature. After 6 hours the thick slurry was filtered and the filtrate cooled to 0° C. The filtrate was then quenched with 5% hydrochloric acid and the organic layer removed. The aqueous layer was extracted with chloroform, the organics combined, dried (MgSO4) and evaporated under reduced pressure to give 55 g of 2,4-di(benzyloxycarbonyl)butylphosphinic acid (6) as a light yellow liquid. The liquid was purified by flash chromatography and eluted using 3:1 hexanes/ethyl acetate containing 5% trifluoroacetic acid to give 40 g (7%) of the desired product. Rf 0.28(3:1 Hex./EtOAc 5% TFA);
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=2)[CH2:33][CH2:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=3)[CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COC(=O)c1ccc(CCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCc2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Yield: 56.3 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (88 mg, 0.27 mmol) and methyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)benzoate (100 mg, 0.27 mmol) in 25 mL of 1,4-dioxane were added Na2CO3 (100 mg, 0.94 mmol) and 3 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added in one portion and the reaction mixture was stirred at reflux for 18 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate=1:1) to give methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenethyl)benzoate (80 mg, 56%) as a yellow sold. LC-MS: 527 [M+H]+, tR=1.87 min.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([NH:25][CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:22][CH2:23][CH3:24].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:25]([CH:26]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH3:27])[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CCCCNC(C)c1ccccc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCCN(C(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1)C(C)c1ccccc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and butyl-(1-phenyl-ethyl)-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H31NO5 [M+H]+414.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(OC(Cl)=O)C.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:26][CH2:27][CH:28]([O:31][CH2:32][CH2:33][CH2:34][NH:35][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:29][CH2:30]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCOC1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCOC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.4 g (16.2 mmol) 3-(3-pyridyl)-acrylic acid and 2.3 g (16.2 mmol) TEA were suspended in 50 ml abs. tolueneand a solution of 1.5 ml (15.5 mmol) chloroformic ethyl ester in 20 ml abs. tolueneis added dropwise under moisture exclusion and gentle cooling. This yellow suspension is stirred two hours at RT and then a solution of 3.5 g (14.1 mmol) 3-(1-benzylpiperidine-4-yloxy)-propylamine in 20 ml abs. tolueneis added dropwise. The mixture is stirred at RT and subsequently extracted by shaking in the heat three times with 10 ml water, 2M sodium hydroxide solution and again with water, respectively. The organic phase is concentrated under vacuum and the orange colored, oily residue is chromatographically purified twice over silica gel with CHCl3/CH3OH/NH4OH (90/9/1 and 95/5/0 to 90/10/0) and crystallized twice from 10 ml acetic acid ethyl ester. Colorless crystals with a MP of 100-102° C. were recovered; yield: 1.9 g (35%).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.O[CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:20]([NH:21][C:22](=[O:45])[CH2:23][CH:24]([NH:31][S:32]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)(=[O:34])=[O:33])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][S:18](=[O:47])(=[O:46])[N:17]([CH3:48])[C:16]=2[CH:49]=1.[CH3:50][N:51]1CCOC[CH2:52]1.N(C)C.S([O-])(=O)(=O)C>C(Cl)Cl.C1COCC1>[CH3:50][N:51]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:20]([NH:21][C:22](=[O:45])[CH2:23][CH:24]([NH:31][S:32]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)(=[O:33])=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][S:18](=[O:47])(=[O:46])[N:17]([CH3:48])[C:16]=2[CH:49]=1)[CH3:52]
Reactant: CN1c2cc(CO)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O
Reactant: CN1CCOCC1
Agent: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: CS(=O)(=O)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1ccc2c(c1)N(C)S(=O)(=O)CC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Methanesulfonic anhydride (100 mg, 0.55 mmol) was added to a THF (5 mL) solution of N-(7-hydroxymethyl-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazin-4-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Step D) (200 mg, 0.345 mmol) and N-methylmorpholine (0.11 mL, 0.55 mmol). After 30 min stirring, Me2NH (1.73 mL, 3.45 mmol, 2.0 M in THF) was added to this freshly prepared mesylate solution. After stirring overnight, the mixture was diluted with CH2Cl2 (30 mL), washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica (0-5% MeOH in CH2Cl2) provided the title compound. MS (+ESI, m/z): 607 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH:14](O)=[O:15].O>C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][CH:14]=[O:15])=[CH:9][CH:8]=1
Reactant: Nc1ccc(Cc2ncc[nH]2)cc1
Reactant: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=CNc1ccc(Cc2ncc[nH]2)cc1

Procedure:
In a 200 ml round-bottom flask is placed a solution of 8.0 g of p-(1-imidazolylmethyl)aniline prepared as described in Reference Example 3, and 30 ml of formic acid in 80 ml of toluene. The flask was fitted with a water separator, and the solution was refluxed for 4 hours. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 6.4 g of p-(1-imidazolylmethyl)-N-formylaniline as colorless prisms. M.P.: 121°-123° C. To a suspension of 0.48 g of 50% sodium hydride in 50 ml of dry dimethylformamide was added 2.01 g of the formylaniline and mixture was heated to 100° C. A solution of 1.81 g of ethyl α-bromopropionate in 30 ml of dry dimethylformamide was added to the mixture and the reaction mixture was heated at 100° C. for 16 hours. After removal of the solvent under reduced pressure, 50 ml of dichloromethane was added to the residue, and the solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane-ethanol (20:1 by volume) to give 1.58 g of N-formyl-N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester as a pale brown oil. Then, a solution of 1.58 g of the resulting ester and 5 ml of concentrated hydrochloric acid in 50 ml of ethanol was stirred for 40 hours at room temperature. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 1.18 g of N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester dihydrochloride as pale yellow crystals. M.P.: 154°-159° C.
Reaction SMILES: [CH2:1]=O.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][CH2:9][NH2:10].Cl.[OH-].[Na+]>O.C(OCC)(=O)C.CN(C=O)C>[S:3]1[C:4]2[CH2:8][CH2:9][NH:10][CH2:1][C:5]=2[CH:6]=[CH:7]1
Reactant: C=O
Reactant: NCCc1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: c1cc2c(s1)CCNC2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Formaldehyde (37% in H2O, 3.82 g, 47 mmol) was added dropwise to a flask equipped with a magnetic stirring bar containing neat 2-(thiophen-2-yl)ethanamine (5 g, 39.3 mmol). The mixture was heated to 90° C. for 2 h and then allowed to cool down to room temperature. The reaction was then diluted with water and ethyl acetate. The organic layer was collected and dried with sodium sulfate, reduced in vacuo to give a thick oil. The thick oil was dissolved in anhydrous DMF (25 mL) and added dropwise to a DMF solution saturated with HCl gas (HCl gas was bubbled in DMF for 15 min at 10° C.). The reaction was stirred for 1 h and then poured unto crushed ice and rendered basic (pH 10) with 5 N NaOH. The mixture was extracted three times with dichloromethane. All the organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, reduced in vacuo and placed on a vacuum line to give a thick oil. Yield 5.47 g. MS (M+H)+ 140.