Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:42]=[CH:41][C:12]2[O:13][CH2:14][C:15]3[N:40]=[CH:39][CH:38]=[CH:37][C:16]=3[C:17](=[CH:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][C:24]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([OH:27])[C:23]([CH3:36])([CH3:35])[CH2:22]3)[C:11]=2[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:24]2([OH:27])[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH:18]=[C:17]3[C:16]4[CH:37]=[CH:38][CH:39]=[N:40][C:15]=4[CH2:14][O:13][C:12]4[CH:41]=[CH:42][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:43])=[O:3])=[CH:10][C:11]3=4)[CH2:22][C:23]2([CH3:36])[CH3:35])=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yloxy)-2-methyl-propionic acid ethyl ester (158 mg, 0.261 mmol) in methanol (3 mL) was added sodium hydroxide (1 N in water, 1 mL). Following a slight exotherm, the mixture clarified. An additional aliquot of sodium hydroxide (1 N, 1 mL) was added after 1 h and the mixture was allowed to stir an additional 1 h at rt. The solvents were evaporated under reduced pressure and the residue dissolved in water (2.5 mL). The basic solution was neutralized (pH=7) with hydrochloric acid (1 N) and the titled compound was precipitated and collected by suction filtration (86 mg, 57%).
Reaction SMILES: [OH:1][CH:2]1[CH2:10][CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:3]1>C(Cl)Cl>[O:1]=[C:2]1[CH2:10][CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(O)CC2C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CCC(=O)CC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 5-hydroxyhexahydro-1H-isoindole-2(3H)-carboxylate (48.98 g, 203.0 mmol) in DCM (500 mL) at 0° C. was added DMP (103.31 g, 243.6 mmol) portionwise. After addition, the reaction mixture was stirred at 0° C. for 0.5 h and then moved to rt overnight, cooled down to 0° C. and washed with a mixture of NaHCO3/Na2S2O3 saturated solution (v/v, 1/1, 500 mL), then stirred at 0° C. for 0.5 h and filtered. The filter cake was washed with DCM (250 mL×3) and the filtrate was extracted with DCM (250 mL×3). The combined organic phases were washed with brine (500 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as yellow oil (48.58 g, 100%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([OH:18])[C:10](=[CH:16][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4].[I-:19].[Na+]>CC(C)=O>[I:19][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([OH:18])[C:10](=[CH:16][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4]
Reactant: CCOC(=O)c1ccc(CNC(=O)CCl)cc1O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(CNC(=O)CI)cc1O
Temperature: 25 °C
Yield: 130.8 %

Procedure:
Ethyl N-chloroacetyl4-aminomethylsalicylate (0.11 g, 0.40 mmoles) was dissolved in acetone (5 mL) and sodium iodide (0.06 g, 0.40 mmoles) was added. The solution was refluxed for 2.5 hours, then cooled to room temperature and filtered. The filtrate was evaporated to dryness to afford a white solid of ethyl N-iodoacetyl4-aminomethylsalicylate (0.19 g, 100% yield) (m.p. 105°-108° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]2[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=2I)[CH2:12][CH2:11]1)[C:5]#[N:6].[CH3:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]2[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=2[N:32]2[CH:31]=[C:30]([CH3:29])[CH:34]=[N:33]2)[CH2:12][CH2:11]1)[C:5]#[N:6]
Reactant: Cc1cn[nH]c1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C#N)cc3F)CC2)c1
Product: Cc1cnn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C#N)cc3F)CC2)c1
Yield: 20 %

Procedure:
The title compound was prepared according to the procedure described for example 294 from 3-Fluoro-4-[4-(2-iodo-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile (compound CL) and 4-Methyl-1H-pyrazole (20% yield, white foam, MS (m/e): 468.3 (M+H, 100%)
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:65][C:66]1[S:67][C:68]2[CH:74]=[CH:73][CH:72]=[CH:71][C:69]=2[N:70]=1>>[S:67]1[C:68]2[CH:74]=[CH:73][CH:72]=[CH:71][C:69]=2[N:70]=[C:66]1[S:65][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1
Reactant: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1
Reactant: Sc1nc2ccccc2s1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCSc3nc4ccccc4s3)CC2)c(N2CCCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzothiazole, to thereby yield the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([NH:23]C(=O)C(F)(F)F)=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].O1CCOCC1.[OH-].[Na+]>CO>[NH2:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:13]([C:11](=[O:12])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:14][CH2:15][CH2:16]2
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(NC(=O)C(F)(F)F)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(N)ccc32)cc1

Procedure:
16 g of 1-[3-(4cyano-phenyl)propionyl]-6-trifluoracetylamino-1,2,3,4-tetrahydro-quinoline are dissolved in 70 ml of methanol and 50 ml of dioxan and stirred with 200 ml of 1N sodium hydroxide solution for 2 hours at 40° C. Then the mixture is extracted with methylene chloride, the organic phase is dried over sodium sulphate and concentrated by evaporation.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[O-]CC.[Na+].Cl.Cl.Cl[CH2:13][C:14]1[CH:19]=[C:18]([CH2:20][N:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][N:15]=1.Cl>C(O)C.O>[CH3:22][N:21]([CH2:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:5][CH2:4][CH2:3][NH2:2])[CH:19]=1)[CH3:23]
Reactant: CN(C)Cc1ccnc(CCl)c1
Reactant: NCCS
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ccnc(CSCCN)c1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Cysteamine hydrochloride (3.75 g) was added to a stirred solution of sodium ethoxide (prepared from 2.83 g sodium) in ethanol (200 ml) and the mixture was cooled to less than 10°. 2-Chloromethyl-4-dimethylaminomethylpyridine dihydrochloride (7.3 g) was added portionwise and the solution was stirred for 1 hour. Water (200 ml) was added, the pH was adjusted to ca. 4 with hydrochloric acid and the volume was reduced to ca. 100 ml. The solution was extracted with chloroform, the aqueous phase was basified to pH 12 and extracted with chloroform to give 2-[4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (4.7 g) as an oil.
Reaction SMILES: [Cl-].[Cl-].[Ca+2].[C:4]([NH:7][C:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][C:29]3[C:34]([N:35]=2)=[CH:33][CH:32]=[C:31]([C:36]2([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:38][CH2:37]2)[N:30]=3)=[C:23]([F:45])[CH:22]=1)([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])(=[O:6])[CH3:5].[BH4-].[Na+]>O.CCO>[F:45][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][C:8]([NH:7][C:4](=[O:6])[CH3:5])([CH2:9][OH:10])[CH2:14][OH:15])[CH:26]=[CH:25][C:24]=1[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[C:31]([C:36]1([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:38][CH2:37]1)[N:30]=2
Reactant: CCOC(=O)C(CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)(NC(C)=O)C(=O)OCC
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(=O)NC(CO)(CO)CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of CaCl2 (0.188 g, 1.70 mmol) in 1.3 mL water was added a slurry of diethyl 2-acetamido-2-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)malonate (0.400 g, 0.678 mmol) in about 15 mL EtOH total. To this slurry was added NaBH4 (0.128 g, 3.39 mmol). The mixture bubbled and became warm, and was cooled briefly with an ice bath, then allowed to stir at ambient temperature overnight. 10 mL THF was added, followed by additional NaBH4 (0.128 g, 3.39 mmol). After 5 h, the reaction mixture was concentrated in vacuo, partitioned between DCM and 1N aq. HCl, and extracted with DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The material was treated with 10% MeOH in DCM and adsorbed onto 2 g silica gel, dried, and passed through a Redi-Sep® pre-packed silica gel column (40 g) using 0-10% MeOH/DCM. The product-containing fractions were concentrated to give N-(4-(3-fluoro-4-(5-(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-1-hydroxy-2-(hydroxymethyl)butan-2-yl)acetamide as a white solid. MS (ESI) m/z: calculated: 505.2; Observed: 506.0 (M++1).
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20](Cl)=[O:21])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>O1CCCC1.C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]([NH:5][CH3:3])=[O:21])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CC1
Reactant: CCN(CC)CC
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methylamine in tetrahydrofuran (THF) (2.0 M, 3.5 mL) was mixed with triethylamine (2.1 mL, 15 mmol). The resulting mixture was added to a solution of 1-(4-chlorophenyl)cyclopropanecarbonyl chloride in methylene chloride (15.0 mL) at 0° C. The resulting mixture was stirred at room temperature (about 25° C.) for 30 min, and was then quenched with saturated sodium bicarbonate (25 mL). The quenched mixture was extracted with ethyl acetate (3×40 mL). The combined ethyl acetate extracts were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to provide the product, 1-(4-chlorophenyl)-N-methylcyclopropanecarboxamide, which was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14]C)[N:11]=[C:10]([CH2:16][CH2:17][CH2:18]O)[CH:9]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C:8]1[CH:9]=[C:10]2[N:11]([CH2:18][CH2:17][CH2:16]2)[C:12](=[O:14])[CH:13]=1)([CH3:4])[CH3:3]
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)cc(CCCO)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [I-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc2n(c(=O)c1)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
A solution of 3-[4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)-2-pyridinyl]-1-propanol (5.16 g, 16.59 mmol) in dichloromethane (250 ml) was treated with pyridine (2.94 ml, 36.47 mmol) and trifluoromethanesulfonic anhydride (3.1 ml, 19.88 mmol) and stirred at room temperature for 10 min before being treated with tetrabutylammonium iodide (30.61 g, 82.95 mmol) and stirred at room temperature for a further 4 h. Water was then added and the mixture was extracted three times with diethyl ether and the combined organic extracts washed again with water. The organic extracts were dried with magnesium sulphate and evaporated. The residue was chromatographed on silica eluting with 0-10% methanol in dichloromethane to give the desired product (3.93 g, 14.09 mmol)
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([NH:12][CH:13]([CH3:15])[CH3:14])[CH:6]=1)C.[ClH:17]>>[ClH:17].[CH:13]([NH:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[N:8]=1)[C:4]([OH:16])=[O:3])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1cc(C)nc(NC(C)C)c1
Agent: Cl
Product: Cc1cc(C(=O)O)cc(NC(C)C)n1
Temperature: 25 °C

Procedure:
A solution of 2-isopropylamino-6-methyl-isonicotinic acid ethyl ester (3.90 g, 17.5 mmol) in 32% aq. HCl (100 mL) is stirred at 70° C. for 5 h before it is cooled to rt and concentrated. The residue is dried under HV to give 2-isopropylamino-6-methyl-isonicotinic acid hydrochloride (4.20 g) as an orange resin; LC-MS: tR=0.52 min; [M+1]+=195.09.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.[CH3:28][OH:29]>>[CH3:28][O:29][C:9]1([C:7]2[S:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:27]=[CH:26][C:5]=3[N:6]=2)[CH:10]=[CH:11][C:12](=[N:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:13]=[CH:14]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ccc(C)cc4s3)cc2)cc1
Reactant: CO
Product: COC1(c2nc3ccc(C)cc3s2)C=CC(=NS(=O)(=O)c2ccc(C)cc2)C=C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
To the sulfonamide (0.1 g) dissolved in methanol (2 mL) was added BTIB (1.1 eq.) in one portion as a solid. The resulting suspension was stirred at room temperature for 5 hours. The precipitate formed was collected on a filter, washed with ice cold methanol (2 mL) and dried under vacuum to give the title compound.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]#[CH:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>O.C(N)(CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:21])=[CH:8][CH:9]=2)=[CH:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)NC(C)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(C)N
Solvent: O
Product: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(C(C)(C)C)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To 0.50 g (1.54 mmol) trifluoro-methanesulfonic acid 4-(2-acetylamino-propyl)-phenyl ester (I53.2) and 0.32 g (2.00 mmol) 4-tert.butylphenylacetylen in 3.0 mL water and 3.0 mL sec-butylamine are added 0.10 g (0.14 mmol) bis(triphenyphosphine)dichloropalladium and the mixture is stirred at r.t. for 4 h and at 80° C. for 1 h. The reaction mixture is allowed to cool to r.t. and is then partitioned between EtOAc and citric acid (10% in water). The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified twice by column chromatography (silica gel; DCM/MeOH 9/1 and aluminium oxide DCM/EtOAc 4/1). The resulting product is triturated with MeOH.
Reaction SMILES: C[SiH](C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17](=[O:35])[N:18](COCC[Si](C)(C)C)[N:19]=[C:20]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:21]=1>ClCCl.FC(F)(F)C(O)=O>[NH:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]=[C:8]1[C:16]1[C:17](=[O:35])[NH:18][N:19]=[C:20]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:21]=1
Reactant: C[SiH](C)CCOCn1c(-c2cc(-n3ccnc3)nn(COCC[Si](C)(C)C)c2=O)nc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(-n2ccnc2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 mg of 4-[1-(2-dimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-6-imidazol-1-yl-2-(2-trimethylsilanylethoxymethyl)-2H-pyridazin-3-one are dissolved in 2 ml of a 1:1 mixture of dichloromethane and trifluoroacetic acid, and the mixture is stirred at room temperature for 2 hours. The volatile components are then distilled off, the residue is dissolved in 1 ml of methanol, and 1 ml of a two molar aqueous sodium hydroxide solution is added. The solution is stirred at room temperature for 12 hours and then put directly onto the preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)) to isolate the product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([C:26]3[C:27]([CH2:36][N:37]4[C@@H:41]([CH3:42])[C@@H:40]([C:43]5[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=5)[O:39][C:38]4=[O:57])=[N:28][C:29]([N:32]4[CH2:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)[CH:19]=2)[CH:7]=[CH:8][C:9]=1[O:10]CC1C=CC=CC=1)(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([C:26]3[C:27]([CH2:36][N:37]4[C@@H:41]([CH3:42])[C@@H:40]([C:43]5[CH:44]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:46]=[C:47]([C:49]([F:51])([F:52])[F:50])[CH:48]=5)[O:39][C:38]4=[O:57])=[N:28][C:29]([N:32]4[CH2:33][CH2:34][CH2:35]4)=[CH:30][CH:31]=3)[CH:19]=2)[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(OCc3ccccc3)c(C(C)=O)c2)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(O)c(C(C)=O)c2)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (4S,5R)-3-({3-[3′-acetyl-4′-(benzyloxy)-4-methoxybiphenyl-3-yl]-6-azetidin-1-ylpyridin-2-yl}methyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 257 Step A) (42 mg, 0.053 mmol) and 10% Pd/C (20 mg, 0.053 mmol) in EtOAc (2 ml) was degassed and flushed with H2 using a balloon. The mixture was stirred at RT under H2 for 6 hours, then, flushed with nitrogen, and filtered washing with EtOAc. The filtrate was concentrated and the residue purified by TLC eluting with 3:2 hexanes/EtOAc to afford the title compound. Mass spectrum (ESI) 700.2 (M+1). 1H NMR (500 MHz, CD3OD): (atropisomers) δ 8.05 (s, 1H); 7.96 (s, 1H); 7.91-7.70 (m, 3H); 7.61 (dd, J=2.3, 8.7 Hz, 1H); 7.49-7.36 (m, 2H); 7.13 (d, J=8.2 Hz, 1H); 6.98 (d, J=8.7 Hz, 1H); 6.38 (d, J=8.5 Hz, 1H); 5.70 (br d, J=75.7 Hz, 1H); 4.69 (m, 1H); 4.43-3.73 (m, 9H); 2.68 (s, 3H); 2.42 (m, 2H); 0.65 (br d, J=37.5 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[N:19][C:20]#[N:21])SC)[CH:12]=[CH:13][CH:14]=1>O.C(O)C>[C:20]([N:19]=[C:16]([NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=1)[NH:1][CH2:2][C:3]([OH:5])=[O:4])#[N:21]
Reactant: CSC(=NC#N)Nc1cccc(Cl)c1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CN=C(NCC(=O)O)Nc1cccc(Cl)c1
Yield: 89.6 %

Procedure:
Three grams (39.9 mmol) of glycine and 1.5 g (37.2 mmol) of sodium hydroxide are mixed in 10 cm3 of water and added to 6 g (26.5 mmol) of N-(3-chlorophenyl)-N'-cyano-S-methylisothiourea in solution in 40 cm3 of 95% ethanol. The mixture is reflux heated for 1 hour. After cooling, the resulting precipitate is filtered and then washed with 2×50 cm3 of ethyl ether. The resulting solid is dissolved in 50 cm3 of 1N sodium hydroxide solution. This solution is washed with 3×10 cm3 of dichloromethane and then acidified with a 3N solution until a pH close to 2 is obtained. The white solid which forms is then filtered and washed in 2×10 cm3 of water, following which it is dried in vacuo. 6 g of N-[cyanoimino(3-clorophenylamino)methyl]-2-aminoethanoic acid (yield 89%) is obtained with a melting point of 109° C.
Reaction SMILES: [CH2:1]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:2][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]#[CH:5].[N:22]([Si](C)(C)C)=[N+:23]=[N-:24]>CN(C=O)C.CO.[Cu](I)I>[N:22]1[NH:23][N:24]=[C:4]([C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2][CH2:1][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#C[C@H](CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)c1cn[nH]n1
Temperature: 100 °C

Procedure:
To a solution of (S)-di-tert-butyl pent-4-yne-1,3-diyldicarbamate in DMF/MeOH (3.7 mL, 1.2:1) was added azidotrimethylsilane (330 μL, 2.38 mmol) and copper iodide (15 mg, 0.079 mmol). The mixture was heated at 100° C. for 16 h, cooled to rt then filtered through celite. The filtrate was concentrated in vacuo and the crude residue was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound. LCMS: Rt=0.68 min, m/z=342.1 (M+1) Method 2m_acidic.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([CH:18]=O)[O:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:25](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([C:18]#[N:25])[O:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C=O)cc21
Reactant: CCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Product: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C#N)cc21

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1c) using 4-{[t-butyl(dimethyl)silyl]oxy}-4,5,6,7-tetrahydro-1-benzofuran-2-carboxaldehyde (4.3 g, 15.3 mmol) that was obtained in Example 7 (7b), hydroxylamine hydrochloride (1.2 g, 17 mmol), triethylamine (4.3 ml, 31 mmol), and N,N′-dicyclohexylcarbodiimide (3.5 g, 17 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (3.0 g) in a yield of 71% as a colourless oily product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:25]([N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCc1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Yield: 100.8 %

Procedure:
A solution of 6.0 g of methyl 3-(1H-imidazol-4-yl)propionate and 11 ml of triethylamine in 31 ml of dimethylformamide is treated with a solution of 9.65 g of triphenylmethyl chloride in 110 ml of dimethylformamide for 2 h at room temperature under nitrogen. The reaction mixture is poured onto 700 g of ice, and the resulting solid is collected by filtration and recrystallized from ether to yield 13.83 g of methyl 3-(1-tritylimidazol-4-yl)propionate, NMR (CDCl3) δ=2.75 (m, 4H), 3.05 (s, 3H), 6.5-7.5 (m, 17H).