Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][C:37]([NH:44]C(=O)C)=[N:38][C:39]=2Cl)(=O)C1C=CC=CC=1.SC([OH:51])C.C[O-].[Na+]>C(O)(=O)C>[C@H:11]1([N:34]2[CH:42]=[N:41][C:40]3[C:39](=[O:51])[NH:38][C:37]([NH2:44])=[N:36][C:35]2=3)[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: CC(=O)Nc1nc(Cl)c2ncn([C@H]3O[C@@H](COC(=O)c4ccccc4)[C@H](OC(=O)c4ccccc4)[C@@H]3OC(=O)c3ccccc3)c2n1
Reactant: CC(O)S
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc2c(ncn2[C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Yield: 86.3 %

Procedure:
A mixture of 12 (0.58 g, 0.88 mmol), mercaptoethanol (0.25 ml, 3.53 mmol) and NaOMe (0.76 ml, 3.53 mmol, 35% weight solution in MeOH (10 ml)) was refluxed for six hours. The reaction mixture was cooled, neutralized with glacial acetic acid and evaporated to dryness. The solid obtained was washed with CHCl3 and the residue was crystallized from water to yield pure 13 (0.215 g, 86%) as white crystal: m.p. 248° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)N.OS(O)(=O)=O.N([O-])=O.[Na+].[BrH:20]>O>[Br:20][C:7]1[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH3:10]
Reactant: COc1ccc(C)c(N)c1
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C)c(Br)c1
Temperature: 3 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-methoxy-2-methylaniline (5.00 g, 36.4 mmol) in water (144 mL) at 10° C., was added conc. H2SO4 (56 mL), while maintaining internal temperature below 25° C. After 1 h at rt, the mixture was cooled to 3° C. and a solution of sodium nitrite (3.77 g, 54.7 mmol) in water (20 mL) was added dropwise over 30 min, keeping the internal temperature below 5° C. After 1 h at 3° C., the yellow heterogeneous mixture was poured into a 5° C. solution of CuBr (52.0 g, 364 mmol) in 48% aqueous HBr (260 mL). The dark mixture was heated at 60° C. for 2 h, allowed to cool to rt and extracted with Et2O (3×) (solid Na2S2O3 was added in the extraction process for partial decoloration). The combined organics were washed with 1 N NaOH (3×), 10% aq. Na2S2O3 and brine, dried (Na2SO4) and concentrated, affording the title compound as an orange liquid which was used without further purification in the next Step. 1H NMR (500 MHz, acetone-d6): δ 7.24 (d, 1H), 7.14 (d, 1H), 6.87 (dd, 1H), 3.80 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:25])=[O:6].C=O.[C:33](O)(=O)C.[BH4-].[Na+]>C(#N)C>[C:29]([C:28]1[CH:27]=[CH:26][C:4]([C:5]([NH:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:17])([F:18])[F:19])=[CH:10][C:9]=2[CH3:25])=[O:6])=[CH:3][C:2]=1[NH:1][CH3:33])#[N:30]
Reactant: CC(=O)O
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(N)c1
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CNc1cc(C(=O)Nc2c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C)ccc1C#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
3-Amino-4-cyano-N[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (3.01 g, 6.95 mmol) (Example I2) was dissolved in acetonitrile (50 ml) and aqueous formaldehyde (36.5% w/v) (0.64 ml, 6.95 mmol) and acetic acid (30 ml) were added successively. The reaction mixture was stirred at ambient temperature for 45 minutes. Then sodium borohydride (0.44 g, 6.95 mmol) and more acetic acid (5 ml) were added. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution washed with aqueous sodium hydroxide (1N). The aqueous phase was extracted three times with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:5) to give 4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-methylamino-benzamide (1.80 g, 58% yield). M.p. 204-206° C. 1H-NMR (400 MHz, CDCl3): 7.53 (d, 1H), 7.37 (s, 3H), 7.23 (s, 1H), 7.10 (q, 1H), 5.88 (d, 1H), 3.02 (d, 3H), 2.35 (s, 6H) ppm. The method as described in Example P1 was then used to prepare Compound No. A3 of Table A.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]2=[N:6][C:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[CH:14]=[CH:13][C:5]3=[N:6][C:7]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[N:4]3[N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: Clc1ccc2nc3c(n2n1)CCCC3
Product: c1cc2nc3c(n2nc1N1CCCCC1)CCCC3
Temperature: 0 °C

Procedure:
A solution of 5.0 g of 2-chloro-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole in 30 ml of piperidine was stirred and heated at reflux for 72 hours. The reaction mixture was poured into 200 ml of ice water and the tan solid which formed was separated by filtration and air dried. It was then recrystallized from a mixture of ethanol and water to give 2-(1-piperidinyl)-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole melting at about 184°-185° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].N1C=CC=CC=1.[CH3:24][O:25][CH2:26][C:27](Cl)=O.[OH-].[Na+]>C1COCC1>[Cl:14][C:13]1[C:8]([C:6]2[CH:5]=[CH:4][C:3]3[C:15](=[O:16])[NH:17][C:27]([CH2:26][O:25][CH3:24])=[N:1][C:2]=3[N:7]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCC(=O)Cl
Reactant: NC(=O)c1ccc(-c2ncccc2Cl)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCc1nc2nc(-c3ncccc3Cl)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 6-amino-3′-chloro-[2,2′]bipyridinyl-5-carboxylic acid amide (0.5 g, 2.02 mmol) in anhydrous THF (10 mL) under N2 atmosphere. Add drop wise pyridine (0.36 g, 4.04 mmol) and methoxyacetyl chloride (0.48 g, 4.04 mmol) to the reaction mixture and stir at room temperature overnight. Add 10% aq. NaOH (10 mL) and reflux for 4 hours. Concentrate in vacuum, adjust the pH to 6.0 using AcOH, collect the solid by filtration and dry under vacuum to give 7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>[H][H].[OH-].[OH-].[Pd+2]>[NH:1]1[CH2:6][CH2:5][NH:4][CH:3]=[C:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [H][H]
Reactant: CCOC(=O)c1cnccn1
Agent: [Pd+2]
Agent: [OH-]
Product: CCOC(=O)C1=CNCCN1
Yield: 102 %

Procedure:
A solution of ethyl pyrazine-2-carboxylate (60 g) in ETOH (500 ml) was subjected to catalytic reduction using palladium hydroxide on carbon (5.0 g), in hydrogen at 3 atm for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 62.8 g of ethyl 1,4,5,6-tetrahydropyrazine-2-carboxylate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C)C=O.S(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:18])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cncc(Br)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cncc(Br)c1
Temperature: 25 °C

Procedure:
To a mixture of 5-bromonicotinic acid (10 g) in thionyl chloride (25 mL) was added anhydrous dimethylformamide (DMF) (0.5 mL). The whole was heated to reflux for overnight. After cooling to RT, the excess thionyl chloride was removed under reduced pressure. A white solid (3) (11 g) was obtained, which was used for the next step without further purification.
Reaction SMILES: [N+](C1C=CC=CC=1C1C=CC(C[N:17]2[C:21]([CH2:22][O:23][CH3:24])=[C:20]([Cl:25])[N:19]=[C:18]2[CH2:26][CH2:27][CH2:28][CH3:29])=CC=1)([O-])=O.C(O)(=O)C>[Fe].CO>[CH2:26]([C:18]1[NH:17][C:21]([CH2:22][O:23][CH3:24])=[C:20]([Cl:25])[N:19]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1nc(Cl)c(COC)[nH]1

Procedure:
A solution of 4.40 g of 1-[(2'-nitrobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole, 2.10 g of iron powder, 4.25 mL of glacial acetic acid, and 200 mL of methanol was refluxed for 5 hours. After cooling, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The precipitated iron salts were removed by filtration through Celite®, and the resulting solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. Column chromatography on silica gel (elution: 10-30% ethyl acetate/benzene) furnished 2.95 g of 1-[2'-aminobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole; NMR (200 MHz, CDCl3): δ7.43 (d, 2H); 7.19-7.04 (m, 4H); 6.80 (m, 2H); 5.19 (s, 2H); 4.33 (s, 2H); 3.70 (br s, 1H); 3.28 (s, 3H); 2.59 (t, 2H); 1.67 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(C)[CH:15]=[O:16].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][O:2][C:3]1[S:4][C:5]([CH:15]=[O:16])=[CH:6][CH:7]=1
Reactant: COc1cccs1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To a solution of 2-methoxythiophene (79 mg, 0.69 mmol) in 3.5 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (0.30 mL, 2.5 M in hexanes) dropwise. After stirring at −78° C. for 20 minutes, dimethylformamide (0.27 mL, 3.5 mmol) was added in a single portion and the reaction mixture allowed to warm to room temperature while stirring, before being poured into 25 mL of 1 N hydrochloric acid. Organics were extracted with ether (2×25 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (10-12% ethyl acetate in hexanes) to give 5-methoxy-2-thiophenecarbaldehyde (71 mg, 72%). Used without further characterization.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[H-].[Na+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: COc1ccc(CNc2nc(C)nc(Cl)n2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a solution of 4-chloro-N-(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (160 g, 604 mmol) in DMF (800 mL) at 0° C., was added sodium hydride (18.86 g, 786 mmol) slowly over min. 1-(Chloromethyl)-4-methoxybenzene (91 mL, 665 mmol) was slowly added over 15 min. The reaction mixture was stirred at 0-5° C. for 30 min and allowed to warm to room temp 25° C. After 1 h, cold water (2.5 L) was added and the mixture was stirred overnight. The resulting slurry was filtered, washed with water (150 mL, ×2) and dried to afford 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine as a solid (215.3 g, 559 mmol, 93% yield). LCMS (ES, pos.): Cacld for C20H21ClN4O2: 384.1. found: 385.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J=8.12 Hz, 4H); 6.81-6.95 (m, 4H); 4.74 (s, 2H); 4.69 (s, 2H); 3.81 (s, 6H); 2.45 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](O)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([Cl:23])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Yield: 92.9 %

Procedure:
2-Butyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (444 mg, 1.58 mmol) was dissolved in dry DCM (15 mL) at rt and under an atmosphere of nitrogen. Oxalyl chloride (0.15 mL, 1.73 mmol) was added dropwise and the reaction mixture was refluxed for 1.5 h. DMF (0.08 mL) was added followed by oxalyl chloride (0.15 mL, 1.73 mmol) in 2 portions and the reaction mixture was refluxed for another 6 h. The solvents were evaporated and the residue was partitioned between water and DCM. The combined organic layers were washed with water and the two phases were separated using a phase separator. Evaporation of the organic phase gave the title compound (440 mg, 88%) as a brown oil with approximately 95% purity according to 1H-NMR and was used without further purification; 1H-NMR (400 MHz, CDCl3): δ 7.96-8.00 (m, 2H), 7.53-7.62 (m, 3H), 3.74-3.80 (t, 2H), 1.78-1.87 (m, 2H), 1.39-1-50 (m, 2H), 0.98 (t, 3H); 13C-NMR (100 MHz, CDCl3): δ 156.3, 137.1, 132.7, 129.6, 129.2, 127.6, 123.7, 40.9, 30.1, 20.1, 13.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:17].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH:5]=[CH:4][C:3]=1[C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NS(=O)(=O)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cold (ice/water) solution of {2-chloro-4-[(2-aminophenyl)amino]phenyl}(2-methylphenyl)methanone (0.67 g, 2.0 mmol)(disclosed in WO 98/32730) in pyridine (10 mL) was added benzenesulfonyl chloride (0.32 mL, 2.5 mmol). The reaction mixture was warmed to room temperature. After stirring for 48 h, the reaction mixture was poured into ice water. The precipitate was filtered off, washed with water, and diethyl ether to afford the crude product. Crystallization from acetic acid afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([CH:23]=O)=[CH:10][CH:9]=1)[CH3:2].C(O)=O.[OH-].[Na+].[CH3:32][NH:33]C=O>>[CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([CH2:23][NH:33][CH3:32])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CNC=O
Reactant: CCN(CC)CCCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CCN(CC)CCCNc1ccc(CNC)c2sc3ccccc3c(=O)c12

Procedure:
A solution of 1-[[3-(diethylamino)propyl]amino]-9-oxothioxanthen-4-carboxaldehyde (3.3 g, 8.96 mmol) and 3 g of formic acid in 50 mL of N-methylformamide was allowed to reflux for 2 h. The mixture was basified with 5 mL of a 5N sodium hydroxide solution and extracted into chloroform (3×150 ml). The organic layer was dried over sodium sulfate, concentrated in vacuo, and a crude oil was dissolved in a 3N aqueous HCl solution (50 ml) and heated on a steam bath for 3 h. The above mixture was cooled, basified with 30 mL of 35% NaOH, extracted into chloroform (3×150 ml), the organic layer dried over sodium sulfate and concentrated in vacuo to afford a brown oil. The brown oil was purified by flash chromatography (silica gel; 5% triethylamine/Et2O, then 5% Et3N/EtOAc, then triethylamine/methanol/EtOAc (5:5:90)) to afford 1.1 g of 1-[[3-(diethylamino)propyl]amino]-4-(methylaminomethyl)thioxanthen-9-one, as a clear orange gum. The above gum was converted into the corresponding dihydrochloride by treatment with 6N HCl in ether to afford 1.04 g of the dihydrochloride.3/2 hydrate as a yellow powder, m.p. 222°-224° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:22]([Si:26]([CH3:46])([CH3:45])[O:27][CH2:28][CH2:29][N:30]([CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C:31](=[O:34])[CH2:32]Cl)([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[C:41]([Si:38]([CH3:40])([CH3:39])[O:37][CH2:36][CH2:35][N:30]([CH2:29][CH2:28][O:27][Si:26]([CH3:45])([CH3:46])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:31]([CH2:32][O:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)=[O:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCC(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
(R)-tert-Butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (1.0 g, 3.741 mmol) was dissolved dry N,N-dimethylformamide (10 mL) and cooled in an ice bath. To this was added portionwise a 60% dispersion of sodium hydride in mineral oil (344 mg, 8.604 mmol). The mixture was then warmed to 10° C. for 0.5 hours, then cooled in an ice bath and N,N-bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-chloro-acetamide (2.13 g, 4.67 mmol) added slowly in dry N,N-dimethylformamide (5 mL). The reaction mixture was warmed to ambient temperature and stirred overnight. Analysis of the reaction mixture by 1H NMR indicated 75% conversion to product. The reaction mixture was cooled in an ice bath and a 60% dispersion of sodium hydride in mineral oil (68 mg, 0.748 mmol) added. After a few minutes N,N-bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-chloro-acetamide (0.46 g, 0.426 mmol) was added. The reaction mixture was warmed to ambient temperature over 1 hour. The reaction mixture was then poured into water (50 mL) and extracted with diethyl ether (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL). The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo to give (R)-[4-({bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-carbamoyl}-methoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid (2.2 g, 45.9%) which was used in step 14-E without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH:7]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8]([OH:10])=[O:9].[OH-].[Na+].O>C1COCC1>[CH3:16][S:13]([CH2:12][CH2:11][CH:7]([NH:6][C:2]([O:4][CH3:5])=[O:3])[C:8]([OH:10])=[O:9])(=[O:14])=[O:15]
Reactant: CS(=O)(=O)CCC(N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NC(CCS(C)(=O)=O)C(=O)O
Temperature: 25 °C
Reaction time: 9 h
Yield: 14.6 %

Procedure:
Methyl chloroformate (2.6 mL, 33 mmol) was added dropwise to a stirred suspension of 2-Amino-4-methanesulfonyl-butyric acid (5.03 g, 27.8 mmol) and NaOH (5 N in H2O, 13.3 mL, 66.6 mmol) in THF (50 mL). After stirring at room temperature for 9 h, additional methyl chloroformate (5.2 mL, 66.6 mmol) and NaOH (5 N in H2O, 30 mL, 150 mmol) were added. After another 14 h, the reaction mixture was poured into H2O. The aqueous phase was washed with DCM 2× then acidified to pH 1 with 10% HCl. The acidified aqueous phase was extracted 3× with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated to provide 4-Methanesulfonyl-2-methoxycarbonylamino-butyric acid (970 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:16][OH:17])=[C:6]([CH:15]=1)[CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1C=CC=CC=1>[C:18]([O:17][CH2:16][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:6]=1[CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1ccc(Cl)cc1C(O)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)OCc1ccc(Cl)cc1C(O)c1ccccc1

Procedure:
To a solution of 97 g. of the compound of Example 1 in 550 ml. of benzene, 75 ml. of acetic anhydride is added and the mixture is gently refluxed for 3 hours. The cooled solution is washed with aqueous sodium bicarbonate, then with water. The organic phase is dried over sodium sulphate and evaporated to dryness. The residue, after trituration with light petroleum, is crystallized from a mixture of ethyl ether and benzol. M.p. 86°-88° C. Yield 60 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Yield: 80.7 %

Procedure:
A stirred solution of 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268 A1)(0.21 g, 0.0008 mole) in a mixture of DME (10 ml) and water (30 ml) under argon was treated with 4-boronobenzoic acid (0.14 g, 0.0008 mole), sodium carbonate (0.39 g, 0.0037 mole) and tetrakis (triphenylphosphine)palladium (0)(16 mg), then heated under reflux for 4 hours. The mixture was dried (Na2SO4) and concentrated in vacuo to leave the title compound as a white solid (0.19 g, 78%).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:14])[CH:2]=[CH2:3].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCCCCC>[CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCc1ccc2ccccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Yield: 95 %

Procedure:
A mixture of 2-(2-propenyl)-1-naphthol (Example 118 Part A; 101.9 g, 0.550 mole), t-butyldimethylsilyl chloride (100.0 g, 0.660 mole), and imidazole (93.6 g, 1.375 mole) in N,N'-dimethylformamide was stirred at room temperature for 6.5 hours. It was then poured into saturated aqueous sodium bicarbonate, and the crude product isolated by extraction with hexane. The residue was distilled at reduced pressure to provide the title compound (155.2 g, 95%), bp 135°-140° (0.1 torr).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(N(CC)CC)C>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH2:1][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: CCOC(=O)Cl
Reactant: Cc1nccn1Cc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nccn1Cc1ccc([N+](=O)[O-])cc1

Procedure:
24.8 g of 2-methyl-1-(4-nitrobenzyl)imidazole was reacted with 22 ml of ethyl chloroformate in the presence of 32 ml of triethylamine to obtain 13.9 g of ethyl 1-(4-nitrobenzyl)imidazol-2-ylacetate.