Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]=[C:6]([NH2:10])[CH:7]1[CH2:9][CH2:8]1)[CH3:2].[F:12][C:13]([F:31])([F:30])/[C:14](/O)=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)=O>>[CH2:1]([O:3][C:4](=[O:11])[C:5]1[C:14]([C:13]([F:12])([F:31])[F:30])=[CH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)=[N:10][C:6]=1[CH:7]1[CH2:8][CH2:9]1)[CH3:2]
Reactant: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C=C(N)C1CC1
Product: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1

Procedure:
In analogy to the procedure described in example 152E], 3-amino-3-cyclopropyl-acrylic acid ethyl ester (J. P. Célérier, E. Deloisy, P. Kapron, G. Lhommet, P. Maitte, Synthesis 1981, 130–133) was reacted with (Z)-4,4,4-trifluoro-3-hydroxy-1-(4-trifluoromethoxy-phenyl)-but-2-en-1-one (example 152D]) to give the title compound as colorless oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[ClH:22].Cl.[NH2:24][CH2:25][C:26]([NH2:28])=[NH:27]>>[ClH:22].[ClH:22].[NH2:28][C:26]1[CH:25]=[N:24][C:9]2[CH2:10][CH2:11][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:6][CH2:7][C:8]=2[N:27]=1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CCN(C2CCC2)CC1
Reactant: N=C(N)CN
Agent: Cl
Product: Nc1cnc2c(n1)CCN(C1CCC1)CC2

Procedure:
This compound was prepared analogous to Example 22 from 1-cyclobutyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)-azepine and α-amino-acetamidine dihydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1Br

Procedure:
60 g of crude diethyl (2-bromo-3,4,5,6-tetrafluorobenzoyl)-malonate are introduced into 150 ml of water, 0.6 g of 4-toluenesulphonic acid is added and the mixture is heated under reflux for 6 hours. It is extracted with methylene chloride and the extract is washed with water, dried with Na2SO4 and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=CC)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:29]=[O+][O-].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[O:29])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=[O+][O-]
Reactant: CC=Cc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Reaction time: 8 h

Procedure:
{(2R)-7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (10.5 g, 25.9 mmole) dissolved in 400 mL of methylene chloride was treated with excess ozone at −78° C. Diisopropylethylamine (11.5 mL, 66.0 mmole) was then added dropwise over 30 min and the mixture allowed to come to room temperature and stir overnight under a nitrogen atmosphere. The mixture was then diluted to 600 mL with methylene chloride, washed three times with 100 mL portions of 2N HCl (aq), twice with 200 mL portions of saturated aqueous sodium bicarbonate and with 200 mL of saturated brine. The solution was dried over magnesium sulfate, filtered and concentrated in vacuum to a crude brown oil, which was column chromatographed on silica gel with 10% hexane/methylene chloride to give 7.52 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ(2 H); doublet 7.62 δ(1 H); doublet 7.4 δ(2 H); doublet 7.0 δ(1 H); multiplet 4.4-4.6 δ(2 H); multiplet 4.2 δ(3 H); singlet 2.4 δ(3 H).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: CN1CCCC1=N
Product: COc1cccc(NC(=O)N=C2CCCN2C)c1
Temperature: 25 °C

Procedure:
Conversion of the hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g; 0.05 mole) to the free base (4.9 g. assuming 100% conversion) is carried out in the usual manner. After drying over K2CO3, the benzene layer is stirred at room temperature and 7.45 g. (0.05 mole) of m-methoxyphenylisocyanate is added. The reaction mixture is stirred overnight and then taken to dryness in vacuo to give a white solid residue of 1-m-methoxyphenyl-3-(1-methyl-2-pyrrolidylidene)urea, m.p. = 123°-125° C. Recrystallizations from acetone affords the pure product, m.p. = 128°-129.5° C.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][CH2:6][CH2:7][C:8]1[C:13]([OH:14])=[C:12]([C:15]([CH3:17])=[O:16])[CH:11]=[CH:10][C:9]=1[OH:18].[CH2:19]([O:21][C:22](=[O:28])[C:23](OCC)=O)[CH3:20].Cl>C(O)C.CCOCC>[OH:18][C:9]1[CH:10]=[CH:11][C:12]2[C:15](=[O:16])[CH:17]=[C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:28])[O:14][C:13]=2[C:8]=1[CH2:7][CH2:6][CH3:5]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCCc1c(O)ccc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C

Procedure:
To a solution of sodium ethoxide (from 19 gm. of sodium and 260 ml of absolute ethanol) under nitrogen atmosphere, add dropwise a solution of 40 gm of 2,4-dihydroxy-3-propylacetophenone and 68 gm of diethyloxalate in 55 ml of absolute ethanol and 55 ml of absolute ether. Heat under reflux for 3.5 hours. Cool to room temperature and pour the mixture into 500 ml of 5% aqueous hydrochloric acid. Extract the mixture twice with ether. Wash the combined organic fractions with water, dry over sodium sulfate and strip to a residue. Reflux the residue for 30 minutes in 150 ml absolute ethanol containing 2.5 ml of concentrated hydrochloric acid. Evaporate most of the ethanol and partition the residue between water and ethyl acetate. Wash the organic fraction with water, aqueous sodium bicarbonate solution and again with water. Dry over sodium sulfate and strip to a residue. Crystallize the residue from ethyl acetate-hexane to obtain a first crop (mp 155°-162° C.). Strip the mother liquors to dryness and chromatograph the residue over silica gel, eluting with a mixture of ethylacetate-hexane (1:1). Crystallize the resulting product from ethyl acetate to obtain a second crop. (mp 165°-167° C. lit. 166°-167° C.).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][Mg]Br>O1CCCC1>[CH3:22][C:12]1([OH:15])[CH2:13][CH2:14][N:9]([CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11]1
Reactant: C[Mg]Br
Reactant: O=C1CCN(CC(c2ccccc2)c2ccccc2)CC1
Solvent: C1CCOC1
Product: CC1(O)CCN(CC(c2ccccc2)c2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 0.28 parts of 1-(2,2-diphenylethyl)-4-piperidinone in 5 parts by volume of tetrahydrofuran under nitrogen atmosphere is added 2 parts by volume of 3 M solution of methylmagnesium bromide. The resultant mixture is stirred for about 2.5 hours and then quenched with the careful addition of 5 parts by volume of 10% ammonium chloride. The mixture is left standing overnight, partitioned between water and ethyl acetate, and the organic layer separated. The organic layer is then dried with brine and magnesium sulfate, and concentrated to give 4-methyl-1-(2,2-diphenylethyl)-4-piperidinol, as yellow solid. This compound is represented by the following structural formula ##STR40##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7](I)[C:6]=2[C:18]=1[F:19].C([Li])CCC.N1([CH:31]=[O:32])CCCCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([CH:31]=[O:32])[C:6]=2[C:18]=1[F:19]
Reactant: O=CN1CCCCC1
Reactant: Fc1ccc(-c2oc3ccc(Cl)c(F)c3c2I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(-c2ccc(F)cc2)oc2ccc(Cl)c(F)c12
Temperature: 78 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a mixture of 5-chloro-4-fluoro-2-(4-fluorophenyl)-3-iodobenzofuran (2.0 g, 5.12 mmol) in THF (15 ml) under a N2 atmosphere in a 50 ml two necked RB flask cooled to 78° C. was added n-butyllithium (0.328 g, 5.12 mmol) slowly, and the mixture stirred at the same temperature for 1 hour. 1-Piperidinecarboxaldehyde (5.79 g, 51.2 mmol) was then added and the mixture was maintained stirring at the same temperature for 3 hours. The reaction mixture was quenched with 1N HCl and extracted with diethyl ether (3×25 ml). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the titled compound (1.2 g, 74%). 1H NMR (400 MHz, CDCl3): δ 10.39 (d, J=2.4 Hz, 1H), 8.18-8.14 (m, 2H), 7.44-7.40 (m, 1H), 7.33 (d, J=9.2, 1H), 7.27-7.23 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-])=O.O(CC)[C:12]([S-])=[S:13].[K+]>>[SH:13][C:12]1[O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:1]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCOC(=S)[S-]
Agent: [K+]
Product: Sc1nc2ccccc2o1

Procedure:
In Scheme 3, substituted phenol E can be nitrated to give the corresponding ortho-nitrophenol F. This material can then be reduced to provide the ortho-aminophenol G. The aminophenol G can subsequently be reacted with potassium ethyl xanthate (potassium (carbodithiolatooxy)ethane) to produce the cyclized 2-mercaptobenzoxazole H. Reaction of the 2-mercaptobenzoxazole H with a chlorinating agent, such as thionyl chloride, affords the desired 2-chlorobenzoxazole J.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:27]=O)=[CH:9][N:10]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:31][NH2:32].[BH4-].[Na+]>CO.O1CCCC1>[C:1]1([C:7]2[C:8]([CH2:27][NH:32][CH3:31])=[CH:9][N:10]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reaction time: 0.25 h
Yield: 87 %

Procedure:
4,5-Diphenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (202 mg) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), 40% methylamine methanol solution (0.5 mL) was added at room temperature, and the mixture was stirred for 15 min. To the reaction mixture was added sodium borohydride (22 mg) at room temperature, and the mixture stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give the title compound as white crystals (yield 181 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and m-anisidine (60 mg, 0.39 mmol). The title compound was obtained as a solid (27 mg, 15% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.49 (1H, s), 9.01 (2H, s), 8.73 (1H, m), 7.31 (1H, m), 7.26 (2H, m), 6.70 (1H, m), 3.80 (3H, s). MS m/z: 454.09, 456.04 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:5]P(=O)(OCC)OCC.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.O1CCCC1.[H-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:5]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Diethyl 3-chloro-4-nitrobenzylphosphonate (2.80 mmol, 0.86 g), tert-butyl 4-oxopiperidine-1-carboxylate (2.80 mmol, 0.557 g) and tetrahydrofuran (4.89 mL) were stirred and sodium hydride (4.19 mmol, 0.168 g) was added. The reaction was stirred overnight at room temperature. Water was added and the reaction extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated under vacuum to afford the intermediate tert-butyl 4-(3-chloro-4-nitrobenzylidene)-piperidine-1-carboxylate (0.85 g).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14]O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.O=P(Cl)(Cl)[Cl:24].O>N1C=CC=CC=1>[Cl:24][CH2:14][CH2:13][C:12]#[C:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[N:5]=[CH:4]2
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: Fc1c(C#CCCCl)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a mixture of 4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (4.6 g, 16.0 mmol) in pyridine (50 mL), was added POCl3 (10.3 g, 67.3 mmol). The resulting solution was stirred at room temperature for 2 hours. Upon completion, the reaction solution was poured into water (250 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica gel column (0˜10% EtOAc in petroleum ether) affording the title compound (2.62 g). 1H NMR (300 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.58 (d, 1H), 7.43 (dd, 1H), 5.87 (dd, 1H), 3.90-3.69 (m, 2H), 3.83 (t, 2H), 2.98 (t, 1H), 2.41-2.29 (m, 1H), 2.06-1.94 (m, 2H), 1.78-1.70 (m, 1H), 1.60-1.54 (m, 2H); LCMS: 307 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[OH:14][CH2:15][C@@H:16]([CH3:48])[C@H:17]([NH:28][C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)Cl>[Si:5]([O:14][CH2:15][C@@H:16]([CH3:48])[C@H:17]([NH:28][C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](CO)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reaction time: 14.25 h

Procedure:
TBDMS-Cl (48 mg, 0.312 mmol) followed by imidazole (28.8 mg, 0.423 mmol) were added to a CH2Cl2 (3 ml) solution of (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (119.5 mg, 0.258 mmol), and the mixture was stirred at ambient condition for 14.25 hr. The reaction mixture was then diluted with CH2Cl2 (30 mL) and washed with water (15 mL), and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resultant crude material was purified with a BIOTAGE® (40 g silica gel; 5% EtOAc/hexanes) to afford (2S,3S)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate, contaminated with TBDMS based impurities, as a colorless viscous oil (124.4 mg). (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was elaborated similarly to (2S,3R)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate. (2S,3S)-silyl ether isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.82 (d, J=4.1, 1H), 7.80 (d, J=4.0, 1H), 7.38-7.07 (m, 16 H), 4.70 (d, J=12.4, 1H), 4.42 (d, J=12.3, 1H), 3.28-3.19 (m, 3H), 2.56 (dd, J=10.1, 5.5, 1H), 1.61 (m, 1H), 0.90 (d, J=6.8, 3H), 0.70 (s, 9H), −0.13 (s, 3H), −0.16 (s, 3H). LC (Cond. 1, where the run time was extended to 4 min): RT=3.26 min; LC-MS: Anal. Calcd. for [M+H]+ C37H44NO3Si: 578.31; found 578.40. (2S,3R)-silyl ether isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.82 (d, J=3.0, 1H), 7.80 (d, J=3.1, 1H), 7.39-7.10 (m, 16H), 4.66 (d, J=12.4, 1H), 4.39 (d, J=12.4, 1H), 3.61 (dd, J=9.9, 5.6, 1H), 3.45 (d, J=9.5, 1H), 3.41 (dd, J=10, 6.2, 1H), 2.55 (dd, J=9.5, 7.3, 1H), 1.74 (m, 1H), 0.77 (s, 9H), 0.61 (d, J=7.1, 3H), −0.06 (s, 3H), −0.08 (s, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:21])[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[N+](=[CH2:24])=[N-]>CCOCC>[C:1]([S:4][CH2:5][CH:6]([CH3:21])[C:7]([N:9]1[CH2:16][C:15]([O:17][CH3:18])([O:19][CH3:20])[CH2:14][C@H:10]1[C:11]([O:13][CH3:24])=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(C)CSC(C)=O)C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC(OC)(OC)CN1C(=O)C(C)CSC(C)=O

Procedure:
A solution of the product from Example 3 in ether is treated with a slight excess of diazomethane. After standing at room temperature, the solvent is evaporated to give (S)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4,4-dimethoxy-L-proline, methyl ester.
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][C@@H:14]([NH:19][C:20](=[O:34])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)=[CH:23][CH:22]=1)[CH2:13][CH2:12]2)=[O:6])([CH3:4])[CH3:3].[CH2:35](OCC)C.ClCCl.C[Mg]Br>O>[CH3:4][C:2]([S@:5]([NH:7][C@H:8]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][C@@H:14]([NH:19][C:20](=[O:34])[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C@@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)=[CH:25][CH:26]=1)[CH2:13][CH2:12]2)[CH3:35])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: ClCCl
Solvent: O
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension, cooled to −45° C., of N-((S)-6-{[(E)-(R)-2-methylpropane-2-sulfinylimino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (0.34 g), diethyl ether (15 ml) and dichloromethane (15 ml) was admixed with methylmagnesium bromide (1.1 ml; 1.4 M in toluene). After warming to room temperature, the mixture was stirred for another 5 hours. The reaction mixture was hydrolyzed cautiously with water and extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate). The product was thus obtained with the molecular weight of 498.69 (C28H38N2O4S); MS (ESI): 499 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([O:38][CH3:39])[C:8]2[N:9]([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[CH:10]=1)=O.[NH3:40]>CO>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:13]=[C:8]4[C:7]([O:38][CH3:39])=[CH:6][C:5]([C:3](=[O:2])[NH2:40])=[CH:10][N:9]4[C:11]=3[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22][CH2:23]1)([CH3:30])([CH3:29])[CH3:31]
Reactant: COC(=O)c1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Reactant: N
Solvent: CO
Product: COc1cc(C(N)=O)cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12

Procedure:
A mixture of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-8-methoxy-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (200 mg) and a solution of ammonia in methanol (7M, 2.65 mL) was heated at 120° C. for 6 hours under microwave irradiation. On cooling, the reaction mixture was concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22]#[N:23]>>[F:11][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[F:10])[N:1]=[C:22]([NH2:23])[C:21]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[CH:4]2
Reactant: COc1ccccc1CCC#N
Reactant: Nc1cc(F)c(F)cc1C=O
Product: COc1ccccc1Cc1cc2cc(F)c(F)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4,5-difluorobenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])=[O:9])=[C:6]([O:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[CH:5]=1)[CH3:3]>C(Cl)Cl.CCOCC>[CH3:3][N:2]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])=[O:9])=[C:6]([O:29][CH:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]2)[CH:5]=1)[CH3:1]
Reactant: CN(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Yield: 60 %

Procedure:
Using a procedure similar to Example 1-G, 2-[4-(N,N-dimethylamino)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide gave the desired product (638 mg, 60%) as a white solid after chromatography and CH2Cl2/ether trituration.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([O:11]CC)=[O:10])[S:6][C:7]=1[I:8])#[N:2].O1CCCC1.O.[OH-].[Na+]>Cl>[C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([OH:11])=[O:10])[S:6][C:7]=1[I:8])#[N:2]
Reactant: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(I)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To a solution of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-iodothiophene-2-carboxylate (1.26 g, 0.00279 mol) in Tetrahydrofuran (20 mL, 0.3 mol) was added water (9.2 mL, 0.51 mol) and 1M NaOH (19.5 mL, 0.0195 mol) and the solution was stirred at room temperature for 2 days. The mixture was acidified by 1M HCl (20 mL), extracted with EtOAc (3×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the product (1.17 g, 99%). LCMS: (FA) ES+, 424, 426. 1H NMR (400 MHz, d1-chloroform) δ: 7.62-7.60 (m, 1H) 7.45-7.41 (m, 1H), 7.36-7.33 (m, 1H).