Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:48])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:50][OH:51].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:48])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:31]3=[O:44])=[CH:45][CH:46]=1)([CH3:22])[CH2:14][C:13]2=[N:50][OH:51])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=O)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=NO)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Reaction time: 120 h

Procedure:
A mixture of 0.5 g of t-butyl α-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate (prepared as described in Example 51), 0.2 g of hydroxylamine hydrochloride, 0.2 g of pyridine and 5 ml of methanol was allowed to stand at 25°-30° C. for 5 days. Ethyl acetate and an aqueous solution of potassium carbonate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluted with a 20:1 by volume mixture of benzene and ethyl acetate) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[N:15](C)[CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>ClC(Cl)(Cl)C>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18]([N:15]1[CH:10]2[CH2:11][CH2:12][CH:13]1[CH:14]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9]2)=[O:19]
Reactant: CN1C2C=C(c3ccc(Cl)cc3)CC1CC2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC(Cl)(Cl)Cl
Product: O=C(OCC(Cl)(Cl)Cl)N1C2C=C(c3ccc(Cl)cc3)CC1CC2
Yield: 92.3 %

Procedure:
Racemic 3-(4-Chloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene (4.98 g, 21.31 mmol) in 1,1,1-trichloroethane (60 mL) was heated at reflux and 2,2,2-trichloroethyl chloroformate (3.23 mL, 23.44 mmol) was added dropwise over 10 minutes. The reaction was refluxed for 3 hours, cooled and concentrated to a clear oil. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded racemic 3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylic acid 2,2,2-trichloro-ethyl ester (7.77 g, 92.2%) as a clear oil which had the following properties: 1H NMR CDCl3 δ: 7.25 (s, 4H), 6.41 (m, 1H), 4.85 (m, 1H), 4.73 (s, 1H), 4.68-4.76 (m, 2H), 3.12 (d, J=17 Hz, 1H), 2.25 (m, 2H), 2.03 (m, 2H), 1.75 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[F:16][C:17]1[CH:18]=[C:19]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:13]([OH:15])=[O:14])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: COCCOc1ncc(C(=O)O)cc1Br
Reactant: OB(O)c1ccc(F)c(F)c1
Product: COCCOc1ncc(C(=O)O)cc1-c1ccc(F)c(F)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2-methoxyethoxy)-3-pyridinecarboxylic acid (CAN 912454-34-3) and B-(3,4-difluorophenyl)-boronic acid, (CAN 168267-41-2) as starting materials; MS (ESI): 308.3 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:37][CH2:36][C:35]1[CH:38]=[CH:39][C:32]([CH3:31])=[CH:33][CH:34]=1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: Cc1ccc(CN)cc1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccc(C)cc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 4-methylbenzylamine
Reaction SMILES: [C:1]([C:5]1[CH:48]=[CH:47][C:8]([C:9]([NH:11][C@@H:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:35][CH:34]=4)=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[C:13]([NH:15][CH2:16][C:17](O)=[O:18])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:49][S:50]([NH2:53])(=[O:52])=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@@H:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]4[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:37][CH:38]=4)=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[C:13]([NH:15][CH2:16][C:17]([NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[O:18])=[O:14])=[O:10])=[CH:47][CH:48]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NCC(=O)O)cc3)nc2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NCC(=O)NS(C)(=O)=O)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
TEA (32.1 μl, 0.23 mmol) was added to a suspension of (S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine Compound 297 (75.0 mg, 0.11 mmol), methanesulfonamide (12.1 mg, 0.13 mmol), HATU (52.6 mg, 0.14 mmol) and DMAP (1.41 mg, 0.01 mmol) in DCM (2 mL). The resultant yellow suspension was stirred at RT for 3 h. The reaction mixture was washed with saturated aqueous NaHCO3 (2 mL) and the mixture passed through a phase separation cartridge. The organic phase was concentrated in vacuo to afford a yellow solid. The crude product was purified by chromatography (EA/1% AcOH in hexanes) to afford 9 mg (11%) (S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-((2-(methylsulfonamido)-2-oxoethyl)amino)-1-oxopropan-2-yl)benzamide, Compound 381 as a yellow solid. LCMS-ESI (m/z) calculated for C40H49N5O6S: 727.3; found 728.0 [M+H]+, tR=10.51 min (Method 10).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][Br:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:11]([O-])([OH:13])=[O:12].CCCCCC.CCOC(C)=O>CCOCC>[N+:11]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][Br:10])=[CH:2][CH:3]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: BrCCCc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CCCBr)cc1

Procedure:
2 g of P2O5/silica gel (65% w/w) (10 mmol) (Hajipour; Kooshki; Ruoho. Tetrahedron Letters 2005, 46, 5503) and 3-phenylpropylbromine (10 mmol, 1.98 g) was ground for 30 seconds, and then 5 mL of HNO3 65% was added. The mixture was ground with a pestle at r.t. until a deep-yellow color appeared (2 minutes). When TLC analysis (n-hexane:EtOAc 90:10) showed complete disappearance of 3-phenylpropylbromide (10 min), ether (100 ml) was added to the reaction mixture and the solid was separated through a short pad of silica gel and washed with ether (3×20 mL). The filtrate was washed with 10% NaHCO3 (3×20 mL) and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue was purified by short column chromatography (n-Hexane:EtOAc, 90:10). 3-(4-nitrophenyl)-propylbromide was obtained (8.3 mmol, 2.02 g 83%) as a yellow oil. 1H NMR (CDCl3): δ 8.2 (d, J=6.3), 7.38 (d, 2H, 6.3), 3.3 (t, 2H, J=7.8), 2.55 (t, 2H, J=7.8), 2.12 (m, 2H). 13C NMR (CDCl3): δ 145.7, 144.9, 129.7, 123.5, 36.7, 34.7, 32.4. Anal. Calculated for C9H10BrNO2: C, 44.29H, 4.13; N, 5.74%. Actual: C, 44.50; H, 48.30; N, 5.80%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.CS(C)=O.[BH4-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70.8 %

Procedure:
To a mixture of 1-benzyloxy-4-((E)-2-nitro-vinyl)-benzene (1.0 g, 3.9 mmol) described in Manufacturing Example 1-1-1, acetic acid (1 mL) and dimethyl sulfoxide (17 mL) was added sodium borohydride (250 mg, 6.3 mmol) at room temperature while cooling appropriately, and the reaction mixture was stirred for 40 minutes at room temperature. Water was added to the reaction mixture. The reaction mixture was partitioned into ethyl acetate and water. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (710 mg, 70%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[O:12][C:11]([CH3:21])([CH3:20])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[O:28]1[CH2:27][CH:26]1[CH2:24][O:19][C:15]1[CH:14]=[C:13]2[C:18]([CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=3)[CH2:10][C:11]([CH3:21])([CH3:20])[O:12]2)=[CH:17][CH:16]=1
Reactant: ClCC1CO1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC3CO3)cc2O1

Procedure:
Reaction of 4-(3-Trifluoromethylphenyl)-2,2-dimethyl-7-chromanol with epichlorohydrin, by an analogous method to that described in Example 1, gave 7-(2,3-epoxypropoxy)-4-(3-trifluoromethylphenyl)-2,2-dimethylchroman. Reaction of this epoxide with methylamine, by an analogous method to that described in Example 2 gave 4-(3-trifluoromethyl-phenyl-7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethylchroman, (benzoate salt, m.p. 145-157°).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15](N3C=NC=N3)[C:16]=2[N:17]=1.[CH3:24][O:25][CH2:26][CH2:27][OH:28]>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15]([O:28][CH2:27][CH2:26][O:25][CH3:24])[C:16]=2[N:17]=1
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Product: COCCOc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Potassium tert-butoxide (4 mL; 1M in THF) was added to a suspension mixture of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (1 g) and 2-methoxyethanol (0.32 mL) in DCM (50 mL). After stirring at room temperature for 10 minutes, the mixture was diluted with DCM (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford 6-chloro-4-(2-methoxy-ethoxy)-pyrido[3,2-d]pyrimidin-2-ylamine as a beige solid (0.91 g, yield: 90%) which was characterized by its mass spectrum as follows: MS (m/z) 225.0 [M+H]+.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([S:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(SCc2ccccc2)cc1
Yield: 68.1 %

Procedure:
A mixture of 37.2 g (300 mmol) of benzylmercaptan, 36.3 g (300 mmol) of 4-fluorobenzonitrile and 42 g of potassium carbonate in 700 ml of 2-butanone is refluxed for 7 hours. The solvent is evaporated off under vacuum and the residue is taken up with water and petroleum ether. The crystals formed are filtered off and washed with water and then with petroleum ether to give 46 g of 4-(benzylthio)benzonitrile in the form of crystals melting at 85° C.
Reaction SMILES: ClCC1C=CC(O[CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=CC=1.O[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>>[CH3:15][Si:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][O:11][CH2:10][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CCOCOc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(COCC[Si](C)(C)C)cc1

Procedure:
The 1-chloromethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-benzene used at the alkylating agent was prepared in analogy to Example 5(a)-(c) from methyl 4-hydroxybenzoate by introducing the SEM group to give methyl 4-(2-trimethylsilanylethoxymethyl)-benzoate. Subsequent reduction with lithium aluminium hydride gave [4-(2-trimethylsilanylethoxy-methoxy)-phenyl]-methanol and chlorination of this gave 1-chlormethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-benzene as a colourless oil; MS: 272 (M)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([C:22]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([O:32][Si](C)(C)C)=[C:24]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:23]=1)[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([O:13][Si](C)(C)C)=[C:5]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:4]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.O>O1CCCC1>[CH3:41][Si:2]([CH3:1])([C:3]1[CH:4]=[C:5]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]([OH:13])=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1)[C:22]1[CH:23]=[C:24]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:25]([OH:32])=[C:26]([C:28]([CH3:30])([CH3:31])[CH3:29])[CH:27]=1
Reactant: CC(C)(C)c1cc([Si](C)(C)c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc([Si](C)(C)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 9.8 g (16 mmol) of dimethylbis(3,5-di-tert-butyl-4-trimethylsilyloxyphenyl)silane in 50 ml of tetrahydrofuran is slowly added 10.6 g (32 mmol) of tetrabutylammonium fluoride trihydrate. The reaction mixture is stirred for 1 hour at room temperature and to it is added 0.8 g (14 mmol) of glacial acetic acid. The reaction mixture is poured into 250 ml of water and the solution is extracted (2×125 ml) with methylene chloride. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed in vacuo to give 7.3 g of an orange residue which crystallizes on standing. The residue is recrystallized from heptane to give 1.2 g (17%) of a white solid; mp. 186°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:16]2[CH2:17][CH2:18][N:13]([CH2:11][CH3:12])[CH2:14][CH2:15]2)[C:3]=1[CH:4]=[O:5]
Reactant: CCN1CCNCC1
Reactant: O=Cc1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2cccc(Cl)c2C=O)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of 2-chloro-6-fluorobenzaldehyde (5.0 g, 31.5 mmol), 1-ethylpiperazine (8.0 mL, 63.0 mmol), and potassium carbonate (5.0 g, 36.2 mmol) in anhydrous DMF (30 mL) was stirred at 90° C. overnight. DMF was evaporated. The viscous mixture was poured in water (200 mL). The mixture was extracted with diethyl ether (3×100 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 2-chloro-6-(4-ethylpiperazin-1-yl)benzaldehyde (7.4 g, 93% yield). The product was used without further purification.
Reaction SMILES: [H][H].[Si:3]([O:10][CH2:11][C@@H:12]([CH3:44])[C@H:13]([NH:24]C1(C2C=CC=CC=2)C2C=CC=CC=2C2C1=CC=CC=2)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>CCOC(C)=O.C(Cl)Cl.[Pd]>[NH2:24][C@@H:13]([C@H:12]([CH3:44])[CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4])[C:14]([OH:16])=[O:15]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A balloon of hydrogen was attached to a mixture of (2S,3S)-benzyl 4-(tert -butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (836 mg, 1.447 mmol) and 10% Pd/C (213 mg) in EtOAc (16 mL) and the mixture was stirred at room temperature for ˜21 hr, where the balloon was recharged with H2 as necessary. The reaction mixture was diluted with CH2Cl2 and filtered through a pad of diatomaceous earth (CELITE®-545), and the pad was washed with EtOAc (200 mL), EtOAc/MeOH (1:1 mixture, 200 mL) and MeOH (750 mL). The combined organic phase was concentrated, and a silica gel mesh was prepared from the resulting crude material and submitted to a flash chromatography (8:2:1 mixture of EtOAc/1-PrOH/H2O) to afford (2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid as a white fluffy solid (325 mg). (2S,3R)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was similarly elaborated to (2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid. (2S,3S)-amino acid isomer: 1H NMR (Methanol-d4, δ=3.29 ppm, 400 MHz), 3.76 (dd, J=10.5, 5.2, 1H), 3.73 (d, J=3.0, 1H), 3.67 (dd, J=10.5, 7.0, 1H), 2.37 (m, 1H), 0.97 (d, J=7.0, 3H), 0.92 (s, 9H), 0.10 (s, 6H). LC/MS: Anal. Calcd. for [M+H]+ C11H26NO3Si: 248.17; found 248.44. (2S,3R)-amino acid isomer: 1H NMR (Methanol-d4, δ 3.29 ppm, 400 MHz), 3.76-3.75 (m, 2H), 3.60 (d, J=4.1, 1H), 2.16 (m, 1H), 1.06 (d, J=7.3, 3H), 0.91 (s, 9H), 0.09 (s, 6H). Anal. Calcd. for [M+H]+ C11H26NO3Si: 248.17; found 248.44.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([SH:14])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br)([O-:17])=[O:16].O>O1CCCC1>[Cl:3][C:4]1[C:5]([S:14][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N+:15]([O-:17])=[O:16])=[N:6][CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1
Reactant: FC(F)(F)c1cnc(S)c(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1CSc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.3 %

Procedure:
2 g of 60 wt % sodium hydride were added to 45 ml of tetrahydrofuran under stirring at room temperature, followed by drop-wise addition thereto of a solution of 9.9 g of 3-chloro-2-mercapto-5-trifluoromethylpyridine in 40 ml of tetrahydrofuran. After completion of the drop-wise addition, the reaction mixture was heated under reflux for 30 minutes, and cooled to room temperature, followed by drop-wise addition thereto of a solution of 10 g of 2-nitrobenzyl bromide in 60 ml of tetrahydrofuran. After completion of the drop-wise addition, stirring was continued at room temperature for 15 hours. The reaction mixture was poured into water, subjected to extraction with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent:methylene chloride:hexane=4:1) to obtain 12 g of 2-(3-chloro-5-trifluoromethyl-2-pyridylthiomethyl)nitrobenzene.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:4]1=2.CC1(C)C(C)(C)OB([C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[NH:33][C:29]=3[CH:28]=2)O1>>[F:18][C:15]1[CH:16]=[CH:17][C:4]2[C:3](=[CH:2][C:27]3[CH:36]=[CH:35][C:30]4[NH:31][C:32](=[O:34])[NH:33][C:29]=4[CH:28]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:14]=1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Fc1ccc2c(c1)OCc1ccccc1C2=CBr
Product: O=c1[nH]c2ccc(C=C3c4ccccc4COc4cc(F)ccc43)cc2[nH]1

Procedure:
Following procedures essentially as described in Example 219, using 11-bromomethylene-3-fluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 1.05 eq.) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (1 eq.). Purify crude product on silica gel, eluting with 60% to 100% ethyl acetate/CHCl3 to afford a light yellow solid. Triturate with acetone to afford the title compound as a white solid. HPLC (ISO60-10) t=4.09 min, 100%; MS [ES] 357 (M−H), 359 M+H); 1H-NMR (DMSO-d6) δ 10.56 (s, 1H), 10.46 (s, 1H), 7.56 (m, 2H), 7.35 (t, 1H, J=7.5 Hz), 7.23 (t, 1H, J=7.5 Hz), 6.99 (d, 1H, J=7.5 Hz), 6.94 (s, 1H), 6.78 (td, 1H, J=12.0, 4.2 Hz), 6.71 (d, 1H, J=8.4 Hz), 6.66 (d, 1H, J=8.4 Hz), 6.59 (dd, 1H, J=10.6, 2.6 Hz), 6.57 (s, 1H), 5.83-4.71 (br d, 2H).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Cl:7][C:8]1[C:12]([S:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:11][S:10][N:9]=1.[OH2:18]>C1COCC1>[Cl:7][C:8]1[C:12]([S:13]([CH2:14][CH2:15][CH2:16][CH3:17])(=[O:1])=[O:18])=[N:11][S:10][N:9]=1
Reactant: O
Reactant: CCCCSc1nsnc1Cl
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)c1nsnc1Cl
Reaction time: 24 h

Procedure:
A solution of oxone™ (12 g, 0.0195 mol) in H2O (60 mL) was vigorous stirred as 3-chloro-4-butylthio-1,2,5-thiadiazole (2.1 g, 0.01 mol) in THF (30 mL) was added dropwise. After 24 h, the THF was evaporated and the residue extracted with ether (3×). Extracts were washed with H2O, dried, and solvent evaporated to give a clear liquid. Radial chromatography eluting with 30% EtOAc/hexane gave a colorless liquid (2.3 g). (Compound 2).
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:22]([OH:32])=[CH:21][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18](O)=[O:19])[CH3:2].S(Cl)(Cl)=O.[CH3:37][NH:38][CH3:39]>ClCCl.O>[CH3:37][N:38]([CH3:39])[C:18](=[O:19])[CH2:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:21]=[C:22]([OH:32])[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:24][C:3]=1[CH2:1][CH3:2]
Reactant: CNC
Reactant: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccccc1CCC(=O)O
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccccc1CCC(=O)N(C)C

Procedure:
A solution of 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)phenyl)propionic acid and several equivalents of thionyl chloride in dichloromethane was kept at room temperature for 3 hours, and then poured into a stirred solution of 40% dimethylamine in water. The organic layer was washed with aqueous hydrochloric acid, washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to provide the desired title product. NMR, MS.