Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:17]2[C:18]([CH3:47])=[C:19]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([NH:39][C@@H:40]([CH:44]([CH3:46])[CH3:45])[C:41]([OH:43])=[O:42])(=[O:38])=[O:37])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)=[O:22])[O:20][C:16]=2[CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49].C(Cl)Cl>>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]2[C:18]([CH3:47])=[C:19]([C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([NH:39][C@@H:40]([CH:44]([CH3:45])[CH3:46])[C:41]([OH:43])=[O:42])(=[O:38])=[O:37])=[CH:32][CH:31]=4)=[CH:28][CH:29]=3)=[O:22])[O:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]
Reactant: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(OCCNC(=O)OC(C)(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(OCCN)c12

Procedure:
The product of Example 177, (S)-2-(4′-{[4-(2-tert-butoxycarbonylamino-ethoxy)-3-methyl-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-3-methyl-butyric acid, was treated with 40% TFA/methylene chloride solution at ambient temperature for four hours to afford (S)-2-(4′-{[4-(2-amino-ethoxy)-3-methyl-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-3-methyl-butyric acid as a brown solid (TFA salt). MS: calc'd for {M−H]−: 564.65. Found: 564.51.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[O:16])[CH2:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH3:2].[C:18]1([Mg]Cl)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1COCC1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:16])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:15])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccccc1
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccccc1)c1ccccc1

Procedure:
Analogously to Example 1, 1.0 g of 4-methyl-4-phenyl-2-oxopentanoic acid-ethyl ester is converted with 2.14 ml of a 2 M phenylmagnesium chloride-THF solution into 980 mg of product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][CH:16]([CH:20]4[CH2:22][CH2:21]4)[CH:17]4[CH2:19][CH2:18]4)=[N:13][CH:12]=[C:11]([C:23]([NH2:25])=[O:24])[C:7]=3[NH:8][C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=2)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:14]([NH:15][CH:16]([CH:17]5[CH2:19][CH2:18]5)[CH:20]5[CH2:22][CH2:21]5)=[N:13][CH:12]=[C:11]([C:23]([NH2:25])=[O:24])[C:7]=4[NH:8][C:9]=3[CH:10]=2)=[CH:35][N:36]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: NC(=O)c1cnc(NC(C2CC2)C2CC2)c2c1[nH]c1cc(Cl)ccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: NC(=O)c1cnc(NC(C2CC2)C2CC2)c2c1[nH]c1cc(-c3cnc(N)nc3)ccc12
Temperature: 100 °C

Procedure:
A mixture of 7-chloro-1-[(dicyclopropylmethyl)amino]-5H-pyrido[4,3-b]indole-4-carboxamide (7.1 g, 20.0 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-ylamine (6.2 g, 28 mmol), Pd2(dba)3 (1.83 g, 2.0 mmol), tricyclohexylphosphine (1.4 g, 5.0 mmol), and K3PO4 (1.27 M in water, 53.8 mL, 68.3 mmol) in dioxane (400 mL) was purged with nitrogen for 20 min, heated to 100° C. for 4 h, cooled to room temperature, and concentrated. The residue was diluted with 50% brine, and extracted with EtOAc (×3). The combined organics were washed with brine, dried (sodium sulfate) and purified by flash chromatography to give the title compound as a white solid. 1H NMR (500 MHz, CD3SOCD3) δ 11.50 (s, 1H); 8.61 (s, 2H); 8.45 (s, 1H); 8.43 (d, 1H); 7.92 (s, 1H); 7.83 (br s, 1H); 7.49 (dd, 1H); 7.18 (br s, 1H); 6.78 (s, 2H); 6.51 (d, 1H); 3.63 (q, 1H); 1.38 (m, 2H); 0.51 (m, 2H); 0.36 (m, 6H). LRMS (APCI) calc'd for (C23H23N7O) [M+H]+, 414.2. found 414.1.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[O:9].[CH2:19]([O:26][C@H:27]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([C:39](O)=[O:40])[CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C)C=O.O>[CH2:19]([O:26][C@H:27]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C@H:29]([C:39](=[O:40])[NH:1][N:2]2[CH:6]=[CH:5][C:4]([Br:7])=[C:3]2[C:8](=[O:9])[NH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Reactant: Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
1-Amino-3-bromo-N-(3,5-difluorophenyl)-1H-pyrrole-2-carboxamide (1.5 g, 4.75 mmol), (2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.99 g, 3.08 mmol) and diisopropylethylamine (2.8 ml, 16.08 mmol) were dissolved in dimethylformamide (30 ml) and the mixture cooled at 0° C. To this mixture, T3P (50% solution in ethyl acetate, 2.1 ml, 7.19 mmol) dissolved in DMF (5 ml) was dropwise added. Once the addition is over, the mixture was stirred at room temperature for 48 h. To this mixture, water was added and extracted twice with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulphate, filtered and the solvents evaporated under reduced pressure. The residue was purified by flash chromatography (0% to 25% hexanes/AcOEt) to yield 1.42 g (74% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[CH2:19][CH2:20][C:21](O)=[O:22].S(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][OH:22]
Reactant: CCOc1ccc(Cc2cc(Br)c(CCC(=O)O)cc2Cl)cc1
Solvent: CSC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc(Br)c(CCCO)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a stirred 0° C. solution of 3-(2-bromo-5-chloro-4-(4-ethoxybenzyl)phenyl) propanoic acid (BK) (0.5 g, 1.26 mmol) in 8 mL of THF was added BH3 in Me2S (2M, 3.15 mL, 6.29 mmol). After stirring for 30 min at 0° C., the mixture was warmed to room temperature and stirred overnight. The reaction solution was slowly quenched with dropwise addition of water until no more gas evolved. The reaction mixture was taken up in 20 mL of ethyl acetate, washed with saturated Na2CO3, water and brine, and then dried over Na2SO4, filtered and concentrated to obtain 0.268 g of crude intermediate BL, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(O)=O.CN(C)C=O>CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.[Cl-].[Ru+2].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(C[N+](=O)[O-])c1ccc(F)cc1
Agent: [Ru+2]
Agent: Cc1ccc(S(=O)(=O)[N-][C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O=CO
Product: O=[N+]([O-])CC(O)c1ccc(F)cc1
Reaction time: 16 h
Yield: 80 %

Procedure:
A 50 ml Schlenk flask was charged with 1.831 g (10.0 mmol) of 1-(4-fluorophenyl)-2-nitroethanone, 3.35 ml (24.0 mmol) of triethylamine, 2.26 ml (60.0 mmol) of formic acid, 10 ml of dimethylformamide (DMF), and 31.8 mg (0.05 mmol, S/C=200) of RuCl[(S,S)-Tsdpen](p-cymene) under an atmosphere of argon, and stirring was carried out at 30° C. for 16 hours. The reaction solution was poured into water and extracted with ether, and the organic layer was washed with saturated brine and then dried with anhydrous sodium sulfate. After removing the drying agent, the solvent was distilled off, and the oil so obtained was purified by silica gel column chromatography (eluant; n-hexane:ethyl acetate=9:1) to give 1.48 g of optically active 1-(4-fluorophenyl)-2-nitroethanol. 1H-NMR supported it was the target product, and the yield was 80%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([C:9]2[S:31][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][N:8]=2)=[CH:11][CH:12]=1
Reactant: O=C(NCC(=O)c1cccs1)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2ncc(-c3cccs3)s2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a dry nitrogen atmosphere N-[2-(thien-2-yl)-2-oxoethyl]-4-trifluoromethylbenzamide (5.6 g of the solid from Step D) was added to a stirred suspension of [2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (3.6 g, 0.0090 mole) in 150 ml of toluene. The resultant mixture was heated at reflux for four hours, then was allowed to cool to room temperature, and was stirred for approximately 18 hours. The mixture was heated at reflux for three hours and then was cooled. The solvent was removed from the mixture by evaporation under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (3:1) to yield 2.84 g of 2-(4-trifluoromethylphenyl)-5-thien-2-ylthiazole, as a solid, mp 153.5°-155° C.
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]#[N:10])[N:4]=1.[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19](=[O:27])[N:10]=2)[N:4]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CN(CC(=O)OC(C)(C)C)c1cncc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(CC(=O)OC(C)(C)C)c1cncc(-c2nc(=O)c3ccccc3s2)n1
Yield: 26.5 %

Procedure:
tert-Butyl [methyl(6-cyano-2-pyrazinyl)amino]acetate (1.00 g, 4.03 mmol) and methyl thiosalicylate (1.36 g, 8.06 mmol) were dissolved in toluene (50 ml), and triethylamine (1.70 ml, 12.1 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.41 g, 26%) as pale yellow crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([N+:14]([O-:16])=[O:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18].[H-].[Na+].I[CH3:22].O>CN(C=O)C>[CH3:22][O:1][CH:2]1[CH2:7][C:6]([N+:14]([O-:16])=[O:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18]
Reactant: CI
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CC(O)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CC(c2ccccc2)([N+](=O)[O-])CN(C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
A solution of 1.15 g (4.595 mmol) rac-3-Hydroxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one (example A.10, step 1) in 11.5 ml DMF was cooled to 0° C. 220 mg (5.514 mmol) NaH (60% in oil) was added. The temperature rose to 3° C. The mixture was stirred at 0° C. for 15 minutes. 430 ul (6.893 mmol) iodomethane was added and the mixture was stirred at 0° C. for 30 minutes. 6.5 ml water was added and the solvent was removed in vacuo. The residue was taken in ethyl acetate. The solution was washed twice with water. The washings were reextracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 500 mg (42%) of the title compound as a light brown solid. MS (m/e): 265.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][SH:21])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[N:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]([NH:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)[S:32][CH:33]=2)=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[N:30]=[C:31]([NH:34][CH2:35][CH:36]5[CH2:37][CH2:38]5)[S:32][CH:33]=4)=[CH:27][N:28]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CS)c2CC1
Reactant: Brc1ccc(-c2csc(NCC3CC3)n2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ccc(-c4csc(NCC5CC5)n4)cn3)c2CC1
Temperature: 100 °C
Yield: 93 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-mercaptomethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.078 g, 0.239 mmol) in anhydrous dioxane (1.1 mL), add N-[4-(6-bromo-pyridin-3-yl)-thiazol-2-yl]-cyclopropylmethylamine (0.067 g, 0.218 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.0055 mmol), Xantphos (6.3 mg, 0.011 mmol) and diisopropylethylamine (0.076 mL, 0.44 mmol) at room temperature. Purge the reaction mixture with nitrogen and heat the mixture at 100° C. overnight. Cool the reaction mixture to room temperature. Dilute with DCM (50 mL) and filter through Celite®. Concentrate the filtrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (0:100 to 25:75 EtOAc/hexane over 33 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-{5-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-pyridin-2-ylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.113 g, 94%) as a pale yellow foam. MS (ES+) m/z: 557.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]12[CH2:12][CH2:11][C:8]([C:13]3[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=3)([CH2:9][CH2:10]1)[O:7][CH2:6]2.[C:21]([C:25]1[O:29][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[N:27][N:26]=1)([CH3:24])([CH3:23])[CH3:22].[F-].[Cs+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]12[CH2:12][CH2:11][C:8]([C:13]3[CH:18]=[CH:17][C:16]([C:34]4[CH:33]=[CH:32][C:31]([NH:30][C:28]5[O:29][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:26][N:27]=5)=[CH:36][CH:35]=4)=[CH:15][CH:14]=3)([CH2:9][CH2:10]1)[O:7][CH2:6]2
Reactant: COC(=O)CC12CCC(c3ccc(Cl)cc3)(CC1)OC2
Reactant: CC(C)(C)c1nnc(Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)o1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C(C)(C)C)o5)cc4)cc3)(CC1)OC2
Temperature: 90 °C
Yield: 57.7 %

Procedure:
To a solution of [1-(4-chloro-phenyl)-2-oxa-bicyclo[2.2.2]oct-4-yl]-acetic acid methyl ester (0.29 g, 0.984 mmol) and (5-tert-butyl-[1,3,4]oxadiazol-2-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine (0.338 g, 0.984 mmol) in dioxane (8 ml) and water (0.8 ml), was added caesium fluoride (0.448 g, 2.95 mmol) and Pd(amphos)Cl2 (0.070 g, 0.098 mmol). The mixture was flushed with nitrogen for three times and heated at 90° C. for 16 hours. The reaction mixture was filtered, and the solid was washed with water (10 ml) and ethyl acetate (3 ml) to afford crude {1-[4′-(5-tert-butyl-[1,3,4]oxadiazol-2-ylamino)-biphenyl-4-yl]-2-oxa-bicyclo[2.2.2]oct-4-yl}-acetic acid methyl ester (0.27 g, 58%) as white solid. [MS+1] 476.31.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]([C:29]2[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[C:31]([O:37][CH2:38][CH2:39][OH:40])[C:30]=2[F:41])[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:12]=[CH:11][C:10]=1[C:42]#[N:43])(C)(C)C.ClCCl.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[CH2:35]([C:33]1[CH:32]=[C:31]([O:37][CH2:38][CH2:39][OH:40])[C:30]([F:41])=[C:29]([CH:16]([NH:15][C:13]2[CH:14]=[C:9]3[C:10](=[CH:11][CH:12]=2)[C:42](=[NH:43])[NH:7][CH2:8]3)[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:24]=[CH:25][CH:26]=[CH:27][N:28]=3)[N:18]=2)[CH:34]=1)[CH3:36]
Reactant: CCc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1cc(OCCO)c(F)c(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
To a mixture of [2-cyano-5-({[5-ethyl-2-fluoro-3-(2-hydroxyethoxy)phenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}amino)benzyl]carbamic acid t-butyl ester (34.2 mg) and dichloromethane (1.5 mL) there was added a 4N hydrogen chloride-ethyl acetate solution, and the mixture was stirred at room temperature for 4 hours. Toluene (10 mL) was added to the mixture, and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (12.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)#[CH:13].C(N(CC)CC)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution (70 ml) of 4-chloro-N-hydroxybenzenimidoyl chloride (3.28 g) and methyl 4-ethynylbenzoate (3.00 g) in tetrahydrofuran was added dropwise a solution (5 ml) of triethylamine (2.8 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into dilute hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, volume ratio) to give methyl 4-[3-(4-chlorophenyl)-5-isoxazolyl]benzoate (4.40 g, yield 81%). Recrystallization from hexane-acetone gave colorless prism crystals. melting point: 225–226° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5](Br)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:12][C:13](=[O:17])/[CH:14]=[CH:15]/[CH3:16].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C1(N(C)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC#N>[NH2:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5](/[C:15](=[CH:14]/[C:13](=[O:17])[CH3:12])/[CH3:16])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(N)c(Cl)cc1Br
Reactant: C/C=C/C(C)=O
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CC#N
Product: CC(=O)/C=C(\C)c1cc(Cl)c(N)cc1C#N
Temperature: 90 °C
Yield: 23.7 %

Procedure:
5-amino-2-bromo-4-chlorobenzonitrile (0.5 g, 2.16 mmol), (E)-pent-3-en-2-one (0.273 g, 3.24 mmol), Pd2(dba)3 (0.020 g, 0.022 mmol), di-tert-butyl(2′-methyl-[1,1′-biphenyl]-2-yl)phosphine (0.020 g, 0.065 mmol), and N-cyclohexyl-N-methylcyclohexanamine (0.633 g, 3.24 mmol) were combined in a 20 dram vial and CH3CN (4 mL) was added. The vial was evacuated and backfilled with N2, and the reaction was heated at 90° C. for 3 h. The reaction was cooled to room temperature and diluted with water, extracting 3× with EtOAc. The organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The material was purified by flash column chromatography (0-100% EtOAc/Hex). (E)-5-amino-4-chloro-2-(4-oxopent-2-en-2-yl)benzonitrile (120 mg) was obtained as a yellow solid.
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>N1C=CC=CC=1>[CH3:18][C:17]([Si:14]([CH3:16])([CH3:15])[O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:2][NH:3][CH2:4][CH2:5]2)([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc2c(cc1O)CNCC2
Agent: Br
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2
Yield: 100 %

Procedure:
A mixture of 1.0 g of 1,2,3,4-tetrahydro-6,7-isoquinolinediol hydrobromide and 2.45 g of t-butyl dimethylsilyl chloride in 25.0 mL of pyridine is heated under reflux for 4.5 hours, cooled, poured into water and extracted with diethyl ether. The diethyl ether extract is washed with brine, dried, filtered. The filtrate is evaporated to yield a brown oil. This oil is purified by Kugelrohr distillation to yield 1.6 g of the desired product as a yellow solid, b.p. 155° C., 350 torr.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[F:8][C:9]([F:19])([F:18])[CH2:10][C@@H:11]([CH3:17])[C@@H:12]([C:14](O)=[O:15])[NH2:13].CO>C1COCC1>[NH2:13][C@@H:12]([C@H:11]([CH3:17])[CH2:10][C:9]([F:8])([F:18])[F:19])[CH2:14][OH:15]
Reactant: C[C@H](CC(F)(F)F)[C@H](N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](CC(F)(F)F)[C@H](N)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of lithium borohydride (14.5 mL of a 2M solution in THF, 29 mmol) at 0° C. was added chlorotrimethylsilane (7.38 mL, 58 mmol) dropwise over a period of 30 min. The ice bath was removed and the resulting slurry was stirred at 25° C. for 30 min. The reaction mixture was cooled to 0° C. and 5,5,5-trifluoro-L-alloisoleucine (2.7 g, 16.98 mmol) was added in portions as a solid over a period of 15 min. The reaction mixture was allowed to warm slowly to 25° C. as the ice bath melted. After 3 days at 25° C., the reaction mixture was cooled to 0° C., and methanol (22 mL) was carefully added over a period of 30 min. The solution was stirred at 25° C. for an additional 40 min, then concentrated under reduced pressure in a water bath at 60° C. The resulting slurry was made basic with 20% sodium hydroxide (10 mL). Water (10 mL) was added, and the entire aqueous layer was extracted with methylene chloride (100 mL) and dried over MgSO4. The organic phase was filtered and evaporated to produce (2S,3R)-2-amino-5,5,5-trifluoro-3-methylpentan-1-ol as a crude oil (2.6 g, 89.6%).
Reaction SMILES: [CH:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[Na+].[Cl:15][CH:16]([Cl:18])C.C(OS([O-])(=O)=O)C.C([S+](C(CCCCCCCCCC)C)CC)(CCCCCCCCCCCCCC)C.CCCCCCCC>C(Cl)(Cl)Cl>[Cl:15][C:16]1([Cl:18])[CH:12]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2
Reactant: CC(Cl)Cl
Reactant: C1=CCCCCCCCCCC1
Agent: CCCCCCCCCCCCCCC(C)[S+](CC)C(C)CCCCCCCCCC
Agent: CCOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCCCCCCC
Solvent: ClC(Cl)Cl
Product: ClC1(Cl)C2CCCCCCCCCCC21
Yield: 98 %

Procedure:
Cyclododecene (41.5 g), chloroform (225 ml), 50% aqueous sodium hydroxide solution (275 ml), dichloroethane (60 ml), sec-hexadecyl sec-dodecyl ethylsulphonium ethylsulphate (0.3 g) and n-octane (12 ml) were stirred together at ambient temperature for 10 hours. The product was recovered in a similar manner to that described in Example I(b) (yield 98%)