Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([Cl:33])=[O:32].Cl>CN(C=O)C.C(OCC)(=O)C.O>[ClH:17].[ClH:33].[Cl:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[Cl:17])[NH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=2)[CH2:5][CH2:6]1
Reactant: NCCN1CCC(Nc2ccc(Cl)c(Cl)c2)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)NCCN2CCC(Nc3ccc(Cl)c(Cl)c3)CC2)c1
Reaction time: 2 h

Procedure:
The product of step (iv) above (0.5 g) and triethylamine (1.1 ml) were dissolved in DMF (10 ml), 3-methoxybenzoylchloride (0.11 ml) was added dropwise. After 2 hours, water and ethyl acetate were added, the organic phase separated, dried and evaporated. Purification of the residue by chromatography (dichloromethane:methanol, 95:5) gave an oil which was treated with 1.0M ethereal hydrogen chloride solution to give the titled product as a solid (0.15 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C[N:30](C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.N>CN(C=O)C>[NH2:30][C:14]([C:11]1([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:15]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Agent: Cl
Agent: N
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(N)=O)CC1
Yield: 20.6 %

Procedure:
To a solution of 4-benzyloxycarbonylamino-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.09 g, 5.52 mmol) in DMF (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.27 g, 6.63 mmol), 1-hydroxy-7-azabenzotriazole (0.373 g, 2.76 mmol) and triethylamine (0.924 mL, 6.63 mmol), followed by ammonia (0.5 M in MeOH, 13.3 mL, 6.63 mmol). After 18 h the mixture was concentrated and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate, the organic layer dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 6% methanol:dichloromethane to give the title compound (0.43 g). MS: m/z=378.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:8]2[CH:9]3[CH2:12][CH2:13][CH:7]2[C:6]([CH3:14])([C:10]3=[CH2:11])[CH2:5][CH2:4][CH2:3]1.C(O)(=[O:18])C>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:11])[CH:12]2[C:3]3([CH2:14][CH:6]1[CH2:5][CH2:4]3)[C:2]([CH3:15])([CH3:1])[CH2:8][CH2:7][C:13]2=[O:18]
Reactant: C=C1C2CCC3C2C(C)(C)CCCC13C
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC3(C2)C1C(=O)CCC3(C)C
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A four neck flask of 2 L was charged with 500 g of longifolene and 250 ml of acetic acid, and 250 ml of a boron trifluoride diethyl ether complex was dropwise added thereto in 4 hours while stirring at 20° C. to carry out isomerization reaction. This reaction mixture was washed with ice and water, a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution and refined by distillation, and after refined by distillation, it was mixed with 1800 ml of methylene chloride and 900 ml of a 0.5 mole/L sodium hydrogencarbonate aqueous solution, followed by slowly adding thereto 400 g of 3-chloroperbenzoic acid at 10° C. or lower. After finishing the reaction, the reaction mixture was washed with a 1 mole/L sodium hydroxide aqueous solution and water and concentrated under reduced pressure to obtain a crude product. It was dissolved in 3 L of toluene, and 260 ml of a boron trifluoride diethyl ether complex was slowly dropwise added thereto at 5° C. or lower. After finishing the reaction, the reaction mixture was washed with water and refined by distillation to thereby obtain 270 g of 1,1,5,5-tetramethylhexahydro-2H-2,4a-methano-naphthalene-8-one. This was dropwise added to 640 ml of a 2.1 mole/L methyl lithium/diethyl ether solution at 5° C. or lower to carry out alkylation, and after finishing the reaction, the reaction mixture was washed with a saturated ammonium chloride aqueous solution and water. This reaction product was charged into an autoclave of 1 L together with 30 g of the nickel/diatomaceous earth catalyst for hydrogenation (N-113, manufactured by Nikki Chemical Co., Ltd.) to carry out dehydration hydrogenation (hydrogen pressure: 6 MPa·G, reaction temperature: 250° C., reaction time: 6 hours).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:14])[CH:11]=1)[C:5]([O:7]C)=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:52].Cl.[NH2:54][C@@:55](C)([CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[C@H:56]([OH:70])[CH2:57][NH:58][C:59]1([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]#[CH:69])[CH:63]=2)[CH2:61][CH2:60]1>O1CCCC1.CO.O.O.[OH-].[Li+]>[ClH:52].[ClH:52].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:14])[CH:11]=1)[C:5]([NH:54][C@@H:55]([CH2:71][C:72]1[CH:73]=[C:74]([F:79])[CH:75]=[C:76]([F:78])[CH:77]=1)[C@H:56]([OH:70])[CH2:57][NH:58][C:59]1([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]#[CH:69])[CH:63]=2)[CH2:61][CH2:60]1)=[O:7]
Reactant: C#Cc1cccc(C2(NC[C@@H](O)[C@@](C)(N)Cc3cc(F)cc(F)c3)CC2)c1
Reactant: CCCCN(C)Cc1cc(Br)cc(C(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#Cc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)c3cc(Br)cc(CN(C)CCCC)c3)CC2)c1
Reaction time: 16 h

Procedure:
Methyl 3-bromo-5-{[butyl(methyl)amino]methyl}benzoate (113 mg, 0.36 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (30 mg, 0.72 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (5 mL), and diisopropylethylamine (250 μL, 1.44 mmol), HATU (170 mg, 0.45 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}-3-methylbutan-2-ol dihydrochloride prepared as in Example SP-264 (170 mg, 0.4 mmol) are added. The reaction stirred at room temperature 16 h. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (1 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 638.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1.BrC1C=C(C2C=NC3N(C(C4(C5C=CC(OC)=CC=5)CC4)=NN=3)N=2)C=CC=1.Br[C:50]1[CH:51]=[C:52]([C:56]2[CH:61]=[N:60][N:59]3[C:62]([C:65]4([C:68]5[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][CH:69]=5)[CH2:67][CH2:66]4)=[N:63][N:64]=[C:58]3[N:57]=2)[CH:53]=[CH:54][CH:55]=1>O.C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:75][O:74][C:71]1[CH:70]=[CH:69][C:68]([C:65]2([C:62]3[N:59]4[N:60]=[CH:61][C:56]([C:52]5[CH:53]=[CH:54][CH:55]=[C:50]([C:11]6[CH:10]=[N:9][N:8]([CH3:7])[CH:12]=6)[CH:51]=5)=[N:57][C:58]4=[N:64][N:63]=3)[CH2:67][CH2:66]2)=[CH:73][CH:72]=1
Reactant: COc1ccc(C2(c3nnc4nc(-c5cccc(Br)c5)cnn34)CC2)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(C2(c3nnc4ncc(-c5cccc(Br)c5)nn34)CC2)cc1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2(c3nnc4nc(-c5cccc(-c6cnn(C)c6)c5)cnn34)CC2)cc1
Temperature: 150 °C

Procedure:
Sodium carbonate (19.1 mg, 0.180 mmol) in water (0.10 mL) was added to a mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.7 mg, 0.0900 mmol), tetrakis(triphenylphosphine)palladium(0) (2.0 mg) and a 25.4 mg of a mixture of two regioisomers: 6-(3-bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine and 7-(3-bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]-triazolo[4,3-b][1,2,4]triazine in ethanol (300 μL) and toluene (300 μL). The resulting mixture was heated at 150° C. for 1 h. After cooling, the mixture was concentrated and diluted with methanol. The resulting solution was filtered, and the filtrate was subject to preparative RP-HPLC to give the two regioisomers. Analytical LCMS: (M+H)+=424.1. Isomer-I: Rt=1.732 min; Isomer-II: Rt=1.764 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[NH:8][C:7]=1[CH3:16])[CH3:2].[H-].[Na+].[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[N:8]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:29]=2)[C:7]=1[CH3:16])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(Br)cc12
Reactant: ClCc1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(Cc2cccc(OCc3ccccc3)c2)c2ccc(Br)cc12
Yield: 60.1 %

Procedure:
1-[(3-Benzyloxyphenyl)methyl]-5-bromo-2-methyl-1-1H-indole-3-acetic acid ethyl ester. Using the procedure described in Example 1, Part F, 592 mg (2 mmol) of 5-bromo-2-methyl-1H-indole-3-acetic acid ethyl ester (Example 51, Part A) was reacted with 80 mg (2 mmol) of 60% NaH/mineral oil and 465 mg (2 mmol) of 3-benzyloxybenzylchloride and after workup of the reaction mixture and chromatograpy on silica(eluted with 33% EtOAc/hexane) there was obtained 592 mg (60%) of 1-[(3-benzyloxyphenyl)methyl]-5-bromo-2-methyl-1H-indole-3-acetic acid ethyl ester as an oil.
Reaction SMILES: O.[OH-].[Li+:3].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:54]OC)[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:12]=1[C:13]([O:15]C)=[O:14])([CH3:7])[CH3:6].[C:57](=O)=[O:58]>O1CCOCC1>[OH:4][C:5]([C:8]1[NH:9][C:10]([CH3:54])([O:58][CH3:57])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:12]=1[C:13]([O-:15])=[O:14])([CH3:6])[CH3:7].[Li+:3]
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC1(C)NC(C(C)(C)O)=C(C(=O)[O-])N1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 16 h

Procedure:
15 ml of an aqueous solution containing 243 mg of lithium hydroxide monohydrate were added, whilst ice-cooling, to a solution of 2.72 g of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 82 (a)] in 33 ml of dioxane, and the resulting mixture was stirred at 5°-10° C. for 16 hours. At the end of this time, a small piece of dry ice was added to the reaction solution, and the reaction solution was concentrated by distillation under reduced pressure to a volume of about 15 ml. The concentrate was mixed with ethyl acetate and a saturated aqueous solution of sodium chloride and stirred. The resulting reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give a glassy salt of lithium 4-(1-hydroxy-1-methylethyl)-2-methoxy-methyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate. The whole of this product was dissolved in 25 ml of N,N-dimethylacetamide, and 533 mg of potassium carbonate were added to the resulting solution, after which a solution of 1.13 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (purity degree:74%) in 5.6 ml of N,N-dimethylacetamide was added dropwise to the mixture, whilst ice-cooling. The mixture was then stirred at 50° C. for 3 hours, after which it was diluted with ethyl acetate and water. The mixture was then extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure. The resulting crystalline residue was washed with diethyl ether, to give 2.70 g of the title compound, melting at 144°-146° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11]([O:13]C)=[O:12])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[O:7])=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H]1C[C@@H]1C(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
Methyl cis-2-(4-bromobenzoyl)cyclopropanecarboxylate (10.34 g, 36.52 mmol) was dissolved in MeOH (100 mL), and then 15 mL 50% aqueous NaOH solution was added. The reaction mixture was stirred at 40° C. for 3 days. Solvent was removed by rotary evaporation and the residue was dissolved in water. Concentrated HCl was added to adjust the acidity to pH 1. The precipitate that formed was collected by filtration and dried in a vacuum oven overnight to give trans-2-(4-bromobenzoyl)cyclopropanecarboxylic acid (9.43 g, 95%). LC-MS ret. time 2.51, m/z 270 (MH+); 1H NMR (400 MHz, CD2Cl2) δ 1.68 (m, 2H), 2.38 (m, 1H), 3.22 (m, 1H), 7.67 (m, 2H), 7.90 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.OP([O-])(O)=O.[K+].[C-:22]#[N:23].[K+]>CN(C=O)C.O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([OH:15])[CH2:14][C:22]#[N:23])[N:12]=2)=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CC(=O)c1coc(-c2ccc(F)cc2)n1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC(O)c1coc(-c2ccc(F)cc2)n1
Temperature: 80 °C
Yield: 21.2 %

Procedure:
A solution of 1-(2-(4-fluorophenyl)oxazol-4-yl)ethanone (250 mg, 1.22 mmol) in DMF-H2O (7 mL; 2:5 v/v) was cooled to 0° C. and KH2PO4 (327 mg, 2.4 mmol) was added, followed by KCN (116 mg, 1.8 mmol). The reaction mixture was stirred at 80° C. 10 h and then diluted with water. The organic product was extracted with EtOAc and the combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 8-12% EtOAc in petroleum ether) to afford 3-(2-(4-fluorophenyl)oxazol-4-yl)-3-hydroxypropanenitrile (60 mg, yield 21%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=0.7 Hz, 1H), 8.03-7.98 (dd, J=8.9 Hz, 5.4 Hz, 2H), 7.40-7.34 (t J=8.9 Hz, 2H), 6.13-6.12 (d, J=5.3 Hz, 1H), 4.93-4.87 (m, 1H), 2.98-2.93 (dd, J=8.9 Hz, 5.8 Hz, 2H). MS (ESI) m/z: Calculated for C12H9FN2O2: 232.06. found: 233.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:32][CH3:33])[N:3]=1.[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([O:45][CH3:46])=[O:44])#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:33][O:32][C:14]1[CH:15]=[C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([C:35]#[C:34][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (I72) (0.350 g, 0.717 mmol) in dimethylformamide (2.5 mL) and triethylamine (0.450 mL) was added methyl 2-(2-ethynylphenyl)acetate (I4: prepared according to the procedure of Peng, C. et al.; Adv. Synth. Catal. 2008, 350, 2359-2364 or as described below) (0.137 g, 0.789 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.025 g, 0.036 mmol), CuI (0.014 g, 0.072 mmol) and triphenylphosphine (0.019 g, 0.072 mmol). The reaction mixture was heated under microwave irradiation at 120° C. whilst stirring for 15 minutes. The reaction mixture was diluted with ethyl acetate and water then the resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water, brine, dried (magnesium sulfate), filtered and evaporated to give a brown solid. The solid was purified by flash column chromatography on silica gel (10-50% ethyl acetate/petroleum ether) to give the title compound (I5) (0.360 g, 80%) as an orange crystalline solid; 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 3.11 (s, 4H), 3.60 (s, 4H), 3.71 (d, 3H, J=1.0 Hz), 189 (s, 3H), 3.96 (s, 2H), 6.55 (s, 1H), 6.59 (s, 1H), 7.26-7.45 (m, 3H), 7.68 (d, 1H, J=7.6 Hz), 7.83 (s, 1H), 827 (d, 1H, J=7.3 Hz), and 8.60 (s, 1H). LCMS Method B: rt 9.55 min; m/z 626.4 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[CH2:13]([O:15][C:16]([C:18]1([NH2:27])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:13]([O:15][C:16]([C:18]1([NH:27][C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3cc[nH]c23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 1H-indole-7-carboxylic acid (250 mg, 1.55 mmol), 2-Amino-indan-2-carboxylic acid ethyl ester (318 mg, 1.55 mmol), HATU (886 mg, 2.33 mmol) in anhydrous DMF (8 mL) is added DIPEA (385 μL, 2.33 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-60% EtOAc in heptane) to give a pure product (57) as white solid (378 mg, 70%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>CN(C=O)C>[CH3:22][O:21][C:17]([C:18]1[S:19][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=2[CH:4]=1)=[O:20]
Reactant: O=Cc1c(Br)cccc1Br
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Br)cccc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.8 %

Procedure:
To the solution of the compound (6.64 g, 25.16 mmol) obtained in Step 1 in DMF (90 ml), potassium carbonate (7.65 g, 55.35 mmol) and methyl thioglycolate (2.7 ml, 30.19 mmol) were added in that order, and then the reaction mixture was heated at reflux with stirring for 6 hours. After the termination of the reaction, the resulting reaction solution was cooled to room temperature, extracted with ethyl acetate, and then washed with water and brine. Subsequently, the reaction solution was dried over MgSO4, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=40:1), thus obtaining the title compound as a white solid (5.72 g, 21.09 mmol, 84%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:37])[C:12]=1[CH2:13][CH2:14][C@H:15]1[O:20][CH2:19][C@@H:18]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[N:17]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:16]1.[C:38]([O:42][C:43]([NH:45][C@H:46]([C:62](O)=[O:63])[CH:47]([C:55]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=1)[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>N1C=CC=CC=1.C1COCC1>[C:38]([O:42][C:43]([NH:45][C@H:46]([C:62]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:37])[C:12]=1[CH2:13][CH2:14][C@H:15]1[O:20][CH2:19][C@@H:18]([CH2:21][OH:22])[N:17]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])[CH2:16]1)=[O:63])[CH:47]([C:55]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=1)[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)=[O:44])([CH3:40])([CH3:41])[CH3:39]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
POCl3 (0.579 mL, 6.21 mmol) was added to a solution of tert-Butyl (2R,5S)-2-[2-(3-amino-5-fluoropyridin-4-yl)ethyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate (2.65 g, 5.64 mmol) and N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine [Patterson, D. E., et al. Org. Proc. Res. Dev. 2009, 13, 900-906.] (2.13 g, 5.64 mmol) in pyridine (28 mL) at −15° C. The reaction stirred for 30 min then warmed to 0° C. and stirred for 3 hours. The reaction was quenched with saturated aqueous KH2PO4, then brine and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford a brown viscous oil. The resulting oil was dissolved in THF (28 mL) and a 1M solution of TBAF (11.3 mL, 11.3 mmol) in THF was added and the reaction stirred at ambient temperature overnight. The reaction was quenched with saturated aqueous KH2PO4 and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. Purification on silica gel (330 g) eluting with a gradient of 0-100% CHCl3 to 70:20:10 CHCl3/EtOAc/MeOH afforded the title compound (2.07 g, 2.90 mmol, 51% yield) as a white solid, MS (ESI): m/z=715.48 (MH+); 100% pure by LCMS.