Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]1[C:13]([CH3:16])=[N:14][N:15]=[C:7]1[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Na+].[Na+].B(O)(O)[C:24]1[CH:29]=[N:28][CH:27]=[C:26]([F:30])[CH:25]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:12][C:10]1[CH:11]=[C:2]([C:24]2[CH:29]=[N:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH:3]=[C:4]2[C:9]=1[N:8]1[C:13]([CH3:16])=[N:14][N:15]=[C:7]1[CH2:6][CH2:5]2
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1nnc2n1-c1c(F)cc(Br)cc1CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1c(F)cc(-c3cncc(F)c3)cc1CC2

Procedure:
7-Bromo-9-fluoro-4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinoline (157-5, 0.25 g, 0.89 mmol) was dissolved in toluene (6.3 mL), and an aqueous 2.0 M sodium carbonate solution (2.8 mL), an ethanolic solution (2.8 mL) of 5-fluoropyridin-3-yl-3-boronic acid (0.19 g, 1.33 mmol) and tetrabutylammonium bromide (0.29 g, 0.89 mmol) were added. The mixture was deoxygenated under reduced pressure and flushed with nitrogen. After having repeated this cycle several times catalyst Pd(OAc)2 (0.01 g, 5 mol %) was added and the resulting suspension was heated under reflux for 18 h. After cooling, ethyl acetate (10 mL) and water (10 mL) were added and the organic layer was separated. The water phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered over a short plug of CELITE and evaporated under reduced pressure. The crude compound was purified by flash chromatography on silica gel to obtain title compound (white solid); 1H NMR (CDCl3, 500 MHz) δ 8.67 (t, J=1.5 Hz, 1H), 8.52 (d, J=2.7 Hz, 1H), 7.59 (ddd, J=2.0, 2.6 Hz, JHF=9.2 Hz, 1H), 7.39 (dd, J=1.9 Hz, JHF=14.6 Hz, 1H), 7.41 (d, J=1.7 Hz, 1H), 3.13 (t, J=7.5 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.65 (d, JHF=8.3 Hz, 3H); MS (ESI): m/z=299 [M+H]+.
Reaction SMILES: [NH:1]([C:8]([C:10]1[N:11]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH:1]([C:8]([C:10]1[N:11]([CH2:27][C:28]([OH:30])=[O:29])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:14][CH:13]=2)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CC(=O)O

Procedure:
70 mg (0.15 mmol) of tert-butyl {2-(anilinecarbonyl)-5-[(3,3-dimethylbutanoyl)-amino]-1H-indol-1-yl}acetate from Example LIII, 0.50 ml of trifluoroacetic acid and 1 ml of dichloromethane are stirred together at RT for one hour. The solvent is removed under reduced pressure and the residue is dried in vacuo.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])(=[O:5])[CH3:4].O>CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1cccc(C#N)c1
Solvent: O
Solvent: CCOCC
Product: N#Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Br2 (1 mmol) was dropwise added to a solution of 3-acetylbenzonitrile (1 mmol) in Et2O (15 ml) at 0° C., and then the mixture was stirred at r.t. for 4 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and was concentrated to give an oil, i.e., 3-(2-bromoacetyl)benzonitrile, which was directly used for the next step without purification.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl[C@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[Li+].[Cl-]>CN(C=O)C.CCOC(C)=O>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][C@@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: C[C@@H](Cl)C(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](ON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Reaction time: 120 h
Yield: 37.7 %

Procedure:
Prepared according to Yamawaki et al. Bioorg. Med. Chem. 2007, 15, 6716. To a slurry of N-hydroxyphthalimide (517 mg, 3.17 mmol) and potassium carbonate (657 mg, 4.76 mmol) in DMF (4.5 mL) was added (R)-tert-butyl 2-chloropropanoate (522 mg, 3.17 mmol). Additional DMF (4.5 mL) was added after the slurry became viscous. After stirring for 5 d it was diluted with EtOAc and poured into LiCl soln (5% aq, 90 mL). The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with LiCl (5% aq), brine, dried over Na2SO4 and concd in vacuo. The crude residue was purified by silica gel chromatography (EtOAc-Heptane, 0-50%), affording the title compound (348 mg, 38%) as a white solid. LCMS: Rt=0.89 min, m/z=314.0 (M+23) Method 2m_acidic; 1H NMR (400 MHz, CDCl3) δ 7.87-7.81 (m, 2H), 7.75 (dd, J=5.5, 3.1 Hz, 2H), 4.79 (q, J=6.8 Hz, 1H), 1.61 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:9][CH:10]2[C:22](=[O:23])[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:7][N:8]=1.Cl[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>CN(C)C=O.C(O)C>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[CH3:28][O:27][C:25]([N:14]1[C:13]2[CH2:12][CH2:11][CH:10]([CH2:9][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH3:3])[C:22](=[O:23])[C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:26]
Reactant: COC(=O)Cl
Reactant: Cc1nccn1CC1CCc2[nH]c3ccccc3c2C1=O
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)n1c2c(c3ccccc31)C(=O)C(Cn1ccnc1C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.075 g) was added to a solution of 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (0.7 g) in dimethylformamide (10 ml) and the mixture was stirred at room temperature for 30 min. Methyl chloroformate (0.3 ml) was added and stirring continued at room temperature for 4 h. The resulting solution was basified with sodium carbonate (100 ml) filtered, and the filtrate was extracted with ethyl acetate (2×50 ml). The combined organic extracts and solid were washed with water (3×50 ml), dried (Na2SO4) and evaporated in vacuo to give a solid. Purification by flash chromatography (A) gave a solid, which was dissolved in ethanol (5 ml) and added to a solution of maleic acid (0.018 g) in ethanol (5 ml) to give the title compound (0.07 g) m.p. 91°-92°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)#[CH:20]>CCCCCCC.CCOC(C)=O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[C:20][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=2)=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C)ncn2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C#Cc2cc(C)ncn2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 6-methyl-pyrimidin-4-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (52 mg, 46%); 1H NMR δ (CDCl3): 8.99 (s, 1H), 7.32 (d, J=8.60 Hz, 2H), 7.22 (s, 1H), 7.17 (d, J=8.43 Hz, 2H), 3.83 (s, 3H), 2.51 (s, 3H); LCMS m/z: 224.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[S:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])([O-:5])=[O:4].[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:7]=1[S:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH:19][C:31]([O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32])([O-:5])=[O:4]
Reactant: N[C@@H](CSc1ccc(C(F)(F)F)cc1[N+](=O)[O-])C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](CSc1ccc(C(F)(F)F)cc1[N+](=O)[O-])C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 67 ml of 2.5N aqueous sodium hydroxide and 5.3 g of S-(2-nitro-4-trifluoromethylphenyl)-L-cysteine obtained in Reference Example 10 is stirred at room temperature for 30 minutes. Two point seven ml of benzyloxycarbonyl chloride and 19 ml of 1N aqueous sodium hydroxide are simultaneously added dropwise to the mixture at ice bath temperature over a period of 30 minutes. The resulting mixture is stirred at room temperature for further 2.5 hours and extracted with ethyl ether. The aqueous layer is acidified slightly with 1N hydrochloric acid and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl ether to yield 5.5 g of S-(2-nitro-4-trifluoromethylphenyl)-N-benzyloxycarbonyl-L-cysteine as pale yellow crystals, m.p. 150°-153° C.
Reaction SMILES: [O-]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+].S(=O)(=O)(O)O.CN(C)C=O.[Br:23][C:24]1[CH2:28][CH:27]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:39](=[O:46])[NH:40][CH:41]([CH:43]2[CH2:45][CH2:44]2)[CH3:42])=[O:30])[N:26]([C:47]2[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][N:48]=2)[N:25]=1>C(OCC)(=O)C.O>[Br:23][C:24]1[CH:28]=[C:27]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:39](=[O:46])[NH:40][CH:41]([CH:43]2[CH2:45][CH2:44]2)[CH3:42])=[O:30])[N:26]([C:47]2[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][N:48]=2)[N:25]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
0.24 g of potassium peroxodisulfate and 0.02 g of sulfuric acid were added to 3 ml of an N,N-dimethylformamide solution containing 0.10 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxamide, followed by heating and refluxing. After 1.5 hours, the reaction liquid was left to cool and introduced into 10 ml of water, and then ethyl acetate was added, followed by extraction. The organic layer (the ethyl acetate layer) was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/2) to obtain 0.09 g of the desired product (melting point: 231-233° C.).
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)=[O:24])[CH2:18][C@@H:17]1[C:36](O)=[O:37])=[O:15])([CH3:12])([CH3:11])[CH3:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:36]([C@H:17]1[CH2:18][C@H:19]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)=[O:24])[CH2:20][CH2:21][N:16]1[C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(F)(F)F)nc2)C[C@@H]1C(=O)O
Reactant: Nc1ccccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(F)(F)F)nc2)C[C@@H]1C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Benzene-1,2-diamine (131 mg, 1.21 mmol) was added to a mixture of (2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-2-carboxylic acid (500 mg, 1.16 mmol), BOP (563 mg, 1.27 mmol) and DIEA (0.403 mL, 2.31 mmol) in DMF (5 mL), and the resulting solution was stirred at room temperature for 8 hours. Water (20 mL) was added to the reaction mixture and then extracted with ethyl acetate (2×30 mL). The organic layers were dried over MgSO4 and concentrated to give a red solid. Purification was done by Companion (ReadySep, 40 g, silica gel packed) with methanol/methylenechloride from 1-5% to give the title compound as a white solid 550 mg (91%). LC-MS: 523.3, 521.3; (t=2.3 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12].[OH-].[K+].C(O)C.[C:18](=S)=[S:19]>O>[SH:19][C:18]1[N:8]([CH2:9][CH2:10][CH2:11][OH:12])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: S=C=S
Reactant: Nc1ccccc1NCCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCCn1c(S)nc2ccccc21
Reaction time: 6 h

Procedure:
To a stirred mixture of 93 parts of 3-(2-aminophenyl)amino-1-propanol, 45.5 parts of potassium hydroxide and 600 parts of an ethanol solution 85% in water are added dropwise 60.8 parts of carbon disulfide. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated and the residue is taken up in 1500 parts of water. The whole is filtered over hyflo and the filtrate is acidified with acetic acid. The oily product solidifies on scratching. It is filtered off, washed with water and dried, yielding 2-mercapto-1H-benzimidazole-1-propanol; mp. 110° C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C@@:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:19].C[O-].[Na+].Cl>CO>[CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C@@:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:19]
Reactant: CN1C(=O)C[C@]2(c3ccccc3)CCCC[C@H]2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)C[C@]2(c3ccccc3)CCCC[C@@H]2C1=O
Reaction time: 8 h
Yield: 95 %

Procedure:
N-Methyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline (2.0 g) in 100 ml of methanol was treated with 400 mg of sodium methoxide and the mixture was refluxed for 30 minutes. It was allowed to stand overnight at 25°, then poured into 1 N hydrochloric acid and extracted with ether. The ether extracts were washed successively with water and brine, then dried (MgSO4) and the ether evaporated to yield 1.9 g of an oil. NMR (CDCl3): methylene envelope from 70 to 140 cps (8H); singlet at 177 cps (3H); multiplet at 145 to 205 cps (3H); singlet at 434 cps (5H).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[O:27]1[CH2:28][CH2:29][N:24]([C:3]2[N:8]=[C:7]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]3=[CH:5][N:4]=2)[CH2:25][CH2:26]1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: C1COCCN1
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2nc(N3CCOCC3)ncc2c(=O)[nH]1

Procedure:
A stirred solution of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and morpholine (1.25 g) in pyridine (20 ml) was heated under reflux for 45 hours. The reaction mixture was evaporated under reduced pressure to yield a crude product which was washed with water and twice recrystallised from methanol to yield the title compound, 0.25 g, m.p. 175.5°-177° C.
Reaction SMILES: P(N(C)C)(N(C)C)N(C)C.[C:11](Br)(Br)([F:13])[F:12].[CH3:16][O:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[C:27](=[O:28])[CH2:26][CH:25]([CH:29]=O)[CH2:24]2)=[CH:20][CH:19]=1.[PH4+]>C1COCC1>[F:12][C:11]([F:13])=[CH:29][CH:25]1[CH2:24][N:23]([CH2:22][C:21]2[CH:31]=[CH:32][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:27](=[O:28])[CH2:26]1
Reactant: COc1ccc(CN2CC(C=O)CC2=O)cc1
Reactant: FC(F)(Br)Br
Agent: CN(C)P(N(C)C)N(C)C
Agent: [PH4+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(C=C(F)F)CC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
In a three necked flask under argon, (Me2N)3P (11.53 ml, 0.063 mol) is added to a solution of CF2Br2 (6.6 g, 0.031 mol) in THF (30 ml) at −78° C. (appearance of a white precipitate) and warmed to room temperature. A solution of the 1-(4-methoxy-benzyl)-5-oxo-pyrrolidine-3-carbaldehyde a3 (3.7 g, 0.016 mol) in THF (30 ml) is added dropwise to the pre-formed phosphonium salt. After 1 h, the reaction mixture is filtered through celite and concentrated in vacuo. The reaction mixture is diluted with hexane, washed with brine, dried over MgSO4 and concentrated in vacuo to afford the crude olefin which is purified by column chromatography on silicagel (CH2Cl2/MeOH: 99/01 (v/v)) to afford 2.45 g of the difluorovinyl derivative a4 (58%).
Reaction SMILES: N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][OH:20].[Br:22][C:23]1[CH:24]=[CH:25][C:26](O)=[N:27][C:28]=1[F:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:20][CH2:19][CH2:18][CH2:17][N:16]([CH3:21])[CH3:15])=[N:27][C:28]=1[F:29]
Reactant: CN(C)CCCO
Reactant: Oc1ccc(Br)c(F)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(Br)c(F)n1
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
(E)-Diisopropyl diazene-1,2-dicarboxylate (15.80 g, 78.13 mmol) was added drop wise to 3-(dimethylamino)propan-1-ol (8.06 g, 78.13 mmol), 5-bromo-6-fluoropyridin-2-ol (10 g, 52.09 mmol) and triphenylphosphine (20.49 g, 78.13 mmol) in DCM (150 mL) cooled to 0-5° C. under an inert atmosphere. The resulting solution was stirred at ambient temperature for 16 h then the solvent, removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and the solid removed by filtration and discarded. The filtrate was acidified with hydrogen chloride in dioxane. The solid was collected by filtration then dissolved in a sat. aqueous solution of Na2CO3 (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford the desired material (9.00 g, 62.3%). NMR Spectrum: 1H NMR (300 MHz, CDCl3) δ 1.89-1.98 (2H, m), 2.26 (6H, s), 2.34 (2H, t), 4.30 (2H, t), 6.53 (1H, d), 7.74 (1H, t). Mass Spectrum: m/z (ES+)[M+H]+=277.
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:26][C:27]([F:30])([F:29])[F:28])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH2:19][CH:20]2[O:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C([O-])=O.O.[CH3:39][C:40]([CH3:42])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1>[CH:40]([N:22]1[CH2:23][CH2:24][O:25][CH:20]([CH2:19][O:18][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH2:26][C:27]([F:30])([F:29])[F:28])[C:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])=[CH:17]3)[CH2:21]1)([CH3:42])[CH3:39]
Reactant: CC(C)=O
Reactant: O=C(c1cc2cc(OCC3CNCCO3)ccc2n1CC(F)(F)F)N1CCOCC1
Agent: O=C([O-])C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCOC(COc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3CC(F)(F)F)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of morpholin-4-yl-[5-(morpholin-2-ylmethoxy)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone as trifluoroacetate salt (example 1, step 2, 120 mg, 1.0 eq.) in tetrahydrofuran (2 mL) were successively added water (0.004 mL, 1.1 eq.), acetone (0.019 mL, 1.5 eq.), acetic acid (0.040 mL, 3.0 eq.) and a solution of sodium cyanoborohydride in tetrahydrofuran (1M, 0.33 mL, 1.5 eq.). The reaction mixture was stirred at 55° C. overnight and concentrated in vacuo. Water (5 mL) and hydrochloric acid (1N, 1.5 mL) were added to the residue and the solution was washed with ethyl acetate and then basified by addition of an aqueous solution of potassium carbonate. The aqueous fraction was extracted with ethyl acetate and the combined organic layers were washed with brine. The organic residue was purified on silica, eluting with 98:2 dichloromethane/methanol, to yield 45 mg (43%) of the desired product as white foam. MS (m/e): 470.5 (MH+, 100%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.CN(C)C=O.O>[CH2:7]([C:5]1[S:6][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=2)=[CH:3][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: CCOC(=O)c1cc(Br)sc1CC
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)sc1CC
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a mixture of ethyl 5-bromo-2-ethylthiophene-3-carboxylate (4.61 g) synthesized above, 4-(trifluoromethyl)phenylboronic acid (5.00 g), sodium carbonate (3.71 g), water (20 mL) and N,N-dimethylformamide (100 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane adduct (1.43 g). The reaction mixture was deaerated, and stirred under an argon atmosphere at 80° C. for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19, volume ratio) to give the title compound (5.18 g, 90%) as a white solid.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25]O)=[C:15]1[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:66]>C(Cl)Cl>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][Br:66])=[C:15]1[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1c(CCO)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1c(CCBr)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution was made with 1 eq 2-[1-benzhydryl-2-({[tert -butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indol-3-yl]ethanol and CH2Cl2 (0.12M). Then 0.76 eq of 1,3-bis(diphenylphosphino)propane was added and the solution was cooled to 0° C. under N2. Then 1.3 eq of CBr4 was added to give a light yellow solution. The reaction was allowed to return to room temperature. After three hours and 15 minutes the solvent was removed. Purified using a flash column with silica gel and 1:5 EtOAc/Hexane as eluent to give 1-benzhydryl-3-(2-bromoethyl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indole (yellow-brown gum) in 90% yield.