Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH3:10])[C:6]=2[CH:11]=1.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[F:21].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[F:21][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:13]=1[NH:12][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH3:10])[C:6]=2[CH:11]=1)[C:17]#[N:18]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: Cn1cnc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1cnc2ccc(Nc3ccc(C#N)cc3F)cc21
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture containing 6-bromo-1-methyl-benzimidazole (2.38 mmol), 4-amino-3-fluoro-benzonitrile (3.57 mmol), XPhos (0.95 mmol), Cs2CO3 (7.14 mmol) and Pd(OAc)2 (0.71 mmol) in dry toluene (8 mL) was stirred at 110° C. for approximately 16 h. The mixture was diluted (EtOAc), washed (H2O), dried (Na2SO4) and concentrated to yield the desired product 3-fluoro-4-[(3-methylbenzimidazol-5-yl)amino]benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccc(F)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccc(F)cc2)CC1)c1ccccc1
Yield: 44.1 %

Procedure:
0.63 g (0.003 mol) of 1-(4-fluoro-benzyl)-piperidin-4-ol and 2.09 ml (0.015 mol) of triethylamine were dissolved in 30 ml of toluene, treated with 1.04 ml (0.009 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.415 g (44%) of 1-(4-fluoro-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil. MS: me/e=314 (C19H21FNO2+).
Reaction SMILES: Cl.N1C=CC=CC=1.[Cl:8][C:9]1[C:10]([O:28]CC(O)=O)=[CH:11][C:12]2[CH2:13][CH2:14][C:15]3([CH2:25][CH2:26][CH3:27])[C:20]([C:21]=2[C:22]=1[Cl:23])=[CH:19][C:18](=[O:24])[CH2:17][CH2:16]3>>[Cl:8][C:9]1[C:10]([OH:28])=[CH:11][C:12]2[CH2:13][CH2:14][C:15]3([CH2:25][CH2:26][CH3:27])[C:20]([C:21]=2[C:22]=1[Cl:23])=[CH:19][C:18](=[O:24])[CH2:17][CH2:16]3
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)CC2
Agent: Cl
Solvent: c1ccncc1
Product: CCCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)CC2
Temperature: 190 °C
Reaction time: 0.25 h

Procedure:
Pyridine hydrochloride (20 g, 173 mmole) is melted and heated to 190° C. and then (+) [(3,4-dichloro-6,7,8,8a,9,10-hexahydro-6-oxo-8a-propyl-2-phenanthrenyl)oxy]acetic acid (Example 3) (325 mg, 1 mmole) is added and stirred for 15 minutes at 190° C. The mixture is poured into crushed ice (200 g) and the product extracted with ether. The organic extract is washed with water, then with brine and dried over MgSO4. Evaporation of the solvent gave (+)3,4-dichloro-6,7,8,8a,9,10-hexahydro-2-hydroxy-6-oxo-8a-propylphenanthrene.
Reaction SMILES: [F:1][C:2]([F:16])([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH:27][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:2]([F:1])([F:16])[C:3]([F:4])([F:5])[F:6])=[CH:15][CH:14]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: COc1cccc(CCN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cccc(CCNC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2)c1
Yield: 96.1 %

Procedure:
A solution of 4-pentafluoroethyl-benzoic acid (500 mg, 2.08 mmol), 2-(3-methoxyphenyl)-ethylamine (361 mg, 2.29 mmol), 4-methylmorpholine (632 mg, 6.24 mmol), and HBTU (1.19 g, 3.12 mmol) in DMF (38 mL) was stirred at RT for 16 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (746 mg, 96%). Light yellow solid, MS (ISP) 374.2 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH2:19][OH:20])[CH:16]([N:21]=[N+:22]=[N-:23])[C:15]1=[O:24])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]=[O:20])[CH:16]([N:21]=[N+:22]=[N-:23])[C:15]1=[O:24])([C:10]([CH3:12])([CH3:13])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chromium trioxide (0.06 mol) is added to a solution of pyridine (0.12 mol) in methylene chloride (150 ml) and the mixture is stirred at room temperature for 15 min. A solution of N-(t-butyldimethylsilyl)-3-azido-4-(2-hydroxyethyl)-azetidin-2-one (0.01 mol) in methylene chloride (10 ml) is then added all at once. After stirring at room temperature for 5 min, the mixture is decanted and the dark, gummy residue is washed with more methylene chloride. The combined methylene chloride supernatant is concentrated under vacuum to a residue which is taken up in ether and filtered through celite. The filtrate is washed with 5% hydrochloric acid, 5% sodium bicarbonate solution, and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to yield N-(t-butyldimethylsilyl)-3-azido-4-(2-oxoethyl)-azetidin-2-one.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([CH2:12][CH2:13][CH:14]=[CH2:15])[CH:10]=O.C1C=CC=CC=1.[CH3:22][C:23]([S@:26]([NH2:28])=[O:27])([CH3:25])[CH3:24]>O1CCCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([CH2:12][CH2:13][CH:14]=[CH2:15])/[CH:10]=[N:28]/[S@@:26]([C:23]([CH3:25])([CH3:24])[CH3:22])=[O:27]
Reactant: C=CCC[C@H](C=O)c1cccc(F)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccccc1
Product: C=CCC[C@H](/C=N/[S@](=O)C(C)(C)C)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.1 %

Procedure:
In a 500 mL round-bottomed flask was dissolved (S)-2-(2,3-difluorophenyl)hex-5-enal (3.61 g, 17.2 mmol) (freshly azeotroped with dry benzene) and (R)-2-methylpropane-2-sulfinamide (2.08 g, 17.2 mmol) in tetrahydrofuran (100 mL) to give a yellow solution. Titanium(IV) ethoxide (36.0 mL, 34.3 mmol) was added dropwise, and the mixture was stirred at rt under nitrogen for 6 h. It was transferred to a stirred solution of brine (90 mL) and a white solid was formed. This was filtered through a plug of celite and washed with ethyl acetate. The eluent was concentrated to give a tan oil. The residue was purified by flash column chromatography up to 40% ethyl acetate/hexane afforded the desired product (3.94 g, 73% for 2 steps) as a light yellow oil: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.09 (d, J=4.52 Hz, 1H) 7.02-7.14 (m, 2H) 6.97 (d, J=8.28 Hz, 1H) 5.68-5.87 (m, 1H) 5.02 (d, J=13.05 Hz, 2H) 4.07-4.18 (m, 1H) 2.19 (dt, J=13.30, 6.65 Hz, 1H) 2.05-2.13 (m, 2H) 1.90-2.03 (m, 1H) 1.17 (s, 9H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −137.55 (br. s., 1F) −142.03 (br. s., 1F); 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 167.97 (s, 1C) 151.70-149.09 (m, 1C) 149.93-147.27 (m, 1C) 136.71 (d, J=9.25 Hz, 1C) 128.43 (d, J=9.25 Hz, I C) 122.99-124.42 (m, 1C) 115.88-115.68 (m, 1C) 115.37 (m, 1C) 109.63 (s, 1C) 56.77 (s, 1C) 43.94 (d, J=12.33 Hz, 1C) 30.83 (s, 1C) 30.40 (s, 1C) 21.96 (d, J=5.39 Hz, 3C).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:25]C(=O)C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([OH:23])([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[O:21][CH3:22])[C:5]2=[O:24]>Cl.CO.C(Cl)Cl>[NH2:25][C:3]1[C:2]([NH2:1])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:24])[C:6]([OH:23])([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[O:21][CH3:22])[C:7]2=[O:11]
Reactant: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc(N)c(NC(C)=O)c2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc(N)c(N)c2C1=O
Yield: 46.4 %

Procedure:
N-(5-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (85 mg, 0.19 mmol) was completely dissolved in 6M HCl (1.4 ml) and methanol (0.1 ml), followed by heating for 40 min at 80. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (30 mg, 44%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])[C:12](=[O:22])[N:13]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])[C:12](=[O:22])[N:13]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc3ccccc3c2)C(=O)N(c2ccccc2)c2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCC1(NC(=O)c2ccc3ccccc3c2)C(=O)N(c2ccccc2)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 ml of boron tribromide was added dropwise to a stirred solution of 2.37 g of ethyl 3-[2,3-dihydro-6-methoxy-3-(2-naphthalenecarbonyl)amino-2-oxo-1-phenyl-1H-indol-3-yl]propionate in methylene chloride (20 ml) under ice cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was evaporated to dryness under reduced pressure to afford ethyl 3-[2,3-dihydro-6-hydroxy-3-(2-naphthalenecarbonyl)amino-2-oxo-1-phenyl-1H-indol-3-yl]propionate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][C@@H:21]([CH3:23])[N:20]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:19][C@@H:18]3[CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:29]([O:32][CH2:33][C:34]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]([F:49])=[CH:36][C:35]=1[N:50]1[C:62](=[O:63])[C:61]2[S:60][C:59]3[CH2:58][CH2:57][CH2:56][CH2:55][C:54]=3[C:53]=2[CH:52]=[N:51]1)(=[O:31])[CH3:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[C:29]([O:32][CH2:33][C:34]1[C:35]([N:50]2[C:62](=[O:63])[C:61]3[S:60][C:59]4[CH2:58][CH2:57][CH2:56][CH2:55][C:54]=4[C:53]=3[CH:52]=[N:51]2)=[CH:36][C:37]([F:49])=[CH:38][C:39]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][C@@H:21]([CH3:23])[N:20]([CH:24]4[CH2:25][O:26][CH2:27]4)[CH2:19][C@@H:18]3[CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 25 °C
Yield: 33.8 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-bromo-3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 104e (179 mg, 0.40 mmol), (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]-trideca-1(9),2(7),3-trien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 117d (200 mg, 0.40 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol), K3PO4 (170 mg, 0.8 mmol), sodium acetate (66 mg, 0.8 mmol), acetonitrile (5 mL), water (1.0 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 118a as yellow solid (100 mg, 34%). MS: [M+H]+ 740.3
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:15])[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:18][N:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)s1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccc(Cl)s1)c1ccncc1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
To a suspension of 1-(5-chloro-2-thienyl)-2-(pyridin-4-yl)ethanone (21 mmol) in 13 mL N,N-dimethylformamide, was added N,N-dimethylformamide dimethyl acetal (71.5 mmol). The mixture was refluxed for 3 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol 100:1 to 20:1) to afford 3.3 g (51% yield) of 1-(5-chloro-2-thienyl)-3-(dimethylamino)-2-(pyridin-4-yl)prop-2-en-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:13]1[CH2:15][CH2:14]1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])[CH:13]1[CH2:14][CH2:15]1)(=[O:10])=[O:11]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)OC(C)(C)C)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane (10 ml/mmol) solution of tert-butyl 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)acetate (1 eq.) was added trifluoroacetic acid (13 eq.) at 0° C. and the resulting reaction mixture was stirred at ambient temperature for 2 h. The solvent was evaporated off and the residue dried under vacuum to remove traces of trifluoroacetic acid. The crude product was used in the next step without further purification. Yield: quantitative
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[C:12]2[S:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][CH:37]=[CH:36]1>O.ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[C:12]2[S:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:33][CH2:34][N:35]2[CH:39]=[CH:38][CH:37]=[CH:36]2)[CH2:22][CH2:21]1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1SC1CCNCC1
Reactant: ICCn1cccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1[nH]c2ccc(Cl)cc2c1SC1CCN(CCn2cccc2)CC1

Procedure:
A toluene solution (100 ml) of 5-chloro-2-methyl-3-(piperidin-4-ylthio)-1H-indole (1.09 g, prepared in Example 18), sodium carbonate (0.78 g) and 1-(2-iodoethyl)-1H-pyrrole (0.92 g, prepared according to GALEAZZI, E.; GUZMAN, A.; PINEDO, A.; SALDANA, A.; TORRE, D.; MUCHOWSKI, J. M., Can. J. Chem. (1983) 61, 454-60) is refluxed for 15 hours. The reaction mixture is taken up in a water/dichloromethane mixture. The organic phase is dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (eluent: CH2Cl2 /MeOH:90/10) to give 5-chloro-2-methyl-3-[[1-[2-(1H-pyrrol-1-yl)ethyl]piperidin-4-yl]thio]-1H-indole (0.9 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[Si:10]([CH3:13])([CH3:12])[CH3:11].[Li]CCCC.CON(C)[C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:23]>C1COCC1.CCCCCC>[F:8][C:7]1[C:2]([F:1])=[C:3]([Si:10]([CH3:12])([CH3:11])[CH3:13])[CH:4]=[C:5]([CH3:9])[C:6]=1[C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:23]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(F)c(F)c([Si](C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc([Si](C)(C)C)c(F)c(F)c1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (2,3-difluoro-5-methylphenyl)trimethylsilane (10 g, 0.05 mol) in anhydrous THF (100 mL) at −78° C., under nitrogen, was added dropwise a solution of 2.5 M n-BuLi in hexane (20 mL). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (13.6 g, 0.05 mol) in anhydrous THF (60 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-(2,3-difluoro-6-methyl-4-(trimethylsilyl)benzoyl)piperidine-1-carboxylate, which was purified by column chromatography on silica gel elating with hexane (2 g, 10%). 1H NMR δ 6.90 (m, 2H), 4.00 (m, 4H), 2.20 (s, 3H), 1.47 (s, 9H), 1.30 (m, 4H), 0.35 (s, 9H).
Reaction SMILES: CC(C)([O-])C.[Na+].[C@@H]1(N)CCCC[C@H]1N.CCCCCCCCCCCC.I[C:28]1[CH:29]=[C:30]([CH3:35])[CH:31]=[C:32]([CH3:34])[CH:33]=1.[C:36](=[NH:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>[Cu]I.O1CCOCC1>[CH3:34][C:32]1[CH:33]=[C:28]([N:49]=[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:29]=[C:30]([CH3:35])[CH:31]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Product: Cc1cc(C)cc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 36 h
Yield: 15.5 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (2.0 mg, 0.0105 mmol, 1.0 mol %), sodium tert-butoxide (150 mg, 1.56 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (13 μL, 0.108 mmol, 11 mol %), dodecane (235 μL), 5-iodo-m-xylene (150 μL, 1.04 mmol), benzophenone imine (210 μL, 1.25 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 36 h. The resulting dark brown suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 30:1; 15 mL fractions). Fractions 6-11 provided 46 mg (15% yield) of the product as a pale tan solid. 1H NMR (300 MHz, CDCl3): δ 7.79−7.75 (m, 2H), 7.52-7.40 (m, 3H), 7.34−7.26 (m, 3H), 7.20−7.15 (m, 2H), 6.60 (s, 1H), 6.39 (s, 2H), 2.19 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:14]2[CH2:28][CH2:27][C:17]3([O:22][CH2:21][C:20](=[O:23])[N:19]([CH:24]4[CH2:26][CH2:25]4)[CH2:18]3)[CH2:16][CH2:15]2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:29])[CH:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].C(Cl)Cl>[CH:24]1([N:19]2[CH2:18][C:17]3([CH2:27][CH2:28][N:14]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:38]5[CH:47]=[C:46]6[C:41]([CH:42]=[CH:43][CH:44]=[N:45]6)=[CH:40][CH:39]=5)=[CH:3][C:4]=4[F:29])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:15][CH2:16]3)[O:22][CH2:21][C:20]2=[O:23])[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: COC(=O)CC(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)CC(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Yield: 80.5 %

Procedure:
A solution of methyl 3-(4-bromo-2-fluorophenyl)-3-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)propanoate (1.924 mmol) in 1,4-dioxane (6 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (2.116 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.096 mmol) and 2M aq potassium carbonate (5.77 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The resulting black mixture was diluted with water (50 mL) and extracted with dichloromethane three times. The combined organic layer was treated with Silicycle Si-thiol (100 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-7% methanol/dichloromethane) afforded the title compound as a brown solid (802 mg, 72% yield). MS(ES)+ m/e 518.4 [M+H]+.
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C(O)(C)(C)C>[C:8]([O:7][C:6](=[O:12])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccccn1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl alcohol (650 mL) and di-tert-butylcarbonate (24g) was added 2-aminopyridine (9.4 g) slowly. This mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (18 g).
Reaction SMILES: [C:1]([C@H:3]1[O:8][CH2:7][C@H:6]([CH2:9][O:10][Si](C(C)(C)C)(C)C)[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)#[CH:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:1]([C@H:3]1[O:8][CH2:7][C@@H:6]([CH2:9][OH:10])[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)#[CH:2]
Reactant: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2R,5R)-2-ethynyl-5-(tert-butyldimethylsilyloxy-methyl)morpholine-4-carboxylate (Example 79, step 4) (2.0 g, 5.7 mmol) in 20 mL of THF was added tetrabutylammonium fluoride (1.0 M in THF, 15 mL, 15 mmol). The solution was stirred at ambient temperature for 1 h and then diluted with EtOAc, washed with aqueous NH4Cl, and brine. The solution was dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was chromatographed on an 80 g SiO2 column using a gradient elution of 0-10% MeOH in CHCl3 to give the product as an oil.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([O:15]CC)=[O:14])[CH:7]=2)(=[O:3])[NH2:2].[OH-].[Na+].Cl>CO>[C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=2)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1ccc2cc(C(N)=O)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc2ccc(C(=O)O)cc2[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 103.9 %

Procedure:
To a solution of ethyl 2-carbamoyl-1H-indole-6-carboxylate (3.3 g, 14 mmol) in methanol (50 mL) was added 1 N aqueous sodium hydroxide (71 mL, 71 mmol). The reaction was stirred at room temperature for 17 hours. Then the reaction was acidified to pH 2-3 using 6 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to afford the title compound (2.97 g, 100%). −APCI (M−H) 203.4.