Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:28])[C:11]([CH3:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:8].[CH3:29][O:30][C:31]1[CH:67]=[CH:66][C:34]([CH2:35][N:36]2[CH:40]([CH2:41][CH2:42]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:39][N:38]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=3)[C:37]2=[O:65])=[CH:33][CH:32]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([O:9][C:10](=[O:28])[C:11]([CH3:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:42][CH2:41][CH:40]2[CH2:39][N:38]([CH2:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:60]=3)[C:37](=[O:65])[N:36]2[CH2:35][C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:67][CH:66]=2)=[CH:15][CH:14]=1)[CH3:8]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: COc1ccc(CN2C(=O)N(Cc3ccc(C(F)(F)F)cc3)CC2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2Cc2ccc(OC)cc2)cc1)Oc1ccccc1
Yield: 93.6 %

Procedure:
Cesium carbonate (2.49 g, 7.647 mmol) is added to a solution of 3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (1.77 g, 5.88 mmol) and toluene-4-sulfonic acid 2-[3-(4-methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (3.64 g, 6.47 mmol) in DMF (40 mL). The resultant mixture is stirred at 55° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed, then dried, concentrated, and purified by flash chromatography (acetone/hexanes gradient) to provide the title compound (3.80 g, 94%). 1H NMR (400 MHz, CDCl3): δ 7.57 (d, 2H, J=8.4 Hz), 7.37 (d, 2H, J=7.8 Hz), 7.23-7.19 (m, 4H), 7.13 (d, 2H, J=8.4 Hz), 6.97 (t, 1H, J=7.8 Hz), 6.86 (d, 2H, J=8.4 Hz), 6.81 (d, 2H, J=8.4 Hz), 6.67 (d, 2H, J=7.8 Hz), 4.66, 4.20 (ABq, 2H, J=14.9 Hz), 4.47, 4.43 (ABq, 2H, J=15.5 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.89-3.85 (m, 2H), 3.80 (s, 3H), 3.61-3.55 (m, 1H), 3.31 (t, 1H, J=9.1 Hz), 3.26, 3.08 (ABq, 2H, J=13.6 Hz), 3.00 (t, 1H, J=9.1 Hz), 2.20-2.14 (m, 1H), 1.87-1.78 (m, 1H), 1.38 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+] 691 (M+H)+. Rf=0.46 in 50% acetone in hexanes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=O)[N:12]=2)=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].[I-].[K+]>CN(C=O)C>[CH3:23][S:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:22])=[C:11]([CH2:13][CH2:14][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])[N:12]=3)=[CH:4][CH:3]=2)=[CH:29][CH:28]=1)(=[O:25])=[O:26]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(OCc3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN1CCC[C@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Example 56) (0.32 g, 1.1 mmol), 4-methylsulfonylbenzyl chloride (0.29 g, 1.4 mmol), Cs2CO3 (0.9 g, 2.75 mmol), and potassium iodide (0.24 g, 1.4 mmol) in DMF (5 mL) is stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc (2×), and the combined organic phase is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by flash chromatography [40 g SiO2, elute 20% (10% 2 M NH3 in MeOH/90% CH2Cl2): 80% CH2Cl2 to 70% (10% 2 M NH3 in MeOH/90% CH2Cl2): 30% CH2Cl2] to yield the title compound. MS (m/e): 455.3 (M+1)
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[N:17][C:16]=2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][S:40]([C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=3[F:50])(=[O:42])=[O:41])[C:34]=2[F:51])[CH:12]=[CH:11][N:10]=1>C(Cl)Cl.CO>[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:17][C:16]=2[C:33]2[C:34]([F:51])=[C:35]([NH:39][S:40]([C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=3[F:50])(=[O:42])=[O:41])[CH:36]=[CH:37][CH:38]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCNCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reaction time: 8 h
Yield: 130.6 %

Procedure:
A 4N solution of HCl in 1,4-dioxane (1.1 ml, 4.3 mmol) was added to a stirring solution of 1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperazinecarboxylate (0.36 g, 0.54 mmol) in DCM (8 mL) and MeOH (1 mL) at rt. The reaction was allowed to stir overnight. LCMS analysis indicated complete consumption of the starting material. The volatiles were removed in vaccuo to afford the HCl salt of the desired product of Step C (0.40 g, 100% yield) which was carried forward without further purification. MS (ES+): 568 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[S:57][CH:58]=[C:59]([CH2:61][S:62][C:63]3[C:68]([C:69]#[N:70])=[C:67]([C:71]4[CH:76]=[CH:75][C:74]([O:77][CH2:78][CH2:79]O)=[CH:73][CH:72]=4)[C:66]([C:81]#[N:82])=[C:65]([N:83]4[CH2:87][CH2:86][CH2:85][CH2:84]4)[N:64]=3)[N:60]=2)=[CH:52][CH:51]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([O:16][CH2:79][CH2:78][O:77][C:74]1[CH:73]=[CH:72][C:71]([C:67]2[C:66]([C:81]#[N:82])=[C:65]([N:83]3[CH2:84][CH2:85][CH2:86][CH2:87]3)[N:64]=[C:63]([S:62][CH2:61][C:59]3[N:60]=[C:56]([C:53]4[CH:52]=[CH:51][C:50]([Cl:49])=[CH:55][CH:54]=4)[S:57][CH:58]=3)[C:68]=2[C:69]#[N:70])=[CH:76][CH:75]=1)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCCC2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1

Procedure:
0.89 g (3.82 mmol) of N-(tert-butoxycarbonyl)-L-leucine were initially charged in 10 ml of DMF, and 0.81 g (4.18 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.80 g (5.23 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 1.13 g (8.71 mmol) of N,N-diisopropylethylamine were added. The mixture was stirred until a clear solution had been obtained. 1.00 g (1.74 mmol) of 2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)-6-(pyrrolidin-1-yl)pyridine-3,5-dicarbonitrile was then added, and the mixture was stirred at room temperature for 18 h. The mixture was added to 300 ml of water. The residue formed was filtered off with suction and washed with 50 ml of water. The crude product was dissolved in 50 ml of dichloromethane. The aqueous phase was separated off and the organic phase was dried over sodium sulfate. Removal of the solvent under reduced pressure gave 1.37 g (100% of theory) of the desired target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:42])[C@@H:12]([NH:20][C:21](=[O:41])[CH:22]([NH:33][C:34]([O:36]C(C)(C)C)=O)[C:23]2[CH:32]=[CH:31][C:26]3[N:27]([CH3:30])[CH:28]=[N:29][C:25]=3[CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].ClCCl.C(=O)(O)[O-].[Na+].C(=O)=O.C(N(C(C)C)CC)(C)C.O=C(Cl)OC(Cl)(Cl)Cl>FC(F)(F)C(O)=O.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:42])[C@@H:12]([N:20]2[C:21](=[O:41])[CH:22]([C:23]3[CH:32]=[CH:31][C:26]4[N:27]([CH3:30])[CH:28]=[N:29][C:25]=4[CH:24]=3)[NH:33][C:34]2=[O:36])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(NC(=O)OC(C)(C)C)c2ccc3c(c2)ncn3C)n1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=C=O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)N2C(=O)NC(c3ccc4c(c3)ncn4C)C2=O)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60 %

Procedure:
2-{(S)-2-[2-tert-Butoxycarbonylamino-2-(1-methyl-1 H-benzoimidazol-5-yl)-acetylamino]-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (185 mg, 0.193 mmol) was dissolved at 0° C. in a 30% v/v solution of trifluoroacetic acid in dichloromethane (10 mL, 38.9 mmol). The reaction mixture was slowly warmed to room temperature and stirred for approximately 3.5 hours. The reaction mixture was then cooled to 0° C. and neutralized by the addition of solid sodium bicarbonate until there was no further evolution of carbon dioxide. The reaction mixture was then partitioned between dichloromethane and water and the water layer thoroughly extracted with dichloromethane until no products could be detected in the organic extract as judged by absorption of ultraviolet radiation on silica gel thin layer chromatography plates containing a fluorescent indicator which absorbed at 254 nm. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (≈5 mL), diisopropylethyl amine (180 μL, 1.00 mmol) added and the resulting solution was transferred via cannula to a solution of diphosgene (20 μL, 0.18 mmol) in tetrahydrofuran (≈10 mL) at 0° C. After stirring for 10 minutes the reaction mixture was partitioned between ethyl acetate and water, the water layer separated and extracted with ethyl acetate until no products could be detected in the organic extract as judged by absorption of ultraviolet radiation on silica gel thin layer Chromatography plates containing a fluorescent indicator which absorbed at 254 nm. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel gradient eluted between 0 and 5% v/v methanol in dichloromethane and the isolated product precipitated from a dichloromethane solution with an exess of hexanes to afford 2-{(S)-2-[4-(1-methyl-1H-benzoimidazol-5-yl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester as an off-white solid (60 mg, 60%).
Reaction SMILES: Cl.C([N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]([NH:22][C:23]3[N:28]=[C:27]([NH:29][C@H:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=4)[CH3:31])[C:26]([CH3:39])=[CH:25][N:24]=3)[C:17]([O:20][CH3:21])=[N:18][CH:19]=2)[CH:11]=[N:10]1)C1C=CC=CC=1>[Pd].[OH-].[OH-].[Pd+2].CO.O1CCCC1>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C@@H:30]([NH:29][C:27]2[C:26]([CH3:39])=[CH:25][N:24]=[C:23]([NH:22][C:16]3[C:17]([O:20][CH3:21])=[N:18][CH:19]=[C:14]([C:12]4[CH:11]=[N:10][NH:9][CH:13]=4)[CH:15]=3)[N:28]=2)[CH3:31])=[N:33][CH:34]=1
Reactant: COc1ncc(-c2cnn(Cc3ccccc3)c2)cc1Nc1ncc(C)c(N[C@@H](C)c2ccc(F)cn2)n1
Agent: [Pd+2]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncc(-c2cn[nH]c2)cc1Nc1ncc(C)c(N[C@@H](C)c2ccc(F)cn2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
5N Aqueous hydrochloric acid solution (0.126 mL, 0.63 mmol) and 20% palladium hydroxide on carbon (0.07 g, 0.50 mmol) were added to a solution of (S)—N2-(5-(1-benzyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl)-N4-(1-(5-fluoropyridin-2-yl)ethyl)-5-methylpyrimidine-2,4-diamine (Preparation 9a, 0.214 g, 0.42 mmol) in a 1:1 mixture of methanol/tetrahydrofuran (4 mL) and the reaction mixture was stirred at 50° C. overnight under a hydrogen atmosphere. Further 5N aqueous hydrochloric acid solution (0.126 mL, 0.63 mmol) and palladium catalyst (0.07 g) were then added and the mixture was stirred overnight under a hydrogen atmosphere. The mixture was then filtered through diatomaceous earth (Celite®) and the filter cake was washed with methanol. The combined filtrate and washings were evaporated and a 1:1 mixture of methanol/tetrahydrofuran (4 mL) was added to the residue. 5N aqueous hydrochloric acid solution (0.126 mL, 0.63 mmol) and 20% palladium hydroxide on carbon (0.07 g, 0.50 mmol) were then added to the resulting solution and the reaction mixture was stirred at 50° C. overnight under a hydrogen atmosphere. The mixture was then filtered through Celite® and the filter cake was washed with methanol. The combined filtrate and washings were evaporated to give the title compound (0.166 g, 70%) as a white foam that was used in the next synthetic step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH2:17].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=2)[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1nc(Nc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 29.4 %

Procedure:
A mixture of 6.5 g of 6-chloro-3-nitropicolinonitrile (0.065 mol) and 6.2 g of 3,5-difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70° C. for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using saturated NaCl solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([Sn](CCCC)(CCCC)CCCC)=[N:27][NH:28]2)=[C:24]([F:44])[CH:23]=1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.[Cu](I)I.C(OCC)(=O)C>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:2]3[N:3]=[C:4]4[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]4=[N:6][CH:7]=3)=[N:27][NH:28]2)=[C:24]([F:44])[CH:23]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)cc(F)c12
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(Cl)cc(F)c34)cnc21
Temperature: 90 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (7.6 g, 18.6 mmol) and 6-chloro-4-fluoro-3-tributylstannanyl-1H-indazole (crude from Step 3) were dissolved in DMF (180 ml) and purged with Ar gas. Tetrakis(triphenylphosphine)pallladium (1.07 g, 0.93 mmol) and then copper iodide (707 mg, 3.71 mmol) were added and the flask was stoppered and stirred in a 90° C. oil bath for 20 h. The reaction was cooled and water, ethyl acetate and sodium bicarbonate solution were added. The layers were separated, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with water and sodium chloride solution, then dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) followed by trituration with diethyl ether/hexanes to give 3.9 g (47%) of 2-(6-chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde. (M+H)+=446.
Reaction SMILES: [CH:1]1([CH2:10][CH2:11][NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][C:14]1([CH3:27])[C:18]2([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:19]([CH2:21][CH:15]1[CH2:16][CH2:17]2)=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([CH2:10][CH2:11][NH:12][S:23]([CH2:22][C:18]23[C:14]([CH3:13])([CH3:27])[CH:15]([CH2:16][CH2:17]2)[CH2:21][C:19]3=[O:20])(=[O:25])=[O:24])=[CH:2]1
Reactant: NCCC1C=Cc2ccccc21
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CCC1(CS(=O)(=O)NCCC1=CCc3ccccc31)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-(1H-Indene-1-yl)ethyl)amine (190 mg, 1.19 mmol) and (+)-10-camphorsulfonyl chloride (299 mg, 1.19 mmol) were combined in CH2Cl2 (2 ml), treated with triethylamine (87 μl, 120 mg, 1.19 mmol), and the mixture was stirred at ambient temperature overnight. The mixture was chromatographed on a silica gel column eluted with 25% EtOAc in hexane and the product fractions were evaporated to dryness in vacuo to give N-(2-(1H-inden-3-yl)ethyl)-7,7-dimethyl-2-oxobicyclo(2.2.1)heptane-1-methanesulfonamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][C:14]=1[O:28][CH2:29][CH2:30][F:31])[C:5]2=[O:32].C(N(CC)CC)C.[C]=O.[C:42]([O:45][CH2:46][CH3:47])(=[O:44])C>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:46]([O:45][C:42]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][C:14]=1[O:28][CH2:29][CH2:30][F:31])[C:5]2=[O:32])=[O:44])[CH3:47]
Reactant: CCOC(C)=O
Reactant: Cc1nc2ccc(Br)cc2c(=O)n1-c1ccc(OCCCN2CCCC2)cc1OCCF
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2nc(C)n(-c3ccc(OCCCN4CCCC4)cc3OCCF)c(=O)c2c1
Yield: 63 %

Procedure:
6-bromo-3-{2-fluoroethoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone synthesized in Example 204 (37 mg), palladium(II) acetate (2 mg), dppf (1,1′-bis(diphenylphosphino)ferrocene) (8.2 mg) and triethylamine (22 mg) were mixed in ethanol (5 mL), and the atmosphere in the system was replaced by carbon monoxide. The mixture was then heated under reflux in the carbon monoxide atmosphere for 2 days. Ethyl acetate was added to the reaction liquid, and the solid precipitate was filtered off. The filtrate was concentrated, purified by silica gel thin layer chromatography (chloroform/methanol=10/1), and the title compound (23 mg, 63%) was thus obtained as a light gray solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of ethyl 1H-indole-2-carboxylate (5.68 g, 30 mmol), tert-butyl 2-bromoacetate (6.44 g, 33 mmol), and potassium carbonate in 60 mL of DMF was heated to 80° C. for 2 days. The TLC showed that the reaction stopped at around 50% completion. The reaction was worked up by the addition of water and the aqueous phase was extracted with EtOAc (2×30 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by Combiflash (40 g silica gel cartridge, 0-30% EtOAc in hexane) to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([N:21]([CH3:38])[C:22](=[O:37])[C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)=[C:17](I)[CH:16]=1.C([O-])(O)=O.[Na+]>C1COCC1.[Cl-].[Cl-].[Zn+2].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.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:17]2[CH:16]=[C:15]([Cl:14])[N:20]=[CH:19][C:18]=2[N:21]([CH3:38])[C:22](=[O:37])[C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:35])([F:36])[F:34])[CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Reactant: Clc1cccnc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-chloro-2-iodopyridine (94.2 mg, 393 μmol, CAS RN 77332-89-9) in THF (3 mL) was added isopropylmagnesium chloride (2M solution in THF, 197 μl, 393 μmol) at −40° C. and the reaction mixture stirred for 20 minutes at this temperature. Freshly prepared ZnCl2 solution (1M in THF, 1.57 mL, 1.57 mmol) was added at −40° C. The reaction mixture was allowed to warm to room temperature and was stirred for 90 minutes. A solution of N-(6-chloro-4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (200 mg, 393 μmol, Ex. 72, intermediate) in THF (3 mL) and tetrakis(triphenylphosphine)palladium(0) (22.7 mg, 19.7 μmol) was added. The reaction mixture was stirred for 1 hour at reflux. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). The product was further purified by preparative HPLC (phenomenex gemini column) with a gradient of acetonitrile:water (50:50 to 95:5). Colorless foam (85 mg, 44%). MS (ESI): m/z=494.025 [M+H]+.
Reaction SMILES: [CH:1]1[CH:13]=[CH:12][C:11]2[CH2:14][CH2:15][CH2:16][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13.[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[N+:17]([C:13]1[CH:1]=[C:2]2[C:10]3=[C:11]([CH2:14][CH2:15][CH2:16][N:9]3[C:8]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=3)[CH:12]=1)([O-:19])=[O:18]
Reactant: c1cc2c3c(c1)c1c(n3CCC2)CCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CCC2)CCCC1

Procedure:
Following the procedure of Example 1, step 2, 5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazole (1.7 g, 8.0 mmol) and potassium nitrate (0.80 g, 8.0 mmol) in concentrated sulfuric acid (20 mL) provided 2-nitro-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazole. MS (ES) m/z 257.1.