Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 60 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-nonyl chloroformate. Yield: 60% of theory, C36H45N7O5 (655.8) Rf value: 0.48 (silica gel; dichloromethane/methanol=9:1) ##EQU79##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@@H]2CCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@@H]2CCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.57 g (3.36 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydrofuran-2-yl]propanoate (mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysed with TFA according to General Method 6A. Yield: 1.41 g (purity 92%, 96% of theory)
Reaction SMILES: [C:1]12([C:11]3[CH:31]=[CH:30][C:14]([C:15]([O:17][NH:18][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][CH:25]=[CH:24]5)=[NH:20])=O)=[CH:13][C:12]=3[O:32][CH3:33])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1(C)C=CC=CC=1>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([C:19]3[N:20]=[C:15]([C:14]4[CH:30]=[CH:31][C:11]([C:1]56[CH2:2][CH:3]7[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]7)[CH2:8]5)[CH2:10]6)=[C:12]([O:32][CH3:33])[CH:13]=4)[O:17][N:18]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: COc1cc(C(=O)ONC(=N)c2ccc3[nH]ccc3c2)ccc1C12CC3CC(CC(C3)C1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc(-c3ccc4[nH]ccc4c3)no2)ccc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 96.2 %

Procedure:
The suspension of the product of Step C (0.13 g; 0.293 mmol) and 1 M TBAF in THF (0.3 ml; 0.3 mmol) in anhydrous toluene (5 ml) was refluxed for 1 h under N2, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.12 g; 99%) as a colourless solid. 1H-NMR (CDCl3) 1.78 (s, 6H); 2.01-2.16 (m, 9H); 3.96 (s, 3H); 6.66 (m, 1H); 6.98 (d, 1H, J=8.6 Hz); 7.26 (m, 1H); 7.36 (d, 1H, J=8.14 Hz); 7.48 (d, 1H, J=8.14 Hz); 7.68 (d, 1H, J=1.6 Hz; 7.77 (dd, 1H, J=1.6, 8.1 Hz); 8.01 (dd, 1H, J=1.6, 8.1 Hz); 8.32 (broad s, 1H); 8.51 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[O:12]1[C:20]2[CH:19]=[CH:18][NH:17][C:16](=[O:21])[C:15]=2[CH:14]=[CH:13]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:11][C:4]1[CH:3]=[C:2]([N:17]2[CH:18]=[CH:19][C:20]3[O:12][CH:13]=[CH:14][C:15]=3[C:16]2=[O:21])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=c1[nH]ccc2occc12
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-n2ccc3occc3c2=O)ccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 15 h
Yield: 108.6 %

Procedure:
4-Fluoro-2-methyl-1-nitrobenzene (2.3 mL, 19 mmol) was added to a suspension of furo[3,2-c]pyridin-4(5H)-one (2.115 g, 15.67 mmol) and Cs2CO3 (5.097 g, 15.67 mmol) in anhydrous DMF (100 mL) and the resulting suspension was heated to 125° C. and stirred for 15 h. H2O was added and the aqueous suspension was filtered. The solid was dried under reduced pressure to afford 4.6 g of crude 5-(3-methyl-4-nitrophenyl)furo[3,2-c]pyridin-4(5H)-one, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]([O:26]C)=[O:25])=[N:16]1.[OH-].[Na+].Cl>CCO>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[C:5]([F:14])=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]([OH:26])=[O:25])=[N:16]1
Reactant: COC(=O)c1nn(-c2cc(F)c(N3CCOCC3)cc2F)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(=O)O)c1=O
Yield: 95.9 %

Procedure:
A solution of methyl 1-(2,5-difluoro-4-morpholin-4-ylphenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (2.7 g, 7.1 mmol) and 2 M NaOH aqueous solution (7.2 mL, 14.4 mmol) in EtOH (14 mL) was stirred at room temperature for 16 h. To the mixture was added 1 M HCl aqueous solution (14 mL). The precipitate was collected by filtration and dried over under reduced pressure to give the title compound (2.5 g, 96% yield) as a white solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.00-3.24 (4H, m), 3.67-3.82 (4H, m), 3.88 (3H, s), 7.23 (1H, dd, J=12.7, 7.7 Hz), 7.74 (1H, dd, J=12.8, 7.2 Hz), 8.83 (1H, d, J=1.1 Hz), 14.95 (1H, brs). LC-MS (ESI) m/z 368 [M+H]+.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([OH:12])[CH2:9][CH2:10][OH:11].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>[Cl-].[Na+].O>[Cl:13][C:14]1[N:19]=[C:18]([O:11][CH2:10][CH2:9][CH2:8][OH:12])[CH:17]=[CH:16][N:15]=1
Reactant: OCCCO
Reactant: Clc1ccnc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCOc1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 14.7 %

Procedure:
To a round-bottom flask charged with NaH (336 mg, 8.29 mmol, 60% dispersion in mineral oil) and THF (100 mL), 1,3-propanediol (0.91 mL, 12.6 mmol) was added dropwise [H2 evolution] at rt. The reaction mixture was stirred for 30 min, then 2,4-dichloropyrimidine (5.0 g, 33.6 mmol) was added, and the reaction mixture was stirred for an additional 72 h. Brine was slowly added and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to provide the product (350 mg, 22%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.01 (qt, 2H), 2.43-2.52 (b, 1H), 3.76 (t, 2H), 4.51 (t, 2H), 6.63 (d, 1H), 8.25 (d, 1H) LC-MS: RT=1.05 min, (M+H)+ 189.1.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]([CH3:18])[CH:11]=[C:10]2[C:19]1[N:29]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:22]2=[N:23][CH:24]=[CH:25][C:26]([CH2:27]O)=[C:21]2[CH:20]=1.C(=O)([O-])O.[Na+]>CN(C=O)C.ClCCl>[Cl:3][CH2:27][C:26]1[CH:25]=[CH:24][N:23]=[C:22]2[N:29]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:19]([C:10]3[C:9]4[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:7]([O:6][CH3:5])[CH:8]=4)[N:12]([CH3:18])[CH:11]=3)=[CH:20][C:21]=12
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(-c3cc4c(CO)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(-c3cc4c(CCl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reaction time: 4 h

Procedure:
0.089 cm3 of thionyl chloride and five drops of DMF are added to a solution of 0.4 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-yl]methanol in 4 cm3 of dichloromethane, at a temperature in the region of 20° C. The reaction medium is stirred at this same temperature for 4 hours. Ice is added and the reaction medium is then neutralized with saturated sodium hydrogen carbonate solution. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/ethyl acetate 97.5/2.5 by volume as eluent), 0.234 g of 4-chloromethyl-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=O)[NH:6][CH:7]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1>[Cl:20][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: Cc1c[nH]c(=O)c([N+](=O)[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Clc1ccccc1
Product: Cc1cnc(Cl)c([N+](=O)[O-])c1
Yield: 75.3 %

Procedure:
A solution of 5-methyl-3-nitro-1H-pyridone (3.1 g, 20 mmol) in 50 mL chlorobenzene was treated with pyridine (0.47 g, 6.0 mmol) and phosphorus oxychloride (4.7 g, 30.8 mmol). The mixture was refluxed for 1 h. Upon cooling it was treated with sodium carbonate aq. followed by extraction with CH2Cl2. The organic phase was dried over Mg2SO4 and filtered. The solvent was evaporated in vacuo to give 2.6 g of the titled compound which was further purified by flash chromatography on silica gel (PE:EtOAc, 8:2, v/v). 1H-NMR (CDCl3) δ: 2.45 (s, 3H, CH3), 8.44 (d, 1H, J=2.0 Hz, Py-H), 8.58 (d, 1H, J=2.0 Hz, Py-H); MS (ESI+) m/z 173.0209 [M+H]+, C6H5ClN2O2 requires 172.0040.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]([CH2:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])[CH3:35])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([CH2:36][N:34]([C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])[CH3:35])[CH:38]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1cccc(C(=O)O)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Product: CN(Cc1cccc(C(=O)Oc2ccc(S(=O)(=O)CCN3CC[C@H](Cc4ccccc4)[C@H](O)C3)cc2)c1)C(=O)OC(C)(C)C
Yield: 70 %

Procedure:
The title compound was prepared from (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol and 3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-benzoic acid in 70% yield as a colorless gum.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=3)=[CH:11]/[CH2:12][OH:13])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O[C:22]1[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=3)=[CH:11]/[CH2:12][O:13][C:22]3[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: OC/C=C(\c1ccc(I)cc1)c1ccc(C2CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C3CC3)cc2)cc1C
Temperature: 0 °C

Procedure:
The above allyl alcohol (0.98 g, 2.60 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.545 g, 2.78 mmol; compound VÚFB-21004) and triphenylphosphine (0.782 g, 2.98 mmol) were dissolved in a mixture of anhydrous toluene (12 mL) and tetrahydrofuran (4 mL). The mixture was cooled to 0° C., kept under nitrogen and a degassed solution of diisopropyl azodicarboxylate (0.587 mL, 2.98 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was allowed to warm up to ambient temperature and then was stirred over night. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 8:1) affording methyl (Z)-[4-[3-(4-cyclopropylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]-acetate as solid mass.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[C:59]([N:63]1[C:67]([NH2:68])=[CH:66][C:65]([C:69]([CH3:72])([CH3:71])[CH3:70])=[N:64]1)([CH3:62])([CH3:61])[CH3:60].CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:59]([N:63]1[C:67]([NH:68][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:66][C:65]([C:69]([CH3:72])([CH3:71])[CH3:70])=[N:64]1)([CH3:62])([CH3:61])[CH3:60]
Reactant: CC(C)(C)c1cc(N)n(C(C)(C)C)n1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(Nc2ccc(S(=O)(=O)Nc3nccs3)cc2)n(C(C)(C)C)n1
Temperature: 150 °C
Yield: 24.6 %

Procedure:
To a mixture of 4-iodo-N-thiazol-2-yl-benzenesulfonamide (100 mg, 0.3 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol, 0.04 equiv), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (19 mg, 0.033 mmol, 0.12 equiv) and 2,5-di-tert-butyl-2H-pyrazole-3-ylamine (70 mg, 0.36 mmol, 1.2 equiv) in 4.0 mL of anhydrous 1,4-dioxane was added sodium tert-butoxide (100 mg, 0.90 mmol, 3.0 equiv). The vial was capped, and the reaction mixture was heated 30 min at 150° C. in the microwave. The crude reaction mixture was filtered through celite then concentrated in vacuo. The residue was dissolved in 0.5 mL of 1:1 dimethyl sulfoxide-acetonitrile then purified further via reverse phase HPLC. The appropriate fractions were lyophilized from water-acetonitrile to afford the product as an off-white solid (32 mg, 20%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([CH2:14][OH:15])[CH2:10][O:11][CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.O>[CH3:23][S:24]([O:15][CH2:14][CH:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:13][CH2:12][O:11][CH2:10]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1COCC=C1c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCC1COCC=C1c1cccc(Br)c1
Yield: 115.2 %

Procedure:
A 0° C. solution of (4-(3-bromophenyl)-3,6-dihydro-2H-pyran-3-yl)methanol (0.305 g, 1.08 mmol) in CH2Cl2 (10 mL) is treated with triethylamine (0.218 g, 2.15 mmol) and then methanesulfonyl chloride (0.148 g, 1.29 mmol) and the reaction is stirred at 0° C. for 30 min. The reaction is diluted with water and extracted with CH2Cl2. The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure to afford the title compound (0.432 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.51 (t, J=1.8 Hz, 1H), 7.44-7.41 (m, 1H), 7.31-7.29 (m, 1H), 7.25-7.21 (m, 1H), 6.18 (t, J=2.6 Hz, 1H), 4.33-4.31 (m, 2H), 4.20 (dd, J=1.5, 11.6 Hz, 2H), 4.14-4.08 (m, 1H), 3.72-3.68 (m, 1H), 3.01-2.98 (m, 1H), 2.95 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[N:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][N:33]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]5[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]=5[N:8]4[CH3:11])=[CH:4][CH:3]=3)[C:32](=[O:36])[CH:31]=2)=[N:28][CH:29]=1
Reactant: O=c1cc(-c2ccc(Cl)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 47 %

Procedure:
tert-Butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (200 mg, 0.549 mmol) and 4-(5-chloropyridin-2-yl)pyridin-2(1H)-one (87 mg, 0.42 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (97 mg, 47%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.5, 2.3 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.55 (overlapping dd, J=7.4 Hz, 2H), 7.36 (s, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.08 (dd, J=8.3, 1.6 Hz, 1H), 7.00 (dd, J=7.1, 1.8 Hz, 1H), 4.65 (s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[CH3:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]2)[CH:16]=[N:15][CH:14]=1>>[ClH:11].[CH3:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH:30][CH2:2][CH2:3][OH:4])[CH2:26][CH2:25]2)[CH:16]=[N:15][CH:14]=1
Reactant: BrCCOC1CCCCO1
Reactant: Cc1cncc2cccc(N[C@H]3CC[C@H](N)CC3)c12
Agent: Cl
Product: Cc1cncc2cccc(N[C@H]3CC[C@H](NCCO)CC3)c12

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 121 to obtain the title compound.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1.CI>O1CCCC1.CCCCCC.O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:1])[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
To a stirred solution of diisopropylamine (13.0 g) in tetrahydrofurane (160 mL) was added a solution of n-butyllithium in hexane (51.4 mL; c=2.5 M) at −78° C. The solution was stirred at 0° C. for 15 minutes. The solution was cooled to −78° C. and a solution of methyl (4-fluorophenyl)acetate (18.0 g), dissolved in tetrahydrofurane (40 mL) was added. The solution was stirred at −78° C. for 30 minutes. Methyl iodide (10.0 mL) was added at −78° C., and the solution was allowed to warm up to 0° C. within 1 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 18.9 g of the title compound.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:36]=[CH:35][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]5[O:30][C@@H:31]([CH3:34])[CH2:32][N:33]=5)=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21]C)[CH:17]=3)=[C:9]([F:37])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.ClCCl.C(=O)([O-])O.[Na+]>ClCCl>[N:1]1([C:5]([C:7]2[CH:36]=[CH:35][C:10]([O:11][C:12]3[CH:17]=[C:16]([CH:15]=[C:14]([C:24]4[NH:28][C:27]([C:29]5[O:30][C@@H:31]([CH3:34])[CH2:32][N:33]=5)=[CH:26][CH:25]=4)[CH:13]=3)[O:18][C@@H:19]([CH3:23])[CH2:20][OH:21])=[C:9]([F:37])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN=C(c2ccc(-c3cc(Oc4ccc(C(=O)N5CCC5)cc4F)cc(O[C@@H](C)CO)c3)[nH]2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
(5S)-2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazole (337.8 mg, 0.666 mmol) synthesized in Example (69b) was dissolved in dichloromethane (10 mL), and a boron tribromide/dichloromethane solution (1M, 1 mL, 1 mmol) was added at −78° C. under nitrogen atmosphere, followed by stirring at room temperature for 1 hour. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=2%-8%) to afford the desired compound (93.7 mg, yield 29%) as a pale yellow solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:3]=1.N([O-])=O.[Na+].[I-:22].[K+]>O.Cl>[I:22][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: COc1ccc(Cc2cc(N)ccc2C)cc1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(Cc2cc(I)ccc2C)cc1
Temperature: -2.5 °C

Procedure:
To a cooled (0 to −5° C.), stirred suspension of 4-amino-2-(4-methoxy-benzyl)-1-methyl-benzene (18.3 g) in water (70 mL) and concentrated hydrochloric acid (20 mL) is added a solution of sodium nitrite (5.8 g) in water (20 mL). The suspension is stirred until homogenous and then a solution of potassium iodide (14 g) in water (20 mL) is added. The cooling bath is removed and the solution is stirred at 40° C. for 1 h and at 70° C. for another 1.5 h. After cooling to ambient temperature, aqueous sodium thiosulfate solution is added and the resulting solution is extracted with ethyl acetate. The combined extracts are dried (sodium sulphate) and the solvent is evaporated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 19.1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=O)[CH2:3]1.CO[CH:13](OC)[CH2:14][NH2:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][C:2]1([CH3:1])[CH2:3][C:4]2[NH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:8])[CH2:7]1
Reactant: COC(CN)OC
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2cc[nH]c2C1
Temperature: 60 °C
Yield: 5.3 %

Procedure:
A solution of 5,5-dimethyl-1,3-cyclohexandione (30 g, 0.21 mol), aminoacetaldehyde dimethyl acetal (35 mL, 0.32 mol) and p-toluenesulphonic acid hydrate (1.5 g, 8 mmol) in toluene (250 mL) were heated at reflux for 4 h using Dean-Stark apparatus to remove the water. The toluene was evaporated and the residue dissolved in 3N HCl (250 mL). The solution was heated at 60° C. for 6 h. After this time the mixture was cooled to room temperature and extracted with DCM (6×). The combined organic layers were dried (MgSO4), evaporated and the residue chromatographed on silica gel, eluting with isohexane: EtOAc (4:1→1:1). The fractions containing the desired product were combined, evaporated and the residue triturated with ether. The title compound (1.8 g, 5%) was isolated as a cream solid. mp 177-178° C. 1H NMR (360 MHz, d6-DMSO) 8 1.02 (6H,s), 2.19 (2H,s), 2.63 (2H,s), 6.23 (1H,t, J=3.9 Hz), 6.71 (1H,t, J=3.9 Hz). MS (ES+) 164 (M+1).