Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[N:54]([C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:55]([NH:54][C:57]2[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=2)=[O:56])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)Nc2cccnc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 93 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 3-isocyanatopyridine as the starting materials in 93% yield. LCMS for C29H29ClN9O2 (M+H)+: m/z=570.0.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[S:9])[CH3:2].Cl([O-])(=O)(=O)=O.[Cl:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[CH:25]N(C)C)[N+:17]=1[CH2:29][CH3:30]>C(N(CC)CC)C>[Cl:15][C:16]1[N:17]([CH2:29][CH3:30])[C:18]([CH:25]=[C:6]2[S:5][C:4](=[S:9])[N:3]([CH2:1][CH3:2])[C:7]2=[O:8])=[C:19]2[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: CC[N+]1=C(Cl)c2ccccc2C1=CN(C)C
Reactant: CCN1C(=O)CSC1=S
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(=Cc2c3ccccc3c(Cl)n2CC)SC1=S

Procedure:
This dye was prepared by the interaction of 3-ethyl-rhodanine and 3-chloro-1-dimethylaminomethylene-2-ethyl-1H-isoindolium perchlorate in the presence of triethylamine. The dye after purification by recrystallization from methanol melted at 119° C. MeOH λ max 505 nm.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:7]1[N:8]=[C:9]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[NH:10][C:11](=[O:20])[C:12]=1[CH:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[O:15])[CH3:6].[CH3:27]O>>[CH2:5]([C:7]1[N:8]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[NH:10][C:11](=[O:20])[C:12]=1[CH:13]([CH2:17][CH2:18][CH3:19])[C:14]([O:16][CH3:27])=[O:15])[CH3:6]
Reactant: CCCC(C(=O)O)c1c(CC)nc(N2CCCCC2)[nH]c1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCC(C(=O)OC)c1c(CC)nc(N2CCCCC2)[nH]c1=O

Procedure:
To a solution cold solution of methanol (40 mL) was added thionyl chloride (5.8 mL; 80 mmol) dropwise. The acidic solution was added to a flask containing 2-(4-ethyl-6-oxo-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoic acid (2.416 g; 7.86 mmol) and the mixture was heated to reflux for 18 h. The reaction mixture was concentrated under reduced pressure and the product was used as such in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2Cl)[CH2:7]3)=[CH:4][C:3]=1[F:15].[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH2:20]>CCCCO.O>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[NH:20][CH2:19][CH:18]([O:21][CH3:22])[O:17][CH3:16])[CH2:7]3)=[CH:4][C:3]=1[F:15]
Reactant: COC(CN)OC
Reactant: Fc1cc2c(cc1Br)C(Cl)=NC1CC2C1
Solvent: O
Solvent: CCCCO
Product: COC(CNC1=NC2CC(C2)c2cc(F)c(Br)cc21)OC
Temperature: 100 °C
Yield: 107.7 %

Procedure:
Into a 100-mL 3-necked round-bottom flask was placed a solution of 5-bromo-8-chloro-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene (3.75 g, 13.00 mmol, 1.00 equiv) in n-BuOH (50 mL) and 2,2-dimethoxyethan-1-amine (1.5 g, 14.27 mmol, 1.10 equiv). The resulting solution was stirred at 100° C. for 1.5, diluted with 50 mL of water and extracted with 1×50 mL of ethyl acetate. The organic layers were combined and concentrated under vacuum to afford 5.0 g (crude) of 5-bromo-N-(2,2-dimethoxyethyl)-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraen-8-amine as a yellow oil.
Reaction SMILES: [I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:6].[O-2].[O-2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:42]([CH3:43])=[CH:41][C:21]2[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][C:28](C4C=C5C(C=NN5C)=CC=4)=[N:29][CH:30]=3)[S:24][C:20]=2[C:19]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[CH2:16][OH:17])([CH3:13])([CH3:12])[CH3:11].[C:51](#[N:53])[CH3:52]>O>[I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:14].[O-2:6].[O-2:2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:42]([CH3:43])=[CH:41][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[N:29][CH:28]=[C:27]([C:18]4[CH:15]=[C:52]5[C:21](=[CH:20][CH:19]=4)[N:22]([CH3:23])[N:53]=[CH:51]5)[CH:26]=3)[S:24][C:20]=2[C:19]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:16]([OH:17])=[O:6])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc2nc(-c3ccc(-c4ccc5cnn(C)c5c4)nc3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: CC#N
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Product: Cc1cc2nc(-c3cncc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H2O) to a volume of 114 mL. This stock solution (0.3 mL) was added to a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-6-yl)pyridin-5-yl)benzo[d]thiazol-6-yl)ethanol (15 mg, 0.027 mmol) in 0.75% H2O in ACN (3 mL). The reaction mixture was stirred at room temperature for 45 minutes, quenched with saturated Na2SO3 solution and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated and purified by reverse phase HPLC (H2O/ACN+0.1% TFA) to give the desired product after lyophilization. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.2 (M+H+); found: 597.2, 599.2. 1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1H), 8.98 (s, 1H), 8.67 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.83 (dd, J=8.8, 1.6 Hz, 1H), 7.73 (dd, J=13.4, 5.2 Hz, 2H), 7.60 (d, J=8.0 Hz, 3H), 5.27 (s, 1H), 4.11 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H) (115).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:41][O:42][Si](C)(C)C)[C:8]([O:39][CH3:40])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:38])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+]>ClCCl.C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:41][OH:42])[C:8]([O:39][CH3:40])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:38])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(CO[Si](C)(C)C)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
270 mg of (S)-1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(5-tert-butyl-2-methoxy-3-trimethylsilanyloxymethyl-phenyl)-amide are dissolved in 5 ml dichloromethane, mixed with 833 μl of a 5 M solution of hydrogen chloride in isopropanol and stirred for 30 minutes at ambient temperature. The mixture is divided between dichloromethane and saturated aqueous sodium hydrogen carbonate solution, the aqueous phase is extracted twice with dichloromethane and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the product thus obtained is purified by preparative HPLC (method 3).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[C:7](/[CH2:9]P(OCC)(OCC)=O)\[CH3:8])=[O:5].[Li]CCCC.[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH:26]=O>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:2]([O:3][C:4](=[O:5])[CH:6]=[C:7]([CH3:8])[CH:9]=[CH:26][C:25]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:24]=1[Cl:23])[CH3:1]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C=C(C)C=Cc1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
Triethyl 3-methyl-4-phosphonocrotonate (34.24 g, 0.129 mol, 1.3 eq) was dissolved in THF/DMPU (100 mL/200 mL) and the mixture was cooled to −78° C. BuLi (51.8 mL of a 2.5M solution in hexanes, 1.3 eq) was added dropwise. The mixture was stirred for 20 min and then a solution of 2,4-dichlorobenzaldehyde (17.6 g, 0.1 mol) in THF/DMPU (20 mL/40 mL) was added dropwise. The resulting mixture was stirred for 1 hour and then allowed to warm to room temperature. NH4Cl(sat) was added and the mixture extracted with EtOAc. The organic layers were washed with, water, brine, and dried (MgSO4). Removal of solvent under reduced pressure followed by silica gel chromatography (0-1-2-3% EtOAc in hexanes) gave 23.3 g of 5-(2,4-dichlorophenyl)-3-methylpenta-2,4-dienoic acid ethyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:6]([F:14])[CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:6]([F:14])[CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(S(N)(=O)=O)c(F)c1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(C(=O)CBr)cc1F
Temperature: 70 °C
Yield: 60 %

Procedure:
To a suspension of 4-acetyl-2-(fluoro)benzenesulfonamide from step1(4.0 g, 18 mmol) in acetic acid (90 mL) was added dropwise a solution of bromine (2.9 g, 18 mmol) in acetic acid (10 mL) at 40° C. The mixture was heated at 70° C. for 4 h. After cooled to room temperature, the mixture was concentrated and the residual brown solid was rrecrystallized from ethyl acetate-hexane to give the title compound (3.2 g, 60%).
Reaction SMILES: [C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[N:15]([CH2:28][OH:29])[C:14]2=[O:30])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[CH2:31]([O:38][P:39](N)(=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1C=NN=N1.ClC1C=CC=C(C(OO)=O)C=1>O1CCCC1.ClCCl>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[N:15]([CH2:28][O:29][P:39](=[O:48])([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:38][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:14]2=[O:30])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C(=O)N1CO
Reactant: NP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C(=O)N1COP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(±)-Trans-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-1-hydroxymethyl-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione (0.06 g) in anhydrous tetrahydrofuran (5 ml) was treated with dibenzylphosphoramidate (0.156 ml, 3.5 equivalents) followed by the addition of tetrazole (3% solution in acetonitrile, 2 ml). The reaction mixture was stirred at room temperature for 20 min and cooled to −78° C. A solution of m-chloroperbenzoic acid (70%, 0.162 g) in dichloromethane (2 ml) was added at −78° C. After 5 min at −78° C., the reaction was brought to room temperature and stirred for 5 min Solvents were removed under reduced pressure and the residue was purified by flash chromatography on a silica column, eluted with ethyl acetate, hexane to give phosphoric acid dibenzyl ester trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-dioxo-pyrrolidin-1-ylmethyl ester as a solid (70 mg). 1H NMR (DMSO-d6) 400 MHz δ: 11.10 (s, 1H), 7.32-7.39 (m, 12H), 6.84-7.24 (m, 2H), 5.49 (brs, 2H), 5.03 (m, 4H), 4.61 (dd, 2H), 4.06 (brs, 2H), 2.87 (brs, 2H), 2.07 (brs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([OH:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Oc1ccc(Br)cc1-c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2cc(Br)ccc2OCc2ccccc2)cc1

Procedure:
A solution of 5-bromo-4′-fluoro[1,1′-biphenyl]-2-ol (7.00 g), potassium carbonate (3.80 g) and benzyl bromide (3.27 ml) in DMF (10 ml) was stirred at 60° C. for 5 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chomatography (eluent; hexane→hexane:ethyl acetate=10:1) to give the title compound (8.31 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12](Br)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)O1>C(COC)OC.O>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: COc1ccc(CNc2ncc(Br)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CNc2ncc(-c3cccnc3)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Temperature: 120 °C

Procedure:
A solution of N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine (50 mg, 0.116 mmol) in dimethoxyethane (0.5 mL) and water (0.5 mL) was degassed with nitrogen while adding NaHCO3 (30 mg, 0.347 mmol), and palladium tetrakis triphenylphosphine (13 mg, 0.012 mmol). 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (28 mg, 174 mmol) was added under nitrogen and the mixture was heated to 120° C. overnight. The reaction mixture was concentrated and taken up in ethyl acetate, filtered through silica with ethyl acetate eluant, and the filtrate concentrated to provide N-(4-methoxybenzyl)-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)-5-(pyridin-3-yl)pyridin-2-amine, which was used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1)#[N:2].C(O)(=O)C>C(O)C.O.[Zn]>[C:1]([C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4=NO)nc2c1
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4N)nc2c1

Procedure:
In a 100 ml round-bottomed flask under an argon atmosphere, dissolve 1.58 g of an equimolar mixture of 4-(5-cyano-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 10 ml of ethanol and 10 ml of water and 10 ml of acetic acid, at room temperature, add 1.2 g of zinc in three stages, and stir for approximately one hour to two hours between each addition. Add Celite and filter. The filtrate is concentrated under pressure. The crude product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (9/1 by volume) and then a mixture of dichloromethane and ammonia as a 7N solution in methanol (95/5 by volume). In this way, we obtain 1.4 g of 4-(5-cyano-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a white powder, which is used as it is in the following stage.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:16]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:16]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccco2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1coc(-c2cccc3c2OCCNC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of tert-butyl 9-(2-furyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (150 mg, 0.476 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (100 mg, 83.3%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].[F:14][C:15]([F:20])([F:19])[CH2:16][CH2:17]I>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([CH2:17][CH2:16][C:15]([F:20])([F:19])[F:14])[N:7]=1)=[O:5])[CH3:2]
Reactant: FC(F)(F)CCI
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Product: CCOC(=O)c1nn(CCC(F)(F)F)cc1[N+](=O)[O-]
Yield: 15 %

Procedure:
The product was obtained according to the method described in example 4, step 2 starting from 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester and 1,1,1-trifluoro-3-iodo-propane as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 141 mg (31%) of the desired regioisomer and 68 mg (15%) of 4-nitro-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:20])=[C:11]([CH:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]3=[O:19])[N:12]=2)=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:20])=[C:11]([C:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]=3[O:19][CH3:21])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Temperature: 40 °C
Yield: 66.6 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-cyclopentane-1,3-dione (1.12 g, 3.66 mmol) in acetone (20 ml) was added potassium carbonate (1.04 g, 7.32 mmol), followed by iodomethane (455 μl, 7.32 mmol), and the reaction heated to 40° C. for 6 hours. The solvent was then removed from the crude reaction mixture under reduced pressure and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (780 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:7]=1>ClCCl.[O-2].[O-2].[Mn+4]>[O:20]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]1[CH2:10][CH2:9][CH2:8][N:6]1[CH:7]=[C:3]([CH:2]=[O:1])[N:4]=[N:5]1
Reactant: O=C1c2ccccc2C(=O)N1CCCn1cc(CO)nn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cn(CCCN2C(=O)c3ccccc3C2=O)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
A solution of the regioisomers 21 (0.77 g, 2.69 mmol) in dichloromethane (10 mL) was treated with manganese dioxide (0.94 g, 10.77 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through Celite and concentrated. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.24 g (31% yield) of 22 as a single regioisomer: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.34 (s, 1H), 7.85-7.65 (m, 4H), 4.45 (t, J=12.0 Hz, 2H), 3.77-3.71 (m, 2H), 2.42-2.34 (m, 2H); ESI+ MS: m/z (rel intensity) 285.0 (100, [M+H]+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([OH:31])[CH:25]=2.[C:32]([C@@H:36]1[CH2:41][CH2:40][C@H:39](O)[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33].C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:32]([C@H:36]1[CH2:41][CH2:40][C@H:39]([O:31][C:26]2[CH:25]=[C:24]3[C:29]([CH:30]=[C:21]([CH3:20])[N:22]=[CH:23]3)=[CH:28][CH:27]=2)[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: Cc1cc2ccc(O)cc2cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc2cn1
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (5.14 g, 19.6 mmol) was added to a solution of 3-Methyl-isoquinolin-7-ol (2.08 g, 13.1 mmol) and cis-4-tert-butylcyclohexanol (3.06 g, 19.6 mmol) in Toluene (60 mL, 600 mmol). The mixture was stirred for 15 minutes then Diisopropyl azodicarboxylate (3.86 mL, 19.6 mmol) was added. The mixture was then stirred at room temperature overnight. The solvent was removed under vacuum. The crude product was dissolved in methylene chloride, adsorbed onto silica gel and purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound in 52% yield. ESI-MS(M+H+): 298.46.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH3:17])=[C:11]([CH:14]=[CH2:15])[CH:12]=2)[O:7][C:6]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:4]>[OH-].[OH-].[Pd+2].C(OCC)(=O)C.CO>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH3:17])=[C:11]([CH2:14][CH3:15])[CH:12]=2)[O:7][C:6]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)=[O:4]
Reactant: C=Cc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1N(C)S(C)(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1N(C)S(C)(=O)=O

Procedure:
To 2-(4-Fluoro-phenyl)-6-(methanesulfonyl-methyl-amino)-5-vinyl-furo[2,3-b]pyridine-3-carboxylic acid methylamide (11 mg, 0.027 mmol) was added 8 mg of 20% Pd(OH)2/C and ethyl acetate/methanol 5/1 (5 ml). The reaction flask was evacuated and filled with hydrogen gas from a balloon. After LCMS indicated conversion to product, the reaction mixture was filtered, evaporated to dryness and purified by HPLC to afford 5-Ethyl-2-(4-fluoro-phenyl)-6-(methanesulfonyl-methyl-amino)-furo[2,3-b]pyridine-3-carboxylic acid methylamide. MS (ESI) m/z 406.3 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 1H), 7.96-7.92 (m, 2H), 7.25-7.20 (m, 2H), 5.79 (br s, 1H), 3.32 (s, 3H), 3.19 (s, 3H), 2.99-2.98 (d, 3H), 2.96-2.91 (q, 2H), 1.33-1.29 (t, 3H).