Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:4]2[CH2:9][N:8]([C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]4[CH2:19][CH2:20][CH2:21][C:11]=34)[CH2:7][C@@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@@H:5]2[OH:30])[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH:1]1([C@H:4]2[CH2:9][N:8]([C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N+:13]([O-:39])=[C:12]4[CH2:19][CH2:20][CH2:21][C:11]=34)[CH2:7][C@@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C@@H:5]2[OH:30])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@H](C2CC2)[C@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C[C@H](C2CC2)[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
A solution of tert-butyl [(3R,4R,5S)-5-cyclopropyl-4-hydroxy-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (0.113 g, 0.270 mmol) in anhydrous DCM (2.5 mL) was cooled to 0° C. and mCPBA (0.080 g, 0.33 mmol, 4×0.020 g) was added portion-wise. After 15 min., the reaction mixture was allowed to warm to ambient temperature and was stirred for 2 h. The reaction was quenched by the addition of a solution of Na2S2O3 (0.051 g, 0.32 mmol) in water (1 mL) followed by 4 M aq. NaOH (1 mL). The layers were separated and the organic fraction was concentrated and purified by flash column chromatography (20 g silica gel column, eluting with 0-30% MeOH/EtOAc) to afford the sub-title compound (0.050 g, 43%). LCMS (ESI) m/z calc. for C21H31N4O6 435.2 [M+H]+. found 435.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]2[CH2:23][C:22](=O)[O:21][C:19](=[O:20])[CH2:18]2)[CH:14]=[CH:15][CH:16]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:22]([CH2:23][CH:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=3)[CH2:18][C:19]([OH:21])=[O:20])[NH:9][C:4]=2[CH:3]=1.[ClH:1]
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C1CC(c2cccc(Cl)c2)CC(=O)O1
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1cccc(Cl)c1

Procedure:
By a procedure similar to that of example 1.4, starting from 4-chloro-1,2-phenylenediamine and 3-(3-chlorophenyl)glutaric anhydride, 4-(5-chloro-2-benzimidazolyl)-3-(3-chlorophenyl)butanoic acid•HCl was obtained as light greyish solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH2:3][CH:4]=[CH2:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[O:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCC(O)c1ccc(C#N)cc1
Reactant: COc1ccc(O)cc1OC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: C=CCC(Oc1ccc(OC)c(OC)c1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A cooled (0° C.) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (14.6 g, 84.3 mmol) and 3,4-dimethoxyphenol (19.5 g, 125.4 mmol) in toluene (500 mL) was treated with tributylphosphine (32.14 mL of 97% purity, 25.6 g, 126.4 mmol), followed by 1,1′-(azodicarbonyl)dipiperidine (31.8 g, 126.4 mmol). After addition was complete, the reaction mixture thickened and the temperature rose to 15° C. Additional toluene was added (500 mL), and the mixture stirred at rt overnight. The precipitate of tributylphosphine oxide was then removed by filtration and the filtrate concentrated in vacuo to give 65.8 g of crude product. This was purified by chromatography on silica gel, eluting with toluene:methanol (98:2), to yield 17.9 g of the sub-title compound.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])[CH:17]=1
Reactant: OCc1ccc(Cl)cc1OCC(F)(F)F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2OCC(F)(F)F)c1
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 4.43 (2H, q, J=8.0 Hz), 5.26 (2H, s), 5.79 (1H, d, J=1.6 Hz), 6.91 (1H, d, J=1.6 Hz), 7.10 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.40 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.44 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.69 (1H, d, J=5.2 Hz). [M+H] Calc'd for C18H12ClF3N4O2, 409. Found, 409.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:13][C:12]=2[F:28])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:13][C:12]=2[F:28])=[CH:7][CH:6]=1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(CN=[N+]=[N-])cc3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CN)cc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A solution of 53 (7.16 g, 18.69 mmol) in tetrahydrofuran (THF) (100 mL) was treated with triphenylphosphine (PPh3, 5.88 g, 22.43 mmol, 1.2 equiv) and H2O (3.6 g, 3.6 mL, 0.2 mmol, 11.0 equiv) at 25° C., and the resulting reaction mixture was warmed to 50–55° C. for 12 h. When TLC and HPLC showed the reduction reaction was complete, the reaction mixture was cooled to room temperature before the solvents were removed in vacuo. The residue was directly purified by flash column chromatography (0–15% MeOH-CH2Cl2 gradient elution) to afford the desired N-[3-(4′-Aminomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 54 (5.82 g, 87% yield) as off-white crystals, which were of sufficient purity to be directly used in subsequent reactions. 1H NMR (300 MHz, DMSO-d6) δ 1.85 (s, 3H, COCH3), 3.04 (br. s, 2H, NH2), 3.44 (t, 2H, J=5.4 Hz), 3.78 (m, 3H), 4.18 (t, 1H, J=9.1 Hz), 4.77 (m, 1H), 7.25–7.60 (m, 7H, aromatic-H), 8.20 (t, 1H, J=5.8 Hz, NHCOCH3). LCMS (ESI) m/e 359 (M+2H)2+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[N:7][CH:8]=1)[CH3:2].BrN1C(=[O:17])CCC1=O.C([O-])([O-])=O.[K+].[K+].CO>CS(C)=O.O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][O:17]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1ccc(CC)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: CCc1ccc(C2CO2)nc1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a stirred solution of 400 g (2.974 mol) 5-ethyl-2-vinyl-pyridine dissolved in a mixture of 1000 mL of dimethyl sulfoxide and 106 mL water, was added 741.9 g (4.16 mol) N-bromosuccinimide at 0 to −5° C. Reaction mixture was stirred for 1 hr. The progress of reaction was monitored by TLC and after complete consumption of 5-ethyl-2-vinyl-pyridine, 833 g (6.015 mol) of K2CO3 along with 400 mL methanol was added at 25-30° C. Stirring was continued for 1 hr. and after subsequent work-up 358.49 g (80%) of the desired product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[C:10]1([CH:20]=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>CS(O)(=O)=O>[F:1][C:2]1[C:3](=[O:9])[CH:4]=[C:5]2[C:7](=[CH:8][C:7]3[C:5]([O:6]2)=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:8]=3)[C:20]=1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccc(F)c(O)c1
Reactant: O=Cc1cccc2ccccc12
Agent: CS(=O)(=O)O
Product: O=c1cc2oc3cc(O)c(F)cc3cc-2c(-c2cccc3ccccc23)c1F

Procedure:
Two equivalents of 4-fluororesorcinol (Compound 15) are condensed with one equivalent of naphthalene-1-carboxaldehyde in warm methanesulfonic acid. When the reaction is judged complete by TLC analysis, the intermediate product is precipitated from the reaction solution by the addition of an excess of water. The crude solid is collected on a Buichner funnel, and dried in vacuo. The intermediate is then dissolved in chloroform and treated with an excess of chloramine-T. When the oxidation reaction is complete, as judged by TLC, the volatiles are removed in vacuo and the crude product is purified using flash chromatography to give Compound 57.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH2:26]([NH2:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:26]([NH:28][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:23])[CH3:27]
Reactant: CCN
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2CC

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid ethylamide (70.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (150.0 mg), ethylamine (2.0 M solution in THF, 1.0 mL), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 401; and 1H NMR (DMSO-d6, 400 MHz): δ 8.44 (1H, m), 8.08 (1H, m), 7.95-7.92 (1H, m), 7.75-7.64 (2H, m), 7.53-7.51 (1H, m), 7.41-7.38 (1H, m), 4.21-4.19 (2H, m), 3.32-3.28 (2H, m), 1.34-1.32 (3H, t), 1.17-1.13 (3H, t), —NH proton signal was not observed.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccncc1
Solvent: CC(=O)O
Product: c1ccc2oc(-c3ccncc3)nc2c1
Temperature: 100 °C

Procedure:
A 500 mg portion of pyridine-4-aldehyde was dissolved in 15 ml of acetic acid, and the solution was mixed with 509 mg of o-aminophenol and stirred with heating at 100° C. for 6 hours. The solvent was concentrated under a reduced pressure, and the residual oily matter was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (90 mg) in light yellow color.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-:22].[K+].[K+]>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=2[C:11]([OH:12])=[O:22])=[CH:16][CH:15]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: [K+]
Product: Cn1nc(C(F)F)c(C(=O)O)c1Oc1ccc(Cl)cc1

Procedure:
The title compound was prepared using 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde and 4-chlorophenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.S(Cl)(Cl)=O.[CH3:17]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(F)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cc1OC
Yield: 70 %

Procedure:
To a solution of 4-fluoro-2-methoxybenzoic acid (1.7 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 48 mmol) at 0° C. The resultant mixture was stirred for 12 hours and then solvent was evaporated in vacuo. To the residue, saturated sodium bicarbonate aqueous solution (50 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3). The organic phase was dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 4-fluoro-2-methoxybenzoate (1.3 g, 70%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:37]=[CH:36][C:27]([CH2:28][O:29][C:30](=[O:35])[NH:31][CH:32]([CH3:34])[CH3:33])=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[CH:37]=[CH:36][C:27]([CH2:28][O:29][C:30](=[O:35])[NH:31][CH:32]([CH3:33])[CH3:34])=[CH:26][CH:25]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)NC(=O)OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc(COC(=O)NC(C)C)cc3)n2n1
Temperature: 140 °C
Yield: 138 %

Procedure:
A mixture of (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-butyl-amine (50 mg, 0.19 mmol), isopropyl-carbamic acid 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (from part A, ˜0.5 mmol), K2CO3 (77 mg, 0.56 mmol) and dichlorobis(triphenylphosphine)palladium(II) (6.5 mg, 0.01 mmol) in MeCN/water (2 ml/0.5 ml) was heated in a microwave at 140° C. for 10 min. The reaction was repeated with another half of the bronic ester from Part A. The two reactions were combined for purification. The water layer was removed and the reaction mixture was diluted with MeCN (3 ml) and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (100 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (t, J=7.39 Hz, 3H) 1.19 (d, J=6.62 Hz, 6H) 1.43-1.52 (m, 2H) 1.66-1.73 (m, 2H) 3.41 (td, J=7.06, 5.73 Hz, 2H) 3.87 (d, J=6.84 Hz, 1H) 4.49 (t, J=5.29 Hz, 1H) 5.14 (m, 1H) 6.45 (d, J=9.70 Hz, 1H) 7.46 (d, J=8.16 Hz, 2H) 7.66 (d, J=9.48 Hz, 1H) 7.81 (s, 1H) 8.14 (d, J=8.38 Hz, 2H). LRMS (ESI) m/z 382.2 [(M+H)]+, calc'd for C21H27N5O2: 381.48.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][OH:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1.CS(C)=O>CCOC(C)=O.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]=[O:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1
Reactant: OCc1nn(C2CCCCO2)c2cc(Cl)ccc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1nn(C2CCCCO2)c2cc(Cl)ccc12
Yield: 98 %

Procedure:
A solution of [6-Chloro-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-methanol (1.75 g, 6.58 mmol), IBX (2.76 g, 9.87 mmol) and DMSO (27 mL) was stirred overnight. The reaction was diluted in EtOAc and water. The layers were separated, and the aqueous was extracted with EtOAc (3×100 mL). The organics were combined and washed with saturated NaCl (100 mL). The organic was dried over MgSO4, filtered, and then concentrated to a solid. The solid was dissolved in CH2Cl2, and filtered. The organic was evaporated to yield the desired product (1.707 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[ClH:1].[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([NH:29][C:2]3[C:11]4[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:26][CH:27]=2)[CH:22]=[N:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ncnc2cc(I)ccc12
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Solvent: CC#N
Product: Cl
Product: Ic1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1
Yield: 76.7 %

Procedure:
Prepared according to Procedure A from 4-Chloro-7-iodoquinazoline (0.42 g) and 1-benzyl-1H-indazol-5-ylamine (0.323 g) in acetonitrile (20 ml) at reflux under nitrogen for 18 hours. The mixture was cooled and filtered to give the title compound (0.57 g); m/z (M+1+) 478.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H:46](NC(OC(C)(C)C)=O)[C:47]([NH:49][C@H:50](C(=O)NC1C=CN=CC=1)[C:51](C)(C)C)=O)C1C=CC=CC=1.C(C(NC(=O)[C@H](N1C=CC(C2C=CC([C:101]3[CH:106]=[CH:105][C:104]([C:107](=[O:109])[NH2:108])=[CH:103][CH:102]=3)=CC=2)=C1)CC(O)=O)CO)C1C=CC=CC=1>ClCCCl>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:101]3[CH:102]=[CH:103][C:104]([C:107](=[O:109])[NH2:108])=[CH:105][CH:106]=3)=[CH:33][CH:34]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][C:22]1[CH:51]=[CH:50][N:49]=[CH:47][CH:46]=1)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)Nc1ccncc1)C(C)(C)C
Reactant: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)O)C(=O)NC(CO)Cc4ccccc4)c3)cc2)cc1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Solvent: ClCCCl
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 36 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-[2,2-dimethyl-1(S)-(pyridin-4-yl)carbamoylpropyl]succinamic acid benzyl ester was deprotected. The crude amine salt and crude 3-(4′-carboxamidobiphenyl-4-yl)-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 4(b)) were condensed in wet 1,2-dichloroethane at 90-100° C. to yield 130 mg (36%) of 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(N-(pyridin-4-yl)carbamoyl)propyl]succinamic acid benzyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13](Br)[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cu][C:24]#[N:25]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:24]#[N:25])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: N#C[Cu]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C#N)c1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A mixture of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (990.0 mg, 2.54 mmol) and copper(I) cyanide (273.3 mg, 3.05 mmol) in dry N,N-dimethylformamide (2.5 mL) was heated under reflux for 4 h. The reaction was allowed to cool to 25° C., and the crude reaction mixture was directly purified without further chemical work-up. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 100% hexanes then 3/1 hexanes/ethyl acetate) afforded 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (646.5 mg, 76%) as a very light yellow oil: EI-HRMS m/e calcd for C17H21NO4S (M+) 335.1191, found 335.1185.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]1.[H-].[Na+].CS(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])[CH2:17][CH2:18]3)=[O:12])[N:8]2[CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:4][C:3]=1[O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: CCS(=O)(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)c(Br)cc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)c(Br)cc3n2CC(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of 144 mg (0.26 mmol) [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4-ethanesulfonyl-piperazin-1-yl)-methanone (example 10) in 3 mL N,N-dimethylformamide, were added 13 mg (0.29 mmol; 55% dispersion in mineral oil) sodium hydride. The reaction mixture was stirred 15 min at 70° C. 68 mg (0.29 mmol) 2,2,2-Trifluoroethyl methanesulfonate were added and the solution was stirred another 2 h at 70° C. After cooling to room temperature, the reaction was poured into water and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant, to afford 86 mg (52%) of the title compound as a light-yellow oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[H][H]>O.C(O)C.[Pd](Cl)Cl>[CH3:2][C:3]1[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:6]
Reactant: Cc1c(C(=O)c2ccc(F)cc2)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c(N)cccc1C(=O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 58.7 %

Procedure:
38 ml of hydrochloric acid, 23 g of activated carbon and 12 ml of a solution of 20% palladium chloride in water were added to a solution of 114.7 g of 2-methyl-3-nitro-4'-fluorobenzophenone in 1 liter of ethanol and then a current of hydrogen was passed therethrough for 3 hours. The reaction mixture was filtered and the filter was rinsed with ethanol. The filtrate was concentrated until crystallization began and was iced and then vacuum filtered. The precipitate was empasted with ethanol and dried under reduced pressure to obtain 59.5 g of 2-methyl-3-amino-4'-fluorobenzophenone in the form of white crystals melting at 170° C. Evaporation of the mother liquor and treatment with isopropyl ether gave another 50.5 g of product for a total of 110 g. For analysis, a sample of the product was crystallized from an aqueous solution of 5% hydrochloric acid and melted at 170° C.