Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=1.N1C=CC=CC=1.Cl>ClCCl>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([O:14][CH3:13])[CH:20]=2)=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1F
Reactant: COc1cc(N)ccn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NC(=O)c2cc(F)c(Cl)cc2F)ccn1
Temperature: 25 °C
Reaction time: 43 h
Yield: 87.6 %

Procedure:
A solution of 4-chloro-2,5-difluoro-benzoyl chloride (5 g, 23.70 mmol) in dichloromethane (25 mL) was added dropwise to a mixture of 2-methoxypyridin-4-amine (2.94 g, 23.70 mmol), pyridine (5.75 mL, 71.10 mmol) and dichloromethane (100.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature for 43 hours. The mixture was poured into 1N HCl (50 mL). The mixture was filtered using dichloromethane and the solid was isolated. The solid was dried under vacuum to yield 4-chloro-2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (6.2 g, 88%) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.16-8.05 (m, 1H), 7.97-7.75 (m, 2H), 7.29-7.15 (m, 2H), 3.85 (s, 3H) ppm. ESI-MS m/z calc. 298.03. found 299.3 (M+1)+; Retention time: 1.43 minutes (3 minutes run).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[CH:21]1([NH:26][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([F:13])([F:12])[F:1])=[CH:6][CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccc(NC2CCCC2)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a mixture of 3.94 g of 2,2,2,4′-tetrafluoroacetophenone (20.5 mmol) and 3.35 ml triethylamine (24.0 mmol) in 40 ml of acetonitrile at 0° C. were added 5.9 ml of cyclopentylamine (59.8 mmol). The reaction was allowed to warm to room temperature and then heated to reflux for 14 h. After this time the reaction mixture was cooled to room temperature, concentrated and partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica (hexanes:EtOAc, 4:1) to give the title compound. 1H-NMR (CDCl3) δ 1.53–1.57 (m, 2H), 1.69–1.78 (m, 4H), 2.08–2.13 (m, 2H), 3.88–3.95 (m, 1H), 4.63 (brs, 1H), 6.60 (d, J=8.9 Hz, 2H), 7.92 (d, J=8.9 Hz, 2H). Mass Spectrum (CI+) m/e=258.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]3)=[CH:22][CH:23]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc12
Yield: 53.5 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (about 0.663 mmol) obtained in the last step and triethylamine (1.0 mL) were dissolved in dichloromethane (15 mL). In an ice bath, a dichloromethane solution (10 mL) of 4-chlorobenzoyl chloride (117 mg, 0.669 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench. It was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was rotate evaporated. The resulting residue was chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 159 mg, at a total yield over two steps of reactions of 53.5%.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:5]=1>[OH-].[Na+]>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:7]2[C:8]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][C:6]=2[N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(N2CCCC2)c(Oc2ccc(C)cc2)c(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(Oc2c(N3CCCC3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The methyl ester obtained according to (e) is suspended in 1 N NaOH and heated on the steam bath until a clear solution has formed. The whole is filtered and acidified to pH 3. The 4-(4'-methylphenoxy)-3-(1-pyrrolidinyl)-5-sulphamoylbenzoic acid that has precipitated is recrystallised from methanol; light yellow crystals melting at 230°-233° C. with decomposition.
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH:14]2[CH:10]([C:11]([CH3:26])([CH3:25])[NH:12][CH:13]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](O)=O.C=O>[OH-].[Na+]>[CH2:1]([N:8]1[C:15](=[O:16])[CH:14]2[CH:10]([C:11]([CH3:25])([CH3:26])[N:12]([CH3:28])[CH:13]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: CC1(C)NC(Cc2ccc(Br)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C21
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1C(Cc2ccc(Br)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Temperature: 100 °C
Yield: 85.9 %

Procedure:
A mixture of 3.88 g (9.1 mmol) of (3aRS,4RS,6aSR)-2-benzyl-4-(4-bromo-benzyl)-6,6-dimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione, 85% formic acid (4.9 g, 90 mmol) and 35% formalin solution (2.6 g, 30 mmol) were heated to 100° C. for 5.5 hours. After cooling 1N NaOH (50 ml) was added and the mixture was extracted four times with dichloromethane. The organic phase was concentrated and the residue was separated chromatographically (hexane/ethyl acetate 3:1+1% triethylamine). 3.45 g of (3aRS, 4RS,6aSR)-2-benzyl-4-(4-bromobenzyl)-5,6,6-trimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione were isolated as a yellowish oil. FAB-MS: 441 ([M+H]+, 40); 271 (100); 212 (5); 169 (11); 136 (14); 110 (26); 91 (42).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C=O)C>[CH2:18]([NH:25][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1NCc1ccccc1
Temperature: 80 °C

Procedure:
To a stirring solution of 0.81 g (3.0 mmol) of the above 2-chloro-3-nitro-5-trifluoromethyl-benzoic acid in 6.0 mL of DMF was added 6.0 mL of TEA, followed by 3.0 mmol of Benzylamine. The mixture was heated at 80° C. for 6 h. After cooling to r.t., 3.0 mL of 6N HCl solution was added. The solid was collected, washed with fresh water to give 2-benzylamino-3-nitro-5-trifluoromethyl-benzoic acid. LCMS: 341 (M+1)+. This product was hydrogenated according to the general procedure C to give 0.25 g of 2,3-diamino-5-trifluoromethyl-benzoic acid. LCMS: 221 (M+1)+.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: COCC(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COCC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (39.0 mg, 0.075 mmol) in DCM (754 μL) at 0° C. was added triethylamine (31.5 μL, 0.226 mmol) and 2-methoxyacetyl chloride (13.8 μL, 0.151 mmol). The reaction was stirred at 0° C. for 30 min. The reaction mixture was concentrated under reduced pressure and was purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 55% to 80% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (14.0 mg, 31.5%). 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.30 (m, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.75 (t, J=5.7 Hz, 0.7H), 2.83 (t, J=5.7 Hz, 1.3H), 3.08 (m, 2H), 3.44 (m, 5H), 3.77 (t, J=5.8 Hz, 1.3H), 3.88 (t, J=5.9 Hz, 0.7H), 4.14 (m, 1H), 4.24 (s, 0.7H), 4.28 (s, 1.3H), 4.49 (td, J=7.1, 3.5 Hz, 1H), 4.56 (s, 0.7H), 4.63 (s, 1.3H), 6.88 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 476.5.
Reaction SMILES: Br[CH2:2][C:3]1[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH2:2][C:3]1[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH:20]2
Reactant: CCOC(=O)/C=C/c1ncccc1CBr
Reactant: Clc1ccc2[nH]ccc2c1
Product: CCOC(=O)/C=C/c1ncccc1Cc1cc2cc(Cl)ccc2[nH]1

Procedure:
The benzylic bromide of Step 2 (1.33 g; 4.91 mmol) was coupled with 5-chloroindole according to the procedure described in step 1 of example 2 to yield 1.22 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([O:29]CC)=[O:28].[OH-].[K+]>CCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of ethyl (1RS,2RS,3RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (90 mg, 0.22 mmol) in EtOH (2 ml) containing a few drops of THF was added 6M KOH (0.22 ml, 1.32 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted with EtOAc. The EtOAc extract was washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford the title compound (40 mg, 49%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:12])/[C:8](=[CH:10]/[CH3:11])/[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])/[C:8](=[CH:10]/[CH3:11])/[CH3:9]
Reactant: c1ccccc1
Reactant: C/C=C(\C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C(\C)C(=O)c1ccccc1

Procedure:
Benzene (1 mL), tigloyl chloride (236 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (126 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6]([Cl:15])=[C:7]([O:13][CH3:14])[O:8][C:9]2=[O:10])=[CH:4][CH:3]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:16]1([NH:22][C:23]([NH:1][C:2]2[CH:12]=[C:11]3[C:5]([C:6]([Cl:15])=[C:7]([O:13][CH3:14])[O:8][C:9]3=[O:10])=[CH:4][CH:3]=2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1oc(=O)c2cc(N)ccc2c1Cl
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1oc(=O)c2cc(NC(=O)Nc3ccccc3)ccc2c1Cl

Procedure:
This compound was prepared by reaction of 110 mg (0.5 mmol) of 7-amino-4-chloro-3-methoxyisocoumarin with 60 mg (0.5 mmol) of phenyl isocyanate at room temperature in CH2Cl2 for 24 h. After standard work-up, this isocoumarin was obtained as yellow crystals; mp 203°-204° C.; MS, m/e 344 (M+). Anal. Calc. for C17H13ClN2O4 : C, 59.23; H, 3.08; N, 8.13; Cl, 10.28. Found: C, 59.28; H, 3.82; N, 8.11; Cl, 10.35.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=C)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].COC1C=C(CC[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)C=CC=1C#N>>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C=CCc1ccc(C#N)c(F)c1
Reactant: COc1cc(CCN2CCNCC2)ccc1C#N
Product: N#Cc1ccc(CCN2CCNCC2)cc1F

Procedure:
2-Fluoro-4-[2-(piperazin-1yl)ethyl]benzonitrile was prepared from 2-fluoro-4-(prop-2-en-1-yl)benzonitrile (described above) in an analogous fashion to that described for 2-methoxy-4-[2-(piperazin-1-yl)ethyl]benzonitrile.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30]([CH:32]=1)[NH2:31])([CH3:25])=[O:24].[OH-].[Na+]>COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:31][C:30]2[CH:32]=[C:26]([P:23]([CH3:22])([CH3:25])=[O:24])[CH:27]=[CH:28][C:29]=2[O:33][CH3:34])=[N:3][CH:4]=1
Reactant: COc1ccc(P(C)(C)=O)cc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: COc1ccc(P(C)(C)=O)cc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 48.7 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as prepared in Example 17: 0.077 g, 0.22 mmol) in 1.5 mL of 2-methoxyethanol was added 5-(dimethylphosphoryl)-2-methoxyaniline (0.050 g, 0.21 mmol) as its hydrochloride salt. The mixture was heated in a sealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by prep-HPLC to afford the final compound (52 mg, 48% yield). MS/ES+: m/z=509.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:23][CH2:24]2)[C:6]=1[N:7]1[CH2:13][CH2:12][C@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:47]
Reactant: Nc1cnn(C2CC2)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: Cc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C4CC4)c3N3CC[C@H](N)[C@@H](F)CC3)c(N)s2)c1
Yield: 55 %

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-cyclopropyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxylic acid gave 277 as a yellow solid (228 mg, 55% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.07 (dd, J=7.3, 2.3 Hz, 1H), 7.48 (s, 1H), 7.24-7.19 (m, 1H), 7.11 (dd, J=11.4, 8.4 Hz, 1H), 4.49 (dtd, J=48.3, 8.8, 3.8 Hz, 1H), 3.56-3.48 (m, 1H), 3.47-3.34 (m, 4H), 3.23-3.13 (m, 1H), 2.41 (s, 3H), 2.35-2.21 (m, 1H), 2.19-2.06 (m, 1H), 2.01-1.91 (m, 1H), 1.84-1.72 (m, 1H), 1.19-1.10 (m, 2H), 1.11-1.04 (m, 2H). LCMS (ES+) m/z 488 (M+1)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[O:2]1.[CH3:13][N:14]([C:18](=[O:20])[CH3:19])[CH2:15]CO>>[CH3:13][N:14]([CH2:15][CH2:1][O:9][C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[OH:2])[C:18](=[O:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Reactant: CC(=O)N(C)CCO
Product: CC(=O)N(C)CCOc1ccc([N+](=O)[O-])cc1O
Temperature: 100 °C

Procedure:
0.1 mol (16.7 g) of 3,4-methylenedioxynitrobenzene is introduced into 67 ml of N-methyl-N-acetylethanolamine. The mixture is heated to the region of 100° C., with stirring, and 11 ml of 15N potassium hydroxide solution are then added. After stirring for 4 hours at 100° C., the reaction medium is poured onto 200 g of crushed ice. The unreacted starting material, which is insoluble in an alkaline medium, is removed by filtration. The filtrate is then brought to a pH of 5 with hydrochloric acid. The expected nitro product which has precipitated is filtered off. After washing with water, drying and recrystallization from a 50/50 ethyl acetate/ethanol mixture, the product melts at 158° C.
Reaction SMILES: [ClH:1].[NH2:2][OH:3].[C:4]1([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:3][NH:2][C:17](=[NH:18])[C:16]1[CH:19]=[C:12]([C:11]#[C:10][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:13]=[N:14][CH:15]=1
Reactant: N#Cc1cncc(C#Cc2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N=C(NO)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
Add hydroxylamine hydrochloride (0.55 g, 7.8 mmol) to a suspension of 5-phenylethynylnicotinonitrile (0.20 g, 0.98 mmol) and potassium carbonate (0.68 g, 4.9 mmol) and heat at reflux for 2 h. Cool the reaction mixture to room temperature, filter away any solids and concentrate. Purify by silica gel chromatography, eluting with 40:60 ethyl acetate:hexanes, to obtain the free base of the title compound as a white solid. Dissolve the free base in diethyl ether, add a 1 M solution of hydrogen chloride in diethyl ether (1.1 eq) and collect the resulting precipitated solids by filtration to give the title compound (0.1 g, 37%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:28][OH:29]>C(O)C>[Si:1]([O:8][CH2:9][CH:10]([NH:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]1[CH:12]=[CH:13][C:14]([C:17](=[N:28][OH:29])[NH2:18])=[CH:15][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)CNC(CO[Si](C)(C)C(C)(C)C)c1ccc(C#N)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC(CO[Si](C)(C)C(C)(C)C)c1ccc(C(N)=NO)cc1
Yield: 105.2 %

Procedure:
A solution of tert-butyl 2-(2-(tert-butyldimethylsilyloxy)-1-(4-cyanophenyl)ethylamino)acetate (0.496 g; 1.27 mmol) and 50% aqueous hydroxylamine (0.389 mL; 6.49 mmol) in ethanol (5 mL) was heated at 70° C. for 18 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was poured through a hydrophobic frit and evaporated in vacuo to afford the title compound (0.566 g, 100%). 1H NMR (CDCl3, 400 MHz) δ 7.59 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.00 (br s, 1H), 4.84 (br s, 2H), 3.84-3.81 (m, 1H), 3.68-3.57 (m, 2H), 3.25 (d, J=17.2 Hz, 1H), 3.08 (d, J=16.8 Hz, 1H), 2.60 (br s, 1H), 1.44 (s, 9H), 0.88 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1)#[N:2].[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH2:33][CH2:32]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([C:7]([C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:26]5[C:21](=[N:22][CH:23]=[CH:24][CH:25]=5)[NH:20][C:19]4=[O:27])[CH2:14][CH2:13]3)[CH:5]=1)=[O:9])[CH2:33][CH2:32]2
Reactant: N#Cc1ccc(C(=O)O)cc1N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)N2CCc3cc(F)ccc32)cc1N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
70 mg (0.19 mmol) 4-cyano-3-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-benzoic acid and 30 mg (0.21 mmol) 5-fluoro-2,3-dihydro-(1H)-indole in 0.10 mL (0.72 mmol) TEA and 1.5 mL DMF were mixed with 65 mg (0.20 mmol) TBTU and the mixture was stirred for 1 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([C:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=3)[N:19]([CH2:30][C:31]#[CH:32])[C:18]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH2:39][OH:40])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(CC)CC>C(Cl)Cl>[CH:11]1([C:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=3)[N:19]([CH2:30][C:31]#[CH:32])[C:18]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH:39]=[O:40])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: C#CCn1c(-c2ccccc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCn1c(-c2ccccc2C=O)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.5 eq., 2M solution in DCM) was added at −70° C. under N2— atmosphere to a solution of DMSO (5 eq.) in anhydrous DCM and the mixture was stirred for 30 min; a solution of methyl 3-cyclohexyl-2-[2-(hydroxymethyl)phenyl]-1-prop-2-yn-1-yl-1H-indole-6-carboxylate in DCM was then added and stirring was continued at the same temperature for 30 min. before NEt3 (8 eq.) was added. After stirring at 0° C. for 20 min. the mixture was diluted with DCM, washed with water, 1N HCl, saturated aq. NaHCO3 solution and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The obtained yellow solid was used in the next step without purification. MS (ES+): 400.5 (M+H+).
Reaction SMILES: I[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.C[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C)C=O>[CH3:32][Si:3]([CH3:33])([CH2:2][N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]1=[O:35])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Reactant: COc1ccccn1
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)Cn1ccccc1=O
Yield: 44 %

Procedure:
A solution of Compound 4 (60 mg) and 2-methoxypyridine (0.11 mL) in N,N-dimethylformamide (1 mL) was heated at 70° C. for 16 hours. The reaction mixture was concentrated under vacuum and the residue was directly eluted on a silica gel column using 4% ethanol in dichloromethane to obtain the required product in 44% yield (25 mg).