Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:31])=[C:5]1[C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C2C=C3C(=CN(Cc4ccccc4)C(C(=O)NCCC(=O)O)=C3O)NC2=O)cc1
Temperature: 25 °C
Yield: 146 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.072 mmol), β-alanine (854 mg, 9.6 mmol) and NaOMe solution (14.4 mL, 7.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound. MS: (+) m/z 474.30 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8](=[NH:37])[C:9]1[S:10][C:11]([S:35][CH3:36])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[CH:24]=3)[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8](=[NH:37])[C:9]1[S:10][C:11]([S:35][CH3:36])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])[CH:24]=3)[CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(C(O)C(F)(F)F)c2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(C(=O)C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
In a reaction vial, (imino-{5-methylsulfanyl-4-[3′-(2,2,2-trifluoro-1-hydroxy-ethyl)-biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (30 mg, 0.051 mmol, as prepared in Example 28, step c) and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (31 mg, 0.072 mmol, Lancaster Synthesis, Windham, N.H.) were dissolved in DCM (2 mL). To that solution, wet DCM (1 mL, 4 μL H2O) was added slowly via a syringe. After 1 hr of stirring at rt, the reaction was evaporated and the residue was partitioned between Et2O (30 mL) and 10% Na2S2O3-saturated NaHCO3 (1:1, 15 mL). The aqueous layer was washed with an additional portion of Et2O. The combined organic washes were dried with MgSO4 and concentrated in vacuo to give 30 mg (quantitative yield) of the title compound that was used without purification. 1H-NMR (CDCl3; 400 MHz) δ 8.28 (br s, 1H), 8.26 (t, 1H, J=1.7 Hz), 8.08–8.13 (m, 1H), 7.99–8.04 (m, 1H), 7.96 (s, 1H), 7.91–7.95 (m, 1H), 7.82–7.86 (m, 1H), 7.62–7.71 (m, 2H), 2.59 (s, 3H), 1.51 (s, 9H). 19F-NMR (CDCl3; 400 MHz) δ −84.93 (s). ESI-MS (m/z): Calcd. for C25H23F3N2O5S3: 487.6 (M+H); found: 487.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH3:9][C:10](C)([CH3:14])[C:11](O)=O.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O>S(=O)(=O)(O)O.O.[N+]([O-])([O-])=O.[Ag+]>[C:10]([C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=1)([CH3:14])([CH3:11])[CH3:9]
Reactant: CC(C)(C)C(=O)O
Reactant: N#Cc1ccncc1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CC(C)(C)c1cc(C#N)ccn1
Yield: 42.3 %

Procedure:
A mixture of 4-cyanopyridine (10 g, 96 mmol), trimethylacetic acid (9.8 g, 96 mmol), and silver nitrate (1.63 g, 9.6 mmol) in 10% aqueous sulfuric acid (100 ml) at 70° C. was treated with a solution of ammonium peroxodisulfate (21.9 g, 96 mmol) in water (120 ml) according to the method of Description 10. Purification by column chromatography on silica eluting with 10% Et2O in iso-hexanes gave the title compound (6.5 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.N1C=CC=CC=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl>[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35]([N:19]1[CH2:18][CH2:17][C:16](=[C:15]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]3[CH:22]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:36]
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Reactant: O=C(Cl)Cc1cccs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cccs1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
To a solution of 1.0 gm (3.22 mmole) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine and 0.29 mL of pyridine in 20 mL of dry CH2Cl2 at 0° C. and under an argon atmosphere was added dropwise 0.438 mL (3.55 mmol) of 2-thiopheneacetyl chloride. After 30 minutes the mixture was washed with 1.0 N aqueous NaOH and then brine. The organic portion was dried over Na2SO4, filtered and converted in vacuo to provide a residue which was purified via flash chromatography (3% MeOH in CH2Cl2) and treated with activated carbon to provide the title compound as a glass.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:6]=1)C.O.Cl>[OH-].[Na+]>[CH2:23]([NH:22][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([OH:26])=[O:3])[CH:24]=[CH2:25]
Reactant: C=CCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 24 h

Procedure:
Ethyl-3-allylamino-4-phenoxy-5-sulphamyl-benzoate (1 g) was dissolved in 1N sodium hydroxide (15 ml) and left standing at room temperature for 24 hours. Then water (5 ml) was added, and the pH was adjusted to 3 by the addition of 4N hydrochloric acid. The precipitated 3-allylamino-4-phenoxy-5-sulphamyl-benzoic acid was collected and dried. The melting point was 233°-225° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:10]=2[C:11]#[N:12])[CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:10]=2[C:11]#[N:12])[CH:7]=1
Reactant: Nc1ccccc1B(O)O
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(Br)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(-c3ccccc3N)cnc12
Temperature: 80 °C
Yield: 62 %

Procedure:
A mixture of 6-bromo-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (500 mg, 1.28 mmol), 2-aminophenylboronic acid (175 mg, 1.28 mmol), Cs2CO3 (623 mg, 1.92 mmol) and Pd(PPh3)4 (74 mg, 0.06 mmol) in 1,4-dioxane (30 mL) and water (1.0 mL) was heated to 80° C. for 16 hr under N2. The mixture was filtered and the filtrate was concentrated and purified by chromatography column on silica gel using 50% of EA in PE as eluant to give the crude product (320 mg, 59.1%) as a yellow solid. MS (ESI, m/e) [M+1]+ 403.9.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([N:11]1[CH2:12][C:13](=[O:14])[N:9]([CH2:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:10]1=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CNC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccccc2)C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
A solution of the product from step (a) (5.9 g) in DMF (15 ml) was added under N2 to a stirred suspension of anhy. K2CO3 (3.5 g) in DMF (15 ml), followed by the addition of benzyl bromide (4.3 g, Aldrich). After additions were complete, the mixture was stirred at room temperature for 16 hours, then poured into ice-water and extracted with ethyl acetate (×3). The combined extracts were washed with brine, dried over MgSO4 and evaporated to give a yellow oil which was flash chromatographed through a silica column using ethyl acetate to give the desired product as a yellow oil (7.0 g).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:27][C:28]1[C:36]2[O:35][CH2:34][C:33](=[O:37])[C:32]=2[CH:31]=[CH:30][C:29]=1[O:38][CH3:39]>C1COCC1.O>[CH3:39][O:38][C:29]1[CH:30]=[CH:31][C:32]2[C:33](=[O:37])[CH2:34][O:35][C:36]=2[C:28]=1[CH2:27][CH:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc2c(c1CBr)OCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1CC(C(C)=O)C(C)=O)OCC2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.3 %

Procedure:
A solution of acetylacetone (0.100 g, 1.00 mmol) in THF (2.5 mL) was added with a 1 M solution of tetrabutylammonium fluoride in THF (1.00 mL, 1.00 mmol) and water (1 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with a solution of 7-(bromomethyl)-6-methoxybenzofuran-3(2H)-one (0.257 g, 1.00 mmol) in THF (2 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added with a 1 M solution of tetrabutylammonium fluoride in THF (1.00 mL, 1.00 mmol), and the mixture was stirred at room temperature for additional 5 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 3[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]pentane-2,4-dione (0.0533 g, 19%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[NH:13]1[CH:17]=[N:16][C:15]([C:18]#[N:19])=[N:14]1>N1C=CC=CC=1.CCOC(C)=O.[Cu]I>[CH3:12][O:11][C:5]1[CH:4]=[N:3][C:2]([N:13]2[CH:17]=[N:16][C:15]([C:18]#[N:19])=[N:14]2)=[C:7]2[NH:8][CH:9]=[CH:10][C:6]=12
Reactant: N#Cc1nc[nH]n1
Reactant: COc1cnc(Cl)c2[nH]ccc12
Agent: [Cu]I
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cnc(-n2cnc(C#N)n2)c2[nH]ccc12
Temperature: 150 °C
Yield: 38 %

Procedure:
7-Chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridine (4 g, 21.90 mmol), 1H-1,2,4-triazole-3-carbonitrile (6.18 g, 65.7 mmol) and copper (I) iodide (1.252 g, 6.57 mmol) were combined in pyridine (6 mL) in a sealed tube. The mixture was heated to 150° C. for 6 hrs. After cooling to room temperature, the mixture was diluted with EtOAc (3000 mL), washed with 5% NaHCO3 (100 mL), brine (100 mL) and concentrated. The residue was purified by silica gel column using 30% EtOAc in hexanes mixture to give 1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazole-3-carbonitrile (2 g, 8.33 mmol, 38.0% yield). LCMS: m/z 241.1 (M+H), 1.67 min (method 8).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@@H:7]([CH:26]([CH3:28])[CH3:27])[NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C:23](=[O:25])[CH3:24])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[C@@H:7]([CH:26]([CH3:27])[CH3:28])[N:8]([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C:23](=[O:25])[CH3:24])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)ccc2c1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1ccc2cc(S(=O)(=O)N(CCC(C)C)[C@@H](C(=O)OC(C)(C)C)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a solution of N-(6-acetoxy naphthalene-2-sulfonyl)-D-valine tert-butyl ester (3.15 g, 7.48 mmol) in N,N-dimethylformamide (15 mL) is added potassium carbonate (3.09 g, 22.36 mmol), followed by 1-bromo-3-methyl butane (1.79 mL, 14.94 mmol), and the reaction is allowed to stir at ambient temperature for 16 h. Another equivalent of 1-bromo-3-methyl butane (0.9 mL, 7.5 mmol) is added and the reaction is allowed to stir for 16 h at ambient temperature. The reaction is poured over water and extracted three times with dichloromethane. The combined organic extracts are washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by column chromatography and eluted with a gradient of 2-7% (hexanes-ethyl acetate) to afford the title compound as a yellow oil (2.5 g, 68% yield), along with N-isoamyl-N-(6-(3-methylbutoxy)naphthalene-2-sulfonyl)-D-valine tert-butyl ester as a yellow oil (0.3 g, 7.7% yield). LCMS (m/z): (492.26; M+1).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=1.O>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:3]2[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]3/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/3)[CH2:5][CH2:4]2)=[CH:29][CH:28]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added potassium carbonate (345 mg) and 1-chloro-4-(chloromethyl)benzene (103 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (110 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH:21][S:22]([CH:25]4[CH2:27][CH2:26]4)(=[O:24])=[O:23])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].FC(F)(F)C1C=CC(C2C3CCC(N)C=3C=NC=2)=CC=1>>[F:11][C:8]([F:9])([F:10])[C:7]1[CH:6]=[CH:5][C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH:21][S:22]([CH:25]4[CH2:27][CH2:26]4)(=[O:23])=[O:24])[C:16]=3[CH:15]=[N:14][CH:13]=2)=[CH:3][CH:2]=1
Reactant: O=S(=O)(NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21)C1CC1
Agent: NC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Product: O=S(=O)(NC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21)C1CC1
Yield: 4 %

Procedure:
In analogy to the procedure described for the preparation of (rac)-cyclopropanesulfonic acid [4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-amide (example 91), replacing (rac)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-ylamine with (rac)-4-(4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-ylamine (example 93). The title compound was obtained as a light brown oil in 4% yield. MS: 383.4 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[S:20][CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.Cl.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]([NH:8][C:1]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:10])=[C:12]1[S:20][CH3:21]
Reactant: CSc1[nH]c2ccccc2c1C(=O)NCc1ccccc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CSc1c(C(=O)Nc2ccccc2)c2ccccc2n1CCCN(C)C

Procedure:
A solution of 2-(methylthio)-N-phenyl-1H-indole-3-carboxamide [XXV: R8 =H] (1.8 g, 6.4 mmol) in EtOH (400 mL) was treated with 3-(dimethylamino)propyl chloride hydrochloride (10.0 g, 64 mmol) and K2CO3 (13 g, 96 mmol ) and heated under reflux for 3 hours. A further 10 equivalents of the reagents were then added, and the mixture was heated under reflux for a further 48 hours. EtOH was removed under reduced pressure, and the residue was diluted with water to give crude product. This was chromatographed on alumina, eluting with CH2Cl2 containing 0.2% MeOH, to give 1-[3-(dimethylamino)propyl]-2-(methylthio)-N-phenyl-1H-indole-3-carboxamide [XXVI: R8 =H, R9 =(CH2)3NMe2 ] (0.49 g, 21%) as an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[C:1]1([CH2:7][C:8](=[NH:9])[O:13][CH2:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: N#CCc1ccccc1
Agent: Cl
Product: CCOC(=N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
2-Phenylacetonitrile was dissolved in anhydrous ethanol (2 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 2-phenylacetimidate hydrochloride (1.7 g, 99%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.36-7.35 (m, 5H), 4.39 (q, J=7.0 Hz, 2H), 3.99 (s, 2H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:17]([OH:19])=O.[CH3:20][O:21][C:22](=[O:44])[C@@H:23]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:24]([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH3:20][O:21][C:22](=[O:44])[C@@H:23]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:17]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([C:11]5[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=5)[C:6]=4[C:2]=3[CH3:1])=[O:19])=[CH:41][CH:42]=2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: Cc1c(C(=O)O)oc2cccc(-c3cccnc3)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5cccnc5)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To 3-methyl-4-pyridin-3-yl-benzofuran-2-carboxylic acid (123 mg, 0.49 mmol) in 4 mL of DMF was added (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (352 mg, 0.97 mmol), BOP (429 mg, 0.97 mmol), and N,N-diisopropylethylamine (0.17 mL, 0.97 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine, and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of solvent in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 115 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid methyl ester, obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][NH:20][N:21]=[C:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>ClCCl.O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([CH2:19][NH:20][N:21]=[C:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[O:12]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: CNN=C(C)C(=O)OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(C)=NNCC(=O)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
2 g (10.1 mmol) of 2,4-dichlorphenylacetic acid were initially charged in 50 ml of dichloromethane, 1.1 ml (1.67 eq) of oxalyl chloride and a drop of DMF were added and the mixture was heated at the boil under reflux until the evolution of gas had ceased. The mixture was concentrated under reduced pressure, and two more times, dichloromethane was added and the mixture was concentrated again, and the residue was then taken up in 5 ml of dichloromethane. The solution obtained in this manner was, at 0° C., added dropwise over a period of 20 min to a solution of 1.4 g (1.1 eq) of methyl 2-(methylhydrazono)propionate and 2.9 ml of triethylamine (2.1 eq) in 20 ml of dichloromethane. The mixture was then stirred at room temperature overnight, and 30 ml of water were added. The aqueous phase was removed and the organic phase was concentrated. The residue obtained was purified by column chromatography (silica gel, gradient n-heptane/ethyl acetate). This gave a total of 0.7 g of methyl 2-{[2-(2,4-dichlorophenyl)acetyl]methyl-hydrazono}propionate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[C:9]([NH2:12])[C:8]([F:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:6]=1)=[O:4].[CH3:21][Sn](C)(C)C>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>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:21])=[C:9]([NH2:12])[C:8]([F:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1Cl
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1C
Temperature: 130 °C
Yield: 38.2 %

Procedure:
4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine-2-carboxylic acid methyl ester (0.400 g, 1.269 mmol), tetramethylstannane (3.41 g, 19.04 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.089 g, 0.127 mmol) were combined and heated to 130° C. for 25 min in a CEM microwave reactor. The cooled reaction mixture was concentrated onto silica gel and purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (0.143 g, 38.2% yield): 1H NMR (CDCl3) δ 7.88 (m, 2H), 7.41 (m, 2H), 4.41 (br s, 2H), 3.96 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:30]=[CH:29][S:28][C:27]=1[C:31](Cl)=[O:32].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]([C:27]4[S:28][CH:29]=[CH:30][C:26]=4[CH3:25])=[O:32])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccsc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Yield: 53.6 %

Procedure:
As described for Example 9, 0.314 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.177 g (1.1 mmol) of 3-methyl-2-thiophenecarbonyl chloride in 5 ml of dichloromethane and 0.111 g of triethylamine for 2 hours at room temperature to give crystals. Recrystallization from dichloromethane-hexane gives 0.235 g of crystals, m.p. 201°-204° C.