Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([NH:12]C(=O)C(F)(F)F)[CH:9]=[CH:8][C:7]=1[S:19](Cl)(=[O:21])=[O:20])(=[O:4])=[O:3].[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[CH2:31][O:30][B:29]([OH:32])[C:28]=2[CH:33]=1.N1C=CC=CC=1>C(#N)C>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]([S:19]([NH:23][C:24]2[CH:25]=[CH:26][C:27]3[CH2:31][O:30][B:29]([OH:32])[C:28]=3[CH:33]=2)(=[O:20])=[O:21])=[C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:11]=1
Reactant: CS(=O)(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CC#N
Solvent: c1ccncc1
Product: CS(=O)(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a stirred solution of 2-(methylsulfonylmethyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (680 mg, 1.8 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (400 mg, 2.7 mmol) in 10 mL of ACN was added pyridine (290 uL, 3.6 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. A solution of this crude compound in 7M ammonium in MeOH (10 mL) was stirred in a sealed tube at 50° C. for 4 hours. After concentrated, the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a white solid (498 mg, yield 70%). MS calcd for (C15H17BN2O6S2): 396.2. MS found (ESI negative): (M−H)−=395.1. 1H NMR (DMSO-d6) δ (ppm): 9.95 (s, 1H), 9.20 (bs, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.47 (d, J=8.8 Hz, 1H), 4.85 (s, 2H), 4.71 (s, 2H), 2.82 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:29])([F:28])[CH2:25][C@H:24]1[C:30](O)=[O:31])=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[F:29][C:26]1([F:28])[CH2:27][N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])[C@H:24]([C:30](=[O:31])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)Nn1cccc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
1-Amino-N-phenyl-1H-pyrrole-2-carboxamide (500 mg, 2.48 mmol), (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (687 mg, 2.73 mmol), HATU (1.04 g, 2.73 mmol) and diisopropylethylamine (476 μl, 2.73 mmol) were dissolved in a mixture of 6 mL of dichloromethane and 6 mL of DMF and stirred at room temperature overnight. The dichloromethane was removed under vacuum and 25 mL of water were poured over the remaining solution. A precipitated appeared and the suspension was stirred overnight. The solid was filtered and washed with water to furnish 1.05 g (97% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].ClC1C=CC=C(F)C=1C=O.CNC>>[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1ccc2ccccc21
Reactant: C[N+](C)=Cc1c(F)cccc1Cl
Agent: CNC
Agent: O=Cc1c(F)cccc1Cl
Agent: [Cl-]
Product: CN(C)C(c1c(F)cccc1Cl)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (2-chloro-6-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-6-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.C(O)(=O)C.O.CN(C)/[CH:17]=[CH:18]/[C:19]([C:21]1[CH:22]=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27])=O>CS(C)=O>[O:8]=[C:6]1[NH:7][C:2]2[N:1]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=3)[C:26]([O:28][CH3:29])=[O:27])[CH:18]=[CH:17][C:3]=2[C:4](=[O:9])[NH:5]1
Reactant: COC(=O)c1cc(C(=O)/C=C/N(C)C)ccc1OC
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc3c(=O)[nH]c(=O)[nH]c3n2)ccc1OC
Temperature: 99 °C
Reaction time: 1.5 h
Yield: 106.4 %

Procedure:
6-Aminouracil (14.32 g, 112.7 mmol) was added to glacial acetic acid (112.5 mL) and water (75 mL) and the mixture heated to 99° C. A solution of methyl 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-methoxybenzoate (15 g, 56.3 mmol) in DMSO (75 mL) was then added over 180 minutes. The reaction was stirred at 99° C. for a further 90 minutes and cooled to 60° C. Water (75 mL) was then added and the reaction maintained at 60° C. for a further 60 minutes and then filtered off to afford a beige solid. The solid was washed with fresh water (75 mL) and dried visibly dry thus affording 19.6 g of water wet solid (9).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[OH-].[K+].Br[CH2:16][CH2:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:24]([O:23][P:19]([CH2:18][CH2:17][CH2:16][O:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])([O:20][CH2:21][CH3:22])=[O:26])[CH3:25]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CCOP(=O)(CCCBr)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(CCCOC[C@H](C)NC(=O)OC(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1 eq, from the previous step) in THF (0.1 M) at room temperature was added KOH (5 eq), tetrabutylammonium bromide (0.1 eq), and diethyl 3-bromopropylphosphonate (2 eq). The reaction was stirred at room temperature overnight. The mixture was concentrated en vaccuo and then taken up in DCM/water. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried over anhydrous MgSO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% ethyl acetate in hexanes and then 100% ethyl acetate to give the product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:11]([C:21](=O)[C:22]([CH3:32])([CH3:31])[CH2:23][O:24]C3CCCCO3)=[C:10](O)[C:9]2=[O:35])=[CH:4][CH:3]=1.O.[NH2:37][NH2:38].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:11]3[C:21]([C:22]([CH2:23][OH:24])([CH3:32])[CH3:31])=[N:38][NH:37][C:10]=3[C:9]2=[O:35])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1C(C(=O)C(C)(C)COC2CCCCO2)=C(O)C(=O)N1c1ccc(Br)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1C1c2c(C(C)(C)CO)n[nH]c2C(=O)N1c1ccc(Br)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A mixture of 1-(4-bromophenyl)-4-(2,2-dimethyl-3-tetrahydro-2H-pyrane-2-yloxypropionyl)-3-hydroxy-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (1.51 g, 2.77 mmol), hydrazine hydrate (0.204 mL, 4.16 mmol) and acetic acid (3 mL) was stirred at 95° C. for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (150 mL) was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was triturated with ethyl acetate to give 5-(4-bromophenyl)-3-(1-hydroxymethyl-1-methylethyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (1.02 g, yield: 81%) as colorless solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[CH3:12][C:13]1[CH:21]=[C:17]([C:18](O)=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1.Cl>O>[OH:19][CH2:18][C:17]1[CH:21]=[C:13]([CH3:12])[CH:14]=[CH:15][C:16]=1[OH:22]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
To a suspension of LiAlH4 (2.5 g, 66 mmol) LiAlH4 in freshly distilled THF (8 ml) at 0° C. under argon, was added dropwise with stirring a solution of 5-methylsalicylic acid (5 g, 33 mmol) in freshly distilled THF (80 ml). Addition was complete in 0.75 hours and the reaction stirred at ambient temperature overnight. Careful addition of water (5 ml) was followed by the addition of ice (10 ml) and concentrated HCl (1 ml). The solvent was decanted and the residue treated with ethyl ether and ice water. The pH of the mixture was adjusted to pH 1 with concentrated HCl and the organic layer combined with the decanted solvent, washed with brine, dried (MgSO4) and evaporated. The residue was subjected to chromatography (eluant: ethyl ether/hexane) to give 2-hydroxymethyl-4-methylphenol as a white solid (3.1 g, 68%).
Reaction SMILES: BrC1C=CC([N:8]([C:15]2[C:24]3[C:19](=CC=CC=3)[CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)=CC=1.C([Li])CCC.C(O[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1)(C)C.O>C1COCC1.C(Cl)(Cl)Cl>[CH3:41][C:36]1([CH3:42])[C:37]([CH3:40])([CH3:39])[O:38][B:34]([C:18]2[CH:17]=[CH:16][C:15]([NH2:8])=[CH:24][CH:19]=2)[O:35]1
Reactant: Brc1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 24 h

Procedure:
3.7 g (10 mmol) of (4-bromophenyl)naphthalen-1-yl-phenylamine was dissolved in 100 ml of THF and cooled to −78° C. 4.8 ml (12 mmol) of 2.5M n-butyllithium was added slowly to the THF solution and maintained at the same temperature as above for an hour to allow reaction. 2.2 g (12 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added to the reactant solution, maintained at the same temperature as above for an hour to allow reaction, heated to room temperature (RT) and stirred for 24 hours. Water was added to end the reaction, and 300 ml of chloroform was added. The resulting organic layer was washed with 200 ml of water and dried with anhydride magnesium sulfate. 3.4 g of Naphthalen-1-yl-phenyl[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylamine (intermediate A) was obtained through silica chromatography with a yield of 81%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([NH:13][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=2[N+:10]([O-:12])=[O:11])=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(C)n1
Solvent: CCO
Product: Cc1cc(Nc2ccc(C#N)cc2)c([N+](=O)[O-])c(C)n1

Procedure:
A solution of 4-chloro-2,6-dimethyl-3-nitropyridine (9.80 g, 52.5 mmol) and 4-aminobenzonitrile (6.20 g, 52.5 mmol) in ethanol (160 ml) was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (200 ml), and washed with saturated aqueous sodium bicarbonate (100 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure to give a gum which was crystallised by adding ether (100 ml) and sonicating for 5 minutes. The yellow solid (9.80 g, 70%) was filtered off and dried in vacuo, mp 171°-172° C.
Reaction SMILES: [CH2:1]([O:8]/[N:9]=[C:10](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22](=[O:23])[NH:21][NH:20][C:19]2=[O:24])=[CH:14][CH:13]=1)\[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([O:8]/[N:9]=[C:10](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:19](=[O:24])[N:20]=[N:21][C:22]2=[O:23])=[CH:14][CH:13]=1)\[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C(=N\OCc1ccccc1)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Solvent: ClCCl
Product: C/C(=N\OCc1ccccc1)c1ccc(N2C(=O)N=NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To (E)-4-(4-(1-(benzyloxyimino)ethyl)phenyl)-1,2,4-triazolidine-3,5-dione (I-5a: 56 mg, 0.173 mmol) in CH2Cl2 (1.727 mL) was added SiO2—HNO3 (112 mg). The mixture was stirred at room temperature for 30 minutes, filtered, concentrated in vacuo and dried to give (E)-4-(4-(1-(benzyloxyimino)ethyl)phenyl)-3H-1,2,4-triazole-3,5(4H)-dione (I-4b: 29 mg, 52%) as a red solid. 1H NMR (400 MHz, CD3CN) δ ppm 2.31 (s, 3 H) 5.28 (s, 2 H) 7.38 (d, J=7.07 Hz, 1 H) 7.43 (t, J=7.20 Hz, 2 H) 7.46-7.54 (m, 4 H) 7.86-7.94 (m, 2 H).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (65 mg, 0.112 mmol) was dissolved in dichloromethane (0.6 ml) and trifluoroacetic acid (0.35 ml, 4.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was redissolved in dichloromethane (0.6 ml) and ethylenediamine (0.46 ml, 6.8 mmol) was added. The solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 30 mg (59%) of 2-(6-chloro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow powder. MS: (M+H)+=449.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[N:7]/[NH:8][C:9]([NH2:11])=[O:10])=[C:4]([F:14])[CH:3]=1.BrBr.CCOCC>CC(O)=O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]2[NH:11][C:9](=[O:10])[NH:8][N:7]=2)=[C:4]([F:14])[CH:3]=1
Reactant: NC(=O)N/N=C/c1ccc(Br)cc1F
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=c1[nH]nc(-c2ccc(Br)cc2F)[nH]1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A solution of compound 59a (7.2 g, 28 mmol) in AcOH (30 mL) was treated with Br2 (8.8 g, 55 mmol). The resulting solution was stirred at 95° C. for 2 h. The resulting solution was allowed to cool to rt and treated with Et2O (50 mL). The solids formed were collected by filtration to obtain compound 59b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H5BrFN3O: 258.0 (M+H). Found: 258.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[S:7][C:6]=2[CH:14]=1.Cl.[NH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[N:31](S(C3C=CC=CC=3)(=O)=O)[C:30]3[CH:29]=[CH:28][N:27]=[C:26]([Cl:41])[C:25]=3[CH:24]=2)[C:18]1=[O:42]>>[Cl:41][C:26]1[C:25]2[CH:24]=[C:23]([CH2:22][N:19]3[CH2:20][CH2:21][C@H:17]([NH:16][S:10]([C:8]4[S:7][C:6]5[CH:14]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[CH:9]=4)(=[O:12])=[O:11])[C:18]3=[O:42])[NH:31][C:30]=2[CH:29]=[CH:28][N:27]=1
Reactant: NC1CCN(Cc2cc3c(Cl)nccc3n2S(=O)(=O)c2ccccc2)C1=O
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2c(Cl)nccc2[nH]1

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and 3-amino-1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-2-one hydrochloride as the starting material. The crude product is purified by column chromatography eluting with a gradient of 1% MeOH/CH2Cl2 to 3% MeOH/CH2Cl2 to give the product as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:7].[C:18]1([CH2:24][S:25](Cl)(=[O:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:18]1([CH2:24][S:25]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:7])(=[O:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: O=C(OCCCc1cccnc1)C1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCc1cccnc1)[C@@H]1CCCN1S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A solution of 3-(3-Pyridyl)-1-propyl pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and α-toluenesulfonyl chloride (160 mg; 0.9 mmol) in methylene chloride (20 mL) was treated with triethylamine (90 mg; 0.9 mmol) and stirred for 2 hours at room temperature. The reaction mixture was filtered to remove solids and applied directly to a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 150 mg (43%) of compound 1 (Table I) as a clear oil, 1H NMR (300 MHz, CDCl3): δ1.81-1.85 (m, 2H); 1.95-2.02 (m, 3H); 2.10-2.25 (m, 1H); 2.69-2.74 (t, 2H); 2.85-2.97 (m, 1H); 3.24-3.27 (m, 1H); 4.16-4.20 (m, 2H); 4.29 (d, 1H); 4.34 (m, 1H); 4.45 (d, 1H); 7.20-7.25 (m, 1H); 7.35 (m, 3H); 7.49-7.52 (m, 3H); 8.46 (s, 2H). Anal. Calcd. for C20H24N2O3S: C, 61.83; H, 6.23; N, 7.21. Found: C, 61.59; H, 6.24; N, 7.17.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:16][C@H:15]2[NH2:17])=[CH:10][CH:9]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1.O.[OH-].[Na+].O>CCO>[NH2:17][C@@H:15]1[CH2:16][C@H:14]1[C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COCCOCOc1ccc([C@@H]2C[C@H]2N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N[C@@H]1C[C@H]1c1ccc(O)cc1

Procedure:
A solution of (trans)-2-(4-((2-methoxyethoxy)methoxy)phenyl)cyclopropanamine (Intermediate L, 62 mg, 0.26 mmol) and p-TsOH.H2O (60 mg, 0.31 mmol) in EtOH (5 mL) was heated at 75° C. for 2 h. The pH of the reaction was adjusted to 7 with NaOH (10% aqueous solution), the mixture was poured into water (10 mL) and extracted with EtOAc (4×10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent a brownish residue was obtained (44 mg, 4-((trans)-2-aminocyclopropyl)phenol contaminated with p-TsOH) that was used in the next step without further purification.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](=[O:29])[CH3:28]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:10]([N:4]1[CH2:3][CH:25]([C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])[CH:26]([C:27](=[O:29])[CH3:28])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)/C=C/c1ccc(F)cc1F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (7.82 g, 32.9 mmol) in CH2Cl2 (40 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-4-(2,4-difluoro-phenyl)-but-3-en-2-one (4.0 g, 21.9 mmol) and trifluoroacetic acid (0.17 mL, 0.21 mmol) in CH2Cl2 (10 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, CH2Cl2/MeOH 98:2) afforded 6.2 g (89%) of the title compound as a yellow oil. ES-MS m/e: 316.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[C:18]([O:17][C:15]([NH:14][CH2:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:22])=[O:2])=[CH:6][CH:7]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)Cc1ccc(CCCNC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.4 %

Procedure:
4-(3-(Tertiarybutoxycarbonylamino)propyl)phenylacetic acid methyl ester (2.0 g) was dissolved in 50% aqueous methanol (100 ml) with sodium hydroxide (1 g) and stirred at room temperature for 14 h. The methanol was removed under vacuum and the residual aqueous solution was acidified to pH1 using 1N hydrochloric acid, and the resulting precipitate extracted into ethyl acetate (2×100 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated under vacuum to give the required product as a white solid (1.82 g). δ (360 MHz, CDCl3) 1.44 (9H, s, COC(CH3)3, 1.78 (2H, m, CH2CH2CH2NH), 2.60 (2H, t, J=7.5 Hz, CH2CH2CH2NH), 3.13 (2H, m, CH2CH2CH2NH), 3.60 (2H, s, CH2CO2H), 4.57 (1H, br, s, NH), 7.12 (2 H, d, J=8.0 Hz, ArH), 7.19 (2H, d, J=8.0 Hz, ArH); m/e (CI) 294 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20]>>[NH2:22][CH2:21][C:18]1[C:19]([NH2:20])=[N:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:4][CH:5]=2)=[N:9][C:17]=1[C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Product: NCc1c(N)nc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=412.9 (M+H+), was prepared from 4-trifluoromethyl-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][C:14]=1[C:15]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:16]
Reactant: Cc1nc(-c2cccs2)ccc1C(=O)O
Reactant: Nc1ccc2cccnc2c1
Product: Cc1nc(-c2cccs2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (7 mg, 0.05 mmol) and 2-methyl-6-(2-thienyl)-nicotinic acid (10 mg, 0.05 mmol) as a yellow solid. 1H NMR (400 MHz, MeOH-d4) δ (ppm): 8.82 (dd, 1H), 8.58 (s, 1H), 8.34 (dd, 1H), 7.85-8.0 (m, 3H), 7.76 (m, 2H), 7.55 (dd, 1H), 7.48 (dd, 1H), 7.16 (dd, 1H), 2.70 (s, 3H).