Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:10]([O:14]C(OC(OC(C)(C)C)=O)=O)(C)(C)C>CN(C)C1C=CN=CC=1.C(#N)C.C(O)(=O)C.Cl>[O:9]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2][NH:1][C:10]1=[O:14]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCC1(O)CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C1NCC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.65 g (5.0 mmol) of 1-(aminomethyl)-cyclohexanol, 1.2 g (5.5 mmol) di-tert.-butyldicarbonate ((Boc)2O) and 0.611 g 4-dimethylaminopyridine were dissolved in 50 ml acetonitrile and agitated overnight at room temperature. The mixture was then fully turned over, the residue was dissolved in 20 ml acetic acid and again turned over. The residue was taken up in 25 ml 1 M hydrochloric acid and extracted with 50 ml toluene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O>>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]1[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccccc2Cl)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 2-chlorobenzaldehyde gave the title compound as white crystals m.p.: 154° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20](O)=[O:21])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49]>CN(C)C=O>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([NH:49][CH2:48][CH2:47][N:46]([CH3:50])[CH3:45])=[O:21])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)O)cc(C(C)(C)C)n1CCc1ccc(F)cc1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCN(C)C)cc(C(C)(C)C)n1CCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
A 910 mg portion of 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylic acid was dissolved in 10 ml of N,N-dimethylformamide, and under ice-cooling 748 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 527 mg of 1-hydroxybenzotriazole were added, followed by stirring at the same temperature for 1 hour. A 0.65 ml portion of N,N-dimethylethane-1,2-diamine was added to the reaction liquid, and after stirring at room temperature for 15 hours, the solvent was evaporated under a reduced pressure. Ethyl acetate was added to the residue and, after washing with a saturated sodium bicarbonate aqueous solution, water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the solvent under a reduced pressure, the residue was washed with ethyl acetate to obtain 783 mg of 5-tert-butyl-N-[2-(dimethylamino)ethyl]-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide as a colorless solid. A 783 mg portion of this product was dissolved in 5 ml of methanol, and 1 ml of 4 M hydrogen chloride/ethyl acetate was added under ice-cooling, followed by stirring at the same temperature for 30 minutes. The solvent was evaporated under a reduced pressure, and the resulting residue was solidified with methanol-ethyl acetate to obtain 360 mg of 5-tert-butyl-N-[2-(dimethylamino)ethyl]-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide as a colorless solid.
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[C:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[S:18][C:12]=2[N:11]([CH3:35])[C:10]1=[O:36])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:16]2[C:13]3[C:14](=[O:15])[N:9]([CH2:8][CH2:7][CH2:6][OH:5])[C:10](=[O:36])[N:11]([CH3:35])[C:12]=3[S:18][C:17]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:33][CH:32]=1
Reactant: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)sc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-1-methyl-2,4-dioxo-1,2-dihydro thieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (40 mg, 0.068 mmol) in THF (3 mL) and water (3 mL) was added LiOH.H2O (8.6 mg, 0.20 mmol). The reaction was stirred at RT for 15 min then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-1-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (13 mg, 38.9% yield) as a white solid. 1H NMR (CDCl3) δ: 7.26-7.24 (m, 2H), 7.23 (d, J=6.0 Hz, 2H), 7.20 (s, 3H), 7.16 (d, J=8.5 Hz, 4H), 7.11 (d, J=8.0 Hz, 2H), 6.93 (dd, J=19.3, 5.2 Hz, 4H), 4.18 (dd, J=14.0, 8.0 Hz, 9H), 3.60-3.44 (m, 1H), 3.23 (t, J=7.1 Hz, 2H), 1.96-1.85 (m, 4H). LCMS: MH+ 491 and TR=3.276 min.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:22])[NH:6][C:7](=[O:21])[NH:8][C:9]=1[C:10](=[O:20])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=1)([CH3:3])[CH3:2].[Cl:23][C:24]1[N:29]=[C:28]([Cl:30])[CH:27]=[C:26]([CH2:31]Cl)[N:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>CN(C=O)C>[Cl:23][C:24]1[N:25]=[C:26]([CH2:31][N:8]2[C:9]([C:10]([C:11]3[CH:12]=[C:13]([CH:14]=[C:15]([CH3:17])[CH:16]=3)[C:18]#[N:19])=[O:20])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:22])[NH:6][C:7]2=[O:21])[CH:27]=[C:28]([Cl:30])[N:29]=1
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Cl)nc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a mixture of 5-isopropyl-6-(3′-cyano-5′-methylbenzoyl)-2,4-pyrimidinedione (1.19 g, 4 mmol), 2,4-dichloro-6-chloromethyl-pyrimidine (790 mg, 4 mmol), anhydrous powdered potassium carbonate (552 mg, 4 mmol), and lithium iodide (536 mg, 4 mmol), was added DMF (20 ml). The mixture was stirred at room temperature for overnight and evaporated in vacuo. The residue was then purified by silica gel column chromatography (eluent, EA:hexane (1:2)) to afford 476 mg (26%) of 3-[3-(2,6-dichloro-pyrimidin-4-ylmethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl]-5-methyl-benzonitrile as a pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([NH2:12])=[CH:10][CH:11]=1.C([O:16][CH:17]=[C:18]([C:24]#[N:25])[C:19](OCC)=O)C>C1(C)C=CC=CC=1>[C:24]([C:18]1[C:17](=[O:16])[C:10]2[CH:11]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:13])[S:8][C:9]=2[NH:12][CH:19]=1)#[N:25]
Reactant: COC(=O)CCCc1ccc(N)s1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Product: COC(=O)CCCc1cc2c(=O)c(C#N)c[nH]c2s1
Temperature: 25 °C
Yield: 9.8 %

Procedure:
A mixture of 4-(5-amino-thiophen-2-yl)-butyric acid methyl ester (1.00 g, 5.0 mmol) and ethyl (ethoxymethylene)cyanoacetate (930 mg, 5.5 mmol) in 50 mL of toluene is heated at reflux for 1 hour. The reaction mixture is concentrated and 50 mL of Dowtherm-A is added. The mixture is heated at reflux for 3 hours and cooled to room temperature. The crude reaction mixture is passed through a short pad of silica gel, eluting with dichloromethane followed by 10% methanol in dichloromethane. The crude product is further purified by flash column chromatography eluting with 10% methanol in dichloromethane followed by another flash column chromatography eluting with 10% methanol in ethyl acetate to provide 136 mg of methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)butanoate as a tan solid.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].N1C=CC=CC=1.ClC(OCC)=O>C(N(CC)CC)C.C1COCC1.C1COCC1.C(Cl)Cl.C(Cl)Cl.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.[Cu]I>[CH2:18]([O:17][C:15]([C:3]1[C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:7][N:6]=[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1cc(C(=O)OC(C)(C)C)ncc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C(=O)OC(C)(C)C)ncc1C#C[Si](C)(C)C
Temperature: 105 °C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
A mixture of tert-butyl 5-bromo-4-(ethoxycarbonyl)picolinate (483 mg, 1.4 mmol), trimethylsilylacetylene (206 mg, 2.1 mmol), Pd(PPh3)2Cl2 (99 mg, 0.14 mmol) and CuI (45 mg, 0.21 mmol) in triethylamine (3 mL) and THF (2 mL) in a sealed tube was passed through a stream of Ar for 5 min, and then heated at 105° C. for 1 h. The mixture was diluted with THF/CH2Cl2 (1:1), filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give a residue, which was dissolved in CH2Cl2 (5 mL) and pyridine (0.5 mL) at 0° C. To this solution was added ethyl chloroformate (0.25 mL) and the resulting mixture was stirred at 0° C. for 30 min. The mixture was diluted with CH2Cl2, washed with sat. aq. K2HPO4 solution and dried over MgSO4. The product was purified by flash column chromatography (SiO2, 10% EtOAc/CH2Cl2) to afford a yellow solid (380 mg, 75%). LC-MS: m/z 363 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: CC(C)(O)CCl
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)COc1ccc(Br)cc1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
To a solution of 1-chloro-2-methylpropan-2-ol (434.4 mg, 4 mmol) in DMF (10 mL) was added K2CO3 (552 mg, 4 mmol) and 4-bromophenol (346 mg, 2 mmol), the reaction was stirred at 140° C. for 48 hours. About of 10% 4-bromophenol was remained and the reaction was poured into 30 mL of water, extracted with EA (20 mL×3), washed with 30 mL of water and brine, concentrated and purified on TLC (EA:PE=1:3) to give yellow solid. MS (m/z): 196 (M−50)+
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([C:22]2[N:34]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:25]3=[N:26][CH:27]=[C:28]4[CH:32]=[N:31][N:30]([CH3:33])[C:29]4=[C:24]3[CH:23]=2)=[CH:12]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:10][CH2:9][OH:8])[CH:12]=[C:13]2[C:22]1[N:34]([S:35]([C:38]2[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=2)(=[O:36])=[O:37])[C:25]2=[N:26][CH:27]=[C:28]3[CH:32]=[N:31][N:30]([CH3:33])[C:29]3=[C:24]2[CH:23]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2CCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2CCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
7-(1-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-methoxy-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.130 g, 0.212 mmol, prepared using U from Preparation #P.1.1 with (2-bromoethoxy)(tert-butyl)dimethylsilane) was dissolved in MeOH (5 mL) then HCl (37% aqueous, 0.15 g, 1.3 mmol) was added. The mixture was stirred at rt for about 15 min. The mixture was concentrated under reduced pressure to give 2-(5-methoxy-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-1-yl)ethanol (0.10 g, 91%): LC/MS (Table 2, Method b) Rt=2.19 min; MS m/z: 516 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])=O>C(O)C>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: O=C(CBr)c1ccccc1Br
Reactant: Nc1ccccn1
Solvent: CCO
Product: Brc1ccccc1-c1cn2ccccc2n1

Procedure:
A solution of 2-aminopyridine (1.63 g) and 2-bromo-1-(2-bromophenyl)-ethanone (4.8 g) in dry ethanol (40 mls) was heated under reflux for 1 hour. The mixture was concentrated in vacuo. The residue was treated with dilute sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate was washed with water and brine then dried and evaporated. Flash chromatography produced the sub-title compound as a light grey oil. MS MW 272/274 bp 272.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[OH-].[K+].[CH2:12](I)[CH3:13]>C(O)C>[CH2:12]([N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9])[CH3:13]
Reactant: COc1ccc[nH]c1=O
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cccc(OC)c1=O

Procedure:
A mixture of 3-methoxy-2(1H)-pyridone (12.5 g., 0.10 moles), potassium hydroxide (8.0 g., 0.12 moles) and ethyl iodide (31.2 g., 0.02 moles) in 200 ml. ethanol is heated at reflux for 4 hours. Proceeding as previous preparations affords 1-ethyl-3-methoxy-2(1H)-pyridone as a clear yellow oil (14.1 g., 92%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11](Cl)=[O:12])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:11]([C:7]4[N:8]([CH3:10])[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=4)=[O:12])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A dry flask was charged with 5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (0.207 g, 1.03 mmol) and THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.390 g, 0.94 mmol, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=O)[CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[CH:21][N:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.O1CCCC1.B.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[CH:21][N:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2CCc3cnccc3C2=NN1c1cccc(Cl)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Clc1cccc(N2CCC3CCc4cnccc4C3=N2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
2-(3-Chlorophenyl)-4,4a,5,6-tetrahydropyrido[3,4-h]cinnolin-3(2H)-one (from Example 5 above; 66 mg) was placed in a flask under nitrogen. Borane tetrahydrofuran complex (1.0M in THF; 3 ml) was added and the solution stirred for 16 hours at ambient temperature. The mixture was added to methanol (3 ml) with stirring and then concentrated hydrochloric acid (0.5 ml) was added cautiously. The mixture was heated under reflux for 30 minutes, then cooled to room temperature and the volatiles removed on a rotary evaporator. The resultant product was partitioned between NaHCO3 (aqueous) and ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated to give a solid which was chromatographed eluting with ethyl acetate to give a solid which was recrystallised from isopropanol to yield the title compound as yellow crystals (14 mg).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([CH2:28]OS(C)(=O)=O)=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:34])([CH3:3])[CH3:2].[CH3:35][NH2:36]>>[CH3:35][NH:36][CH2:28][C:26]1[CH:25]=[CH:24][C:17]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:34])=[N:15][C:16]=2[CH:27]=1
Reactant: CN
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(COS(C)(=O)=O)ccc21
Product: CNCc1ccc2c(c1)nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
A mixture of methanesulfonic acid 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl ester (10 mg, 0.02 mmol) and methylamine (1M in THF, 0.5 mL) was stirred at ambient temperature for 12 h then the solvent evaporated. The residue was purified by prep-HPLC (gradient 10%-100% B) to give 8.1 mg (94%) of 1-[5-methylaminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=2)=[O:13])[CH:9]=[C:8]([Cl:24])[C:3]=1[C:4]([O:6]C)=[O:5].C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:13])[CH:9]=[C:8]([Cl:24])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(Cl)cc(C(=O)NCc2cccc(OC)c2)cc1Cl
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reaction time: 3 h
Yield: 80 %

Procedure:
A suspension of 2,6-dichloro-4-[[(3-methoxybenzyl)amino]carbonyl]benzoic acid, methyl ester (11.83 g, 32.1 mmol) in dichloromethane (400 mL) was cooled to ˜−78° C. (dry ice-acetone bath) and boron tribromide (1M in dichloromethane; 100 mL, 100 mmol) was added. The mixture was stirred in the cooling bath for 3 h and then allowed to stand at room temperature for 72 h. The supernatant was decanted off and water (300 mL) was added to each of the supernatant and the residue. The mixtures were stirred at ˜40° C. for 1 h and then the solids were collected by filtration, combined and air-dried to give 2,6-dichloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid (8.73 g, 80% yield) as a cream-colored solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:25]2[CH2:29][C:28]3[CH2:30][C:31]4[C:32]([O:38][CH3:39])=[CH:33][CH:34]=[CH:35][C:36]=4[O:37][C:27]=3[C:26]2=[O:40])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]3[CH2:22][O:21]C(C)(C)[O:19]3)[N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCCC1>[CH:1]1([CH2:7][C@H:8]([N:25]2[CH2:29][C:28]3[CH2:30][C:31]4[C:32]([O:38][CH3:39])=[CH:33][CH:34]=[CH:35][C:36]=4[O:37][C:27]=3[C:26]2=[O:40])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([OH:19])[CH2:22][OH:21])[N:13]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(C[C@@H](O)CO)n2)C1
Temperature: 23 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
A solution of (S)-3-cyclohexyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide (140 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was treated with 2N HCl (2.05 mL, 0.31 mmol). The mixture was stirred for 4 hours at 23° C. The reaction mixture after aqueous work-up and silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-3-cyclohexyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide (68.1 mg, 52.7%), as a white solid. 1H NMR (DMSO-d6) δ: 10.80 (s, 1H), 7.52 (s, 1H), 7.22 (t, J=8.3 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 6.39 (s, 1H), 4.93 (d, J=4.9 Hz, 2H), 4.70 (br. s., 1H), 4.37 (d, J=19.1 Hz, 1H), 4.09 (dd, J=13.4, 4.2 Hz, 1H), 3.99 (d, J=19.1 Hz, 2H), 3.88 (d, J=7.8 Hz, 1H), 3.83-3.86 (m, 1H), 3.76 (br. s., 2H), 3.53 (s, 3H), 1.50-1.83 (m, 7H), 0.81-1.31 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.O.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])=[CH:6][CH:5]=1)=[O:11]
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccc2Cl)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Combine methyl-4-bromobenzoate (1.0 g, 4.65 mmol), 2-chlorophenylboronic acid (799 mg, 5.1 mmol), Pd(OAc)2 (51 mg, 0.46 mmol) and sodium carbonate (1.5 g, 13.9 mmol) in DMF (20 mL) and water (2.0 mL) with stirring. Purge the reaction mixture with argon, add triphenylphosphine (61 mg, 0.23 mmol) and purge again with argon. Place the sealed reaction in an oil bath maintained at 80° C. and allow to stir for 1 hour. Cool the reaction to room temperature, dilute with ethyl acetate and filter through a short plug of celite with additional ethyl acetate. Wash the organics with water, dry over MgSO4, filter and evaporate. Purification by flash column chromatography yields 2′-chlorobiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in THF (0.25M) and add an equal volume of 1M NaOH. Stir vigorously at room temperature for 15 hours. Upon completion, acidify the reaction with conc. HCl and extract with ethyl acetate. Evaporation of the solvent yields 762 mg (67%) of the title compound. MS (ES): m/z 231.1 (M−H).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:5]=[CH:4]1.C([O-])(O)=O.[Na+].[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOC(C)=O.CO>[NH:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:7][C:6]=2[N:5]=[CH:4]1
Reactant: c1nc2c([nH]1)CCNC2
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A mixture of 2.0 g of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine dihydrochloride, 2.36 g of NaHCO3 and 2.45 g of N-(benzyloxycarbonyloxy)succinimide in 80 ml of dioxane/water mixture (50/50; v/v) is stirred for 16 hours at RT. The reaction mixture is extracted with EtOAc, the organic phase is washed with a saturated solution of NaHCO3, with 0.1M HCl solution, with saturated NaCl solution, it is dried and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM/MeOH mixture. 1.9 g of the expected compound is obtained.