Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[NH:23][C:24](=O)[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34]2[S:38][C:37](=[O:39])[NH:36][C:35]2=[O:40])=[CH:29][CH:28]=1)[CH3:8])(C)(C)C.[ClH:43]>O1CCOCC1>[ClH:43].[CH2:16]([O:15][C:13]1[CH:12]=[CH:11][C:10]2[N:23]=[C:24]([CH2:25][O:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH:34]4[S:38][C:37](=[O:39])[NH:36][C:35]4=[O:40])=[CH:31][CH:32]=3)[N:7]([CH3:8])[C:9]=2[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCc3ccccc3)cc21
Reaction time: 19 h

Procedure:
N-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-benzyloxyphenyl]-N-methylcarbamic acid t-butyl ester (4.27 g) (obtained in Example 2-1) was dissolved in 4N hydrochloric acid in dioxane (30 ml) and the resulting mixture was allowed to stand at room temperature for 19 hours. The reaction mixture was concentrated and to the residue was added ethyl acetate to form crystals. The crystals were washed with ethyl acetate and dried in vacuo to afford the title compound (4.27 g).
Reaction SMILES: [O-][CH2:2]C.[Na+].[F:5][C:6]([F:23])([F:22])[C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[C:10]([CH2:12][C:13]#[N:14])=[O:11].CI>CCO>[F:5][C:6]([F:22])([F:23])[C:7]1[CH:8]=[C:9]([C:10](=[O:11])[CH:12]([CH3:2])[C:13]#[N:14])[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=1
Reactant: N#CCC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CC(C#N)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of sodium ethoxide (0.127 g, 1.87 mmol) in EtOH (5 mL) was treated with 3,5-bis(trifluoromethyl)benzoyl acetonitrile (0.500 g, 1.78 mmol) portionwise over 5 min. The reaction was heated at reflux for 30 min before the addition of methyl iodide (0.41 mL, 6.6 mmol). Heating at reflux was continued for a further 2 h before the reaction mixture was allowed to cool and concentrated in vacuo. The residue was partitioned between H2O (10 mL) and EtOAC (20 mL) and the aqueous phase was separated and re-extracted with EtOAC (2×20 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography on silica gel (0-20% EtOAc in hexanes gradient) to afford 3-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-3-oxopropanenitrile. 1H NMR (500 MHz, CDCl3) δ 8.21 (s, 2H), 8.10 (s, 1H), 4.42 (q, J=7.1 Hz, 1H), 1.71 (d, J=7.1 Hz, 6H).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([CH3:8])[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH3:18])[CH2:16][CH3:17]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH:7]([CH3:8])[CH2:6][NH:5][CH2:4][C:3]1([CH3:18])[CH2:16][CH3:17]
Reactant: CCC1(C)CN(Cc2ccccc2)CC(C)C1N
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCC(C)C1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.4 g) and 4-amino-1-benzyl-3,5-dimethyl-3-ethylpiperidine (2.2 g, 8.9 mmol) in methanol (15 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 10 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,5-dimethyl-3-ethylpiperidine as a semi solid. Yield 1.1 g (79%), C9H20N2, m/z 157(M+1).
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:11]1)=[O:5].[CH3:35][NH:36][CH3:37]>>[CH3:35][N:36]([CH3:37])[C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:11][N:12]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[CH2:13]1)=[O:5]
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1F)NC1CN(C2CCC(c3ccccc3)CC2)C1
Reactant: CNC
Product: CN(C)c1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
2-Fluoro-N-{[1-(4-phenyl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide (as prepared in Example 66, 50 mg, 0.11 mmol) was treated with dimethyl amine (Aldrich, 40 wt. % in water, ˜2 mL) in a sealed tube under microwave irradiation at 120° C. for 20 min. The solvent was removed and the residue was purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][CH:17]=[CH:18][C:19]=4[C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1.[Br:20]Br>C(O)(=O)C>[Br:20][C:17]1[S:16][C:15]2[CH2:14][C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[N:10][NH:11][C:12]=3[C:19]=2[CH:18]=1
Reactant: BrBr
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(Br)cc2-3)cc1
Temperature: 80 °C
Yield: 91 %

Procedure:
6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.13 g, 0.5 mmol) was added with a solution of bromine in glacial acetic acid (0.5 mL of a 3 M solution). The reaction mixture was heated at 80° C. for 12 hr. The solution was cooled to room temperature and poured into ice water. The resultant precipitate was filtered, washed with water to provide the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.16 g, 0.46 mmol) as yellow solid in 91% yield.
Reaction SMILES: CC(O[C@H:5]1[C:15](=O)[N:14](CCN(C)C)C2C=CC=CC=2S[C@H:6]1[C:22]1[CH:23]=[CH:24][C:25](OC)=[CH:26][CH:27]=1)=O.CCOP(OCC)(CC1C=CC(C2[S:50]C3C=CC=CC=3N=2)=CC=1)=O>>[S:50]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:6]=[CH:5][CH:15]=[N:14]1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccccc3s2)cc1)OCC
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Product: C1=Cc2ccccc2SN=C1

Procedure:
Diltiazem, KB-944 (Fostedil)
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[C:43](Cl)[N:44]=1)[C:38]([O:40][CH3:41])=[O:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:43]2[CH:42]=[C:37]([CH:36]=[C:35]([Cl:34])[N:44]=2)[C:38]([O:40][CH3:41])=[O:39])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Cl)nc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A mixture of 100 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 56 mg of methyl 2,6-dichloroisonicotinate, 95 mg of potassium phosphate, 6 mg of bis(tri-tert-butylphosphine)palladium(0), and 2.0 mL of dimethylacetamide was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 66 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-6-chloroisonicotinate as a pale yellow oily compound. ESI+: 614
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C#N

Procedure:
The title compound was prepared from [2-amino-4-cyano-5-(isopropyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J31) (304 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (460 mg, 73%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C@@H:24]([NH:34][C:35](=[O:45])[O:36][C@H:37]1[C:41]([CH3:43])([CH3:42])[CH2:40][O:39][C:38]1=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([NH:32][CH3:33])=[O:31])[C:13](=[O:23])[NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16].C(N(CC)CC)C>ClCCl>[CH3:33][NH:32][C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]([NH:34][C:35](=[O:45])[O:36][C@H:37]1[C:41]([CH3:42])([CH3:43])[CH2:40][O:39][C:38]1=[O:44])[C:12](=[O:11])[C:13](=[O:23])[NH:14][C@@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])=[O:31]
Reactant: CNC(=O)NCCCC[C@H](NC(=O)O[C@@H]1C(=O)OCC1(C)C)C(O)C(=O)N[C@H](C)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)NCCCC[C@H](NC(=O)O[C@@H]1C(=O)OCC1(C)C)C(=O)C(=O)N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalylchloride (0.058 mL, 0.67 mmol) in anhydrous dichloromethane (2 mL) was cooled to −60° C. under nitrogen. Anhydrous dimethylsulfoxide (0.095 mL, 1.34 mmol) was then added dropwise, and the resulting solution was stirred for 10 min. A solution of (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamate (150 mg, 0.30 mmol) in dichloromethane (3 mL) was then added. After 15 min, triethylamine (0.212 mL, 1.52 mmol) was added to the reaction mixture, which was kept cold for 2 min. and then allowed to warm to room temperature. After 40 min, the reaction mixture was subjected directly to column chromatography on silica gel. Elution with 10% acetone in ethyl acetate afforded (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl (1S)-5-{[(methylamino)carbonyl]amino}-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate as a colorless gum after drying under vacuum (82 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ 9.26 (d, J=8 Hz, 1H); 7.99 (d, J=8 Hz, 1H); 7.40-7.33 (m, 4H); 7.31-7.23 (m, 1H); 5.92-5.84 (m, 1H); 5.71-5.63 (m, 1H); 5.40 (s, 1H); 5.08-4.96 (m, 1H); 4.85-4.78 (m, 1H); 4.16 (1/2Abq, J=8 Hz, 1H); 4.06 (1/2Abq, J=8 Hz, 1H); 3.04-2.91 (m, 2H); 2.55 (part of d overlapping DMSO, 3H); 1.74-1.61 (m, 1H); 1.46 (d, J=7 Hz, 1H); 1.45-1.29 (m, 5H); 1.12 (s, 1H); 1.05 (s, 1H). ES-LCMS m/493 (M+H) HRMS C24H34N4O7 m/491.2505 (M+H)cal. 491.2490 (M+H)Obs.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[C:15]([S:24]([CH3:26])=[O:25])=[N:14]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[C:15]([S:24]([CH3:26])(=[O:9])=[O:25])=[N:14]1
Reactant: Cn1nc(S(C)=O)c(=O)c2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1nc(S(C)(=O)=O)c(=O)c2ccccc21
Reaction time: 0.08 h
Yield: 104.1 %

Procedure:
A quantity of 6.16 g (0.027 mole) of 85% m-chloroperbenzoic acid was added to a solution of 6.6 g (0.03 mole) of 1-methyl-3-(methylsulfinyl)-4(1H)-cinnolinone in 100 ml of chloroform. The temperature rose to 45° C. After 5 minutes the solution was brought to reflux for 5 minutes, cooled, mixed with 200 ml of 5% sodium bicarbonate and stirred for 10 minutes. Additional chloroform (300 ml) was added to dissolve the separated product. The organic layer was separated, dried over anhydrous potassium carbonate and concentrated to give 6.7 g (94.4%) of white product melting at 202°-204°. Recrystallization from chloroform-methanol gave pure product melting at 204°-206° C.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][C:14]([C:20](O)=[O:21])=[CH:13]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:45])[C@@H:28]([NH2:44])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:32][CH:31]=1>>[CH3:25][O:26][C:27](=[O:45])[CH:28]([NH:44][C:20]([C:14]1[N:15]=[CH:16][C:17]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:9][C:8]1[CH:23]=[CH:24][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)=[CH:19][CH:18]=2)=[O:21])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cnc(C(=O)O)cc3c2)cc1
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2cn1
Yield: 75.5 %

Procedure:
870 mg (2.71 mmol) of 6-(4-tert-butylphenoxy)-isoquinoline-3-carboxylic acid (example 295) was reacted with 871 mg (2.71 mmol) of (2S)-amino-3-(4-benzyloxy-phenyl)-propionic acid methyl ester as described in general procedure A. The crude product was purified by flash column chromatography on silica using 3:2 hexane/ethyl acetate as eluent to afford 1.205 g of 3-(4-benzyloxy-phenyl)-2-{[6-(4-tert-butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-propionic acid methyl-ester as a white solid. LCMS 590 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][C:12]2([C:17]([O:19]C)=[O:18])[CH2:14][CH2:15][CH2:16][CH:11]2[C:10]1=[O:21].Cl>[Li+].[OH-].CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][C:12]2([C:17]([OH:19])=[O:18])[CH2:14][CH2:15][CH2:16][CH:11]2[C:10]1=[O:21]
Reactant: COC(=O)C12CCCC1C(=O)N(c1c(C)cccc1C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(C)c1N1CC2(C(=O)O)CCCC2C1=O
Temperature: 70 °C
Yield: 82.3 %

Procedure:
Methyl 2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxylate (400 mg, 1.4 mmol) suspended in 5 mL of 1 M LiOH in 90% methanol was heated at 70° C. After cooling to room temperature, the reaction mixture was diluted with water, the pH adjusted to ˜1 with concentrated HCl and the product was extracted twice with ethyl acetate (15 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated to yield 2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxylic acid (315 mg, 82% yield). LC-MS Rt (retention time): 1.44 min, MS: (ES) m/z 274 (M+H+).
Reaction SMILES: CC1C=CC(C(O[C@@H]([C@H](OC(=O)C2C=CC(C)=CC=2)C(O)=O)C(O)=O)=O)=CC=1.[F:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH2:42][CH2:41]1)[N:36]([C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[CH:56][C:55]=1[O:64][CH3:65])[CH:35]2[CH2:66][C:67]([O:69]C)=[O:68].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:41][CH2:42][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH2:44][CH2:45]1)[N:36]([C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[CH:56][C:55]=1[O:64][CH3:65])[C@H:35]2[CH2:66][C:67]([OH:69])=[O:68]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: Cc1ccc(C(=O)O[C@H](C(=O)O)[C@H](OC(=O)c2ccc(C)cc2)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
(2S,3S)-2,3-Bis[(4-methylbenzoyl)oxy]succinic acid-methyl {8-fluoro-2-[4-(3-methoxyphenyl)-piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (25.1 g) are suspended in ethyl acetate (250 ml) and shaken with saturated aqueous sodium bicarbonate solution (250 ml) until both phases are clear. The phases are separated and the organic phase is concentrated in a rotary evaporator. The residue is dissolved in 1,4-dioxane (250 ml) and 1N sodium hydroxide solution (77.4 ml) and stirred at room temperature for 18 h. Subsequently, the pH is adjusted to 7.5 using 1N hydrochloric acid (ca. 50 ml), MIBK (240 ml) is added, then the pH is readjusted to 7.0 using 1N hydrochloric acid (ca. 15 ml). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in ethanol (90 ml) and concentrated, then again dissolved in ethanol (90 ml) and concentrated. The solidified foam is dried at 45° C. for 18 h in the VDO using entraining nitrogen. A total of 12 g of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydro-quinazolin-4-yl}acetic acid are thus obtained as an amorphous solid, corresponding to 81.2% of theory.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:16])[NH2:15])=[CH:11][CH:10]=[C:9](B1OC(C)(C)C(C)(C)O1)[CH:8]=2)=[O:3].C(=O)([O-])O.[Na+].Br[C:32]1[CH:37]=[C:36]([CH2:38][OH:39])[CH:35]=[CH:34][N:33]=1>O.O1CCOCC1.[Cl-].[Na+].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>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:15])=[O:16])=[CH:11][CH:10]=[C:9]([C:32]1[CH:37]=[C:36]([CH2:38][OH:39])[CH:35]=[CH:34][N:33]=1)[CH:8]=2)=[O:3]
Reactant: CC1(C)OB(c2ccc3c(C(N)=O)c(NC(N)=O)[nH]c3c2)OC1(C)C
Reactant: OCc1ccnc(Br)c1
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: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)Nc1[nH]c2cc(-c3cc(CO)ccn3)ccc2c1C(N)=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 23.6 %

Procedure:
A solution mixture of 2-aminocarbonylamino-3-carbamoylindole-6-boronic acid pinacol ester (Compound 6-1, 90 mg, 0.26 mmol), sodium hydrogen carbonate (55 mg, 0.65 mmol), 2-bromopyridine-4-methanol (58 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium (0) (15 mg, 0.013 mmol) in water-1,4-dioxane (1:3, 15 mL) was stirred at 100° C. for 6 hours. Brine (5 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (5 mL). The organic layer was dried over anhydrous magnesium sulfate, and was filtered throught Celite® pad. After the solvent was evaporated under reduced pressure, the resultant solid was washed with ethanol (2 mL), and dried under reduced pressure to give the title compound (20 mg) as a brown solid (yield 23%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37]O)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH2:37][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[CH2:29][CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCc1ccccc1CO
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1ccccc1COc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(=O)OC

Procedure:
In a similar manner as described for example B31, 845.5 mg of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 412 mg of (2-ethylphenyl)methanol, 1.06 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 928 mg of di-tert-butyl azodicarboxylate in 25 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][NH:8][C:9]=1[C:10]([O:12]C)=O)=[O:4].[NH2:14][NH2:15]>CO>[NH:6]1[C:5]2[C:3](=[O:4])[NH:14][NH:15][C:10](=[O:12])[C:9]=2[N:8]=[CH:7]1
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Reactant: NN
Solvent: CO
Product: O=c1[nH][nH]c(=O)c2[nH]cnc12
Temperature: 115 °C
Yield: 60 %

Procedure:
1H-Imidazole-4,5-dicarboxylic acid dimethyl ester (592 mg, 3.21 mmol) is combined with hydrazine (600 mg, 18.8 mmol) and MeOH (10 mL). The reaction mixture is heated to 115° C. for 30 min. Cool and filter off the resulting precipitate. Wash with additional water. Combine the precipitate with hydrazine (1.38 mL) and reflux for 4 h. Pour the reaction mixture into ice water and adjust the to pH 2 with HCl (12 N). The new precipitate is isolated by filtration to afford the title product (293 mg, 60%)
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][N:23]4[CH2:26][CH2:25][CH2:24]4)[CH:18]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.CO.[ClH:29]>>[ClH:29].[ClH:29].[ClH:29].[N:23]1([CH2:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([CH:10]2[CH2:9][NH:8][CH2:11]2)[CH2:21][CH2:20]3)[CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCc3cc(CN4CCC4)ccc3C2)C1
Agent: Cl
Solvent: CO
Product: c1cc2c(cc1CN1CCC1)CCN(C1CNC1)C2
Reaction time: 0.5 h
Yield: 100 %

Procedure:
3-[6-(Azetidin-1-yl-methyl)-1,2,3,4-tetrahydro-isoquinolin-2-yl]-azetidine-1-carboxylic acid tert-butyl ester (2.042 mmol, 2 equiv.) was dissolved in hydrogen chloride in methanol (1.25 M, 10 equiv., 16 ml) and stirred for 30 minutes at boiling temperature. After monitoring by thin-layer chromatography, the methanol was removed and the residue was dissolved in ethanol/acetone (1:5, 20 ml). The hydrochloride was precipitated with diethyl ether (50 ml), filtered, washed with diethyl ether and dried in vacuo to yield the desired product. Yield: 100%
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14]O>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)CCCCc1ccccc1
Product: COC(=O)CCCCc1ccccc1

Procedure:
5-Phenylpentanoic acid (10.0 g) was dissolved in 250 mL of methanol and sparged with hydrogen chloride gas at room temperature for 15 minutes. The solvent was then removed under vacuum. Methyl 5-phenylpentanoate obtained was used in the next step without further purification.