Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[NH:2][C:3]([C:10]([O:12]CC)=[O:11])=[C:4]2[CH2:9][O:8][CH2:7][CH2:6][C:5]=12.[OH-].[Na+]>CO>[N:1]1[NH:2][C:3]([C:10]([OH:12])=[O:11])=[C:4]2[CH2:9][O:8][CH2:7][CH2:6][C:5]=12
Reactant: CCOC(=O)c1[nH]nc2c1COCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1[nH]nc2c1COCC2
Temperature: 0 °C

Procedure:
Ethyl 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylate (0.97 g, 4.94 mmol) was dissolved in methanol (20 ml) and cooled to 0° C. with an ice bath. Sodium hydroxide 2 M solution (4.94 ml, 9.89 mmol) was added and the mixture was allowed to cool to RT with stirring. The mixture was stirred for 26 h during which additional 7 ml of sodium hydroxide 2 M solution was added. The solvent was evaporated and the pH adjusted to 2 with 1 M HCl. The formed precipitate was filtered and washed with water. The white solid was dried with vacuum at 40° C. 1H-NMR (400 MHz; d6-DMSO): δ 2.69 (t, 2H), 3.81 (t, 2H), 4.68 (s, 2H), 13.09 (bs, 1H).
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].[C:9]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[CH3:25])=[S:14])(=O)[CH3:10].BrCC([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=O>O>[CH3:25][C:17]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=1[NH:15][C:13]1[S:14][CH:10]=[C:9]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[N:12]=1
Reactant: CC(=O)NC(=S)Nc1cc([N+](=O)[O-])ccc1C
Reactant: O=C(CBr)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc(-c2cccnc2)cs1
Temperature: 27.5 °C

Procedure:
In a reactor, introduce methanol (1120 L), potassium carbonate (287 kg, 2076.70 mol) and 1-acetyl-3-(2-methyl-5-nitro-phenyl)-thiourea (67 kg, 264.53 mol). 2-bromo-1-pyridin-3-yl-ethanone (Int4) (52 kg, 259.96 mol) was then added and temperature maintained at 25-30° C. for 4 hours. Water (692 L) was added to the reaction mixture and precipitate filtered, washed with water and diisopropylether. The product was then dried in a tray drier at 45-50° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[C:20](=O)[CH2:19]1)=[O:17].[CH3:33][NH2:34]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[CH:20]([NH:34][CH3:33])[CH2:19]1)=[O:17]
Reactant: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Reactant: CN
Solvent: C1CCOC1
Product: CNC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 24B 5-chloro-thiophene-2-carboxylic acid {(1S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-oxo-cyclopentyl}-amide was reacted with methylamine (using a saturated solution in THF) to give 5-chloro-thiophene-2-carboxylic acid {(S)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methylamino-cyclopentyl}-amide. Crystalline white solid. MS 489.3 ([M+H]+).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@H:14](OS(C(F)(F)F)(=O)=O)[CH:13]([O:24][CH3:25])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.O>CN(C=O)C>[C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:13]([O:24][CH3:25])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: COC1O[C@H](COC(=O)c2ccccc2)C[C@@H]1OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC1O[C@H](COC(=O)c2ccccc2)C[C@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a solution of [(2S,4S)-5-methoxy-4-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]methyl benzoate (compound 32c, 400 mg, 1.04 mmol) in DMF (3 mL) was added pyrrolidine (142 mg, 2.0 mmol) at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted by water and extracted with EtOAc, the organic layers were combined and concentrated in vacuo to afford 230 mg crude product of [(2S,4R)-5-methoxy-4-pyrrolidin-1-yl-tetrahydrofuran-2-yl]methyl benzoate (compound 32d) as an oil, which was used in next step without further purification. MS obsd. (ESP) [(M+H)+]: 306.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][N:11]=[C:5]2[N:4]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]1=[O:17].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:24][CH:25]=3)[N:11]=[C:5]2[N:4]([CH2:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:3]1=[O:17]
Reactant: Cn1c(=O)c2c[nH]nc2n(CC(C)(C)C)c1=O
Reactant: ClCc1ccc(-c2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2cn(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.4 %

Procedure:
5-methyl-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (236 mg, 1.0 mmol), 4-(4-(chloromethyl)phenyl)pyridine (305 mg, 1.5 mmol) and potassium carbonate (414 mg, 3.0 mmol) are suspensed in 3 mL of DMF. The reaction mixture is stirred at room temperature overnight, and then diluted with 100 mL of water. The mixture is extracted with methylene chloride four times (40 mL×4). The combined organic phase is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated to dryness to give 510 mg of crude product, which is used in the next step without further purification. MS (ESI) m/z 404.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2.[OH-].[Na+].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)ccc2NC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(Cl)ccc2NC1C(F)(F)F
Reaction time: 8 h
Yield: 41.5 %

Procedure:
The ester from Step 2 (1.7 g, 5.6 mmol) and 2.5 N sodium hydroxide (4.4 mL, 11 mmol) were mixed in tetrahydrofuran (25 mL), methanol (10 mL), and water (25 mL). After stirring overnight, contents were concentrated in vacuo to remove the THF and methanol. The aqueous solution remaining was extracted with diethyl ether (2×100 mL). The resulting aqueous layer was acidified with 2 N HCl causing the precipitation of an oil. The oil was purified by flash chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1). Fractions containing the desired product were combined, and concentrated in vacuo. The residue was triturated with dichloromethane, and filtered to afford the 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid as a yellow solid (0.645 g, 41%): mp 187.8-188.8° C. 1H NMR (acetone-d6, 300 MHz) 7.69 (s, 1H), 7.36 (s, 1H), 7.15 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=8.0 Hz), 6.60 (brs, 1H), 5.20 (m, 1H). ESHRMS m/z 276.0040 (M−H, Calc'd 276.0039). Anal. Calc'd for C11H7NO2F3Cl+2.6% H2O: C, 46.39; H, 2.98; N, 4.92. Found: C, 45.99; H, 2.54; N, 4.85.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:54]([O:56][CH3:57])=[O:55])=[C:25]([CH:53]=3)[O:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[N:32](C(OC(C)(C)C)=O)[CH:31]=[C:30]4[CH2:43][CH2:44][C:45]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:46])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:54]([O:56][CH3:57])=[O:55])=[C:25]([O:26][C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][CH:31]=[C:30]5[CH2:43][CH2:44][C:45]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:46])[CH:53]=3)[CH2:19][CH2:20]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1Oc1ccc2c(c1)c(CCC(=O)N1CCOCC1)cn2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1Oc1ccc2[nH]cc(CCC(=O)N3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 70C (300 mg) in dioxane (2 mL) was treated with concentrated aqueous hydrogen chloride (0.378 mL) and stirred at room temperature overnight. The solution was concentrated and the residue was used for the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([O:15]C)=[O:14])[CH:9]=[CH:8]2.[OH-].[Li+]>O1CCCC1>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2
Reactant: COC(=O)c1ccc2cccc(CN)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCc1cccc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.3 %

Procedure:
Part C--To a solution of methyl 8-aminomethyl-2-naphthoate (0.75 g, 0.0035 mol) in dry tetrahydrofuran (50 mL), cooled to 0° C., was added a solution of lithium hydroxide (0.5 M, 5.83 mL). All was stirred at ambient temperature over 20 hours. Another aliquot of lithium hydroxide was added and all was stirred for an additional 20 hours. The solid was collected and the filtrate was evaporated to dryness under reduced pressure. The solids were triturated with diethyl ether to give 8-aminomethyl-2-naphthoic acid (0.67 g, 0.0033 mol, 95%) as a white solid. mp=223-225° C.; 1H NMR (DMSO) d 8.6 (s, 1H), 8.1-7.9 (m, 1H), 7.8-7.7 (m, 4H), 7.55-7.5 (m, 1H), 7,45-7.35 (m, 2H), 4.2 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[O:14]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([O:12][CH3:11])=[O:14])(=[O:23])=[O:22])=[O:26])[N:7]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C

Procedure:
To an anhydrous suspension of 1.4 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 25 ml of methylene chloride was added with stirring at ambient temperature and pressure 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. The mixture was thereafter stirred for 16 hours and filtered. The filtrate was evaporated to dryness, the residue was triturated with butyl chloride and the product removed by filtration. The product thus obtained melted at 165°, and had absorption peaks in the infrared at 1550, 1600, 1680 and 1700 cm-1 and in the NMR spectrum at 2.5, 3.65, 4.0 with an aromatic multiplet at 7.2-8 ppm.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>>[NH3:3].[CH3:51][O:52][CH:53]1[CH2:58][CH2:57][N:56]([C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([C:4]4[N:3]([CH3:2])[C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[N:5]=4)[CH:13]=3)[CH2:19]2)=[O:25])[CH2:55][CH2:54]1
Reactant: COC1CCNCC1
Reactant: Cn1c(-c2cccc(N3CCC[C@@H](C(=O)O)C3)c2)nc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC1CCN(C(=O)[C@@H]2CCCN(c3cccc(-c4nc5ccccc5n4C)c3)C2)CC1
Product: N
Temperature: 35 °C
Yield: 77.1 %

Procedure:
Method M—Step a To a mixture of (R)-1-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid hydrochloride (obtained as described in general method 1, step d) (0.01 g, 0.30 mmol) (obtained as described in method A, step d) in dcm (2.5 mL), HATU (0.12 g, 0.33 mmol), TEA (0.09 mL, 0.63 mmol) and 4-methoxypiperidine (0.04 g, 0.33 mmol) were added. The reaction mixture was heated at 35° C. overnight, cooled to room temperature, washed with ammonium chloride solution (3 mL), filtered through a phase separator and organic solvent was removed. The crude was then purified by SCX column (eluent: first dcm:MeOH/1:1 then NH3 in MeOH (2N)) and flash chromatography (eluent: gradient from EtOAc:cyclohexane/10:0 to 0:10) to obtain 0.05 g of the title compound (38%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: NCCO
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NCCO)n2n1)c1cccnc1
Temperature: 120 °C
Yield: 29.3 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and ethanolamine (44 μL; 0.73 mmol; 5.0 eq), heated at 120° C., to give the title compound as a white solid (15 mg, 28%). HPLC, Rt: 1.91 min. (purity 97.9%). LC/MS, M+(ESI): 366.8, M−(ESI): 364.9.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.C1C=CC=CC=1>C(O)C1C=CC=CC=1>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:42]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: c1ccccc1
Solvent: OCc1ccccc1
Product: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)OCc3ccccc3)cccc12
Temperature: 100 °C
Yield: 87 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.4 gram of p-toluenesulfonic acid monohydrate in 10 ml of benzyl alcohol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 5 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residue, giving a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine benzyl ester di(p-toluenesulfonate) in 87% yield; mp. 150°-153° C.
Reaction SMILES: CO[CH:3](OC)[CH:4](Cl)[CH3:5].Cl.CC([O-])=O.[Na+].[NH2:15][C:16]1[NH:21][C:20](=[O:22])[NH:19][C:18](=[O:23])[CH:17]=1>O>[CH3:5][C:4]1[C:17]2[C:18]([OH:23])=[N:19][C:20]([OH:22])=[N:21][C:16]=2[NH:15][CH:3]=1
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Reactant: COC(OC)C(C)Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1c[nH]c2nc(O)nc(O)c12
Temperature: 95 °C
Yield: 92.3 %

Procedure:
To a mixture of 2-chloropropionaldehyde dimethyl acetal (5.84 g, 42.1 mmol) in H2O (26 mL) was added conc. HCl (1 mL). After heating at 95° C. for 15 min (or until the solution turns homogenous), NaOAc (5.2 g) was added to neutralize the excess HCl. The resulting solution was then transferred to a separate flask containing a suspension of 6-aminouracil (4 g, 31.5 mmol) and NaOAc (2.6 g) in H2O (52 mL). After heating the mixture at reflux overnight, the reaction was cooled and the precipitates were collected by filtration to give 5-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (4.8 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[N:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[NH2:16]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:16][C:15]2[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:13]([O:12][CH3:11])[CH:14]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Cl)c1cncc(Cl)n1
Reactant: COc1cc(N)cc(OC)c1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2cncc(Cl)n2)cc(OC)c1

Procedure:
The product from Example 15B was reacted with 3,5-dimethoxyaniline and TEA in CH2Cl2 as described in Example 15C to afford the title compound. MS (DCI/NH3) m/z 294 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[CH2:26]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)([OH:11])[C:8]([O:10][CH3:26])=[O:9])=[CH:5][CH:4]=1
Reactant: O=C(O)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CI
Product: COC(=O)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
38.5 g (0.115 mol) of 4,4′-di(trifluoromethyl)benzilic acid, 30.5 g (0.20 mol) of DBU, and 56.8 g (0.40 mol) of methyl iodide are reacted in 400 ml acetonitrile analogously to step I.10.3. The product is purified by flash chromatography (eluant cyclohexane/ethyl acetate 95:5). Yield: 20.05 g of white crystals (46% of theory); melting point: 68° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc2c(c1)[C@@H](OCc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)[C@@H](OCc1ccccc1)CC2
Reaction time: 8 h

Procedure:
To a solution of the title compound of Step 3 (62.7 mg, 0.175) in 1.00 ml of THF was added 1.00 ml of 6 N NaOH and 1.00 ml MeOH. The resulting mixture was stirred overnight. The mixture was acidified to neutral pH, concentrated and the title compound was purified on a Biotage MPLC.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([C:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[NH:66][CH:65]=2)[CH:59]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([C:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[NH:66][CH:65]=2)[CH:59]=1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: c1ccc2c(-c3cc([C@@H]4CCCN4)ccn3)c[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(-c2c[nH]c3ccccc23)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (75 mg, 0.29 mmol), HOBt (46 mg, 0.33 mmol) and HBTU (127 mg, 0.33 mmol) in DMF (5 mL) is stirred at room temperature for 30 min. Then a solution of 3-((S)-4-pyrrolidin-2-yl-pyridine-2-yl)-1H-indole (15) in DMF (5 mL) is added, followed by diisopropylethylamine (198 mg, 1.50 mmol). After stirring at room temperature for 2 h, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 5%˜40%) to give ((S)-1-Cyclohexyl-2-{(S)-2-[2-(1H-indol-3-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester as a yellow solid (120 mg, 78%). Mass M/Z=503.34 [M+1]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH:12]([CH3:14])[CH3:13])[C@@:7]([CH2:16][CH2:17][OH:18])([OH:15])[CH2:6][CH2:5]2.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:18][CH2:17][CH2:16][C@:7]2([OH:15])[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[C@H:8]2[CH:12]([CH3:13])[CH3:14])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@@H]1c2ccc(F)cc2CC[C@@]1(O)CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC[C@]2(O)CCc3cc(F)ccc3[C@H]2C(C)C)cc1
Temperature: 0 °C
Yield: 84.5 %

Procedure:
28.5 g (0.113 mol) of [1R,2R]-(-)-2-[6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl]ethanol were dissolved in 150 ml of pyridine and treated portionwise within 30 minutes at 0° with 31.5 g (0.165 mol) of p-toluenesulphonyl chloride. After 90 minutes the reaction solution was poured into ice-water and extracted with ether. The organic phase was washed in succession with 3N hydrochloric acid, water and a saturated sodium carbonate solution. After drying over magnesium sulphate and evaporation of the solvent under reduced pressure, the remaining oily residue was recrystallized from ether/hexane, yielding 38.8 g (85%) of [1R,2R]-(-)-2-[6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl]ethyl p-toluenesulphonate as white crystals, m.p. 65°-67°; [α]D20 =-54.1° (c=1, methanol).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:9]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:10]#[N:11])[CH2:7][CH3:8].[OH2:18]>C(OCC)C>[CH2:15]([C:9]([CH2:6][CH2:7][CH3:8])([CH2:12][CH2:13][CH3:14])[C:10]([NH2:11])=[O:18])[CH2:16][CH3:17]
Reactant: CCCC(C#N)(CCC)CCC
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCC(CCC)(CCC)C(N)=O
Temperature: 10 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
In a 2-liter flask an 80% aqueous solution of 550 g of sulphuric acid was placed. While stirring, 110 g (0.66 mol) of tri-n-propylacetonitrile were added over a period of 20 minutes and at room-temperature. The temperature of the reaction medium rose to 80° C after which it was brought up to 105°-110° C for 6 hours. The solution was then cooled to 10° C and slowly poured into iced water (1000 g of purified water and 200 g of ice.) A pasty precipitate gradually formed as the solution was added to the iced water. As soon as the operation was finished, the mixture was stirred for 15 minutes and the precipitate centrifuged out and taken up twice in 350 g of ethyl ether. The ethereal solution was first washed twice with 200 g of water containing 10% of sodium bicarbonate and then twice with 250 g of water. The mixture was dried for 24 hours over 125 g of anhydrous sodium sulphate after which the sodium sulphate was centrifuged out. The ether was then eliminated by means of a rotatory evaporator which provided an oil which crystallized into fine needles which were left under vacuum until a constant weight was obtained. By this means, 113 g of crude tri-n-propylacetamide were obtained which represents a yield of 92.6%. The crude product was then dissolved by heating in 150 g of petroleum ether. After dissolution, 1.15 g of CECA WSL black was added and the mixture refluxed for 30 minutes. The black was then filtered off while the mixture was still hot. The filtrate was cooled to -15° C for 3 hours after which the precipitate which formed was centrifuged out and dried for 24 hours in a drying-oven at 40° C under 20 mm. Hg vacuum. In this way, 98.5 g of pure tri-n-propylacetamide were obtained which represents a yield in pure product of 87.1%. M.P. 69° C.