Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([CH2:27][NH:28][C:29]3[N:33]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=4[Cl:41])[N:32]=[N:31][N:30]=3)=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[C:3]([OH:5])(=[O:4])[CH3:2].[Cl:41][C:35]1[C:36]([Cl:40])=[CH:37][CH:38]=[CH:39][C:34]=1[N:33]1[C:29]([NH:28][CH2:27][C:26]2[C:21]([N:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[N:30][N:31]=[N:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2CNc2nnnn2-c2cccc(Cl)c2Cl)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O
Product: Clc1cccc(-n2nnnc2NCc2cccnc2N2CCNCC2)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Trifluoroacetic acid (45 mL) was added to a solution of Example 315C (5.72 g, 11.32 mmol) in dichloromethane (220 mL) at 0° C. After 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The residue was partitioned between dichloromethane and 1.0 N sodium hydroxide. The organic solvent was removed and the residue was purified by preparative HPLC on a Thermoquest, hyperprep HS C18 column (250×21.2 mm., 8 μm particle size) using a gradient of 5% to 75% acetonitrile to ammonium acetate (10 mM) over 20 minutes at a flow rate of 21 mL/min to provide the title compound. MS (ESI+) m/z 405.4 (M+H)+; Rt=1.37 min. 1H-NMR (400 MHz, DMSO-d6) δ 8.180 (m, 1H); 7.942 (m, 1H); 7.728 (m, 1H); 7.668 (m, 1H); 7.612 (m, 2H); 7.000 (m, 1H); 4.498 (m, 2H); 2.961 (m, 4H); 2.842 (m, 4H); 1.891 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2](=[O:1])[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=c1ccc([N+](=O)[O-])cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
[Ref. Mederski, W. W. K. R., et al. Tetrahedron, 1999, 55, 12757-12770.] To a solution of 2-hydroxy-5-nitropyridine (1.07 g, 7.64 mmol) in dry methylene chloride (50 mL) were added phenylboronic acid (1.86 g, 15.3 mmol), cupric acetate (1.71 g, 9.41 mmol), pyridine (1.2 mL, 15.3 mmol), triethylamine (2.1 mL, 15.3 mmol) and activated 4 Å molecular sieves (2 g). The resulting mixture was stirred in air at rt for 2 d. The mixture was then filtered through celite and washed with methylene chloride. The crude material was purified by silica gel chromatography, eluting with CH2Cl2:EtOAc (85:15) to give the title compound as a white solid. LC-MS (ES, Pos.): 217 [MH+], and 1H NMR (CDCl3, 400 MHz): δ=6.67 (d, J=10.1 Hz, 1H), 7.39-7.42 (m, 2H), 7.53-7.58 (m, 3H), 8.17 (dd, J=10.1, 3.1 Hz, 1H), 8.67 (d, J=3.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:35][CH3:36])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:47])[C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40]>>[CH3:37][N:38]([CH3:47])[C:39]([N:41]1[CH2:42][CH2:43][N:44]([C:20]([N:11]2[C@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH2:35][CH3:36])[N:9]=[C:10]2[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH:32]([CH3:33])[CH3:34])=[O:21])[CH2:45][CH2:46]1)=[O:40]
Reactant: CCC1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)Cl)C1c1ccc(Cl)cc1
Reactant: CN(C)C(=O)N1CCNCC1
Product: CC[C@@]1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)N2CCN(C(=O)N(C)C)CC2)[C@@H]1c1ccc(Cl)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4-ethyl-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine-1-carboxylic acid dimethylamide (Aldrich) to give the title compound. LC-MS: 666.3 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=4)=[CH:16][C:9]=23)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[N:18]=4)=[CH:16][C:9]=23)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nccc(-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)n1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nccc(-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)n1
Temperature: 100 °C
Yield: 30 %

Procedure:
To a suspension of 4-[3-(4-chlorophenyl)-benzo[c]isoxazol-5-yl]-pyrimidin-2-ylamine in toluene (1.5 mL) at room temperature, was added acetic anhydride (0.5 mL). The mixture was heated at 100° C. for 3 hours. The reaction mixture was diluted with water (6 mL) and the precipitate filtered then washed with toluene (2×6 mL). Purification was achieved by silica gel chromatography (4:1 ethyl acetate/hexane then 2% methanol/dichloromethane), followed by a 5% aqueous sodium bicarbonate wash (1×50 mL) to give the title compound as a yellow solid (12 mg, 30% yield). 1H NMR (500 MHz, d6-DMSO) δ 10.62 (s, 1H), 8.85 (s, 1H), 8.75 (d, 1H), 8.31 (d, 1H), 8.25 (d, 2H), 8.02 (d, 1H), 7.85 (d, 1H), 7.75 (d, 2H), 2.3 (s, 3H) ppm. LC-MS (ES+) m/e=365.13 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[S:16](Cl)(Cl)(=[O:18])=[O:17]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:16]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:18])=[O:17])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1cc(Br)cnc1Cl
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)N1CCOCC1
Temperature: -40 °C
Yield: 36.7 %

Procedure:
A 50 mL round-bottomed flask was charged with 5-bromo-2-chloropyridin-3-amine (0.863 g, 4.2 mmol) and pyridine (5 mL). To this solution, DMAP (0.13 g, 1.0 mmol) and morpholine (0.36 mL, 4.2 mmol) were added in. The mixture was chilled to −40° C. in a dry ice/acetone bath. Then sulfuryl chloride (0.36 mL, 4.6 mmol) was added dropwise into the mixture while stirring. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere at 25° C. for 15 h. The mixture was diluted with aqueous sodium bicarbonate and extracted by DCM (3×). The combined organic was dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (1 to 50% EtOAc/DCM) gave N-(5-bromo-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.55 g, 37% yield) as a tan crystalline solid. MS (ESI positive ion) m/z: 358 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 3.07-3.12 (m, 4H), 3.58-3.62 (m, 4H), 8.07 (d, J=2.15 Hz, 1H), 8.42 (d, J=2.35 Hz, 1H), 10.19 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[C:12]1([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)Oc1ccccc1
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: O=C1Cc2ccc(-c3ccccc3)cc2N1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
2.4 g of 6-bromo-2-indolinone are placed in 60 ml of dimethoxyethane, 1.9 g of phenylboric acid in 8 ml of ethanol and 0.3 g of tetrakistriphenylphosphine palladium are added and to this mixture 12 ml of 2N sodium carbonate solution are added dropwise at ambient temperature. The mixture is stirred for 6 hours at 85° C. After cooling the catalyst is filtered off, the solvent is eliminated and the residue is washed with 100 ml of water and 20 ml of 1N sodium hydroxide solution. The residue is purified through a silica gel column with petroleum ether/ethyl acetate (8:2) as eluant.
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5](P(=O)(OCC)OCC)[C:4](=[O:15])[NH:3]1.C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH2:24][CH2:25][CH3:26].[CH2:27]([C:31]1[N:32]([CH2:38][C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)[C:33]([CH:36]=O)=[CH:34][N:35]=1)[CH2:28][CH2:29][CH3:30]>CN(C=O)C.O.C(Cl)Cl>[CH2:27]([C:31]1[N:32]([CH2:38][C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)[C:33](/[CH:36]=[C:5]2\[NH:6][C:2](=[O:1])[N:3]([CH2:23][CH2:24][CH2:25][CH3:26])[C:4]\2=[O:15])=[CH:34][N:35]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCI
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: CCOP(=O)(OCC)C1=NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (1.5 g, 6.33 mmol) in DMF (4 mL) is added K2CO3 and then 1-iodobutane (0.79 mL, 6.96 mmol). This mixture is stirred for 16 hours at room temperature. To this yellow mixture is added methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate (1.05 g, 3.5 mmol). After 2 hours methylene chloride (10 mL) was added to aid stirring. The mixture was stirred for 16 hours. After diluting the reaction mixture with water it was extracted with ethyl acetate. This extract was washed with water and brine. The extract was dried over MgSO4,filtered and then concentrated until crystallization was apparent. The solid was collected and dried.
Reaction SMILES: Cl.COC(=O)[C@H]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])CC1C=CC(NC(OC(C)(C)C)=O)=C(C)C=1CO.Cl.[CH3:37][O:38][C:39](=[O:58])[C@@H:40]([CH2:46][C:47]1[C:48]([CH2:56][Cl:57])=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][N:51]=[CH:50]2)CC(OC)=O>>[ClH:57].[CH3:37][O:38][C:39](=[O:58])[C@H:40]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:46][C:47]1[C:48]([CH2:56][Cl:57])=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][N:51]=[CH:50]2
Reactant: COC(=O)[C@@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1CO)NC(=O)OCc1ccccc1
Reactant: COC(=O)C[C@H](Cc1ccc2[nH]ncc2c1CCl)C(=O)OC
Agent: Cl
Product: COC(=O)[C@@H](Cc1ccc2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Yield: 99 %

Procedure:
2-(R)-Benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionic acid methyl ester hydrochloride was reacted in a manner analogous to the preparation of 2-(S)-(4-chloromethyl-1H-indazol-5-ylmethyl)-succinic acid dimethyl ester hydrochloride. Title compound was obtained as an orange solid in 99% yield. 1H NMR (300 MHz, CD3OD): δ=8.43 (s, 1H), 7.50 (d, J=8.8, 1H), 7.38 (d, J=8.4, 1H), 7.24 (m, 5H), 5.06 (d, J=11.0, 1H), 4.98 (d, J=4.8, 2H), 4.56 (dd, J1=5.7, J2=9.3, 1H), 3.71 (s, 3H), 3.42 (dd, J1=5.5, J2=14.3, 1H), 3.17 (dd, J1=9.3, J2=14.1, 1H). MS m/e (M+H)+=402.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[O:24][C:23]([CH3:26])=[CH:22][C:21]3=[O:27])[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2].CCCC(C)C.C(O)C.C(NCC)C>>[C:1]([C:3]1[C@@H:4]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[O:24][C:23]([CH3:26])=[CH:22][C:21]3=[O:27])[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1cccc2c(=O)cc(C)oc12
Solvent: CCO
Solvent: CCNCC
Solvent: CCCC(C)C
Product: CCOC(=O)C1=C(C)NC(C)=C(C#N)[C@H]1c1cccc2c(=O)cc(C)oc12

Procedure:
536 mg (1.45 mmol) of racemic ethyl 5-cyano-2,6-dimethyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydropyridine-3-carboxylate (example 7) are separated into the enantiomers by preparative HPLC on a chiral phase [column: Chiralpak AS-H, 250 mm×4.6 mm; eluent: isohexane/ethanol 3:1 (v/v)+0.2% diethylamine; flow rate: 1 ml/min; W detection: 220 nm]:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Cl)[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=C3C(I)=[CH:31]2)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:38][C:37]3[CH:36]=[N:35][C:34]([S:7]([CH3:1])(=[O:9])=[O:8])=[N:30][CH:31]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cccnc21
Product: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cn1

Procedure:
was prepared following the protocol of Scheme 191, substituting 1 benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 581 with 1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-b]pyridine in Step 1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]([CH3:14])[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[C:15](Cl)(Cl)=[O:16].C1(C)C=CC=CC=1.[CH3:26][S:27][CH2:28][CH2:29][NH2:30]>ClCCCl>[CH3:1][N:2]([C:3]1[N:4]([CH3:14])[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)[C:15]([NH:30][CH2:29][CH2:28][S:27][CH3:26])=[O:16]
Reactant: O=C(Cl)Cl
Reactant: CSCCN
Reactant: CNc1cc(-c2cccnc2)nn1C
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CSCCNC(=O)N(C)c1cc(-c2cccnc2)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
To a solution of methyl-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-amine (150 mg, 0.8 mmol) in ice-cold DCE (2 mL) under N2 was added a solution of phosgene in toluene (20%, 0.43 mL, 0.88 mmol). The ice bath was removed after 30 min, and the mixture was stirred at room temperature for 1 h and at reflux for 2 h. The mixture was cooled to room temperature and then more phosgene (0.86 mL, 1.76 mmol) was added. The mixture was stirred at reflux for 90 min and then cooled in an ice bath. To this was added a solution of 2-methylthioethylamine (80 mg, 0.88 mmol) in DCE (2 mL). The ice bath was removed after 10 min, and the reaction mixture was stirred at reflux for 14 h, cooled, and diluted with DCE (30 mL). The diluted reaction mixture was washed with saturated NaHCO3 (20 mL), dried over MgSO4, adsorbed onto silica gel and purified using silica gel chromatography eluting with a gradient of methanol in dichloromethane to afford 1-methyl-1-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-3-(2-methylsulfanyl-ethyl)-urea as a yellow gum (14 mg, 6%): 1H NMR (400 MHz, CDCl3) δ 8.99 (d, J=1.5 Hz, 1H), 8.57 (dd, J=4.8, 1.5 Hz, 1H), 8.08 (ddd, J=8.1, 2.1, 2.1 Hz, 1H), 7.34 (dd, J=7.9, 4.8 Hz, 1H), 6.52 (s, 1H), 4.88 (br t, J=5.5 Hz, 1H), 3.80 (s, 3H), 3.41 (q, J=6.3 Hz, 2H), 3.24 (s, 3H), 2.61 (t, J=6.3, 2H), 2.06 (s, 3H); ESIMS (m/z) 292.2 [M+2].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(OCC)(=O)C>[N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([NH:25][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)=[O:11])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: Nc1cnc2ccccc2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (2R)-2-{[(tert-butoxy)carbonyl]amino}-4-[4-(trifluoromethyl)phenyl]butanoic acid V (0.97 g, 2.79 mmol) and 3-aminoquinoline VI (0.45 g, 3.10 mmol) in ethyl acetate (30 mL) was added DMT-MM (1.0 g, 3.63 mmol). After being stirred at r.t. overnight, the reaction was washed with water, 1N HCl, aq. sat. NaHCO3, water and dried over Na2SO4. The solvent was removed under reduced pressure to afford tert-butyl N-[(1R)-1-[(quinolin-3-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamate (1.23 g, 2.59 mmol, 93% yield). ESIMS found for C25H26F3N3O3 m/z 474 (M+H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C([O:32]C(NC1CCN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[C:22]([OH:32])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Product: Cl
Product: NC1CCN(S(=O)(=O)c2cccc3c(O)ncc(Cl)c23)C1

Procedure:
Intermediate 16 is used in the method of Example 6, Step A instead of Intermediate 1, then the resultant is used in the method of Step B in a similar manner, and then the title compound is obtained as hydrochloride according to the method described in Example 7.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][S:14][CH3:15])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:24](OC1C=CC([N+]([O-])=O)=CC=1)=[O:25].[CH3:36][N:37]([CH3:46])[C:38](=[O:45])[C@H:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[NH2:40].Cl.CNC>ClCCCl>[CH3:46][N:37]([CH3:36])[C:38]([C@@H:39]([NH:40][C:24]([N:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=2[N:8]([CH2:12][CH2:13][S:14][CH3:15])[C:9]1=[O:11])=[O:25])[C:41]([CH3:43])([CH3:42])[CH3:44])=[O:45]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CSCCn1c(=O)[nH]c2cccc(C)c21
Reactant: CN(C)C(=O)[C@@H](N)C(C)(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CSCCn1c(=O)n(C(=O)N[C@H](C(=O)N(C)C)C(C)(C)C)c2cccc(C)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of 7-methyl-1-[2-(methylthio)ethyl]-1,3-dihydro-2H-benzimidazol-2-one (0.21 g, 0.93 mmol) in 1,2-dichloroethane (5 mL) were added triethylamine (0.43 mL, 3.1 mmol) and 4-nitrophenyl chloroformate (0.23 g, 1.1 mmol) at 0° C. and the mixture was stirred at rt for 4 h. Then to this mixture was added a solution of N,N-dimethyl-tert-leucinamide (ca. 1.4 mmol, prepared according to the procedure described in steps 1 and 2 of example 3 from dimethylamine hydrochloride) in 1,2-dichloroethane (3 mL) at 0° C. and stirred rt. After 14 h, the reaction was quenched by addition of water (50 mL) and extracted with dichloromethane (50 mL×2). The combined organic layers were washed with water (30 mL×4), brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC eluting with dichloromethane/methanol (10/1) to afford 0.31 g (83%) of the title compound.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH3:2].[Cl:12][CH:13]=[CH:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:12]/[CH:13]=[CH:14]/[CH2:15][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH2:1][CH3:2]
Reactant: CCNCc1cccc(O)c1
Reactant: ClC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCN(C/C=C/Cl)Cc1cccc(O)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of 34.96 g (0.231 mol) of N-ethyl-3-hydroxybenzylamine in 200 ml of dimethylsulfoxide were added 25.64 g (0.231 mol) of 1,3-dichloropropene (E/Z=2/1) and 16.7 g (0.121 mol) of ground potassium carbonate under ice cooling. The mixture was stirred for 4 hours at 50° C., poured into 250 ml of ethyl acetate, washed with 200 ml×2 of water and 200 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to-silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together-and concentrated under reduced pressure to obtain 26.2 g (yield: 50%) of the above identified compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[C:6]([CH:9]=1)C=O.[CH3:11][O:12][CH:13](OC)[O:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:6]([CH:13]([O:14][CH3:15])[O:12][CH3:11])[C:5]([Cl:10])=[N:4][CH:3]=1
Reactant: O=Cc1cc(Br)cnc1Cl
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(OC)c1cc(Br)cnc1Cl

Procedure:
A mixture of 5-bromo-2-chloronicotinaldehyde (981 mg, 2.43 mmol), trimethylorthoformate (1.46 mL, 13.4 mmol) and p-toluenesulfonic acid monohydrate (42.3 mg, 0.222 mmol) in MeOH (18 mL) was refluxed for 16 hours. The mixture was diluted in CH2Cl2 and washed with 10% aqueous potassium carbonate and brine, dried over sodium sulfate, filtered and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([CH2:13][NH:14][C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[S:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:14]([CH2:13][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:15](=[S:16])[N:17]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:4](=[O:5])[CH:3]=1
Reactant: S=C(NCC1CCCCC1)NCC1CCCCC1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)n(CC2CCCCC2)c(=S)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of cyanoacetic acid (Aldrich, 1.23 g, 14.3 mmol) and 1,3-bis(cyclohexylmethyl)thiourea (from step (a), 3.50 g, 13.0 mmol) in acetic anhydride (8.1 mL) was stirred at 70° C. for 2 h under nitrogen. Volatiles were removed in vacuo and the residual oil was dried by evaporation of portions of 10% water-ethanol (3×50 mL). The resulting solids were dissolved in ethanol (12 mL)-water (28 mL) at reflux with adjustment of the pH to 11 by addition of 10% aqueous sodium carbonate. After 1 h, the mixture was cooled to ambient temperature, volatiles were removed under vacuum, and the residue was chromatographed on silica gel. 6-Amino-1,3-bis(cyclohexylmethyl)-1,2-dihydro-2-thioxo-4(3H)-pyrimidinone eluted with 4% methanol in chloroform, and was recrystallized from 2% ethyl acetate in hexanes to provide an off-white powder (2.27 g, 50%), m.p. 147°-150° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]2[N:10]([CH3:21])[N:11]=[C:12]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:3]=12.ClC1N=C[N:26]=C2N(C)N=C(C3OC([N+]([O-])=O)=CC=3)C=12>>[NH2:26][C:2]1[N:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]2[N:10]([CH3:21])[N:11]=[C:12]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:3]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Reactant: CCc1nc(Cl)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1
Product: CCc1nc(N)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1

Procedure:
The procedure described in Example 3b was repeated using 4-chloro-6-ethyl-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine as starting material instead of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, the reaction conditions being the same. The crystalline product was recrystallised from dimethyl formamide to give 4-amino-6-ethyl-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, having decomposition point 294°C.