Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][C:22]([F:26])([F:21])[CH2:23]2)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Clc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Reactant: FC1(F)CNC1
Agent: Cl
Product: FC1(F)CN(c2nc(Cl)nc3c2COCC3c2ccc(Cl)cc2)C1
Yield: 67.9 %

Procedure:
2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation K) (500 mg, 1.584 mmol) and 3,3-Difluoroazetidine hydrochloride (308 mg, 2.377 mmol) were combined and purified as per Preparation Ha to give 2-chloro-8-(4-chlorophenyl)-4-(3,3-difluoro azetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (400 mg, 1.075 mmol, 67.8% yield) as a white solid. LC-MS (M+H)+=372.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.22-7.34 (2H, m), 7.12 (2H, d, J=8.24 Hz), 4.63-4.85 (2H, m), 4.46-4.64 (3H, m), 4.04-4.17 (1H, m), 3.91-4.04 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[CH:22]([O:25][C:26]1[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=1)([CH3:24])[CH3:23]>C1COCC1>[Cl:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:31][C:28]2[CH:27]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[NH:30][N:29]=2)=[N:3][C:2]=1[Cl:1]
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(Cl)c(Cl)cc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 27.3 %

Procedure:
To a mixture of 2,3,6-trichloro-5-nitropyridine (2.61 g, 11.4 mmol) and DIEA (1.90 ml, 11.4 mmol) in THF (50 ml) was added the 5-isopropoxy-1H-pyrazol-3-amine (1.20 g, 8.50 mmol) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 5 days. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (hexane-EtOAc=2.5:1) to give the title compound as a yellow solid (0.77 g, 27%). 1H NMR (400 MHz) δ 12.26 & 11.64 (s, 1H), 10.42 & 10.04 (s, 1H), 8.81 & 8.77 (s, 1H), 6.02 & 5.94 (s, 1H), 4.70 & 4.48 (m, 1H), 1.32 (d, J=6.0 Hz, 3H), 1.27 (d, J=6.0 Hz, 1H). MS: Calcd.: 331. Found: [M+H]+ 332.
Reaction SMILES: [OH2:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]([NH2:33])([CH3:32])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1>CS(C)=O>[CH3:32][C:21]([N:33]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:1])([CH3:20])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1
Reactant: O
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Reactant: CC(C)(N)Cc1ccc2c(c1)OCO2
Solvent: CS(C)=O
Product: CC(C)(Cc1ccc2c(c1)OCO2)N=C(OCc1ccccc1)C(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
1.31 g of 2-benzyloxyphenylglyoxal hydrate are dissolved in 3.5 ml of dimethylsulfoxide, and 0.97 g of α,α-dimethyl-3,4-methylenedioxyphenethylamine are added thereto. The mixture is stirred at 23° C. for 45 minutes, whereby a solution of α-(α,α-dimethyl-3,4-methylenedioxyphenethylimino)-2-benzyloxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]=1)[NH:11][C:10](=[O:16])[C:9]([CH2:17][CH3:18])=[CH:8]3.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:2][C:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]=1)[NH:11][C:10](=[O:16])[C:9]([CH2:17][CH3:18])=[CH:8]3)=[N+:21]=[N-:22]
Reactant: CCc1cc2c([nH]c1=O)c(C)cc1cc(CBr)oc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c([nH]c1=O)c(C)cc1cc(CN=[N+]=[N-])oc12
Temperature: 120 °C
Reaction time: 1.67 h
Yield: 85.5 %

Procedure:
To a solution of the compound obtained in Example 308 (3.04 g, 9.45 mmol) in dimethylformamide (150 ml), sodium azide (1.54 g, 26.6 mmol) was added, and the solution was stirred at 120° C. for 100 minutes. The reaction liquid was condensed under reduced pressure, and the residue was extracted from a solvent mixture of chloroform-methanol (4:1). The organic phase was washed with saturated aqueous NaCl solution, dried over sodium sulfate, and condensed under reduced pressure. The resultant residue was recrystallized from chloroform-methanol-hexane. 2.28 g of the title compound was obtained as colorless needles (84.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.CN1CC[O:19][CH2:18]C1.C(O)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:18]([NH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1)=[O:19]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=CO
Product: CC(C)(C)OC(=O)c1ccc(NC=O)cc1
Reaction time: 18 h

Procedure:
Combined tert-butyl 4-aminobenzoate (15.3 g, 79 mmol), DMAP (1.935 g, 15.84 mmol), N-methylmorpholine (15.67 mL, 143 mmol) in DCM (120 mL) and, after cooling to 0° C., slowly added formic acid (9.11 mL, 238 mmol). After stirring for 18 h, the reaction was concentrated and then partitioned with 1N HCl (100 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layer was washed with brine (50 mL) and dried (MgSO4). The desired product was collected as yellow syrup (16 g).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]([OH:26])[CH2:24][N:25]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>O1CCCC1>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[O:21][CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]([O:26][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:24][N:25]=2)=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Temperature: 50 °C
Yield: 31.6 %

Procedure:
Phenyl isocyanate (2 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(4-tert-butylphenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (3.2 g) in anhydrous tetrahydrofuran (35 cc). The solution obtained is heated to 50° C. for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is purified by chromatography on silica (0.063-0.2 mm; 200 g) contained in a column 3.5 cm in diameter, collecting 20-cc fractions. Fractions 22 to 29, eluted with a mixture of cyclohexane and ethyl acetate (7:3 by volume), are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is again purified by chromatography on silica (0.063-0.2 mm; 200 g) contained in a column 2.5 cm in diameter, collecting 10-cc fractions. Fractions 19 to 25, eluted with a mixture of dichloromethane and methanol (98:2 by volume), are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in ethyl acetate, (5RS, 6SR)-2-(4-tert-butylphenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.4 g), m.p. 80° C., is obtained.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[NH2:38])=[CH:31][CH:30]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:41])[C:37]([CH3:39])([CH3:40])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)N)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1Oc1ccc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 189.1 %

Procedure:
In a 50 mL round-bottomed flask N-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-2-methylalaninamide (Intermediate 80, 144.4 mg) was dissolved in dichloromethane (5 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (27.7 mg, 0.227 mmol), triethylamine (0.158 mL, 1.134 mmol) and triphosgene (67.3 mg, 0.227 mmol) were added. The reaction mixture was stirred at 0° C. After 20 min, the solvent was evaporated under vacuum to afford a yellow solid which was purified via silica gel chromatography (Biotage system, 10 g SNAP column) using as eluent a gradient Cyclohexane/EtOAc from 2:1 to 1:3 in 20 CV; then 1:3 for 5 CV. The collected fractions afforded the title compound as a white solid (139.7 mg).
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([OH:15])(=[O:14])[CH2:12][SH:13]>[OH-].[K+].O>[Cl:10][C:9]1[C:2]2[S:13][C:12]([C:11]([OH:15])=[O:14])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CS
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2cccc(Cl)c2s1
Temperature: 125 °C
Yield: 83.8 %

Procedure:
In a glass pressure bottle, 2,3-dichlorobenzaldehyde (17.5 g, 0.1 mol) was added to a solution of thioglycolic acid (7.0 ml) in potassium hydroxide (12.5 g) and water (100 ml). The bottle was then sealed and heated in a hot oil bath to 125±5° C. for 1.25 hours. The bottle was then removed from the hot oil bath and cooled. A pale yellow precipitate was obtained in the bottle. At ambient temperature, the bottle was opened and sufficient water was added to dissolve the precipitate. The resultant aqueous material was washed with ether and then acidified with hydrochloric acid to produce a pale yellow solid. The pale yellow solid was collected on a filter, washed with water and dried, to produce 17.2 g of 7-chloro-2-benzo[b]thiophenecarboxylic acid (83.8% yield, mp 262-265° C.)
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[S:3][C:2]=1[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH3:25][C:26](OC(C)=O)=[O:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:26]([N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[C:2]([C:10]3([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=4)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[S:3][C:4]=2[CH2:5]1)(=[O:27])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(C2(c3nc4c(s3)CNCC4)CCOCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCc2nc(C3(c4ccc(C(=O)O)cc4)CCOCC3)sc2C1

Procedure:
4-[4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid (40 mg, 0.116 mmol) in pyridine, catalytic amount of 4-dimethylaminopyridine (DMAP), and excess Ac2O were mixed together at room temperature. After the reaction was complete, the mixture was evaporated, washed with water, and extracted with EtOAc. The organic phase was dried and evaporated to give 4-[4-(5-acetyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid. Similar HATU coupling procedure from Example 9 was followed to obtain the title compound. MS found for C26H28N4O3S as (M+H)+477.58. 1H NMR (400 MHz, dmso-d6): δ: 9.53 (s, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.51 (t, J=8.4 Hz, 2H), 7.10 (d, J=7.2 Hz, 1H), 6.92 (t, J=7.6 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.54 (t, J=7.6 Hz, 1H), 4.84 (s, 2H), 4.61-4.57 (m, 2H), 3.69-3.57 (m, 6H), 2.80-2.29 (m, 6H), 2.05-1.98 (m, 3H).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][C@H:13]1[C:14](=[O:27])[N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][C@H:13]1[C:14](=[O:27])[N:15]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N
Reaction time: 3 h
Yield: 97.4 %

Procedure:
Preparation A3, Step 1: (1R,2S,5R)-Tert-butyl 2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (4.0 g) in MeOH (30 mL) was charged with 10% Pd/C, Degussa (600 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 1 atm of H2 for 3 h and then filtered and concentrated to provide (1R,2S,5R)-tert-butyl 2-amino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.5 g). MS (ES+)=241.1 (M+H)+.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 78.5 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.1 g, 0.38 mmol) was reacted with 4-nitrobenzaldehyde (0.057 g, 0.38 mmol) in the presence of glacial acetic acid (0.023 g, 0.38 mmol) in 1,2-dichloroethane (20 ml), and then reduced by NaCNBH3 (0.03 g, 0.45 mmol) in methanol (5 ml) (Procedure D) to give compound 16d (0.12 g, 80%) as an oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.O1CCOCC1.[F:25][C:26]([F:62])([F:61])[C:27]1[CH:28]=[C:29]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[CH2:30][N:31]1[CH2:38][CH2:37][CH2:36][NH:35][C:34]2[N:39]=[C:40](S(C)(=O)=O)[N:41]=[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:33]=2[C:32]1=[O:53]>C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:40]2[N:41]=[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:33]3[C:32](=[O:53])[N:31]([CH2:30][C:29]4[CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=[C:27]([C:26]([F:62])([F:25])[F:61])[CH:28]=4)[CH2:38][CH2:37][CH2:36][NH:35][C:34]=3[N:39]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nc2c(c(-c3ccccc3)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2nc3c(c(-c4ccccc4)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)CC1
Yield: 69.2 %

Procedure:
1-acetylpiperazine(23.1 mg), diisopropylethylamine(0.1 mL), and 1,4-dioxane (1 mL) were added to 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(methylsulfonyl)-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 16; 83.8 mg). While heated, the mixture was refluxed for 5 hours. Subsequently, the reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. Following removal of the solvent, the residue was purified on a silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain 2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine (63.0 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH2:24].C1C=CC2N([OH:34])N=NC=2C=1.CCN=C=NC[CH2:41][CH2:42]N(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:11]([F:13])([F:14])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH:24][C:41](=[O:34])[CH3:42]
Reactant: On1nnc2ccccc21
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in DMF (5 mL) was added 2,2,2-trifluoropropanoic acid (97 mg, 0.76 mmol), HOBt.H2O (174 mg, 1.14 mmol) and EDC.HCl (217 mg, 1.14 mmol) and DIPEA (196 mg, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; EtOAc in hexane (30-50% afforded the title compound as an off-white solid (0.2 g, 60%): mp 127-128° C.; 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 4H), 7.24 (m, 2H), 6.53 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.86 (br s, 1H), 4.51 (d, J=6.0 Hz, 2H), 4.05 (m, 1H), 2.02 (s, 3H); ESIMS m/z 436.03 ([M+H]+).
Reaction SMILES: CN1C=C(S(Cl)(=O)=O)N=C1.O1C2C=CC(C3C(OCCOC4N=CC(Cl)=CN=4)=NN(C)C=3N)=CC=2OC1.CN(C1C=CC=CN=1)C.[O:47]1[C:51]2[CH:52]=[CH:53][C:54]([C:56]3[C:57]([O:81][CH2:82][CH2:83][O:84][C:85]4[N:90]=[CH:89][C:88]([Cl:91])=[CH:87][N:86]=4)=[N:58][N:59]([CH3:80])[C:60]=3[N:61](S(C3N=CN(C)C=3)(=O)=O)[S:62]([C:65]3[N:66]=[CH:67][N:68]([CH3:70])[CH:69]=3)(=[O:64])=[O:63])=[CH:55][C:50]=2[O:49][CH2:48]1>N1C=CC=CC=1>[O:47]1[C:51]2[CH:52]=[CH:53][C:54]([C:56]3[C:57]([O:81][CH2:82][CH2:83][O:84][C:85]4[N:90]=[CH:89][C:88]([Cl:91])=[CH:87][N:86]=4)=[N:58][N:59]([CH3:80])[C:60]=3[NH:61][S:62]([C:65]3[N:66]=[CH:67][N:68]([CH3:70])[CH:69]=3)(=[O:63])=[O:64])=[CH:55][C:50]=2[O:49][CH2:48]1
Reactant: Cn1cnc(S(=O)(=O)N(c2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)S(=O)(=O)c2cn(C)cn2)c1
Agent: CN(C)c1ccccn1
Agent: Cn1cnc(S(=O)(=O)Cl)c1
Agent: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N
Solvent: c1ccncc1
Product: Cn1cnc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)c1
Reaction time: 48 h

Procedure:
1-Methyl-1H-imidazole-4-sulfonyl chloride (45 mg) was carefully added at room temperature under an atmosphere of nitrogen to a solution of 4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-ylamine (Preparation 48) (50 mg) and dimethylaminopyridine (16 mg) in anhydrous pyridine (2.4 ml). The reaction was stirred for two days, then the mixture was concentrated under reduced pressure and a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml) and brine (6 ml) were sequentially added. The aqueous phase was extracted with ethyl acetate (2×8 ml) and the combined organic phases were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The black residue was purified by preparative TLC (silica) eluted with dichloromethane:methanol (95:5) yielding a mixture of title compound and N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-1-methyl-N-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-1H-imidazole-4-sulfonamide. The title compound was purified by HPLC (5.4 mg).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH2:10]1.Cl[C:23]1[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1.[Cl-].[NH4+]>C(OCC)(=O)C.C(#N)C>[NH2:29][C:27]1[N:28]=[C:23]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:16])[CH2:10]2)[CH:24]=[CH:25][C:26]=1[N+:30]([O-:32])=[O:31]
Reactant: O=C([C@@H]1CCCNC1)N1CCCC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Temperature: 17.5 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
Triethylamine (4.65 kg, 46 mol) was added over a period of 1 h to a mixture of (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (4.8 kg, 22 mol) and acetonitrile (48 L), maintaining a temperature of 15-20° C. The mixture was held at that temperature for 30 min, then was warmed to 38-42° C. 6-Chloro-3-nitropyridin-2-amine (3.8 kg, 22 mol) was added portion-wise, and the mixture was held at 38-42° C. for 3 h. The mixture was then cooled to 15-20° C. and an aqueous solution of ammonium chloride (prepared from 6.24 kg ammonium chloride and 48 L water) and ethyl acetate (48 L) were added sequentially, and the layers were stirred and then separated. The aqueous layer was further extracted with ethyl acetate (2×24 L). The combined organic layers were washed with an aqueous solution of sodium chloride (prepared from 4.8 kg sodium chloride and 24 L water) and then were dried with sodium sulfate (1.92 kg). The organic layer was removed and solvent was evaporated under reduced pressure at 40° C. Ethyl acetate (14.4 L) was added to the crude product, and the mixture was heated to 35-40° C. and was held at that temperature for 15 min. The mixture was cooled to 20-25° C. and held at that temperature for 6 h, then cooled to 10-15° C. and held at that temperature for 1 h. The suspension was centrifuged and the mother liquor was removed. The resulting cake was washed with chilled ethyl acetate (4.8 L) and then was dried at 40-50° C. to afford (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (4.6 kg, 66%). HPLC retention time: 5.30 min (Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase A: 0.1% orthophosphoric acid and 2% acetonitrile in water, Mobile Phase B: acetonitrile; Gradient: 20% B to 90% B over 7 min, then held for 3 min; Flow: 0.8 mL/min; Temperature: 25° C.; UV detection at 210 and 226 nM). Melting point: 118.5-123.5° C. Water content by Karl Fischer titration: 0.36% by weight.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[F:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>>[F:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:6][CH:7]=1)=[O:34]
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1F
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)c2ccccc2F)cc1

Procedure:
Synthesis in analogy to Example 8 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and 2-fluoro-benzoyl chloride to yield 2-fluoro-N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-benzamide. LC/MS at 254 nm; [M+H] 506; Rt 3.438 min.
Reaction SMILES: [K].Cl[C:3]1[N:8]=[C:7](Cl)[C:6]([F:10])=[CH:5][N:4]=1.[CH2:11]([OH:15])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([O:15][C:3]1[N:8]=[C:7]([O:15][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([F:10])=[CH:5][N:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCCCO
Agent: [K]
Product: CCCCOc1ncc(F)c(OCCCC)n1
Reaction time: 5 h
Yield: 85.1 %

Procedure:
A 9.8 g quantity of metal potassium is dissolved in 300 ml of absolute n-butanol, 16.7 g of 2,4-dichloro-5-fluoropyrimidine is added to the solution and the mixture is stirred at 60° to 70° C for 5 hours. After the reaction, the solvent is distilled off, 50 ml of water is added to the residue and the mixture is extracted with 300 ml of toluene. The toluene layer is washed with water, dried and concentrated. The concentrate is distilled at reduced pressure to give 20.6 g of colorless oily 2,4-di(n-butoxy)-5-fluoropyrimidine in a yield of 85.1%, b.p. 125°-126° C/3-4 mm Hg.