Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:36]=[CH:35][C:18]([CH2:19][NH:20][O:21][C@H:22]4[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:39](Cl)(=[O:41])[CH3:40]>N1C=CC=CC=1>[F:38][C:2]([F:1])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:36]=[CH:35][C:18]([CH2:19][N:20]([O:21][C@H:22]4[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]4)[C:39](=[O:41])[CH3:40])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ONCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Solvent: c1ccncc1
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON(Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)C(C)=O)[C@@H]1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.3 %

Procedure:
A solution of N-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzyl}-O-((2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-hydroxylamine (3; 94.4 mg, 0.175 mmol) in pyridine (2 mL) was treated with acetyl chloride (70 μL, 0.98 mmol), and the mixture was allowed to stir at room temperature for 2.5 h. The mixture was then evaporated at room temperature under vacuum to a smaller volume. The concentrate was diluted with EtOAc and washed with 1 N HCl. The aqueous layer was extracted 3 times with EtOAc. The organic fractions were combined and dried with anhydrous MgSO4. The solvent was then evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 50% EtOAc in Hexane going to 90% EtOAc in Hexane in a single step). The title product (96.8 mg, 95%) was isolated as a colorless semi-solid: 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.16 (d, J=8.4 Hz, 2H), 7.87-7.69 (m, 2H), 7.39 (d, J=8.1 Hz, 4H), 5.19 (dd, J=9.3, 6.6 Hz, 2H), 4.71 (d, J=16.1 Hz, 1H), 3.70-3.28 (m, 12H), 3.12 (dd, J=9.2, 7.9 Hz, 1H), 2.24 (s, 3H), 1.60 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 163.17, 141.89, 135.74, 129.76, 128.21, 126.89, 122.44, 121.26, 81.74, 79.82, 73.74, 69.61, 60.33, 58.86, 58.10, 21.05, 18.12; ESIMS m/z 581 (M+H).
Reaction SMILES: CO.[C:3]([OH:11])(=[O:10])[C:4]([CH2:6][C:7]([OH:9])=[O:8])=[CH2:5].C(N(CC)CC)C.Cl([O-])(=O)(=O)=O>[H][H].C1CCCCC=CC=1.[Rh]>[CH3:5][CH:4]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:11])=[O:10]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: [H][H]
Agent: [Rh]
Agent: C1=CCCCCC=C1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(CC(=O)O)C(=O)O
Yield: 91.9 %

Procedure:
To 10 ml of methanol were added 1.301 g (10 m-mol) of itaconic acid, 1.4 ml (10 m-mol) of triethylamine and 8.8 mg (0.01 m-mol) of rhodium cyclooctadiene BCPM complex perchlorate ([Rh(COD)BCPM]+ClO4-). The mixture was stirred in hydrogen atmosphere at 1 atm. for 20 hours at 20° C. and the reaction mixture was concentrated under reduced pressure. To the residue was added 20 ml of an aqueous solution of 1N-NaOH and the mixture was filtered to remove insoluble matter. The filtrate was made acidic with 6N-HCl and extracted with ether. From the ethereal extract, 2-methylsuccinic acid was obtained quantitatively by distilling off the solvent. It was confirmed that the itaconic acid had been converted by 100% in view of a result of 1H-NMR. [α]D22 =-15.51° (c=2.00, EtOH)(optical yield: 91.9%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][CH2:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:18]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1>>[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][CH2:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[C:18]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(Cl)c1ccco1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)c1ccco1
Yield: 29.2 %

Procedure:
Using the general method of Example 47, furoyl chloride (15.8 μL, 0.16 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.05 g, 0.16 mmole) to provide 0.019 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-furamide as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.58 (dd, 3=4.4, 1.5 Hz, 1H), 8.06 (dd, J=8.6, 1.6 Hz, 1H), 7.41 (dd, J=8.5, 4.4 Hz, 1H), 7.33 (m, 1H), 7.08 (dd, J=3.5, 0.6 Hz, 1H), 6.84 (m, 1H), 6.47 (dd, J=3.5, 1.7 Hz, 1H), 4.86 (apparent t, J=7.7 Hz, 2H), 3.59 (apparent q, J=6.5 Hz, 2H), 2.92 (apparent t, J=7.8 Hz, 2H), 1.7-2.1 (m, 6H), 1.51 (m, 2H); 1.00 (t, J=7.3 Hz, 3H); HRMS (EI) calcd for C22H26N6O2 (M+) 406.2117, found 406.2121.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12.[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[OH:25].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[O:25][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12
Reactant: COC(=O)c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 180 °C
Yield: 58.7 %

Procedure:
A mixture of 37 (4.0 g, 17.6 mmol), 2-fluoro-4-nitrophenol (5.5 g, 35.0 mmol) and K2CO3 (12.1 g, 87.5 mmol) in Ph2O was heated at 180° C. for 5 hours. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was collected, dried over anhydrous sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by flash chromatography using hexane—AcOEt (70:30) as an eluent. The product from the column was re-crystallized from a mixture of ethyl acetate-hexanes to afford 38 (3.6 g, 59% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.69 (d, J=5.2 Hz, 1H), 8.47 (dd, J=2.4 and 10.0 Hz, 1H), 8.27 (s, 1H), 7.77 (dd, J=8.0 and 9.2 Hz, 1H), 7.06 (dd, J=0.8 and 5.2 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[C:20]([N+:26]([O-])=O)[CH:19]=3)[CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:26][C:20]1[CH:19]=[C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH:16]=2)[CH:23]=[CH:22][C:21]=1[NH:24][CH3:25]
Reactant: CNc1ccc(Oc2ccnc(NC(=O)C3CCN(C)CC3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CNc1ccc(Oc2ccnc(NC(=O)C3CCN(C)CC3)c2)cc1N

Procedure:
The mixture containing 1-methyl-N-(4-{[4-(methylamino)-3-nitrophenyl]oxy}pyridin-2-yl)piperidine-4-carboxamide in methanol with catalytic amount of Lindlar's catalyst was hydrogenated to yield N-(4-{[3-amino-4-(methylamino)phenyl]oxy}pyridin-2-yl)-1-methylpiperidine-4-carboxamide. MS: MH+=356.2.
Reaction SMILES: [C:1]([OH:5])(=[S:4])[CH2:2][CH3:3].[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]>>[C:1]([S:4][CH2:8][CH:7]([CH3:9])[C:6]([OH:11])=[O:10])(=[O:5])[CH2:2][CH3:3]
Reactant: C=C(C)C(=O)O
Reactant: CCC(O)=S
Product: CCC(=O)SCC(C)C(=O)O
Reaction time: 8 h

Procedure:
A mixture of thiopropanoic acid (50 g) and methacrylic acid (34.1 g) was heated on a steam bath for 3 hours and allowed to stand at room temperature overnight. The reaction mixture was distilled under reduced pressure to give the title compound, b.p. 135°-138° C. (2 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[N+:17]([O-])=O)[N:13]([CH2:20][CH3:21])[C:12](=[O:22])[C:11]2([CH3:24])[CH3:23])=O>[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:7][C:8]3=[CH:9][C:10]4[C:11]([CH3:24])([CH3:23])[C:12](=[O:22])[N:13]([CH2:20][CH3:21])[C:14]=4[CH:15]=[C:16]3[N:17]=2)[CH:25]=[CH:26][N:27]=1
Reactant: CCN1C(=O)C(C)(C)c2cc(NC(=O)c3ccnc(Cl)c3)c([N+](=O)[O-])cc21
Agent: [Ni]
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4ccnc(Cl)c4)nc3cc21

Procedure:
2-(2-Chloro-pyridin-4-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one is prepared from 2-chloro-N-(1-ethyl-3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-isonicotinamide (230 mg) as described in Example 1b using Raney-nickel (50 mg) instead of Pd/C. After filtration the filtrate is poured into ice-water and the precipitate is collected by filtration to give the desired compound (140 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1.[Br:50][C:51]1[CH:52]=[C:53]2[C:58](=[C:59](O)[CH:60]=1)[N:57]=[C:56]([Cl:62])[N:55]=[CH:54]2>C1COCC1.CO>[Br:50][C:51]1[CH:52]=[C:53]2[C:58](=[C:59]([O:36][CH:37]3[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]3)[CH:60]=1)[N:57]=[C:56]([Cl:62])[N:55]=[CH:54]2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cc(Br)cc2cnc(Cl)nc12
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc3cnc(Cl)nc23)CC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (577 mg, 2.20 mmol), di-tert-butylazodicarboxylate (506 mg, 2.20 mmol) and tert-butyl 4-hydroxy-piperidine-1-carboxylate (1.32 g, 6.62 mmol) are taken up in 6 mL THF, stirred for 15 min at 20° C. and then combined with 6-bromo-2-chloro-quinazolin-8-ol (1.16 g, 4.45 mmol). After stirring for 24 h at 20° C. the mixture is diluted with MeOH, the solvent is eliminated in vacuo, the crude product is purified by RP-chromatography (method prep. HPLC1; 20% acetonitrile to 90% in 6 min) and tert-butyl 4-(6-bromo-2-chloro-quinazolin-8-yloxy)-piperidine-1-carboxylate (HPLC-MS: tRet.=1.99 min; method FECB5) is obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:38])[C:23]3[C:24](=[C:26]([CH2:36][CH3:37])[N:27]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[CH:16][N:15]=1)[CH3:12]>C(O)C1C=CC=CC=1>[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:38])[C:23]3[C:24](=[C:26]([CH2:36][CH3:37])[N:27]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)(=[O:40])=[O:41])=[CH:16][N:15]=1)[C:12]1[CH:14]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: OCc1ccccc1
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCc3ccccc3)[nH]c(=O)c2nn1Cc1ccccn1
Reaction time: 14 h
Yield: 77.7 %

Procedure:
Potassium bis(trimethylsilyl)amide (360 mg, 1.81 mmol) was added to a stirred solution of the title compound of Example 1 (200 mg, 0.36 mmol) in benzyl alcohol (5 ml) at 100° C. and the reaction mixture stirred for 14 hours, then allowed to cool. The resulting mixture was partitioned between dichloromethane (10 ml) and brine (10 ml), the phases separated, the aqueous phase extracted with dichloromethane (2×10 ml) and the combined organic solutions dried (Na2SO4) and evaporated under reduced pressure. The residual benzyl alcohol was removed by Kugelrohr distillation, then the crude product purified by column chromatography on silica gel, using dichloromethane:methanol (97.5:2.5) as eluant, to provide the title compound (86 mg, 39%) as a white solid. Found: C, 59.92; H, 5.64; N, 17.60. C31H34N8O4S; 0.40H2O requires C, 59.87; H, 5.64; N, 18.02%. δ (CDCl3): 1.05 (3H, t), 1.29 (3H, t), 2.41 (2H, q), 2.56 (4H, m), 3.05 (2H, q), 3.15 (4H, m), 5.68 (2H, s), 5.75 (2H, s), 7.10 (1H, d), 7.24 (1H, m), 7.42 (3H, m), 7.52 (2H, m), 7.64 (1H, m), 8.58 (1H, d), 8.65 (1H, s), 9.02 (1H, s), 10.58 (1H, s). LRMS: m/z 615 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH3:12]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: N
Solvent: C1COCCO1
Product: NC(=O)Cc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 109 %

Procedure:
Add 2-(4-bromo-phenyl)-acetyl chloride (1.00 g, 4.28 mmol) to a solution of ammonia in dioxane (0.5 M, 15 mL) at room temperature. Stir for 30 min., then quench with water. Extract with DCM (10 mL) and pass through an IST Phase Separator Frit® and concentrate until precipitate appears. Collect precipitate by filtration, wash powder with DCM, then dissolve in methanol, filter and concentrate to give a white powder (1.0 g, 109%). 1H-NMR (300 MHz, MeOD) δ 7.48 (d, 2H), 7.25 (d, 2H), 3.50 (s, 2H).
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[C:5]([CH:10]([C:12]2[N:13]=[N:14][N:15]([CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:16]=2)[NH3+:11])[CH:6]=[CH:7][C:8]=1[F:9].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>O.C(Cl)Cl>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:11][CH:10]([C:5]2[CH:6]=[CH:7][C:8]([F:9])=[C:3]([F:2])[CH:4]=2)[C:12]2[N:13]=[N:14][N:15]([CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:16]=2)=[O:34])=[CH:30][CH:31]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(CC(=O)O)cc1
Reactant: C[Si](C)(C)Cn1cc(C([NH3+])c2ccc(F)c(F)c2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CC(=O)NC(c2ccc(F)c(F)c2)c2cn(C[Si](C)(C)C)nn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a 50 ml round bottom flask equipped with a magnetic-stir bar were added (3,4-difluorophenyl){1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methanaminium chloride (0.500 g, 1.502 mmol), 4-tert-butylphenylacetic acid (0.289 mg, 1.502 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.288 g, 1.502 mmol), 1-hydroxy-7-azabenzotriazole (0.204 mg, 1.502 mmol) and triethylamine (0.629 ml, 2.253 mmol) into 10.0 ml of CH2Cl2. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and the two layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by preparative HPLC (20-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 0.536 g (67%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.347 (m, 2H), 7.190 (m, 3H), 7.040 (m, 2H), 6.970 (m, 2H), 6.223 (d, J=7.60 Hz, 1H), 3.852 (ABq, J=15.29 Hz, 2H), 3.580 (s, 2H), 1.305 (s, 9H), 0.125 (s, 9H). ES-MS [M+1]+: 471.2.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:20].O1CCOCC1.C(OCC)(=O)C>C(Cl)Cl>[ClH:20].[N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[CH:11]=[CH:12][C:13]=1[C:18]#[N:19]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(C#N)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(n1)CCNC2
Temperature: 40 °C
Reaction time: 0.67 h

Procedure:
2-Cyano-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (WO00/09480) (3.74 g) was dissolved in methylene chloride (5.0 mL). 4N HCl-dioxane solution (14 mL) was added thereto. The resultant mixture was stirred at room temperature for 65 minutes, and stirred at 40° C. for 40 minutes. 4N HCl-dioxane solution (8 mL) was further added to the reaction mixture, followed by stirring at 45° C. for 75 minutes. Ethyl acetate was added to the reaction mixture, and the precipitated powder was recovered by filtration, to thereby give the title compound (3.20 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[OH-].[K+].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(Cl)ccc2Cl)c(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2,5-dichloroaniline (1.6 g.) in dry dimethylformamide (10 ml.) potassium hydroxide (1.0 g.) was added in small portions over 5 minutes, and stirring continued for a further 15 minutes. To the resultant solution was added 2-chloro-3,5-dinitrobenzotrifluoride (2.7 g.) in small portions over 5 minutes. When the addition was complete the mixture was stirred for 30 minutes at 20° C, after which concentrated hydrochloric acid was added to acidify the mixture. Industrial methylated spirit (10 ml.) was then added, the mixture stirred for further 15 minutes and then poured into water (150 ml.) The solid precipitate was collected by filtration, washed with water and dried to yield 2(2,5-dichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 125°-126° C.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[CH2:9]([C:11]1[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=1[NH:19][C:20]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])=[S:21])[CH3:10]>ClCCl>[CH3:27][C:23]([N:22]1[C:2](=[O:8])[C:3](=[O:5])[N:19]([C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[CH2:9][CH3:10])[C:20]1=[S:21])([CH3:26])[CH2:24][CH3:25]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCc1cc(C#N)ccc1NC(=S)NC(C)(C)CC
Solvent: ClCCl
Product: CCc1cc(C#N)ccc1N1C(=O)C(=O)N(C(C)(C)CC)C1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
Ethyl chlorooxoacetate (0.82 mL, 7.3 mmol) was added dropwise to a stirring solution of 1-(2-ethyl-4-cyanophenyl)-3-(1,1-dimethyl-propyl)-thiourea (1.0 g, 3.65 mmol) in dichloromethane (30 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated to afford a residue which was triturated with diethyl ether and hexanes to afford 0.71 g (59%) of 4-[3-(1,1-dimethyl-propyl)-4,5-dioxo-2-thioxo-imidazolidin-1-yl]-3-ethyl-benzonitrile as a yellow solid: mp 172.8–173.3° C.; 1H NMR (DMSO-d6): δ 7.92 (s, 1H), 7.80 (d, 1H), 7.52 (d, 1H), 2.50 (m, 2H), 2.19 (m, 2H), 1.76 (2s, 6H), 1.08 (t, 3H), 0.85 (t, 3H); IR (KBr) 3400, 2950, 2260, 1775 cm−1; MS (m/z) 329 (M+).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(Nc1cccc(Cl)c1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-chloroaniline as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.Cl[P:16]([O:22][CH2:23][CH2:24][C:25]#[N:26])[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[C:25]([CH2:24][CH2:23][O:22][P:16]([C:4]1[NH:3][C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=1)[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)#[N:26]
Reactant: N#CCCOP(Cl)N1CCCC1
Reactant: Clc1nc[nH]c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCCOP(c1nc(Cl)c(Cl)[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a stirred solution of 4,5-dichloroimidazole (1.59 g, 11.63 mmol) and triethylamine (1.95 mL, 1.41 g, 13.96 mmol) in CH2Cl2 (30 mL) was added dropwise Chloro(2-Cyanoethoxy) pyrrolidinophosphine (2.40 g, 11.63 mmol) in CH2Cl2 (10 mL) at room temperature. The mixture was stirred for 4 h at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a pale yellow oil (2.93 g, 82%). 31P NMR (CDCl3) δ 123.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[CH2:26][CH2:27][CH2:28][C:29](=[O:33])[N:30]([CH2:31][CH3:32])[C:24]=2[CH:23]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[CH2:26][CH2:27][CH2:28][C:29](=[O:33])[N:30]([CH2:31][CH3:32])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A microwave vessel was charged with 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (57.5 mg, 0.182 mmol), 8-amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (44.7 mg, 0.219 mmol), 10-camphorsulfonic acid (5.0 mg, 0.022 mmol) and isopropyl alcohol (2 mL) and heated at 120° C. for 60 minutes in a microwave reactor (sealed vessel). The reaction mixture was quenched with a slurry of saturated, aqueous NaHCO3 and stirred for 2 h. The resulting precipitate was filtered, washed with water (5×2 mL), ether (2×2 mL) and dried under vacuum to afford product 65.7 mg, 69%) as a tan solid that had the following properties: mp: 228-235° C.; LC/MS (ESI+): 483 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.38-9.35 (m, 2H), 8.53 (m, 1H), 8.19 (s, 1H), 7.48-7.45 (m, 2H), 7.36-7.26 (m, 3H), 6.98 (d, J=8.3, 1H), 3.55 (br s, 2H), 2.74 (d, J=4.1, 3H), 2.50 (m, 2H), 2.10-1.85 (m, 4H), 0.93 (t, J=7.0, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])CCC.[I:29]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(OCC)C.CCOC(C)=O>[I:29][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc(I)c(NC(=O)OC(C)(C)C)cn1
Temperature: -19.5 °C
Reaction time: 1.25 h

Procedure:
To a solution of tert-butyl 6-methylpyridin-3-ylcarbamate (9 g, 43.2 mmol) in diethyl ether (150 mL) was added TMEDA (5.27 g, 6.85 mL, 45.4 mmol) and the solution was cooled down to −75° C. n-Butyl lithium (1.6 M solution in hexane, 72.1 mL, 115 mmol) was added dropwise over 20 minutes. The orange suspension was stirred for 1.25 hours at temperatures between −14 to −25° C. After cooling down to −75° C. a solution of iodine (16.8 g, 66.1 mmol) in diethyl ether (150 mL) was added dropwise over 45 minutes below −68° C. The resulting mixture was stirred at −75° C. for 30 minutes before stirring in an ice bath for 1.75 hours. The reaction mixture was poured on 10% aqueous Na2S2O3 solution (300 mL) and EtOAc (200 mL) and the layers were separated. The aqueous layer was extracted twice with EtOAc (100 mL). The organic layers were washed with 10% aqueous Na2S2O3 solution (100 mL) and brine (100 mL), dried over MgSO4, filtered, treated with silica gel (30 g) and evaporated. The compound was purified by silica gel chromatography on a 330 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). The impure fractions were combined, purified by silica gel chromatography on a 120 g column using an MPLC (Flasmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). The product containing fractions were combined and evaporated until a suspension formed, which was filtered and washed with n-heptane. Colorless solid (2.84 g; 19%). MS (ESI): m/z=335.1 [M+H]+.