Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][C:14]([C:17]([NH:19][C@@H:20]4[CH:25]5[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]5)[CH2:21]4)=[O:18])=[CH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][CH2:30][C:31]([Cl:33])=[O:32].C(N(CC)CC)C.O>C1COCC1>[ClH:33].[N:22]12[CH2:23][CH2:24][CH:25]([CH2:26][CH2:27]1)[C@@H:20]([NH:19][C:17]([C:14]1[O:15][C:16]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH:3]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=1)=[O:18])[CH2:21]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COCC(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Product: Cl

Procedure:
75 mg (0.21 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114), 21 μl (0.31 mmol) of methoxyacetyl chloride and 87 μl (0.62 mmol) of triethylamine are stirred in 2 ml of THF at RT overnight. After addition of water, the solvent is removed under reduced pressure.
Reaction SMILES: O[CH:2]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].C(N(S(F)(F)[F:19])CC)C.O.[OH-].[Na+]>C(Cl)Cl>[F:19][CH:2]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)c1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(F)c1nc2ccccc2[nH]1
Temperature: -78 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
A solution of 3.24 g (0.02 mole) of 1-hydroxyethylbenzimidazole in 50 ml of methylene chloride was added to a solution of 2.44 ml (0.02 mole) of diethylaminosulfur trifluoride in 50 ml of methylene chloride cooled to -78° C. and under a nitrogen atmosphere. The reaction mixture was allowed to warm slowly to room temperature where it was stirred for 4 hours. The mixture was poured into water, the pH adjusted to 8 with aqueous sodium hydroxide solution and the organic layer separated and dried. Removal of the solvent gave 1.25 g of a brown oil which was chromatographed on 100 g of silica gel using 5% methanol chloroform as the eluent, 845 mg.
Reaction SMILES: [C:1]([C:3]1[S:12][C:6]2[S:7][CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1)#[N:2].CC(C)([O-])C.[K+].I[CH2:20][CH2:21][CH2:22][CH3:23].C(OCC)(=O)C>CN(C)C=O.O>[CH2:20]([N:10]1[C:9](=[O:11])[CH2:8][S:7][C:6]2[S:12][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCI
Reactant: N#Cc1cc2c(s1)SCC(=O)N2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)CSc2sc(C#N)cc21
Reaction time: 0.17 h

Procedure:
To a solution of 6-cyano-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine (13.6 g) in N,N-dimethylformamide (270 ml) was added potassium tert-butoxide (9.3 g) under ice cooling. After stirring for 10 minutes under ice cooling, to the reaction mixture was added 1-iodobutane (9.5 ml). After stirring for 8 hours at room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with chloroform. The fractions containing the object compounds were collected and evaporated in vacuo to give 1-n-butyl-6-cyano-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine (13.78 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:37][C:36]3[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=3)=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccc([N+](=O)[O-])cc2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccc([N+](=O)[O-])cc2)c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with 4-nitrobenzaldehyde (58) (0.30 g, 2 mmol) afforded, after workup, a yellow oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/hexane as the eluant to obtain 0.76 g (1.42 mmol, 71%) of 69 as a yellow oil. The oil crystallized from ethyl acetate-pentane to yield red crystalline solid: mp 148°-150° C.; IR (CH2Cl2) 3435, 29980, 1695, 1620, 1598, 1545, 1520, 1470, 1342, 1215, 1102, 858; 1H NMR (CDCl3) δ 1.08 (d, J=6.2 Hz, 3H), 1.19 (d, J=6.2 Hz, 3H), 2.25 (s, 6H), 3.28 (s, 3H), 3.55 (t, J=4.8 Hz, 2H), 4.16 (m, 2H), 4.92 (septet, J=6.2 Hz, 1H), 5.06 (s, 1H), 6.66 (s, 1H), 7.27-8.51 (m, 9H); 13C NMR (CDCl3) δ 19.78, 19.88, 22.45, 22.68, 40.60, 59.26, 63.36, 67.79, 71.19, 103.34, 104.16, 119.97, 122.05, 124.43, 129.24, 129.84, 131.23, 132.97, 137.03, 145.36, 146.17, 148.45, 149.23, 150.50, 167.46, 167.94. Anal. Calcd for C28H31N3O8 : C, 62.57; H, 5.77. Found: C, 62.76, H, 5.82.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH:7]2[NH:9][CH:3]1[CH2:4][CH:5]([C:10]([O:12]C)=[O:11])[CH2:6]2.Br[CH2:16][C:17]1[NH:22][C:21]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[N:20][C@@H:19]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[Cl:35])[C:18]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[Cl:35][C:29]1[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:28]=1[C@H:19]1[C:18]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:17]([CH2:16][N:9]2[CH:3]3[C:2]([F:14])([F:1])[CH2:8][CH:7]2[CH2:6][CH:5]([C:10]([OH:12])=[O:11])[CH2:4]3)[NH:22][C:21]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[N:20]1
Reactant: COC(=O)C1CC2CC(F)(F)C(C1)N2
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1cccc(F)c1Cl
Product: CCOC(=O)C1=C(CN2C3CC(C(=O)O)CC2C(F)(F)C3)NC(c2nccs2)=N[C@H]1c1cccc(F)c1Cl
Yield: 6 %

Procedure:
The title compound was prepared in analogy to Example 1, by using methyl 6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylate 150a (200 mg) and ethyl (4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 98a (400 mg). 30 mg of the title compound was isolated finally after preparative HPLC purification. Preparation of methyl 6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylate 150a:
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].CN1CCOCC1.[F:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](Cl)=[O:48].C(O)C(N)(CO)CO>ClCCl>[OH:7][NH:8][C:9]([C:11]1([S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][N:14]([C:47]([C:46]2[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=2[F:44])=[O:48])[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C(NOC1CCCCO1)C1(S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)CCNCC1
Agent: NC(CO)(CO)CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(c1ccccc1F)N1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)CC1
Reaction time: 2 h

Procedure:
To a solution of N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94, (50 mg) dissolved in dichloromethane (2.5 mL) was added PS-NMM (135 mg, Argonaut) and 2-fluorobenzoyl chloride (12.1 [L) and stirred for 2 hours. To the reaction mixture was added PS-trisamine (50 mg, Argonaut) and the mixture was stirred 1 hour. The reaction mixture was filtered and washed with dichloromethane (2×2 mL) and methanol (1×2 mL). The combined organics were evaporated to afford N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(2-fluorophenylcarbonyl)-4-piperidinecarboxamide (53.5 mg) as a white solid. MS (ES) m/z 583 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]1[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]1=O.[OH-].[Na+]>CCOC(C)=O>[Cl:3][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[N:12][CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cnccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Clc1ccc2cnccc2n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of phosphoryl trichloride (5.17 ml, 56.5 mmol) and 1,6-naphthyridin-2(1H)-one (112) (1.65 g, 11.29 mmol, Alfa Aesar) was stirred at 70° C. for 16 h. The reaction mixture was cooled to RT and was poured onto 150 g of ice carefully. EtOAc (50 mL) was added and the mixture was treated carefully with about 30 mL of 5 M NaOH until the final pH is persistently >10. The mixture was vigorously mixed, then transferred into a separatory funnel. The EtOAc layer was then separated and dried and re-suspended in 30 mL of DCM, the insoluble solids were filtered off. The filtrate was loaded onto a silica gel pad and flushed with 30% EtOAc in hexanes to give a solid after drying. The solid was initially white but changed color to yellow after drying on the high vacuum line over night. Yield; 1.19 g, 64%. The material (113) was used directly in the next step without any further purification.
Reaction SMILES: F[C:2]1[C:7]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:7]([C@@H:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: O[C@H]1CCC[C@@H](c2cccnc2F)C1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@H]1CCC[C@@H](c2cccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 180 °C

Procedure:
A mixture of (rac)-cis-3-(2-fluoropyridin-3-yl)cyclohexanol (250 mg, 1.281 mmol), 4-(pyridin-2-ylamino)phenol (477 mg, 2.56 mmol), and cesium carbonate (834 mg, 2.56 mmol) in NMP (4 ml) was heated in a Biotage™ microwave reactor at 180° C. for 1.5 h. The mixture was partitioned between H2O (15 ml) and CH2Cl2 (30 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×30 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-cis-3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanol as a tan solid. MS (ESI, pos. ion) m/z: 362.0 (M+1). IC50 (uM) 0.011024.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:24]4[N:25]=[CH:26][CH:27]=[C:28]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[C:23]4=[N:22][C:21]=3[CH2:35][S:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[C:56]([O:60][C:61]([N-:63][S:64](N1C=CC(=[N+](C)C)C=C1)(=[O:66])=[O:65])=[O:62])([CH3:59])([CH3:58])[CH3:57]>C(Cl)Cl>[O:32]1[CH2:33][CH2:34][N:29]([C:28]2[C:23]3[N:24]([C:20]([C:17]4[CH:16]=[CH:15][C:14]([N:8]5[CH2:9][CH2:10][N:11]([S:64]([NH:63][C:61](=[O:62])[O:60][C:56]([CH3:58])([CH3:57])[CH3:59])(=[O:65])=[O:66])[CH2:12][CH2:13]5)=[N:19][CH:18]=4)=[C:21]([CH2:35][S:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:22]=3)[N:25]=[CH:26][CH:27]=2)[CH2:30][CH2:31]1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: c1ccc2nc(SCc3nc4c(N5CCOCC5)ccnn4c3-c3ccc(N4CCNCC4)nc3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCN(c2ccc(-c3c(CSc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 6 (137 mg, 0.612 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (1 mL) and DIEA (68.2 μL, 0.486 mmol) were added. (tert-Butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (48.8 mg, 0.162 mmol) was added as a solid and the reaction was stirred at rt for 3 h and then the solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-100% EtOAc/heptane. The resulting product was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-80% EtOAc/heptane to afford the title compound 31a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.55 (d, J=2.2 Hz, 1H), 7.96 (d, J=5.6 Hz, 1H), 7.80-7.92 (m, 3H), 7.71 (d, J=8.1 Hz, 1H), 7.58-7.66 (m, 1H), 7.29-7.48 (m, 2H), 7.24 (d, J=8.8 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 6.04 (d, J=5.9 Hz, 1H), 4.85 (s, 2H), 3.89-4.00 (m, 4H), 3.80-3.89 (m, 4H), 3.62-3.73 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1>C(OCC)(=O)C>[NH2:6][C:7]1[N:11]([C:12]2[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:17]=2)[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1
Reactant: Cc1ccc(-n2nc(C(F)(F)F)nc2N)c(C)c1
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1nc(C(F)(F)F)nc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer were placed 5.83 g (50 mol) of chlorosulfonic acid and then 2.49 g (9.73 mmol) of 4-(5-amino-3-trifluoromethyl-1H-1,2,4-triazol-1-yl)-1,3-dimethylbenzene. The mixture was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and then added onto ice in small portions. Thereto was added 30 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Then, vacuum distillation was conducted to distil off ethyl acetate to obtain a title compound as 3.3 g of a crystal. Yield: 96%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:68][CH2:69][CH2:70][NH:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:68][CH2:69][CH2:70][NH:71][C:72](=[O:78])[O:73][C:74]([CH3:76])([CH3:75])[CH3:77])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300 mg, 0.65 mmol), HATU (296 mg, 0.78 mmol) and N,N-diisopropylethylamine (185 mg, 1.43 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of tert-butyl (2-aminoethyl)carbamate (125 mg, 0.78 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate as white solid. Yield: 350 mg, 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][N:19]1[C:23]([CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:31][CH:32]=2)=[O:27])=[CH:22][CH:21]=[N:20]1.O>CN(C)C=O>[CH3:18][N:19]1[C:23]([CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([C:33]([NH:35][N:36]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:34])=[CH:31][CH:32]=2)=[O:27])=[CH:22][CH:21]=[N:20]1
Reactant: Cn1nccc1CNC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccnn2C)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 70 °C
Yield: 76 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (50 mg, 0.17 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic Acid (1-methyl-1H-pyrazol-5-ylmethyl)amide (49 mg, 0.17 mmol) prepared in Reference Synthetic Example 18 were dissolved in N,N-dimethylformamide (0.50 mL) and heated at 70° C. for 24 hours and cooled to room temperature. After addition of water, the precipitated crystals were recovered by filtration, washed with water and chloroform and dried to give the desired product (yield 76%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].Br[CH2:13][CH2:14]Br.[F-].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH2:14][CH2:13][O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: COc1ccc(Br)c(O)c1O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c2c1OCCO2
Reaction time: 6 h

Procedure:
3-bromo-6-methoxycatechol (16 g) was dissolved in DMF (50 ml), mixed with 1,2-dibromoethane (15 ml) and potassium fluoride (21 g), stirred for 6 hours while heating at 110EC. The resultant was allowed to stand for cooling, mixed with water, and extracted with ether. The organic layer was washed withan aqueous sodium hydroxide solution, water, and a saturated aqueous sodium chloride solution in that order, dried over manganese sulfate anhydride, and then, evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound IIbo-a (5.9 g, 34%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])/[CH:3]=[N:4]/[C:5]1[NH:6][C:7](=[O:15])[C:8]([N+:12]([O-:14])=[O:13])=[C:9]([CH3:11])[N:10]=1.C1CCN2C(=NCCC2)CC1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>CN(C=O)C>[CH2:28]([N:6]1[C:7](=[O:15])[C:8]([N+:12]([O-:14])=[O:13])=[C:9]([CH3:11])[N:10]=[C:5]1/[N:4]=[CH:3]/[N:2]([CH3:1])[CH3:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(/N=C/N(C)C)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1nc(/N=C/N(C)C)n(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85493.2 %

Procedure:
To a suspension of (E)-N,N-Dimethyl-N′-(4-methyl-5-nitro-6-oxo-1,6-dihydropyrimidin-2-yl)formimidamide (53.4 g, 0.24 mmol) in DMF (690 mL) was added DBU (44.6 mL, 0.30 mol) and benzyl bromide (44.4 mL, 0.29 mol) and stirred at room temperature for 1 h. The excess of DBU was neutralized with HCl, and the mixture was concentrated in vacuo. The residue was dissolved in methylene chloride and extracted twice with 2M HCl and water, then dried over Na2SO4 and concentrated. Trituration with ethanol afforded the crystalline product which was washed with ethanol to give the product (64.7 g, 86% yield) and used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=[NH:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27]>>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:9]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[Cl:17])[CH2:24][C:25]([C:26]([F:29])([F:28])[F:27])([OH:30])[N:8]=2)=[CH:4][CH:3]=1
Reactant: N=C(Nc1cc(Cl)ccc1Cl)c1ccc(Br)s1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: OC1(C(F)(F)F)CN(c2cc(Cl)ccc2Cl)C(c2ccc(Br)s2)=N1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a suspension of 5-bromo-N-(2,5-dichloro-phenyl)-thiophene-2-carboxamidine (634 mg, 1.8 mmol) and sodium bicarbonate (227 mg, 2.7 mmol) in 8 mL 2-proponal was added 3-bromo-1,1,1-trifluoroacetone (520 mg, 2.7 mmol). The reaction mixture was heated at 50° C. for 1.5 hrs, then at 80° C. for 4 hrs. After cooling to room temperature, the residue was filtered out and washed with dichloromethane. The filtrate and washings were combined together and concentrated under vacuum to give a light pink solid that was used directly for the next step (820 mg, 99% yield). 1H-NMR (400 MHz, DMSO-d6): δ 3.09 (d, 1H), 3.95 (dd, 1H), 6.31 (d, 1H), 6.91 (d, 1H), 7.15 (m, 1H), 7.33 (dd, 1H), 7.44 (m, 2H).
Reaction SMILES: C(OCC)(=O)C.Cl.C(O[C:13]([N:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=2[F:27])[C:20](=[O:30])[C:19]([C:31]([O:33][CH3:34])=[O:32])=[CH:18]1)C)=O)(C)(C)C.C(=O)([O-])O.[Na+]>O.C(Cl)Cl>[F:29][C:23]1[CH:22]=[C:21]2[C:26](=[C:25]([F:27])[C:24]=1[F:28])[N:17]([NH:15][CH3:13])[CH:18]=[C:19]([C:31]([O:33][CH3:34])=[O:32])[C:20]2=[O:30]
Reactant: COC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CNn1cc(C(=O)OC)c(=O)c2cc(F)c(F)c(F)c21
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To ethyl acetate solution (55 ml) of 4N hydrochloric acid, was added methyl 1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (10.85 g) with ice-cooling, and the mixture was stirred for one hour at the same temperature and then for 14 hours at room temperature. The mixture was concentrated under reduced pressure to obtain a solid. The solid was poured into a mixture comprising methylene chloride (150 ml) and water (150 ml). The suspension was neutralized with sodium hydrogencarbonate. The precipitates were taken out by filtration, washed with water and dried with phosphorus pentaoxide to obtain a solid. The solid was recrystallized from a liquid mixture of methylene chloride and diisopropyl ether to obtain methyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.05 g).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Si:13]([O:12][C:9]1[CH:10]=[CH:11][C:2]([I:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(I)c2cccnc12
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)c2cccnc12

Procedure:
A mixture of Example 201A (10.40 g, 38.4 mmol), tert-butyldimethylsilyl chloride (6.07 g, 40.3 mmol), and imidazole (5.49 g, 80.6 mmol) in DMF (75 mL) at room temperature was stirred for 16 hours, treated with water (300 mL), and extracted with diethyl ether (3×400 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.