Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].N12CCCN=C1CCCCC2.N[C:28]1[CH:44]=[CH:43][C:31]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH:41][CH3:42])=[O:40])[CH:34]=2)=[CH:30][CH:29]=1.CS(C)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:11][C:28]2[CH:44]=[CH:43][C:31]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH:41][CH3:42])=[O:40])[CH:34]=3)=[CH:30][CH:29]=2)=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC#N
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 115 °C
Yield: 59.9 %

Procedure:
1-(4-chloro-3-(trifluoromethyl)phenyl)urea (15 g, 0.0628 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (11.75 ml, 0.078 mol) and 4-(4-aminophenoxy)-N-methylpicolinamide (15.27 g, 0.0628 mol) were mixed with dimethyl sulfoxide (45 ml) and the reaction mass was then heated to 110-120° C. for 12-18 hours. The reaction mass was cooled to room temperature and quenched in water (250 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (150 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureido) phenoxy)-N-methylpicolinamide (sorafenib base) (17.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[BrH:36].[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([Br:36])=[C:12]2[CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1c(Br)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C

Procedure:
To a solution of 2-[2-(5-benzyloxy-1H-indol-3-yl)ethyl]isoindole-1,3-dione (800 mg in a mixture of dry 25 mL tetrahydrofuran and 25 mL dry chloroform) at 0° C. was added pyridinium hydrobromide perbromide (666 mg) and the mixture stirred at 0° C. After 23 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate (3×) and 0.3M sodium bisulfate (3×) then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 7:2) followed by repurification by flash chromatography on silica gel (methylene chloride) gave the title compound (632 mg).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][NH:13][C:14]=2[C:15]#[N:16])=[CH:6][C:5]=1[F:22].[NH2:23]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:23][N:13]1[C:14]([C:15]#[N:16])=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[C:5]([F:22])[CH:6]=2)[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccc(N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c(C#N)c1-c1ccc(N)c(F)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.7 g, 43 mmol) was added in portions to a solution of ethyl 4-(4-amino-3-fluorophenyl)-5-cyano-1H-pyrrole-3-carboxylate (9.0 g, 33 mmol) in DMF (290 mL). The suspension was stirred for 30 min and then (aminooxy)(diphenyl)phosphine oxide (9.9 g, 43 mmol) was added. The reaction was warmed (60° C.) for 4 h and then cooled to rt. The reaction was quenched by slow addition of water (10 mL) and the solvents were evaporated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL) and the solution was washed with saturated aqueous sodium bicarbonate solution (2×250 mL) and brine (250 mL). The organic layer was dried over sodium sulfate and evaporated. The residue was triturated with diethyl ether to give the desired product (7.8 g, 82%); 1H NMR (300 MHz, DMSO-d6) δ 7.57 (s, 1H), 7.05 (dd, J=12.7, 2.0 Hz, 1H), 6.91-6.95 (m, 1H), 6.75 (dd, J=9.5, 8.4 Hz, 1H), 6.57 (s, 2H), 5.36 (s, 2H), 4.09 (q, J=7.0 Hz, 2H), 1.16 (t, J=7.0 Hz, 3H); ES-MS m/z 289.0 (MH)+; HPLC RT (Method B) 2.61 min.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: C1CNCCN1
Product: O=C1N=C(N2CCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-piperazin-1-yl-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperazine following General Procedure C.
Reaction SMILES: F/C(=C\C1C=CC=CC=1)/C(Cl)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=C1/C=C/C1C=CC=CC=1>>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH2:21]
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(Cl)/C(F)=C/c1ccccc1
Product: Nc1ccccc1Nc1ccccn1

Procedure:
(Z)-α-fluorocinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 315.35; mp: 124.5-125.3° C.; 1H-NMR (CDCl3) δ: 8.72-8.66 (1H, m), 7.94 (1H, ddd, J=7.3, 7.3, 1.8 Hz), 7.88-7.83 (1H, m), 7.62-7.55 (2H, m), 7.52-7.25 (8H, m), 7.00 (1H, d, J=38.5 Hz).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[O:26]=[C:27]1[N:36]([CH:37]([CH3:41])[C:38]([OH:40])=O)[CH:35]=[CH:34][C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]1=2.[F:42][C:43]1[C:44]([NH:55][NH2:56])=[N:45][CH:46]=[C:47]([C:49]2[CH:50]=[N:51][N:52]([CH3:54])[CH:53]=2)[CH:48]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:42][C:43]1[C:44]([NH:55][NH:56][C:38](=[O:40])[CH:37]([N:36]2[CH:35]=[CH:34][C:33]3[N:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]2=[O:26])[CH3:41])=[N:45][CH:46]=[C:47]([C:49]2[CH:50]=[N:51][N:52]([CH3:54])[CH:53]=2)[CH:48]=1
Reactant: Cn1cc(-c2cnc(NN)c(F)c2)cn1
Reactant: CC(C(=O)O)n1ccc2ncccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NNc1ncc(-c2cnn(C)c2)cc1F)n1ccc2ncccc2c1=O
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
HATU (1053 mg, 2.7 mmol), 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (470 mg, 1.8 mmol) and 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (421 mg, 2 mmol) (step 1 of General Method K) were taken up in 6 mL of acetonitrile. DIPEA (967 μl, 5.5 mmol) was added and the reaction was stirred for 30 minutes, until reaction was complete. The crude material was concentrated and then purified via MPLC with a gradient 100% DCM to 90% DCM/10% MeOH/1% NH4OH) to yield N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide (500 mg, 67% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@@H:25]([CH2:28][NH2:29])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Si]([N:43]=[C:44]=[O:45])(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@@H:25]([CH2:28][NH:29][C:44]([NH2:43])=[O:45])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
A solution of (S)-(1-(7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)methanamine (Compound 77, 0.16 mmol), DIPEA (207 mg, 1.6 mmol) and TMSNCO (184 mg, 1.6 mmol) in anhydrous CH2Cl2 (5 mL) was stirred at room temperature for 70 hours. The reaction mixture was poured into saturated NaHCO3 aqueous and extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to afford the title compound. MS (m/z): 434 (M+H)+.
Reaction SMILES: [Sn](C)(C)(C)[CH3:2].Br[C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)=[N:9][S:10][C:11]=1[NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[CH3:18])=[O:14]>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:21]1[CH:20]=[C:19]([C:8]2[C:7]([CH3:2])=[C:11]([NH:12][C:13]([C@@H:15]3[CH2:17][C@H:16]3[CH3:18])=[O:14])[S:10][N:9]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: C[Sn](C)(C)C
Reactant: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2C)cc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
Add PdCl2(PPh3)2 (0.15 g, 0.21 mmol) and Sn(CH3)4 (0.79 mL, 1.02 g, 5.71 mmol) to (R,R)—N-[4-bromo-3-(3-fluoro-4-methoxyphenyl)-isothiazol-5-yl]-2-methylcyclopropanecarboxamide (0.55 g, 1.43 mmol) in DMF (3 mL), and stir the reaction mixture at 130° C. in a sealed tube overnight. Dilute with EtOAc (100 mL) and brine (100 mL). Collect the organic phase, dry (K2CO3) and evaporate. Take up the resultant oil in 1:1 MTBE:KF (aqueous, 15%) (50 mL) and stir at reflux for 1 h. Pour the cooled solution over diatomaceous earth and filter with MTBE (100 mL). Collect the organic phase, dry (K2CO3) and evaporate. Chromatography over silica gel, eluting with 10-30% THF in hexane, affords (R,R)—N-[3-(3-fluoro-4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 49.2%. ES-MS: m/e 321.0 (m+1).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@@H:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].[C:28](=O)(ON1C(=O)CCC1=O)[O:29]N1C(=O)CCC1=O.C(N(CC)CC)C>ClC(Cl)C>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([N:4]1[CH2:5][CH2:6][N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:16])[F:17])[C:28]1=[O:29])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1C(F)(F)F)C(C)(C)C
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2C(F)(F)F)C1=O)C(C)(C)C

Procedure:
A solution of Example 138A (225 mg, 0.595 mmol) and disuccinimidyl carbonate (0.183 g, 0.714 mmol) in dichloroethane (6 mL) was treated with triethylamine (99 μL, 0.714 mmol) at 25° C. for 16 h. The mixture was partitioned between 10% sodium carbonate and dichloromethane. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and the solvents were evaporated to give the crude title compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:23][C:24]1[N:25]=[C:26]2[N:31]=[C:30]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)[C:29]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:28]([NH:46][CH:47]([CH3:49])[CH3:48])[N:27]2[CH:50]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1>[CH:47]([NH:46][C:28]1[N:27]2[CH:50]=[C:24]([CH3:23])[N:25]=[C:26]2[N:31]=[C:30]([C:32]2[CH:39]=[CH:38][C:35]([CH2:36][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:34][CH:33]=2)[C:29]=1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([CH3:49])[CH3:48]
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: Cc1cn2c(NC(C)C)c(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Cc1cn2c(NC(C)C)c(-c3ccccc3)c(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)nc2n1
Reaction time: 1 h
Yield: 1.2 %

Procedure:
227.9 mg (0.83 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 6.5 mL NMP. 0.25 mL (1.8 mmol) triethylamine are added and the reaction mixture is stirred for one hour. 280 mg (0.76 mmol) 4-(2-Methyl-5-isopropylamino-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde and 0.08 mL (1.36 mmol) acetic acid are added. The reaction mixture is stirred for three days at room temperature. 176.2 mg (0.83 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 18 hours. Additional 88 mg NaBH(OAc)3 are added and stirring is continued for 26 hours. After the usual work-up and purification by column chromatography and by HPLC 4.9 mg (1.1%) of the desired title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:7]=1.[CH3:17][C:18]1([CH3:39])[CH2:23][O:22][B:21]([C:24]2[CH:25]=[CH:26][C:27]([F:38])=[C:28]([C:30]3[N:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32]#[N:33])[CH:29]=2)[O:20][CH2:19]1.C(C1C(C2C=C(B(O)O)C=CC=2F)=NC=CC=1)#N.Br[C:59]1[N:63]2[N:64]=[CH:65][C:66]([C:68]([F:71])([F:70])[F:69])=[N:67][C:62]2=[N:61][CH:60]=1>>[CH3:17][C:18]1([CH3:39])[CH2:19][O:20][B:21]([C:24]2[CH:25]=[CH:26][C:27]([F:38])=[C:28]([C:30]3[N:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32]#[N:33])[CH:29]=2)[O:22][CH2:23]1.[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:59]2[N:63]3[N:64]=[CH:65][C:66]([C:68]([F:69])([F:70])[F:71])=[N:67][C:62]3=[N:61][CH:60]=2)=[CH:7][C:6]=1[C:8]1[N:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1cccnc1-c1cc(Br)ccc1F
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Agent: CC1(C)COB(c2ccc(F)c(-c3ncccc3C#N)c2)OC1
Agent: N#Cc1cccnc1-c1cc(B(O)O)ccc1F
Product: N#Cc1cccnc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F

Procedure:
2-[5-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]nicotinonitrile was prepared from 2-(5-bromo-2-fluorophenyl)nicotinonitrile (1.36 g, 4.91 mmol) using the method described in Example 2 to give 467 mg (43%) of an approximately 1:1 mixture of 2-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]nicotinonitrile and 3-(3-cyanopyridin-2-yl)-4-fluorobenzeneboronic acid as a grey solid. This was coupled to 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine in 40% yield using the method described in Example 3 to give the title compound as a yellow solid: mp 209-211° C. (EtOAc); 1H NMR (360 MHz, CDCl3) δ 7.46 (1H, s), 7.54 (2H, m), 8.14 (1H, d, J 1.8 Hz), 8.37 (1H, m), 8.64 (1H, s), 8.82 (1H, s), 8.89 (1H, s). Anal. Found: C, 54.97; H, 2.30; N, 21.74%. Required for C18H8F4N6.0.5H2O: C, 54.97, H, 2.31; N, 21.37%.
Reaction SMILES: [CH3:1][C:2]1[NH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[Br:10]N1C(=O)CCC1=O>C(O)(=O)C>[Br:10][C:3]1[C:4]2[S:8][CH:7]=[N:6][C:5]=2[NH:9][C:2]=1[CH3:1]
Reactant: Cc1cc2scnc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Cc1[nH]c2ncsc2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of 5-methyl-4H-pyrrolo[2,3-d]thiazole (2.5 g, 18.09 mmol) in acetic acid (50 mL) was added 1-bromopyrrolidine-2,5-dione (3 g, 18.10 mmol) slowly below 0° C., and then warm to the ambient temperature and allowed to stir for 2 hours at room temperature. The reaction mixture was concentrated, and acetic acid was removed under reduced pressure. The pH was adjusted to around 7 by progressively adding saturated sodium bicarbonate below 0° C., extracted with acetic ester (50 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 25:1→15:1→10:1) to give the title compound (2.5 g, 64%) as an yellow solid. LCMS (M+H+) m/z: calc'd. 215.94. found 219.2.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.OO.N12CC[N+]([O-])(CC1)CC2.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[F:29][B-:30]([F:33])([F:32])[F:31].[Na+]>C1COCC1.C(#N)C>[F:29][B-:30]([F:33])([F:32])[F:31].[C:20]([N+:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1CN2CCN1CC2
Reactant: O=C(Cl)c1ccccc1
Agent: F[B-](F)(F)F
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(c1ccccc1)[N+]12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-benzoyl-4-fluoro-1,4-diazoniabicvclo[2.2.2]octane bis(tetrafluoroborate) 1,4-Diazabicyclo[2.2.2]octane N-oxide is prepared by the reaction of 1,4-diazabicyclo[2.2.2]octane with hydrogen peroxide as described by Farkas in J. Chem. Eng. Data (1968) 13, 278. 1,4-Diazabicyclo[2.2.2]octane N-oxide (12.8 g, 10 mmool) in THF (100 mL) is reacted with benzoyl chloride (14 g, 10 mmol) until the reaction is complete by TLC. The reaction is evaporated, diluted with acetonitrile (100 mL) and sodium tetrafluoroborate (40 g, 20 mmol) added. The solution is stirred overnight at room temperature and then filtered to remove all undissolved salts. The filtrate is evaporated to afford 1-benzoyl-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].FC(F)(F)C(O)=O.[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.[F:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[S:68](Cl)(=[O:70])=[O:69]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:55][CH2:56][N:57]([S:68]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[F:61])(=[O:70])=[O:69])[CH2:58][CH2:59]1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Clc1cnc2nc1Nc1ccc(NCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1F)N1CCC(CCNc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 2-fluorobenzenesulphonyl chloride as the starting materials in 50% yield. LCMS for C30H32ClFN7O2S (M+H)+: m/z=608.1.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][CH:27]([CH2:30][CH3:31])[CH2:28]N.S>C(O)C>[CH3:26][CH:27]([CH2:30][CH3:31])[CH2:28][NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25]
Reactant: CCC(C)CN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCC(C)CNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 115 °C

Procedure:
A stirred suspension of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2 g) and 2-methylbutylamine (3 cc) in anhydrous ethanol (15 cc) is saturated with hydrogen sulphide and the mixture is heated for 1 hour to a temperature in the region of 115° C. After being cooled, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residual yellow paste is taken up with ethyl acetate (30 cc) and distilled water (20 cc). The organic phase is separated, washed with saturated aqueous sodium chloride solution (20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual viscous yellow oil (2.2 g) is purified by chromatography on a column (height: 40 cm; diameter: 3.2 cm) of silica gel (0.04-0.063 mm), eluting with a mixture (92:8 by volume) (300 cc) of ethyl acetate and methanol and collecting 25-cc fractions. Fractions 6 to 11 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-[(2RS)-2-Methylbutyl]-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (1.8 g) is thereby obtained in the form of a viscous yellow oil.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:26])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3F)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 92 %

Procedure:
As described for example 263f, 6-[3-(2,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (219 mg, 92%) which was obtained as a white solid. MS: m/e=428.1 [M−H]−.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:26](=NOC)[C:27]#[N:28])=[C:20]([F:38])[CH:19]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][C:42]=1[NH:50][NH2:51]>>[CH2:33]([C:32]1[C:25]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:10]3[CH:11]=[C:12]([CH2:15][CH2:16][CH3:17])[CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:19][C:20]=2[F:38])=[C:26]([C:27]#[N:28])[N:50]([C:42]2[CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[CH:45]=[CH:46][C:41]=2[Cl:40])[N:51]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCC(=O)C(Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(C)(C)C)cc1F)C(C#N)=NOC
Reactant: NNc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C#N)c1Cc1ccc(-c2cc(CCC)ccc2S(N)(=O)=O)cc1F

Procedure:
The reaction of 3-[[2'-(N-t-butylsulfamoyl)-3-fluoro-5'-n-propylbiphenyl-4-yl]methyl]-2-methoxyimino-4-oxooctanenitrile (from Step C) with 2-chloro-5-nitrophenylhydrazine hydrochloride according to the procedure of Example 1, Step G, yields the title compound.