Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:34])[CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:19][N:18]=2)=[CH:13][CH:12]=1)(=[O:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([O:4][CH:5]([CH3:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:19][N:18]=2)=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C#CCCCC(C)OC(C)=O)cc2)nc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCCCCC(C)OC(C)=O)cc2)nc1
Yield: 98.5 %

Procedure:
In the same manner as above, 0.92 g (yield 98.5%) of 2-(4-(6-acetoxy-1-heptyl)phenyl)-5-decyloxypyrimidine, [α]D20 =-1.2° (c=1, chloroform), is obtained from 0.93 g of optically active 2-(4-(6-acetoxy-1-heptynyl)phenyl)-5-decyloxypyrimidine.
Reaction SMILES: [F:1][C:2]1[C:3]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:4][C:5]2[O:9]C(C3C=CC=CC=3)(C3C=CC=CC=3)[O:7][C:6]=2[CH:22]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:22]=[C:6]([OH:7])[C:5]([OH:9])=[CH:4][C:3]=1[C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24]
Reactant: O=C(c1cc2c(cc1F)OC(c1ccccc1)(c1ccccc1)O2)N1CCOCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(O)c(O)cc1F)N1CCOCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a cooled (ice-bath) solution of (6-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone (5.70 g, 14.06 mMol) in trifluoroacetic acid (60 ml) was added triethylsilane (2.1 eq, 4.7 ml) over 10 min. The mixture was stirred 20 min at 0° C. and 4 h at room temperature. The volatiles were removed under reduced pressure and the residue purified by column chromatography on silica gel (2:1 ethyl acetate/heptane-ethyl acetate-10:1 ethyl acetate/methanol) to afford (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone as liht brown solid (3.19 g, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[CH:41](I)([CH3:43])[CH3:42]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH:41]([CH3:43])[CH3:42])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2]
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Reactant: CC(C)I
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OC(C)C
Yield: 31 %

Procedure:
The same procedure as in Example 48 was repeated, using 335 mg (0.61 mmol) of Compound 47 obtained in Example 47, except that isopropyl iodide was used in place of methyl iodide, to give 112 mg (yield: 31%) of Compound 50 as white crystals.
Reaction SMILES: FN(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C(Cl)(Cl)(Cl)F.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.FF.C[C@]12CC[C@H]3C(=CCC4[C@@H]3CCCC4)C1=CC=C2.[CH3:57][O:58][C:59]1[C:76](F)=[CH:75][C:74]2[C@@H:73]3[C@H:64]([C@H:65]4[C@@:69]([CH2:71][CH2:72]3)([CH3:70])[C:68](=[O:78])[CH2:67][CH2:66]4)[CH2:63][CH2:62][C:61]=2[CH:60]=1.COC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC=2C=1F>>[CH3:57][O:58][C:59]1[CH:76]=[CH:75][C:74]2[C@@H:73]3[C@H:64]([C@H:65]4[C@@:69]([CH2:71][CH2:72]3)([CH3:70])[C:68](=[O:78])[CH2:67][CH2:66]4)[CH2:63][CH2:62][C:61]=2[CH:60]=1
Reactant: COc1cc2c(cc1F)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: COc1ccc2c(c1F)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@@]12C=CC=C1C1=CCC3CCCC[C@@H]3[C@H]1CC2
Agent: FF
Solvent: FC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The fluorination reaction was carried out in a 10 mm NMR tube. To 0.28 mmol of the estratrien methyl ether were added 2.5 ml of CDCl3 by vacuum transfer. The mixture was warmed to room temperature forming a colorless solution. This solution was cooled to -196° C. and 0.28 mmol each of FN(SO2CF3)2 and CFCl3 were added by vacuum transfer. The tube was sealed and warmed to -74° C. and then to 22° C. over a 2 hour period. Near -65° C. the colorless solution began to turn to a pale yellow color. After reaching 22° C. 19F NMR indicated a quantitative amount of (CF3SO2)2NH was formed. Two other fluorine resonances are observed in the ratio of 1:1 with a total area equal to the internal CFCl3 standard. These resonances at -140.2 (m) and -168.6 (m) ppm relative to CFCl3 are assignable to an equimolar mixture of the two monofluoro derivatives of the estratrien, 2-fluoro-1,3,5(10)estratrien-3ol-17one methyl ether and 4-fluoro-1,3,5(10)estratrien-3ol-17one methyl ether, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:30]([O:31][CH2:32][CH:33]([F:35])[F:34])=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH2:26])[CH:22]=[CH:21][C:20]=4[Cl:27])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:30]([O:31][CH2:32][CH:33]([F:35])[F:34])=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH:26][C:38]([C:37]([F:42])([F:36])[CH3:41])=[O:39])[CH:22]=[CH:21][C:20]=4[Cl:27])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C(C)(F)F)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21

Procedure:
The title compound was prepared in accordance with Example 72, step (c) using N-(4-bromo-phenyl)-2-(2-chloro-5-{[amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide (170 mg; 0.30 mmol), 2,2-difluoropropanoic acid (33 mg; 0.30 mmol), HBTU (114 mg; 0.30 mmol), TEA (61 mg; 0.60 mmol) and DMF (3 mL). Yield: 63 mg (32%). 400 MHz 1H-NMR (DMSO-d6, ppm) 10.07 (1H, s) 9.30 (1H, t, J=5.8 Hz) 8.35 (1H, s) 7.87-7.82 (1H, m) 7.73-7.60 (3H, m) 7.53-7.39 (3H, m) 7.33-7.27 (1H, m) 6.99-6.90 (1H, m) 6.66-6.34 (1H, m) 4.59-4.44 (2H, m) 4.30 (2H, d, J=5.8 Hz) 3.71 (2.38H, s, major tautomer) 3.43 (0.41H, s, minor tautomer) 1.74 (3H, t, J=19.6 Hz). MS m/z: 656, 658, 660 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][P:17]([O:22][CH2:23]C)([O:19][CH2:20]C)=[O:18])=[CH:12][N:11]=1.S1C2C=CC=CC=2N=C1C1C=CC(CP(OC)(OC)=O)=CC=1.S1C2C=CC=CC=2N=C1C1C=CC(CP(OCC)(OCC)=O)=CC=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][P:17]([O:19][CH3:20])([O:22][CH3:23])=[O:18])=[CH:12][N:11]=1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccccc3s2)nc1)OCC
Agent: CCOP(=O)(Cc1ccc(-c2nc3ccccc3s2)cc1)OCC
Agent: COP(=O)(Cc1ccc(-c2nc3ccccc3s2)cc1)OC
Product: COP(=O)(Cc1ccc(-c2nc3ccccc3s2)nc1)OC

Procedure:
2-(benzothiazol-2-yl)-5-diethoxyphosphinylmethylpyridine; 2-(benzothiazol-2-yl)-5-di-n-propyloxyphosphinylmethylpyridine; 2-(benzothiazol-2-yl)-5-di-iso-propyloxyphosphinylmethylpyridine; 2-(benzothiazol-2-yl)-5-di-n-butyloxyphosphinylmethylpyridine; 1-(benzothiazol-2-yl)-4-dimethoxyphosphinylmethylbenzene; 1-(benzothiazol-2-yl)-4-diethoxyphosphinylmethylbenzene; 1-(benzothiazol-2-yl)-4-di-n-propyloxyphosphinylmethylbenzene; 1-(benzothiazol-2-yl)-4-di-iso-propyloxyphosphinylmethylbenzene; and 1-(benzothiazol-2-yl)-4-di-n-butyloxyphosphinylmethylbenzene.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:42](O)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:42]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of triphenylphosphine (1.45 g, 5.54 mmol) in methylene chloride (15 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (986 mg, 5.54 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylic acid (1.00 g, 2.77 mmol) in methylene chloride (5 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (832 g, 8.32 mmol), and the resulting suspension was stirred for 3 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide (810 mg, 66%) as an amorphous white solid: EI-HRMS m/e calcd for C21H23ClN6OS (M+) 442.1343, found 442.1343.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][CH:24]([OH:29])[CH2:25][N:26]([CH3:28])[CH3:27])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C(N(CC)C(C)C)(C)C.[C:41]([Si:45]([CH3:48])([CH3:47])Cl)([CH3:44])([CH3:43])[CH3:42]>CN(C)C=O>[Si:45]([O:22][CH2:23][CH:24]([OH:29])[CH2:25][N:26]([CH3:27])[CH3:28])([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:48])[CH3:47]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(OCC(O)CN(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(O)CO[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
3-Dimethylamino-1,2-propanediol (5), (50.1 g, 420.4 mmol) was weighed into a 2 L round bottomed flask with a stir bar. The flask was sealed, flushed with argon, charged with N,N-dimethylformamide (750 mL) and N,N-diisopropylethylamine (111 mL, 630.7 mmol) and cooled to 0° C. t-Butyldimethylchlorosilane (67.0 g, 1.05 equiv.) was weighed into a 500 mL round bottomed flask, sealed and then dissolved in N,N-dimethylformamide (250 mL). The t-butyldimethylchlorosilane solution was transferred to a pressure equalizing dropping funnel and added to the stirring reaction mixture slowly over 20 minutes. The reaction was allowed to come to room temperature while stirring over 3 hours. The reaction was concentrated in vacuo. Saturated bicarbonate (1500 mL) was added to the residue and the mixture transferred to a 4 L separatory funnel. The aqueous phase was extracted with ethyl acetate (3×500 mL). The organic phases were combined, dried over MgSO4, filtered, concentrated and dried under high vacuum to afford 97.81 g (99.7%) of clear, colorless oil that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>CO.[Pd]>[NH2:16][C:14]1[CH:13]=[CH:12][C:4]([C:5]([O:7][C:8]([CH3:10])([CH3:11])[CH3:9])=[O:6])=[C:3]([O:2][CH3:1])[CH:15]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1C(=O)OC(C)(C)C
Yield: 98 %

Procedure:
tert-Butyl 2-methoxy-4-nitrobenzoate (2) (271 mg, 1.07 mmol) was dissolved in MeOH (270 mL) and passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under full H2 mode. The solvent was removed in vacuo to afford tert-butyl 4-amino-2-methoxybenzoate (3) (234 mg, 92%) as a pale yellow solid: m/z 222 [M−H]− (ES−); 1H-NMR (400 MHz, DMSO-d6) δ: 7.41 (1H, d), 6.16 (1H, d), 6.09 (1H, dd), 5.82 (2H, br s), 3.68 (3H, s), 1.45 (9H, s).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[O:14]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15]1>O.CC(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[O:14][CH:18]=[CH:17][C:16]=2[C:19]([OH:21])=[O:20])=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1ccoc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(-c2occc2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
70.7 g of p-toluidine, cooled with a bath of water and ice, are treated with 205 ml of 36% HCl. The mixture is then stirred at 55°-60° C. for 30 min before being cooled to 0° C. again. A solution of 45 g of NaNO2 in 220 ml of water is then introduced. The mixture is stirred for 1 h at 0° C. This cold solution is introduced into a mixture of 49.3 g of 3-furanoic acid, 220 ml of acetone, 23.4 g of CuCl2 and 6.3 g of water, cooled to -5° C. The whole is stirred at 0° C. for 2 h and then at room temperature for 48 h. It is extracted twice with ether and the organic phase is decanted, dried and concentrated to give an oil, which gives crystals when treated with water. The crystals are filtered off and washed with 50 ml of a 50% methanol/water mixture to give 13.4 g of 2-(4-methylphenyl)-3-furanoic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[C:26]1([C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][O:28]1)=O.Cl.C([O-])(O)=O.[Na+]>CN(C)C=O.O>[C:26]1(=[C:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[NH:1][C:2]2=[O:10])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][O:28]1
Reactant: O=C1OCc2ccccc21
Reactant: O=C1Cc2ncccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1Nc2cccnc2C1=C1OCc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To a solution of 1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (50 mg, 0.37 mmol) in anhydrous N,N-dimethylformamide (5.0 ml) was added 1.0M LiHMDS/THF solution (0.74 ml, 0.74 mmol) under N2. After the mixture was stirred at room temperature for 10 minutes, phthalide was added (40 mg, 0.30 mmol), and then it was continuously stirred at room temperature for 4 hours. The mixture was poured into 2M HCl (4.0 ml), heated at 50° C. for 20 minutes and then poured into water (100 ml). After cooled to room temperature, the mixture was basified to pH 9 with saturated NaHCO3 solution, and was stirred at room temperature overnight. The resulting solid was filtered, washed with water, dried under vacuum and triturated with chloroform to give 3-(3H-isobenzofuran-1-ylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a yellow solid (12 mg, 16%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[OH:20][CH2:19][CH2:18][N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1]
Reactant: OCCBr
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1nc2ccccc2n(CCO)c1=O

Procedure:
3,4-Dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (1 g), 2-bromoethanol (1.15 g) and anhydrous potassium carbonate (3 g) were heated under reflux in butanone (100 ml) for 5 hours. The mixture was cooled and the solid was filtered off. The filtrate was evaporated to give an oil which was crystallised from a mixture of benzene and light petroleum (b.p. 60°-80°). It had m.p. 137°-138°.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[O:14]
Reactant: CC(=O)c1cccs1
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1cccs1
Temperature: 25 °C
Reaction time: 15.67 h
Yield: 49.7 %

Procedure:
Ethyl difluoroacetate (1.84 g, 14.8 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (5 mL). To the stirred solution was added 25 weight % sodium methoxide (3.39 g, 15.7 mmol) followed by 2-acetylthiophene (1.72 g, 13.6 mmol). The reaction was stirred at room temperature overnight (15.67 hours), then treated with 3N HCl (8 mL). The organic layer was collected and washed with brine, dried over MgSO4, concentrated in vacuo, and recrystallized from methylene chloride/isooctane to give a brown solid (1.38 g, mp 78°-80° C., 50%). 1H NMR (CDCl3) 300 MHz 14.90 (br s, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.71 (d, J=3.8 Hz, 1H), 7.19 (m, 1H), 6.41 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -126 98 (d); M+204.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].[CH3:14][NH2:15].Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10](=[O:12])(=[O:11])[NH:15][CH3:14])=[O:4]
Reactant: CN
Reactant: COC(=O)c1ccsc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1sccc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
12 g (50 mmol) of 2-chlorosulfonylthiophene-3-carboxylic acid methyl ester are dissolved in 120 ml of absolute chloroform. Thereupon, dry methylamine is conducted into the solution at room temperature until a moist pH paper shows an alkaline reaction with the solution. Thereafter, the mixture is stirred for a further 3 hours at room temperature, whereby a moist pH paper must give an alkaline reaction with the solution to the end. The mixture is poured into 100 ml of 2-N hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with two 50 ml portions of chloroform. The combined organic phases are dried over sodium sulfate and evaporated to give an oil which crystallizes out upon cooling. There is obtained 2-N methylsulfamoylthiophene-3-carboxylic acid methyl ester of melting point 106°-107° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]1([NH2:14])[CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:14][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccccc1F
Reactant: NC1CCC1
Product: N#Cc1ccccc1NC1CCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and cyclobutylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1)=[O:9]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1O

Procedure:
A solution of 5-bromo-2-hydroxybenzoic acid (5.2 g, 23.96 mmol), 3-pyridinamine (2.26 g, 23.96 mmol), EDC (4.59 g, 23.96 mmol), HOBT (3.67 g, 23.96 mmol) and triethylamine (3.34 ml, 23.96 mmol) in DMF (80 ml) was stirred for 3 h. The reaction mixture was filtered. 150 ml water was added to the filtrate to yield a white solid. This was filtered and dried to yield the title compound. 2.8 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[Cl:26][C:27]1[C:33]([N:34]2[CH2:37][CH:36]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH2:35]2)=[CH:32][C:31]([O:45][CH:46]([F:48])[F:47])=[CH:30][C:28]=1[NH2:29].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:26][C:27]1[C:33]([N:34]2[CH2:37][CH:36]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH2:35]2)=[CH:32][C:31]([O:45][CH:46]([F:48])[F:47])=[CH:30][C:28]=1[NH:29][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CN1CCN(C2CN(c3cc(OC(F)F)cc(N)c3Cl)C2)CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(OC(F)F)cc(N4CC(N5CCN(C)CC5)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 105 °C
Yield: 62.2 %

Procedure:
2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9)(120 mg, 0.338 mmol), 2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)aniline (129 mg, 0.372 mmol), palladium(ii) acetate (22.78 mg, 0.101 mmol), XANTPHOS (19.57 mg, 0.034 mmol), DPPF (18.75 mg, 0.034 mmol) and CESIUM CARBONATE (220 mg, 0.676 mmol) were suspended in Dioxane (3382 μl) at rt. The reaction vessel was evacuated and purged with N2 (4 times) and then heated to 105° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through celite and concentrated. Column chromatography (40 g SiO2, 0 to 10% CH3OH—CH2Cl2 gradient elution) gave 2-((2-Chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (139.8 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].O>ClCCl>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:5][CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][CH:7]=[CH2:8])=[O:25])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: C=CCC(C)(C)CCO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCC(C)(C)CCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
In a 500-mL, two-necked round-bottom flask, 3,3-dimethylhex-5-en-1-ol (5.30 g, 0.041 mol) and triethylamine (16 mL, 0.057 mol) were dissolved in dichloromethane (110 mL), and then the mixture was cooled, under nitrogen atmosphere, in an ice bath to 5° C. A dichloromethane (10 mL) solution of 4-nitrobenzoyl chloride (9.1 g, 0.049 mol) was added dropwise in 20 minutes. After the mixture had been stirred at 5-10° C. for 1 hour, water was added. The organic layer was washed with acid, water, brine, dried over sodium sulfate, and filtered. After evaporation of the solvent, the crude product was purified by column chromatography (silica gel; ethyl acetate/hexanes 1/9 as eluant) to give the title compound as a yellow liquid.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](SC)[N:6]=1>CCO>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:2][NH2:3])[N:6]=1
Reactant: CSc1nccc(C)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccnc(NN)n1
Temperature: 0 °C
Reaction time: 50 h
Yield: 21562.2 %

Procedure:
Based on a reported procedure (Vanderhaeghe, Claesen, Bull. Soc. Chim. Belg. 1959, 68, 30). Hydrazine monohydrate (334.7 ml, 6.90 mmol) was added in one portion to a solution of 4-Methyl-2-methylsulfanyl-pyrimidine (357.9 g, 2.55 mol) in abs. EtOH (890 ml). The resulting mixture was refluxed for 50 h, then hydrazine monohydrate (200 ml) was added and refluxing was continued for 50 h (the reaction was monitored by 1H NMR). Then it was cooled to 0° C. to crystallize and 213 g of crude product was isolated by filtration. Recrystallization from ethanol gave the title compound (184.7 g, 59%) as a white solid.