Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([NH:15][NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[CH3:25])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:43][C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=3[CH3:25])=[N:16][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: Cc1cc(Br)ccc1C(=O)NNC(=O)c1ccc(OC(C)C)c(C#N)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1-c1nnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 125 °C

Procedure:
In an oven-dried high-pressure tube, 240 mg (0.58 mmol) of N′-(3-cyano-4-isopropyloxyphenylcarbonyl)-4-bromo-2-methylbenzhydrazide (from Step A) was combined with 40 mL of anhydrous toluene, 300 mg of Lawesson's Reagent (0.74 mmol), and 100 μL of pyridine. The tube was sealed with a plastic/teflon cap and the reaction mixture was heated to 125° C. for 2 h. The resulting mixture was cooled down to rt, solvents were removed under reduced pressure and residual solids were dissolved in 10 mL of pyridine. To this mixture, 0.5 g of phosphorous pentasulfide was added and the mixture heated to 110° C. The reaction mixture was combined with ice-water and extracted 2×100 mL of EtOAc. Combined organic layers were dried over sodium sulfate, and solvents removed under reduced pressure. Pure title compound was isolated by flash chromatography using Biotage 40S (eluant: hexanes/EtOAc-4/1) to yield 239 mg: 1H NMR (500 MHZ, CDCl3) δ 1.49 (d, J=6.5, 6H), 2.65 (s, 3H), 4.79 (sep, J=6.5, 1H), 7.13 (dd, J=9.0, 2.0, 1H), 7.50 (dd, J=9.0, 2.0, 1H), 7.56 (d, J=2.0, 1H), 7.63 (d, J=8.0, 1H), 8.17 (d, J=2.0, 1H), 8.24 (dd, J=8.0, 2.0, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[N:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13]Br)[O:5][CH3:6].C[N+]1([O-])CC[O:20]CC1>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[N:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[O:20])[O:5][CH3:6]
Reactant: COC(=O)N(OC)c1ccccc1CBr
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: COC(=O)N(OC)c1ccccc1C=O
Reaction time: 16 h

Procedure:
A solution of 27.4 g of (2-bromomethyl-phenyl)-N-methoxycarbamic acid methyl ester in 50 ml of acetonitrile is added dropwise at room temperature to 40 g of N-methyl-morpholine-N-oxide in 150 ml of acetonitrile. After stirring for 16 hours, the mixture is concentrated and the residue partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate and, after drying over sodium sulphate, the solvent is distilled from the combined organic phases. The residue is purified on silica gel using ethyl acetate/hexane (1:5% by volume). The title compound is obtained in the form of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]1[C:24](=[O:25])[CH2:23][CH2:22][O:21][CH2:20]1>C(#N)C>[CH2:10]([O:9][C:7]([C:4]1[CH:3]=[C:2]([O:1][CH:19]2[C:24](=[O:25])[CH2:23][CH2:22][O:21][CH2:20]2)[NH:6][N:5]=1)=[O:8])[CH3:11]
Reactant: O=C1CCOCC1Br
Reactant: CCOC(=O)c1cc(O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OC2COCCC2=O)[nH]n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (7.0 g, 45 mmol) and 24.9 g g of potassium carbonate in 500 ml of acetonitrile was added 8.0 g of 3-bromo-tetrahydro-pyran-4-one, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 9.0 g (78%) of the desired product was obtained as a white solid. M.Pt. 121-123° C.; (M+H) 255.
Reaction SMILES: [N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:7])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:49]([O:56][C:57]([C@@H:59]1[CH2:63][C@H:62]([NH:64][C:65]([O:67][CH2:68][CH:69]2[C:81]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[C:75]3[C:70]2=[CH:71][CH:72]=[CH:73][CH:74]=3)=[O:66])[CH2:61][N:60]1[C:82](=[O:91])[C@@H:83]([NH2:90])[CH:84]1[CH2:89][CH2:88][CH2:87][CH2:86][CH2:85]1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[CH2:49]([O:56][C:57]([C@@H:59]1[CH2:63][C@H:62]([NH:64][C:65]([O:67][CH2:68][CH:69]2[C:81]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[C:75]3[C:70]2=[CH:71][CH:72]=[CH:73][CH:74]=3)=[O:66])[CH2:61][N:60]1[C:82](=[O:91])[C@@H:83]([NH:90][C:4](=[O:6])[C@@H:2]([N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7])[CH3:3])[CH:84]1[CH2:89][CH2:88][CH2:87][CH2:86][CH2:85]1)=[O:58])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of Boc-N-Me-Ala-OH (351 mg, 1.73 mmol) in DMF at 0° C. was added DIPEA (1.27 mL, 8.85 mmol) and HATU (626 mg, 1.65 mmol). After 30 min, (2S,4S)-1-((S)-2-amino-2-cyclohexyl-acetyl)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester hydrochloride (0.97 g, 1.57 mmol) was added, the cooling bath removed and the reaction stirred for 1 h. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water, and brine and dried over anhydrous magnesium sulfate. Concentration gave (2S,4S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester (1.2 g) as an oil that was used without further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[C:5]([NH2:12])[C:4]=1[NH2:13].CO[C:16]1C(OC)=C[C:19]2[NH:20][C:21](CCCNC)=N[C:18]=2[CH:17]=1>>[CH3:1][O:2][C:3]1[C:4]2[N:13]=[C:16]([CH2:17][CH2:18][CH2:19][NH:20][CH3:21])[NH:12][C:5]=2[C:6]([CH3:11])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Reactant: COc1cc(C)c(N)c(N)c1OC
Product: CNCCCc1nc2c(OC)c(OC)cc(C)c2[nH]1

Procedure:
Prepared from 3,4-dimethoxy-6-methyl-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]1([PH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(=O)C=C>>[C:1]([CH2:2][CH2:3][P:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CC(=O)OC
Agent: C=CC(=O)[O-]
Product: COC(=O)CCP(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 8.6 g (0.1 mole) and methyl acrylate and 19.5 g (0.105 mole, 5% excess) of diphenyl phosphine was reacted at 15° C. in the routine manner of Example 1. U.V. irradiation resulted in a rapid reaction. After 1 hour, there was no acrylate left unconverted. The expected mono- and diadducts were formed in a weight ration of about 95 to 5. (A sample of the reaction misture which was not irradiated also showed a complete conversion after 22 hours but not after 1 hour). On distillation of the reaction mixture in vacuo, the monoadduct, i.e. 2-carbomethoxyethyl diphenyl phosphine, was obtained as an almost colorless, liquid distillate having a slight yellow tint (Table 3).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.Cl.[CH3:12][NH:13][O:14][CH3:15].C([Mg]Cl)(C)C.O>C1COCC1>[CH3:15][O:14][N:13]([CH3:12])[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:9]
Reactant: COC(=O)C1CCOCC1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCOCC1
Yield: 57.7 %

Procedure:
Methyl tetrahydropyran-4-carboxylate (1.33 mL, 10.0 mmol) was dissolved in THF (20 mL), and N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) added thereto, then the mixture was stirred. Under an argon atmosphere, THF solution of isopropyl magnesium chloride (2.0 mol/L; 15.0 mL, 30.0 mmol) was added dropwise to the reaction mixture at −30° C., and the mixture was stirred at −5° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by distillation under reduced pressure to give N-methoxy-N-methyltetrahydropyran-4-carboxamide (1.00 g, 58%). Boiling point: 125-129° C./8.0 hPa, 1H NMR (CDCl3, δ ppm): 1.57-1.66 (m, 2H), 1.77-1.93 (m, 2H), 2.85-2.94 (m, 1H), 3.18 (s, 3H), 3.44 (ddd, J=2.4, 11.9, 11.9 Hz, 2H), 3.69 (s, 3H), 4.00 (ddd, J=2.4, 11.9, 11.9 Hz, 2H). Step 2: 2-(Benzoimidazol-2-yl)-4-(2-furyl)thiazole (167 mg, 0.625 mmol) obtained in Reference Example 562 was dissolved in THF (5 mL). To the solution was added n-hexane solution of n-butyl lithium (1.58 mol/L; 1.01 mL, 1.56 mmol) at −78° C. under an argon atmosphere, and the mixture was stirred at −78° C. for 10 minutes. The THF solution (1 mL) of N-methoxy-N-methyltetrahydropyran-4-carboxamide (270 mg, 1.56 mmol) obtained in Step 1 was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give a title compound (191 mg, 81%).
Reaction SMILES: [F:1][C:2]1[C:44]([C:45]([F:48])([F:47])[F:46])=[N:43][CH:42]=[CH:41][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:15][C:14]([CH2:38][C:39]#[N:40])([N:16]3[CH:20]=[C:19]([C:21]4[C:22]5[CH:29]=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=5[N:24]=[CH:25][N:26]=4)[CH:18]=[N:17]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:44]([C:45]([F:48])([F:46])[F:47])=[N:43][CH:42]=[CH:41][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[CH2:13][C:14]([CH2:38][C:39]#[N:40])([N:16]3[CH:20]=[C:19]([C:21]4[C:22]5[CH:29]=[CH:28][NH:27][C:23]=5[N:24]=[CH:25][N:26]=4)[CH:18]=[N:17]3)[CH2:15]2)[CH2:10][CH2:11]1)=[O:5]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6ccnc(C(F)(F)F)c6F)CC5)C4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a solution of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (56 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 hours. After removing the solvents in vacuum, the residue was dissolved in a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, the solution was purified by HPLC (method B) to give the title compound. LC-MS: 554.3 (M+H)+; 1H NMR (400 MHz, CDCl3): 9.71 (s, 1H), 8.82 (s, 1H), 8.55 (d, J=4.6 Hz, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.52 (t, J=4.6 Hz, 1H), 7.39 (dd, J1=3.4 Hz, J2=1.5 Hz, 1H), 6.77 (dd, J1=3.6 Hz, J2=0.7 Hz, 1H), 4.18 (m, 1H), 3.75 (m, 2H), 3.63 (dd, J1=7.8 Hz, J2=3.7 Hz, 2H), 3.45 (m, 2H), 3.38 (s, 2H), 3.11 (m, 1H), 2.57 (m, 1H), 1.72 (m, 1H), 1.60 (m, 1H), 1.48 (m, 1H), 1.40 (m, 1H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH:1][N:2]2[N:11]=[C:10]([CH:12]3[CH2:13][CH2:14]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:15])=[O:25])=[CH:19][CH:18]=1
Reactant: Nn1nc(C2CC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(C2CC2)c2ccccc2c1=O

Procedure:
The product from Example 22B and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.79-0.92 (m, 2H) 0.92-1.07 (m, 2H) 2.45-2.55 (m, 1H) 3.67 (s, 2H) 7.32-7.52 (m, 4H) 7.92 (t, J=8.09 Hz, 1H) 7.99-8.14 (m, 1H) 8.31 (t, J=7.32 Hz, 2H) 11.50 (s, 1H); MS (ESI) m/z 354 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[O:9][CH2:10][CH2:11][C:12]4[N:13]([N:14]=[C:15]([C:17]5[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[CH:19][N:18]=5)[CH:16]=4)[C:7]=3[CH:6]=2)[CH2:2]1.Br[CH2:28][CH2:29][O:30]C1CCCCO1>>[CH:22]([N:21]1[C:17]([C:15]2[CH:16]=[C:12]3[N:13]([C:7]4[CH:6]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:28][CH2:29][OH:30])[CH2:4]5)[CH:26]=[CH:25][C:8]=4[O:9][CH2:10][CH2:11]3)[N:14]=2)=[N:18][CH:19]=[N:20]1)([CH3:24])[CH3:23]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Reactant: BrCCOC1CCCCO1
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(CCO)C3)ccc1OCC2

Procedure:
Following the procedures of Example 142, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene 144 was reacted with 2-(2-bromoethoxy)-tetrahydropyran followed by acidic hydrolysis of the THP group to give 169 as a white solid, as illustrated in FIG. 13. 1H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1H); 7.88 (d, J=2.22 Hz, 1H); 7.42 (dd, J=8.35, 2.22 Hz, 1H); 7.26 (d, J=8.32 Hz, 1H); 6.89 (s, 1H); 5.62-5.54 (m, 1H); 4.83 (s, 1H); 4.50 (t, J=6.03 Hz, 2H); 4.06 (s, 2H); 3.94 (t, J=8.52 Hz, 1H); 3.70 (s, 2H); 3.51 (s, 3H); 3.18 (t, J=6.05 Hz, 2H); 2.94 (s, 2H); 1.49 (d, J=6.58 Hz, 6H). LCMS: RT=6.01 min, M+H+=395
Reaction SMILES: F[C:2]1(OC#CC)[CH:7]=C(F)C=C[CH2:3]1.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21]>>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:7][C:2]#[CH:3]
Reactant: CC#COC1(F)C=C(F)C=CC1
Reactant: Oc1ccc(F)cc1Br
Product: C#CCOc1ccc(F)cc1Br

Procedure:
This compound was prepared analogously to 2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-4-fluoro-phenol (15 g, 78 mmol) to give 2-bromo-4-fluoro-1-prop-2-ynyloxy-benzene 15. g (84%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)[C:16](Cl)=[S:17])C>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:16]=[S:17]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCN(CC)C(=S)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(N=C=S)c1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
82.5 g of ethyl m-aminobenzoate was dissolved in 500 ml of toluene and to the solution was added dropwise 83.4 g of N,N-diethylthiocarbamoyl chloride at room temperature with stirring over a period of about 1 hour. The mixture was then refluxed by heating for 5 hours. The toluene was distilled off under reduced pressure, to the residue was added 300 ml of ethyl acetate and the ethyl acetate solution was washed with water. The ethyl acetate was distilled off under reduced pressure and the residue was further subjected to vacuum distillation to obtain 80 g of ethyl m-isothiocyanatobenzoate as oily product. Boiling Point: 125° C./0.6 mm Hg. Yield: 77%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[CH3:11].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])=[C:17](B(O)O)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])=[C:17]([CH2:2][C:3]2[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=2[CH3:11])[CH:18]=1
Reactant: Cc1ccc(C#N)nc1CCl
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(C#N)nc1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1F
Yield: 40.5 %

Procedure:
To a solution of 6-(chloromethyl)-5-methyl-2-pyridinecarbonitrile (132.5 mg) in dry toluene (4 ml) and ethanol (4 ml) was added (5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)boronic acid (250 mg), potassium carbonate (330 mg) and tetrakis(triphenylphosphine)palladium(0) (92 mg) and the mixture stirred under reflux for 2 hours. Solvent was removed in vacuo and water (20 ml) and ether (20 ml) added. Insoluble solid was filtered over Celite and washed with ether. The aqueous layer was further extracted with ether (15 ml) and the combined extracts washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (129 mg, 40%) as a pale buff solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].O>C(O)(=O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[F:16]
Reactant: Nc1ccccc1F
Reactant: O=[N+]([O-])c1cnc2ccc(F)cc2c1Cl
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2ccc(F)cc2c1Nc1ccccc1F

Procedure:
0.4 g (1.8 mmol) of 4-chloro-6-fluoro-3-nitro-quinoline (Example 19c) and 0.17 ml (1.98 mmol) 2-fluoroaniline in 5 ml acetic acid are stirred overnight at rt. Crystals are formed. The mixture is poured into water, the solid material is filtered off and washed with water. The residue is dissolved in CH2Cl2 and washed twice with water. The organic phase is dried over MgSO4 and most of the solvent is evaporated. The title compound is obtained from this solution as yellow crystals by adding hexane. The compound is filtered off, washed with hexane and dried (70° C., high-vacuum). mp: 161-162° C.; MS: 302 (M++1); HPLC: tret=10.24 min (Grad 1).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:19]([OH:25])([CH2:23][CH3:24])[C:20]([OH:22])=[O:21])[CH:15]=[C:16]([F:18])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:19]([OH:25])([CH2:23][CH3:24])[C:20]([O:22][CH3:3])=[O:21])[CH:15]=[C:16]([F:18])[CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCC(O)(C(=O)O)c1cc(F)cc(OCc2ccccc2)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCC(O)(C(=O)OC)c1cc(F)cc(OCc2ccccc2)c1

Procedure:
A solution of diazomethane in diethyl ether was added to a solution of (-)-2-(3-benzyloxy-5-fluorophenyl)-2-hydroxybutyric acid (2.24 g) in diethyl ether (35 ml) until the reaction mixture retained a yellow colouration. The mixture was evaporated to give optically active methyl 2-(3-benzyloxy-5-fluorophenyl)-2-hydroxybutyrate (2.27 g).
Reaction SMILES: [CH3:1][CH:2]([NH2:4])[CH3:3].Cl[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]>C1(C)C=CC=CC=1>[CH:2]([NH:4][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])[CH3:1]
Reactant: CCOC(=O)CCl
Reactant: CC(C)N
Solvent: Cc1ccccc1
Product: CCOC(=O)CNC(C)C
Temperature: 25 °C
Yield: 48.2 %

Procedure:
Propan-2-amine (2001)(59 g, 1.0 mol) and ethyl chloroacetate (122 g, 1.0 mol) were dissolved in toluene (200 mL) and the mixture was stirred at reflux for 2 h. The reaction mixture was allowed to cool to RT, poured into ice-water (500 mL) and extracted with ethyl acetate (3×250 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10-50% EA/PE) to afford the product, ethyl 2-(isopropylamino)acetate (2002) (70 g, 51% yield) as an oil.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](F)=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH:26]([CH3:28])[CH3:27])[N:18]=1)[CH:14]=[C:13]([C:29]([OH:31])=[O:30])[C:12]2=[O:32].Cl.Cl.[NH2:37][CH:38]1[CH2:41][NH:40][CH2:39]1.CN1CCCC1>C(O)C>[NH2:37][CH:38]1[CH2:41][N:40]([C:8]2[C:7]([Cl:6])=[C:16]3[C:11]([C:12](=[O:32])[C:13]([C:29]([OH:31])=[O:30])=[CH:14][N:15]3[C:17]3[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH:26]([CH3:27])[CH3:28])[N:18]=3)=[CH:10][C:9]=2[F:33])[CH2:39]1
Reactant: CC(C)Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To 160 mg of N,N-dimethylformamide were added 55 mg of 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-isopropylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 35 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 80° C. for 30 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 51 mg of the title compound as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:34]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.[W]>[Br:1][C:2]1[C:3]([CH2:15][Br:34])=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:11])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1c(Br)cccc1NC(=O)C(F)(F)F
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(Br)c1CBr)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(3-bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (2.1 g, 7.4 mmol) and benzoyl peroxide (100 mg) in carbon tetrachloride (50 mL) was heated to reflux under irradiation (150 W tungsten lamp). A solution of bromine (0.55 mL, 10.4 mmol) in carbon tetrachloride (3 mL) was then added drop-wise to the refluxing solution, and heating was pursued for 16 h. The reaction mixture was left to cool to RT and diluted with DCM. The organic layer was washed with sodium thiosulfate, and evaporated to dryness to give N-(3-bromo-2-bromomethyl-phenyl)-2,2,2-trifluoro-acetamide as a brown residue which was used without further purification (2.9 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCC[C@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@@H]1CCC[C@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 74.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (436 mg, 0.74 mmol) prepared in Example 78a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (239 mg, 74%) as a colorless solid.