Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1([CH3:10])[CH2:8][O:7][NH:6][C:5]1=[O:9].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=1[CH2:20]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=1[CH2:20][N:6]1[C:5](=[O:9])[C:4]([CH3:10])([CH3:3])[CH2:8][O:7]1
Reactant: CC1(C)CONC1=O
Reactant: Clc1cc(Cl)c(CBr)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2cc(Cl)c(Cl)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.9 %

Procedure:
To a stirred suspension of 1.9 grams (0.029 mole) of crushed 85% pure potassium hydroxide and 1.7 grams (0.005 mole) of tetrabutylammonium bromide in 20 ml of tetrahydrofuran was added dropwise a solution of 3.0 grams (0.026 mole) of 4,4-dimethyl-3-isoxazolidinone (Example 30, Step B) and 7.1 grams (0.026 mole) of (2,4,5-trichlorophenyl)methyl bromide in 50 ml of tetrahydrofuran. The addition required one hour. Upon completion of addition the reaction mixture was stirred at ambient temperature for 1.5 hours and then filtered. The filtrate was diluted with 150 ml of methylene chloride and washed with three 75-ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 10% ethyl acetate in heptane. The appropriate fractions were combined and concentrated under reduced pressure to give 1.6 grams of 2-[(2,4,5 -trichlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][SiH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37](Br)(Br)([Br:39])[Br:38]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([O:10][SiH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:37]([Br:39])[Br:38]
Reactant: CCCC(C)(C)[SiH2]Oc1ccc(C=O)c(F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC(C)(C)[SiH2]Oc1ccc(C=C(Br)Br)c(F)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 26 mmol of 2-fluoro-4-dimethylbutylsilyloxy benzaldehyde in 50 ml of methylene chloride were added dropwise under ice-cooling 110 mmol of triphenyl phosphine and 52 mmol of carbon tetrabromide and the solution was stirred at the same temperature for one hour. The insoluble matter was removed from the reaction solution which was concentrated under reduced pressure to provide a yellow oily product. Purification of the product by a silica gel column chromatography gave 26 mmol of 2-fluoro-4-dimethylbutylsilyloxyphenyl-2,2-dibromoethylene as a colourless oily product.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[C:7](Cl)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[C:10]1([CH:9]=[CH:8][C:7]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)NN
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CC#N
Product: COC(=O)NNC(=O)C=Cc1ccccc1
Reaction time: 15 h
Yield: 94.8 %

Procedure:
To a solution of 27 g (0.3 moles) of methyl carbazate and 250 ml. of acetonitrile a solution of 50 g. (0.3 moles) of cinnamic chloride and 100 ml. of acetonitrile is added. The reaction mixture is heated to boiling for 15 hours. The mixture is cooled and the precipitated white crystals are filtered off. Thus 62,6 g. of the desired compound are obtained, yield 94.8%. M.p.: 165° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[N:18][S:19][C:20]=2[C:21]([O:23]CC)=[O:22])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>O>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[N:18][S:19][C:20]=2[C:21]([OH:23])=[O:22])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1snnc1-c1ccc(OCC(O)CNC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc(-c2nnsc2C(=O)O)cc1

Procedure:
To a solution of 200 mg. of 4-[4(3-t-butylamino-2-hydroxypropoxy)phenyl]-5-carboethoxy-1,2,3-thiadiazole in 15 ml. of methanol is added a solution of 100 mg. of sodium hydroxide in 2 ml. of water, and the reaction mixture is refluxed for 4 hours. It is then cooled, evaporated to a small volume under vacuo, diluted with 25 ml. of water and extracted with ethyl acetate to eliminate the unsaponified product. The aqueous phase is passed through a column of 10 g. of ion exchange resin sold by the Dow Chemical Company under the trademark Dowex 50, acidic type (H+) eluting the column first with water and thereafter with 10% acetic acid solution. The combined acidic eluates are concentrated to a small volume under reduced pressure at low temperature and then lyophilized, to yield 4-[4(3-t-butylamino-2-hydroxypropoxy)phenyl]-5-carboxy-1,2,3-thiadiazole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13](I)[CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:16][CH3:17])=[O:5])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.[Cu]I>[CH2:16]([C:9]1[C:8]2[C:12](=[C:13]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]3=[O:24])[CH:14]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=2)[NH:11][CH:10]=1)[CH3:17]
Reactant: O=C1CCCCN1
Reactant: CCOC(=O)c1cc(I)c2[nH]cc(CC)c2c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(N2CCCCC2=O)c2[nH]cc(CC)c2c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 27.3 %

Procedure:
To a solution of ethyl 3-ethyl-7-iodo-1H-indole-5-carboxylate (D190) (1 g, 2.91 mmol, 1 equiv) in toluene (10 ml) were added 2-piperidinone (346 mg, 3.50 mmol, 1.2 equiv), K3PO4 (1.24 g, 5.83 mmol, 2 equiv), CuI (56 mg, 0.29 mmol, 0.1 equiv) and dimethyl ethylene diamine (62 μl, 0.58 mmol, 0.2 equiv) and the resulting mixture was stirred at 100° C. for 15 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H2O and the layers were separated. The organic phase was dried under MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 1/0) gave ethyl 3-ethyl-7-(2-oxo-1-piperidinyl)-1H-indole-5-carboxylate (B165) (250 mg, 27%) as an off-white solid. [M+H]+=315.4, RT=2.98 min.
Reaction SMILES: FC1C=CC(CNC)=CC=1.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][CH3:19])=[CH:15][CH:14]=1.[F:22][C:23]1[CH:45]=[CH:44][C:26]([CH2:27][NH:28][C:29]([C:31]2[S:35][C:34]([C:36]3[CH:41]=[N:40][CH:39]=[C:38](I)[N:37]=3)=[N:33][C:32]=2[CH3:43])=[O:30])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:45]=[CH:44][C:26]([CH2:27][NH:28][C:29]([C:31]2[S:35][C:34]([C:36]3[CH:41]=[N:40][CH:39]=[C:38]([N:18]([CH2:17][C:16]4[CH:20]=[CH:21][C:13]([O:12][CH3:11])=[CH:14][CH:15]=4)[CH3:19])[N:37]=3)=[N:33][C:32]=2[CH3:43])=[O:30])=[CH:25][CH:24]=1
Reactant: CNCc1ccc(OC)cc1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Agent: CNCc1ccc(F)cc1
Product: COc1ccc(CN(C)c2cncc(-c3nc(C)c(C(=O)NCc4ccc(F)cc4)s3)n2)cc1
Yield: 72 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with (4-methoxy-benzyl)-methyl-amine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro benzylamide, the title compound was obtained in 72% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.55 (s, 1H), 8.06 (s, 1H), 7.29-7.37 (m, 2H), 7.17-7.24 (m, 2H), 6.99-7.07 (m, 2H), 6.80-6.87 (m, 2H), 6.20 (bs, 1H), 4.75 (s, 2H), 4.53 (d, J=4.0 Hz, 2H), 3.74 (s, 3H), 3.11 (s, 3H), 2.70 (s, 3H); MS (ES+) m/z 478.2 (M+1), Rt=1.58 min.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[S:20][CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[N:23]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.O>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.ClCCl>[CH3:18][C:19]1[S:20][CH:21]=[C:22]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[N:23]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: Cc1nc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1nc(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)cs1
Temperature: 90 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (101 mg, 0.347 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (0.10 g, 0.44 mmol), potassium carbonate (147.9 mg, 1.070 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (24.3 mg, 0.0343 mmol) was added acetonitrile (3 mL, 60 mmol) and water (0.3 mL, 20 mmol). The reaction mixture was then stirred in a sealed vial at 90° C. for 8 hours, and then cooled to room temperature. The reaction mixture was poured into dichloromethane, washed once with saturated aqueous NaHCO3, dried over MgSO4, filtered, and evaporated in vacuo. The resulting residue was purified via reverse phase HPLC and lyophilized to yield 22.7 mg (21%) of N-(7-(2-methylthiazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=4.328, M+H=310.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.20 (s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 8.24 (dd, J=8.7, 1.5 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J=8.7 Hz, 1H), 2.76 (s, 3H), 2.08 (ddd, J=12.2, 7.8, 4.7 Hz, 1H), 0.85 (dd, J=9.3, 6.3 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][CH:5]([N+:8]([O-])=O)[CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.Cl>C1COCC1.[Zn]>[CH3:1][C:2]1([CH3:17])[NH:3][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]([NH2:8])[CH2:6][CH2:7]1
Reactant: CC1(C)CCC([N+](=O)[O-])C(c2ccccc2)N1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CCC(N)C(c2ccccc2)N1
Temperature: 25 °C
Yield: 69 %

Procedure:
To 2,2-Dimethyl-5-nitro-6-phenyl-piperidine in 0.4 mL of THF was added 0.2 mL of 6 M HCl and 100 mg (1.5 mmol) of zinc powder. The mixture was stirred at rt until complete by TLC analysis. The mixture was filtered through celite, rinsing with 5 mL of water. The aqueous solution was washed with Et2O (3×5 mL) and was then basified with 1 N NaOH to pH=12. The mixture was extracted with CHCl3 and the extracts were dried via filtration through a plug of cotton and concentrated to give 6 mg (69%) of the title compound as a colorless oil: mass spectrum m/e=205 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[CH2:12]=[O:13]>C(O)(C)(C)C.CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: C=O
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cccc(F)c1CCO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of potassium tertiary-butylate (90 mg, 0.8 mmol) in tert.-butanol (1 ml, synthesis quality, 99%) was added to 2-fluoro-6-nitrotoluene (776 mg, 5 mmol) and paraformaldehyde (150 mg, 5 mmol) in DMSO (2.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. The solution was stirred for 5 min at room temperature and for 30 min at 70° C. (oil bath temperature). It was then left to cool down to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with EtOAc (30 ml) and washed with H2O (20 ml). The aqueous phase was post-extracted with EtOAc (2×20 ml). Drying the organic phases over Na2SO4, filtering and evaporating the solvent under reduced pressure yielded the crude product (1.11 g) which was purified by column chromatography (20 g SiO2, 12×2 cm, solvent: PE 40 ml, PE/EtOAc 10:1 110 ml, 8:1 270 ml, 6:1 210 ml, 5:1 60 ml, 4:1 50 ml). 2-(2-fluoro-6-nitrophenyl)ethanol (653 mg, 71%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:20])[N:9]([CH2:16][C:17]([OH:19])=[O:18])[C:10]2=[O:15])(=[O:4])=[O:3].[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1.O>[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)[O:18][C:17](=[O:19])[CH2:16][N:9]1[C:8](=[O:20])[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:10]1=[O:15]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)Nc1cccc2c1C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.29 %

Procedure:
A mixture of 2-(4-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid (78 mg, 0.262 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-hydroxyethyl)pyridine 1-oxide (110 mg, 0.262 mmol), DMAP (15.97 mg, 0.131 mmol) and EDC (125 mg, 0.654 mmol) in 15 ml of THF was stirred at room temperature for 2 days. The mixture was diluted with water, acidified and extracted twice with EtOAc; the organic layer was then washed with brine, dried over sodium sulfate and evaporated. The residue was triturated with methanol and the title compound was obtained as a pale yellow solid (39 mg, 0.056 mmol, 21.29% yield, MS/ESI+ 700.11 [MH]+, [αD]=−63.94, c=0.355 in DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.29 (br. s., 1H), 8.47 (s, 2H), 7.86 (dd, 1H), 7.81 (dd, 1H), 7.63 (dd, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.46 (d, 1H), 4.38 (d, 1H), 3.93 (d, 2H), 3.41 (dd, 1H), 3.30 (s, 3H), 3.24 (dd, 1H), 1.10-1.31 (m, 1H), 0.48-0.66 (m, 2H), 0.27-0.48 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([CH:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)[N:15]3[C:20]=2[C:19]([NH2:21])=[N:18][CH:17]=[N:16]3)=[CH:8][C:7]=1[O:32][CH3:33].[Cl:37]N1C(C)(C)C(=O)N(Cl)C1=O>CN(C=O)C>[Cl:37][C:13]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:34]=[CH:35][CH:36]=[C:2]([Cl:1])[CH:3]=3)=[C:7]([O:32][CH3:33])[CH:8]=2)=[C:20]2[N:15]([C:14]=1[CH:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24][CH2:23]1)[N:16]=[CH:17][N:18]=[C:19]2[NH2:21]
Reactant: COc1cc(-c2cc(C3CCN(S(C)(=O)=O)CC3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1cc(-c2c(Cl)c(C3CCN(S(C)(=O)=O)CC3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Temperature: 65 °C
Yield: 151.7 %

Procedure:
The compound (15.40 mg, 0.029 mmol) prepared in Example 26 and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.87 mg, 0.015 mmol) were taken up in 2 mL of DMF and heated to 65° C. for 16 hours. The reaction was cooled to room temperature and the DMF removed under vacuum and the reaction mixture submitted for prep-HPLC purification to obtain the title compound (12.8 mg) having the following physical data.
Reaction SMILES: BrC1C(C2C(F)=CC=C([N+]([O-])=O)C=2F)=NN(C)C=1.[Br:19][C:20]1[CH:21]=[N:22][N:23]([CH3:36])[C:24]=1[C:25]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([N+:32]([O-])=O)[C:26]=1[F:35].[Cl-].[NH4+]>O1CCOCC1.O.[Zn]>[Br:19][C:20]1[CH:21]=[N:22][N:23]([CH3:36])[C:24]=1[C:25]1[C:26]([F:35])=[C:27]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:32]
Reactant: Cn1ncc(Br)c1-c1c(F)ccc([N+](=O)[O-])c1F
Agent: Cn1cc(Br)c(-c2c(F)ccc([N+](=O)[O-])c2F)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ncc(Br)c1-c1c(F)ccc(N)c1F
Reaction time: 3 h

Procedure:
A mixture of 4-bromo-3-(2,6-difluoro-3-nitrophenyl)-1-methyl-1H-pyrazole and its regioisomer 4-bromo-5-(2,6-difluoro-3-nitrophenyl)-1-methyl-1H-pyrazole (0.35 g, 1.1 mmol), powdered zinc (0.39 g, 6 mmol) and ammonium chloride (0.6 g, 11 mmol) in dioxane (6 mL) and water (2 mL) were refluxed under good stirring for 3 h. After cooling, the mixture was filtered and the filtrate was concentrated. The residue was taken up with dichloromethane, washed with saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and concentrated. The crude mixture of 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)-2,4-difluoroaniline and its regioisomer 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2,4-difluoroaniline was obtained as a brownish solid (0.33 g, 95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[C:21]([C:32]([F:35])([F:34])[F:33])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C=O)C>[N:36]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[C:21]([C:32]([F:35])([F:34])[F:33])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1)=[N+:37]=[N-:38]
Reactant: O=C(Nc1ccc(Oc2cc(Cl)ncn2)cc1)Nc1ccc(CN2CCCCC2)c(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Oc2ccc(NC(=O)Nc3ccc(CN4CCCCC4)c(C(F)(F)F)c3)cc2)ncn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of N-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(3-trifluoromethyl-4-(piperidin-1-ylmethyl)-phenyl)-urea (Example 128; 350 mg, 0.69 mmol) and NaN3 (91 mg, 1.4 mmol) in 7 ml of DMF is stirred for 2 h at 70° C. The resulting mixture is concentrated in vacuo, the residue diluted with AcOEt and water, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated to yield the title compound: MS: [M+1]+=513.
Reaction SMILES: [N:1]([C:4]1([CH3:22])[CH2:10][CH2:9][CH2:8][CH2:7][N:6]2[C:11](=[O:21])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=[C:5]12)=[N+]=[N-]>[Pd]>[NH2:1][C:4]1([CH3:22])[CH2:10][CH2:9][CH2:8][CH2:7][N:6]2[C:11](=[O:21])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=[C:5]12
Reactant: CC1(N=[N+]=[N-])CCCCn2c1nc(-c1ccncc1)cc2=O
Agent: [Pd]
Product: CC1(N)CCCCn2c1nc(-c1ccncc1)cc2=O

Procedure:
10-azido-10-methyl-2-pyridin-4-yl-7,8,9,10-tetrahydro-6H -pyrimido[1,2-a]azepin-4-one was reduced by using H-Cube™ technology (from THALES Nanotechnology, full H2, Pd/C as catalyst, 1 mL/min and 50° C.). After an acid-basic work-up, (+/−)10-amino-1 0-methyl-2-pyridin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one was obtained and the compound was used as such in the next step.
Reaction SMILES: OS(O)(=O)=O.[O:6]=S(=O)=O.[Cl:10][C:11]([F:23])([C:19]([F:22])([F:21])[Cl:20])[C:12]([F:18])([F:17])[C:13](F)([F:15])I>>[Cl:10][C:11]([F:23])([C:19]([F:22])([F:21])[Cl:20])[C:12]([F:18])([F:17])[C:13]([F:15])=[O:6]
Reactant: FC(F)(Cl)C(F)(Cl)C(F)(F)C(F)(F)I
Reactant: O=S(=O)=O
Agent: O=S(=O)(O)O
Product: O=C(F)C(F)(F)C(F)(Cl)C(F)(F)Cl
Temperature: 110 °C

Procedure:
A 1 L three-necked flask, fitted with a stir bar and condenser, was charged with 3.0 g of HgO (yellow), 125 mL of 20% oleum, 25 mL of 65% oleum and 75.6 g of 3,4-dichloro-1-iodoperfluorobutane. After the reaction mixture was heated at 110° C. for 2 hours, the condenser was replaced by a distillation head with a 250 mL flask for receiver cooled with ice water. Volatiles were collected, washed with 98% sulfuric acid to remove sulfur trioxide and redistilled to give 40.3 g of 3,4-dichloroperfluorobutyryl fluoride, bp 72°-75° C., 99.8% GC purity.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.O=[C:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[C:20](O)=[O:21]>>[CH2:16]1[C:15]2[C:20](=[O:21])[O:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][C:2]=3[C:14]=2[CH2:19][CH2:18][NH:17]1
Reactant: Oc1cccc2ccccc12
Reactant: O=C(O)C1CNCCC1=O
Agent: Cl
Product: O=c1oc2c(ccc3ccccc32)c2c1CNCC2
Yield: 29.4 %

Procedure:
Prepared by the method described in Example 1 from 1-napthol (10.0 g, 0.069 moles) and 4-oxo-3-piperidinecarboxylate hydrochloride (9.6 g, 0.05 moles). Recrystallization from 2-propanol/N,N-dimethylformamide yielded the product (3.7 g), mp 227°-230° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:17][C:16]1[C:9]2[C:8]([N:6]3[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]3)=[N:13][CH:12]=[N:11][C:10]=2[NH:14][CH:15]=1
Reactant: Cc1c[nH]c2ncnc(N3CCN(C(=O)OC(C)(C)C)[C@@H](C)C3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Reaction time: 8 h
Yield: 77.8 %

Procedure:
The Boc-protected piperazine from step A (1.5 g, 4.5 mmol) was added to a 1:1 mixture of trifluoroacetic acid and dichloromethane (10 ml). The reaction was stirred overnight, then concentrated under vacuum, diluted with dichloromethane, and neutralized with sat. aq. sodium bicarbonate. The layers were separated, and the aqueous layer was back extracted with more dichloromethane. The combined organic fractions were dried over MgSO4 and concentrated under vacuum to give (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.80 g, 3.5 mmol, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[S:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11].O1[CH2:21][CH2:20]CC1.O>CN1CCNCC1.C(O)(=O)C>[CH3:12][C:7]1[S:6][C:5]2[NH:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[N:1]=[C:10]([N:11]3[CH2:21][CH2:20][N:4]([CH3:5])[CH2:3][CH2:2]3)[C:9]=2[CH:8]=1
Reactant: C1CCOC1
Reactant: Cc1cc(C#N)c(Nc2ccccc2N)s1
Agent: CN1CCNCC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
2-(2-Aminoanilino)-5-methylthiophene-3-carbonitrile (2.0 g) is taken in N-methyl-piperazine (12 ml) and acetic acid (2 ml). The solution is heated at 120° C. until completion of reaction. The reaction mass is cooled and tetrahydrofuran is added. The reaction mixture is stirred for 30 minutes. The water is added at 45-50° C., the mixture is cooled up to room temperature and the solid is precipitated out. The solid is filtered off and washed with tetrahydrofuran-water mixture.