Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2(O)C(=O)Nc3cc(Cl)ccc32)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Crude rac-6-chloro-3-hydroxy-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (from Example 6a supra) was suspended in a mixture of triethylsilane (5 mL, 31.3 mmol) (Aldrich) and trifluoroacetic acid (12.5 mL) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate (100 mL) and treated with solid sodium carbonate (10.5 g). After stirring for 30 minutes, mixture was extracted with water (2×100 mL) and brine (100 mL). Aqueous layers were back washed with ethyl acetate (100 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as off-white prisms. (Yield 2.12 g, 77.4% over two steps).
Reaction SMILES: CC1N=C(N2C(=O)NN=C2)SC=1C(OCC)=O.[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19].Br[CH2:34][CH:35]1[CH2:37][C:36]1([F:39])[F:38]>>[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH2:34][CH:35]3[CH2:37][C:36]3([F:39])[F:38])[C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC1(F)CC1CBr
Agent: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Product: CC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Yield: 49 %

Procedure:
Following the procedure as describe in Preparation 16, making variations as required to replace ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one to react with bromomethyl-2,2-difluorocyclopropane, the title compound was obtained as a yellow solid in 49% yield: mp 146-148° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.00 (t, J=9.0 Hz, 2H), 3.65-3.48 (m, 2H), 3.20-3.13 (m, 2H), 2.51 (s, 3H), 2.41 (s, 3H), 2.05-2.18 (m, 1H), 1.68-1.56 (m, 1H), 1.38-1.27 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 190.8, 160.1, 155.1, 154.9, 125.8, 114.8 (t), 42.4, 42.1, 41.1 (d), 30.4, 20.2 (t), 18.6, 14.9 (t); MS (ES+) m/z 316.9 (M+1).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH:11]1([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:13][CH2:12]1>C1COCC1>[CH:11]1([C:14]([CH:16]2[CH2:18][CH2:17]2)([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[OH:15])[CH2:13][CH2:12]1
Reactant: O=C(C1CC1)C1CC1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1nccs1)(C1CC1)C1CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 0.953 mL, 2.38 mmol) was added to a stirred, cooled −78° C. mixture of thiazole (0.169 mL, 2.383 mmol) in THF (5.0 mL) and the mixture was stirred at −78° C. for 15 min. A solution of the dicyclopropylmethanone (250 mg, 2.27 mmol) in THF (3.0 mL) was added dropwise and the mixture was stirred 30 min at −78° C. and then the temperature was allowed to reach room temperature. The reaction was quenched by addition of water and the mixture was extracted with ethyl acetate (3×). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% ethyl acetate in hexanes) to give dicyclopropyl(1,3-thiazol-2-yl)methanol (412 mg, 2.110 mmol, 93% yield). MS APCI: [M-OH]+ m/z 179.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:9]2)=[CH:4][CH:3]=1.[C:30]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([N:40]3[CH2:39][CH2:38][N:37]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:42][CH2:41]3)=[CH:7][CH:6]=2)[N:9]=[C:10]([C:20]([C:26]([F:27])([F:29])[F:28])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:11]1
Reactant: OC(C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 46.1 %

Procedure:
1-(4-Bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (500.0 mg, 1.00 mmol) prepared in Step 5 of Preparation 24, 1-BOC-piperazine (241.0 mg, 1.30 mmol), Pd2(dba)3 (45.0 mg, 0.05 mmol), BINAP (62.0 mg, 0.10 mmol) and sodium t-butoxide (144.0 mg, 1.50 mmol) were added to toluene (10.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 280.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C1COCC1.Br[C:7]1[C:8]([Cl:28])=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([CH3:26])[CH:19]=[C:20]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]3=[N:14][C:13]=2[CH3:27])[S:10][CH:11]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1.Cl.CCO>C(OCC)(=O)C.[Zn].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.Cl[Pd]Cl.[Fe+2]>[ClH:28].[Cl:28][C:8]1[C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)=[CH:11][S:10][C:9]=1[C:12]1[N:16]2[N:17]=[C:18]([CH3:26])[CH:19]=[C:20]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]2=[N:14][C:13]=1[CH3:27]
Reactant: Cc1cccc(Br)n1
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3Cl)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3scc(-c4cccc(C)n4)c3Cl)c(C)nc12
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 19.7 %

Procedure:
Reike® Zn (0.5 g/mL solution in THF (1.9 mL, 1.45 mmol) is added to a flask containing 3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.73 mmol). The slurry is heated at 65° C. for 1 hour, placed in a centrifuge for 5 minutes, and the resulting solution is transferred to a flask containing 2-bromo-6-methyl-pyridine (0.12 g, 0.73 mmol) and PdCl2(dppf) (0.018 g, 0.024 mmol). The reaction is heated at 65° C. overnight, diluted with ethyl acetate (20 mL), and washed with a sat. solution of NH4Cl (15 mL). The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified by silica gel chromatography using a hexanes and ethyl acetate gradient. The resulting product is dissolved in dichloromethane (5 mL), treated with a 1 M solution of HCl in EtOH (0.35 mL, 0.35 mmol) and concentrated. The residue is recrystallized from ethyl acetate and hexanes furnish the title compound (0.033 g, 0.072 mmol, 11%). 1H-NMR (CDCl3), δ 0.95 (t, J=7.3 Hz, 6H), 1.73-2.02 (m, 4H), 2.68 (s, 3H), 2.81 (s, 3H), 3.21 (s, 3H), 3.88-3.98 (m, 1H), 7.25 (s, 1H), 7.65 (d, J=7.5 Hz, 1H), 8.09 (d, J=7.5 Hz, 1H), 8.33 (dd, J=7.5, 7.1 Hz, 1H), 9.26 (s, 1H) ppm. LC/MS (m/z): calcd. for C23H26Cl2N4S (M+H)+: 424.2; found: 424.2.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[S:12][C:11]([C:13]#N)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.[O:26]1CCCC1>>[C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[S:12][C:11]([CH:13]=[O:26])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(Oc2ccc(C#N)s2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1ccc(Oc2ccc(C=O)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a tetrahydrofuran (70.0 mL) solution of 5-p-tolyloxy-thiophene-2-carbonitrile (2.00 g, 9.29. mmol) described in Manufacturing Example 48-1-1 was added dropwise diisobutyl aluminum hydride (0.97 M n-hexane solution, 23.9 mL, 23.2 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 3 hours at room temperature. The reaction mixture was cooled to room temperature and extracted with ethyl acetate after addition of water. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (958 mg, 47.2%).
Reaction SMILES: [Al].[C:2]([NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([N+:18]([O-])=O)=[CH:13][C:12]=1[OH:21])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Co].[Cr].[Ni]>[NH2:18][C:14]1[C:15]([Cl:17])=[CH:16][C:11]([NH:10][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:12]([OH:21])[CH:13]=1
Reactant: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1ccccc1
Agent: [Co]
Agent: [Cr]
Agent: [Ni]
Product: Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl

Procedure:
Using the procedure described above and 5.0 g of a chromium-containing Raney cobalt catalyst containing about 20-30 weight percent aluminum, 1.5 to 2.5 weight percent nickel and the remainder cobalt, 2-benzamido 4-chloro 5-nitrophenol is hydrogenated for a total of 4 hours to obtain the corresponding amine, 5-amino 2-benzamido 4-chlorophenol. Analysis of a sample of the reaction mixture taken and analyzed in accordance with the procedure used in the preceding example, show that the purity of the product is 98.4 percent and the presence of 0.1 percent of dechlorinated by product. The azo, azoxy and hydroxylamine intermediate products are soluble in the final filtrate and thus are easily removed from the product. No starting material is detected.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9]C2CCCCO2)[O:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CO.Cl>[OH:9][CH2:8][C:5]1[O:6][CH:7]=[C:2]([CH3:1])[C:3](=[O:16])[CH:4]=1
Reactant: Cc1coc(COC2CCCCO2)cc1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1coc(CO)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 0.61 g of 5-methyl-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one in 3 mL of methanol, 0.03 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 0.5 g of potassium carbonate and chloroform were added, and the mixture was stirred for 30 minutes. The insoluble substance was filtered off, the solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=9:1 to obtain 0.26 g of 2-hydroxymethyl-5-methyl-4H-pyran-4-one as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](S)[S:8][C:4]=2[CH:3]=1.S(Cl)([Cl:15])(=O)=O>C(Cl)Cl>[Cl:15][C:7]1[S:8][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Fc1ccc2nc(S)sc2c1
Solvent: ClCCl
Product: Fc1ccc2nc(Cl)sc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-fluorobenzo[d]thiazole-2-thiol (14.0 g, 0.075 mol) was suspended in dry DCM (100 mL) under nitrogen and cooled to 0° C. Sulfuryl chloride (18.5 mL) was then added dropwise and the reaction was allowed to warm to RT and stirred for 1 h. The reaction mixture was then poured on to crushed ice and extracted with DCM (4×300 mL). The combined organic extract was given brine wash (2×150 mL), dried (Na2SO4) and concentrated. The crude compound was purified by column chromatography (Silica 100-200 mesh; 3-7% ethyl acetate in hexane) to provide 2-chloro-6-fluorobenzo[d]thiazole as a white solid.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:19]1[N:20]=[C:21]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)[CH:22]=[CH:17][N:18]=1
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1CCN(c2ccnc(C(F)(F)F)n2)CC1
Reaction time: 48 h
Yield: 91.2 %

Procedure:
4-Piperidone monohydrate hydrochloride (XXVII, 3.37 g, 21.9 mmol) was added to a stirred mixture of methylene chloride (50 mL) and saturated aqueous sodium carbonate (8 mL). 4-Chloro-2-(trifluoromethyl)pyrimidine (IV, 4.0 g, 21.9 mmol) was then added to the mixture which was then stirred for 2 days. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo to give the product as a white solid (4.9 g, 92%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:42][C:43](=[O:46])[CH2:44][CH3:45].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:42][C:43](=[O:46])[CH2:44][CH3:45])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCC(=O)CBr
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)OC(C)(C)C)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reaction time: 72 h

Procedure:
A solution of tert-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.07 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.186 ml), followed by 1-bromo-2-butanone (0.08 ml). The resultant solution was allowed to reach room temperature and stirred for a further 72 h. Methanol (1 ml) was added and the resultant solution concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 10:1, 5:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:5, ethyl acetate and methanol:ethyl acetate 1:9) to give the title compound (0.07 g) as a gum.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8].Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:41])=[CH:25][N:24]=1>>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH:20][C:23]3[N:28]=[C:27]([NH:29][C:30]4[C:31]([C:32](=[O:33])[NH:34][CH3:35])=[CH:36][CH:37]=[CH:38][C:39]=4[F:40])[C:26]([Cl:41])=[CH:25][N:24]=3)=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: CN(C)CCCOC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCCN(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a yellow foam (35 mg, 21%). LCMS (m/e) 572 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.48-9.34 (m, 2H), 8.62-8.51 (m, 1H), 8.20 (s, 1H), 7.54-7.37 (m, 3H), 7.36-7.24 (m, 1H), 7.10 (d, 1H, J=9.1 Hz), 6.94 (d, 1H, J=8.7 Hz), 4.14-3.86 (m, 4H), 3.70-3.43 (m, 2H), 2.74 (d, 3H, J=4.4 Hz), 2.21-2.00 (m, 8H), 1.97-1.82 (m, 2H), 1.63-1.48 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.C(OC(N[NH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:31]3[CH2:32][CH2:33][CH:28]([NH2:27])[CH2:29][CH2:30]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CC(C)(C)OC(=O)NNC1CCNCC1
Product: NC1CCN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CC1
Yield: 18.1 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (50 mg, 0.11 mmol) and 4-(tert-butoxycarbonylamino)aminopiperidine (39 mg, 0.2 mmol) were reacted according to GP8 to give 6.5 mg of the title compound (166JO55). MS (ESI) 327 (MH+). Purity for MH+ (UV/MS) 100/99.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:10])([F:20])[F:21])=[CH:14][CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: Fc1cnc(Cl)nc1Nc1ccc(OC(F)(F)F)cc1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-trifluoromethoxyaniline gave 2-chloro-5-fluoro-N4-(4-trifluoromethoxyphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.11 (d, 1H, J=2.1 Hz), 7.68 (dd, 2H, J=2.4 and 7.6 Hz), 7.26 (dd, 2H, J=3 and 8.7 Hz), 7.0 (bs, 1H); 19F NMR (CD3OD): δ −16517 and −44523; LCMS: purity: 94%; MS (m/e): 308 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[N:17]=[CH:16][C:10]3[N:11]=[CH:12][NH:13][C:14](=O)[C:9]=3[CH:8]=2)=[N:4][N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:14]1[C:9]2[CH:8]=[C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)[N:17]=[CH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Cc1nnc(-c2cc3c(=O)[nH]cnc3cn2)o1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2cc3c(Cl)ncnc3cn2)o1

Procedure:
6-(5-Methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-one (0.5 g) was treated with phosphorus oxychloride in the usual manner to give the title compound (0.17 g) as an orange solid; δH CDCl3 9.68 (1H,s), 9.30 (1H,s), 8.96 (1H,s), 2.75 (3H,s); m/z (M+1+) 248.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=[O:5].C[C:15](=[O:19])[O:16]CC>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH:4]([OH:5])[C:15]([OH:19])=[O:16]
Reactant: CCOC(C)=O
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Product: O=C(O)C(O)c1c(F)cccc1C(F)(F)F

Procedure:
The 2-fluoro-6-trifluoromethylbenzaldehyde (48.4 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 49.7 g. (84%). EA, MS(FD).
Reaction SMILES: N1CCCC1.[C:6]([O:10]CC)(=[O:9])[C:7]#[CH:8].C(N(CC)CC)C.[OH:20][N:21]=[C:22](Cl)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>C(OCC)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:7]([C:6]([OH:10])=[O:9])=[CH:8][O:20][N:21]=2)=[CH:24][CH:25]=1
Reactant: C#CC(=O)OCC
Reactant: COc1ccc(C(Cl)=NO)cc1
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(-c2nocc2C(=O)O)cc1
Temperature: 0 °C
Yield: 2.7 %

Procedure:
A solution of pyrrolidine (0.63 mL, 7.5 mmol) in diethyl ether (6 mL) was added during 15 min to a solution of ethyl propiolate (0.76 mL, 7.5 mmol) in diethyl ether (6 mL) at 0° C. with stirring. The resulting solution was stirred for 30 min at rt, whereafter triethylamine (1.04 mL, 7.5 mmol) was added and the reaction was chilled to 0° C. again and a solution of N-hydroxy-4-methoxybenzenecarboximidoyl chloride (1.39 g, 7.5 mmol) in diethyl ether (10 mL) was added during 30 min. The temperature was allowed to go to rt and was washed with 1 M HCl and water, dried (Na2SO4) and evaporated. The crude intermediate was dissolved in acetic acid (3 mL) and conc. HCL (3 mL) and the mixture was refluxed for 2 h. The solvents were evaporated and the mixture was partioned between ethyl acetate and cold aqu. NaOH (0.5 M). The aqueous phase was acidified by conc. HCl and filtered. The crystals were purified by silica gel chromatography (DCM:MeOH 19:1 to 5:1) to give a white solid (45 mg), which was used in the next step without further analysis or purification (ca. 90% pure). MS 220 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60]([NH2:63])=[C:59]([NH2:64])[CH:58]=1>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:63][C:60]3[CH:61]=[CH:62][C:57]([O:56][CH3:55])=[CH:58][C:59]=3[NH2:64])=[O:24])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Reactant: COc1ccc(N)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC(=O)CCCCCNC(=O)C=C2c3ccccc3-c3ccccc32)c(N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
6-(2-(9H-fluoren-9-ylidene)acetamido)hexanoic acid (335 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-methoxy-o-phenylenediamine (166 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (332 mg, 73% yield) as a brown solid. 1H NMR (DMSO-d6) δ1.39 (m, 2H, CH2), 1.55 (m, 2H, CH2), 1.62 (m, 2H, CH2), 2.29 (t, J=8.0 Hz, 2H, CH2CO), 3.27 (m, 2H, NCH2), 3.62 (s, 3H, OCH3), 4.84 (s, 2H, benzene-NH2), 6.08 (d, J=8.0 Hz, 1H, Ar—H), 6.28 (s, 1H, Ar—H), 6.95 (d, J=8.0 Hz, 1H, Ar—H), 7.10 (s, 1H, ═CH—CO), 7.33 (m, 2H, Ar—H), 7.40 (m, 2H, Ar—H), 7.76 (d, J=8.0 Hz, 1H, Ar—H), 7.82 (m, 2H, Ar—H), 8.58 (t, J=4.0 Hz, 1H, CONH), 8.72 (d, J=8.0 Hz, 1H, Ar—H), 9.02 (s, 1H, benzene-NH). LC-MS (m/z) 456 (M+1).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=O)(C)(C)C.[CH3:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>>[NH2:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([O:16][CH2:17][C:18]([N:23]([CH3:22])[CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)=[O:20])=[N:11][C:10]=1[CH3:21]
Reactant: CNC1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccc(C(F)(F)F)cc3)CC2)nc(C)c1N

Procedure:
The title compound was synthesized from Compound 9 and N-methyl-1-(4-(trifluoromethyl)benzyl)-piperidine-4-amine in the same manner as in Example 64 and recrystallized from methylene chloride.