Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:31])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[CH:16]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[Na+].O>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:31])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][OH:23])[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(C(=O)c2cccc(CCO)c2)cnn1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-4-[3-(2-tert-butyldimethylsiloxyethyl)-benzoyl]pyrazole (1.2 g, 3.0 mmol) in tetrahydrofuran (25 ml) was added tetrabutylammonium fluoride (3.6 ml, 3.6 mmol, 1 M solution in tetrahydrofuran). After 1 h, the reaction mixture was poured into brine and the product was extracted into ethyl acetate. The organic layer was dried over sndium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatiwaphy (elution gradient: 40-100% ethyl acetate/hexane) to give 5-amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl)benzoyl]pyrazole (0.8 g).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)[CH:18]=1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Reactant: NCc1cccc(C(F)(F)F)c1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3cccc(C(F)(F)F)c3)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 3-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 488.5. HPLC (Condition A), Rt: 4.86 min (HPLC purity: 66.8%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:23]=[CH:22][C:12]3[N:13]=[C:14]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])[S:15][C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:23]=[CH:22][C:12]3[N:13]=[C:14]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])[S:15][C:11]=3[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCNC(=O)Nc1nc2ccc(C#Cc3ccccc3)cc2s1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CCNC(=O)Nc1nc2ccc(/C=C\c3ccccc3)cc2s1
Reaction time: 36 h
Yield: 41 %

Procedure:
A suspension of 1-(6-phenylacetylenyl-2-benzothiazolyl)-3-ethylurea (0.032 g, 83% purity by weight, 0.083 mmol) and Lindlar catalyst (0.030 g, 5% weight purity, 0.012 mmol, 0.15 eq) in 2 mL ethanol was purged with nitrogen gas, followed by bubbling of hydrogen gas. It was stirred under hydrogen atmosphere for about 36 hours. The mixture was taken up in 10 mL MeOH, filtered, concentrated, and purified by preparative TLC to give 0.011 g (41%) of the desired compound. LC/MS 324 (M+1); LC retention time 2.84 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([C:14]([OH:16])=O)[N:13]=1.[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:27]=[CH:28][C:29]([NH:32][C:14]([C:12]2[N:13]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[O:10][C:11]=2[C:17]([F:20])([F:19])[F:18])=[O:16])=[CH:30][CH:31]=1
Reactant: COc1ccccc1-c1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3OC)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O4 (m/e) 504. obsd 505 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].C(=O)(O)[O-].[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>O1CCCC1.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19](=[O:20])[CH2:18][S:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a stirred solution of 2-amino-5-nitrobenzenethiol (1.72 g, 10.11 mmol) in tetrahydrofuran (10 mL) was added sodium bicarbonate (2.80 g, 33.4 mmol) as a solution in water (40.0 mL). To this dark red solution was added 2-chloroacetyl chloride (0.885 mL, 11.12 mmol). The resulting mixture, which turned faint red, was then stirred at room temperature overnight. The mixture was then diluted with water and extracted three time with dichloromethane. The combined organics were dried, filtered, concentrated, and then chromatographed in 10% ethyl acetate in dichloromethane, giving the desired product (1.02 g, 48.0%). 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 8.24 (d, J=2.7 Hz, 1H), 8.07 (dd, J=9.0, 2.7 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 3.60 (s, 2H); MS-EI: (m/z, %) 210 (M+, 100), 181 (40), 131 (46).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:4][CH:3]=1.[CH:16]([OH:19])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:2]1[N:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:4][CH:3]=1)([CH3:18])[CH3:17]
Reactant: CC(C)O
Reactant: Brc1cccc(COC2CCCCO2)n1
Product: CC(C)Oc1cccc(COC2CCCCO2)n1

Procedure:
The title-compound was prepared from 6-bromo-2-[(tetrahydropyran-2-yl)oxymethyl]pyridine prepared following the procedure given for Example 11 part a and isopropyl alcohol following the procedure given for Example 11 part b, 1H NMR (250 MHz, CDCl3), δ 1.32 (6H, d, J=6.2 Hz, 2 of CH3), 1.6-1.9 (6H, Me, 3 of CH2), 3.56 (1H, m, CH2O), 3.91 (1H, m, CH2O), 4.53 (1H, d, J=13.7 Hz, CH2O), 4.76 (1H, d, J=13.6 Hz, CH2O), 4.79 (1H, m, CHO), 5.29 (1H, septet, J=6.2 Hz, CH), 6.55 (1H, d, J=8.2 Hz, Ar—H), 6.96 (1H, d, J=7.3 Hz, Ar—H), 7.53 (1H, dd, J=8.2 and 7.3 Hz, Ar—H); MS (ES+) m/e 252 [MH]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[O:52][CH2:51][CH2:50]1>CN(C=O)C>[O:49]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH:65][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[O:52][CH2:51][CH2:50]1
Reactant: Nc1cccc(-c2ccc3c(c2)OCCO3)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3c(c2)OCCO3)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.5 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-phenylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.011 g of product in 39% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[OH:10].Cl[CH2:22][S:23][CH3:24]>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[O:10][CH2:22][S:23][CH3:24]
Reactant: CSCCl
Reactant: CCCc1cc(NC(=O)OC(C)C)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(NC(=O)OC(C)C)cc(C)c1OCSC
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of 3-methyl-4-hydroxy-5-n-propylaniline (1.65 g) and ethyl acetate (20 ml) was added to an ethyl acetate solution containing 10 g of phosgene at 0° to 5° C. The resulting mixture was gradually heated and, after the solution became clear, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-methyl-4-hydroxy-5-n-propylphenyl isocyanate. the thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and isopropanol (1.0 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-methyl-4-hydroxy-5-n-propylphenyl)carbamate (1.70 g). Sodium hydride (0.28 g, 60% dispersion in mineral oil) was added to dimethylformamide (50 ml). To the resulting mixture was added isopropyl N-(3-methyl-4-hydroxy-5-n-propylphenyl)carbamate (1.70 g) under 5° C. The resulting solution was stirred at a temperature of 20° C. for 30 minutes, and (chloromethyl)methylsulfide (0.67 g) was added thereto in 5 minutes. The mixture was heated at 90° C. for 10 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-methyl-4-methylthiomethyloxy-5-n-propylphenyl)carbamate (Compound No. 14) (1.90 g) in a yield of 61.0%. nD21.4
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])([CH3:18])[CH2:7][CH:8]([NH:12][C:13](=[O:17])[CH2:14][O:15][CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.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>>[Cl:41][C:26]1[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])=[N:28][C:23]([NH:1][C:2]2[CH:21]=[CH:20][C:5]3[C:6]([CH3:19])([CH3:18])[CH2:7][CH:8]([NH:12][C:13](=[O:17])[CH2:14][O:15][CH3:16])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:24][CH:25]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCC(=O)NC1CC(C)(C)c2ccc(N)cc2NC1=O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)COC)CC3(C)C)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-acetylamino)-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from N-(8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2-methoxy-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (40 mg, 38%) HPLC purity=99%, LCMS=572 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.72 (s, 1H), 9.40 (s, 1H), 9.34 (s, 1H), 8.51 (m, 1H), 8.18 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.49-7.44 (m, 2H), 7.31-7.27 (m, 2H), 7.16 (s, 1H), 7.10 (d, 1H), 4.23-4.21 (m, 1H), 3.82 (s, 2H), 3.33 (s, 3H), 2.73 (d, J=4.8 Hz, 3H), 2.22-2.18 (m, 1H), 1.92-1.88 (m, 1H), 1.33 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:54])[CH:14]([NH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][C:44]4=[O:53])[CH2:39][CH2:38]3)=[O:36])[CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21](S(CC[Si](C)(C)C)(=O)=O)[CH:20]=[CH:19]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+]>C(#N)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:54])[CH:14]([NH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][C:44]4=[O:53])[CH2:39][CH2:38]3)=[O:36])[CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][CH:20]=[CH:19]4)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(CC(NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCCCC4)CC3)ccc21
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: O=C(NC(Cc1ccc2[nH]ccc2c1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 80 °C
Yield: 70 %

Procedure:
A mixture of 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4′]bipiperidinyl-1′-yl-2-oxo-1-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5-ylmethyl]-ethyl}-amide (52 mg, 0.067 mmol), cesium fluoride (51 mg, 0.33 mmol) in acetonitrile (5 mL) was heated at 80° C. for 4 h. The solvents were removed in vacuo and the residue was subjected to chromatography on silica gel using methylene chloride/methanol/triethylamine (93:5:2) as eluent to afford the title compound as a white solid (70% yield). 1H-NMR (CD3CN, 500 MHz) δ 9.30 (s, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.39 (d, J=8.2 Hz, 0.6H), 7.36 (d, J=8.2 Hz, 0.4H), 7.24-7.21 (m, 1H), 7.19 (t, J=7.9 Hz, 1H), 7.12-7.09 (m, 1H), 7.06 (d, J=8.2 Hz, 0.6 H), 7.02 (d, J=8.2 Hz, 0.4 H), 6.95 (t, J=7.4 Hz, 1, 4.04-3.93 (m, 1H), 3.07-3.02 (m, 1.6H), 2.95 (dd, J=13.7, 7.1 Hz, 0.4H), 2.85-2.72 (m, 3H), 2.56-2.37 (m, 3H), 2.42-2.37 (m, 1H), 1.99-1.95 (m, 7H), 1.76-1.51 (m, 8H), 1.45-1.40 (m, 3H). LC/MS: tR=1.91 min, 612.44 (MH)+.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][N:13]1[CH:22]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[S:31][CH3:32])[C:21]2[C:20](=[O:33])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:14]1=[O:44]>ClCCl>[CH3:32][S:31]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:23]=1[CH:22]1[C:21]2[C:20](=[O:33])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:14](=[O:44])[N:13]1[CH3:12])[C:27]#[N:28])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Solvent: ClCCl
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)=O
Reaction time: 0.67 h

Procedure:
3-chloroperoxybenzoic acid (77%, 15.3 mg, 0.068 mmol) is added at room temperature to a solution of 4-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methylsulfanyl-benzonitrile (INTERMEDIATE 7, 41 mg, 0.076 mmol) in dichloromethane (1 mL), and the mixture is stirred for 40 min. The reaction mixture is concentrated under reduced pressure and purified by reversed phase HPLC (X-Bridge C18, gradient of acetonitrile in water, 0.1% NH4OH) yielding the two diasteromers of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[N:6])[CH3:2].[N+:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])#[C-:11].[NH4+].[Cl-].C(Cl)Cl>COCCOCCOC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]1[N:6]=[CH:11][NH:10][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CCOC(C#N)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOCCOC
Solvent: ClCCl
Product: CCOC(OCC)c1nc[nH]c1C(=O)OC
Temperature: 75 °C
Yield: 26 %

Procedure:
A mixture of diethoxyacetonitrile (38.72 mmol, 1 equiv.) and methyl isocyanoacetate (99.1 mmol, 1.4 equiv.) in dry bis(2-methoxyethyl)ether (20 ml) was added to a suspension of 30-35% KH (54.2 mmol, 1.4 equiv.) in dry bis(2-methoxyethyl)ether (30 ml). The resulting mixture was heated overnight at 70-80° C. The reaction mixture was then cooled to 25° C., and sat. NH4Cl solution (20 ml) was added. DCM (100 ml) was added, and the phases were separated. The aqueous phase was extracted with DCM (2×75 ml) and the combined organic phases were dried over Na2SO4 and filtered, and the solvent was removed in vacuo. Cold ether (10 ml) was added to the brown oil so obtained, and the resulting solid was filtered out and washed with ether. The desired product was thus obtained in the form of a yellow solid. Yield: 26%
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([O:12]C)(=O)/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8]>>[OH:12][C:4]1[CH2:5][CH:6]([C:7]([O:9][CH3:10])=[O:8])[N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: COC(=O)/C=C/C(=O)OC
Product: COC(=O)C1CC(O)=NN1C
Temperature: 25 °C

Procedure:
Methyl hydrazine (12 ml, 228 mmol) was added dropwise to dimethyl fumarate (32.8 g, 228 mmol) at −5° C. The mixture was stirred under warming to rt for 16 h and then heated to 100° C. for 3 h. The crude reaction product (36 g, quantitative) was used for the next step without purification. [[M+H]+=159.1]
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([S:24][C:25]4[CH:41]=[CH:40][C:28]5[N:29]=[C:30]([NH:32]C(=O)OC(C)(C)C)[S:31][C:27]=5[CH:26]=4)=[N:22][N:23]=3)[N:20]=2)=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([S:24][C:25]4[CH:41]=[CH:40][C:28]5[N:29]=[C:30]([NH2:32])[S:31][C:27]=5[CH:26]=4)=[N:22][N:23]=3)[N:20]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Temperature: 20 °C
Yield: 36.1 %

Procedure:
4×0.1 cm3 of trifluoroacetic acid (containing 10% of anisole) are added to a mixture of 127 mg of 1,1-dimethylethyl (6-{[6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate in 5 cm3 of dichloromethane stirred at 20° C., this addition taking place over 7 h, until the starting product has disappeared. The reaction mixture is then concentrated under reduced pressure, so as to recover 186.5 mg of yellow powder which is purified by chromatography on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μm), elution being carried out with a gradient of dichloromethane then dichloromethane/methanol: 99.5/0.5, 99/1, 98.5/1.5, 98/2, 97.5/2.5, 97/3. 36.6 mg of 6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-amine are thus obtained in the form of a whitish powder, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].[C:11](Cl)(Cl)=[S:12].[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]2[O:10][C:11](=[S:12])[O:9][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(F)c1O
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1cc(F)c2oc(=S)oc2c1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
3,5-Difluorobenzene-1,2-diol (670 mg, 4.6 mmol) was stirred in dry chloroform (8 mL), treated with thiophosgene (580 mg, 5.0 mmol), cooled to 5-10° C., and treated dropwise with 10% NaOH solution (4.2 g, 11 mmol) over 45 min. After 30 min, the volatiles were removed by rotary evaporation and the residual solid was collected by filtration and washed with water. The solid was dissolved in ethyl acetate (30 mL), washed with water (2×20 mL), washed with saturated NaCl (1×10 mL), dried (Na2SO4), and evaporated. The residue was purified by chromatography on silica with a 0-20% ethyl acetate-hexane gradient to give the title compound (710 mg, 82%): 1H NMR (400 MHz, CDCl3) δ 6.95 (ddd, J=6.8, 2.3, 1.4 Hz, 1H), 6.89 (td, J=9.5, 2.3 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −109.99 (s), −127.93 (s); EIMS m/z 188.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[C:16]([CH3:18])[N:17]=[C:4]2[N:3]=1.[CH3:19][NH:20][CH3:21]>CN(C=O)C.O.ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([N:20]([CH3:21])[CH3:19])[N:5]2[N:15]=[C:16]([CH3:18])[N:17]=[C:4]2[N:3]=1
Reactant: Cc1nc2nc(Cl)c(-c3ccccc3)c(Cl)n2n1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1nc2nc(Cl)c(-c3ccccc3)c(N(C)C)n2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 500 mg 5,7-dichloro-2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described above) in 25 mL DMF were added 0.8 mL of a dimethylamine solution (60% in water). The mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with water and dichloromethane. The phases were separated and the water layer was extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The residue was suspended in diethylether and stirred for 5 hours. The desired product was filtered, dried and was used without further purification for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([O:33]CC5C=CC=CC=5)=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCc5ccccc5)cc4)ccc(F)c32)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(O)cc4)ccc(F)c32)cc1
Reaction time: 1 h

Procedure:
(1S,2S)-2-{4-[(R)-4-(4-Benzyloxy-phenoxy)-7-fluoro-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid ethyl ester (Intermediate 6, 0.76 g, 1.3 mmol) is dissolved in 1:1 MeOH/ethyl acetate (20 mL) and hydrogenated at 2 Bar for 1 hour using 10% palladium on carbon as the catalyst. The mixture is filtered through CELITE filter aid and the solvent removed under vacuum the title compound. (Yield 0.60 g). LC (METHOD 6): tR=0.64 min; Mass spectrum (ES+): m/z=449 [M+H]+.