Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](/[C:8](/O)=[CH:9]\[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20].C1C(=O)N(Br)C(=O)C1.[CH3:38][C:39]([CH3:44])([CH3:43])[C:40](=[S:42])[NH2:41]>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[N:41]=[C:40]([C:39]([CH3:44])([CH3:43])[CH3:38])[S:42][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20]
Reactant: CC(C)(C)C(N)=S
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (3.0 g, 6.55 mmol) in DMA (25 mL) was added NBS (1.165 g, 6.55 mmol). After stirring for 1 h at rt, 2,2-dimethylpropanethioamide (0.767 g, 6.55 mmol) was added and the reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and extracted five times with water. The organic layer was dried over anhydrous NaSO4, adsorbed onto silica gel, and purified via column chromatography, eluting with 0-50% EtOAc/DCM. The desired fractions were combined and concentrated to generate 1.31 g (2.36 mmol, 36.0% yield) of the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 8.56 (d, J=5.4 Hz, 1H), 7.41-7.58 (m, 6H), 6.57 (d, J=5.4 Hz, 1H), 1.42 (s, 9H). MS (ESI): 555.0 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[O:35][N:34]=[C:33]([CH3:36])[CH:32]=4)[CH:26]=3)[CH2:22][C:21](=[O:37])[NH:20][C:9]=2[CH:10]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from [4-methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example M84) (0.33 g, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (163 mg, 64%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:32])[N:18]([NH:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.[OH-].[NH4+]>[NH2:1][CH2:4][C:5]1[C:13]2[S:12](=[O:14])(=[O:15])[N:11]=[C:10]([C:16]3[C:17](=[O:32])[N:18]([NH:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To the solution of the product of Example 353D (357 mg, 0.62 mmol) in pyridine (4.6 mL) and concentrated ammonium hydroxide (3 mL) was added triphenylphosphine (397 mg, 1.51 mmol) at room temperature. The solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with 30% hexane/toluene and the solid was filtered to give the title compound (250 mg, 90%). MS (ESI−) m/z 446 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 0.21 (m, 2 H) 0.46 (br d, J=8.09 Hz, 2 H) 1.00 (m, 1 H) 4.12 (s, 2 H) 5.98 (t, J=6.43 Hz, 1 H) 7.12 (m, 1 H) 7.22 (s, 1 H) 7.58 (m, 1 H) 7.72 (d, J=7.72 Hz, 1 H) 8.04 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.[CH2:16](Br)[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:12][C:11]1[CH:13]=[CH:14][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:15])=[CH:7][C:8]=1[O:9][CH3:10])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCBr
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1ccc(/C=C/C(=O)OC)cc1OC
Yield: 91.7 %

Procedure:
4.16 g (20.0 mmol) ferulic acid methyl ester was dissolved in 115 ml 2-butanone. 2.09 ml (22.0 mmol) n-butyl bromide and 11.06 g (80 mmol) potassium carbonate were added. The reaction suspension was then heated at reflux temperature for 20 hours. The reaction mixture was filtered. The filtrate was concentrated by evaporation. The crude product was recrystallised from 42 ml isopropyl alcohol and yielded 4.85 g (92%) methyl (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoate as white crystals.
Reaction SMILES: [CH:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([CH:1]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=1)[CH2:19][CH3:20]
Reactant: O=C(O)c1cccc(C=Cc2ccccc2)c1
Reactant: CCCN
Product: CCCNC(=O)c1cccc(C=Cc2ccccc2)c1

Procedure:
Using preparation method 1, 74B (224 mg, 1 mmol) was reacted with n-propylamine (90 μL, 65 mg, 1.1 mmol). The product was purified by flash chromatography on SiO2 using CH2Cl2/hexanes 40:60 to CH2Cl2/hexanes 60:40. White crystals were obtained (154 mg, 58%). NMR 1H (ppm, CDCl3): 7.92 (s, 1H), 7.60 (t, J3=7.7 Hz, 2H), 7.51 (d, J3=7.8 Hz, 2H), 7.40 (t, J3=7.6 Hz, 1H), 7.36 (t, J3=7.5 Hz, 2H), 7.29-7.26 (m, 1H), 7.18 (d, J3=16.4 Hz, 1H), 7.10 (d, J3=16.3 Hz, 1H), 6.12 (br. s, 1H), 3.47-3.40 (m, 2H), 1.65 (sext., J3=7.2 Hz, 2H), 1.00 (t, J3=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7](=[O:15])[C:6]2=[C:16]([CH3:19])[CH:17]=[CH:18][N:5]2[N:4]=1.[Br:20][C:21]1[C:22]([NH2:28])=[N:23][CH:24]=[N:25][C:26]=1Cl.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:28][C:22]1[N:23]=[CH:24][N:25]=[C:26]([NH:1][CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7](=[O:15])[C:6]3=[C:16]([CH3:19])[CH:17]=[CH:18][N:5]3[N:4]=2)[C:21]=1[Br:20]
Reactant: Cc1ccn2nc(CN)n(-c3ccccc3)c(=O)c12
Reactant: Nc1ncnc(Cl)c1Br
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc(CNc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Yield: 95 %

Procedure:
2-(Aminomethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (420 mg, 0.97 mmol) was treated with 5-bromo-6-chloropyrimidin-4-amine (304 mg, 1.46 mmol), cesium fluoride (222 mg, 1.46 mmol) and N,N-diisopropylethylamine (0.508 mL, 2.92 mol) according to Preparation 13. The residue was purified using SP1® Purification System (0% to 10%, dichloromethane-methanol) to give 394 m g (95% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2.[C:28](Cl)(=[O:34])[CH2:29][CH2:30][C:31](Cl)=[O:32]>>[C:12]([C:11]1[CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([N:25]([CH3:27])[CH3:26])=[CH:7][CH:8]=2)[O:3][C:2]=1[N:1]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:34])#[N:13]
Reactant: COc1cc(C2C(C#N)=C(N)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Reactant: O=C(Cl)CCC(=O)Cl
Product: COc1cc(C2C(C#N)=C(N3C(=O)CCC3=O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC

Procedure:
The title compound was prepared from 2-amino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene and succinyl chloride as a yellow solid by a procedure similar to that described for Example 80. 1H NMR (CDCl3): 7.12 (d, J=1.8, 1H), 6.89-6.85 (m, 2H), 6.47 (m, 1H), 6.26 (d, J=2.7, 1H), 4.79 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.96 (s, 4H), 2.92 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27]C(=O)C(C)(C)C.Cl>O1CCOCC1>[NH2:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:34])=[CH:3][C:2]=1[F:1]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)cc(F)c3o2)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Yield: 52 %

Procedure:
3.90 g of Compound 25 was dissolved in 180 ml of dioxane, 180 ml of concentrated hydrochloric acid was added and the mixture was heated at reflux for 3 hours. The reaction solution was cooled on ice, and the precipitated crystals were collected by filtration and recrystallized from methanol/chloroform to give 1.31 g (52%) of Compound 26.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([NH:26][C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[N:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(NC(=O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 125 (123 mg, 0.267 mmol) in EtOAc (20 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue is triturated with Et2O to give 50 mg of the product 126. 1H NMR (DMSO-d6) δ 12.9 (s, 1 H), 9.70 (s, 2 H), 8.35-8.15 (m, 2 H), 7.60-7.40 (m, 2 H), 7.20-6.90 (m, 10), 5.70 (s, 2 H); LC/MS: 3.20 m/z 360 (M++1).
Reaction SMILES: C1(C([NH:20][CH:21]2[C:34](=[O:35])[N:23]3[CH:24]([P:29]([OH:33])([O:31][CH3:32])=[O:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1>CC(C)=O>[C:37]1([CH3:47])[CH:38]=[CH:39][C:40]([S:43]([OH:46])(=[O:44])=[O:45])=[CH:41][CH:42]=1.[NH2:20][CH:21]1[C:34](=[O:35])[N:23]2[CH:24]([P:29]([OH:33])([O:31][CH3:32])=[O:30])[C:25]([CH3:27])([CH3:28])[S:26][C@H:22]12
Reactant: COP(=O)(O)C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COP(=O)(O)C1N2C(=O)C(N)[C@H]2SC1(C)C
Reaction time: 0.25 h

Procedure:
To a stirred slurry of 4.72 g. (0.010 mole) 6-triphenylmethylamino-2,2-dimethyl-3-(O-methylphosphono)penam in 50 ml. of dry acetone was added 1.90 g. (0.010 mole) of p-toluenesulfonic acid monohydrate at ambient temperature. The solids dissolved slowly to afford a clear solution. After stirring for about 15 minutes the product started to precipitate. After stirring for about one hour the product was removed by filtration and washed with acetone. 1H-nmr (DMSO-d6) ppm (δ): 1.62 (s,3,CH3), 1.70 (s,3, CH3), 3.62 (d, J=11,3, OCH3), 3.88 (d, J=11,1,C-3), 5.05 (m,1,C-6), 5.37 (d, J=4,1, C-5). IR(Nujol mull): 1765 cm-1 (β-lactam).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#N.[C:9](#N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:9]#[C:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1ccccc1
Reactant: N#Cc1ccncc1
Product: C(#Cc1ccncc1)c1ccccc1
Reaction time: 20 h
Yield: 44 %

Procedure:
The procedure was identical to Example 2, with the exception that 4-cyanopyridine (0.208 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 20 h at 65° C. showed the presence of 0.88 mmol (44% yield) of 4-(phenylethynyl)pyridine, and no remaining 4-cyanopyridine in the reaction mixture.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]=1[C:19]([O:21]C)=O.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28].O>CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[NH:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[C:19](=[O:21])[N:25]([CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28])[C:3]2=[O:23])([CH3:16])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1C(=O)OC
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C

Procedure:
Diusopropylethylamine (3.20 g, 25 mmol) was added to a stirred suspension of methyl-3-[(t-butoxycarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (8.00 g, 25 mmol) and aminoglutarimide hydrochloride (4.07 g, 25 mmol) in DMF (60 ml). The mixture was heated to 120° C. for 24 hours and then cooled to room temperature. The mixture was poured into cold water (300 ml) and extracted with ethyl acetate (4×100 ml each). The combined ethyl acetate extracts were washed with water (2×50 ml), brine (50 ml) and dried. Solvent was removed in vacuo and the product purified by flash chromatography (dichloromethane/ethyl acetate 8 to 2) to yield 4.66 g of recovered starting material and 3.31 g (82%) of the product as a white solid: mp 180–182° C.; 1H NMR (CDCl3) δ 8.51 (s, 1H), 7.81–7.67 (m, 3H), 5.54 (b, 1H), 5.03–4.96 (dd, J=5.2 and 11.2 Hz, 1H), 4.66 (d, J=6.3 Hz, 2H), 2.95–2.74 (m, 3H), 2.18–2.14 (m, 1H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 170.99, 168.08, 167.95, 167.07, 155.86, 139.17, 135.00, 134.61, 132.15, 128.22, 122.82, 79.81, 49.21, 40.53, 31.33, 28.32, 22.58; Anal. Calcd for C19H21N3O6: C, 58.91; H, 5.46; N, 10.85. Found: C, 59.08; H, 5.51; N, 10.69.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:10][C:9]1[N:8]=[C:6]([C:5]2[CH:30]=[CH:31][CH:32]=[C:3]([C:2]([F:34])([F:33])[F:1])[CH:4]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(C(F)(F)F)c3)nn2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(C(F)(F)F)c4)n3n2)cc(OC)c1OC
Yield: 3.3 %

Procedure:
In a similar manner as described for Example 1, 3-(trifluoromethyl)-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 14) (0.12 g, 0.25 mmol) in 1,2-dichloroethane (20 mL) and phosphorus oxychloride (0.28 mL, 3.0 mmol) gave 5-methyl-7-[3-(trifluoromethyl)phenyl]-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.0038 g) as a yellow solid. 1H NMR (CD3OD): δ9.08 (s, 1H), 8.72 (d, J=7.7 Hz, 1H), 8.59 (s, 1H), 7.76-7.65 (m, 2H), 7.00 (s, 2H), 6.99 (s, 1H), 3.76 (s, 3H), 3.74 (s, 6H), 2.60 (s, 3H). MS m/z 460 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[O:5][C:6]1[C:7](=[O:23])[O:8][C:9]([CH3:22])([CH3:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:21][C:9]1([CH3:22])[O:8][CH:7]([OH:23])[C:6]([O:5][C:4]2[CH:24]=[CH:25][C:26]([F:27])=[C:2]([F:1])[CH:3]=2)=[C:10]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC1(C)OC(O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a 0° C. solution of 3-(3,4-difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one (500 mg, 1.27 mmol) in 10 mL of THF was added DIBAL (1.5M in toluene, 2.8 mL, 4.2 mmol). Warmed to r.t., and stirred 30 min. The reaction was quenched with acetone, followed by 0.5M sodium potassium tartrate and stirred overnight. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated. Crystalization from CH2Cl2 /toluene provided 350 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([O:28][CH3:29])=[CH:7][C:8]2[C:17]3[CH2:16][CH2:15][N:14]([C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][C:12]=3[C:11](=O)[NH:10][C:9]=2[CH:27]=1.[CH3:30]I>CN(C)C=O>[CH3:3][O:4][C:5]1[C:6]([O:28][CH3:29])=[CH:7][C:8]2[C:17]3[CH2:16][CH2:15][N:14]([C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][C:12]=3[CH2:11][N:10]([CH3:30])[C:9]=2[CH:27]=1
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(C(=O)c1ccccc1)C3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)N(C)CC1=C2CCN(C(=O)c2ccccc2)C1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A stirred suspension of 0.017 m of NaH (washed with petroleum ether) in 50 ml of dimethyl formamide was treated in portions with 5 g (0.0137 m) of 1,2,3,4-tetrahydro-8,9-dimethoxy-3-benzoyl-benzo[c][2,7]naphthyridin-5(6H)-one. After stirring for 10 min, the reaction was treated with 5 g (0.035 m) of CH3I and stirred an additional 45 min. Dilution with water to 250 ml and filtration gave 4.8 g (93%) of crude material. Crystallization from methanol/CH2Cl2 afforded pure material, mp 241°-243° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.Cl[C:26]([O:28][CH2:29][CH2:30][Cl:31])=[O:27]>O>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[NH:8][C:26](=[O:27])[O:28][CH2:29][CH2:30][Cl:31]
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(N)c([N+](=O)[O-])cc1NC(=O)OCCCl
Temperature: 90 °C

Procedure:
0.6 mol (100 g) of 4-methyl-2,5-diamino-nitrobenzene and 0.36 mol (50 g) of potassium carbonate are introduced into 500 ml of dioxane to which 145 ml of water have been added. The mixture is heated to 90° C., whilst stirring, and 0.6 mol (86 g) of chloroethyl chloroformate is then added gradually, in the course of 10 minutes. When the addition has ended, the heating is maintained for 10 minutes at 90° C. The reaction medium is cooled to 15° C. and the desired product is then filtered off. After washing with a small amount of dioxane and then with water and alcohol, the product is recrystallised from dioxane and then dried in vacuo. It melts at 192° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), was treated with mesylchloride (1.05 eq) and triethylamine (1.05 eq) in CH2Cl2 under argon at RT to give after purification by prep. HPLC the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:14]([O:16][C:17]([C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH2:34]Br)=[O:18])[CH3:15].[Br-]>C(#N)C>[CH2:14]([O:16][C:17]([C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH2:34][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18])[CH3:15]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1COc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
Phenol (0.518 g, 5.5 mmol) is combined with anhydrous acetonitrile (20 mL) and cesium carbonate (2.3 g, 10 mmol) and allowed to stir at room temperature under nitrogen. To the reaction is added 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.97 g, 5.00 mmol). The reaction is monitored by TLC until all of the bromide is consumed. The reaction is diluted with ethyl ether (100 mL), then 0.1N NaOH (50 mL) is added. The two phases are separated, then the organic layer is washed with water (50 mL) and brine (50 mL). The organic layer is dried over anhydrous sodium sulfate, then concentrated. The material is further purified using flash chromatography to yield 1.75 g or 86% yield of the product.
Reaction SMILES: CN(C)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:6].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1>CCO.O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)=[O:6])[CH3:23])=[CH:18][CH:17]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: CN(C)CCC(=O)c1cccc(F)c1
Solvent: O
Solvent: CCO
Product: C[C@H](NCCC(=O)c1cccc(F)c1)c1ccc(Br)cc1
Temperature: 80 °C
Yield: 20.3 %

Procedure:
A solution of 3-dimethylamino-1-(3-fluoro-phenyl)-propan-1-one (17 g, 0.087 mol) and (S)-1-(4-bromophenyl)-ethanamine (17 g, 0.087 mol) in a mixture of EtOH (50 mL) and H2O (50 mL) was refluxed at 80° C. overnight. The solvent was removed under vacuum, and the residue was purified by column chromatography to afford (S)-3-(1-(4-bromophenyl)-ethylamino)-1-(3-fluorophenyl)-propan-1-one (6.2 g, 20%).
Reaction SMILES: [F:1][S:2]([F:14])([F:13])([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][S:2]([F:14])([F:13])([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:16][C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(S(F)(F)(F)(F)F)cc1
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A mixture of 5.40 g (23.3 mmol) 4-pentafluorosulfanyl-benzaldehyde, 2.42 g (23.3 mmol) malonic acid, 0.20 g (2.3 mmol) piperidine and 10.0 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (4 h). The reaction mixture was poured into a solution of 100 ml ice and 60 ml 6N HCl. The precipitate was isolated, washed with water, then with n-heptane and dried in vacuum at 40° C. Yield: 5.73 g (90%) 3-(4-pentafluorosulfanyl-phenyl)-acrylic acid.