Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][P:9]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[C:38]([C:41]1[N:42]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[C:60]([S:62]([CH3:65])(=[O:64])=[O:63])[C:59]([CH2:66]O)=[C:58]([F:68])[CH:57]=3)=[CH:52][C:51]=2[F:69])[CH:43]=[C:44]([C:46]([OH:49])([CH3:48])[CH3:47])[N:45]=1)([CH3:40])[CH3:39].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:12]([O:11][P:9]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:66][C:59]2[C:60]([S:62]([CH3:65])(=[O:63])=[O:64])=[CH:61][C:56]([C:53]3[CH:54]=[CH:55][C:50]([N:42]4[CH:43]=[C:44]([C:46]([OH:49])([CH3:47])[CH3:48])[N:45]=[C:41]4[C:38]([C:32]4[C:33]([Cl:37])=[CH:34][CH:35]=[CH:36][C:31]=4[Cl:30])([CH3:40])[CH3:39])=[C:51]([F:69])[CH:52]=3)=[CH:57][C:58]=2[F:68])=[O:28])=[CH:24][CH:25]=1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cc(F)c(CO)c(S(C)(=O)=O)c3)cc2F)c(C(C)(C)c2c(Cl)cccc2Cl)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(O)c1cn(-c2ccc(-c3cc(F)c(COC(=O)Cc4ccc(OP(=O)(OCc5ccccc5)OCc5ccccc5)cc4)c(S(C)(=O)=O)c3)cc2F)c(C(C)(C)c2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-Dimethylaminopyridine (0.19 g, 1.6 mmol) was added to a solution of 2-(4-(bis(benzyloxy)phosphoryloxy)phenyl)acetic acid (0.67 g, 1.6 mmol), 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol (prepared in the manner described in PCT Publication No. WO 2010/138598, 0.4 g, 0.6 mmol), and N,N′-dicyclohexylcarbodiimide (0.37 g, 1.8 mmol) in CH2Cl2 (5 mL). The mixture was stirred at rt for 30 mins. After this time, the reaction mixture was filtered, and the organic solvents were removed under reduced pressure to yield the crude product. The crude product was purified by column chromatography using a mixture of CHCl3 and methanol (9:1) to afford (4′-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)-3,3′-difluoro-5-(methylsulfonyl)biphenyl-4-yl)methyl 2-(4-(bis(benzyloxy)phosphoryloxy)phenyl)acetate (0.4 g, 0.4 mmol, 60% yield). 1H NMR (400 MHz, CHCl3-d) δ 1.60 (s, 6H), 2.03 (s, 6H), 2.99 (s, 3H), 3.65 (s, 2H), 5.11 (d, J=8.4, 2H), 5.67 (s, 2H), 6.62 (s, 1H), 6.88 (t, J=7.6, 1H), 6.8-7.98 (m, 22H), 7.98 (s, 1H). LCMS: (Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% MeCN: 98% H2O: 10 mM NH4COOH; Solvent B=98% MeCN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min) retention time: 2.38 min; LCMS (ES-API), m/z 1005.2 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][N:15]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[CH:30]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[N:35]=1)([CH3:32])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(O)C.O>[CH:30]([O:33][C:34]1[N:35]=[C:36]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[S:12][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[N:14][N:15]=4)[CH:9]=3)[N:4]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=3)(=[O:21])=[O:22])[CH:3]=2)[CH:37]=[CH:38][CH:39]=1)([CH3:32])[CH3:31]
Reactant: CC(C)Oc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 29.3 %

Procedure:
A yellow suspension of 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (300 mg, 0.536 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CombiPhos Catalysts, Inc., Princeton, N.J.; 198 mg, 0.751 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II) (Aldrich; 18.99 mg, 0.027 mmol), and potassium phosphate (341 mg, 1.609 mmol) in a mixture of IPA (3.5 mL) and H2O (1.50 mL) was stirred at 100° C. for 10 min. The mixture was partitioned between EtOAc (80 mL) and H2O (50 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-60% EtOAc/Hex) furnished 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (89.3 mg, 0.157 mmol, 29%) as a colorless oil. MS (ESI, pos. ion) m/z: 569.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[CH2:20]=O.[ClH:22]>C(O)=O>[ClH:22].[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]1[CH3:20]
Reactant: C=O
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Agent: Cl
Solvent: O=CO
Product: COc1cc2c(cc1OC)C(C(CO)CO)N(C)CC2
Reaction time: 10 h
Yield: 50 %

Procedure:
To 0.0125 mole (3.33 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 15 ml of a 37% aqueous formaldehyde solution and 15 ml of 99% formic acid are added. The reaction mixture is then kept at 100° C. for 10 hours. After cooling 50 ml of a 15% aqueous hydrochloric acid solution are added to the reaction mixture, which is then evaporated under reduced pressure. After thoroughly dehydrating the reaction mixture it is triturated with a small amount of acetone to yield the aimed compound with a melting point of 199° to 201° C. (ethanol/ether).
Reaction SMILES: [Cl:1][CH:2]([C:7]1([C:16]([F:19])([F:18])[F:17])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)[C:3]([F:6])([F:5])[F:4].[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>C(Cl)Cl>[N+:20]([C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([CH:2]([Cl:1])[C:3]([F:6])([F:5])[F:4])([C:16]([F:19])([F:18])[F:17])[O:11][C:10]=2[CH:12]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccccc2O1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
613 g of 2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 2 were dissolved in 1.2 1 of methylene chloride and the solution was added dropwise to a mixture of 400 ml of 65% strength nitric acid and 400 ml of concentrated sulphuric acid at 0°-10° C. The mixture was subsequently led at room temperature for 2 hours. It was then poured carefully onto 2 1 of ice-water and extracted with methylene chloride. The combined organic phases were washed twice with water, dried and concentrated. The yield was 652 g (93% of theory). The NMR spectra showed the following characteristic absorptions: 19F-NMR: -66.4 and -79.2 ppm. 1H-NMR: 4.81 ppm.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[NH3:12]>CN(C=O)C>[S:7]1[CH:8]=[CH:9][C:5]2[CH:4]=[C:3]([CH2:2][NH2:12])[CH:11]=[CH:10][C:6]1=2
Reactant: N
Reactant: BrCc1ccc2sccc2c1
Solvent: CN(C)C=O
Product: NCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.6 %

Procedure:
A solution of 5-bromomethylbenzo[b]thiophene (3.0 g, 13.20 mmol) in DMF (15 ml) was added to a solution of 25% aqueous ammonia (10 ml, 132 mmol) in DMF (10 ml). The reaction mixture was stirred for 4 hours at room temperature. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using first ethyl acetate/heptane (1:1;60 ml) and subsequently DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.40 g (19%) of ((benzo[b]thiophen-5-yl)methyl)amine.
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].[CH3:5][CH:6]([OH:9])[C:7]#[CH:8].CCN(CC)CC.[O-]Cl.[Na+]>C(Cl)Cl>[CH3:2][C:1]1[CH:8]=[C:7]([CH:6]([OH:9])[CH3:5])[O:4][N:3]=1
Reactant: CC=NO
Reactant: C#CC(C)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)O)on1
Reaction time: 18 h
Yield: 20.4 %

Procedure:
To a stirring solution of 5.2 mL (84.9 mmol) of acetaldehyde oxime, 6.7 mL (85.5 mmol) of 3-butyn-2-ol, and 1.2 mL (8.6 mmol) of Et3N in 20 mL of CH2Cl2 at 0° C. was added 275 mL of NaOCl over a period of 2 h 45 min. The ice bath was removed and stirring was continued at r.t. for 18 h. Chloroform was added, and the layers were separated. The organic layer was extracted with CHCl3 (2×) and with the extract of a mixture of (80 mL CHCl3: 10 mL H2O: 10 mL MeOH) (2×). The combined extracts were dried over Na2SO4, filtered and concentrated. Purification by flash silica gel chromatography (2% MeOH/CHCl3) provided 2.2 g of 1-(3-methylisoxazol-5-yl)ethanol as an orange-yellow oil in 20% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (275 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13](F)=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([C:13]1[CH:12]=[C:11]2[C:16]([C:17](=[O:18])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([CH:20]([CH3:22])[CH3:21])[O:10]2)=[CH:15][CH:14]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1oc2cc(F)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1oc2cc(N=[N+]=[N-])ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
To a solution of 3-(4-chlorophenyl)-7-fluoro-2-isopropyl-chromen-4-one (4.0 g, 12.7 mmol) in dry dimethylformamide (120 ml) is added sodium azide at room temperature. The reaction mixture is heated at 90° C. for 16 h, cooled to room temperature and partitioned between ethyl acetate and water. The organic phase is washed with water and brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography on silica gel using iso-hexane:ethyl acetate (10:1) as the eluent, followed by recrystallisation from iso-hexane, gives the title compound.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:14][C:15]1[N:16]=[C:17]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:18]=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cncc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of 5 g of tert-butyl 1-piperazinecarboxylate, 4 g of 2,6-dichloropyrazine and 9.5 ml de DIPEA in 40 ml of n-butanol is heated at reflux for 3 hours. It is concentrated under vacuum, the residue is taken up in 100 ml of EtOH, the system is left to stand overnight and the crystalline product formed is isolated with suction. This gives 4.7 g of the expected product, m.p.=108° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[N+:17]([O-])=O)(=[O:4])=[O:3]>CO.CN(C=O)C>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[NH2:17])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)CCCNc1ccc(C#N)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)CCCNc1ccc(C#N)cc1N
Yield: 57.7 %

Procedure:
A solution of 4-(3-methanesulfonyl-propylamino)-3-nitro-benzonitrile (3.0 g, 10.6 mmol) in MeOH/DMF (60 ml, 1/1) was hydrogenated on a PARR hydrogenator at 50 psi for 4 h. The solution was filtered and concentrated. The residue was triturated with EtOAc to give 4-(3-methanesulfonyl-propylamino)-3-amino-benzonitrile 1.55 g (58%) as a tan solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11]OC)[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23].C(O)(=O)C>CO>[CH3:23][C:22]([CH3:24])([CH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:6]([OH:18])=[C:7]([C:14]([CH3:17])([CH3:15])[CH3:16])[CH:8]=1)[CH:21]=[O:25]
Reactant: COCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A solution of 25 grams (0.1 mole) of 2,6-di-tert.butyl-4-methoxymethylphenol and one gram (0.015 mole) of KOH in 100 milliliters of methanol was heated to 60° C. 9 grams (0.125 moles) of isobutyraldehyde was added to the solution during a period of 10 minutes and the reaction mixture was heated under reflux for 3 hours. After the mixture had cooled to room temperature it was poured into 125 milliliters of 1% acetic acid. The solid that precipitated was filtered off and allowed to dry. There was obtained 28.5 grams (98.2% of theory) of 2,2-dimethyl-3-(3,5-di-tert.butyl-4-hydroxyphenyl) propionaldehyde with a melting point of 72° to 74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:24])([F:23])[F:22])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)#[N:32].C(=O)([O-])O.[Na+]>O1CCCC1>[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[CH2:10][C:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)([C:21]([F:22])([F:24])[F:23])[O:13][N:12]=3)[CH:15]=2)=[O:38])=[CH:35][CH:34]=1)#[N:32]
Reactant: Nc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)Nc2cccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 3-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenylamine (0.300 mg, 0.79 mmol) (Example I3) in tetrahydrofuran (4 ml) was added pyridine (0.128 ml, 1.59 mmol). 4-Cyano-benzoyl chloride (0.176 g, 1 mmol) was added under vigorous stirring at ambient temperature. The reaction mixture was stirred for 3 hours at ambient temperature. Aqueous sodium hydrogen carbonate (saturated) was added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give Compound No. A4 of Table A (0.342 g, 85% yield). 1H-NMR (400 MHz, CDCl3): 8.68 (s, 1H), 8.10 (s, 1H), 8.0 (m, 2H), 7.75 (m, 3H), 7.49 (s, 2H), 7.42 (m, 3H), 4.12 (d, 1H), 3.72 (d, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:17])[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[CH3:2][C:3]1([CH3:17])[CH2:8][N:7]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:22]3[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=3)[CH:26]=2)[CH2:6][CH2:5][N:4]1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1
Reactant: CC1(C)CNCCN1c1ccc(C#N)cn1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: Cl
Product: CC1(C)CN(C(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)CCN1c1ccc(C#N)cn1
Yield: 33 %

Procedure:
This compound was synthesized from 6-(2,2-dimethylpiperazin-1-yl)nicotinonitrile hydrochloride and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (50 mg, yield 33%). 1H NMR (400 MHz, MeOD) δ 8.43 (d, J=1.8 Hz, 1H), 8.29-8.22 (m, 2H), 7.75-7.72 (m, 3H), 6.88 (d, J=9.0 Hz, 1H), 4.05-3.85 (m, 4H), 3.67 (m, 2H), 1.67-1.47 (m, 6H). MS (ESI) m/z: Calculated for C22H19F3N6O2: 456.15. found: 457.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[N-]=[C:12]=[S:13]>>[Cl:1][C:2]1[C:3]([N:9]=[C:12]=[S:13])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [N-]=C=S
Reactant: Nc1ncc(Cl)cc1Cl
Agent: Cl
Product: S=C=Nc1ncc(Cl)cc1Cl

Procedure:
3,5-Dichloro-2-amino pyridine (8.15, 0.05 mol) was treated with thiophosgenes (10% soln. in toluene, 55 ml). The mixture was refluxed until clear solution was obtained and no further hydrochloric acid gas was being evolved. The mixture was cooled, and the solid which crystallised was removed by filtration. The mother liquors, after evaporation and crystallisation of the residual oil, yielded 5.5 g. (55%) of the required isothiocyanate as pale yellow needles m. pt. 45°-6°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=4)[CH:16]=3)[C:11](=[O:24])[N:10]([CH3:25])[CH:9]=2)[CH:7]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.C(Cl)Cl>[F:26][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:7][C:6]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[CH:16]=2)[C:11](=[O:24])[N:10]([CH3:25])[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(-c4cc(N)ccc4F)c3c2)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cc(-c2ccc3c(=O)n(C)cc(-c4cc(NS(C)(=O)=O)ccc4F)c3c2)cn1
Yield: 85.7 %

Procedure:
4-(5-Amino-2-fluorophenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (25 mg, 0.07 mmol) in pyridine (0.1 mL) and anhydrous CH2Cl2 (0.3 mL) was treated with methanesulfonyl chloride (0.007 mL, 0.09 mmol) in a manner similar to Example 33. After a similar work up, silica gel chromatography, eluting with 50-100% EA in hexane over 4 min and continuing isocratic 100% EA, gave the title compound (24 mg, 0.06 mmol) as a white solid in 78% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.06 (s, 3H), 3.56 (s, 3H), 3.85 (s, 3H), 7.22-7.45 (m, 4H), 7.59 (s, 1H), 7.76 (dd, J=8.34, 1.52 Hz, 1H), 7.85 (s, 1H), 8.16 (s, 1H), 8.29 (d, J=8.34 Hz, 1H), 9.82 (s, 1H). LCMS (M+H)+ 427.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:14]C(=O)OC(C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:14][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)[CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(CO)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 59A, 277 mg (0.91 mmol) were dissolved in 10 ml of dichloromethane and admixed at 0° C. with 0.7 ml (9.1 mmol) of trifluoroacetic acid, then stirred at room temperature for 1 hour. The mixture was concentrated on a rotary evaporator. The crude product was taken up in 20 ml of toluene and again concentrated on a rotary evaporator under reduced pressure. The crude product was purified by preparative HPLC [Method 19]. This gave 124 mg (43% of theory) of the target compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(C2OCCO2)cc1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(NCc2ccc(C3OCCO3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a tetrahydrofuran (200 mL) solution of 4-[1,3]dioxolane-2-ylbenzaldehyde (6.32 g, 35.5 mmol) described in Manufacturing Example 73-1-1, aniline (2.08 mL, 35.5 mmol) and acetic acid (10.2 mL, 178 mmol) was added sodium triacetoxyborohydride (15 g, 71 mmol). This mixture was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (4.16 g, 46%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 44 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (300 mg, 0.61 mmol), a different batch of 2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (180 mg, 0.55 mmol), and p-toluenesulfonic acid (278 mg, 1.46 mmol) were weighed into a 40 mL vial. 25 mL of iPrOH was added and the mixture was heated to 130° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 30 mL of DCM. 3 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (190 mg, 0.242 mmol, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.20 Hz, 1H), 7.76 (dd, J=8.61, 2.20 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.35-7.46 (m, 3H), 7.26 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.92 (t, J=6.68 Hz, 1H), 6.66 (d, J=2.38 Hz, 1H), 6.53 (d, J=5.13 Hz, 1H), 6.47 (dd, J=8.61, 2.38 Hz, 1H), 4.05 (q, J=7.08 Hz, 2H), 3.97 (s, 3H), 3.31-3.34 (m, 2H), 3.08-3.15 (m, 4H), 3.02 (s, 3H), 2.74 (t, J=6.78 Hz, 2H), 2.51-2.60 (m, 4H), 1.22 (t, J=6.96 Hz, 3H). MS (ESI): 783 [M+H]+.