Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:21][OH:22])=[NH:15])[CH:11]=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(C(F)(F)F)cc(-c2ccc(Cl)cc2)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cc(C(F)(F)F)cc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
A mixture of 6-(4-chloro-phenyl)-4-trifluoromethyl-pyridine-2-carbonitrile (example B.5) (3.6 g, 13 mmol), hydroxylamine-hydrochloride (3.275 g, 47 mmol) and sodium carbonate (2.7 g, 47 mmol) in EtOH (60 ml) and water (60 ml) was stirred under argon atmosphere at 100° C. for 4 h. The EtOH was evaporated, the mixture was diluted with water and stirred for 1 h at 0° C. The crude product was filtered and dried in HV to give the pure title compound as a light yellow solid (3.54 g, 88%). MS (ISP) 316.1 [(M+H)+] and 318 [(M+2+H)+]; mp 180-186° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:3])[CH3:2].[C:22](Cl)(=[O:24])[CH3:23].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH:1]([C:4]1[C:5]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:6][C:7]([C:22](=[O:24])[CH3:23])=[C:8]([O:10][CH3:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a clear solution of 2-Isopropyl4-methoxy-1-(toluene-4-sulfonyl)-benzene (5.3 g, 16.56 mmol) in DCE (50 ml) was added acetyl chloride (2.0 g, 24.84 mmol) and AlCl3 (3.3 g, 24.84 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hrs and quenched by H2O (10 ml). Ten minutes after quenching, the aqueous solution was extracted into CH2Cl2. The combined extracts was washed with H2O, dried wover Na2SO4, filtered and concentrated. Flashed chromatography on silica gel (0 to 30% EtOAc in Hex) gave 1-[4-Isopropyl-2-methoxy-5-(toluene4-sulfonyl)-phenyl]-ethanone (4.7 g, 79%) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:20][O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)=CCOc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCC=C(C)C)ccc1C=O

Procedure:
10.6 g (206 mmol) of 2-hydroxy4-(3-methylbut-2-enyloxy)benzaldehyde and 5.4 ml of dimethyl sulfate were dissolved in 102 ml of distilled acetone, the solution was added 25.5 g of potassium carbonate, and the resulting mixture was refluxed for 5 hours. The mixture was filtered and the filtrate concentrated in vacuo to give 8.3 g of an yellow oil from which 5.4 g of 2-methoxy4-(3-methylbut-2enyloxy)benzaldehyde was isolated by column chromatography over silica gel 60 (Merck 0.063-0.200 mm, 400 g) using petroleum ether-ethyl acetate (9:1, 1000 ml), (4:1, 500 ml) as eluents.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([N+:20]([O-:22])=[O:21])[C:13]([O:18][CH3:19])=[C:14]([CH2:16][OH:17])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:17][CH2:16][C:14]1[CH:15]=[C:10]([C:6]([CH3:9])([CH3:7])[CH3:8])[CH:11]=[C:12]([N+:20]([O-:22])=[O:21])[C:13]=1[O:18][CH3:19])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(CO)cc(C(C)(C)C)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(COS(C)(=O)=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.20 ml methanesulphonic acid chloride are added to an ice-cooled solution of 3.43 g (5-tert-butyl-2-methoxy-3-nitro-phenyl)-methanol and 2.40 ml triethylamine in 30 ml dichloromethane. The solution is stirred for 2 h while cooling with ice and then diluted with dichloromethane. The dilute solution is washed three times with water and once with saturated aqueous saline solution, dried (MgSO4) and evaporated to dryness.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=1>C(C1C=CC(C#CCCCCCC)=CC=1)#CCCCCCC.C(#N)C1C=CC=CC=1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C#CCCCCCC
Agent: CCCCCCC#Cc1ccc(C#CCCCCCC)cc1
Solvent: N#Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: CCCCCCC#Cc1ccc(Cl)cc1
Reaction time: 23 h
Yield: 70.5 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 4-chlorobenzonitrile (0.275 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 23 h at 65° C. showed the presence of 1.41 mmol (70% yield) of 1-chloro-4-(1-octynyl)benzene, 0.11 mmol 1,4-bis(1-octynyl)benzene and no remaining 4-chlorobenzonitrile in the reaction mixture.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6](=[O:36])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[O:15])=[CH:10][C:9]=1[C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[CH3:2].CC(O)(C)C.[K].Cl>COCCOC>[Cl:34][C:30]1[CH:29]=[C:28]([C:27]2[C:9]3[C:8](=[CH:13][CH:12]=[C:11]([C:14]([C:16]4[S:17][CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:20]=4)=[O:15])[CH:10]=3)[NH:7][C:6](=[O:36])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[O:37])[CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(C(=O)c2nc(-c3ccccc3)cs2)cc1C(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [K]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(=O)c3nc(-c4ccccc4)cs3)ccc2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A mixture of intermediate (17) (0.048 mol) in DME (250 ml) was cooled on an ice bath and 2-methyl-2-propanol, potassium salt (0.096 mol) was added portionwise. The mixture was stirred at a low temperature for 15 min, poured out into ice water and acidified with HCl 3N. The precipitate was filtered off, washed with water, pasted up with CH3CN and diethyl ether, then dried, yielding 17.3 g (70%) of ethyl 4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-[(4-phenyl-2-thiazolyl)carbonyl]-3-quinolinecarboxylate (intermediate 18), mp 261° C.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([O:35][CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.S([O-])(=O)(=O)C.[SH:49][C:50]1[N:55]=[CH:54][CH:53]=[CH:52][N:51]=1>>[N:51]1[CH:52]=[CH:53][CH:54]=[N:55][C:50]=1[S:49][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([O:35][CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Reactant: Sc1ncccn1
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCSc3ncccn3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 34, from tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate via the corresponding mesylate by reaction with 2-mercaptopyrimidine there was obtained tert-butyl (3RS,4RS)-4-{4-[2-(pyrimidin-2-ylsulphanyl)-ethyl]-phenyl}-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil, which was used in the following step without further purification and characterization.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[C:12]([O:19][CH3:20])=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:12]([O:19][CH3:20])=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)c(OC)n1
Product: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)n1

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 3-amino-2,6-dimethoxypyridine gave 2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.57 (d, 1H, J=8.7 Hz), 8.02 (d, 1H, J=2.7 Hz), 6.40 (d, 1H, J=8.1 Hz), 4.03 (s, 3H), 3.98 (s, 3H); 19F NMR (CDCl3): −344640; LCMS: purity: 90%; MS (m/e): 285 (M+).
Reaction SMILES: Cl.C(OCC)(=O)C.C(Cl)[Cl:9].[O:11]=[C:12]1[N:16]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:15][C@H:14]([CH2:38][O:39][C:40](=[O:51])[CH2:41][N:42](C(OC(C)(C)C)=O)[CH3:43])[O:13]1>CCOCC>[ClH:9].[O:11]=[C:12]1[N:16]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:15][C@H:14]([CH2:38][O:39][C:40](=[O:51])[CH2:41][NH:42][CH3:43])[O:13]1
Reactant: ClCCl
Reactant: CN(CC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CNCC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A 4 N hydrochloric acid-ethyl acetate solution (5 ml, 20 mmol) was added at 0° C. to a methylene chloride solution (10 ml) that contained the N-tert-butoxycarbonyl-N-methylaminoacetic acid (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ester (1.15 g, 2.0 mmol) obtained in step A. The obtained mixture was stirred at a room temperature for 5 hours. Thereafter, ether was added to the reaction mixture, so that powders were completely precipitated and collected by filtration. The filtrate was washed with ether and hexane, and was then dried under reduced pressure, so as to obtain methylaminoacetic acid (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ester hydrochloride (967 mg, 95%) in the form of white powders.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[C:14]=1[CH3:21]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:19][C:16]1[C:15]([CH3:20])=[C:14]([CH3:21])[C:13]([CH3:12])=[CH:18][C:17]=1[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)c(C)c1C
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1cc(C(O)C(=O)c2ccccc2)c(C)c(C)c1C
Yield: 70.7 %

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and 1,2,3,4-tetramethylbenzene (0.60 ml, 4 mM were dissolved in dichloroethane (5 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 10 minutes. Using the same procedure as in Example 1, 2',3',4',5'-tetramethylbenzoin was obtained (378.2 mg, 70.7% yield).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][C:12]=1[CH2:13][CH:14]([C:20](=O)[CH3:21])[C:15](OCC)=[O:16]>CO>[NH2:7][C:6]1[N:8]=[C:15]([OH:16])[C:14]([CH2:13][C:12]2[CH:23]=[C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:26][C:11]=2[O:10][CH3:9])=[C:20]([CH3:21])[N:5]=1
Reactant: CCOC(=O)C(Cc1cc(CC(=O)OC)ccc1OC)C(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CO
Product: COC(=O)Cc1ccc(OC)c(Cc2c(C)nc(N)nc2O)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Guanidine carbonate (0.443 g) was added to a solution of the product from step (iii) (0.52 g) in MeOH (10 ml) and stirred at 50° C. for 15 h. The solvent was evaporated and the residue stirred in EtOAc (10 mL) and water (10 mL), the resulting solid was filtered off. Further product was collected by evaporation of the filtrate, the solids were combined to give the subtitle compound as a yellow solid, 0.607 g.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1>>[CH3:16][C:17]1[N:18]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]3)[CH:19]=[CH:20][N:21]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C1CCCc2cc(OCCCl)ccc21
Product: Cc1nccn1CCOc1ccc2c(c1)CCCC2=O
Yield: 66 %

Procedure:
According to the method of Example 1, Step 2, 6-(β-chloroethoxy)-1-tetralone (0.208 g, 0.93 mmol) and 2-methylimidazole (0.137 g, 1.67 mmol) were reacted to provide the title compound (0.166 g, 66%) as a cream colored solid: CI-MS m/e 270 (M+), 271 (M++1);
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[C:7](=[O:21])[CH:6]=2.[C:22]1([CH2:28][C:29]#[CH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[CH2:12][N:8]1[C:7](=[O:21])[CH:6]=[C:5]2[C:10]([N:11]=[C:2]([C:30]#[C:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=[N:4]2)=[CH:9]1
Reactant: C#CCc1ccccc1
Reactant: O=c1cc2ncc(Br)nc2cn1Cc1ccc(F)c(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1cc2ncc(C#CCc3ccccc3)nc2cn1Cc1ccc(F)c(F)c1

Procedure:
The coupling of 7-bromo-2-(3,4-difluorobenzyl)-2H-5,8-diazaisoquinolin-3-one (0.80 g, 2.28 mmol) with 3-phenyl-1-propyne (0.71 mL, 5.74 mmol) using triethylamine (0.64 mL, 4.59 mmol), CuI (0.031 g, 0.16 mmol), and Pd(Ph3P)4 (0.106 g, 0.092 mmol) in dimethylformamide (6 mL) is carried out as described in Example 1, Step (2). The resulting red oil is evaporated onto silica gel and purified on a 3.5×20 cm silica gel column eluted with hexanes/ethyl acetate 3:1. The resulting red solid is triturated with ethyl ether and dried. This will afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8](O)[CH3:9].[Cl:28]CCl>S(Cl)(Cl)=O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([Cl:28])[CH3:9]
Reactant: ClCCl
Reactant: CC(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a solution of 0.96 g of 3-[3-chloro-4-(1-hydroxyethyl)phenyl]-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 20 mL of dichloromethane, 0.2 mL of thionyl chloride and a catalytic amount (2 to 3 drops) of N,N-dimethylformamide were added, and stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured into 20 mL of ice water, and the organic phase was collected, washed with water (20 mL×1) and then saturated sodium hydrogen carbonate aqueous solution (20 mL×3), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and then the solvent was distilled off under reduced pressure to obtain 0.88 g of the aimed product as yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.CN(C)[C:16](=[O:18])C.O1CCCC1.[H-].[Na+]>CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:18][CH3:16])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CC(=O)N(C)C
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(SC)nc(Cl)c1C(=O)O
Reaction time: 0.33 h

Procedure:
A mixture of 4,6-dichloro-5-carboxy-2-methylthiopyrimidine (prepared in Example 320(1)) 5.00 g, N,N-dimethylacetamide 50 ml, tetrahydrofuran 20 ml and sodium hydride (60%) 1.673 g is stirred for 20 minutes on an ice bath. Methanol 5 ml is dropped thereto over a period of 30 minutes and the mixture is stirred for 15 minutes. The reaction mixture is diluted with a 10% aqueous citric solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The resulting solid is triturated with hexane in ice to give 4-chloro-5-carboxy-6-methoxy-2-methylthiopyrimidine as a slightly brown crystalline powder, 4.61 g. mp 179-181° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9](=[O:23])[NH:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.O[C@H:25]([C@H:27]1[CH2:31][N:30]([C@@H:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH3:33])[C:29](=[O:42])[CH2:28]1)[CH3:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:25]([C@H:27]4[CH2:31][N:30]([C@@H:32]([C:34]5[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=5)[CH3:33])[C:29](=[O:42])[CH2:28]4)[CH3:26])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Reactant: COc1ccc(-c2cc3ncn(C4CC4)c3c(=O)[nH]2)cc1OC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(OC)c(OC)c4)cc4ncn(C5CC5)c34)CC2=O)cc1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
3-cyclopropyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4 (5H)-one 2.37 (48.9 mg, 0.157 mmol), lactam alcohol 1.05 (63 mg, 0.24 mmol), and PPh3 (63 mg, 0.24 mmol) were taken up in THF (1.6 mL). To the resulting suspension was added DEAD (38 μL, 0.24 mmol) dropwise. The resulting mixture was heated to 40° C. and stirred 15 h. The solution was then diluted with DCM and concentrated directly onto silica gel. Purification by silica gel chromatography (35% to 55% to 65% to 100% acetone in hexanes) gave (R)-4-((R)-1-(3-cyclopropyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.38.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].O[NH:9][C:10]([C:12]1[N:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1)=[NH:11]>>[CH2:2]([C:1]1[O:6][N:11]=[C:10]([C:12]2[N:13]=[N:14][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])=[O:35])[CH2:22][CH2:23]3)=[CH:16][CH:17]=2)[N:9]=1)[CH2:3][CH2:4][CH3:5]
Reactant: N=C(NO)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCCC(=O)Cl
Product: CCCCc1nc(-c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)no1
Yield: 48 %

Procedure:
Following the procedure as described in Example 4, making variations only as required to use valeryl chloride in place of propionyl chloride to react with N-hydroxy-6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxamidine, the title compound was obtained as white crystals in 48% yield (0.110 g). m.p. 175° C. 1H NMR (300 MHz, CDCl3) 7.90 (d, J=9.3 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.67-7.48 (m, 2H), 7.30 (d, J=7.5 Hz, 1H), 7.00 (d, J=9.3 Hz, 1H), 4.15-3.65 (m, 6H), 3.32 7.30 (t, J=4.9 Hz, 2H), 2.95 (t, J=7.7 Hz, 2H), 1.92-1.75 (m, 2H), 1.48-1.35 (m, 2H), 0.90 (t, J=7.3 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 166.5, 142.0, 134.3, 134.3, 132.3, 129.4, 127.3, 127.2, 127.1, 126.9, 126.8, 126.8, 111.8, 46.4, 44.6, 44.3, 41.2, 28.5, 26.3, 22.1, 13.5. MS (ES+) m/z 461.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[C:29](F)(F)C(O)=O.C=O.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(Nc2ncnc3cnc(NCC4CCNCC4)nc23)cc1Cl
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-piperidinylmethylamino]pyrimido[5,4-d]pyrimidine by reaction with trifluoroacetic acid and subsequent reductive amination with formaldehyde and sodium cyanoborohydride. Melting point: 198°-201° C.; Rf : 0.65 (alumina; methylene chloride/methanol=20:1)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C(OC(=O)[NH:38][CH2:39][CH2:40][NH2:41])(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:38][CH2:39][CH2:40][NH:41][C:18]([C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:21]=[C:22]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:23]=[CH:24][C:2]=2[Cl:1])[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)=[O:19]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCNC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to the method described for Example 3 using 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105) and tert-butyl(2-aminoethyl)carbamate. The residue was dissolved in DCM (10 mL) and treated with 4M HCl in dioxane (5 mL) with stirring at room temperature for 4 hours. The reaction was concentrated in vacuo and eluted through an SCX-2 column using MeOH followed by 7N NH3 in MeOH; followed by reverse phase chromatography eluting with 5-95% MeCN (with 0.1% NH3) in water (with 0.1% NH3); followed by silica gel column chromatography eluting with 1-5% 7N NH3/MeOH in DCM and finally trituration with TBME.