Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCOC(=O)CCCCc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 74.2 %

Procedure:
Ethyl 5-(6-cyano-2-pyridyl)valerate (0.34 g, 1.5 mmol) and methyl thiosalicylate (0.40 g, 2.4 mmol) were dissolved in toluene (2 ml), and triethylamine (0.43 ml, 3.1 mmol) was added thereto. The reaction mixture was refluxed for 14 hrs and subjected to a silica gel (25 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated. The residue was recrystallized from ethanol-hexane to give the titled compound (0.41 g, 76%) as white crystals.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C1(C)C=CC=CC=1>[CH2:1]([NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)c1ccccc1
Temperature: 80 °C
Yield: 83 %

Procedure:
27 g of stearylamine was dispersed in 100 ml of toluene. To this dispersion was added 13 g of benzoyl chloride at 70° C. An exothermic reaction occurred and the temperature of the mixture increased to 80° C. The reaction mixture was heated to 100° C. and that temperature was maintained for about 20 hours until generation of hydrogen chloride gas was terminated. The reaction mixture was cooled, from which white crude crystals were separated. The thus obtained white crystals were neutralized with sodium hydroxide and were then recrystallized from alcohol. This recrystallization gave white crystals melting at 85° C. to 87° C. The yield was 83%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=[C:5]2[Cl:22].[CH3:23][O-:24].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:24][CH3:23])[C:6]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=[C:5]2[Cl:22]
Reactant: N#Cc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C#N)cc1
Temperature: 105 °C
Reaction time: 9 h

Procedure:
A heterogeneous mixture of 4-((6-bromo-2,4-dichloroquinolin-3-yl)methyl)benzonitrile (650 mg, 1.16 mmol, Intermediate 44: step c) and sodium methoxide (314 mg, 5.81 mmol) in dry toluene (2.2 mL) was heated at 105° C. After 9 hours, the mixture was cooled to ambient temperature and filtered through Celite®, rinsing with DCM. The filtrate was concentrated and the crude was purified by flash column chromatography (silica gel, 0-5% EtOAc-Hexanes) to provide the title compound as a white solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:36]3[NH:40][C:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)=[CH:38][CH:37]=3)[CH2:14][C@H:15]3[CH2:35][CH2:34][C:17]4(O[C@H](C5C=CC=CC=5)[C@@H](C5C=CC=CC=5)[O:18]4)[CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl>O1CCCC1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:36]3[NH:40][C:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)=[CH:38][CH:37]=3)[CH2:14][C@H:15]3[CH2:35][CH2:34][C:17](=[O:18])[CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CC[C@H](CC(c2ccc(S(=O)(=O)C3CC3)cc2)c2ccc(-c3ccccn3)[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]ethyl}-1H-pyrrol-2-yl)pyridine (70 mg) in tetrahydrofuran (3 mL) was added 1M hydrochloric acid (3 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (45 mg, yield 94%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 435 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[C:16]([C:17](OCC)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]3[CH:22]=2)[CH:6]=[CH:7][CH:8]=1>C(Cl)(Cl)(Cl)Cl>[OH:18][CH2:17][C:16]1[C:11]2[N:12]([CH:22]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:10]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cccn2cc(-c3cccc(OC)c3)nc12
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(-c2cn3cccc(CO)c3n2)c1

Procedure:
From 2d (yield: 83%) as an oil; IR (CCl4) 2956, 1550, 1253 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 3H), 5.05 (s, 2H), 6.74 (t, 1H, J=7 Hz), 6.89 (dd, 1H, J=2.5, 8 Hz), 7.06 (d, 1H, J=7 Hz), 7.34 (t, 1H, J=8 Hz), 7.51 (d, 1H, J=8 Hz), 7.54 (d, 1H, J=2.5 Hz), 7.83 (s, 1H), 8.03 (d, 1H, J=7 Hz); 13C NMR (100 MHz, CDCl3) δ 55.4, 62.6, 108.4, 111.4, 112.4, 113.9, 118.6, 121.4, 124.6, 129.7, 129.8, 134.9, 144.6, 144.9, 160.0; MS m/z 254 (M+, 58), 253 (100), 238 (12), 225 (22), 210 (16).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH:12]=O)=O>C(O)C>[CH3:12][C:10]1[N:1]=[C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]2=[N:8][CH:9]=1
Reactant: CC(=O)C=O
Reactant: Nc1cccnc1N
Solvent: CCO
Product: Cc1cnc2cccnc2n1
Yield: 60.5 %

Procedure:
2,3-Diaminopyridine (2.0 g) and a 40% aqueous pyruvic aldehyde solution (3.30 g) were refluxed in ethanol for 20 minutes. The reaction solution was concentrated, and the residue was recrystallized from 2-propanol, collected by filtration, and dried to give 3-methylpyrido[2,3-b]pyrazine (1.61 g, 60%).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[K].[OH:9][N:10]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])[C:12]#[N:13]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:5][O:9][N:10]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])[C:12]#[N:13]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: Cc1ccccc1
Product: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Reaction time: 1.5 h
Yield: 4.7 %

Procedure:
To a mixture of 924 g of toluene and 13.6 g (0.042 mol) of tetra-n-butylammonium bromide were simultaneously added dropwise 127 g (1.01 mol) of dimethyl sulfate and 1460 g of an aqueous solution containing 268 g (0.84 mol, E/Z=19/81) of the potassium salt of α-hydroxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetonitrile produced in accordance with Example 3-(2) over 5 hours while keeping at 20°-25° C., and the reaction was subsequently allowed to proceed at the same temperature for 1.5 hours. The aqueous layer was removed from the reaction mixture by phase separation, and the organic layer was washed with 1000 g of 5% aqueous sodium hydroxide solution and then washed twice with 250 g of 10% saline solution. The organic layer was concentrated under reduced pressure and dried, which afforded 245 g of α-methoxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetonitrile. The analysis by high performance liquid chromatography revealed that the content and yield of α-methoxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetonitrile was 89.6% and 88.6% (E/Z=17/83), respectively, and the content and yield of the nitron compound as a by-product was 4.8% and 4.7% yield (E/Z=91/9), respectively.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:12][C:13]#[CH:14].[Cl-].[NH4+]>CN(C=O)C>[CH2:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: c1ccc2c(c1)CCNC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C#CCN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To 1,2,3,4-tetrahydro-isoquinoline (9.4 mmol) in DMF (10 ml), 3-bromo-propyne (4.5 mmol) is added at 0° C. and stirred at room temperature for 18 h. After the reaction mixture is treated with saturated ammonium chloride, the mixture is extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. The crude product is applied to a silica gel column chromatography, which is eluted with following solvents: n-hexane and n-hexane:AcOEt=1:1 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 91.2%, Rf=0.67 (n-hexane:AcOEt=1:5).
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][C@H:7]([NH:35]C(=O)OC(C)(C)C)[C:8](=[O:34])[N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([C:20]4[CH:29]=[CH:28][C:27]5[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=5[CH:21]=4)[N:19]=3)[CH2:11][CH2:10]2)[NH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:35][C@@H:7]([CH2:6][C:4]1[NH:3][CH:2]=[N:1][CH:5]=1)[C:8]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]=4[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(C(=O)[C@@H](N)Cc5cnc[nH]5)CC4)n3)ccc21

Procedure:
250 mg (0.42 mmol) of tert-butyl ((S)-1-(3H-imidazol-4-ylmethyl)-2-oxo-2-{4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-piperidin-1-yl}ethyl)carbamate are dissolved in 20 ml of dichloromethane and 1 ml of trifluoroacetic acid and stirred at room temperature for 12 h. The reaction mixture is washed with 0.1 N NaOH, the organic phase is dried over sodium sulfate and purified by column chromatography on silica gel. The crude product is dissolved in acetone, and a pH of 4 is set using 1 N HCl. A white precipitate forms in the process, which is filtered off with suction, washed with ether and dried in vacuo. Yield: 200 mg of “A63” hydrochloride, white solid; ESI: 492 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:15](OCC)=[O:16]>C(OCC)C>[O:16]=[CH:15][CH:9]([C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1cc(C)cc(Cl)c1
Solvent: CCOCC
Product: CCOC(=O)C(C=O)c1cc(C)cc(Cl)c1
Yield: 61.4 %

Procedure:
Prepared analogously to the method described in Example N(v) above from ethyl 3-chloro-5-methylphenylacetate (4.89 g; 23 mmol; from step (iv) above), ethyl formate (3.3 g; 41.4 mmol) and Na (0.63 g; 27.6 mmol; added in small lumps) in dry ethyl ether (50 mL) to yield 3.4 g (61%) of the sub-title compound as a clear oil which slowly crystallised on standing.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:13]2[CH:23]=[CH:24][C:25]([C:27]([O:29]CC)=[O:28])=[CH:26][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)C>[CH2:3]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:13]2[CH:23]=[CH:24][C:25]([C:27]([OH:29])=[O:28])=[CH:26][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccccc1Cl
Yield: 82.6 %

Procedure:
Ethanol (8 ml) and 10% sodium hydroxide aqueous solution (3.7 g) are added to 2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole (0.635 g) (example 16), and the solution is refluxed for 4 hours. After the reaction solution is cooled, its acidity is adjusted to pH 6 with 10% hydrochloric acid. The sediment is gathered, washed with water, dried under reduced pressure, and thus, 2-benzyl-5-carboxy-1-(2-chlorobenzyl) benzimidazole (143) (0.488 g) is obtained.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:32]([N:26]1[CH2:27][CH:11]2[CH:12]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C:10]2=[O:13])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (5 drops) is added to a solution of 4,4-diphenyl-cyclohex-2-en-1-one (155 g) and N-butoxymethyl-N-trimethylsilylmethyl-benzylamine (202 cc) in dry dichloromethane (1,000 cc) and the reaction mixture is refluxed for 45 minutes. N-Butoxymethyl-N-trimethylsilylmethyl-benzylamine (50 cc) and trifluoroacetic acid (3 drops) are added and the mixture is stirred for a further 45 minutes under reflux before adding further N-butoxymethyl-N-trimethylsilylmethyl-benzylamine (25 cc) and trifluoroacetic acid (3 drops). The reaction mixture is stirred under reflux for 45 minutes and then treated with potassium carbonate (50 g) and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in isopropyl ether (200 cc) and the solution is cooled at 0° C. for 1 hour. The crystals are drained, washed with isopropyl ether (2 * 15 cc) and dried to give (3aRS,7aRS)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone (193 g) in the form of white crystals melting at 132° C.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]=[CH:14]2)[NH:6][N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([NH:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:32]=1.CN(C)CCN>O1CCOCC1.[Cu]I>[C:40]([NH:39][C:33]1[CH:32]=[C:31]([N:6]2[C:7]3[C:12](=[C:11]([N:13]4[CH:17]=[C:16]([C:18]5[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=5)[N:15]=[CH:14]4)[CH:10]=[CH:9][CH:8]=3)[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)[CH:38]=[CH:37][C:34]=1[C:35]#[N:36])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)c1n[nH]c2cccc(-n3cnc(-c4cccnc4)c3)c12
Reactant: CC(C)(C)Nc1cc(Br)ccc1C#N
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)c1nn(-c2ccc(C#N)c(NC(C)(C)C)c2)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Temperature: 150 °C
Yield: 46.6 %

Procedure:
A solution of compound (1a) (200 mg), copper(I) iodide (50 mg), cesium carbonate (430 mg), 4-bromo-2-(tert-butylamino)benzonitrile (250 mg), and N,N-dimethylethane-1,2-diamine (0.11 mL) in 1,4-dioxane (3.3 mL) was stirred overnight under heating at 150° C. After completion of the reaction, the reaction solution was allowed to standing still for cooling, filtered, and the filtrate was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried by the addition of anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was purified by neutral silica gel column chromatography (chloroform/ethyl acetate/methanol) to obtain compound (1b) (146 mg, yield 47%) as a white foamy substance.
Reaction SMILES: C([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[OH:17])[C:7]([NH:18]C(=O)C(F)(F)F)=[N:6]1)(C)(C)C.[Cl:25][C:26]1[C:27](F)=[CH:28][C:29]([F:52])=[C:30]([S:32]([N:35](CC2C=CC(OC)=CC=2OC)[C:36]2[S:37][CH:38]=[N:39][N:40]=2)(=[O:34])=[O:33])[CH:31]=1.CO>Cl>[NH2:18][C:7]1[NH:6][N:5]=[CH:9][C:8]=1[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][C:27]1[C:26]([Cl:25])=[CH:31][C:30]([S:32]([NH:35][C:36]2[S:37][CH:38]=[N:39][N:40]=2)(=[O:33])=[O:34])=[C:29]([F:52])[CH:28]=1
Reactant: CC(C)(C)n1cc(-c2cc(Cl)ccc2O)c(NC(=O)C(F)(F)F)n1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: Cl
Solvent: CO
Product: Nc1[nH]ncc1-c1cc(Cl)ccc1Oc1cc(F)c(S(=O)(=O)Nc2nncs2)cc1Cl

Procedure:
The title compound was prepared from N-[1-tert-Butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-3-yl]-2,2,2-trifluoroacetamide (Preparation 209) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 247) using Method B above with the exception that heating at 55° C. in HCl (gas) saturated methanol for 16 hours was used to remove the protecting groups. Purification by preparative HPLC afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH2:29])[CH2:27][CH3:28])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][CH3:28])=[N:25][C:21]=2[CH:20]=1
Reactant: CC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine, TBTU and DIPEA in THF.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:18](I)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)#[CH:23]>>[F:1][C:2]1[C:3]2[N:4]([C:18]([C:23]#[C:22][C:24]3[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Fc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Reactant: C#Cc1cnc(N)nc1
Product: Nc1ncc(C#Cc2cnc3c(F)cc(-c4ccc(C(F)(F)F)cc4)cn23)cn1

Procedure:
The title compound was prepared from 8-fluoro-3-iodo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.29 step 6) (350 mg, 0.85 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2) (122 mg, 0.85 mmol) according to general procedure II. Obtained as an off-white solid (116 mg, 29%). MS (ISP) 398.2 [(M+H)+]; mp 286° C.
Reaction SMILES: [OH-].[Na+].[NH:3]([CH:10]1[C:15]2=[N:16][CH:17]=[C:18](C(O)=O)[C:19](=[O:20])[N:14]2[CH:13]([CH3:24])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>O>[NH:3]([CH:10]1[C:15]2=[N:16][CH:17]=[CH:18][C:19](=[O:20])[N:14]2[CH:13]([CH3:24])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC1CCC(Nc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CCC(Nc2ccccc2)c2nccc(=O)n21
Temperature: 25 °C
Yield: 46.9 %

Procedure:
To a solution of 0.4 g. of sodium hydroxide in 10 ml. of water 1.0 g. (3.34 mmoles) of 9-anilino-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is added. The solution is stirred for 5 hours in a hydrogen gas atmosphere at 70°-80° C. The reaction mixture is then cooled to room temperature, the precipitated crystals are filtered and washed with water. 0.4 g. (46.9%) of 9-anilino-6-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one is obtained. Melting point: 160°-162° C. The product melts at 165°-167° C. after recrystallization from acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:27]=[N:28][CH:29]=1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Reactant: CCC(=O)NCc1cncc(Br)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)NCc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1
Temperature: 110 °C
Yield: 17.6 %

Procedure:
To a mixture of 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-22, 168 g, 0.55 mmol) and N-(5-bromo-pyridin-3-ylmethyl)-propionamide (122 mg, 0.5 mmol) in DMF (3 mL), purged with argon for 1 min, was added bis(triphenylphosphine)palladium (II)chloride (38 mg, 0.054 mmol) and 1 N aq. Na2CO3 (2.5 mL). Then, the resulting reaction mixture was heated in a microwave at 110° C. for 45 min. After cooling to room temperature, it was diluted with EtOAc (5 mL) and poured into a satd. aq. solution of NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (3×5 mL) and combined organics were washed with water and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by prep-HPLC to afford the title compound (30 mg, 18%) as a white solid. MS: 342.1 (M+H+)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([F:32])[F:31])=[CH:24][CH:23]=1.[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35].N1C=CN=C1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[Si:37]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([F:32])[F:31])=[CH:24][CH:23]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 16 h
Yield: 99.9 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 12e (4 g, 8.43 mmol) was dissolved in 40 mL dichloromethane, followed by addition of DMAP (103 mg, 0.84 mmol), TBSCl (1.4 g, 9.27 mmol) and imidazole (1.72 g, 25.3 mmol) in turn. The reaction mixture was stirred for 16 hours. 40 mL saturated sodium bicarbonate were added before the reaction mixture was stirred and partitioned. Thereafter, the organic extract was washed with 0.1 N hydrochloric acid (20 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 12f (4.96 g, pale yellow solid), yield: 100%.