Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([NH:4][C:5]1[CH:10]=[C:9]([C:11](=[N:13]O)[CH3:12])[CH:8]=[CH:7][N:6]=1)[CH3:3].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[O-]CC.[K+].[N:30]#[C:31][NH2:32].[OH-].[Na+].[OH-].[NH4+]>C(#N)C.C(OCC)C.C(O)C>[CH2:2]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[N:13]=[C:31]([NH2:32])[NH:30][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[CH3:3]
Reactant: CCNc1cc(C(C)=NO)ccn1
Reactant: N#CN
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: CC#N
Product: CCNc1cc(-c2c[nH]c(N)n2)ccn1
Reaction time: 0.08 h
Yield: 52 %

Procedure:
Sodium (370 mg., 15.5 mmoles) was dissolved in 25 ml. of absolute ethanol at room temperature under a nitrogen atmosphere and to this was added 2.7 g. (15 mmoles) of 1-(2-ethylamino-4-pyridyl)-1-ethanone oxime (Example IIB). The reaction mixture was stirred until homogeneous (5 minutes), then 3.0 g. (16 mmoles) of p-toluenesulfonyl chloride was added, and the mixture was stirred at room temperature under nitrogen for one hour. The mixture was subsequently added to a solution of potassium ethoxide (prepared by dissolving 630 mg. of potassium in 25 ml. of absolute ethanol) and the resulting mixture was stirred at room temperature under nitrogen for one hour. The resulting gelatinous suspension was diluted with 200 ml. of diethyl ether and filtered. The ether filtrate was extracted with (4×25 ml.) 2 N hydrochloric acid and the combined acid extracts concentrated to dryness. The residue was dissolved in 20 ml. of water, 1.35 g. (32 mmoles) of cyanamide was added and the mixture brought to pH 4.5 by the dropwise addition of 2 N sodium hydroxide solution. The mixture was heated at steam bath temperature for 1 hour, and was then cooled and made basic with concentrated ammonium hydroxide. The reaction mixture was concentrated to dryness and extracted with i-propanol. Removal of the i-propanol gave an oil which was taken up in 25 ml. of acetonitrile. Addition of diethyl ether to the acetonitrile solution resulted in the formation of a precipitate. Filtration and recrystallization of the solids from i-propanol gave 1.55 g. (52%) of the desired product, m.p. 200°-202° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([CH3:22])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16]OS(C)(=O)=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[C:7]([CH3:8])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:28]2[C:27](=[O:29])[C:26]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]3[C:24]2=[O:34])[N:14]=1)[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOS(C)(=O)=O)cs1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN2C(=O)c3ccccc3C2=O)cs1
Temperature: 85 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
2-Methyl-2-[(4-{2-[(methylsulfonyl)oxy]ethyl}-1,3-thiazol-2-yl)thio]propionic acid tert-butyl ester (123 g) synthesized in Example 5 was dissolved in N,N-dimethylformamide (800 mL), potassium phthalimide (59.7 g) was added thereto and the mixture was stirred for 2 hr at 85° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (136 g) as a slightly yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cc(OCc3ccccc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccnc2cc(OCc3ccccc3)ccc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a suspension of 7-(benzyloxy)quinolin-4-ol (72 g, 287 mmol) in toluene (134 mL) was added phosphoryl trichloride (44 g, 287 mmol, Tianjin FuChen Chem. Co. Ltd.). The suspension was heated to 120° C. for 1 hour. The reaction mixture was then cooled to 70° C. and diluted with EtOAc (600 mL). The resulted mixture was stirred for 30 minutes while cooling down to 15° C. using an ice bath. The mixture was neutralized with 3 M NaOH aqueous solution to pH 7˜8 while maintaining the temperature of the solution under 20° C. The aqueous layer was separated and extracted with EtOAc (200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a pale yellow solid (70.8 g, 91.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([O:33][CH2:34][CH3:35])=[N:28]2>>[CH2:34]([O:33][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[NH:22][CH2:11][C:10]([C:13]([F:14])([F:16])[F:15])([OH:17])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:20][CH3:21])([CH3:18])[CH3:19])[N:28]=1)[CH3:35]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: CCOc1ccc2c(N)cccc2n1
Product: CCOc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Yield: 44 %

Procedure:
Analogously to Example 20, 500 mg (1.6 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 363 mg (1.9 mmol) of 5-amino-2-ethoxyquinoline are reacted to form 338 mg of the product.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[C:45]([C:53]([O:55][CH3:56])=[O:54])(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.P([O-])([O-])([O-])=O.[OH-].[Na+]>C(OCC)C.CCCCCC.CC(O)C>[C:53]([O:55][CH3:56])(=[O:54])[C@@H:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[OH:52]
Reactant: COC(=O)C(=O)c1ccccc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
A reaction mixture was formed by admixing (i) 50 mg NAD, (ii) 4 ml of 2-propanol and (iii) 5 mmoles of methyl benzoylformate, Compound 4, in a liquid medium containing 1 gm of lyophilized PED alcohol dehydrogenase preparation, 75 ml of 50 mM phosphate buffer, pH 7.1, and 25 ml of hexane. The pH of the reaction was maintained constant by addition of 1N NaOH. The reaction mixture was maintained at room temperature until product formation stopped. When product formation stopped, (R)-methyl mandelate, Compound 4a, was isolated by removal of the hexane layer and extraction of the aqueous layer with ethyl ether (3×75 ml).
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][O:6][CH:7]([O:25][CH3:26])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21]C(=O)C.C(Cl)(Cl)Cl.CO>CO>[CH3:26][O:25][CH:7]([O:6][CH3:5])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21]
Reactant: COC(COCCOCCOCCOCCOC(C)=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(COCCOCCOCCOCCO)OC
Reaction time: 0.5 h
Yield: 76 %

Procedure:
1 N NaOH/Methanol (1 ml) was added to a stirring solution of acetic acid 2-(2-{2-[2-(2,2-dimethoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethyl ester (Compound 4) (110 mg, 0.34 mmol) in methanol (3 ml) at ambient temperature. The reaction was monitored by TLC (CHCl3/MeOH, 9:1) and was completed within 30 minutes. The solvent was evaporated and the residue purified by flash chromatography (CHCl3/MeOH, 9:1) to afford the product (73 mg, 76%) as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH3:14][CH:15]1[CH:19]=[CH:18][CH:17]([CH3:20])[NH:16]1>>[CH3:14][CH:15]1[CH:19]=[CH:18][CH:17]([CH3:20])[N:16]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC1C=CC(C)N1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: CC1C=CC(C)N1c1ccc(C#N)c2ccccc12
Yield: 3.4 %

Procedure:
The title compound (1 mg, 3% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 2,5-dimethyl-2,5-dihydro-1H-pyrrole (45 mg, 0.468 mmol).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:33])[C:7]2=[O:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:40]>ClCCl.C(OCC)(=O)C>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:40])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:33])[C:7]2=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2cc(-c3cc(-c4nnc(CC(C)C)o4)ccc3C)c(=O)n(C3CCCC3)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nnc(CC(C)C)o2)cc1-c1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 152.6 %

Procedure:
To a solution of 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl}-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (40.0 mg, 0.08 mmol) in dichloromethane (3 mL) at 0° C. was added 3-chloroperoxybenzoic acid (0.04 g, 0.19 mmol). The mixture was stirred at 0° C. for 1 hour, then was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure to give 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]-oxadiazol-2-yl)-2-methyl-phenyl}-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.06 g). The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][C:7]([F:10])([F:9])[F:8])[CH3:2]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:11][C:12]([F:13])([F:14])[F:15])[CH2:6][C:7]([F:8])([F:10])[F:9])[CH3:2]
Reactant: CCOC(=O)C(=CC(F)(F)F)CC(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(F)(F)F)CC(F)(F)F
Yield: 99.1 %

Procedure:
4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)-but-2-enoic acid ethyl ester (5.0 g, 20.0 mmol) in THF (20 mL) was treated with Pd/C (2.5 g, 5%), and H2 (1 atm.) at 25° C. for 17 h. The reaction mixture was filtered through a pad of the Celiteg reagent, rinsed with Et2O (50 mL) and the filtrate was distilled to remove Et2O and THF to afford the product as colorless liquid (5.0 g, 99%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:38])[CH2:5][CH2:6][NH:7][C:8](=[O:37])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[O:24])[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.[CH:48]1([C:51](Cl)=[O:52])[CH2:50][CH2:49]1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:38])[CH2:5][CH2:6][NH:7][C:8](=[O:37])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=2)=[O:24])[CH:16]2[CH2:17][CH2:18][N:19]([C:51]([CH:48]3[CH2:50][CH2:49]3)=[O:52])[CH2:20][CH2:21]2)=[CH:11][CH:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCNCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCN(C(=O)C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{4-[1-piperidin-4-yl-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoyl-amino}propionic acid methyl ester hydrochloride (0.20 g) in DMF (5 mL) was added diisopropylethylamine (0.30 mL) and cyclopropylcarboxylic acid chloride (0.16 mL). The mixture was stirred at 25° C. overnight. Water (100 mL) and ethyl acetate (100 mL) were added, the phases separated and the organic phase was washed with a solution of NH4Cl (sat., 2×50 mL) and water (50 mL). Upon drying with MgSO4 the solvent was evaporated and the residue purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([O:12][CH3:13])[CH:6]=[CH:5][C:4]=1I.[C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1)#[CH:16].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([O:12][CH3:13])[CH:6]=[CH:5][C:4]=1[C:16]#[C:15][C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1
Reactant: C#Cc1cnn(C)c1
Reactant: COc1ccc(I)c(OC)c1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C#Cc2cnn(C)c2)c(OC)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 71 %

Procedure:
To a mixture of 2,4-dimethoxy-3-nitro-iodobenzene (0.95 mmol), 0.122 g (1.15 mmol) of 4-ethynyl-1-methyl-1H-pyrazole, 0.028 g (0.04 mmol) of dichlorobis(triphenylphosphine)palladium (II) and 8 mg (0.042 mmol) of copper (I) iodide 4 mL of anhydrous acetonitrile and 2 mL of triethylamine were added under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 1 hour, when TLC indicated a consumption of the iodobenzene. The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography (silica gel; dichloromethane:ethyl acetate 9:1) to give the title compound in 71% yield as creamy crystals. H1 NMR (CDCl3) 3.88 (s, 3H, Me); 3.9 (s, 3H, OMe); 4.07 (s, 3H, OMe); 6.7 (d, 1H, CH, J=8.9 Hz); 7.44 (d, 1H, CH, J=8.9 Hz); 7.56 (s, 1H, CH pyr); 7.62 (s, 1H, CH pyr).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@H:11]1[CH2:15][CH2:14][C@@H:13]([C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[NH:12]1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>C(O)C>[CH2:3]([CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]([OH:26])[C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[NH:12]1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccc2c(c1)OCO2)[C@@H]1CC[C@H](CCc2ccccc2)N1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: OC(c1ccc2c(c1)OCO2)C1CCC(CCc2ccccc2)N1
Reaction time: 1 h

Procedure:
1.35 g (0.035 mole) of sodium borohydride was added to a stirred solution of 2.70 g (0.0057 mole) of ±cis 2-[phenethyl]-5-[(3,4-methylenedioxy)benzoyl]pyrrolidine in 270 ml ethanol, at 0° temperature. After 1 hour at 0°, the mixture was poured into 100 ml of 10% ammonium chloride solution. The mixture was evaporated in vacuo to remove the ethanol, the residue was cooled to 0°, and 50 ml of a saturated sodium carbonate solution was added. The product was extracted into ethyl acetate, the extract was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate-hexane to give 1.72 g (93%) of the desired ±cis erythro 2-[phenethyl]-5-[(3,4-methylenedioxy)-α-hydroxybenzyl]pyrrolidine (IX), m.p. 122°-123° (dichloromethane-hexane). (Step 7)
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[N:5]=[CH:4][N:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3][CH:4]=[N:5][C:6]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: Cc1ccccc1-c1ncnc(Cl)c1C
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1-c1ncnc(-c2ccccc2)c1C
Yield: 87 %

Procedure:
Next, into a recovery flask equipped with a reflux pipe were put 1.9 g of 4-chloro-5-methyl-6-(2-methylphenyl)pyrimidine obtained in Step 1, 1.7 g of phenylboronic acid, 1.1 g of sodium carbonate, 0.105 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 1 hour. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and was dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 9:1 and the obtained fraction was concentrated, so that 5-methyl-6-(2-methylphenyl)-4-phenylpyrimidine was obtained (a white solid, yield of 87%). A synthesis scheme (q-2) of Step 2 is shown below.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([N:13]1[CH:17]=[N:16][N:15]=[CH:14]1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[O:18]([C:26]1[CH:27]=[C:28]([SH:32])[CH:29]=[CH:30][CH:31]=1)[Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[OH:18][C:26]1[CH:27]=[C:28]([S:32][CH2:2][CH2:3][N:4]([N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: N#Cc1ccc(N(CCBr)n2cnnc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCSc2cccc(O)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-[(2-bromo-ethyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02148=CAB03031, 146 mg, 0.50 mmol), 3-(tert-butyl-dimethylsiloxy)-thiophenol (240 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMF (10 mL) was stirred for 48 hours at room temperature. The mixture was transferred into a separation funnel and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was crystallised from methanol. Yield: 93 mg (55%) to colourless crystals. 1H-NMR (400 MHz, d6-DMSO) δ=3.14 (t, J=7.0 Hz, 2H), 4.02 (t, J=7.0 Hz, 2M, 6.53 (d, J=9.0 Hz, 2H), 6.62 (ddd, J=7.8, 2.0, 0.8 Hz, 1H), 6.70-6.72 (m, 2H), 7.10 (dd, J=7.8, 7.8, 1H), 7.70 (d, J=9.0 Hz, 2H), 8-94 (s, 2H), 9.60 (s, 1H, —OH). 13C-NMR (100 MHz, d6-DMSO) δ=29.53, 52.46, 102.38, 112.86, 113.57, 115.36, 119.00, 130.11, 133.94, 135.82, 143.50, 150.71, 157.90, 169.59. LRMS (FAB+): 338.2 (100, [M+H]+). Found: C, 60.6; H, 4.53; N, 20.8%; C17H15N5OS (337.4) requires C, 60.52; H, 4.48; N, 20.76%.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][N:24]=1>CN1C(=O)CCC1>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: COC(=O)c1cnc(Br)s1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)s1

Procedure:
3,4-Dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1, 0.300 g, 0.961 mmol) was dissolved in NMP (3 ml). TEA (267 μl, 1.922 mmol) was added followed by the addition of methyl 2-bromo-1,3-thiazole-5-carboxylate (0.213 g, 0.961 mmol) at room temperature. Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 20 minutes and was partitioned between water and EtOAc. The organic layer was washed with water and combined organic phase was dried over magnesium sulfate and concentrated to give the desired product. (432 mg).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: O=C1CCC(O)(c2cccnc2)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cccnc4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-pyridin-3-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Cl.[CH3:2][NH:3][NH:4][C:5](=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]1([CH3:22])[C:14]([C:19](Cl)=O)=[CH:15][CH:16]=[CH:17][CH:18]=1>C(OCC)C>[CH3:2][N:3]1[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:22])=[N:12][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:4]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CNNC(=N)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccccc1-c1nc(-c2ccccc2)nn1C
Temperature: 120 °C
Yield: 76 %

Procedure:
A mixture of 0.56 g. of benzimidic acid 2-methylhydrazide hydrochloride and 3.8 g. of o-toluic acid chloride is heated under stirring at about 120° C. After cooling and addition of diethyl ether, the hydrochloride of the triazole is collected on filter and then suspended in a sodium bicarbonate aqueous solution. The free base is extracted with diethyl ether and the organic phase, after drying over sodium sulfate, is evaporated. The crude compound is purified by distillation at 160° C/0.1 mm Hg. Yield 76%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=[CH:31][C:30]=1[N:44]1[CH2:49][CH2:48][C:47]2[C:50]3[CH2:56][CH2:55][CH2:54][CH2:53][C:51]=3[S:52][C:46]=2[C:45]1=[O:57])(=[O:26])[CH3:25].CC([O-])=O.[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[C:45](=[O:57])[C:46]3[S:52][C:51]4[CH2:53][CH2:54][CH2:55][CH2:56][C:50]=4[C:47]=3[CH2:48][CH2:49]2)=[CH:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 43.4 %

Procedure:
A sealed tube was charged with the mixture of 5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one 130c (400 mg, 1.06 mmol), (2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 111a (512 mg, 1.06 mmol), Pd(dppf)Cl2 (87 mg, 0.1 mmol), K3PO4.3H2O(566 mg, 2.12 mmol), and NaOAc (174 mg, 2.12 mmol) in CH3CN (25 mL). The system was evacuated and then refilled with N2. The reaction mixture was heated at 110° C. for 2 h. Then, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 10:1 methylene chloride/methanol to give 315a as a brown solid (300 mg, 43%). MS: [M+H]+ 652