Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[CH:15]=2)=[CH:10][CH:9]=1)[CH3:7].[CH:26](N1CCOCC1)=[O:27]>C1COCC1.ClCCl.Cl>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=3)=[C:16]([F:25])[CH:15]=2)=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(-c3ccc(C=O)[se]3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
27.5 ml (0.16 mol) of TMP are initially introduced at −20° C. in 100 ml of THF, and 100 ml (0.16 mol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min at this temperature, a solution of 50.2 g (0.15 mol) of 2-(4′-ethyl-3-fluorobiphenyl-4-yl)selenophene in 400 ml of THF is added. When the addition is complete, the batch is warmed to RT and left at this temperature for 30 min. The solution is cooled to −70° C., and 17.0 ml (0.17 mol) of N-formylmorpholine are added. The reaction mixture is warmed to RT and stirred for 1 h. the solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is washed with water, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is taken up in dichloromethane and purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from toluene. 5-(4′-Ethyl-3-fluorobiphenyl-4-yl)selenophene-2-carbaldehyde is obtained as a brown solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([Br:24])(Br)(Br)Br.[F:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31](CO)[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl>[Br:24][CH2:20][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH2:27][CH2:26][F:25])[CH:34]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(OCCF)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FCCOc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
PPh3 (3.08 g, 11.8 mmol) and CBr4 (2.93 g, 8.82 mmol) were added to a solution of 37 (1.00 g, 5.88 mmol) in DCM (20 mL) under nitrogen and stirred at room temperature for 1 h. The reaction mixture was filtered, concentrated and chromatographed to isolate the 49 as a colorless solid (0.85 g, 62% yield).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:29][C:30](=[O:32])[CH3:31])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH3:19]>>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:12][CH2:13][N:14]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:29][C:30](=[O:32])[CH3:31])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[CH3:19])[CH2:15][CH2:16]1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)Cl)cc1
Agent: Cl
Product: CC(=O)NC(C)(C)c1ccc(C(C)N2CCN(c3ccc(F)cc3F)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2,4-difluorophenyl)piperazine dihydrochloride instead of phenylpiperazine and N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide obtained in Example 60(2) instead of N-(4-chloromethylphenylmethyl) acetamide, the title compound was obtained as a white amorphous solid.
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1
Reactant: O=C(NCC1Cc2ccccc2C1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCC1Cc2ccccc2C1
Yield: 90.8 %

Procedure:
10.6 g (37.7 mmol) of 2-(benzyloxycarbonylaminomethyl)indan was dissolved in 100 ml of methanol, to which 1.3 g of palladium on carbon was added and stirred for 4 hours in the stream of hydrogen. The catalyst was removed by filtration, the solvent was evaporated, and 5.04 g of 2-(aminomethyl)indan was obtained. The obtained compound was immediately dissolved in 150 ml of methylene chloride, to which 100 ml of water and 6.2 g of potassium carbonate were added, and the mixture was vigorously stirred. 8.02 g (38.0 mmol) of 4-chlorobenzenesulfonyl chloride was added thereto portionwise under ice-cooling, followed by stirring for 30 minutes. The organic phase was collected, dried and the solvent was removed by distillation. The crystalline residue was recrystallized from a solvent mixture of ethyl acetate and hexane to obtain 9.82 g of 2-[(4-chlorophenyl)sulfonylaminomethyl]indan as colorless needles. Yield: 76%
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:18]=[C:17](I)[C:16]([OH:20])=[C:15](I)[CH:14]=1>COCCOC.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:18]=[C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]([OH:20])=[C:15]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(I)c(O)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a stirred solution of phenylboronic acid (4.95 g, 40.57 mmol), Ba(OH)2.H2O (10.48 g, 55.33 mmol), and Pd(OAc)2 (0.414 g, 1.84 mmol) in DME/H2O (110 mL/20 mL) was added 3,5-diiodo-4-hydroxybenzoic acid methyl ester (7.45 g, 18.44 mmol). The mixture was stirred at 85° C. for 3 h and was then cooled and concentrated. The residue was partitioned between ethyl acetate/2N HCl. The organic phase was dried (MgSO4) and concentrated to give a solid which was triturated with diethyl ether/petroleum ether to give 3.51 g (62.5%) of product as a white solid. 1H NMR (DMSO-d6) δ 9.27 (s, 1H), 7.27 (s, 2H), 7.25-7.40 (m, 10H), 3.81 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C=O)cc(F)c1Oc1ccc(C#N)cn1
Yield: 66.9 %

Procedure:
Using a method similar to Example 710, Step 2, using 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (Journal of Organic Chemistry (1986), 51(2H), 4072-3.) (2.84 g, 16.7 mmol), 6-chloronicotinonitrile (2.31 g, 16.7 mmol) and K2CO3 (3.46 g, 25.0 mmol) gives 6-(2-fluoro-4-formyl-6-methoxy-phenoxy)-nicotinonitrile (3.04 g) as a white solid. 1HNMR (CDCl3): 9.94 (s, 1H), 8.37 (s, 1H), 7.98 (d, 1H), 7.36 (m, 2H), 7.20 (d, 1H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](I)[CH:5]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[CH:5]=1
Reactant: COC(=O)c1ccnc(I)c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccnc(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound, MS: m/e=281.0 (M+) was obtained as a light brown solid (59% yield) by the reaction of 2-iodo-isonicotinic acid methyl ester with 3,4-dichlorophenyl boronic acid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][N:11]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[CH3:32])[C:12]([C:14]1[S:25][C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]2[CH:15]=1)=[O:13].N>>[CH3:10][N:11]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[CH3:32])[C:12]([C:14]1[S:25][C:17]2=[N:18][C:19]3[CH:24]=[CH:23][C:22]([N+:1]([O-:4])=[O:2])=[CH:21][C:20]=3[N:16]2[CH:15]=1)=[O:13]
Reactant: C[C@H]1CCCC[C@H]1N(C)C(=O)c1cn2c(nc3ccccc32)s1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: C[C@H]1CCCC[C@H]1N(C)C(=O)c1cn2c(nc3ccc([N+](=O)[O-])cc32)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under ice-cooling, fuming nitric acid (0.28 ml) was added to concentrated sulfuric acid (22 ml) solution of (+)-(1R,2S)-N-methyl-N-(2-methylcyclohexyl)thiazolo [3,2-a]benzoimidazole-2-carboxamide (2.2 g) and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into ice water and neutralized with a 28% aqueous ammonia solution and then the resulting precipitate was collected by filtration to obtain (1R,2S)-N-methyl-N-(2-methylcyclohexyl)-6-nitrothiazolo [3,2-a]benzoimidazole-2-carboxamide. This was treated in the same manner as in Production Example 1 to obtain the title compound (242 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:34][CH3:35])([C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:46]([N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23][C:24]([CH2:34][CH3:35])([C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:36])[NH:12][CH:11]2[C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=2[CH3:44])[C:9]1=[O:45])(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reaction time: 2 h
Yield: 23.5 %

Procedure:
At room temperature, to a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-methanesulfonylaminocarbonyl-propoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (400 mg, 0.58 mmol) and acetic anhydride (71 mg, 0.69 mmol) in DCM (20 mL) was added DMAP (7 mg, 0.06 mmol) slowly. After the mixture was stirred for 2 h, the solution was washed by 0.5N HCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (100 mg).
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:24])[C:10]2[N:11]=[CH:12][N:13]([C:22]=2[N:23]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].CC(N(C)C)=O.[C:31](Cl)(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(=O)(O)[O-].[K+]>N1C=CC=CC=1>[C:31]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[C:22]3[N:23]=[C:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[NH:8][C:9](=[O:24])[C:10]=3[N:11]=[CH:12]2)[CH2:15][C@@H:16]1[OH:17])(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an oven-dried 100 mL round-bottomed flask containing a stir bar was added N2-isobutyryl-2′-deoxyguanosine (0.75 g, 1 eq.). The flask was fitted with a septum and dry dimethylacetamide (DMA, 32 mL) and dry pyridine (16 mL) were added via cannula, with swirling and stirring. The flask was purged with argon gas, the slurry was allowed to cool 10 min. in an ice bath, and palmitoyl chloride (2.5 eq.) was added dropwise over 5 min. The mixture was allowed to stir while it slowly warmed to 25° C. After 24 h, the mixture was poured into 200 mL of 0.5 M potassium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×30 mL H2O, air dried, and finally dried under high vacuum giving a white powder. This crude product was purified by flash chromatography (silica gel bed, eluted with chloroform-methanol) giving a white powder. 1H-NMR and elemental analysis data were consistent with the assigned structure.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([SH:8])=[N:5][N:4]=1.[H-].[Na+].Cl[C:12]1[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:7][C:6]([S:8][C:12]2[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=2)=[N:5][N:4]=1
Reactant: N#Cc1nccnc1Cl
Reactant: CSc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nnc(Sc2nccnc2C#N)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(methylthio)-1,3,4-thiadiazole-2-thiol (821 mg, 5.0 mmol) in DMF and benzene (10 ml, 1/1) was added NaH (60% dispersion in mineral oil, 220 mg, 5.5 mmol) slowly at 0° C. under nitrogen atmosphere. The resulting suspension was stirred at 0° C. for 15 minutes and then to the mixture was added 3-chloropyrazine-2-carbonitrile (698 mg, 5.0 mmol). The reaction was stirred at 80° C. for 4 hr. The reaction was then cooled to room temperature and quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the title compound as a white solid.
Reaction SMILES: C[Mg+].[Br-].CCOCC.[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].[C:16]1([CH3:24])[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>C1(C)C=CC=CC=1>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[C:22]([C:17]1[C:16]([CH3:24])=[CH:21][CH:20]=[CH:19][CH:18]=1)=[NH:23])([CH3:11])[CH3:10]
Reactant: CC(C)NC(C)C
Reactant: Cc1ccccc1C#N
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=N)N(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of MeMgBr in ether (12.9 mL, 3.0 M, 38.7 mmol) was added to a solution of diisopropylamine (3.91 g, 38.7 mmol) in toluene (60 mL) at 50° C. The mixture was stirred for 1 h and a white precipitate formed. Next, the mixture was cooled to 0° C. and tolunitrile (4.53 g, 38.7 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 16 h subsequently. The mixture was quenched with water (100 mL). The organic phase was separated from the aqueous phase and the latter was extracted with diethylether (150 mL) twice. The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure giving a sticky residue. This residue was triturated with ligroin giving 4.40 g (52%) pure product.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([F:10])=[N:6][CH:7]=[CH:8][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH3:26]>C(Cl)Cl>[NH2:26][CH2:2][CH2:3][C:4]1[C:5]([F:10])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: OCCc1cccnc1F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: NCCc1cccnc1F
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.20 g (1.42 mmol) of 3-(2-hydroxyethyl)-2-fluoropyridine in 8 ml of dry CH2Cl2 cooled to -40° C. was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. After stirring for 30 min at -40° C., 30 ml of cold (-78° C.) NH3 (l) was added. The mixture was stirred for 30 min at -40° C., and then concentrated in vacuo to afford 1.03 g of crude salt which was washed twice with 20 ml diethyl ether to yield 0.82 g of 3-(2-aminoethyl)-2-fluoropyridine as a trifluoromethanesulfonic acid salt.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][N:4]=1.[CH3:18]I>>[CH3:18][N:4]1[CH:5]=[C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:7]=[CH:8][C:3]1=[O:2]
Reactant: CI
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Temperature: 80 °C

Procedure:
A mixture of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (235 mg, 1.00 mmol) and CH3I (426 mg, 3.00 mmol) was heated at 80° C. for 3 hours. The mixture was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, and evaporated to dryness to afford 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one that was directly used in next step without further purification.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1C=CC(S(O[CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)(=O)=O)=CC=1.O>CN(C)C=O>[CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(O)cc12
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(OC3CCOCC3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
Cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methanone (5.2 g) synthesized in the above-mentioned (3) was dissolved in dimethylformamide (100 mL), and potassium phosphate (7.4 g) and tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (9.0 g) synthesized by the method of EP-A-1367058 were added to the mixture at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, water (150 mL) was added and the mixture was extracted with diethyl ether (100 mL×2). The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10, volume ratio) to give the title object compound (7.1 g, 99%) as a pale-yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:33]([F:36])([F:35])[F:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:33]([F:34])([F:36])[F:35])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (5.00 g) and 37% formalin (3.0 mL) in the same manner as in the synthesis of Example 1 was dissolved in chloroform (50 mL), and triethylamine (11.1 mL) and 3-cyano-4-methoxy-5-trifluoromethylbenzoylchloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (j).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][C:15]3[NH:14][C:13](=O)[CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[CH:12]=[CH:11][C:10]2[C:9](=[O:18])[CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:16][C:15]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21
Product: O=C1CC(c2ccccc2)Cc2nc(Cl)ccc21

Procedure:
In analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V. V.; Granik, V. G. Khim. Geterotsikl. Soedin. 1991, (1) 86-92) 7-phenyl-7,8-dihydro-1H,6H-quinoline-2,5-dione was treated with phosphoryl chloride (POCl3) to give after chromatographical separation the title compound as a colorless solid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([F:24])([F:23])[F:22])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([O:27][CH3:28])[C:3]=1[C:4]#[N:5].O.[NH2:30][NH2:31]>C(O)C>[CH3:26][NH:25][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:30][NH:31]3)=[C:6]([O:27][CH3:28])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([F:22])([F:24])[F:23])[N:13]=1
Reactant: NN
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Solvent: CCO
Solvent: O
Product: CNc1nc(-c2cc(OC)c3c(N)n[nH]c3c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Yield: 54.9 %

Procedure:
2-Fluoro-4-{2-(methylamino)-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile (131 mg, 0.331 mmol) was dissolved in ethanol (3 mL) in a 5 mL sealable vial. Hydrazine monohydrate (0.487 mL, 9.94 mmol) was added, the vial was capped, and the reaction was heated at 100° C. overnight. The reaction was concentrated, dissolved in 2 mL of DMSO and purified in HPLC (HPLC condition: open-access Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 mL/min, 18% CH3CN/H2O, 0.1% TFA to 43% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. To the water left behind was added saturated NaHCO3, then extracted with EtOAc (3×15 mL). The organic was washed with brine, dried over MgSO4, filtered, concentrated, and transferred to a haystack vial. Water (1 mL) was added, and the resulting mixture was freeze dried to afford the title compound (74 mg) as a light yellow solid. LC-MS (ES) m/z=408 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.95-2.03 (m, 2H), 2.05 (bs, 2H), 2.77 (d, J=3.3 Hz, 3H) 3.47 (d, J=8.8 Hz, 1H) 3.62 (d, J=4.6 Hz, 1H), 3.87 (s, 3H), 4.98 (bs, 2H), 5.08 (bs, 1H), 6.39 (bs, 1H), 6.64 (bs, 1H), 6.88 (bs, 1H), 7.43 (bs, 1H), 11.50 (bs, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][C@@:11]([NH:34]C(=O)OC(C)(C)C)([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:18]=2)[C:10]1=[O:42]>C(Cl)Cl>[NH2:34][C@@:11]1([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[N:18]=2)[CH2:12][CH2:13][N:9]([CH3:8])[C:10]1=[O:42]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(N)CCN(C)C2=O)n1
Reaction time: 8 h
Yield: 89 %

Procedure:
Trifluoroacetic acid (5 mL, 67.31 mmol) was added to a solution of tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (3.83 g, 7.84 mmol) (which may be prepared as described in Description 13a) in DCM (50 mL) at 20° C. and the reaction was stirred overnight. The reaction was concentrated and a further portion of trifluoroacetic acid (2 ml) added. Stirring was continued for 3 hrs then solid K2CO3 was added (care: gas evolved) and the mixture was diluted with water. The phases were separated and the organic layer was dried (Na2SO4). The solvent was evaporated to give (3S)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (D14a) (2.71 g, 6.9775 mmol, 89% yield) as a yellow oil. The NMR was the same as that produced by the R isomer in Description 14 but with some impurities present.