Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[N:10]=2)=[CH:5][C:4]=1[CH3:30].[Si](I)(C)(C)C>C(#N)C.ClCCl>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:19]2([C:17]([NH:16][C:11]3[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([C:6]4[CH:5]=[C:4]([CH3:30])[C:3](=[O:2])[NH:8][CH:7]=4)[N:10]=3)=[O:18])[CH2:20][CH2:21]2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(C2(C(=O)Nc3ccc(C)c(-c4cnc(OC)c(C)c4)n3)CC2)c1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: ClCCl
Product: COc1cccc(C2(C(=O)Nc3ccc(C)c(-c4c[nH]c(=O)c(C)c4)n3)CC2)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)-1-(3-methoxyphenyl)cyclopropanecarboxamide (41 mg, 0.10 mmol) in acetonitrile (2 mL) was added TMS-Iodide (28.0 μL, 0.20 mmol). The reaction was stirred at 50° C. for 20 min. The reaction solution was diluted with dichloromethane and washed with saturated NaHSO3 (2×), brine, dried over MgSO4 and concentrated. The crude product was dissolved in DMSO (1 mL) and purified by reverse phase HPLC (Gilson, 10-99% CH3CN in water) to yield the desired product. ESI-MS m/z calc. 389.4. found 390.5 (M+1)+. Retention time 1.41 minutes.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:25])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])=[O:10])[CH3:8].OS([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:3][O:4][C:5](=[O:25])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[C:16]([Br:1])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])=[O:10])[CH3:8]
Reactant: BrBr
Reactant: COC(=O)CN(C)C(=O)c1c(OC)ccc2cc(OC)ccc12
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CN(C)C(=O)c1c(OC)ccc2c(Br)c(OC)ccc12
Yield: 66.8 %

Procedure:
A solution of bromine (1.75 mL, 34.05 mmol) in acetic acid (40 mL) was added over 25 minutes to a stirred solution of N-[(2,6-dimethoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (10.70 g, 33.72 mmol, described in Example 2) in acetic acid (120 mL). After an additional 10 minutes the reaction was diluted with water (900 mL) and NaHSO3 (2.0 g) was added. The resulting precipitate was collected by filtration, washed with water and dried to give 8.93 g (67% yield) of the title compound, m.p. 142°-144° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](Cl)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1.O>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
To a mixture consisting of 19.4 g. of L-leucine, 15.7 g. of sodium carbonate, and 500 ml. of water, cooled to 0° C., is added a solution of 19.1 g. of 9-fluorenylmethylchloroformate in 200 ml. of tetrahydrofuran, and the resulting mixture is stirred at 0° C. for one hour and at room temperature for 15 hours. The mixtue is then acidified with 3 N hydrochloric acid and concentrated to remove the solvent. The residue is extracted with ethyl acetate, and the extract is washed with 100 ml. of 10% hydrochloric acid and with 100 ml. of water, dried, and evaporated to dryness to give a residue of N-9-fluorenylmethoxycarbonyl-L-leucine, which is slurried with n-hexane, isolated, and dried; m.p. 76°-79° C.; [α]D25 -28.7° (1.01% in methanol). To a mixture consisting of 15.2 g. of this intermediate product, 37 g. of pentachlorophenol, and 300 ml. of N,N-dimethylformamide, cooled to 5° C., is added 9.8 g. of dicyclohexylcarbodiimide, and the resulting mixture is kept at 4° C. for 2 days. It is then filtered, and the filtrate is evaporated to dryness to give a residue of N-9-fluoroenylmethoxycarbonyl-L-leucine pentachlorophenyl ester, which is triturated with n-hexane, isolated and dried; m.p. 119°-121° C.; [α]D25 -35.4° (1.00% in methanol).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C.Cl.[NH2:32][CH2:33][C:34]#[N:35].Cl>CN(C=O)C>[F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:35][CH2:34][C:33]#[N:32])[C:4]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NCC#N
Temperature: 25 °C

Procedure:
A solution of 3.0 g (0.008 mol) of product of Example 103, 1.72 g (0.017 mol) of triethylamine and 0.79 g (0.008 mol) of aminoacetonitrile hydrochloride in 30 ml of DMF was stirred at 50° C. for 24 hours. The reaction mixture was cooled to room temperature and poured into 3.7% HCl. This solution was extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4) . The dry ether phase was concentrated in vacuo to 2.56 g of a brown semi-solid oil. The crude product was recrystallized in hexane/ethyl acetate to 0.9 g (28) of product as a beige solid; mp 87°-89° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13](=[O:16])[CH2:14][CH3:15])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.C(O)(=O)C.[BrH:21].Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[CH3:1][NH:2][C:3]1[S:4][C:5]([C:13](=[O:16])[CH:14]([Br:21])[CH3:15])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1nc(NC)sc1C(=O)CC
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(NC)sc1C(=O)C(C)Br

Procedure:
To a solution of ethyl 2-methylamino-5-propionyl-4-thiazolecarboxylate (7.4 g) and 30% hydrogen bromide acetic acid (10 ml) in acetic acid (50 ml) was added pyridinium hydrobromide perbromide (13.0 g) at ambient temperature and the mixture was stirred for an hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give ethyl 2-methylamino-5-(2-bromopropionyl)-4-thiazolecarboxylate (7.4 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(OCC)C>[O:20]([C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: CCOCC
Solvent: O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccccc1
Yield: 24 %

Procedure:
A mixture of 12.3 g. of 1-benzyl-3,4-epoxypyrrolidine, 13.2 g. of phenol and 3 drops of water was heated at 120° C. under nitrogen gas for 20 hr. The mixture was cooled and dissolved in 100 ml. ethyl ether. The ethereal solution was extracted with 2×50 ml. of 5% sodium hydroxide and then washed with water. After being dried with anhydrous sodium sulfate, the solvent was evaporated and the residue weighed 14.3 g. Two crystallization from cyclohexane gave analytically pure product melting at 101°-104° C. The yield was 24% of theory.
Reaction SMILES: C([NH:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=O)C.[ClH:22]>O.CO>[ClH:22].[NH2:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: O
Solvent: CO
Product: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 12.9 g of 10-acetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 650 ml of 2N aqueous hydrochloric acid solution is heated to boiling for 2 hours, cooled and then concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 80° C. 4 g (of the 14.8 g obtained in total) are dissolved in 250 ml of distilled water and the solution is stirred for 16 hours at a temperature in the region of 20° C. The crystals formed are separated out by filtration, washed successively with 25 ml of distilled water and 25 ml of methanol and then air-dried at a temperature in the region of 20° C. The product obtained (3.5 g) is stirred in suspension for 10 minutes in 100 ml of boiling methanol and, after cooling and storing for 1 hour at 5° C., is isolated by filtration, washed with 20 ml of chilled methanol and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 2.1 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one hydrochloride are thus obtained, decomposing without melting at about 240° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 5.70 (broad s, 1H: CH--N+ --Cl-); 7.48 and 7.58 (2t, J=7.5 Hz, 1H each: --H7 and --H8); 7.72 and 8.76 (2s, 1H each: --H of the imidazole); 7.98 and 8.09 (2d, J=7.5 Hz, 1H each: --H6 and --H9); 9.47 (cplx, 3H: N+ H3Cl-); 12.80 (cplx, 1H: --NH--)].
Reaction SMILES: [CH2:1]([C@@H:7]1[C@@H:12]([OH:13])[C:11]([CH3:16])([CH2:14][OH:15])[O:10][C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([C@@H:7]1[C@@H:12]([OH:13])[C:11]([CH3:16])([CH2:14][O:15][S:18]([CH3:17])(=[O:20])=[O:19])[O:10][C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC[C@H]1C(=O)OC(C)(CO)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC[C@H]1C(=O)OC(C)(COS(C)(=O)=O)[C@@H]1O

Procedure:
2-(R)-Hexyl-3-(R)-hydroxy-4-methyl-4-hydroxymethylbutyrolactone (prepared as described in example 7) is reacted with 1 eq. of methanesulfonylchloride and 3 eq. of triethylamine in dry methylene chloride at 0° C. to afford 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-methanesulfonyloxymethylbutyrolactone
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].C1COCC1.[Br:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43](F)[C:42]=1[Cl:49]>CS(C)=O>[Br:40][C:41]1[C:42]([Cl:49])=[C:43]([O:8][C:7]2[C:6]([F:9])=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=2[Cl:1])[CH:44]=[C:45]([Cl:47])[CH:46]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: Fc1cc(Cl)cc(Br)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2Cl)c1F
Temperature: 110 °C
Yield: 50.6 %

Procedure:
6-chloro-2-fluoro-3-methylphenol (3.3 g, 20.55 mmol) and 18-crown-6 (1.086 g, 4.11 mmol) were dissolved in dry DMSO (50 mL) and treated with 20% potassium t-butoxide in THF (11.50 g, 20.55 mmol) for 15 minutes at room temperature. 1-bromo-2,5-dichloro-3-fluorobenzene (7.21 g, 29.6 mmol) was added in one portion and the reaction mixture heated at 110° C. for 3 days at which time LC-MS indicated nearly complete consumption of phenol and formation of a major new product. Addition of water to the reaction mixture resulted in a brown gummy oil which was extracted with EtOAc. The organic phase was isolated, washed with brine four times, dried over MgSO4, filtered and concentrated to dryness to give a brown syrup. This material was filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized from EtOH and a few drops of water. This mixture was cooled in an ice bath, filtered, and the precipitate washed with three portions of cold EtOH to give 2-[(3-bromo-2,5-dichlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (4.0 g, 10.40 mmol, 50.6% yield) as a cream solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (s, 1H), 7.29-7.47 (m, 2H), 6.81 (s, 1H), 2.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].S(OC)(O[CH3:34])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:34])[C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]

Procedure:
3-(4-chloro-3-ethoxycarbonylamino-6-fluoro-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.96 g) was stirred with dimethyl sulfate (0.72 ml) and potassium carbonate (0.33 g) in N,N-dimethylformamide (10 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated to give the title compound (1.1 g, oil).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:32]=2[CH3:46])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[C:20]([C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:2]3[N:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:32]=2[CH3:46])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)nc(Nc2ccc(CCO)cc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCO)cc2)n1
Temperature: 95 °C
Yield: 75.6 %

Procedure:
A mixture of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (1) (1.0 g; 3.11 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (1.5 g; 3.57 mmol), tetrakis(triphenylphosphine)palladium (560 mg; 0.5 mmol), 1N sodium carbonate (8 mL), and 1,2-dimethoxyethane (40 mL) was heated at 95° C. in a sealed pressure vessel for 16 hr. The mixture was cooled to room temperature, treated with water (70 mL) and extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (2×40 mL) and brine (1×40 mL), dried over solid sodium sulfate, and evaporated under reduced pressure. The resulting residue was chromatographed on silica using methanol/CH2Cl2 (1:9) as eluent to provide 1.2 g of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (2) as a light tan solid. MS 511.23 (M+H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:28]O.Cl>CO.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:28][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenyl)piperidine-1-carboxylate (1.26 g, 3.59 mmol) (from example 25, step 1) was dissolved in MeOH (50 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.143 g, 3.59 mmol) dissolved in water (5.00 mL) was added during 5 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.220 mL, 3.59 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 20 min. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (17.93 mL, 107.58 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield trans-methyl 2-(4-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.1 g, 95%) as a brown solid, 1.1 g. MS m/z 321 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([CH:27]([CH:29]4[CH2:31][CH2:30]4)O)=[N:25][N:26]=[C:18]1[C:17](=[O:32])[NH:16]3)=[O:12])[CH2:6][CH2:5]2.ClCCl.C(N(S(F)(F)[F:42])CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([CH:27]([CH:29]4[CH2:31][CH2:30]4)[F:42])=[N:25][N:26]=[C:18]1[C:17](=[O:32])[NH:16]3)=[O:12])[CH2:6][CH2:5]2
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1nnc(C(O)C3CC3)n12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1nnc(C(F)C3CC3)n12
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A mixed solution of 60 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-[cyclopropyl(hydroxy)methyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and 3 mL of dichloromethane was cooled to −70° C., and 100 μL of N,N-diethylaminosulfur trifluoride was added thereto, followed by slowly warming to −20° C. over 4 hours. The reaction liquid was returned to room temperature and stirred overnight. To the mixed liquid were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, followed by extraction with chloroform, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3). To the obtained solid was added 4 mL of methanol, followed by warming and washing. The precipitate was collected by filtration and dried under reduced pressure to obtain 31 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-[cyclopropyl(fluoro)methyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[CH3:29][N:30]([CH:32](OC)OC)[CH3:31]>CN(C=O)C>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[C:3]1[C:2]([N:1]=[CH:29][N:30]([CH3:32])[CH3:31])=[N:20][C:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N=CN(C)C)nc2n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 68 %

Procedure:
To a suspension of 210 mg (1 mmol) of 7-amino-6-(2,6-dichlorophenyl)-2-[3-(diethylamino) propylamino]-pyrido[2,3-d]pyrimidine from Example 20 in 0.8 mL of DMF was added 0.8 mL of DMF dimethyl acetal. The mixture was stirred at room temperature for 5.5 hours, then concentrated in vacuo. The residual oil was distributed between dichloromethane and water. The organic phase was dried over magnesium sulfate, then concentrated to a glass that was crystallized from acetonitrile to give 160 mg (68%) of N'-[6-(2,6-dichlorophenyl)-2-{3-(diethylamino) propylamino}-pyrido[2,3-d]pyrimidin-7-yl]-N, N-dimethylformamidine, mp 100°-104° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([C:18]1[C:13]2[O:12][CH2:11][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Reactant: O=C(Cl)c1ccccc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(=O)c1ccccc1)OC[C@@H]2c1ccc(C(C)C)cc1
Yield: 74 %

Procedure:
Using (+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 37 and benzoyl chloride, the title compound was obtained in the same manner as in Example 38.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ncc(C(F)(F)F)cn4)CC2)C3)CC1
Temperature: 25 °C

Procedure:
A mixture of (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned; 110 mg}, 2-chloro-5-trifluoromethyl-pyrimidine (76 mg), K2CO3 (100 mg), and dimethyl sulfoxide (1.5 mL) is stirred at 110° C. for 3 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 30:70→10:90) to give the title compound. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15](C3CCCCO3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([NH:25][C:40]([C:36]4[O:35][CH:39]=[CH:38][CH:37]=4)=[O:41])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg) in DCM (1 ml) was added DIPEA (131 μl) followed by 2-furancarbonyl chloride (39 mg) (available from ABCR) and the mixture stirred at RT for 1 h, then the solvent was removed. To a mixture of the residue in methanol (2 ml) was added 4M hydrochloric acid in 1,4-dioxane (2 ml) and the mixture stirred at RT for 2 h. Purification of the residue by mass directed preparative HPLC (Method A), followed by freeze drying gave the title compound as an off white solid (13 mg).