Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:17][CH2:16][CH2:15]1)[CH2:6]2.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[S:27].O>ClCCl>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[C:11]=2[CH3:14])[CH2:6][C:7]2([CH2:15][CH2:16][CH2:17]2)[CH2:8]1)=[S:27]
Reactant: S=C=Nc1ccccc1Br
Reactant: COc1cc2c(c(C)c1C)NCC1(CCC1)C2
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(c(C)c1C)N(C(=S)Nc1ccccc1Br)CC1(CCC1)C2

Procedure:
To a solution of 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (810 mg) in 4 mL dichloromethane was added 1-bromo-2-isothiocyanatobenzene (525 μL) at room temperature. The mixture was allowed to reflux overnight. Water was used to quench the mixture and EtOAc was used for extraction. The combined organic phases were washed with brine, dried and evaporated. The residue was passed through a column ( dichloromethane:EtOAc=10:2) to give N-(2-bromophenyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-carbothioamide (1.5 g) as a white solid. 1H-NMR (300 MHz, CDCl3) δ=8.54-8.22 (d, J=6.95 Hz, 1H); 7.61-7.39 (m, 2H); 7.38-7.22 (m, 1H); 7.15-6.87 (m, 1H); 6.69 (s, 1H); 5.72-5.38 (d, J=13.1 Hz, 1H); 3.86 (s, 3H); 3.39-3.25 (d, J=13.1 Hz, 1H); 2.85-2.67 (m, 2H); 2.46-2.28 (m, 1H); 2.14 (s, 3H); 2.12 (s, 3H); 2.07-1.79 (m, 3H); 1.79-1.62 (m, 2H) ppm.
Reaction SMILES: [C:1]1(O)[C:5](=[O:6])[C:3](=O)[C:2]=1[OH:7].[NH2:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1>C(O)(C)C>[CH3:16][C:14]1([CH3:17])[CH2:15][CH:10]([NH:9][C+:1]2[C:2]([O-:7])=[C:3]([NH:9][CH:10]3[CH2:11][C:12]([CH3:19])([CH3:18])[NH:13][C:14]([CH3:17])([CH3:16])[CH2:15]3)[C+:5]2[O-:6])[CH2:11][C:12]([CH3:19])([CH3:18])[NH:13]1
Reactant: O=c1c(O)c(O)c1=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CC(C)O
Product: CC1(C)CC(Nc2c([O-])[c+](NC3CC(C)(C)NC(C)(C)C3)[c+]2[O-])CC(C)(C)N1
Yield: 90.4 %

Procedure:
In an autoclave, 114.0 g of quadratic acid (1.0 mole), 390.8 g of 4-amino-2,2,6,6-tetramethylpiperidine (2.5 moles), and 800 cc of isopropanol were heated for five hours to 140° C. and then for 15 hours to 210° C. After cooling, the solid was suctioned off and dried. The thusobtained crude product was eluted three times with boiling methanol, washed with cold methanol, and then exhaustively dried, yielding as the remainder 353.1 g of white crystals (yield: 90.4%, mp>400° C., decomposition).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:4](=[O:21])[CH2:3]1.CC(C1C=C(C(C)C)C(S([N:37]=[N+:38]=[N-:39])(=O)=O)=C(C(C)C)C=1)C>C1COCC1>[N:37]([CH:3]1[C:4](=[O:21])[N:5]([CH2:17][CH:18]2[CH2:19][CH2:20]2)[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[C:2]1=[O:1])=[N+:38]=[N-:39]
Reactant: O=C1CC(=O)N(CC2CC2)c2ccccc2N1CC1CC1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Temperature: -30 °C

Procedure:
For this substrate General Procedure 4-K was modified in the following manner. Initially the product from Step A was suspended (not a solution) in THF at −78° C., and following addition of the KN(TMS)2 solution, this suspension was allowed to warm to −30° C., during which the suspension became a solution, and was re-cooled to −78° C. Upon re-cooling to −78° C. a precipitate began to form, therefore the reaction flask containing the mixture was partially raised above the cooling bath until the internal temperature rose to −50° C.; then the trisyl azide solution was added. The cooling bath was removed and the mixture allowed to warm to −20° C. whereupon the mixture had become a nearly homogenous solution, and the AcOH was added. Then the mixture was treated as described in the general procedure. 3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was purified by trituration with hot to room temperature EtOAc, followed by recrystalization from hot to −23° C. CHCl3/EtOAc/EtOH (5:5:1) and isolated as a white solid.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]([S:11]([CH2:14][S:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)(=[O:17])=[O:16])(=[O:13])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1.O.Cl>ClCCl>[CH2:1]([CH:5]1[CH2:6][CH2:7][CH:8]([S:11]([C:14]([S:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N+:37]=[N-:38])(=[O:13])=[O:12])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCC(S(=O)(=O)CS(=O)(=O)C2CCC(CCCC)CC2)CC1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCC1CCC(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCC(CCCC)CC2)CC1
Reaction time: 0.25 h
Yield: 20.6 %

Procedure:
In 91 g of dichloromethane were dissolved 10.5 g (0.025 mol) of the bis(4-n-butylcyclohexylsulfonyl)methane prepared above and 7.5 g (0.038 mol) of p-toluenesulfonylazide. The solution was cooled on an ice bath, to which 3.7 ml (0.0025 mol) of diazabicyclo[5.4.0]-7-undecene (DBU) was added dropwise at a temperature below 5° C. The solution was ripened at the temperature for 15 minutes, after which 38 g of water and 10 g of 12N conc. hydrochloric acid were added. The organic layer was separated and washed with 50 g of water. The solvent was distilled off in vacuum, leaving an oily matter. It was purified by silica gel column chromatography (using dichloromethane as a developing solvent), obtaining 2.3 g of the desired bis(4-n-butylcyclohexylsulfonyl)diazomethane. The yield was 20%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(C(F)(F)F)cc1)N1CCN(C2CCCC2)CC1
Yield: 51 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (51%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc(Cl)cc1C(=O)OC
Yield: 61 %

Procedure:
To a solution of methyl 2-amino-5-chlorobenzoate (15 g) and triethylamine (12 ml) in methylene chloride (150 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (10 ml). The mixture was stirred at room temperature for further two hours. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and water, followed by drying. The solvent was distilled off to afford a pale yellow crystals (13.4 g, 61%), m.p. 48°-49° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:15]=[C:14]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[N:13]=2)[CH2:8][CH2:7]1.[OH-].[Na+].[C:38](OCC)(=[O:40])C>CN(C)C=O>[O:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([CH:38]=[O:40])=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:15]=[C:14]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)[N:13]=2)[CH2:8][CH2:7]1
Reactant: CCOC(C)=O
Reactant: c1ccc(N2CCN(c3nc(N4CCOCC4)cc(N4CCOCC4)n3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Reaction time: 0.08 h
Yield: 80 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. Phosphorus oxychloride (0.12 ml, 1.3 mmol) was added to dimethylformamide (0.3 ml, 4.0 mmol) at 0 degrees Celsius, and this was agitated for 5 minutes at 0 degrees Celsius. To this solution, 4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was dissolved in dimethylformamide (6 ml) and added, and this was agitated under heating for 1 hour at 100 degrees Celsius. After 2N NaOH solution was added to make the reaction liquid basic, extraction was carried out 2 times with ethyl acetate. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=2:3), and 350 mg of 4,6-dimorpholino-5-formyl-2-(4-phenylpiperazin-1-yl)pyrimidine (yield 80%) was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 142 are shown below.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31]>>[F:24][C:25]1[CH:26]=[C:27]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1ccc(F)c(F)c1
Product: COc1cc2ncn(-c3nc(-c4ccc(F)c(F)c4)c(C(=O)O)s3)c2cc1OC
Yield: 20.8 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3,4-difluorophenylboronic acid (23.7 mg, 0.15 mmol) gave 4-(3,4-Difluoro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (8.7 mg, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (s, 1 H); 8.22-8.32 (m, 1 H); 7.88-8.00 (m, 1 H); 7.80 (s, 1 H); 7.55 (dt, 1 H); 7.39 (s, 1 H); 3.88 (s, 3 H), 3.85 (s, 3 H). MS 418 m/z (M+1 ).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[CH:14]=[C:15]([C:31]([NH:33][CH3:34])=[O:32])[C:16](=[O:30])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:18]=2[CH3:19])=[O:12])=[CH:6][CH:5]=1>C(O)(=O)C.C1COCC1>[Br:1][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:11]([C:13]1[CH:14]=[C:15]([C:31]([NH:33][CH3:34])=[O:32])[C:16](=[O:30])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:18]=1[CH3:19])=[O:12]
Reactant: BrBr
Reactant: CNC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C(=O)C(Br)c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of bromine (30 mg, 19 mmol) in acetic acid—THF was added dropwise to a solution of 5-[(4-chlorophenyl)acetyl]-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (75 mg, 0.162 mmol). After the addition, stirring was continued at RT overnight. The solvents were removed and the residue was purified on an Xterra C8 column using a gradient of acetonitrile/water. Freeze drying of the mixture afforded the title compound (86 mg, 95%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:37][C:38]1[C:43]([NH2:44])=[CH:42][CH:41]=[CH:40][N:39]=1>C(Cl)Cl>[NH2:44][C:43]1[C:38]([NH:37][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])=[N:39][CH:40]=[CH:41][CH:42]=1
Reactant: Nc1cccnc1N
Reactant: O=C(O)CCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1cccnc1NC(=O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[(phenylmethoxy)carbonylamino]butanoic acid (1.1 eq) was dissolved in methylene chloride (0.2M) followed by the addition of 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCA) (1.2 eq) and triethylamine (1.5 eq). The mixture was stirred at room temperature under nitrogen for 30 mins, followed by addition of 2,3-diaminopyridine. The mixture was then stirred at room temperature for 48 hrs., quenched with saturated sodium carbonate and extracted with ether. The organic phase was concentrated in vacuo and chromatographed on silica gel. (10% MeOH/CH2Cl2). EI-MS m/z 329 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]=[O:4])=[O:2].[C:5]1([PH:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[OH:2][CH:1]([P:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:18])[CH:3]([OH:4])[P:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:18]
Reactant: O=[PH](c1ccccc1)c1ccccc1
Reactant: O=CC=O
Solvent: c1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)C(O)C(O)P(=O)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Yield: 90 %

Procedure:
7.73 g of 30% aqueous glyoxal solution (40 mmols glyoxal), 16.17 g (80 mmols) of diphenylphosphine oxide and 40 ml of benzene were introduced into a round bottom flask. The initial pH of the reaction mixture was heated for 30 min with a water bath at 40° C. The precipitated white product was separated by filtration and weighed 16.64 g (90% yield) m.p. 211°-214° C. After recrystallization from dimethylsulfoxide-acetonitrile 3:2, V:V gave a sample of 1,2-dihydroxy-1,2-bis(diphenylphosphinyl)ethane m.p. 216°-217° C. Anal. Calcd for C26H24O4P2 : C, 67.53; H, 5.23. Found: C, 67.42; H, 5.34.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][NH2:25])[O:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][NH:25][S:36]([CH3:39])(=[O:38])=[O:37])[O:15][C:14]3=[O:26])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: NC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(aminomethyl)-4-phenyl-oxazolidin-2-one (14 mg, 0.035 mmol) and triethylamine (0.01 mL, 0.07 mmol) in dichloromethane (0.4 mL) at 0° C. was added mesyl chloride (0.005 mL, 0.05 mmol). The reaction mixture was stirred for 10 min and was then quenched with saturated NaHCO3 aqueous solution. Water and dichloromethane was added and the organic was washed with brine, dried (MgSO4), and concentrated. Purification by prep-LC (10-90% Acetonitrile/water (0.05% ammonium acetate) gave 5 mg (31%). 1H NMR (acetone-d6) δ (ppm) 7.45-7.51 (m, 4H), 7.32-7.42 (m, 5H), 6.94-6.97 (m, 4H), 6.66 (t, 1H, J=6.6 Hz), 5.56 (d, 1H, J=5.6 Hz), 4.51, (dd, 1H, J=10.1, 4.7 Hz), 3.59-3.72 (m, 2H), 3.04 (s, 3H). HPLC-MS calculated C23H21ClN2O5S (M+H+): 473.1, found: 473.1.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Product: CCn1c(=O)ccc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 175 °C
Yield: 49 %

Procedure:
A mixture of 8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (145 mg, 0.61 mmol) and 500 μL of 4-fluoroaniline was heated at 175° C. for 10 minutes. The reaction mixture was cooled to room temperature, and the resultant solid was washed with 1:1 hexane:ethyl acetate. The solid was purified by flash chromatography eluting with ethyl acetate to provide 85 mg (49%) of 8-ethyl-2-(4-fluorophenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 215-217° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].[N-]=C=O>CC#N.C(OCC)(=O)C>[N:22]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=C=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CN1CCCC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol), pyrrolidine (34 μL, 0.403 mmol) and K2CO3 (112 mg, 0.806 mmol) in MeCN (5 mL) was stirred at 50° C. for 18 hrs. HPLC analysis still showed starting material and therefore, the reaction mixture was further stirred at 100° C. for 1 h to afford completion. The mixture was cooled to room temperature and ethyl acetate (20 mL) was added, the organic phase was washed with water (20 mL) and then brine (20 mL), and dried over MgSO4, and solvent evaporated. The resulting oily solid was dissolved in DCM (5 mL) and stirred overnight with polystyrene methylisocyanate (“PS-isocyanate” 276 mg, 0.4 mmol, 1.46 mmol/g) to remove any excess pyrrolidine. The polymer was filtered and the organic phase was remove in vacuo, to afford 2-pyrrolidin-1-yl-N-(3-quinoxalin-2-ylphenyl)acetamide (45 mg, 40% yield). LCMS calculated for C20H20N4O (M+H): 333.41. found 333.21. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.95 (s, 1H), 9.51 (s, 1H), 8.55 (s, 1H), 8.20-8.14 (m, 2H), 8.08-8.02 (m, 1H), 7.95-7.82 (m, 3H), 7.58-7.50 (m, 1H), 3.40 (s, 2H), 2.65-2.55 (m, 4H), 1.85-1.75 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:15]2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:15]2)=[CH:11][CH:10]=1)[CH2:39][C:35]1[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCC1=Cc2ccc(CNCc3ncc[nH]3)cc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCC1=Cc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
The compound (27.3 mg) obtained in Example 11-14 was dissolved in methanol (1.37 ml) and added with sodium cyanoborohydride (9.0 mg) and 1-methyl-2-imidazole carboxaldehyde (11.8 mg). The solution was adjusted to pH 4 by addition of acetic acid, followed by stirring at room temperature for 3 hours. Then, the reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (31.5 mg) of the subject compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=1.Cl[CH2:20][CH2:21][CH2:22][CH:23]([O:29]C(=O)C)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[OH:29][CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21][CH2:20][N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C:3]([OH:2])=[O:18])[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: COC(=O)COc1cccc(CNS(C)(=O)=O)c1
Product: CCCCCC(O)CCCN(Cc1cccc(OCC(=O)O)c1)S(C)(=O)=O

Procedure:
The title compound was prepared from [3-(methanesulfonylamino-methyl)phenoxy]-acetic acid methyl ester (Preparation 10) and acetic acid 1-(3-chloropropyl)-hexyl ester using the alkylation procedure described in U.S. Pat. No. 4,033,996. 1H NMR (CDCl3) δ 7.31-7.26 (m, 1 H), 7.02-6.84 (m, 3H), 4.68 (s, 2H), 4.35 (s, 2H), 3.91-3.89 (m, 1 H), 3.20-3.12 (m, 2H), 2.83 (s, 3H), 1.94-1.92 (m, 1H), 1.79-1.24 (m, 12H), 0.87 (t, 3H); MS 400 (M+ -1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C([Li])CCC.[CH3:21][Sn:22](Cl)([CH3:24])[CH3:23]>CCOCC>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([Sn:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)n1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Sn](C)(C)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
2,6-Di(trifluoromethyl)-4-(trimethylstannyl)pyridine was prepared from 8.7 g 4-bromo-2,6-di(trifluoromethyl)-pyridine, 12.4 ml butyllithium (24M in hexane) and 6 g trimethyltin chloride in 200 ml ether according to the procedure of Example 3, part (g), and was obtained (11 g) as a yellow semi-solid.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2C)[C@H:5]([OH:19])[C@@H:4]1[OH:20].[N:21]1C=CC=C[CH:22]=1.O=S(Cl)Cl>CC#N>[Cl:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[NH:21][CH3:22])[C@H:5]([OH:19])[C@@H:4]1[OH:20]
Reactant: c1ccncc1
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O

Procedure:
Compound 3c was prepared by the same procedure as described for the preparation of 3a using 2c41 (2.9 g, 9.78 mmol), pyridine (1.54 g, 1.57 mL, 19.46 mmol), CH3CN (5 mL), and SOCl2 (5.82 g, 3.56 mL, 48.91 mmol): yield 1.95 g (63%); MS m/z 315 (M+H)+; 1HNMR (DMSO-d6) δ 7.91 (bs, 1H, H-2), 6.78 (q, 1H, 8CH3—NH), 6.50 (bs, 2H, 6-NH2), 5.70 (d, 1H, H-1′, J1′,2′=5.0 Hz), 5.41 (d, 1H, 2′-OH, J2′-2′OH=5.6 Hz), 5.32 (d, 1H, 3′-OH, J3′-3′OH=5.3 Hz), 5.18 (ddd, 1H, H-2′, J1′,2′=5.0 Hz, J2′,3′=5.4 Hz, J2′-2′OH=5.6 Hz), 4.33 (ddd, 1H, H-3′, J2′,3′=5.4 Hz, J3′,4′=4.4 Hz, J3′-3′OH=5.3 Hz), 3.91-4.02 (bm, 2H, H-4′,5′-CH2), 3.76-3.82 (m, 1H, 5′-CH2), 2.88 (d, 3H, 8NH—CH3, J=4.5 Hz).