Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].OS(O)(=O)=O>S([O-])([O-])(=O)=O.[Ag+2].O>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[Br:1])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Reaction time: 3 h

Procedure:
Bromine (17.4 ml) was added dropwise over 40 min to a stirred mixture of 4-tert-butylnitrobenzene (59.5 g, 332 mmol), silver(II)sulfate (56.5 g, 181 mmol), H2SO4 (300 ml), and H2O (33 ml) at RT. The mixture was stirred for a further 3 h and then poured into 0.1 M Na2S2O5/H2O (1 L). The solid was filtered, washed with H2O, Et2O, and CH2Cl2. The filtrate layers were separated. The aqueous fraction was extracted with Et2O. The combined organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The yellow solid was triturated with hexanes to give a pale yellow crystalline solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:39]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40]>CN(C=O)C.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:48][C:39]([CH3:41])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:40])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccc(Oc2ccccc2)c1)c1ccccc1
Reaction time: 0.08 h
Yield: 97.2 %

Procedure:
3-Phenoxybenzoic acid (3.00 g, 14.0 mmol) was dissolved in DMF (45 mL), and the solution was added with EDCI (4.03 g, 21.0 mmol) and HOBT monohydrate (1.07 g, 7.00 mmol) under ice-cooling, followed by stirring at the same temperature for 5 minutes. Then, the mixture was added with cumylamine (4.03 mL, 28.0 mmol) and stirred at room temperature for 2 hours. The reaction mixture was added with water and 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. The residue was purified by slurry using hexane to obtain 3-phenoxy-N-(1-methyl-1-phenylethyl)benzamide (4.51 g, yield 97%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C([N:27]1[CH2:30][CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][N:33]=2)[CH2:28]1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:27]2[CH2:28][CH:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([I:38])=[CH:34][N:33]=3)[CH2:30]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: Ic1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)nc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(I)cn2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
4-nitrophenyl chloroformate (692 mg g, 3.44 mmol) was added to a stirred solution of 2-(1-Benzhydryl-azetidin-3-yloxy)-5-iodo-pyridine (1.01 g, 2.29 mol) in dichloromethane (40 mL) at ambient temperature. The resulting solution was stirred at ambient temperature for 18 hr. The solvent was removed in vacuo and the product purified by flash chromatography on silica gel (25 g) eluting with dichloromethane to afford the title compound as a colourless solid (474 mg, 47%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>O1CCCC1>[N:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:5]2[C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=[C:4]2[Br:3])=[CH:19][CH:20]=1
Reactant: ClCc1ccncc1
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Br)n(Cc2ccncc2)c1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a suspension of 195 milligrams (mg) (8.13 mM) of sodium hydride in 20 ml of anhydrous tetrahydrofuran was added, in portions, 2 g (8.13 mM) of isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate. The resulting suspension was cooled to 0° C. and 1.03 g (8.13 mM) of 4-chloromethylpyridine was added. The reaction mixture was stirred overnight at 50° C. The precipitated sodium chloride was removed by filtration and concentration in vacuo of the filtrate gave 2.5 g (92%) of isopropyl N-(4-pyridylmethyl)-2-bromo-4-methyl-5-imidazole carboxylate as a tan solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:14]2[CH2:15][NH:16][CH2:17][CH2:18][CH2:19][N:13]2[N:12]=1)=[O:10].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:16]2[CH2:17][CH2:18][CH2:19][N:13]3[N:12]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:20]=[C:14]3[CH2:15]2)=[O:28])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=C(NOC1CCCCO1)c1cc2n(n1)CCCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCCn3nc(C(=O)NOC4CCCCO4)cc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (0.0283 g, 0.101 mmol) and 4-methoxybenzoic acid (0.016 g, 0.105 mmol) in methylene chloride (1 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.0434 g, 0.114 mmol) and N-methylmorpholine (0.0333 mL, 0.303 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride (2 mL) and washed with aqueous NaHCO3 (2 mL). The aqueous layer was extracted with additional methylene chloride (3 mL) and the combined organic layers concentrated to afford Intermediate 30 as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:9][CH2:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl.[Cl:35]CCl>C(O)C>[ClH:35].[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: ClCCl
Reactant: CCOC(=O)C1=CCCN(CCOCCC2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=CCCN(CCOCCC2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester (1.3 g, 3.1 mmol) was dissolved in ethanol (10 ml) and a 4 N sodium hydroxide solution (2.3 ml) was added. The mixture was stirred at room temperature for 4 h. A 4 N hydrochloric acid solution was added until pH 1. Dichloromethane (400 ml) was added and the mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated with acetone, dissolved in acetone (50 ml) and left for crystallization. This afforded 0.45 g of the title compound as a solid.
Reaction SMILES: C1N=C2C(NC(NC2=NC=1)=O)=O.[CH3:13][C:14]1[N:25]=[C:24]2[C:17](=[N:18][C:19]([NH:21][C:22]2=[O:23])=[O:20])[N:16]([CH2:26][C@H:27]([OH:34])[C@H:28]([OH:33])[C@H:29]([OH:32])[CH2:30][OH:31])[C:15]=1[CH3:35].CC(C(O)C[O:41][P:42]([OH:45])([OH:44])=[O:43])=O>>[P:42]([O-:45])([O-:44])([O-:43])=[O:41].[CH3:13][C:14]1[N:25]=[C:24]2[C:17](=[N:18][C:19]([NH:21][C:22]2=[O:23])=[O:20])[N:16]([CH2:26][C@H:27]([OH:34])[C@H:28]([OH:33])[C@H:29]([OH:32])[CH2:30][OH:31])[C:15]=1[CH3:35]
Reactant: CC(=O)C(O)COP(=O)(O)O
Agent: Cc1nc2c(=O)[nH]c(=O)nc-2n(C[C@H](O)[C@H](O)[C@H](O)CO)c1C
Agent: O=c1[nH]c(=O)c2nccnc2[nH]1
Product: O=P([O-])([O-])[O-]

Procedure:
The terms “lumazine synthase” or “LS” are used interchangeably with “6,7-dimethyl-8-ribityllumazine synthase” and refer to a plant or fungal enzyme that catalyzes the condensation of 3,4-dihydroxy-2-butanone 4-phosphate with 4-ribitylamino-5-amino-2,6-dihydroxypyrimidine (RAADP) to yield orthophosphate and 6,7-dimethyl-8-(1′-D-ribityl)-lumazine (DMRL).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[N:18]2[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)([C:22]([NH2:24])=[O:23])[CH2:20][O:21][C:16]3=[C:17]2[C:12](=[CH:13][CH:14]=[CH:15]3)[NH:11]1.C(#N)C>C(O)(=O)C>[Br:1][C:15]1[C:16]2[O:21][CH2:20][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)([C:22]([NH2:24])=[O:23])[N:18]3[C:10](=[O:9])[NH:11][C:12]([C:17]=23)=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)C1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Solvent: CC(=O)O
Solvent: CC#N
Product: NC(=O)C1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
N-Bromosuccinimide (40 mg, 0.2 mmol) was added to a solution of 2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide, acetonitrile (5 mL) and acetic acid (3 mL) and cooled to 0° C. The reaction mixture was stirred for 1 h and then concentrated to remove residual acetic acid. The resulting residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7-bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (0.040 g. 60%). LCMS calculated for C15H12BrN4O3 (M+H)+: m/z=375.1, 377.1. found: 375.0, 376.9.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.CCCCCC>[Si:20]([O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCCCC1CCO
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC1CCCCC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.3 %

Procedure:
In dry DMF (200 ml) was dissolved 2-(2-hydroxyethyl)cyclohexanone (7.86 g) followed by addition of imidazole (9.53 g) and tert-butyldimethylchlorosilane (10 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with hexane (500 ml), washed successively with aqueous sodium hydrogen carbonate, diluted hydrochloric acid, aqueous sodium hydrogen carbonate, and aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was further subjected to vacuum distillation to give 7.55 g of 2-[2-(tert-butyldimethylsilyloxy)ethyl]cyclohexanone as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.COC1N=C([Sn](CCCC)(CCCC)CCCC)C([N+]([O-])=O)=CC=1.FC(F)(F)S(O[C:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[C:48]([O:53][CH3:54])[CH:49]=2)[CH:44]=1)(=O)=O>>[CH3:12][O:11][C:4]1[N:3]=[C:2]([C:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[C:48]([O:53][CH3:54])[CH:49]=3)[CH:44]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: CCCC[Sn](CCCC)(CCCC)c1nc(OC)ccc1[N+](=O)[O-]
Product: COc1ccc2c(c1)CCC(c1nc(OC)ccc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 2-chloro-6-methoxy-3-nitropyridine according to an analogous synthetic method to Preparation Example 76, 6-methoxy-3-nitro-2-tributylstannylpyridine (5.5 g) and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (1.5 g) were used according to an analogous synthetic method to Preparation Example 77 to provide 6-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)-3-nitropyridine (933 mg). This compound (930 mg) was used according to an analogous synthetic method to Example 30 to provide the title compound (340 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[C:7](Cl)[C:6]=1[N+:16]([O-:18])=[O:17])[CH2:2][CH3:3].[NH3:22]>>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]([NH2:22])[C:8]([CH3:14])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:2][CH3:3]
Reactant: N
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(C)c(Cl)c1[N+](=O)[O-]
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C)c(N)c1[N+](=O)[O-]

Procedure:
This compound was prepared in a similar manner by reaction of N,N-di-n-propyl-3-chloro-2,6-dinitro-4-methylaniline with ammonia. The crystalline product melts at 126°-127°C.
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1.Cl[CH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:19][C:17]1[N:18]=[C:8]2[C:7]([NH:6][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][N:9]2[C:16]=1[CH3:20]
Reactant: Cc1ccccc1CCl
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 13.2 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesylate (1.0 g, 2.7 mmol), α-chloro-o-xylene (0.38 g, 2.7 mmol) and diisopropylethylamin (0.76 g, 5.9 mmol) in dimethylformamide (7 ml) were stirred at 50° C. for 7 h and at room temperature for 72 h. The solvent was evaporated and the residue was treated with a mixture of methylene chloride, water and a small amount of diisopropylethylamin. The solid that formed was isolated by filtration and washed with ethylacetate to give 0.11 g (13%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]1([O-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>CS(C)=O>[O:17]([C:2]1[CH:9]=[C:8]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccccc2)cc1Oc1ccccc1

Procedure:
2,4-Dichlorobenzonitrile (12.04 g, 0.07 mole) was treated with 17.8 g sodium phenolate (0.155 mole) in 100 ml DMSO at 100°-110°C during 48 hours under nitrogen and stirring. Then, the DMSO was evaporated and the residue was dissolved in ether. The ether solution was then washed with water. After evaporation of the ether, the product was recrystallized from MeOH. Yield 11.5 g; mp 85°-86°C.
Reaction SMILES: O1[CH:24]2[C:25](=[O:26])[C@:2]31[O:29][C@:3]13[C@:22]([CH3:27])([CH2:23]2)[C@@H:21]2[C@H:6]([C@H:7]3[C@:18]([CH3:28])([CH2:19][CH2:20]2)[C@@H:10]([CH:11]([CH3:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:9][CH2:8]3)[CH:5]=[CH:4]1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH2:44].OO>O1CCCC1>[CH3:16][O:15][CH:12]([O:13][CH3:14])[CH:11]([CH3:17])[C@@H:10]1[C@:18]2([CH3:28])[C@H:7]([C@H:6]3[C@H:21]([CH2:20][CH2:19]2)[C@:22]2([CH3:27])[C@:3]([OH:29])([CH2:2][C@@H:25]([OH:26])[CH2:24][C@@H:23]2[OH:44])[CH:4]=[CH:5]3)[CH2:8][CH2:9]1
Reactant: O
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]45O[C@]46OC(C[C@]5(C)[C@H]3CC[C@]12C)C6=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of tetrahydrofuran was dissolved 8.5 g of the 1α,2α;4α,5α-diepoxy-21,21-dimethoxy-20-methylpregn-6-en-3-one obtained in Example 76, followed by dropwise addition of 100 ml of a 1.0M solution of lithium tri-sec-butylborohydride in tetrahydrofuran under ice-cooling. After completion of dropwise addition, the mixture was stirred at room temperature for 2 hours. The excess reducing agent was decomposed with water and the residual alkylborane was decomposed with alkaline hydrogen peroxide, followed by extraction with ethyl acetate. The extracts were pooled, washed with aqueous sodium chloride solution, and dried over sodium sulfate, followed by concentration under reduced pressure. Recrystallization of the concentrate from ethyl acetate gave 2.90 g of 21,21-dimethoxy-20-methylpregn-6-ene-1α,3β,5α-triol showing the following physical properties.
Reaction SMILES: Cl[C:2]([F:27])([F:26])[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]([O:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:27][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1OC(C)C
Yield: 90.8 %

Procedure:
A mixture of 3.0 g (0.007 mol) of product of Example 12, 0.72 g (0.007 mol) of triethylamine and 0.36 g of Pd/C (10%) in 30 ml of ethanol was hydrogenated with 501 kPa hydrogen pressure at 50° C. for 1 hour and filtered. The filtrate was concentrated, the residue dissolved in ether, washed with 3.7% aqueous HCl, dried (MgSO4) and concentrated in vacuo to 2.74 g of a brown oil. This oil was kugelrohr distilled at 67 Pa, pot temperature 90° C., to give 2.45 g (90.8%) of product as a yellow solid; mp 29°-31° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:9]2[C:8]([N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]3[CH3:1])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=3)[N:10]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCC3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a solution of methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (880 mg, crude) in dioxane (25 ml) was added Pd(PPh3)4 (100 mg, 0.09 mmol), 4-fluorophenylboronic acid (485 mg, 3.47 mmol), K3PO4 (735 mg, 3.46 mmol) and water (3 ml). The resulting solution was stirred for 1 hour at 90° C. under an inert atmosphere of nitrogen, and then concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1%-10% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (330 mg).
Reaction SMILES: I[C:2]1[C:3]([NH2:20])=[N:4][C:5]([S:18][CH3:19])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[NH2:29][C:26]1[N:27]=[CH:28][C:23]([C:21]#[C:22][C:2]2[C:3]([NH2:20])=[N:4][C:5]([S:18][CH3:19])=[N:6][C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:24][CH:25]=1
Reactant: CSc1nc(N)c(I)c(-c2cccc(C(F)(F)F)c2)n1
Reactant: C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nc(N)c(C#Cc2ccc(N)nc2)c(-c2cccc(C(F)(F)F)c2)n1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 850 mg (2.1 mmol) 5-iodo-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine, 1.5 g (12.4 mmol) 5-ethynyl-2-amino-pyridine, 39 mg (0.21 mmol) CuI, 145 mg (0.21 mmol) PdCl2(PPh3)2 and 2.9 mL triethylamine in 15 mL dry DMF. Yield after purification by RP-HPLC: 427 mg (52%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]([NH:53][C:54]2[CH:55]=[C:56]([C:60]3[N:69]=[C:68]([NH:70][C:71]4[CH:72]=[C:73]5[C:77](=[CH:78][CH:79]=4)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]5)[C:67]4[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=4)[N:61]=3)[CH:57]=[CH:58][CH:59]=2)=[O:10])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: O=C(O)CN1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CN5CCOCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-morpholinoacetic acid (16 mg, 0.11 mmol), PyBOP (57 mg, 0.11 mmol), DIEA (96 μL, 0.55 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture and stirred for 1.5 h. Added two more 0.5 equivalents of activated acid while stirring 1.5 hr between each addition. Diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [C:1]([NH:9][OH:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:17]([C:19]([CH2:26][CH3:27])([C:23](Cl)=[O:24])[C:20](Cl)=[O:21])[CH3:18]>C(Cl)Cl>[C:1]([N:9]1[C:20](=[O:21])[C:19]([CH2:26][CH3:27])([CH2:17][CH3:18])[C:23](=[O:24])[O:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: O=C(NO)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1(CC)C(=O)ON(C(=O)c2ccccc2)C1=O
Yield: 72.3 %

Procedure:
A mixture consisting of 1.37 g (0.0100 mol) of benzohydroxamic acid, 10 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round-bottom flask. The mixture was cooled in an ice bath and 2.00 g (0.101 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period. The reaction mixture was stirred for one hour at room temperature after which time all the benzohydroxamic acid had dissolved. The solution was evaporated under reduced pressure, and to the residue was added 100 ml of cold water. The insoluble viscous oil was rubbed with a glass rod to effect solidification. The solid was filtered and dried to give 1.89 g (75.9%) of crude 2-benzoyl-4,4-diethylisoxazolidine-3,5-dione: mp 76-79° C. Recrystallization of 1.72 g of crude isoxazolidine-3,5-dione from 20 ml of absolute ethanol gave 1.56 g of pure 2-benzoyl-4,4-diethylisoxazolidine-3,5-dione: mp 87-88° C. (lit 87-88° C.) G. Zinner and R. Moll, Arch. Pharm., 299. (6), 562-8(1966), CA 65 10575f; IR (Nujol) 1817 (s, C=0), 1762 (s, C=0), 1714 (s, C=0) and 694 (s, aromatic C-H bend) cm-1 ; NMR (acetone-d6) δ 7.46 (m, 5, aromatic C--H), 1.87 (q, 4, CH2), 1.00 (t, 6, CH3).