Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]([CH3:41])=[C:39]2[S:42][C:43]([Sn](CCCC)(CCCC)CCCC)=[CH:44][C:38]2=[N:37]1>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:43]3[S:42][C:39]4[C:38](=[N:37][N:36]([CH3:35])[C:40]=4[CH3:41])[CH:44]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nn(C)c(C)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c2sc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc2nn1C
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (100 mg, 0.200 mmol), 2,3-dimethyl-5-(tributylstannyl)-2H-thieno[3,2-c]pyrazole (176 mg, 0.399 mmol) and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.100 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 2 hours. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 10-60% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (65 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 (d, J=12.38 Hz, 1H), 1.96-2.25 (m, 1H), 2.46 (s, 3H), 3.55-3.71 (m, 1H), 3.82 (d, J=11.87 Hz, 1H), 3.92 (s, 3H), 4.05 (d, J=11.12 Hz, 3H), 4.28-4.38 (m, 1H), 4.40-4.51 (m, 2H), 7.37 (d, J=4.80 Hz, 1H), 7.96 (d, J=4.80 Hz, 3H), 8.63 (s, 1H), 9.26 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H21FN6O2S, 417. found, 417.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:16]=[N:17][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:19][CH:20]=3)[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:25]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:16]=[N:17][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:19][CH:20]=3)[CH2:9][O:10][CH2:11][C:12]([NH2:25])=[N:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)Oc1ccc(C2(c3cccc(Br)c3)COCC(=S)N2)cn1
Reactant: N
Solvent: CO
Product: NC1=NC(c2ccc(OC(F)F)nc2)(c2cccc(Br)c2)COC1
Temperature: 100 °C

Procedure:
A dried pressure tube was charged under an argon atmosphere with a dispersion of 5-(3-bromo-phenyl)-5-(6-difluoromethoxy-pyridin-3-yl)-morpholine-3-thione (1.0 g) in a solution of ammonia (7M) in methanol (30 ml). The tube was sealed and heated at 100° C. for 3 hours. After cooling, the reaction mixture was evaporated to dryness and dissolved in dichloromethane, then loaded onto an SCX-cartridge. A 1:1-mixture of dichloromethane and methanol was passed through the column to remove impurities, and the aminoxazine was eluted with ammonia in methanol (2M solution). The (RS)-5-(3-bromo-phenyl)-5-(6-difluoromethoxy-pyridin-3-yl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as a yellow foam (0.82 g, 83% of theory). MS (ISP): m/z=399 [M+H]+.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:10])([CH:7]([F:9])[F:8])[CH2:5][OH:6].[F:11][C:12]([F:19])([F:18])[C:13]([F:17])=[C:14]([F:16])[F:15].FF>CCOCC.O>[CH:7]([C:4]([CH2:5][O:6][C:14]([CH:13]([C:12]([F:19])([F:18])[F:11])[F:17])([F:16])[F:15])([F:10])[F:3])([F:9])[F:8]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: OCC(F)(F)C(F)F
Agent: FF
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: FC(F)C(F)(F)COC(F)(F)C(F)C(F)(F)F
Yield: 80 %

Procedure:
Into a 3-liter autoclave were poured 84 g (1.35 mol) of KOH, 800 ml of H2O and 600 g (4.5 mol) of 2,2,3,3-tetrafluoropropanol: CHF2CF2CH2OH. Then, 681 g (4.5 mol) of hexafluoropropene: CF2═CFCF3 was introduced thereto. After completion of the reaction, the reaction solution was separated into two layers, and the lower layer was washed with water three times to separate the solution. After that, refining by distillation was carried out, and 1,015 g (3.6 mol) of a fluorine-containing chain ether (B1a): CHF2CF2CH2OCF2CHFCF3 was obtained (yield 80%).
Reaction SMILES: B(Cl)(Cl)Cl.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CO.ClC(Cl)(Cl)[C:22]#[N:23]>C(Cl)Cl>[C:22](#[N:23])[C:7]1[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5]
Reactant: Nc1ccccc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccccc1N
Yield: 46 %

Procedure:
To 2 ml of a solution of 2M of boron trichloride in methylene chloride were added a solution of 0.93 g of aniline in 10 ml of methylene chloride, 1.2 ml of trichloroacetonitrile and 1.2 ml of stannic chloride under ice-cooling. The mixture was refluxed on an oil bath for 24 hr. and poured into a mixture of 16 g of potassium carbonate and 32 ml of methanol under ice-cooling. The mixture was refluxed on an oil bath for 1 hr., filtered to remove the insoluble material and evaporated under reduced pressure. The residue was mixed with water and extracted with ether. The ether layer was washed with dilute HCl, dried over anhydrous magnesium sulfate and evaporated. The residue was purified on a Lobar column. The eluate with 5% ethyl acetate-methylene chloride was evaporated and the residue was recrystallized from ether-petroleum ether to give 0.538 g of anthranilonitrile as crystals melting at 48°-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[N:20]3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([CH2:24][NH2:25])=[N:20]3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncn(Cc2cnc(OC(F)F)c(-c3cccc(Cl)c3)c2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: NCc1ncn(Cc2cnc(OC(F)F)c(-c3cccc(Cl)c3)c2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
To a cooled solution, −78° C., of 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbonitrile (Example 156, 345 mg, 0.95 mmol) in DCM (5 mL) was slowly added diisobutylaluminum hydride (135.64 mg, 0.95 mmol). The mixture was stirred at −78° C. for 1 h. The reaction was quenched with wet sodium sulphate and stirred at room temperature for 30 min. The white aluminum precipitate was filtered and the filtrate concentrated under reduced pressure. Purification (FCC, SiO2, 40-100% EtOAc/DCM, followed by 0-10% MeOH/DCM) afforded the title compound (37 mg, 10%). 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 7.81-7.40 (m, 5H), 5.45 (s, 2H), 3.85-3.82 (m, 2H). [M+H]=366.20.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[CH:19]=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:24]([C:28]1[CH:32]=[C:31]([N:33]=[C:34]=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[C:22]4[NH:21][C:20](=[O:23])[CH:19]=[N:18][C:17]=4[N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)c2ccccc12
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4ncc(=O)[nH]c34)c3ccccc23)n(-c2ccccc2)n1
Yield: 17 %

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a white solid (11 mg, 17%).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]1COCC1.[CH3:10][O:11][C:12]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:13].C[Mg]Br>CCOCC.[NH4+].[Cl-]>[CH3:10][O:11][C:12]([CH:14]1[CH2:19][CH2:18][C:17]([OH:20])([CH3:5])[CH2:16][N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:13]
Reactant: COC(=O)C1CCC(=O)CN1C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOCC
Product: COC(=O)C1CCC(C)(O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Cerium chloride (0.21 g, 0.86 mmol) was dried in vacuo at 90° C. for 1 hour, then at 140° C. for 1.5 hours. After cooling to room temperature, 2.8 mL of THF was added, and the suspension was stirred for 1 hour. 5-Oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.10 g, 0.39 mmol) was added, and the mixture was stirred at 0° C. for 2 hour. Methyl magnesium bromide (0.14 mL of a 3M solution in ether) was added dropwise at −50° C, and the mixture was immediately warmed to room temperature and stirred for 30 minutes. Additional methyl magnesium bromide was added following the preceeding procedure until the reaction was complete as determined by 1H NMR of an aliquot worked up as described below. The mixture was diluted with saturated aqueous NH4Cl, extracted 3 times with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated, affording ca. 0.08 g of crude 5-hydroxy-5-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a colorless oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17]Br.O.Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
Potassium phthalimide (836 mg) was added to a solution of 2-methoxy-5-nitrobenzyl bromide (1.01 g) in dimethylformamide (41 ml) and stirred at room temperature for 10 minutes. Water and 2 N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then, the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was washed successively with ethyl acetate and hexane to give 1.2 g of the titled compound (yield, 94%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH3:18])=[N:12][C:11]=1[NH2:19].N>O1CCCC1>[NH2:19][C:11]1[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[C:13]([CH2:16][O:17][CH3:18])[N:12]=1
Reactant: COCc1ccc(C(=O)OC)c(N)n1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COCc1ccc(CO)c(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103.1 %

Procedure:
To a mixture of lithium aluminum hydride (80%, 220 mg, 4.6 mmol) and tetrahydrofuran (5 mL) was added 2-amino-6-methoxymethyl-nicotinic acid methyl ester (300 mg, 1.5 mmol) described in Manufacturing Example 26-1-4 at 0° C., which was stirred for 20 minutes at the same temperature. An aqueous 28% ammonia solution was added dropwise to the reaction mixture at 0° C. The mixture was warmed to room temperature and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (260 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14](OC)=[O:15].[BH4-].[Na+].CO.O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)Cc1nc(-c2ccccc2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCO
Temperature: 60 °C

Procedure:
Methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (compound [5]; 170 g) obtained in Example 2 was dissolved in tetrahydrofuran (935 mL) and sodium borohydride (27.81 g) was added at room temperature. This suspension was heated to 60° C. and stirred, and methyl alcohol (57.9 mL) was added dropwise over 1 hr. After dropwise addition, the reaction mixture was cooled to room temperature and water (35 mL) was added dropwise. The mixture was stirred at room temperature for 1 hr and filtered to remove solid components. The solid components were washed with tetrahydrofuran and the washing was combined with the previous filtrate, which was followed by concentration under reduced pressure. Ethyl acetate (1 L) was added to the residue and after dissolution, water (1 L) was added for partitioning. The aqueous layer was again extracted with ethyl acetate (0.5 L), and the organic layers were combined and washed successively with saturated sodium hydrogencarbonate solution (1 L) and saturated brine (1 L) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give crude crystals (compound [6]; 149 g). The crystals were recrystallized from a mixed solvent of n-hexane (1 L) and ethyl acetate (0.2 L) to give the title compound (compound [6]; 134 g, yield 89.7%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([S@@:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[N:14]/[S@:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccco1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)/N=C/c1ccco1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
In a round-bottomed flask, furan-2-carbaldehyde (800 mg, 8.33 mmol) was dissolved in THF (20 ml) and (S)-2-methylpropane-2-sulfinamide (1.21 g, 10.0 mmol) and titanium(IV) ethoxide (3.5 ml, 16.7 mmol) were added. The reaction mixture was stirred at room temperature for 5 h then slowly quenched by dropwise addition of brine (5 ml) which resulted in the formation of a thick precipitate. The reaction mixture was diluted with ethyl acetate and stirred vigorously at room temperature for 15 min. The suspension was filtered over Celite and rinsed with ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-25% EtOAc) to give 1.48 g (89%) of (S)-2-methyl-propane-2-sulfinic acid 1-furan-2-yl-meth-(E)-ylideneamide as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:14]=[C:15]1[C:20](=[O:21])[CH:19]2[CH2:22][CH2:23][N:16]1[CH2:17][CH2:18]2.Cl>CC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[CH:9]([CH2:14][CH:15]2[C:20](=[O:21])[CH:19]3[CH2:22][CH2:23][N:16]2[CH2:17][CH2:18]3)[C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: C=C1C(=O)C2CCN1CC2
Reactant: CC(=O)CC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)C(CC1C(=O)C2CCN1CC2)C(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 93.10 g (0.47 mole) 1-(4-chlorophenyl)-1,3-butanedione in 500 ml acetone add 60.0 g (0.39 mole) 2-methylene-3-quinuclidinone. Stir the solution at reflux for about 24 hours. Follow the progress of the reaction by thin-layer chromatography on silica gel (EtOAc:MeOH, 9:1). At the completion of the reaction, chill the solution in an ice/water bath. Acidify dropwise with 35 ml concentrated hydrochloric acid to precipitate the product. Collect the precipitate by filtration to obtain the title compound as a mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-])=O)[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:14])=[C:7]([CH2:15][OH:16])[CH:6]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CCO>[NH2:22][C:19]1[CH:18]=[C:17]([Br:25])[C:3]([O:4][C:5]2[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:14])=[C:7]([CH2:15][OH:16])[CH:6]=2)=[C:2]([Br:1])[C:20]=1[CH3:21]
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(CO)c(O)c(C(C)C)c2)c1Br
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(N)cc(Br)c(Oc2cc(CO)c(O)c(C(C)C)c2)c1Br
Yield: 22 %

Procedure:
A mixture of compound 4-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-hydroxymethyl-6-isopropylphenol of Part 10A (85 mg, 0.18 mmol), Na2S2O4 (467 mg, 2.68 mmol) and EtOH (2 mL) was prepared in a microwave safe reaction vial. After irradiation for 5 minutes at 170° C. a saturated aqueous solution of NaHCO3 (5 mL) was added to the reaction mixture. The organic phase was removed in vacuo and the aqueous phase was extracted with EtOAc and the organic phase was dried over Na2SO4. Concentration in vacuo gave a residue that was purified on column (silica gel, gradient elution: n-heptane/EtOAc from 1:0 to 7:3) to give 18 mg (22%) of 4-(4-amino-2,6-dibromo-3-methylphenoxy)-2-hydroxymethyl-6-isopropylphenol as a light yellow foam.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:7](=[O:21])[CH2:8][N:9]([C:15]([S:17][CH2:18][C:19]#[CH:20])=[O:16])[CH2:10][P:11](Cl)(Cl)=[O:12].C(Cl)Cl.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(OCC)C>[CH3:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:7](=[O:21])[CH2:8][N:9]([C:15]([S:17][CH2:18][C:19]#[CH:20])=[O:16])[CH2:10][P:11]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:12]
Reactant: C1COCCN1
Reactant: C#CCSC(=O)N(CC(=O)OCCOCC)CP(=O)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCSC(=O)N(CC(=O)OCCOCC)CP(=O)(N1CCOCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2-Ethoxy)ethyl-N-[(propargylthio)carbonyl]-N-[dichlorophosphinylmethyl]glycinate (10.5 g.; 0.028 mol.) was dissolved in 50 ml. of diethyl ether and 50 ml. of methylene chloride. To the solution was added a solution of morpholine (9.7 g.; 0.11 mol.) in 100 ml. of diethyl ether. The resulting mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with 3% ammonium hydroxide, brine, 5% hydrochloric acid and again with brine. The ether layer was separated, dried and concentrated in vacuo. The residue was purified using a silica gel column with acetonitrile as the eluent to yield (2-ethoxy)ethyl-N-[(propargylthio)carbonyl]-N-[bis(morpholino)phosphinylmethyl]glycinate, dihydrate as an oil (nD25 =1.5200) having the following analysis:
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[NH:4][CH2:3]1.Br[C:21]1[CH2:25][O:24][C:23](=[O:26])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[K+].[K+].N#N.O>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[OH:1][CH:2]1[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][CH2:11]2)[C:5](=[O:19])[N:4]([C:21]2[CH2:25][O:24][C:23](=[O:26])[CH:22]=2)[CH2:3]1
Reactant: O=C1C=C(Br)CO1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCC2O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(C1=CC(=O)OC1)CC2O
Temperature: 90 °C

Procedure:
To a round bottom flask was charged tert-butyl 4-hydroxy-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (300 mg, 1.11 mmol), 4-bromofuran-2(5H)-one (271 mg, 1.66 mmol), Pd(OAc)2 (24.9 mg, 0.111 mmol), Xantphos (96 mg, 0.166 mmol), and K2CO3 (307 mg, 2.22 mmol). The flask was sealed, vacuumed and back filled with N2 and filled with dioxane (4.5 mL) and H2O (60.0 μL, 3.33 mmol). The reaction mixture was heated at 90° C. overnight, then filtered through CELITE®, and evaporated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM) to give the title compound. LC/MS: [(M+1)]+=353
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]([CH3:25])[CH3:24])[C:11]=2[N:10]=1.[C:26](O)([C:28](F)(F)F)=[O:27]>C(O)(=O)C>[CH2:21]([C@H:13]1[N:12]([CH:23]([CH3:24])[CH3:25])[C:11]2[N:10]=[C:9]([C:8]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[CH2:2][NH:1][C:26](=[O:27])[CH3:28])[N:18]=[CH:17][C:16]=2[N:15]([CH3:19])[C:14]1=[O:20])[CH3:22]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C(C)C
Solvent: CC(=O)O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNC(C)=O)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 102, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 126) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91), and with acetic acid instead of benzoic acid. LCMS (0.05% TFA): 383.2 m/z (M+H)+; 1H-NMR (MeOD, 500 MHz): δ: 8.51 (s, 1H), 8.46 (d, 1H, J=5.0 Hz), 8.04 (s, 1H), 7.84 (d, 1H, J=5.0 Hz), 4.70 (d, 2H, 10.5 Hz), 4.61 (m, 1H), 4.33 (m, 1H), 3.31 (s, 3H), 1.85 (s, 3H), 1.83 (m, 1H), 1.69 (m, 1H), 1.35 (d, 3H, J=6.5 Hz), 1.32 (d, 3H, J=6.5 Hz), 0.77 (t, 3H, J=7.5 Hz).