Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNC(=O)C1C=CC(N2CCC(=O)N(C3C=CC(C#N)=C(C(F)(F)F)C=3)C2=O)=CC=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33].C1CCN2C(=NCCC2)CC1.[NH2:49][C:50]1[CH:59]=[CH:58][C:53]([C:54]([NH:56][CH3:57])=[O:55])=[C:52]([F:60])[CH:51]=1>CS(C)=O>[CH3:57][NH:56][C:54]([C:53]1[CH:58]=[CH:59][C:50]([NH:49][CH2:33][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[CH:51][C:52]=1[F:60])=[O:55]
Reactant: C=CC(=O)OCC
Reactant: CNC(=O)c1ccc(N)cc1F
Agent: CNC(=O)c1ccc(N2CCC(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C2=O)cc1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCNc1ccc(C(=O)NC)c(F)c1
Reaction time: 24 h

Procedure:
Synthesis of N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-2,4-dioxo-tetrahydropyrimidin-1(2H)-yl}benzamide 1.3.2(1), (X═O, R1=CH3). Ethyl acrylate (8 g, 80 mmol) and DBU (0.81 g, 5.4 mmol) were added to a solution of 4-amino-N-methyl-2-fluorobenzamide (9 g, 53.6 mmol) in DMSO (90 ml) and stirring was continued for 24 h at 70° C. (LCMS control). The reaction mixture was subjected to lyophilization, the residue was recrystallized from aqueous alcohol. It gave ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate 5. LCMS (M+H)+ 269. 1H NMR (DMSO-d6, 400 MHz) δ 7.57 (br. s, 1H), 7.48 (t, J=8.8 Hz, 1H), 6.47 (br. s, 1H), 6.42 (d, J=8.8 Hz, 1H), 6.33 (d, J=14.8 Hz, 1H), 4.07 (q, J=7.2 Hz, 2H), 3.32 (br. m, 2H), 2.73 (d, J=4.4 Hz, 3H), 2.55 (t, J=6.4 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H). The solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (425 mg, 1.87 mmol) 3.1 and ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate (500 mg, 1.87 mmol) 5 (R1=CH3) in CH2Cl2 (10 ml) was stirred for 5 h. The reaction mixture was evaporated in vacuo, and the product was isolated by colomn chromatography on SiO2 (eluent—n-hexane:AcOEt:Et3N=1:1:0.03). It gave ethyl N-[4-(methylcabamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]-carbamoyl}-β-alaninate 6(1) (R1=CH3, X═O). LCMS (M+H)+ 481. HCl (2.5 ml) was added to the solution of ethyl N-[4-(methylcabamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]-carbamoyl}-β-alaninate (500 mg, 1.04 mmol) 6(1) in AcOH (5 ml) and the resultant mixture was stirred for 15 h. The reaction mixture was poured into water, the product was extracted with EtOAc. Organic layer was dried over Na2SO4, evaporated in vacuo and by means of colomn chromatography on SiO2 (eluent—n-hexane:AcOEt=1:1) N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-2,4-dioxo-tetrahydropyrimidin-1(2H)-yl}benzamide 1.3.2, (X═O, R1=CH3) was isolated; Ki1.3.2(1)=85.6 nM, LCMS (M+H)+ 435. 1H NMR (DMSO-d6, 400 MHz): δ 8.29 (d, J=7.6 Hz, 1H), 8.23 (br. m, 1H), 8.11 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.67 (t, J=8.4 Hz, 1H), 7.39 (d, J=12.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 4.02 (t, J=6.4 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H), 2.77 (d, J=4.4 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]1([CH2:7][CH2:8][S:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(SCCc2ccccc2)cc1
Yield: 66.8 %

Procedure:
A mixture of 2-phenylethylmercaptan (72.3 mmol, 10.0 g), 4-bromobenzaldehyde (79.6 mmol, 14.7 g) and potassium carbonate (116 mmol, 16 g) were stirred in dimethylformamide (100 ml) at 110° C. for 48 hours. The solution was cooled and diluted with water (200 ml). The aqueous was extracted with ether (3×200 ml) and the combined ether layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified on silica gel using hexane:ethyl acetate (9:1) as eluant to afford 11.7 g (67%) of present title product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][N:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:4](=[O:12])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.BrN1C(=O)CCC1=O>[CH3:1][O:2][N:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][Br:20])[C:4](=[O:12])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CON(C(=O)Oc1ccccc1)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CON(C(=O)Oc1ccccc1)c1ccccc1CBr
Temperature: 25 °C
Yield: 68.6 %

Procedure:
A mixture of 324 g (1.3 mol) of phenyl N-methoxy-N-(2-methylphenyl)carbamate (Example 2b), 258 g (1.45 mol) of N-bromosuccinimide and 1 g of azoisobutyronitrile in 1 l of CCl4 is irradiated using a 300 W UV lamp for about 6 hours, whereby the reaction mixture is heated to boiling. 13 g of N-bromosuccinimide are then added and the mixture is irradiated for a further 8 hours. It is then cooled to room temperature and the precipitated succinimide is filtered off. The organic phase is then extracted with water, dried over MgSO4 and concentrated. The residue crystallizes and is stirred with cyclohexane. 300 g (68%) of the title compound are obtained as a beige solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]([C:26]3[S:30][C:29]([C:31]4([OH:39])[CH2:36][O:35]C(C)(C)[O:33][CH2:32]4)=[N:28][CH:27]=3)[CH:22]=[C:23]([CH3:25])[CH:24]=2)[N:13]=1)(C(C)(C)C)(C)C.Cl>O1CCCC1.CO>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]([C:26]3[S:30][C:29]([C:31]([OH:39])([CH2:36][OH:35])[CH2:32][OH:33])=[N:28][CH:27]=3)[CH:22]=[C:23]([CH3:25])[CH:24]=2)[N:13]=1
Reactant: Cc1cc(Nc2nccc(OCCO[Si](C)(C)C(C)(C)C)n2)cc(-c2cnc(C3(O)COC(C)(C)OC3)s2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nccc(OCCO)n2)cc(-c2cnc(C(O)(CO)CO)s2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.3 %

Procedure:
To a solution of 5-[5-(3-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-2,2-dimethyl-1,3-dioxan-5-ol (185 mg, 0.32 mmol) in tetrahydrofuran (1.6 mL) was added hydrochloric acid (1.0 N, 970 μL, 0.97 mmol) at room temperature. The mixture was stirred at room temperature for 2.5 h, then diluted with methanol, filtered, and purified by reverse phase HPLC (10:90 to 90:10 acetonitrile:water with a 0.1% trifluoroacetic acid modifier). The combined fractions were dried on a lyophilizer, dissolved in methanol, and the TEA salt converted to the free base using StratoSpheres SPE PL-HCO3 MP-Resin (0.9 mmol) cartridges to give 2-[5-(3-{[4-(2-hydroxyethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]propane-1,2,3-triol (75 mg, 0.18 mmol, 56% yield) as a white foam. MS ESI: [M+H]+ m/z 419.1. 1H NMR (500 MHz, DMSO-d6) δ 9.65 (dd, J=4.3, 15.1, 1H), 8.21 (d, J=5.7, 1H), 7.96 (s, 1H), 7.90 (s, 1H), 7.47 (s, 1H), 7.09 (s, 1H), 6.31 (s, 1H), 4.39 (s, 2H), 3.79-3.72 (m, 2H), 3.72-3.63 (m, 4H), 2.30 (s, 3H). rhSYK activity=+++
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].[CH3:19][C@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:21]1([C@@H:20]([NH:27][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]2[C:15]([O:17][CH3:18])=[O:16])[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
1-tert-Butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (13.29 g, 51.6 mmol, 1 eq.), (S)-(−)-α-methylbenzylamine (6.66 mL, 51.6 mmol, 1 eq.), acetic acid (5.91 mL, 103.0 mmol, 2 eq.) and benzene (200 mL) were mixed at room temperature then refluxed using a Dean-Stark trap for 4 hours. Cooled to 0° C. Added acetic acid (23.66 mL, 412.8 mmol, 8 eq.) followed by the addition of sodium triacetoxyborohydride (21.90 g, 103.0 mmol, 2 eq.). Stirred for 20 minutes at 0° C. then allowed the reaction to warm to room temperature and stirred for 20 hours. Worked up by carefully (foaming) adding sodium carbonate until the pH=10. Extracted the aqueous 3 times with ethyl acetate. The ethyl acetate layers were combined, rinsed once with brine, then dried over sodium sulfate and stripped to give (3R,4S)-1-tert-butyl 3-methyl 4-((1S)-1-phenylethylamino)-piperidine-1,3-dicarboxylate (18.7 g) of an oil as product. Yield=100%. Mass Spec (ESI) detects (M+H)+=363.2.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].C(N(C(C)C)C(C)C)C.[C:19]([O:23][C:24](=[O:39])[NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH3:34])[C:30]2[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=2[NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:19]([O:23][C:24](=[O:39])[NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH3:34])[C:30]2[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=2[N:28]([S:2]([CH3:1])(=[O:5])=[O:3])[CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(S(C)(=O)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
A mixture of 623 mg (3.4 mmol) of methanesulfonic acid anhydride and 0.12 ml (0.7 mmol) of N-ethyl-diisopropylamine was cooled to 0° C. and treated with a solution of 200 mg (0.7 mmol) of (S)-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 2 ml of dichloromethane. The reaction mixture was left to warm to room temperature and stirred during 18 h. For the working-up, the reaction mixture was cooled to 0° C. and treated with a saturated solution of sodium carbonate. The organic layer was separated, washed with a saturated solution of ammonium hydrochloride and water, finally dried over sodium sulphate and evaporated. For purification, the crude material was chromatographed on silical gel using a 96:4-mixture of dichloromethane and ethyl acetate as the eluent. There were obtained 100 mg (40% of theory) of the ((S)-5-methanesulfonyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester as a white foam;
Reaction SMILES: N1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])N=1.[C:12]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1>C1(C)C=CC=CC=1>[C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1nccnn1
Reactant: O=C1CCCC1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nccc2c1CCC2
Yield: 23.1 %

Procedure:
Ethyl 1,2,4-triazine-3-carboxylate (7 g, 45.8 mmol), cyclopentanone (4.9 mL, 55.0 mmol), and pyrrolidine (4.6 mL, 55.0 mmol) in toluene (100 mL) were heated to reflux for 12 h. The mixture was purified by column on silica gel chromatography (PE/EtOAc=5:1) to give the title compound (2.02 g, 25%) as a brown oil. LCMS: 192 (M+1)+
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([O-:16])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[C:4]1([CH2:3][CH2:2][CH2:10][C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CCCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 72 %

Procedure:
The above mentioned ester (13 g) was dissolved in chloroform (200 ml). This solution was added dropwise to the solution obtained by dissolving L-phenylalanine (16.5 g) and Na2CO3 (15.9 g) in water (150 ml) while stirring at room temperature. After that, the mixture was stirred for 7 hours and the insoluble matter thus produced was removed by filtration. The filtrate was acidified to pH 1.0 with 6N HCl. The precipitated crystals were filtered, washed with water, and re-crystallized from 90% aqueous methanol to obtain N-(4-phenylbutyroyl)-L-phenylalanine (11.2 g) having melting point: 178° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[C:4]([CH2:13][CH3:14])[CH:3]=1.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].O>CN(C=O)C.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>[CH2:17]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[C:4]([CH2:13][CH3:14])[CH:3]=1)[CH:16]=[CH2:15]
Reactant: CCOCOc1ccc(Br)cc1CC
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1ccc(OCOCC)c(CC)c1
Temperature: 120 °C

Procedure:
15 g (58 mmol) of 4-bromo-1-ethoxymethoxy-2-ethylbenzene are dissolved in 150 ml of DMF. 26.9 ml (87 mmol) of allyltributyltin are added, and then the mixture is degassed with a nitrogen stream. 1.2 g (1.8 mmol) of dichlorobis (triphenylphosphino)palladium are added, and the medium is heated at 120° C. for 10 hours. The reaction medium is poured into water, and then extracted with ethyl acetate. The residue obtained after drying and concentration is purified by chromatography on a silica column (eluent heptane, and then heptane 95/ethyl acetate 5). A yellow oil is obtained (m=13.6 g, y=100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH2:13]([CH:15]([C:21]([CH3:23])=O)[C:16](OCC)=[O:17])[CH3:14]>>[CH2:21]([C:15]1[C:16](=[O:17])[N:6]2[C:5]([CH3:7])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:3][C:2]2=[N:1][C:13]=1[CH3:14])[CH3:23]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: CCOC(=O)c1sc(N)nc1C
Product: CCOC(=O)c1sc2nc(C)c(CC)c(=O)n2c1C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-amino-4-methyl-thiazole-5-carboxylic acid, ethyl ester (10 g) was reacted with ethyl 2-ethyl-acetoacetate (17 g) in polyphosphoric acid (50 g) under stirring at 100° C. for 4 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered, washed with water until neutral and crystallized from hexane to give 6-ethyl-3,7-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, ethyl ester, m.p. 122°-124° C. (9.9 g) which was reacted with N-bromo succinimide (13.75 g) in benzene (260 ml) at the reflux temperature for 11 hours.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][C:7]1=[O:20].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[O:20]=[C:7]1[CH2:8][C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:6]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)N1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
1(b) 17.4 g of diethyl 1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4,4-dicarboxylate (prepared as described above) were dissolved in a mixture of 350 ml of acetonitrile and 350 ml of water. 11.2 g of potassium persulfate and 37.4 g of dibasic potassium phosphate were then added to the resulting solution, and the mixture was stirred at 65° C. for 1 hour. At the end of this time, insoluble materials were filtered off and the filtrate was freed from the solvent by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, with an aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, eluted with a 1: 2 by volume mixture of ethyl acetate and benzene, to give 5.72 g of diethyl 2-oxoazetidine-4,4-dicarboxylate.
Reaction SMILES: CC(C)([O-])C.[K+].[P:7]([O-:24])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl>CN(C=O)C.C1COCC1>[CH2:36]([P:7]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:24])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CCCCCCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of potassium t-butoxide (6.16 g, 55 mmol), in dry DMF (50 mL), under an argon atmosphere was added dropwise via syringe a solution of dibenzyl phosphite (13.1 g, 50 mmol) in dry DMF (5 mL), and the reaction mixture was stirred at room temperature for 20 min. Then a solution of lauryl bromide (18.6 g, 75 mmol) in dry THF (15 mL), was added dropwise under argon atmosphere, and the mixture was stirred at room temperature for an additional 1 h. After completion of the reaction, the mixture was neutralized with dilute HCl (40 mL) and extracted with ethyl acetate (200 mL), the organic phase was dried, concentrated, and purified by flash chromatography to afford the pure dibenzyl phosphate 14 as a colorless oil (Rf 0.46, silica, ethyl acetate and hexane, 1:2, 10.5 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13].[N+]([O-])([O-])=O.[K+]>OS(O)(=O)=O.O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1nccc2ccccc12
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-chloroisoquinoline (3.6 g, 22.09 mmol) in conc. H2SO4 (24 mL) was added conc. HNO3 (8 mL) drop wise at 0-5° C. Then KNO3 (2.90 g, 28.71 mmol) was added to the reaction mixture portion wise at 0-5° C. The reaction mass was stirred at rt for 2 h and diluted with water then the reaction mixture was filtered. The filter cake was dissolved in 5% methanol in chloroform and was dried over Na2SO4. The organic layer was filtered and concentrated to afford 4.0 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.74 (t, J=6.9 Hz, 2H), 8.55 (d, J=6.3 Hz, 1H), 8.32 (d, J=6.0 Hz, 1H), 8.02 (t, J=8.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH:15]([CH3:17])[CH3:16])[C:5]2=[O:18].CC(O)=O.[Cl:23][C:24]1[C:29]([CH:30]=O)=[C:28]([O:32][CH3:33])[N:27]=[CH:26][CH:25]=1>CO>[Cl:23][C:24]1[CH:25]=[CH:26][N:27]=[C:28]([O:32][CH3:33])[C:29]=1[C:30]1[NH:11][C:10]2=[CH:9][C:8]3[C:7](=[O:14])[N:6]([CH:15]([CH3:17])[CH3:16])[C:5](=[O:18])[C:4]=3[CH:3]=[C:2]2[N:1]=1
Reactant: COc1nccc(Cl)c1C=O
Reactant: CC(C)N1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)C)C3=O
Temperature: -50 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a suspension of 5-amino-2-isopropyl-6-nitroisoindoline-1,3-dione (0.37 g) in 250 mL of MeOH was added 5 mL of AcOH. The resulting solution was degassed with argon and then charged with 10% Pd/C (0.12 g, 50% wet) and hydrogenated at 40 psi of hydrogen for 16 h. Another 2 mL of AcOH was added to the mixture and then solids were filtered off. The filtrate was cooled to −50° C. and a solution of 4-chloro-2-methoxynicotinaldehyde (0.31 g, 1.78 mmol) in 200 mL of MeOH was added dropwise under inert atmosphere. The resulting solution was allowed to warm up to rt and stirred for 16 h. Solvent was evaporated and the oily residue was purified by column chromatography (7.5% MeOH in dichloromethane) to give title compound as a solid (0.23 g, 29.3%). 1H NMR (500 MHz, CDCl3) δ58.18 (s, 1H), 8.12 (d, 1H), 8.03 (s, 1H), 7.90 (d, 1H), 6.92 (d, 1H), 6.75 (d, 1H), 5.39 (s, 2H), 4.56 (p, 1H), 3.72 (s, 3H), 3.61 (s, 3H), 1.50 (d, 6H). ESI MS: m/z 371.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:43][C:44]1[CH:68]=[CH:67][C:47]2[CH2:48][CH2:49][C:50]3[C:51]([C:64]([NH2:66])=[O:65])=[N:52][N:53]([C:55]4[CH:63]=[CH:62][C:58]5[O:59][CH2:60][O:61][C:57]=5[CH:56]=4)[C:54]=3[C:46]=2[CH:45]=1>CN(C=O)C>[O:59]1[C:58]2[CH:62]=[CH:63][C:55]([N:53]3[C:54]4[C:46]5[CH:45]=[C:44]([NH:43][C:5](=[O:7])[C:4]6[C:8]([Cl:11])=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=6)[CH:68]=[CH:67][C:47]=5[CH2:48][CH2:49][C:50]=4[C:51]([C:64]([NH2:66])=[O:65])=[N:52]3)=[CH:56][C:57]=2[O:61][CH2:60]1
Reactant: O=C(O)c1cc(Cl)ncc1Cl
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(N)cc1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
2,5-Dichloroisonicotinic acid (1.65 g, 0.0086 mol), HATU (3.27 g, 0.0086 mol) and finally Et3N (2.32 mL, 0.0166 mol) were added to a solution of the title compound of step 4 of Example 161 (2 g, 0.00574 mol) in 29 mL of DMF. The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was confirmed by monitoring the disappearance of the title compound of step 4 of Example 161 in LC/MS. The crude reaction mixture was concentrated to about 10 mL of DMF. Upon addition of water to this DMF residue, a white solid was formed. This white solid was triturated in water for 20 min and filtered. The solid was collected, dissolved in THF, and dried with MgSO4. Removal of the solvent afforded a brown solid that was triturated in warm CH3CN (80° C.) to give 2.2 g of the title compound (yield 73%). Mp: 292-293° C. 1H NMR (300 MHz, d6-DMSO): δ 2.90-2.92 (m, 4H), 6.09 (s, 2H), 6.94-7.04 (m, 2H), 7.12 (d, 1H, J=2 Hz), 7.26-7.38 (m, 4H), 7.51 (s, 1H), 7.81 (s, 1H), 8.61 (s, 1H), 10.54 (s, 1H). M+1=523.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (example 149) (115 mg, 0.279 mmol) and triethylamine 0.558 mmol) in anhydrous DMF (2 ml) was stirred at RT for 1 hour. After this time, isobutyryl chloride (35 μl, 0.335 mmol) was added and stirring was continued at RT overnight. The reaction was partitioned between water and EtOAc and the aqueous phase was extracted into EtOAc. The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo. The sample was then purified via preparative HPLC at low pH to yield the title compound (60 mg, 45%).