Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>C1COCC1>[CH3:30][N:31]([CH3:35])[C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2
Reactant: CN(C)C(=O)Cl
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NC(=O)N(C)C)c3C2=O)ccc1OC
Yield: 34.3 %

Procedure:
A solution of (3R)-3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-ethoxy-4-methoxy-phenyl)-N,N-dimethyl-propionamide (1.1 g, 2.8 mmol) and dimethylcarbamyl chloride (0.5 mL, 5.4 mmol) in THF (5 mL) was heated to reflux for 2 days. The solvent was removed in vacuo to give a solid, which was purified with prep HPLC to give (3R)-3-[7-(3,3-dimethyl-ureido)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (450 mg, 34% yield): mp 105-107° C.; 1HNMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH3), 2.90 (s, 3H, CH3), 3.05 (dd, J=6, 16 Hz, 1H, CHH), 3.09 (s, 9H,3CH3), 3.46 (dd, J=9.15 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.07 (q, J=7 Hz, 2H, CH2), 4.22 (d, J=17 Hz, 1H, NCHH), 4.41 (d, J=17 Hz, 1H, NCHH), 5.63 (dd, J=6, 9 Hz, 1H, NCH), 6.91-6.96 (m, 4H, Ar), 7.39 (t, J=8 Hz, 1H, Ar), 8.30 (d, J=8 Hz, 1H, Ar), 9.99 (s, 1H, NH); 13CNMR (CDCl3) δ 14.76, 35.57, 36.31, 36.38, 37.45, 48.70, 53.35, 55.97, 64.53, 111.46, 112.63, 115.07, 116.27, 117.57, 119.16, 131.90, 133.02, 139.61, 141.54, 148.55, 149.08, 155.49, 149.69, 170.15. Analy. Calculated for C25H32N4O5+1.2H2O: C, 61.26; H, 7.07; N, 11.43; H2O, 4.41. Found: C, 60.89; H, 6.95; N, 11.10; H2O, 4.04.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14].N1C=CC=CC=1>ClCCl>[C:1]([O:14][CH2:13][CH:11]1[CH2:10][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CO1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCC1CO1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
Benzoyl chloride (1.2 mL, 10.0 mmol) was added to a solution of glycidol (0.67 mL, 10.0 mmol) and pyridine (0.81 mL, 10.0 mmol) in anhydrous dichloromethane at 0° C. The reaction mixture was further stirred at 0° C. for 60 min. The reaction mixture was then concentrated to dryness under reduced pressure, diluted with ethyl acetate, and washed with 10% citric acid twice followed by the addition of a saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4 and concentrated to dryness to yield 1.8 g (100%) of Oxiran-2-ylmethyl benzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CCO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1cc(N2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 4,6-dichloropyrimidine (1.0 equiv.) in EtOH (0.44 M) was added morpholine (1.0 equiv.) followed by triethylamine (1.10 equiv.). The resulting mixture was stirred at RT for 16 hours. The reaction mixture was then concentrated in vacuo and dried under high vacuum over 20 h to yield 4-(6-chloropyrimidin-4-yl)morpholine as a white solid in 93% yield. LCMS (m/z) (M+H)=200.0/201.8, Rt=0.35 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.53-3.71 (m, 4H) 3.72-3.83 (m, 4H) 6.51 (s, 1H) 8.39 (s, 1H) 11.75 (br. s., 1H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)C1C=CC=CC=1)([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:3](=[O:4])[CH2:2][Br:1])([CH3:8])[CH3:7]
Reactant: COc1cccc(N(c2ccccc2)C(C)C)c1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(N(C(=O)CBr)C(C)C)c1
Reaction time: 8 h

Procedure:
Bromoacetyl bromide (8.76 mL) in methylene chloride (100 mL) is added dropwise to a 0° C. solution of N-Isopropyl-N-(3-methoxy-phenyl) aniline, prepared as in Part A, (16.22 g, 98.3 mmol) in methylene chloride (200 mL) and triethylamine (13.8 mL) and the resultant mixture is allowed to attain RT overnight. The reaction mixture is washed with 1N hydrochloric acid (3×100 mL), water (2×100 mL), brine (100 mL), dried (MgSO4), and concentrated in vacuo to afford N-Isopropyl-N-(3-methoxy-phenyl) bromoacetamide(23.16 g) as a dark mobile oil which is used without further purification: 1H NMR (300 MHz, CDCl3) δ7.38 (t, 1H, J=8.0), 7.01 (dd, 1H, J=8.1, 2.2), 6.81(d, 1H, J=7.6), 6.79 (s, 1H), 4.95 (m, 1H, J=6.8), 3.88 (s, 3H), 3.60 (s, 2H), 1.06 (d, 6H, J=6.8).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH3:23][O:24][CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:36]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([CH2:25][O:24][CH3:23])=[CH:27][CH:28]=2)=[O:37])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: COCc1ccc(C(=O)O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: COCc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) were added 4-((methyloxy)methyl)-1-naphthalenecarboxylic acid (207 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) and recrystallized from ethyl acetate-hexane to give the title compound (340 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[C:5]([O:7]CC)=[O:6].CO.[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(C)c1C(=O)O

Procedure:
A mixture of ethyl 2-methoxy-6-methylbenzoate (5.0 g, 25 mmol), water (10 ml), methanol (40 ml) and sodium hydroxide (2.1 g, 50 mmol) is heated under reflux with stirring. The reaction mixture is diluted with water (150 ml) and acidified with concentrated hydrochloric acid. The solid material is collected by filtration, washed with water and dried yielding dark yellow crystals, 2.1 g, mp 136° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:9]1[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH3:15])[CH:14]=1>CN(C=O)C.[Cl-].[Na+].O>[CH3:15][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[N+:16]([O-:18])=[O:17])[O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1cccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cccnc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Rinse 35% oil dispersion of KH (12 g, 11 mmol) with 100 mL hexanes twice and dry under vacuum before cooling in an ice bath. Add 100 mL dry DMF then a solution of 3-hydroxypyridine (10 g, 105 mmol) in 100 mL DMF dropwise. Treat with a solution of 5-fluoro-2-nitrotoluene (16.3 g, 105 mmol) in 50 mL DMF to obtain a dark solution. Stir at ambient temperature for 1 hour, pour the mixture into 1 liter of brine and extract twice with 200 mL of EtOAc. Combine the extracts and wash twice with 500 mL brine, dry over MgSO4 and concentrate to 24 g of a dark oil. Purification by chromatography 20% EtOAc in hexanes give the title compound as an oil: ISMS 231 (M+1); C12H10N2O3: calcd: C, 62.61; H, 4.38; N, 12.17. found: C, 62.63; H, 4.58; N, 12.06.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:13]N1C(=O)CCC1=O.C(=[N:28][C:29]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:30]=1[C:31]#[N:32])C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[NH2:28][C:29]1[CH:36]=[C:35]([CH2:37][Br:13])[CH:34]=[CH:33][C:30]=1[C:31]#[N:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(N=Cc2ccccc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1N
Yield: 47.2 %

Procedure:
2.2′-Azobisisobutyronitrile (AIBN) (1.31 g, 8 mmol) is added to a solution of N-bromosuccinimide (6.87 g, 38 mmol) and 2-benzylideneamino-4-methylbenzonitrile (7 g, 31.8 mmol) in carbon tetrachloride (250 mL), and the reaction mixture refluxed under nitrogen overnight. The reaction mixture is cooled and filtered through a plug of celite, and the celite washed with carbon tetrachloride (100 mL). The combined filtrate is washed with 1N HCl, saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The crude product is purified by column chromatography on silica with 10-20% ethyl acetate/hexanes. The combined product fractions are concentrated, and the resulting sticky solid is washed with ethyl ether/hexanes to give the product as a pale yellow solid (3.26 g, 15 mmol).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OCc2ccccc2)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 81.4 %

Procedure:
A mixture of 6.06 g (0.02 mol) of product of Example 3, 16 g of benzyl bromide, 3 g of potassium carbonate and 50 ml of acetone was held at reflux for 2 hours and concentrated. The residue was treated with water and extracted with ether. The ether solution was dried and concentrated. The residue was kugelrohr distilled at 13 Pa (pot temperature 50° C.) to remove excess benzyl bromide. The residue was crystallized from hexane to give 6.4 g (81%) of product; mp 56°-58.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (13.52 g) and piperazine (11.89 g) were dissolved in DMF (100 mL), and to the solution potassium carbonate (15.89 g) was added. The mixture was stirred at room temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, chloroform was added to the residue, and the mixture was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1 to chloroform:ammonia-saturated methanol=10:1) to obtain a free base of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]=1[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1>[C:17]1([N:16]2[C:12]3[C:9](=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:15]=[CH:14][CH:13]=3)[CH2:10][NH:11][C:23]2=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1c(Nc2ccccc2)cccc1Oc1ccccc1
Solvent: C1CCOC1
Product: O=C1NCc2c(Oc3ccccc3)cccc2N1c1ccccc1
Temperature: 25 °C

Procedure:
The product of example 1c above, 2-phenoxy-6-(phenylamino)benzyl amine, (0.165 g 0.57 mmol) was dissolved in dry tetrahydrofuran (5 mL) and stirred under argon at room temperature. 1,1′-Carbonyldiimidazole (0.120 g, 0.74 mmol) dissolved in dry tetrahydrofuran (2 mL) was added and the mixture stirred at room temperature. The solvent was evaporated in vacuo, to give the crude product which was flash chromatographed on silica gel eluted with 0–2% methanol in methylene chloride to give to the title compound as a white amorphous solid. mp 225–227° C.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=2)O1>>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(Br)n2)cc1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)Cc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 3 using 3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C1b) and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (C2) and isolated as a white solid (2.3 g, 81%): 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.23-8.16 (m, 2H), 8.08 (d, J=8.2 Hz, 2H), 8.03-7.96 (m, 2H), 7.49-7.38 (m, 2H), 3.78 (s, 2H), 3.65 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −60.82; ESIMS m/z 362 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH:11]=[C:10]([CH:12]=O)[N:9]=[CH:8]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH:11]=[C:10]([CH:12]=[CH:22][CH:23]=[O:24])[N:9]=[CH:8]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cn(-c2ncccn2)cn1
Product: O=CC=Cc1cn(-c2ncccn2)cn1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 1-(2-pyrimidinyl)-1H-imidazole-4-carboxaldehyde (prepared as described in Reference Example 10) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 201 (M+H)+.
Reaction SMILES: O[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:16]([C:18]([OH:20])=[O:19])[NH2:17].[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>>[C:21]1(=[O:26])[N:17]([CH:16]2[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[CH3:15])[C:2]=3[O:20][C:18]2=[O:19])[C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccccc1Oc1cccc(C(N)C(=O)O)c1O
Product: Cc1ccccc1Oc1cccc2c1OC(=O)C2N1C(=O)c2ccccc2C1=O
Temperature: 200 °C
Yield: 12.1 %

Procedure:
A mixture of 2-[2-hydroxy-3-(o-tolyloxy)phenyl]glycine (10.6 g) and phthalic anhydride (5.7 g) was heated in an oil bath (200° C.) for 5 minutes. After cooling, the reaction mixture was subjected to column chromatography on silica gel (280 g) and eluted with benzene to give 3-phthalimido-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (1.8 g). mp 168°-170° C.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:14]>C1(C)C=CC=CC=1>[Br:14][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][CH2:12][OH:13]
Reactant: Br
Reactant: OCCC(CCO)c1ccccc1
Solvent: Cc1ccccc1
Product: OCCC(CCBr)c1ccccc1
Temperature: 180 °C

Procedure:
3-Phenylpentane-1,5-diol (452 mg, 2.51 mmol) was dissolved in 48% aqueous hydrobromic acid (284 μL, 2.51 mmol) and toluene (2.5 mL), placed in a sealed tube, and heated in a microwave oven at 180° C. for 10 minutes. The mixture was cooled and purified by column chromatography on silica gel, eluting with 0-100% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.57 (br s, 1H), 1.81-1.97 (m, 2H), 2.08-2.23 (m, 2H), 2.97 (quintet, J=5.0 Hz, 1H), 3.06-3.14 (m, 1H), 3.24-3.31 (m, 1H), 3.42-3.49 (m, 1H), 3.49-3.56 (m, 1H), 7.17-7.25 (m, 3H), 7.28-7.33 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][NH:7][C:6]2=[N:10][CH:11]=[CH:12][C:5]=12.[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C)C(=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc[nH]c2nccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (36.141 g, 903.62 mmol) in N,N-dimethylacetamide (118 mL) at −5° C. (ice/salt bath) was added a dark solution of 4-chloropyrrolo[2,3-d]pyrimidine (119.37 g, 777.30 mmol) in N,N-dimethylacetamide (237 mL) slowly. The flask and addition funnel were rinsed with N,N-dimethylacetamide (30 mL). A large amount of gas was evolved immediately. The mixture became a slightly cloudy orange mixture. The mixture was stirred at 0° C. for 60 min to give a light brown turbid mixture. To the mixture was slowly added [2-(trimethylsilyl)ethoxy]methyl chloride (152.40 g, 914.11 mmol) and the reaction was stirred at 0° C. for 1 h. The reaction was quenched by addition of 12 mL of H2O slowly. More water (120 mL) was added followed by methyl tert-butyl ether (MTBE) (120 mL). The mixture was stirred for 10 min. The organic layer was separated. The aqueous layer was extracted with another portion of MTBE (120 mL). The organic extracts were combined, washed with brine (120 mL×2) and concentrated under reduced pressure to give the crude product 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine as a dark oil. Yield: 85.07 g (97%); LC-MS: 284.1 (M+H)+. It was carried to the next reaction without purification.
Reaction SMILES: O.[NH:2]([CH2:7][C:8]([O-:10])=[O:9])[CH2:3][C:4]([O-:6])=[O:5].[Na+].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>O>[CH2:17]([O:16][C:14]([N:2]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4]([OH:6])=[O:5])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])CNCC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN(CC(=O)O)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 81.1 %

Procedure:
Disodium iminodiacetate monohydrate (11.7 g, 0.060 m) was dissolved in water (40 ml) and cooled to 0°. Benzyl chloroformate (13.3 g, 0.078 m) was added in portions as the pH of the solution was kept at 9-12 by addition of 2N sodium hydroxide solution as needed. When addition was complete the mixture was stirred an additional 3 hours at 0°-10° C., then extracted with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to give 13.0 g (81%) of N-benzyloxycarbonyliminodiacetic acid (V-C).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:19][O:18][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:21]3[S:20][CH:24]=[CH:23][N:22]=3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2nccs2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.52 min.; [M+H]+: 409.72 g/mol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14](=[NH:16])[CH3:15])(=[O:12])=[O:11])[CH:6]=[C:7]([I:9])[CH:8]=1)#[N:2].N[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClC1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14](=[N:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:15])(=[O:12])=[O:11])[CH:6]=[C:7]([I:9])[CH:8]=1)#[N:2]
Reactant: CC(=N)NS(=O)(=O)c1cc(I)cc(C#N)c1
Reactant: Nc1ccccc1
Solvent: Clc1ccccc1
Product: CC(=Nc1ccccc1)NS(=O)(=O)c1cc(I)cc(C#N)c1

Procedure:
A solution of 367 mg. (1 mmole) of N-(3-cyano-5-iodophenylsulfonyl) acetamidine in 10 ml. of chlorobenzene is heated with 205 mg. (2.2 mmoles) of aniline and the reaction mixture heated to reflux for 3 hours. The reaction mixture is cooled in an ice bath and filtered to remove the precipitate of aniline hydrochloride. The filtrate is treated with hexane affording crystalline N-(3-cyano-5-iodophenylsulfonyl)-N'-phenyl acetamidine.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH2:17][CH2:16][NH:15][CH2:14][C:10]=2[N:11]=[CH:12][N:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[N:24][C:23]([N:26]2[CH:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[C:22]2[NH:32][CH:33]=[C:34]([C:35](=[O:39])[C:36](O)=[O:37])[C:21]=12.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[N:24][C:23]([N:26]2[CH:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[C:22]2[NH:32][CH:33]=[C:34]([C:35](=[O:39])[C:36]([N:15]3[CH2:16][CH2:17][C:9]4[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=5)=[N:13][CH:12]=[N:11][C:10]=4[CH2:14]3)=[O:37])[C:21]=12
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
Part E: To a solution of 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride (0.137 g, 0.55 mmol) in DMF (15 mL) at 25° C. was added sequentially 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.151 g, 0.50 mmol), N-methylmorpholine (0.220 mL, 2.00 mmol), and TBTU (0.177 g, 0.55 mmol), and the mixture was stirred at 25° C. for 18 h. The reaction mixture was concentrated under vacuum, and the residue dissolved in hot methanol. The solution was allowed to cool slowly to room temperature. The precipitate was recovered by filtration, washed with methanol, and dried under vacuum to provide 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione (0.122 g, 49%) as an off-white solid; HRMS: 496.1835 (M+H)+ [calc'd: 496.1840]; 1H NMR (500 MHz, DMSO-d6) δ 12.44 (br s, 1H), 9.24 (m, 1H), 9.17 (s, 2/3H), 9.08 (s, 1/3H), 8.77 (m, 1/3H), 8.67 (m, 2/3H), 8.34 (s, 2/3H), 8.26 (s, 1/3H), 8.12-8.00 (m, 2H), 7.87 (m, 1H), 7.58 (m, 1/3H), 7.53 (m, 2/3H), 4.92 (s, 4/3H), 4.72 (s, 2/3H), 3.93 (m, 1/3H), 3.91 (s, 1H), 3.85 (s, 2H), 3.70 (m, 2/3H), 3.32 (m, 1/3H), 3.18 (m, 2/3H), 2.50 (s, 2H), 2.49 (s, 1H).