Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])[CH3:2].Br.C(N(CC)CC)C.[C:28]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:30])[CH3:29].C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH:9][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:31][C:28](=[O:30])[CH3:29])=[CH:40][CH:39]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)c1ccc(OC(C)=O)cc1
Reaction time: 3 h

Procedure:
17.3 g (0.05 mol) of L-alanyl-L-phenylalanine ethyl ester·HBr was suspended in 250 ml of dichloromethane, and to this susension were added 5.1 g (0.05 mol) of triethylamine and 9 g (0.05 mol) of p-acetoxybenzoic acid, and then 9.6 g (0.05 mol) of 1-ethyl-3(3-dimethylaminopropyl)carbodiimide·HCl was added in an ice bath. This mixture was stirred for three hours, and then was washed with a 0.1% aqueous solution of Na2CO3 and with a 0.1 N HCl solution three times and then with distilled water three times, and was dried over anhydrous sodium sulfate. Dichloromethane was removed from the dried mixture under reduced pressure to obtain p-acetoxybenzoyl-L-alanyl-L-phenylalanine ethyl ester.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.Cl.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:25][CH:26]=1>>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:34])([F:19])[F:33])=[CH:26][N:25]=3)[CH2:28][CH2:29]2)=[O:13])=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Agent: Cl
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Yield: 85.6 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (253 mg) described in Preparation Example 16 and 1-(5-trifluoromethylpyridin-2-yl)piperazine dihydrochloride (319 mg) and by the reaction and treatment in the same manner as in Example 94, the title compound (408 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][N:3]1[CH:7]([CH3:11])[C:8]([OH:10])=O.[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH2:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH:15][C:8](=[O:10])[CH:7]([N:3]1[C:2](=[O:1])[CH2:6][S:5][CH2:4]1)[CH3:11]
Reactant: Cc1cccc(C)c1N
Reactant: CC(C(=O)O)N1CSCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1NC(=O)C(C)N1CSCC1=O
Yield: 45.7 %

Procedure:
A mixture of 2-(4-oxo-3-thiazolidinyl)propionic acid (2.00 g), 2.6-dimethylaniline (1.38 g), and dicyclohexylcarbodiimide (2.35 g) in chloroform (15 ml) was refluxed for 48 hours. The resultant precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with diethyl ether and recrystallized from ethanol to give N-(2,6-dimethylphenyl)-2-(4-oxo-3-thiazolidinyl)propionamide (1.45 g) as colorless prisms.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[N:9]([CH:13]=[CH:14][N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][C:13]1[N:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[N:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2cccn3ccnc23)cc1
Solvent: ClCCl
Product: Brc1cnc2c(-c3ccccc3)cccn12

Procedure:
Combine 2 g (10.3 mmol) of the product from Example 4 with 1.8 g (10.3 mmol) of N-bromosuccinimide in 50 ml of methylene chloride, and stir for 10 minutes at room temperature. Wash the reaction mixture with 50 ml of 10% potassium carbonate. Dry the methylene chloride layer over sodium sulfate, treat with charcoal, filter, and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)[CH3:2].[CH3:13][NH:14][NH2:15]>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:12])[N:14]([CH3:13])[NH2:15])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CNN
Reactant: CCOc1ccc(N=C=S)cc1
Solvent: CCO
Product: CCOc1ccc(NC(=S)N(C)N)cc1
Yield: 79.5 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 2.5 g (0.0698 mole) of 4-ethoxyphenyl isothiocyanate and 3.22 g (0.0698 mole) of methylhydrazine in 100 ml of ethanol yielded 12.5 g of 4-(4-ethoxyphenyl)-2-methyl-3-thiosemicarbazide as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[OH:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl.[CH3:13]O>>[OH:2][C:3]1([C:9]([O:11][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: CO
Reactant: O=C(O)C1(O)CCNCC1
Agent: Cl
Product: COC(=O)C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxy-4-piperidinecarboxylic acid hydrochloride salt (1 g, 5.1 mmol) was added to a 2% hydrochloric acid solution in methanol (25 mL) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt (1 g, 92%) as a white solid. δH (400 MHz, DMSO-d6) 9.06 (broad, 2H), 5.89 (broad, 1H), 3.68 (m, 3H), 3.14 (m, 2H), 3.02 (m, 2H), 2.07 (m, 2H), 1.79 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:34]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]3)=[O:31])[C:25]=2[CH3:33])(=[O:11])=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: OC1CCNCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)N1CCC(O)CC1

Procedure:
5-[5-(3,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol) was coupled with piperidin-4-ol (30 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (25 mL) to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Br)=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14]>CN(C=O)C.[Cu]I>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: Nc1ccc(Br)c2ccccc12
Agent: [Cu]I
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c2ccccc12
Temperature: 120 °C

Procedure:
To a stirred solution of 1-amino-4-bromonaphthalene (5 g, 22.5 mmol) in DMF (30 mL) was added CuCN (10.1 g, 112.5 mmol), CuI (8.7 g, 45 mmol) and the mixture was heated to 120° C. in a sealed tube for 24 h. After completion of the reaction (TLC), the mixture was filtered and the filtrate was evaporated to give the crude product which was purified by column chromatography over silica gel (EtOAc in Hexanes, 5%) to furnish the desired compound.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Reactant: CCCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.53 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.53 ml (5.0 mmol) of 1-pentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 3 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4). After the solvent was distilled off, the residue was recrystallized from ether to yield 1.11 g (59%, white crystal) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[N:5]2.[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2](/[CH:30]=[CH:29]/[C:28]([O:32][CH3:33])=[O:31])[CH:3]=3)[N:8]=2)=[CH:17][CH:16]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(-c2nc3ccc(Br)cc3nc2-c2ccc(OC)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A solution of 6-bromo-2,3-bis(4-methoxyphenyl)quinoxaline (100 mg, 0.24 mmol, 1.00 equiv), methyl acrylate (40.8 mg, 0.47 mmol, 2.00 equiv), Pd(OAc)2 (5.3 mg, 0.02 mmol, 0.10 equiv), PPh3 (24.8 mg, 0.09 mmol, 0.40 equiv) in DMF/Et3N (4/2 mL). The resulting solution was stirred overnight at 100° C. under an inert atmosphere. The mixture was concentrated under vacuum and purified via silica gel column (ethyl acetate/petroleum ether (1:30)), yielding 80 mg (79%) of (E)-methyl 3-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yl)acrylate as a yellow solid.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=O)=O.[C-:35]#[N:36].[Na+]>CS(C)=O.CN(C)C1C=CN=CC=1>[C:35]([CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:21][CH2:22][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:24][CH2:25]4)[C:9]=3[C:8]1=2)#[N:36]
Reactant: [C-]#N
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (900 mg, 1.76 mmol, 1.00 equiv) in 6 mL of DMSO at room temperature. NaCN (600 mg, 12.24 mmol, 6.96 equiv) and 4-dimethylaminopyridine (100 mg, 0.82 mmol, 0.47 equiv) were added and the resulting solution was stirred for 2 h at 80° C. After cooling to room temperature, the reaction was quenched with water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to provide tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (709 mg, 91%) as a white solid. MS: m/z 443 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:16]3[CH2:19][CH3:20])=[C:12]([NH2:26])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(C)C.Cl.[OH-].[OH-].[Pd+2]>[C:1]1([CH2:7][CH2:8][O:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([CH:21]4[CH2:25][CH2:24][CH2:23][O:22]4)[N:16]3[CH2:19][CH3:20])=[C:12]([NH2:26])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CCn1c(-c2ccco2)nc2c(N)nc(OCCc3ccccc3)nc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(C)O
Product: CCn1c(C2CCCO2)nc2c(N)nc(OCCc3ccccc3)nc21
Yield: 46.7 %

Procedure:
To a solution of 2-(2-phenylethoxy)-8-(furan-2-yl)-9-ethyl-9H-purin-6-ylamine (150 mg, 0.43 mmol) in 45 mL of isopropanol and 2 drops of concentrated HCl was added 150 mg of Pd(OH)2, and the mixture was shaken with hydrogen at 170 psi and 65° C. for 7 hours. The catalyst was filtered off, washed with warm methanol, and the filtrate was concentrated to dryness. The residue was flash chromatographed on a silica gel column eluting with cyclohexane, -EtOAc-CH3OH (60:33:7) to give 2-(2-phenylethoxy)-8-(tetrahydrofuran-2-yl)-9-ethyl-9H-purin-6-ylamine (71 mg, 47%) as chromatographically pure solid: mp 121–123° C.; 1H NMR (Me2SO-d6) δ 1.33 (t, 3H, J=7.1 Hz, CH2CH3), 1.87–2.30 (m, 3H, H-3-Fur and H-4-Fur), 2.55–2.75 (m, 1H, H-3-Fur), 3.02 (t, 2H, J=6.9 Hz, CH2CH2Ph), 3.83 (m, 2H, H-5-Fur), 4.15 (q, 2H, J=7.1 Hz, CH2CH3), 4.41 (t, 2H, J=6.9 Hz, CH2CH2Ph), 5.14 (t, 1H, J=6.6 Hz, H-2-Fur), 7.17–7.40 (m, 7H, H-Ph and NH2). Anal. (C19H23N5O2) C, H, N.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3]1.CN.[CH3:12][N:13](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:12][NH:13][C:7]([CH:4]1[CH2:3][C:2](=[O:1])[NH:6][CH2:5]1)=[O:9]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C1CC(C(=O)O)CN1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)C1CNC(=O)C1

Procedure:
In an analogous manner to that described in Example 24f, by condensing (S)-1-(4-benzyloxy)-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent there is obtained (S)-1-(4-benzyloxy)-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=325 (M+H)+; [α]589=+32.02° (c=1.037, CH2Cl2).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@:5]([NH2:15])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:16])[C@:5]([NH:15][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@](C)(N)Cc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@](C)(Cc1ccc(O)cc1)NC(=O)OCc1ccccc1

Procedure:
To a suspension of (S)-2-amino-3-(4-hydroxy-phenyl)-2-methyl-propionic acid methyl ester hydrochloride in ethyl acetate (25 mL) was added 1N NaHCO3 solution (12.5 mL) and the mixture was stirred rapidly at ambient temperature for the addition of neat benzyl chloroformate (1.01 eq.). Following addition, the reaction mixture was stirred for an additional hour; TLC and LCMS analysis showed the reaction to be complete. The mixture was partitioned and the organic phase was separated and dried over Na2SO4 and concentrated. The crude product was used directly in the subsequent reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][CH2:31][N:32]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])[CH:26]=[CH:27][CH:28]=2)[C:10]1=[O:43].[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][CH2:31][N:32]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])[CH:26]=[CH:27][CH:28]=2)[C:10]1=[O:43]
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCCN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Agent: Cl
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 140 °C
Yield: 100 %

Procedure:
A mixture of 190 mg (0.3 mmol) of 2-[3-[3-[3-(2,4-dichlorophenyl)-7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-propyl]-isoindole-1,3-dione and 1 ml of aniline was heated at 140° C. for 35 minutes and then cooled. The mixture was added to 40 ml of 2M aqueous hydrochloric acid and the precipitated product was filtered off, washed with 2M aqueous hydrochloric acid, then with water and finally dried to give 200 mg (100%) of 2-[3-[3-[3-(2,4-dichlorophenyl)-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-propyl]-isoindole-1,3-dione as a pale brown solid. [Mass spectrum (ESI) MH+ =649].
Reaction SMILES: C1(COC(=O)[NH:10][C@@H:11]([CH2:20][OH:21])[C:12](=[O:19])[NH:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)C=CC=CC=1>CO.[Pd]>[NH2:10][C@@H:11]([CH2:20][OH:21])[C:12]([NH:13][N:14]1[CH:15]=[CH:16][CH:17]=[CH:18]1)=[O:19]
Reactant: O=C(N[C@@H](CO)C(=O)Nn1cccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H](CO)C(=O)Nn1cccc1

Procedure:
(S)-Phenylmethyl-[1-(hydroxymethyl)-2-oxo-2-(1H-pyrrol-1-ylamino)ethyl]carbamate (4.90 g) was dissolved in 100 ml of methanol over 5% Pd/C (500 mg). The solution was hydrogenated at atmospheric pressure and room temperature until absorption of 80% of the theoretical amount of hydrogen. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by flash column chromatography (silica gel, ethyl acetate/methanol 4:1) to afford the desired product as a powder. Recrystallization from ethyl acetate/methanol/hexane gave the product as needles (1.37 g), m.p. 135°-137° C.
Reaction SMILES: S(=O)(=O)(O)O.FC(F)(F)C(O)=O.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.N([O-])=O.[Na+].[N-:25]=[N+:26]=[N-].[Na+]>O>[N:18]([C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=1)=[N+:25]=[N-:26]
Reactant: Nc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
Prepared in analogy to J. Org. Chem. (1989) 54:5938-5945. To a solution of sulfuric acid (40 mL) and trifluoroacetic acid (200 mL) was added 4-fluoroaniline (22.1 mL, 0.23 mol) dropwise. Then under ice-cooling a solution of sodium nitrite (20.6 g, 0.3 mol) in water (200 mL) was added over 30 min at 15-18° C. The solution was then stirred for 30 min while kept in the ice bath. A solution of sodium azide (25.42 g, 0.39 mol) in water (150 mL) was added dropwise over 30 min. Mixture was foaming and temperature went up to 10° C. while cooling with an ice bath. Reaction mixture was stirred without cooling for 1 h, then extracted with diethyl ether. The combined organic layers were washed with water two times. Then the combined organic layers were diluted with saturated aqueous sodium carbonate solution (500 mL) until the mixture became basic. The organic phase was separated and washed with brine, extracted again with diethyl ether. The organic layers were dried over sodium sulfate and evaporated at 40° C., minimum 50 mbar (already distillation of product), to afford the title product (30.42 g, 96%) as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]4[CH2:22][O:21]4)[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(#N)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32][CH2:22][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[OH:21]
Reactant: COC(=O)c1ccccc1S
Reactant: Clc1ccc2ccc(/C=C/c3cccc(C4CO4)c3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1SCC(O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a stirred solution of epoxide 30 (37 g, 0.120 mol) in a mixture of dimethylformamide (140 ml) and acetonitrile (200 ml) was added methyl-2-mercaptobenzoate (20.0 g, 0.145 mol), followed by addition of anhydrous potassium carbonate (19.8 g, 0.145 mol). The reaction mixture was stirred overnight, filtered and concentrated. The resulting mixture was poured into water (2.0 L), stirred and extracted with ethylacetate (1.0 L). The organic layer was washed with water (500 ml) and brine (500 ml), dried over anhydrous sodium sulphate, evaporated and subjected to FC (EtOAc/hexanes) to afford product as a pale yellow solid 46 (18.0 g, 31% yield).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([C:56]#[N:57])[CH:53]=[CH:52][C:51]=3[CH3:58])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([C:56]#[N:57])[CH:53]=[CH:52][C:51]=3[CH3:58])[N:48]=[CH:49][C:42]=12)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(C#N)ccc1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2cc(C#N)ccc2C)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
Trimethylaluminium (2M in toluene) (0.472 mL, 0.94 mmol) was added to a solution of 5-methylpyridin-2-amine (102 mg, 0.94 mmol) in toluene (10 mL) at 0° C. under nitrogen in a microwave vial. The reaction mixture was stirred at 0° C. for 20 mins and then (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(5-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AM7) (300 mg, 0.47 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated in the microwave at 120° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and the concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water and DCM (50 mL). The organic layer was separated and the aqueous layer re-extracted with DCM (30 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% Et2O in isohexane to afford the product (125 mg, 37.2%). 1H NMR (400 MHz, CDCl3) 0.99 (9H, s), 2.27 (3H, s), 2.29 (3H, s), 3.69-3.72 (2H, m), 3.81 (2H, t), 4.16-4.24 (2H, m), 6.07-6.09 (1H, m), 7.16-7.41 (6H, m), 7.51 (1H, s), 7.53 (1H, s), 7.63-7.65 (4H, m), 7.68-7.72 (2H, m), 8.08-8.08 (1H, m), 8.14 (1H, d), 8.37 (1H, s), 8.57 (1H, s), 8.67 (1H, s); m/z (ES+) (M+H)+=712.6; HPLC tR=3.65 min.