Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51](Cl)(=[O:53])=[O:52])([O-:44])=[O:43]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([NH:35][S:51]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N+:42]([O-:44])=[O:43])(=[O:52])=[O:53])[CH2:11][C@@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NS(=O)(=O)c3ccccc3[N+](=O)[O-])CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (3S*,5R*)-3-Amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.83 mmol) in CH2Cl2 (1 mL) are added pyridine (1 mL) and o-nitrobenzenesulfonyl chloride (274 mg, 1.2 mmol) at 0° C., then the mixture is stirred at room temperature. After 20 h, the reaction mixture is quenched by H2O (30 mL) and extracted with EtOAc (100 mL). The organic layer is successively washed with 5% aqueous KHSO4, H2O, and brine, then dried over Na2SO4 and concentrated in reduced pressure. The residue is purified by silica gel column chromatography to afford the title compound as brown amorphous material. MS: 670 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 4.14 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].C(O)C.[F:13][C:14]([F:23])([F:22])[C:15](=O)[C:16](OCC)=[O:17]>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:9]=[C:16]([OH:17])[C:15]([C:14]([F:23])([F:22])[F:13])=[N:8]2
Reactant: Nc1cccc(F)c1N
Reactant: CCOC(=O)C(=O)C(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Oc1nc2c(F)cccc2nc1C(F)(F)F
Temperature: 90 °C
Reaction time: 3 h
Yield: 196.5 %

Procedure:
To an ACE sealable tube was added 3-fluorobenzene-1,2-diamine (475.99 mg, 3.77 mmol), ethanol (5 ml) and ethyl trifluoropyruvate (0.500 ml, 3.77 mmol) at rt. The tube was sealed and placed in an oil bath at 90° C. The mixture was stirred at 90° C. for 3 hr, cooled to rt and the LC/MS showed starting diamines and three new peaks. More ethyl trifluoropyruvaate (0.2 ml) was added and the mixture was stirred at 90° C. overnight. The reaction mixture was cooled to rt and LC/MS showed no diamines, and two of the three new peaks remained. The reaction mixture was concentrated to give a dark solid, diluted with dichloromethane/dimethylformamide (3/1, 60 ml) and washed with HCl (1 N, 2×20 ml) and an aquious solution of sodium thiosulfate (0.1 M, 2×20 ml). The combined aq. layers were back-extracted with dichloromethane/dimethylformamide (3/1, 2×20 ml). The combined organic layers were washed with water and concentrated to give a dark solid (1.72 g). The solid was dissolved in acetone and silica gel (46 g) was added. The mixture was dried in vacuo, loaded on a silica gel column and purified by flash chromatography (CH3CN/CHCl3=1/8, 1/6 then 1/4) to give the title compound 112a (474.9 mg, 2.046 mmol, 54.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[CH2:9][O:8]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[NH:22][C:21](=[O:23])[N:20]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[C:19]=2[CH:31]=1>CC(O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[NH:22][C:21](=[O:23])[N:20]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH2:9][CH:7]([OH:8])[CH2:6][O:5][C:4]4[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=4[O:2][CH3:1])[CH2:26]3)[C:19]=2[CH:31]=1
Reactant: COc1ccccc1OCC1CO1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1CC1CCCNC1
Solvent: CC(C)O
Product: COc1ccccc1OCC(O)CN1CCCC(Cn2c(=O)[nH]c3ccc(Cl)cc32)C1
Yield: 28 %

Procedure:
A mixture of 4 parts of [(2-methoxyphenoxy)methyl]oxirane, 5.3 parts of 6-chloro-1,3-dihydro-1-(3-piperidinylmethyl)-2H-benzimidazol-2-one and 120 parts of 2-propanol is stirred and refluxed for 5 hours. The reaction mixture is cooled and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 2.5 parts (28%) of 6-chloro-1,3-dihydro-1-{1-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-piperidinylmethyl}-2H-benzimidazol-2-one; mp. 167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](I)=[CH:5][N:4]=1.[Cl:12][C:13]1[C:18](B(O)O)=[CH:17][CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:13]1[C:18]([C:6]2[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COc1ncc(I)c(OC)n1
Reactant: OB(O)c1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2cccnc2Cl)c(OC)n1

Procedure:
2,4-Dimethoxy-5-iodo-pyrimidine (1 g, 3.76 mmol) was dissolved in degassed n-PrOH (20 ml) and then 2-chloropyridine-3-boronic acid (882 mg, 5.61 mmol), Na2CO3 (800 mg, 7.6 mmol), PPh3 (98 mg, 0.37 mmol) and Pd(OAc)2 (40 mg, 0.19 mmol) were added. The suspension was stirred at reflux for 4 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and DCM. The organic phase was dried (Na2SO4) and evaporated to give the title compound that was used without further purification in the next step (quantitative yield).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O>C(O)C.O1CCCC1.O.NN>[F:1][C:2]([F:26])([F:27])[CH:3]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[CH2:4][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1CC(Nc1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: NCC(Nc1cccc([N+](=O)[O-])c1)C(F)(F)F
Reaction time: 19 h
Yield: 77.2 %

Procedure:
To a solution of 2-(3,3,3-trifluoro-2-((3-nitrophenyl)amino)propyl)isoindoline-1,3-dione (C15, 209 mg) in ethanol (3 mL) and tetrahydrofuran (3 mL), hydrazine monohydrate (132 μL) was added at room temperature, and the mixture was stirred at the same temperature for 19 hours. The insoluble matter was removed by filtration, and then the solvent was evaporated under reduced pressure to obtain 3,3,3-trifluoro-N2-(3-nitrophenyl)propane-1,2-diamine (C16, 106 mg).
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:37]2[CH:36]=[CH:35][C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:45][C:46]1[N:55]=[C:54]([NH2:56])[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([CH2:57]Br)[CH:52]=2)[N:47]=1>>[NH2:45][C:46]1[N:55]=[C:54]([NH2:56])[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([CH2:57][C:38]3[C:34]4[CH:35]=[CH:36][C:37]5[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=5[NH:32][C:33]=4[CH:41]=[CH:40][CH:39]=3)[CH:52]=2)[N:47]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: Nc1nc(N)c2cc(CBr)ccc2n1
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2cc(Cc3cccc4c3C=Cc3ccccc3N4)ccc2n1

Procedure:
9-[(2,4-Diaminoquinazolin-6-yl)methyl]dibenz[b,f]azepine (Formula I: Ar=2,4-diaminoquinazolin-6-yl; W=CH2; X=N; Z=CH═CH; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using dibenz[b,f]azepine (154 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylquinazoline hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:12][C:13](=O)[CH3:14]>C(O)C>[CH3:14][C:13]1[N:1]=[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]2[CH:12]=1
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: CC(=O)CBr
Solvent: CCO
Product: Cc1cn2cccc([N+](=O)[O-])c2n1

Procedure:
20.0 g of 2-amino-3-nitropyridine and 22 g of bromoacetone are boild in 1 l ethanol for 55 hours under reflux. The mixture is then cooled in an icebath, the crystalline hydrobromide filtered off under suction and washed with ethanol. After drying in a vacuum at 50° C. the yield of the title compound of m.p. 300° C. (decomposition) is 17.2 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH3:28][NH:29][CH:30]1[CH2:32][CH2:31]1.C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH:30]1([N:29]([CH3:28])[C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:26])[CH2:32][CH2:31]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Reactant: CNC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1)C1CC1
Temperature: 70 °C
Reaction time: 22 h
Yield: 86.9 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (140 mg, 0.377 mmole), N-methyl cyclopropylamine (161 mg, 2.26 mmole), N-ethyldiisopropylamine (527 ul, 3.02 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 566 ul, 0.943 mmole) in tetrahydrofurane (5 ml) was stirred for 22 hours at 70° C. The solution is loaded on silicagel (1.5 g) and purified by chromatography on a 10 g Silicycle cartridge with ethyl acetate as eluent affording N4-cyclopropyl-N4,1-dimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (139 mg, 86.9%) as a white solid. mp.: 172-5° C., MS: m/z=415.4 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:17]([CH3:40])([CH3:39])[S:18](=[O:38])(=[O:37])[C:19]([CH2:34][CH2:35][OH:36])([CH3:33])[C@:20]([C:23]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=2F)([CH3:22])[N:21]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[NH4+].[Cl-]>[CH3:40][C:17]1([CH3:39])[S:18](=[O:38])(=[O:37])[C:19]2([CH3:33])[CH2:34][CH2:35][O:36][C:24]3[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=3[C@@:20]2([CH3:22])[N:21]=[C:16]1[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)C(C)(CCO)S(=O)(=O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCCC2(C)S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 43.2 %

Procedure:
To a solution of crude tert-butyl N-tert-butoxycarbonyl-N-[(5R)-5-(2-fluoro-5-nitro-phenyl)-6-(2-hydroxyethyl)-2,2,5,6-tetramethyl-1,1-dioxo-1,4-thiazin-3-yl]carbamate (0.18 g, 0.31 mmol) in DMF (1.8 ml) was added cesium carbonate (0.25 g, 0.77 mmol). The resulting mixture was stirred at ambient temperature for 7 h. Extra cesium carbonate (0.36 g) was added and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with 30 ml of saturated NH4Cl and extracted with EtOAc. The organic extract was washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Biotage column (25 g), eluting with a gradient of 5% to 40% EtOAc in hexane, to provide tert-butyl N-[(11bR)-3,3,4a,11b-tetramethyl-10-nitro-4,4-dioxo-5,6-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (0.076 g, 43% yield) as a light-yellow solid. m/z (ESI) 591.1 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)=[N:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34]>C1(C)C=CC=CC=1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:27]1[C:6](/[CH:7]=[CH:8]/[C:3]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[N:11][N:4]=2)=[N:24][N:25]=[C:26]1[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Reactant: NNC(=Nc1ccccc1Cl)c1ccncn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccncn4)n3-c3ccccc3Cl)o2)ccn1

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 (200 mg, 0.75 mmol) in 20 mL of PhMe was added 0.5 mL of POCl3. The mixture was stirred at reflux for 2 h. After removal of solvent, the residue was dissolved in 20 mL of dichloromethane and added to 150 mg (0.6 mmol) of N-amino-N′-(2-chlorophenyl)pyrimidine-4-carboxamidine 5. The mixture was stirred at ambient temperature for 2 h. After removal of solvent, the residue was suspended in 20 mL of PhMe and refluxed for 3 h. After removal of solvent, the residue was purified by column (0-5% of methanol in dichloromethane) to give 4-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)pyrimidine as a solid. Yield: 30 mg.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CN(C)C(=S)[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[OH:19].[OH-].[Na+]>C1COCC1>[SH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[OH:19]
Reactant: COc1cccc(SC(=S)N(C)C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(S)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
With cooling with ice, lithium aluminium hydride (11.9 g, 288 mmol) was added to a THF (300 mL) solution of the compound (46.65 g, 192 mmol) synthesized in the above (3). After stirred at room temperature for 3 hours, 4 N NaOH was added, and filtered. The filtrate was concentrated and distilled under reduced pressure to obtain the intended compound (24.11 g, 80%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C@:15]3(C)[CH2:20][C:19](=[O:21])[N:18]([CH3:22])[C:17](=[N:23]C(=O)OC(C)(C)C)[NH:16]3)[CH:12]=[CH:13][CH:14]=2)[C:5]([OH:8])=[CH:6][CH:7]=1.[C:32](O)([C:34](F)(F)F)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C@@:15]3([CH2:32][CH3:34])[NH:16][C:17](=[NH:23])[N:18]([CH3:22])[C:19](=[O:21])[CH2:20]3)[CH:12]=[CH:13][CH:14]=2)[C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(-c3cc(Cl)ccc3O)c2)NC1=NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@]1(c2cccc(-c3cc(Cl)ccc3O)c2)CC(=O)N(C)C(=N)N1
Yield: 60 %

Procedure:
(S)-tert-butyl 4-(3-(3-chloro-6-hydroxyphenyl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1═R6=Me, R21=3-chloro-6-hydroxyphenyl) (23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH2Cl2 at RT for 30 min. The volatiles were removed in vacuo. The residue was redissolved in acetonitrile (5 mL) and evaporated again to afford 17 mg of the crude product as a yellow solid. The crude product was purified via reverse phase HPLC to provide 10 mg (60%) of (S)-6-(3-(3-chloro-6-hydroxy-phenyl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4(1H)-one (CF4; R1═R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1HNMR (CDCl3, 300 MHz): 11.4 (br s, 1H), 7.6-4.25 (m, 3H), 7.24-6.84 (m, 3H), 3.68 (brs, 1H), 5.18 (brs, 1H), 3.39 (d, J=16.1 Hz, 1H), 3.20 (s, 3H), 2.95 (d, J=15.8 Hz, 1H), 1.74 (s, 3H). MS (ESI): MH+=344.1. HPLC (A) Rt=5.07 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[N:21]=[CH:20][C:19](C=O)=[CH:18][N:17]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C2ON=C(C3N=CC([CH2:45][NH:46][CH:47]4[CH2:50][CH:49]([C:51]([OH:53])=[O:52])[CH2:48]4)=NC=3)N=2)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[N:21]=[CH:20][C:19]([CH2:45][NH:46][C@@H:47]4[CH2:50][C@H:49]([C:51]([OH:53])=[O:52])[CH2:48]4)=[CH:18][N:17]=3)[N:12]=2)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2nc(-c3cnc(CNC4CC(C(=O)O)C4)cn3)no2)cc1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ncc(C=O)cn3)no2)cc1
Product: CC(C)Cc1ccc(-c2nc(-c3ncc(CN[C@H]4C[C@@H](C(=O)O)C4)cn3)no2)cc1

Procedure:
The title compound was prepared from 2-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrimidine-5-carbaldehyde by procedures analogous to those described in Examples (1A-1B) for the preparation of 3-({5-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrazin-2-ylmethyl}-amino)-cyclobutanecarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)(O)=[O:14].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.N(CC)(CC)CC>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][NH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CN)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
A mixture of 3,5-dimethoxybenzenemethanamine (3.34 g, 20 mmol), 4-(4-carboxyphenyl)-1-piperazinecarboxylic acid, 1-(1,1-dimethylethyl) ester (6.13 g, 20 mmol), EDCI (4.2 g, 22 mmol), HOBT (2.97 g, 22 mmol), N(CH2CH3)3 (12 ml) and DCM (80 ml) was stirred overnight at r.t. The solvent was evaporated. The residue was purified by column chromatography (eluent: petroleum ether/EtOAc 2/1). The desired fractions were collected and the solvent was evaporated. Yield: 5.3 g of 4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (58.24% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:23][C:22](=O)[O:21]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:10][C:9]=1[NH:17][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:33]=[CH:32][CH:31]=[C:28]([C:29]#[N:30])[CH:27]=1)=[O:25])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Product: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)c1

Procedure:
Prepared from (2-amino-4-isopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G47) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light red solid (100 mg).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.BrC1C(C)=CC(C)=CC=1C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.CN(C)[CH:31]=[O:32]>C1COCC1.[Cl-].[Na+].O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[CH:31]=[O:32]
Reactant: COc1ccncc1
Reactant: CN(C)C=O
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccncc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flask is charged with 1.7M tert-butyllithium in pentane (47.1 mL, 80.1 mmol) and THF (20 mL), and cooled to −78° C. 2-Bromomesitylene (6.0 mL, 39 mmol) is added dropwise. The mixture is stirred for 1 h, and 4-methoxypyridine (3.0 mL, 30 mmol) is added dropwise. The mixture is warmed to −23° C. and stirred for 3 h. The mixture is cooled again to −78° C. and dimethylformamide (3.5 mL, 45 mmol) is added. After 1 h, brine (50 mL) is added to the mixture at −78° C. and warmed to room temperature. The mixture is extracted with ether and the combined organic layer is dried over Na2SO4. Concentration followed by silica gel chromatography eluting with a 0 to 6% methanol-dichloromethane gradient gives 4-methoxy-pyridine-3-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ ppm 4.01 (s, 3H), 6.94 (d, J=5.8 Hz, 1H), 8.65 (d, J=5.8 Hz, 1H), 8.90 (s, 1H), 10.46 (s, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[CH:24]=[C:25]([CH2:38][N:39]4[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]4)[CH:26]=[N:27][C:28]=3[NH:29][C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=3)[N:17]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:70][S:71](Cl)(=[O:73])=[O:72]>ClCCl>[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:17]=[C:18]([C:23]3[C:28]([NH:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)=[N:27][CH:26]=[C:25]([CH2:38][N:39]4[CH2:44][CH2:43][N:42]([S:71]([CH3:70])(=[O:73])=[O:72])[CH2:41][CH2:40]4)[CH:24]=3)[N:19]=[C:20]([CH3:22])[N:21]=2)=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3cnc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
TFA (4.00 mL, 51.9 mmol) was added slowly to an ice-bath cooled stirred solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(2-methoxypyrimidin-5-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (413 mg, 0.551 mmol) in dichloromethane (5.00 mL, 78 mmol) and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum to remove as much TFA as possible. The sticky residue was taken up in dichloromethane (5.00 mL) to which triethylamine (0.384 mL, 2.76 mmol) and methanesulfonyl chloride (0.129 mL, 1.654 mmol) were slowly added at 0° C. The mixture was stirred at 0° C. for 1 h and concentrated. The crude product was partitioned between 1 N NaOH(aq) and dichloromethane (20 mL each), and the separated aqueous layer was extracted with dichloromethane (2×20 mL) The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product which was purified by flash column chromatography (ISCO Combiflash system, pure DCM to 3% MeOH in DCM w/NH3) to give N,N-bis(4-methoxybenzyl)-4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (277 mg, 0.381 mmol, 69.1% yield) as a brown foam. m/z (ESI, +ve ion) 727.2 (M+H)+.