Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:18])([Cl:17])[CH:3](O)[CH:4]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].S(Cl)([Cl:21])=O>>[Cl:1][C:2]([Cl:18])([Cl:17])[CH:3]([Cl:21])[CH:4]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)C(=O)C(C(O)C(Cl)(Cl)Cl)n1cncn1
Product: CC(C)(C)C(=O)C(C(Cl)C(Cl)(Cl)Cl)n1cncn1
Temperature: 60 °C
Yield: 98 %

Procedure:
393.3 g (1.25 mol) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one were introduced into 750 ml of thionyl chloride, while stirring, and the mixture was heated to 60° C. for 36 hours. Thereafter, the excess thionyl chloride was distilled off in vacuo. The residue was taken up in 1.5 liters of methylene chloride and the methylene chloride mixture was washed with 10% strength sodium bicarbonate solution until neutral, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. 408.9 g (98% theory) of 1,1,1,2-tetrachloro-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one of melting point 111°-113° C. were obtained.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1.[CH:17]1([C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C.O>[CH:17]1([C:23]2[N:27]([C:2]3[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=3)[CH:26]=[CH:25][N:24]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1OC
Reactant: c1c[nH]c(C2CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(-n2ccnc2C2CCCCC2)cc1OC
Temperature: 100 °C
Yield: 100.7 %

Procedure:
A mixture of methyl 4-fluoro-2-methoxy-5-nitrobenzoate 8.57 g, 2-cyclohexylimidazole 5.61 g, potassium carbonate 10.34 g and N,N-dimethylacetamide 75 mL was heated at 100° C. for 5 hours in nitrogen atmosphere. The reaction liquid was diluted with ethyl acetate, poured in water and the organic layer was separated. The organic layer was washed with brine, dried over magnesium sulfate and removed of the solvent by distillation to provide 13.52 g of the title compound.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]([CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:18])[C:9]=2[N:19]=1)[CH2:3][CH2:4][CH3:5]>O1CCOCC1.CO>[ClH:1].[ClH:1].[NH2:18][C:10]1[C:9]2[N:19]=[C:6]([CH2:2][CH2:3][CH2:4][CH3:5])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:8]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4M HCl in dioxane (12 mL) was added to a solution of the product from step (v) (6.7 g) in MeOH (100 mL) and stirred at rt for 18 h. The solvent was evaporated under reduced pressure, the residue triturated with diethyl ether, filtered and dried. Yield 5.53 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].B#B.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1CO
Temperature: 25 °C

Procedure:
To a stirred solution of 21.6 g. (0.10 mol.) of N-t-butoxycarbonyl-DL-proline in 100 ml. of dry tetrahydrofuran at room temperature is added 50 ml. of a 1 molar diborane solution in tetrahydrofuran at such a rate that the temperature of the reaction mixture is maintained at 25°-30°. After the addition is complete, the reaction mixture is stirred at room temperature for an additional hour. Water is then cautiously added to the reaction mixture, the tetrahydrofuran is removed in vacuo, the residue is diluted with ether, and this solution is washed thoroughly with 5% aqueous sodium hydroxide. The ether solution is dried and concentrated in vacuo to obtain 1-(t-butoxycarbonyl)-2-pyrrolidinemethanol.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C@@H:34]1[CH:39]2[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]2)[CH2:35]1>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:33][C@@H:34]2[CH:39]3[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]3)[CH2:35]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1
Reactant: Nc1cc(OCc2cccc(I)c2)c(C(=O)O)cc1Cl
Reactant: N[C@H]1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1cc(OCc2cccc(I)c2)c(C(=O)N[C@H]2CN3CCC2CC3)cc1Cl
Reaction time: 0.75 h
Yield: 25.6 %

Procedure:
A solution of 4-amino-5-chloro-2-[(3-iodophenyl)methoxy]benzoic acid (3.23 g, 8.0 mmol) in anhydrous tetrahydrofuran (4 mL) and anhydrous N,N-dimethylformamide (4 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.46 g, 9.9 mmol), stirred for 45 minutes, and degassed over 15 minutes under a stream of nitrogen. A solution of (R)-3-aminoquinuclidine (1.54 g, 12.2 mmol) in anhydrous tetrahydrofuran (4 mL) was added, and the mixture was stirred at room temperature for 18 hours, warmed to 55°±5° C. for three hours, and concentrated in vacuo. The residue was partitioned between 3.0N sodium hydroxide (50 mL) and toluene (100 mL) containing some 2-propanol, and the organic layer was separated. The aqueous solution was extracted with toluene (50 mL) containing some 2-propanol, and the combined organic solution was concentrated in vacuo. The residue was washed with water to remove most of the imidazole, then dried azeotropically with toluene, taken up in tetrahydrofuran, and filtered through a short column of alumina (eluted with 10% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, taken up in warm acetone, and filtered. After a few hours, a solid had crystallized, and this was collected and dried in vacuo to afford (following second crop) 1.05 g (26%) of colorless solid; mp 101.5°-104° C., [α]D22 +6.50° (C=1 in methanol).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29]4)=[CH:24][CH:23]=3)[C:16]2=[CH:15][N:14]=1.C(O)(C(F)(F)F)=O.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl.CO>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][N:28]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:29]4)=[CH:24][CH:23]=3)[C:16]2=[CH:15][N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(C(=O)OC(C)(C)C)CC5)n[nH]c3n2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(S(C)(=O)=O)CC5)n[nH]c3n2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 7-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (10.0 mg, 0.0191 mmol) in dichloromethane (0.10 mL) was treated with TFA (0.10 mL). The mixture was stirred at r.t. for 1 h. The volatiles were evaporated. The residue was dissolved in acetonitrile (0.5 mL) and N,N-diisopropylethylamine (30.0 μL). To the mixture was added methanesulfonyl chloride (2.0 μL, 0.026 mmol). The mixture was stirred at r.t. for 30 min, and then diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=502.1.
Reaction SMILES: [C:1]1([S:7][C:8]2([O:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=3[N+:23]([O-])=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O.C(O)(=O)C.[Fe]>[C:1]1([S:7][C:8]2([O:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:14][C:13]=3[NH2:23])[CH2:9][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Iron powder (13.5 g, 241 mmol) was added to a suspension of 2-(1-phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)nitrobenzene (Description 4, 11.27 g, 30.1 mmol) in water (300 mL) and acetic acid (75 mL) and the mixture was stirred at 80° C. overnight. The mixture was cooled and filtered through celite, washing with ether. The filtrate was extracted with ether, the combined organic fractions were washed with aqueous sodium hydroxide (1M), dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (90:10 increasing to 80:20), to give the title compound as a yellow solid (8 g, 78%). 1H NMR (360 MHz, CDCl3) δ 7.48 (2H, m), 7.34-7.23 (3H, m), 7.15 (1H, d, J 8.74 Hz), 6.60-6.56 (2H, m), 3.78 (2H, br s), 1.49-1.46 (2H, m), and 1.39-1.35 (2H, m).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[SH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.Cl>CN(C)C=O>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([S:7][C:8]4[CH:13]=[CH:12][C:1]([OH:4])=[CH:10][CH:9]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: Oc1ccc(S)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(Sc2ccc(-c3ccc(Sc4ccc(O)cc4)cc3)cc2)cc1
Temperature: 25 °C
Yield: 34 %

Procedure:
Potassium carbonate (75.9 g, 0.55 mol) was charged to a 2 liter flask equipped with a stirrer, condenser, dropping funnel, thermometer and nitrogen purge. Dimethylformamide (200 ml) was added and the solution heated to 80°-90° C. 4-mercaptophenol (69.3 g, 0.55 mol) in 200 ml of dimethylformamide was added to the stirred reaction mixture over one hour. The reaction mixture was maintained at 100°-110° C. for two hours. Solid 4,4'-dibromobiphenyl (78 g, 0.25 mol) was then added over one hour. The reaction mixture was refluxed for 18 hours, cooled to room temperature, and poured into 10% HCl. The white to yellow solid was collected with suction and washed with water. The solid was treated with 5-10% NaOH and filtered once more with suction. The mother liquor was acidified to pH≈2 and the solid collected and recrystallized from chlorobenzene/methanol. A 34% yield of pure HPSB was obtained having a melting point of 214°-217° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Br:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>CO>[Br-:8].[CH3:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=1[CH2:9][C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccccn1
Solvent: CO
Product: Cc1cccc[n+]1CC(=O)c1ccccc1
Product: [Br-]
Yield: 61.6 %

Procedure:
2-Picoline (10.0 g, 0.1 mol) was added to a solution of alpha-bromoacetophenone (21.4 g, 0.1 mol) in methanol (150 mL). The solution was heated to reflux for 1 hr. The solvent was evaporated under vacuum to yield a solid which was recrystallised from ethyl acetate/methanol. The resulting white solid was dried under vacuum to give 2-methyl-1-(2-oxo-2-phenyl-ethyl)-pyridinium bromide (18.0 g, 86%).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH:6]1[CH:13]2[CH:9]([O:10][CH:11]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12]2)[CH:8]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[O:7]1.O.[OH-].[Li+].C(O)(=O)C>O1CCCC1>[CH2:35]([NH:34][C:32](=[O:33])[NH:31][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[C:28]=1[N:29]=[CH:30][N:22]2[CH:8]1[CH:9]2[O:10][CH:11]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][CH:13]2[CH:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])[O:7]1)[CH3:36]
Reactant: CCNC(=O)Nc1ncnc2c1ncn2C1OC(CCC(=O)OC)C2OC(C=Cc3ccccc3)OC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCNC(=O)Nc1ncnc2c1ncn2C1OC(CCC(=O)O)C2OC(C=Cc3ccccc3)OC21
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
3-{6-[6-(3-Ethyl-ureido)-purin-9-yl]-2-styryl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl}-propionic acid methyl ester (5.0 g, 10 mmol) was dissolved in tetrahydrofuran (300 mL). Water (100 mL) was added, followed by lithium hydroxide (1.0 g, 25 mmol). The solution was allowed to stir 16 h at room temperature. It was acidified to pH 5 with acetic acid, concentrated in vacuo, then extracted with chloroform (300 mL). The organic extract was evaporated, redissolved in ethyl acetate and precipitated with heptane to afford the final product (3.9 g, 80%). 1H-NMR (300 MHz, d6 DMSO)1.14 (t 3H, J=7 Hz), 1.90 (m, 2H), 2.19 (m, 2H), 3.26 (q, 2H, J=6 Hz), 4.17 (m, 1H), 4.93 (ψt, 1H, J=6 Hz), 5.43 (dd, 1H, J=3 Hz, 7 Hz), 5.84 (d 1H, J=6 Hz), 6.24 (d, 1H, J=3 Hz), 6.28 (dd, 1H, J=7 Hz, 13 Hz), 6.90 (d, 1H, J=16 Hz), 7.35 (m, 3H), 7.51 (d, 2H, J=7 Hz), 8.56 (s, 1H), 8.61 (s, 1H), 9.30 (t, 1H, J=6 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([F:16])([C:13]([O-:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:51]1([CH2:58][CH2:59][NH:60][C:61](=[O:92])[C@H:62]([CH3:91])[C@H:63]([C@@H:66]2[CH2:70][CH2:69][CH2:68][N:67]2[C:71](=[O:90])[CH2:72][C@@H:73]([O:88][CH3:89])[C@@H:74]([N:79]([CH3:87])[C:80](=[O:86])[C@H:81]([CH:83]([CH3:85])[CH3:84])[NH2:82])[C@@H:75]([CH3:78])[CH2:76][CH3:77])[O:64][CH3:65])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=[CH:52]1>ClCCl.CN(C)C=O>[CH:51]1([CH2:58][CH2:59][NH:60][C:61](=[O:92])[C@H:62]([CH3:91])[C@H:63]([C@@H:66]2[CH2:70][CH2:69][CH2:68][N:67]2[C:71](=[O:90])[CH2:72][C@@H:73]([O:88][CH3:89])[C@@H:74]([N:79]([CH3:87])[C:80](=[O:86])[C@@H:81]([NH:82][C:13]([C@@:10]2([F:16])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:15])[CH:83]([CH3:84])[CH3:85])[C@@H:75]([CH3:78])[CH2:76][CH3:77])[O:64][CH3:65])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=[CH:52]1
Reactant: CC(C)(C)OC(=O)N1CC[C@](F)(C(=O)[O-])C1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(F)CCN(C(=O)OC(C)(C)C)C1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of #170 (18.2 mg, 0.076 mmol, 1 eq.) in dichloromethane (1.8 mL) and N,N-dimethylformamide (0.3 mL) was added N,N-diisopropylethylamine (0.040 mL, 0.228 mmol, 3 eq.) followed by HATU (29.2 mg, 0.076 mmol, 1 eq.). After stirring for 10 minutes at room temperature, #176 (45 mg, 0.076 mmol, 1 eq.) was added. The reaction was stirred at room temperature for 18 hours and additional HATU (29 mg, 0.076 mmol, 1 eq.) was added. After 8 hours the reaction was concentrated in vacuo to provide #183 (61.0 mg, quantitative) which was taken into the next step without further purification. LC-MS (Protocol Q1): m/z 826.6 [M+Na+], retention time=1.05 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11](F)=[CH2:12])=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2F)[N:6]=1)=[O:4].C([Sn](CCCC)(CCCC)C([F:32])=C)CCC.ClC1C=CC(B2OC(C)(C)C(C)(C)O2)=C(F)C=1C(F)C>>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:16]=[C:17]([O:22][CH3:23])[C:18]([Cl:21])=[CH:19][C:20]=2[F:32])[N:6]=1)=[O:4]
Reactant: C=C(F)c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Reactant: C=C(F)[Sn](CCCC)(CCCC)CCCC
Agent: CC(F)c1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Product: C=Cc1c(N)nc(-c2cc(OC)c(Cl)cc2F)nc1C(=O)OC

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-fluorovinyl)pyrimidine-4-carboxylic acid methyl ester (utilized tributyl-(1-fluorovinyl)stannane prepared according to the procedures found in Bull. Chem. Soc. Jpn. 2002, 75(11), 2497-2502) (Compound 9): 1H NMR (CDCl3) δ 7.67 (dd, 1H), 7.22 (dd, 1H), 5.52 (br s, 2H), 5.23 (dd, 1H), 4.9 (dd, 1H), 3.99 (d, 3H), 3.95 (s, 3H).
Reaction SMILES: [CH:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:38])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[CH:18][CH:17]=2)[CH2:7][CH2:6][C:5]1=[O:39])=O.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:36][C:33]1[CH:32]=[CH:31][C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]([N:8]3[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:4]([CH2:3][CH2:1][N:44]4[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]4)[C:5](=[O:39])[CH2:6][CH2:7]3)=[O:38])=[CH:17][CH:18]=2)=[O:37])=[CH:35][CH:34]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC=O)c4ccccc43)cc2)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CCN4CCN(C)CC4)c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.1 %

Procedure:
To a mixture of 1-formylmethyl-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (380 mg) and 4-methylpiperazine (73.4 mg) in a mixture of methanol (10 ml) and acetic acid (0.5 ml) was added sodium cyanoborohydride (46.1 mg) and the mixture was stirred at ambient temperature for 5 hours. The mixture was poured into a mixture of chloroform and saturated aqueous sodium hydrogen carbonate and the mixture was stirred at ambient temperature for 30 minutes. The solution was extracted with chloroform and washed with brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to a silica gel column (20g, 5% methanol in chloroform). The solvent was evaporated in vacuo and the residue was solidified with diethyl ether to give 5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1-[2-(4-methyl-1-piperazinyl)ethyl]-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (115 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[N:10]=[C:9]1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([Cl:33])=[CH:35][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a suspension of methyl 3-benzyl-2-chloro-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.20 g, 0.37 mmol) in isopropyl alcohol (4 mL) was added N,N-diisopropylethylamine (0.13 mL, 0.77 mmol) and p-chlorobenzylamine (0.11 mL, 0.91 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 80% EtOAc/hexanes) to afford methyl 3-benzyl-2-[(4-chlorobenzyl)amino]-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.12 g, 75%). LC-MS: (FA) ES+434.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[N+:20]([C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])([O-:22])=[O:21].[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.O=S(Cl)Cl>C(Cl)(Cl)Cl>[N+:20]([C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25]([NH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:26])([O-:22])=[O:21]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NCC(=O)OCc1ccccc1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])OCc1ccccc1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of benzyl glycinate.PTS salt (1.589 g, 4.716 mmol) in chloroform (20 mL) was added triethylamine (1.95 mL, 14. 148 mmol) at ice cold temperature. A solution of 2,4-dinitrobenzoyl chloride (prepared from 2,4-dinitrobenzoic acid, 1.0 g and SOCl2, 10 mL, refluxed for 2 h and evaporated the solvents) in chloroform (5 mL) was added to the above solution for 10 min and stirred for 1 h. After completion of the reaction, it was diluted with chloroform (100 mL). The chloroform layer was washed with water (2×50 mL), brine (50 mL) and dried over anhyd Na2SO4. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform:methanol (98:02) as eluents to give the product as an off-white color solid (1.55 g, 92%), mp 116-118° C. 1H NMR (400 MHz, CDCl3): δ 8.91 (1H, d, J=2.0 Hz), 8.52 (1H, dd, J=8.2, 2.2 Hz), 7.77 (1H, d, J=8.4 Hz), 7.38 (5H, s), 6.52-6.55 (1H, m), 5.24 (2H, s), 4.31 (2H, d, J=5.2 Hz); LC-MS (negative ion mode): m/z 358 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.ClC1C(C(F)(F)F)=CC=CC=1C(NC(C1(N(C)C)CCCC1)C1C=CC=CC=1)=O.[Br:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[C:48]=1[C:49](O)=[O:50].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Br:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[C:48]=1[C:49]([NH:1][CH:2]([C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:50]
Reactant: Cc1cccc(Br)c1C(=O)O
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cccc(Br)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
To {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (50 mg, 0.23 mmol) in DCM (5 ml) was added 2-bromo-6-methylbenzoic acid (108 mg; 0.5 mmol), followed by 1-hydroxybenzotriazole (45 mg; 0.3 mmol) and PS-DCC (400 mg of 1.3 mmol/g loading, 0.52 mmol) and the mixture shaken at room temperature for ca. 2 days. The reaction mixture was filtered through a phase-separation cartridge and the filtrate stirred with saturated aqueous sodium bicarbonate for 30 min. The lower layer was removed, passed through another phase-separation cartridge and loaded onto an SCX cartridge which was eluted with 2 column volumes each of DCM, 50% methanol-DCM, methanol and 1M ammonia in methanol. The product containing fractions were evaporated to afford the title product (82 mg; 82%). 1H NMR (CDCl3) δ: 0.95-1.10 (2H, m), 1.40-1.60 (2H, m), 1.60-1.80 (2H, m), 1.80-1.90 (2H, m), 2.23 (6H, s), 2.33 (3H, m), 5.13 (1H, d J=6 Hz), 6.97 (1H, br s), 7.10-7.15 (2H, m), 7.24-7.34 (3H, m), 7.38-7.41 (1H, m), 7.46-7.48 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 415 (MH+). C22H2779BrN2O requires 414. Ret. time 1.93 min.