Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C@@H:10]1[C@@H:15]([NH2:16])[CH2:14][C@H:13]2[CH2:17][C@@H:11]1[C:12]2([CH3:19])[CH3:18].C(N(CC)CC)C.[C:27](Cl)(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C@@H:10]1[C@@H:15]([NH:16][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][C@H:13]2[CH2:17][C@@H:11]1[C:12]2([CH3:19])[CH3:18]
Reactant: CCCCCC(=O)Cl
Reactant: CC1(C)[C@H]2C[C@H](N)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCC(=O)N[C@H]1C[C@H]2C[C@@H]([C@@H]1CCOC1CCCCO1)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a atmosphere of argon, to a mixture of (1S,2S, 3S,5R)-10-(tetrahydropyran-2-yloxy)methylpinan-3-ylamine (20 g; prepared in reference example 8), triethylamine (25 ml) and anhydrous tetrahydrofuran (200 ml), a solution of caproyl chloride (13 ml) in anhydrous tetrahydrofuran (30 ml) was dropped and the mixture was stirred for 2 hrs at room temperature. The diluted solution with diethyl ether was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to give the title compound (28 g) having the following physical data:
Reaction SMILES: C(OC(=O)C1C=CC=C(C#C[C:13]2[CH:25]=[CH:24][C:16]3[O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][O:21][C:15]=3[CH:14]=2)C=1)C.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])=[CH:31][CH:30]=1)#[CH:28].IC1C=CC2OCC(C)(C)COC=2C=1>>[CH3:22][C:19]1([CH3:23])[CH2:18][O:17][C:16]2[CH:24]=[CH:25][C:13]([C:28]#[C:27][C:29]3[CH:34]=[CH:33][C:32]([C:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:36])=[CH:31][CH:30]=3)=[CH:14][C:15]=2[O:21][CH2:20]1
Reactant: C#Cc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CCOC(=O)c1cccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)c1
Agent: CC1(C)COc2ccc(I)cc2OC1
Product: CC1(C)COc2ccc(C#Cc3ccc(C(=O)N4CCOCC4)cc3)cc2OC1

Procedure:
The title compound is prepared in analogy to 3-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-benzoic acid ethyl ester (10) from (4-ethynyl-phenyl)-morpholin-4-yl-methanone and 7-iodo-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (5) as a yellow viscous oil, MS (ESI) 392.3 (M+H)+.
Reaction SMILES: P(=O)(O)O.C[O:6][P:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:19]([CH3:37])=[C:18]2[CH2:38][C:39]([NH2:41])=[O:40])(=[O:10])[O:8]C.C[Si](Br)(C)C.CO>C(Cl)Cl>[NH2:41][C:39](=[O:40])[CH2:38][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][P:7](=[O:6])([OH:10])[OH:8])[CH:16]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:19]=1[CH3:37]
Reactant: COP(=O)(CCCOc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1-c1ccccc1)OC
Agent: C[Si](C)(C)Br
Agent: O=[PH](O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1c(CC(N)=O)c2cc(OCCCP(=O)(O)O)ccc2n1Cc1ccccc1-c1ccccc1
Reaction time: 0.75 h
Yield: 33.3 %

Procedure:
[3-[[3-(2-Amino)-2-oxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-5-yl]oxy]propyl]phosphonic acid. [3-[[3-(2-Amino-2-oxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester (130 mg, 0.25 mmol) and 0.3 mL (3 mmol) of trimethylsilyl bromide in 2 mL of methylene chloride was stirred for 16 hours, 5 mL of MeOH added, stirred 0.75 hours and concentrated at reduced pressure. The residue was crystallized from EtOAc/MeCN/HOAc/water to give 41 mg (33% yield) of [3-[[3-(2-amino-2-oxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-5-yl]oxy]propyl]phosphonic acid, mp, 200-202° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16].[O:17]([CH2:24][CH2:25]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16]
Reactant: BrCCOc1ccccc1
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(N2CCN(CCOc3ccccc3)CC2)cc(=O)n(C)c1=O
Yield: 64 %

Procedure:
1.12 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)pyrimidinedione and 1.4 g of phenoxyethyl bromide were dissolved in 5 ml of ethanol, and 1.0 g of triethylamine was then added, followed by heating under reflux for 1 hour. Furthermore, 0.6 g of phenoxyethyl bromide was added, and the solution was heated under reflux for 2 hours. The precipitated crystals were collected by filtration, washed with water, dried and then recrystallized from hexane/ethanol to obtain 1.1 g (yield: 63%) of 1,3-dimethyl-6-[4-(2-phenoxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:23]1[CH:27]=[CH:26]N=C1)=O.C(N(CC)CC)C.Cl.C(N)C>C(#N)C>[C:1]1([CH:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]2[CH2:9][CH:10]([C:12]([NH:23][CH2:27][CH3:26])=[O:14])[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Yield: 114 %

Procedure:
To a solution of 7.5 g (28 mmole) of 1-(diphenylmethyl)azetidine-3-carboxylic acid in 75 ml of acetonitrile was added 6.0 g (37 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated at 60° C. for two hours and successively treated with 3.1 g (30.8 mmole) of triethylamine and 2.52 g (30.8 mmole) of ethylamine hydrochloride. The reaction was stirred at 60° C. for an additional hour, the solvent evaporated in vacuo and the residue dissolved in chloroform. After washing with water and drying over magnesium sulfate, the chloroform layer was evaporated in vacuo to give 9.4 g of 1-(diphenylmethyl)-N-ethyl-3-azetidinecarboxamide, mp 91°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[C:10]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)[CH:11]=O.C1(P(=[CH:46][CH:47]=[O:48])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[C:10]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)[CH:11]=[CH:46][CH:47]=[O:48]
Reactant: Cc1ccc(C(=C(C=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1ccc(C(=C(C=CC=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Yield: 89.9 %

Procedure:
A solution of 3,3-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal (1.35 g, 3.8 mmoles) and triphenylphosphoranylidene acetaldehyde (1.16 g, 3.8 mmoles) in benzene was heated at reflux for 3 hours. The solvent was removed and the residue purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride. The fractions containing material having Rf =0.9 [methanol-methylene chloride; 1:20 (v/v)] were combined and concentrated to give 1.3 g of the title compound; m.p.=88°-108° C.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13](O)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.C([N:25]1CCOCC1)C.C(OC(Cl)=O)C(C)C.N>O1CCCC1.C(OCC)(=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([NH2:25])=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1
Reactant: CCN1CCOCC1
Reactant: Cc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Reaction time: 0.17 h

Procedure:
5 g of BOC-D-Cys(MBzl)-OH are dissolved in 60 cc of dry tetrahydrofuran, the solution is cooled to -15°, 1.85 cc of N-ethylmorpholine are added, and then 1.92 cc of chloroformic acid isobutyl ester are added, and the mixture is stirred for 10 minutes. Dry ammonia gas is subsequently passed through the solution at -15° while stirring, stirring is continued for 2 hours, whereby the temperature rises to room temperature. The reaction mixture is diluted with approximately 800 cc of ethyl acetate, is washed with water, and the organic phase is dried over sodium sulphate. Concentration, filtration, washing with ethyl acetate/ether and drying are effected, and the title compound is obtained. M.P. 140°; [α]D20 = +26° in dimethyl formamide.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:29]([CH3:41])[C:30](=[O:40])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]CO)[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[Br:5][CH2:2][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH3:41])=[O:40]
Reactant: CCCCN(C)C(=O)COCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)COCCCCCCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
9.3 g of tetrabromomethane and 7.4 g of triphenyl phosphine were added at -15° C. to a solution of 5.52 g of the product of Step B in 55 ml of methylene chloride and the reaction mixture was stirred for one hour at 0° C., then chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 6.22 g of the expected product.
Reaction SMILES: [S:1]([CH2:11][N+:12]#[C-:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:14]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[O:22][CH2:23][O:24][C:16]=2[CH:15]=1.[C-]#N.[Na+]>>[O:24]1[C:16]2[CH:15]=[CH:14][C:19]([C@@H:20]3[O:21][CH:13]=[N:12][C@@H:11]3[S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])=[CH:18][C:17]=2[O:22][CH2:23]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@H]2c2ccc3c(c2)OCO3)cc1

Procedure:
In a manner analogous to Preparation 1, tosylmethylisocyanide (0.23 g, 1.20 mmol), piperonal (0.19 g, 1.26 mmol) and NaCN (5.9 mg, 0.12 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 346.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13]Br.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: BrCCCCBr
Reactant: Nc1cccc(O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1cccc(N2CCCC2)c1
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A solution of m-aminophenol (12.6 gm, 0.115 moles) and 1,4-dibromobutane (50 gm, 0.23 moles) was heated to 130° C. for 12 hr. The mixture was cooled to room temperature and triturated with diethylether and then ethyl acetate. The residue was dissolved in ethyl acetate and extracted with 1 M NaOH, water, and sat. NaCl. After drying the organic layer with MgSO4, filtering, and evaporating solvent under vacuum, the crude product was purified by silica gel chromatography to give a pale yellow solid. The solid was refluxed with 500 ml toluene and 17 ml triethylamine (0.12 moles) for one hr, cooled to room temperature and washed with water and sat. NaCl. The solution was dried again over MgSO4, filtered, and evaporated under vacuum to give 3-pyrrolidinylphenol as a white solid (6.0 gm, 0.037 moles, 32%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[Br:6][C:7]1[CH:8]=[CH:9][C:10](F)=[N:11][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:2]1([C:10]2[CH:9]=[CH:8][C:7]([Br:6])=[CH:12][N:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Fc1ccc(Br)cn1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Brc1ccc(N2CCC2)nc1
Temperature: 95 °C
Yield: 85.7 %

Procedure:
A mixture of azetidine HCl salt (590 mg, 6.3 mmol), 5-bromo-2-fluoropyridine (1.11 g, 6.3 mmol), Cs2CO3 (4.1 g, 12.6 mmol) and dry DMSO (7 mL) was stirred and heated at 95° C. for 20 h. The reaction mixture was cooled and filtered. The solid was treated with H2O, extracted with CH2Cl2×3. The combined organic layers were dried, filtered to provide 1.15 grams (86%) of desired product as a light yellow solid. MS (M+H)=213.0/215.0. 1H NMR (CDCl3) δ 8.18 (d, 1H), 7.50 (dd, 1H), 6.18 (d, 1H), 4.03 (t, 4H), 2.40 (q, 2H).
Reaction SMILES: [CH2:1]([S:6](Cl)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1>N1C=CC=CC=1.ClCCl>[F:34][C:31]([F:32])([F:33])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:15]=[CH:16][C:11]([NH:10][S:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[CH:12][CH:13]=2)[CH2:22][CH2:21]1)=[O:24]
Reactant: CCCCCS(=O)(=O)Cl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCS(=O)(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4 %

Procedure:
1-Pentanesulfonyl chloride (0.034 g, 0.30 mmol) was added slowly to a solution of [4-(5-aminopyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone in pyridine (2 mL) at 0° C. The mixture was stirred at 25° C. for 16 hours and then diluted with dichloromethane. The organic phase was washed with water and saturated NaCl solution, dried over anhydrous MgSO4. After removal of dichloromethane, the product was purified by column chromatography to afford the title compound in 4% yield (2.7 mg). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.87, 7.74, 7.61, 7.36, 6.94, 4.47, 4.11, 3.87, 3.68, 3.60, 3.42, 2.99, 1.77, 1.32, 0.88. MS (ES+) m/z 485.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[F:1][C:2]1[C:3]([CH2:11][OH:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=Cc1cc2c(cc1F)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1cc2c(cc1F)OCO2
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of 6-fluoro-benzo[1,3]dioxole-5-carbaldehyde (700 mg, 4.2 mmol) in MeOH (50 mL) was added NaBH4 (320 mg, 8.4 mmol) in portions at 0° C. The mixture was stirred at this temperature for 30 min and was then concentrated in vacuo to give a residue. The residue was dissolved in EtOAc and the organic layer was washed with water, dried over Na2SO4, and concentrated in vacuo to afford (6-fluoro-benzo[1,3]dioxol-5-yl)-methanol (650 mg, 92%), which was directly used in the next step.
Reaction SMILES: [H-].[Na+].CS(C)=O.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1.Br[CH2:21][CH2:22][CH2:23]Br>CC(OC)(C)C>[F:7][C:8]([F:18])([F:19])[C:9]1[CH:10]=[C:11]([C:15]2([C:16]#[N:17])[CH2:23][CH2:22][CH2:21]2)[CH:12]=[CH:13][CH:14]=1
Reactant: BrCCCBr
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
The mixture of sodium hydride (1.312 g, 54.7 mmol) and DMSO was stirred for about 10 minutes at room temperature. Then a solution of 2-(3-(trifluoromethyl)phenyl)acetonitrile (5 g, 24.86 mmol) and 1,3-dibromopropane (5.02 g, 24.86 mmol) in MTBE (80 mL) was added dropwise via dropping funnel. After addition, the mixture was stirred for about 12 hours, and quenched with 60 mL of water. The aqueous phase was extracted with MTBE (3×30 mL). The combined organic layers were washed with water (3×30 mL) and brine (3×30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel column (20:1 Hexanes/ethyl acetate) to obtain the title compound as a transparent liquid (3.8 g, 63.4%). LC-MS: m/z (M+H) 226.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44](=[O:52])[NH:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][NH2:51])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:38]1[C:39]2[CH:40]([CH2:42][O:43][C:44](=[O:52])[NH:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][NH:51][C:11]([C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[C:3]([NH:14][C:15]5[S:16][C:17]6[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=6[N:19]=5)=[N:4][C:5]=4[CH:10]=3)=[O:12])[C:41]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:35]=[CH:36][CH:37]=1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCNC(=O)OCC3c4ccccc4-c4ccccc43)ccc21
Yield: 75.5 %

Procedure:
[2-(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (106 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (80 mg), [2-(2-amino-ethoxy)-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (80 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[C:19]([CH3:22])[N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:17][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:18])[N:7]3[C:19]([CH3:22])=[CH:20][S:21][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][NH:28]3)[CH3:3])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 110 °C
Yield: 50.8 %

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.105 g, 0.327 mmol) (1st peak from Example 23, step 1 chiral separation), 6-bromo-9H-purine (0.117 g, 0.588 mmol), and N,N-diisopropylethylamine (0.114 mL, 0.654 mmol) in ethanol (1.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (0.073 g, 51%). LCMS calculated for C20H16F2N7OS (M+H)+: m/z=440.1. Found: 440.0. 1H NMR (DMSO-d6, 500 MHz) δ 8.05 (2H, s), 7.34 (1H, br s), 7.18 (1H, m), 7.12 (2H, m), 6.84 (1H, s), 7.01 (1H, s), 5.07 (1H, m), 2.43 (3H, s), 1.31 (3H, d, J=7.0 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −111 ppm.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Temperature: 150 °C
Yield: 81.9 %

Procedure:
29.2 g (157 mmol) of 1,1-dimethylethyl 1-piperazine-carboxylate, 37 g (157 mmol) of 2,5-dibromopyridine and 21.7 g (157 mmol) of potassium carbonate suspended in 27 ml of dimethyl sulfoxide (DMSO) are introduced into an autoclave. The mixture is then heated at 150° C. for 21 hours. The reaction mixture is allowed to cool to room temperature, it is taken up in ethyl acetate and water and the insoluble material is then separated out by filtration. The aqueous phase is separated out and extracted twice with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, eluting with a 99/1 mixture of dichloromethane and methanol. 44 g of product are thus obtained in the form of a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N:14]([CH2:17][C:18]([O:20][CH2:21]C)=[O:19])=[N+:15]=[N-:16].C[O-].[Na+]>CO.[Cl-].[Na+].O>[N:14]([C:17](=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)[C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(=Cc1ccc(-n2ccnc2)cc1)N=[N+]=[N-]
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of 4-(1-imidazolyl)benzaldehyde (1.41 g, 8.16 mol) and ethyl azidoacetate (10.6 g, 81.7 mmol) in MeOH (50 ml) under nitrogen atmosphere is added sodium methoxide (28 wt. % solution in MeOH, 13,2 ml, 65 mmol) dropwise. Stirring is continued for 1.5 h. Then, the reaction mixture is diluted with brine (100 ml) and extracted with three portions of ether. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give methyl 2-azido-3-[4-(1-imidazolyl)phenyl]-2-propenate.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])=[O:38])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: O=C=NC(=O)Cc1ccccc1F
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5F)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 308 (320 mg, 0.90 mmol) and (2-fluoro-phenyl)-acetyl isocyanate (600 mg, 3.35 mmoL) [A. J. Hill et al. JACS, 62; 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and gradient eluted with EtOAc, to MeOH/EtOAc (20:80), to afford the title compound 309b in 42% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.10 (s, 1H), 10.58 (s, 1H), 8.42(d, 1H, J=5.5 Hz), 7.94(d, 1H, J=1.1 Hz), 7.82-7.77 (m, 2H), 7.65 (s, 1H), 7.45-7.30 (m, 4H), 7.19-7.16 (m, 2H), 6.54(dd, 1H, J1=0.7 Hz, J2=5.4 Hz), 4.04(q, 2H), 3.83 (s, 2H), 1.38(t, 3H). MS (m/z): 534.1 (M+H) (found).