Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=O.C(O)(C)C.[NH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[ClH:1].[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:15]2[NH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]=2[CH2:13][CH2:12][NH:11]1
Reactant: O=CCCCCl
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Solvent: CC(C)O
Product: Cl
Product: ClCCCC1NCCc2c1[nH]c1ccccc21
Yield: 31.6 %

Procedure:
200 parts of a 17.5% strength by weight solution of γ-chlorobutyraldehyde in xylene, 212 parts of isopropanol, 52 parts of 3-(β-aminoethyl)-indole and 388 parts of a 10% strength by weight aqueous sulfuric acid were stirred for 5 hours at 82° C., the mixture was cooled and the product was filtered off under suction and washed with 100 parts of isopropanol. 36 parts (31.6%) of 1-(γ-chloropropyl)-1,2,3,4-tetrahydro-β-carboline hydrochloride of melting point 216°-220° C. were obtained (cf. Example 1).
Reaction SMILES: [C-]#[N:2].[K+].S(=O)(=O)(O)O.[CH3:9][C:10](O)([CH3:21])[CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20].[C:23](=[O:26])([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH3:9][C:10]([NH:2][CH:23]=[O:26])([CH3:21])[CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1cc(C)c(CC(C)(C)O)c(C)c1
Reactant: O=C([O-])[O-]
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C)c(CC(C)(C)NC=O)c(C)c1

Procedure:
90 mL of glacial acetic acid and 33 g of potassium cyanide are combined while cooling with ice. 90 mL of sulfuric acid and 90 mL of glacial acetic acid are then added dropwise at 20° C. 65 g of 2-methyl-1-(2,4,6-trimethylphenyl)propan-2-ol is slowly added to the solution at constant temperature. After the addition has ended, the mixture is stirred for a further hour. The mixture is poured onto ice water, neutralized with sodium carbonate solution, and extracted with diethyl ether. The solvent is distilled off under reduced pressure and the residue is fractionally distilled. Yield: 55 g (74%); bp0.1: 155° C.
Reaction SMILES: CS(Cl)(=O)=O.C1CCNCC1.[CH2:12]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]([F:50])([F:49])[C:29]1[CH:30]=[C:31]([CH:46]=[CH:47][CH:48]=1)[C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:37])=[O:33].C1(N=C=O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:12]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:43]2[CH2:44][CH2:45][CH:40]([CH2:39][NH:38][C:36](=[O:37])[CH2:35][NH:34][C:32](=[O:33])[C:31]3[CH:46]=[CH:47][CH:48]=[C:29]([C:28]([F:50])([F:49])[F:27])[CH:30]=3)[CH2:41][CH2:42]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccc(Cc2ccccc2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: O=C=Nc1ccccc1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A chloroform (1.0 mL) solution of methanesulfonyl chloride (4.2 mg, 0.037 mmol) and a (piperidinomethyl)polystyrene (54 mg, 2.7 mmol base/g resin) were added to a chloroform (1.0 mL) solution of 4-(benzyl)benzyl alcohol (8.7 mg, 0.044 mmol), and the resulting mixture was stirred at 25° C. for 15 hours. 4-[[N-(3-(Trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (15.1 mg, 0.044 mmol) and KI (2 mg) were then added to the reaction mixture, and the resulting mixture solution was further stirred at 65° C. for 5 hours. Phenyl isocyanate (5.2 mg) was added to the cooled reaction mixture, and the obtained mixture was stirred at 25° C. for 1 hour. The resulting reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (20 mL). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated to thereby afford 1-(4-benzylbenzyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 926) as an off-white oil (5.6 mg, 29%). The purity was determined by RPLC/MS (94%). ESI/MS m/e 524.1 (M++H, C30H32F3N3O2).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[N:14][OH:15])[O-])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:28]=[C:27]([Cl:37])[CH:26]=1.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:32][C:31]([C:29]3[CH:28]=[C:27]([Cl:37])[CH:26]=[C:25]([Cl:24])[CH:30]=3)([C:33]([F:34])([F:36])[F:35])[O:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: [O-]C(=NO)c1ccc(Br)c2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3ccccc23)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a stirred solution of 4-bromo-1-naphthalenecarboxylate oxime (i.e. the product from Step A) (2.33 g, 9.3 mmol) in N,N-dimethylformamide (6.0 mL) was added N-chlorosuccinimide (1.70 g, 12.7 mmol). The reaction mixture was stirred for 1 h at room temperature, and then a solution of 1,3-dichloro-5-[1-(trifluoromethyl)ethenyl]benzene (i.e. the product from Step B of Example 1) (2.70 g, 11.2 mmol) and triethylamine (4.5 mL, 32.0 mmol) in N,N-dimethylformamide (9.0 mL) was added. After stiffing for additional 2 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexanes/ethyl acetate as eluent to afford the title compound as a white solid (2.9 g, 64% yield).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:19](=[O:21])[CH3:20])[C:10]([O:14][CH2:15][CH:16]=[CH:17]C)=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:31](O)C>O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:19](=[O:21])[CH:20]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]([O:14][CH2:15][C:16]([CH3:17])=[CH2:31])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1
Reactant: CC=CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: CCO
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=C(C)COc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-methylallyloxy-8-acetylcoumarin (2.04 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.2 g of product m.p. 158-160° C., 1H-NMR (CDCl3) δ: 1.74 (s, 3H); 2.43 (s, 3H); 4.55 (s, 2H); 4.98 (d, 2H, J=15 Hz); 6,16 (s, 1H); 6.93 (d, 1H, J=8;9 Hz); 7.02 (d, 1H, J=16 Hz); 7.43-7.53 (m, 4H); 7.61 (d, 1H, J=8.9 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[NH:19])([O-:18])=[O:17]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCSCc1cccnn1
Product: N=C(NCCSCc1cccnn1)N[N+](=O)[O-]

Procedure:
Reaction of 3-[(2-aminoethyl)thiomethyl]pyridazine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(3-pyridazinylmethylthio)ethyl]guanidine. Similarly, by the procedure of Example 2(iii), there is obtained N-methyl-N'-nitro-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)[CH:12]=[N:13][C:14]=2[Cl:15])=[CH:3][CH:2]=1.[CH2:23]=O.Cl>C(O)=O>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH3:23])[CH:12]=[N:13][C:14]=2[Cl:15])=[CH:3][CH:2]=1
Reactant: Clc1ncc(OC[C@@H]2CCCN2)cc1C=Cc1ccncc1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CCC[C@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(2-(S)-pyrrolidinyl-methoxy)pyridine from Example 33 (110 mg, 0.27 mmol) was added formalin (38%, 3.0 mL) and formic acid (88%, 1.5 mL). The mixture was refluxed for five hours then cooled to room temperature. Hydrochloric acid (36%, 0.3 mL) was added, and the mixture was extracted with Et2O (3×8 mL). The aqueous layer was heated under vacuum to dryness. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl3 /MeOH 10:1 to afford an oil (72 mg, 83%). MS (CI/NH3) m/z 330 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.70-2.10 (m, 4H), 2.38-2.40 (m, 1H), 2.51 (s, 3H), 2.65-2.76 (m, 1H), 3.10-3.19 (m, 1H), 3.96-4.10 (m, 2H), 6.96-7.04 (m, 1H), 7.39-7.44 (m, 2H), 7.53 (s, 1H), 7.52-7.60 (m, 1H), 8.05-8.08 (m, 1H), 8.63-8.67 (m, 1H).
Reaction SMILES: [S:1]1[C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][N:3]=[CH:2]1.C(O)(C(F)(F)F)=O.[Br:27][C:28]1C(Cl)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1>C(Cl)Cl>[Br:27][C:28]1[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[S:1][CH:2]=[N:3][CH:4]=3)[CH2:12][CH2:11]2)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cncs2)CC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Br)c(N2CCN(Cc3cncs3)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 73.8 %

Procedure:
tert-Butyl 4-(thiazol-5-ylmethyl)piperazine-1-carboxylate (0.350 g, 1.23 mmol, 1.1 eq) was dissolved in DCM (3.9 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (3.9 mL). Stirring was continued at this temperature for 1 h. Solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. The resulting 5-(piperazin-1-ylmethyl)thiazole (supposedly 0.230 g, 1.23 mmol, 1 eq) was suspended in iPrOH (2.4 mL) and DIPEA (0.70 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.280 g, 1.12 mmol, 1 eq) was added and the mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.330 g, 67%); 1H-NMR (500 MHz, DMSO-d6): δ 2.51-2.58 (br s, 4H, piperazine N(CH2)2), 3.01-3.10 (m, 4H, piperazine N(CH2)2), 3.82 (s, 2H, NCH2), 6.98 (s, 2H, NH2), 7.78 (s, 1H, thiazole 4-H), 8.16 (s, 1H, pyridine 6-H), 9.03 (s, 1H, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=2.17 min—399/401 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:11]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=1>>[CH2:3]([N:2]([CH3:1])[C:11]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: Clc1cncc(Cl)n1
Product: CN(Cc1ccccc1)c1cncc(Cl)n1
Yield: 70 %

Procedure:
In a procedure analogous to Example 1, reaction of N-methyl benzylamine and 2,6-dichloropyrazine furnished the product (70%).
Reaction SMILES: C(O[C:6]1[C:14](OC)=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=1OC)CCC.[NH2:19]CC1(N(C)C)CCOCC1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:10]([NH2:19])(=[O:11])[C:9]1[CH:13]=[CH:14][CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C1(CN)CCOCC1
Reactant: CCCCOc1c(OC)cc(C(=O)O)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
4-n-butoxy-3,5-dimethoxybenzoic acid represented by Formula 90 (6 g, 23.60 mmol) prepared in Preparative Example 2 above was slowly added to a solution of 4-(aminomethyl)-N,N-dimethyltetrahydro-2H-pyran-4-amine represented by Formula 95 (3.73 g, 23.60 mmol) and diisopropylethylamine (12.36 mL, 70.78 mmol) in DMF (80 mL) at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 8.97 g, 23.60 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and ethyl acetate was added to the remaining concentrate to prepare a solution. The prepared solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. Then, after drying the organic layer with magnesium sulfate (MgSO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (chloroform/methanol, 10:1) using silica gel (SiO2). After dissolving the obtained organic product in ethyl acetate, 2 M-ethylether chloride solution (14.16 mL, 28.31 mmol) was added thereto, followed by agitation at 45° C. for 15 minutes. Thereafter, the solvent was filtered to obtain a product in a powder form and the product was recrystallized in ethanol-methanol to thus produce a benzamide compound represented by Formula 6 as a desired product (VVZ-005; 6.77 g, 66% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cccc(F)c4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid (17 mg, 0.057 mmol), N3-(3-Fluoro-phenyl)-1H-indazole-3,5-diamine (14 mg, 0.057 mmol) and PyBroP (27 mg, 0.057 mmol) in methylene chloride (1 ml) was added diisopropylethylamine 20 μL. The mixture was allowed to stir overnight at room temperature and the titled compound (7.5 mg, 25%) was purified with HPLC. MS (ESI) m/z=493 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ8.02 (s, 1H), 7.38-7.30(m, 3H), 7.23-7.15 (m, 2H), 7.01-6.99 (m, 2H), 6.91-6.86 (m, 2H), 6.58-6.53 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1)(=[O:9])=[O:8].C(N(CC)CC)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:19])=[CH:13][CH:12]=1)(=[O:8])=[O:9]
Reactant: C1COCCN1
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(CC(=O)O)cc2)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(CC(=O)N3CCOCC3)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.4 %

Procedure:
To a solution of {4-[(2,4-dimethoxybenzylsulfamoyl)methyl]phenyl}acetic acid (356 mg) in DMF (15 ml) were added triethylamine (237 mg), morpholine (97 mg) and HATU (392 mg). The mixture was stirred at room temperature for 17 h, then added to water (200 ml) and extracted with ethyl acetate. After washing with water, 1 M hydrochloric acid, sodium hydrogencarbonate solution and sodium chloride solution, the organic phase was dried over magnesium sulfate and concentrated. This gave the product (313 mg) with a molecular weight of 448.5 g/mol (C22H28N2O6S).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[CH2:30]([O:32][C:33](=[O:55])[C@H:34]([OH:54])[C@H:35]([NH:43][C:44](=[O:53])[C:45]1[CH:50]=[CH:49][C:48]([F:51])=[C:47](Br)[CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:31].C([O-])([O-])=O.[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[C:1]([O:5][C:6]([C:8]1[C:9]([C:47]2[CH:46]=[C:45]([C:44](=[O:53])[NH:43][C@H:35]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:34]([C:33]([O:32][CH2:30][CH3:31])=[O:55])[OH:54])[CH:50]=[CH:49][C:48]=2[F:51])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1ccc(F)c(-c2ccccc2C(=O)OC(C)(C)C)c1
Temperature: 100 °C

Procedure:
2-t-Butoxycarbonylphenylboronic acid pinacol ester (173 mg, 568 μmol, 1.2 eq.) and toluene (661 μL) were added to (2R,3R)-3-(3-bromo-4-fluoro-benzoylamino)-2-hydroxy-4-phenyl-butyric acid ethyl ester (201 mg, 474 μmol, 1.0 eq.), followed by EtOH (361 μL) then K2CO3 (131 mg, 947 μmol, 2.0 eq.) predissolved in water (124 μL). The mixture was stirred to aid in dissolution. The reaction vessel was purged with nitrogen then Pd(PPh3)4 (54.7 mg, 47.4 μmol) was added quickly. The reaction vessel was capped and heated to 100° C. for 30 minutes. The organics were removed and evaporated under vacuum to yield 5′-((1R,2R)-1-benzyl-2-ethoxycarbonyl-2-hydroxy-ethylcarbamoyl)-2′-fluoro-biphenyl-2-carboxylic acid t-butyl ester.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][CH:11]3[CH:15](C(OC)=O)[C:16]([O:18][CH3:19])=[O:17].CS(C)=O.[Na+].[Cl-]>O>[CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][CH:11]3[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C(=O)OC)C1CCn2c1cc1c(SC)nccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CC1CCn2c1cc1c(SC)nccc12
Reaction time: 18 h

Procedure:
To a mixture of dimethyl 2-[1-(methylthio)-7,8-dihydro-6H-pyrido[3,4-b]-pyrrolizin-8-yl]malonate (0.59 g, 2.17 mmol) and DMSO (4mL) was added NaCl (0.45 g) in H2O (0.45 mL). After a period of 18 h at 150° C., the reaction mixture was partitioned between ETOAc and H2O. The organic phase was separated, dried over Na2SO4 and evaporated. The title compound was then purified by flash chromatography.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[OH:6][CH2:7][CH:8](S(C)(=O)=O)[C@@H:9](O)[C:10]([OH:12])=[O:11].O1C[C@H]1CC([O-])=O>>[O:6]1[CH2:7][C@H:8]1[CH2:9][C:10]([O-:12])=[O:11].[C:1]([NH3+:5])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)C(CO)[C@@H](O)C(=O)O
Agent: O=C([O-])C[C@@H]1CO1
Product: CC(C)(C)[NH3+]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
t-butyl amine (571mg, 7.81mmol) was added to the reacting solution of D2O containing (S)-4-hydroxy-3-methanesulfonyl hydroxybutyric acid, so prepared from Example 3 and stirred at room temperature for 4 hours. The presence of the target t-butyl anmmonium (R)-3,4-epoxybutyrate in a layer of the reacting solution was confirmed by nuclear magnetic resonance.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:28]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:36][CH2:37][OH:38]>>[CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:28]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH2:36][CH2:37][OH:38])[CH2:24][CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 45.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mL, 0.43 mmol) and 2-bromo ethanol (37 mg, 0.52 mmol) to give 7-cyclopentyl-2-{5-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 48%). MS (ESI) m/z 478.3 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[NH2:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:29]([OH:33])[C:30]([NH2:32])=[O:31].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[NH2:32][C:30](=[O:31])[CH:29]([OH:33])[CH:28]([NH:27][C:14]([C@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To the solution of (R)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid (475 mg, 2.167 mmol) in a mixture of 15 ml of THF and 0.5 ml of DMF at 5° C. were successively added 1-hydroxybenzotriazole (365 mg, 2.383 mmol), 3-amino-2-hydroxy-4-phenylbutanamide (421 mg, 2.167 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC; 457 mg, 2.383 mmol) and DIPEA (0.416 mL; 308 mg, 2.383 mmol). After stirring overnight at room temperature the solvent was evaporated under reduced pressure, water was added to the remaining residue and after stirring for 30 minutes at about 5° C. the precipitate was filtered off. Drying under reduced pressure gave the title compound as an off-white powder (786 mg; yield: 92%) which was used without further purification in the next step.