Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCC1C=NSN=1.[S:8]1[N:12]=[CH:11][C:10]([CH2:13][S:14][CH2:15][CH2:16][SH:17])=[N:9]1.[C:18]([NH:20][C:21](=[N:24][CH3:25])SC)#[N:19]>>[S:8]1[N:12]=[CH:11][C:10]([CH2:13][S:14][CH2:15][CH2:16][S:17][C:21](=[N:24][CH3:25])[NH:20][C:18]#[N:19])=[N:9]1
Reactant: SCCSCc1cnsn1
Reactant: CN=C(NC#N)SC
Agent: BrCc1cnsn1
Product: CN=C(NC#N)SCCSCc1cnsn1

Procedure:
Conversion of 3-bromomethyl-1,2,5-thiadiazole into 2-((1,2,5-thiadiazol-3-yl)methylthio)ethane thiol by the procedure of Example 1 and treatment of this product with N-cyano-N',S-dimethylisothiourea according to the procedure of Example 2 leads to the production of the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:5]1[CH2:4][CH2:3][CH2:2][N:7]2[C:8](=[O:11])[S:9][CH2:10][C:6]=12
Reactant: O=C1N=C(NCCCO)CS1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1SCC2=NCCCN12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 4-[(3-hydroxypropyl)amino]-1,3-thiazol-2(5H)-one (1.36 g) and triphenylphosphine (2.66 g) in THF (15 mL) was added 1.9M diisopropyl azodicarboxylate toluene solution (5.34 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (872 mg).
Reaction SMILES: CS(O)(=O)=O.[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15][OH:16])=[CH:12][CH:11]=1)[CH3:8].[NH2:17][CH2:18][CH2:19][CH2:20]O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:17][CH2:18][CH2:19][CH2:20][O:16][CH2:15][C:13]1[O:14][C:10]([CH2:9][N:7]([CH3:6])[CH3:8])=[CH:11][CH:12]=1
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: NCCCO
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1ccc(COCCCN)o1
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
To a stirred solution of methanesulphonic acid (18 ml) in dry tetrahydrofuran (40 ml) kept at room temperature was added, with stirring, a mixture of 5-[(dimethylamino)methyl]-2-furanmethanol (4.65 g) and 3-amino-1-propanol (6.75 g). After 3 days the suspension was heated on a steam bath for 30 mins. Excess anhydrous sodium carbonate and ethyl acetate (100 ml) were added and the heating continued for 20 mins. The hot suspension was filtered and the residue washed with hot ethyl acetate (3×50 ml). The combined filtrates were evaporated to dryness, water (150 ml) added and the solution extracted with ethyl acetate (3×50 ml). The aqueous fraction was acidified with oxalic acid (5 g) and the solution evaporated to low bulk. Ethyl acetate (100 ml) and excess anhydrous sodium carbonate were added and the suspension heated to boiling point for 30 mins. The hot suspension was filtered and the combined filtrates and washings evaporated to dryness. The oily residue was distilled (100°-110°/0.2 mm) to give the title compound (2.76 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[Na+:21]>C(O)(C)C.C(OCC)C>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O-:4])=[O:2])=[N:6][CH:7]=1.[Na+:21]
Reactant: COC(=O)c1ccc(NCc2cccc(Cl)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: O=C([O-])c1ccc(NCc2cccc(Cl)c2)cn1

Procedure:
To the solution of 7 g of 5-(m-chlorobenzylamino)-pyridine-2-carboxylic acid methyl ester in 30 ml of isopropanol, 15 ml of 2 N aqueous sodium hydroxide are added and the mixture is warmed on the steam bath for 1/2 hour. It is diluted with 20 ml of isopropanol and 20 ml of diethyl ether whereupon a precipitate formes on cooling. It is collected and recrystallized from the mixture of 15 ml of water and 5 ml of isopropanol, to yield the sodium 5-(m-chlorobenzylamino)-pyridine-2-carboxylate melting at 250°-255°.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[CH:7]=1)=[O:4].[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[F:17][C:2]([F:1])([F:16])[C:3]([N:5]([CH3:18])[C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[CH:7]=1)=[O:4]
Reactant: Cc1nc2ccc(NC(=O)C(F)(F)F)cc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(N(C)C(=O)C(F)(F)F)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
A solution of 2,2,2-trifluoro-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (15.0 g, 61.2 mmol) in DMF (100 mL) was treated with K2CO3 (8.448 g, 61.2 mmol) and the reaction mixture was stirred at rt for 1 h, then cooled to 0° C. Iodomethane (3.9 mL, 64.2 mmol) was added dropwise and stirring continued at rt overnight. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organics were washed with brine, dried over Na2SO4 and concentrated to obtain crude 2,2,2-trifluoro-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (16.5 g), (MS: ESI +ve, 259.26 [M+H]).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11]O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[BrH:13].C(OCC)C>C(O)(=O)C>[BrH:13].[Br:13][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[N:2][CH:3]=[CH:4]2
Reactant: OCc1ccc2cnccc2c1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: BrCc1ccc2cnccc2c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of 190 mg (1.19 mmol) of 6-isoquinoline-methanol in 1 ml of glacial acetic acid was treated with 2 ml of 30% HBr in glacial acetic acid and the mixture was heated at 70° C. for 45 minutes. The reaction mixture was cooled, treated with 20 ml of diethyl ether and stirred at 0° C. for 30 min. The resulting solid was filtered off, washed with diethyl ether and dried in a high vacuum. There was obtained 6-bromomethyl-isoquinoline hydrobromide (73% of theory) as a light brown solid; MS: 221, 223 (M)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[F:29])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O.C(Cl)Cl>[F:29][C:19]1[CH:20]=[C:21]([O:24][C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(OC(F)(F)F)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(OC(F)(F)F)cc1F
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)-piperidine-1-carboxylate (420 mg, 0.96 mmol) (from example 58, step 1) was dissolved in MeOH (4 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (40.5 mg, 1.01 mmol) dissolved in water (0.400 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 62 μL, 1.01 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (4.98 mL, 29.91 mmol) and the mixture was stirred at 80° C. for 15 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. Crude trans-methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (365 mg, 94%) was yielded as a colorless oil. MS m/z 405 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:23])(=[O:22])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH:7]=1.CO>>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([NH:13][S:12]([C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:24])=[O:2])[CH:11]=[CH:10][CH:9]=2)(=[O:22])=[O:23])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc(OC)c2)c1
Solvent: CO
Product: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)O)c2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-[3-(3-methoxyphenyl-sulfamoyl)-phenyl]-acrylic acid methyl ester (4i) (0.42 g, 1.2 mmol) in methanol (5.5 ml) 1N NaOH solution (3.6 ml, 3.6 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.38 g, 95%). 1H NMR (DMSO-d6, HMDSO), δ 3.65 (3H, s); 6.40-6.78 (4H, m); 7.16 (1H, m); 7.45-8.09 (5H, m); 10.32 (1H, br s).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21])=[O:7])(C)(C)C.Cl.[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](C(O)=O)=[CH:37]2>O1CCOCC1>[ClH:33].[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]3[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=3[N:30]=1)=[O:21])=[O:7])=[CH:37]2
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1S,2R,4R)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with 5-chloroindole-2-carboxylic acid in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [CH:1]1([CH:7]2[C:13](OC)=[N:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[CH:1]1([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2=[NH:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: COC1=NCCCCC1C1CCCCC1
Reactant: [Cl-]
Solvent: CO
Product: Cl
Product: N=C1NCCCCC1C1CCCCC1

Procedure:
The product of EXAMPLE 93 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29](Cl)[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=2)[N:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=2)[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:24]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: COc1cccc(C(Cl)c2cccc(Br)n2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C(c2cccc(Br)n2)C(c2cccnc2)c2cccnc2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(pyridine-3-ylmethyl)pyridine (2 g, 11.75 mmol) in anhydrous THF (40 mL) @ −78° C. under N2. was added LDA (9.79 mL, 1.8 M) dropwise. The mixture was stirred @ −78° C. for 1 hr and 2-bromo-6-[chloro(6-methoxypyridin-2-yl)methyl]pyridine was added. The mixture was warmed to 0° C. and stirred for 2 hr. The reaction was quenched with saturated aqueous NH4Cl, and extracted 3× with EtOAc. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (1-5% MeOH in CH2Cl2) to give 2-bromo-6-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridine. 1H NMR (500 MHz, CDCl3) δ 8.51 (t, 2H, J=2.7), 8.36-8.28 (m, 2H), 7.69 (dt, 1H, J=8.1, 2.0), 7.58 (dt, 1H, J=8.0, 1.9) 7.50 (d, 1H, J=7.6), 7.38-7.30 (m, 2H), 7.18 (d, 1H, J=7.8), 7.13 (dd, 1H, J=7.9, 4.8), 7.09 (dd, 1H, J=7.8, 4.9), 6.86 (d, 1H, J=7.3), 6.45 (d, 1H, J=8.1), 5.27 (d, 1H, J=12.2), 5.06 (d, 1H, J=12.5), 3.95 (s, 3H), LRMS m/z (M+H) Calcd.: 447.1, found: 447.1. The racemic mixture was separated by ChiralPak AD (40% EtOH in Hexanes+DEA 1 mL/L). The first peak was enantiomer A of 2-bromo-6-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridine, and the second peak was enantiomer B of 2-bromo-6-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridine.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:32][C@H:33]([C:41]([NH2:43])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCC)(=O)C.CC(N(C)C)=O>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:32][C@H:33]([C:41]([NH2:43])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:5]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a solution of Boc-Pro-OH (4.304 g, 20 mmoles) in ethyl acetate (200 mL) at -15° C., N-methylmorpholine (2.2 mL, 20 mmoles) and isobutyl chloroformate (2.6 mL, 20 mmoles) were added. After an activation time of 10 minutes at -15° C., a solution of HCl.Phe-NH2 (4.014 g, 20 mmoles) and N-methylmorpholine (2.2 mL, 20 mmoles) in dimethylacetamide (20 mL) was added. The reaction mixture was stirred at -15° C. for 30 minutes and allowed to warm to room temperature. After stirring for 2 hours at room temperature, the reaction mixture was quenched with 10% potassium carbonate solution (30 mL). The two clear layers were transferred to a separatory funnel, and the organic layer was washed successively with 10% potassium carbonate solution (2×30 mL), saturated sodium chloride solution (1×30 mL), IN HCl (2×30 mL) and saturated sodium chloride solution (2× 30 mL). After drying over anhydrous sodium sulfate, the organic solution was filtered and concentrated on a rotary evaporator under house vacuum. The product was precipitated with hexane, filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Mg+2].[Cl-].[CH2:15]=[O:16]>C(#N)C>[CH:15]([C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])=[O:16]
Reactant: C=O
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: COC(=O)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
Methyl 4-hydroxybenzoate (3.00 g, 19.7 mmol) and magnesium chloride (2.81 g, 29.5 mmol) were stirred in 100 mL of acetonitrile. TEA (10.3 mL, 73.9 mmol) was added via syringe. Paraformaldehyde (12.0 g, 133 mmol) was added in a single portion and the reaction was heated to reflux. The reaction was stirred at reflux for 24 hours and cooled to rt. The reaction was quenched by the addition of approximately 100 mL of 1N HCl and poured into EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography. The clean fractions (by TLC) were concentrated in vacuo to afford 2.06 g (58%) of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 11.54 (s, 1H), 10.27 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.03 (dd, J=8.8, 2.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 3.79 (s, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4Br)=[N:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12>C1(C)C=CC=CC=1.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>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:20]4[CH:19]=[CH:18][CH:17]=[CH:22][N:21]=4)=[N:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1)c1ccccc1-c1ccccn1
Yield: 83 %

Procedure:
A mixture of 484 mg of N-[5-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-pyridinyl]-2-bromobenzamide, 814 mg of 4-(N,N-di-methyl)anilino-tri-n-butyl stannane and 100 mg of tetrakis(triphenylphosphine)palladium (O)is refluxed in degassed toluene for 24 hours. The reaction mixture is concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with ethyl acetate to give 200 mg of the desired product: M+1=528.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[NH:4].[CH3:22][CH2:23]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]([NH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3]2[N:4]=[C:22]([CH3:23])[O:1][N:2]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: COc1ccc(CC(=O)Nc2sccc2C(=N)NO)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: COc1ccc(CC(=O)Nc2sccc2-c2noc(C)n2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3-(N-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide (104 mg, 0.341 mmol) in acetonitrile (2 mL) was added DIPEA (127 mg, 0.987 mmol) and acetyl chloride (48 μL, 0.681 mmol). The resulting solution was stirred at 60° C. for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give 2-(4-methoxyphenyl)-N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)thiophen-2-yl)acetamide. Retention time (min)=6.733, method [7], MS (ESI) 330.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.63 (s, 1H), 7.30-7.35 (m, 3H), 7.00 (d, J=9.2 Hz, 2H), 6.89 (d, J=6.2 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[C:9]([F:17])[CH:8]=1.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.C(=O)=O.CC(C)=O.Cl>O1CCCC1.O>[F:17][C:9]1[CH:8]=[C:7]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:12]=[CH:11][C:10]=1[Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)c1ccc(Br)cc1F
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OB(c2ccc([Si](C)(C)C)c(F)c2)OC1(C)C
Temperature: -78 °C
Yield: 107.3 %

Procedure:
A 2.5 M solution of n-butyllithium (8.5 mL, 21 mmol, 1.1 equiv) was added to a stirred solution of (4-bromo-2-fluorophenyl)trimethylsilane (4.8 g, 19 mmol, 1.0 equiv) in tetrahydrofuran (80 mL) at −78° C. The resulting orange solution was stirred at −78° C. for 15 m. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.4 mL, 21 mmol, 1.1 equiv) was added and the cloudy orange solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and stirred for 20 h. The reaction mixture was diluted with water (200 mL), adjusted to approximately pH 4 using 1M hydrochloric acid, and extracted with dichloromethane (3×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a pale yellow semisolid (6.0 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.55 (dt, J=7.5, 1 Hz, 1H), 7.38-7.42 (m, 2H), 1.34 (s, 12H), 0.29 (d, J=1 Hz, 9H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20].Cl>O.O1CCOCC1.CN(C)C1C=CN=CC=1>[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:1]2[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]2[C:3]([OH:5])=[O:4])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C1CCCCN1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(S(=O)(=O)N2CCCCC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pipecolinic acid (0.331 g, 2.56 mmol) is dissolved in 16 mL mixture of water and p-dioxane (1:1) followed by the addition of triethyl amine (0.78 mL, 5.64 mmol), 4-butoxyphenylsulfonyl chloride (0.67 g, 2.69 mmol), and 4-dimethylaminopyridine (0.031 g, 0.25 mmol). The resulting solution is stirred at room temperature overnight. The reaction mixture is acidified with 1N HCl and extracted three times with ethyl acetate. The combined organic extracts are washed with ammonium chloride, dried (MgSO4), filtered and evaporated to give the crude compound. Cl+ MS: m/z (rel intensity) 342 (M+ +H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[N:12]1([C:18]2([CH2:28][NH2:29])[CH2:21][N:20]([S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH2:19]2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C.C(O)(=O)C(O)=O>ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:28][C:18]1([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:21][N:20]([S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH2:19]1)=[O:5]
Reactant: CCCS(=O)(=O)N1CC(CN)(N2CCOCC2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCCS(=O)(=O)N1CC(CNC(=O)c2ccc(Cl)cc2Cl)(N2CCOCC2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4 %

Procedure:
tert-butyl {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}carbamate (0.98 g, 2.6 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2 eq) was added. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate. The product was extracted into dichloromethane. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}amine which was used without further purification. 2,4-dichlorobenzoyl chloride (0.14 ml, 1.0 mmol) was added to {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}amine in dichloromethane (2 ml) and triethylamine (0.22 ml, 1.6 mmol) at 0° C. The reaction was stirred at 0° C. for 15 mins, before warming to room temperature. After 30 mins, lc-ms showed complete consumption of starting material. The reaction was quenched and the resulting mixture was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by preparative tlc led to 2,4-dichloro-N-{[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as an oil (15 mg, 4%). This was dissolved in hot ethanol (1 ml) and oxalic acid (2 eq) in ethanol (minimum amount) was added. The ethanol was evaporated and the residue triturated with ether to give the oxalate salt of 2,4-dichloro-N-{[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as a white solid (15 mg, 4%). Analytical LCMS: single peak (214 nm), 4.35 min. 1H NMR (400 MHz, DMSO): δ 8.70 (t, J=6.3 Hz, 1 H); 7.71 (d, J=2.0 Hz, 1 H); 7.54-7.46 (m, 2 H); 3.81-3.69 (m, 4 H); 3.59 (d, J=6.3 Hz, 6 H); 3.10-3.04 (m, 2 H); 2.56 (t, J=7.4 Hz, 4 H); 1.74-1.66 (m, 2 H); 0.97 (dd, J=7.4, 7.4 Hz, 3 H).