Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C([O-])(=O)C.[Na+].[Br:18]Br.C(Cl)Cl.CO>C(O)(=O)C>[Br:18][C:8]1[NH:7][C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=1
Reactant: BrBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reaction time: 3 h

Procedure:
100 g of 3-methyl-3,7-dihydropurine-2,6-dione and 49 g of sodium acetate are suspended in 800 ml of glacial acetic acid and heated to an internal temperature of 90° C., and 33.3 ml of bromine are slowly (approx. 3-4 hours) added. The suspension is the stirred at this temperature for 3 hours when, according to TLC (DCM/MeOH 10:1), the reaction is complete. The reaction solution is cooled and filtered with suction. The residue is washed with 100 ml of glacial acetic acid and 500 ml of water and dried in vacuo at 50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([CH2:15][C:16]#[N:17])[CH2:8]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[C:22]([Cl:37])=[CH:21][N:20]=1.Cl.O1CCOCC1>CC(O)C>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:10](=[CH:11][CH:12]=2)[CH:9]2[CH2:13][CH2:14][CH:5]3[CH2:6][N:7]([CH2:15][C:16]#[N:17])[CH2:8]2)=[N:20][CH:21]=1
Reactant: N#CCN1CC2CCC(C1)c1cc(N)ccc12
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(CC#N)C2)ncc1Cl
Temperature: 130 °C

Procedure:
(4-Amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-acetonitrile (30 mg, 0.132 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (48.3 mg, 0.145 mmol, 1.1 eq) were dissolved in IPA (1.2 mL). 4.0 M HCl in dioxane (36 μL, 0.145 mmol, 1.1 eq) was added and the reaction was heated at 130° C. in a microwave for 20 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by preparative HPLC using a gradient of 5-75% acetonitrile/water as the eluting solvent to obtain 2-[5-chloro-2-(10-cyanomethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide as an orange film (13 mg, 19%). LCMS (m/e) 524 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.11 (s, 1H), 8.48 (d, 1H, J=8.3 Hz), 8.07 (s, 1H), 7.95 (dd, 1H, J=1.5 and 8.0 Hz), 7.60-7.53 (m, 1H), 7.35-7.20 (m, 3H), 7.05-6.99 (m, 2H), 4.86 (bs, 1H), 3.55 (s, 2H), 3.10-3.01 (m, 1H), 2.99-2.91 (m, 1H), 2.91-2.83 (m, 2H), 2.64 (s, 3H), 2.58 (d, 2H, J=9.9 Hz), 2.15 (d, 2H, J=8.3 Hz), 1.68 (d, 2H, J=9.4 Hz).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1cccc(F)c1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc(F)c1F
Yield: 87.4 %

Procedure:
2,3-Difluorobenzoic acid (11.6 g, 0.07 mol), thionyl chloride (37.5 ml, 61.1 g, 0.5 mol) and toluene (80 ml) were heated at reflux for 3 h. The solution was cooled and the volatiles were removed in vacuo. The residue was azeotroped with toluene (2×30 ml) to give the product (10.8 g) as a clear yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=1[CH2:20][OH:21])([CH3:3])[CH3:2].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([C:4]1[CH:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:17])([F:18])[F:19])[C:5]=1[CH2:20][O:21][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1)([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)c1cnn(-c2ccccc2OC(F)(F)F)c1CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1nc(OCc2c(C(C)C)cnn2-c2ccccc2OC(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 93.9 %

Procedure:
To an ambient temperature solution of [4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (2.0 g, 6.66 mmol) in degassed toluene (22 mL) is added 6-Chloro-2-methyl-3-nitro-pyridine (1.15 g, 6.66 mmol), cesium carbonate (3.25 g, 9.99 mmol), 2-(Di-t-butylphosphino)-1,1′-binapthyl (332 mg, 0.833 mmol, 12.5 mol %), and palladium (II) acetate (150 mg, 0.666 mmol, 10 mol %). The reaction mixture is heated to 70° C. overnight. The reaction mixture is filtered through a pad of Celite®, is concentrated under reduced pressure, and is chromatographed (0% to 20% EtOAc/Hex) to yield the title compound (2.73 g, 94%). 1H NMR (400 MHz, CDCl3) δ 8.22 (d, 1H, J=8.8 Hz), 7.64 (s, 1H), 7.52 (dd, 1H, J=7.8, 1.7 Hz), 7.49-7.44 (m, 1H), 7.41-7.34 (m, 2H), 6.51 (d, 1H, J=9.2 Hz), 5.35 (s, 2H), 3.05 (sept, 1H, J=7.0 Hz), 2.72 (s, 3H), 1.29 (d, 6H, J=7.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24](/[CH:26]=[C:27]3/[C:28](=[O:33])[NH:29][C:30](=[O:32])[S:31]/3)[CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.CCN(C(C)C)C(C)C.[F:48][C:49]([F:60])([F:59])[O:50][C:51]1[CH:52]=[C:53]([CH2:57][NH2:58])[CH:54]=[CH:55][CH:56]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[O:32]=[C:30]1[NH:29][C:28](=[O:33])/[C:27](=[CH:26]/[C:24]2[CH:23]=[CH:22][N:21]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][C:11](=[O:12])[NH:58][CH2:57][C:53]4[CH:54]=[CH:55][CH:56]=[C:51]([O:50][C:49]([F:48])([F:59])[F:60])[CH:52]=4)[CH2:15][CH2:16]3)[N:25]=2)/[S:31]1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)C1CCN(c2nccc(/C=C3\SC(=O)NC3=O)n2)CC1
Reactant: NCc1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CC(=O)NCc1cccc(OC(F)(F)F)c1)C1CCN(c2nccc(/C=C3\SC(=O)NC3=O)n2)CC1
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
A 2-dram round-bottomed vial was charged with (Z)-3-((tert-butoxycarbonyl)amino)-3-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)propanoic acid, prepared using the general displacement procedure, (25 mg, 0.052 mmol), DMF (1 mL), DIPEA (34.9 μL, 0.209 mmol, 4 equiv.), and (3-(trifluoromethoxy)phenyl)methanamine (7.85 μL, 0.052 mmol, 1 equiv.). The reaction mixture was shaken for 20 minutes then HBTU (29.8 mg, 0.079 mmol, 1.5 equiv.) was added and the reaction mixture was shaken at RT for 3 h. The solvent was removed under reduced pressure (Genevac HT-4) and the resulting solid was washed with water (2×1 mL) and dried under high vacuum to provide 20 mg of (Z)-tert-butyl (1-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)-3-oxo-3-((3-(trifluoromethoxy)benzyl)amino)propyl)carbamate (20 mg, 34.1 mg theoretical, 58.7%).
Reaction SMILES: [CH2:1]([C:14]1[CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[NH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)C.[OH-].[Na+].Cl>O>[CH2:1]([C:14]1[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[NH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCc1c[nH]c(C(=O)O)c1
Yield: 78.9 %

Procedure:
To 10.01 g (32.6 mmol) of methyl 4-tridecylpyrrole-2-carboxylate prepared in Example 32 were added 200 ml of ethanol, 80 ml of water and 5.5 g (131 mmol) of 95% sodium hydroxide and the resulting mixture was heated under reflux for 1 hour. After cooling, 100 ml of water was added thereto. The resulting mixture was acidified with hydrochloric acid and extracted with a mixed solvent of 400 ml of ethyl ether, 100 ml of ethyl acetate and 300 ml of tetrahydrofuran. An aqueous layer was extracted again with 100 ml of ethyl acetate. Then both extracts were combined, washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After concentrating the resulting solution under reduced pressure, the recrystallization of the product from a mixed solvent of hexane and tetrahydrofuran gave 7.55 g of 4-tridecylpyrrole-2-carboxylic acid as white crystals, m.p. 150°-151° C.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[N:9][C:8]=2[N:7]([CH2:20][CH2:21][CH3:22])[C:5]1=[O:6])[CH2:2][CH3:3]>CO.[Ni]>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:19][CH2:18][CH2:17][O:16]3)=[N:9][C:8]=2[N:7]([CH2:20][CH2:21][CH3:22])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccco3)nc2n(CCC)c1=O
Agent: [Ni]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C3CCCO3)nc2n(CCC)c1=O
Yield: 95.9 %

Procedure:
0.35 g 1,3-Dipropyl-8-(2-furanyl)xanthine is dissolved in 50 ml methanol, to which is added 0.5 g Raney nickel and the mixture reduced under a hydrogen atmosphere of 200 psi at 100° C. The mixture is then filtered, the filtrate concentrated to yield 0.34 g of the 1,3-dipropyl-8-(2-tetrahydrofuranyl)xanthine as a white solid, mp 155°-8° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]2[CH2:12][C:13]3[C:25]4[NH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]=4[C:16]4[C:26](=[O:29])[NH:27][CH2:28][C:15]=4[C:14]=3[C:8]=2[CH:7]=1)CCC.[I:38]I.OS([O-])=O.[Na+]>C(Cl)Cl>[I:38][C:6]1[CH:11]=[CH:10][C:9]2[CH2:12][C:13]3[C:25]4[NH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]=4[C:16]4[C:26](=[O:29])[NH:27][CH2:28][C:15]=4[C:14]=3[C:8]=2[CH:7]=1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)-c1c3c(c4c([nH]c5ccccc54)c1C2)C(=O)NC3
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(I)cc1-3
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of 3-tributylstannyl-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Step-1) (16 mg, 0.026 mmol) in dry CH2Cl2 (4 mL) was added a solution of I2 (8 mg, 2 mL CH2Cl2) dropwise. The mixture was stirred at ambient temperature 2 h., then a solution of 10% NaHSO3 was added. After stirring for 10 min. the mixture was filtered. The solid was collected and washed with water, CH2Cl2 and dried under vacuum (100° C., 6 h) to give 6 mg (53%) of Compound I-40, 1H NMR (DMSO-d6, 300 MHz) d 4.29 (s, 2H), 4.96 (s, 2H), 7.33-7.50 (m, 3H), 7.66-7.79 (m, 2H), 8.29 (s, 1H), 8.62 (s, 1H), 8.42 (d, 1H), 12.08 (s, 1H). MS (m/e)=437 (m+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH2:28])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccccc1N
Product: Nc1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 97.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.88 mmol) and o-phenylenediamine (110 mg, 1 mmol) to give 370 mg of the title compound (98%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 9.23 (s, 1H), 7.25 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.13 (dd, 1H, J=8.1 Hz), 6.91 (dt, 1H, J=2, 8.1 Hz), 6.72 (dd, 1H, J=2, 8.1 Hz), 6.54 (dt, 1H, J=8.1, 2 Hz), 5.19~5.27 (m, 1H), 4.85 (br, 2H), 3.10 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.85 (dm, 1H, J=17.1 Hz), 2.61 (d, 2H, J=7.3 Hz), 2.12 (dm, 1H, J=13.5 Hz), 1.81~1.95 (m, 1H).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].[NH2:8][C:9]1[N:13]=[C:12]([S:14][CH3:15])[NH:11][N:10]=1>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:5])[N:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:9]2[N:8]=1
Reactant: CC(=O)CC(C)=O
Reactant: CSc1nc(N)n[nH]1
Solvent: CC(=O)O
Product: CSc1nc2nc(C)cc(C)n2n1
Temperature: 135 °C
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
A mixture of 2,4-pentanedione (11.54 g, 115 mmol), 3-amino-5-methylthio-1H-1,2,4-triazole (15.0 g, 115 mmol), and glacial acetic acid (115 mL) was added to a 1 L RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath to a gentle reflux at 135° C. The mixture was heated for 15 hours. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 and 254 nm. The starting material 3-amino-5-methylthio-1H-1,2,4-triazole elutes rapidly with retention time of 0.7 min, and the product elutes with retention time of 5.0 min. The mixture was cooled to room temperature, then slowly poured into stirring ice/water (750 mL) to precipitate product and stirred ˜20 minutes. Solids were isolated by filtration, rinsed with 250 mL of water, and then dried under reduced pressure to afford the title compound as a powder (15.9 g, 71% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[CH:12](=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C>[N:16]1[CH:17]=[CH:18][C:13](/[CH:12]=[N:1]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][O:5][C:6]3=[O:11])=[CH:14][CH:15]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OCc2c(/N=C/c3ccncc3)cccc21
Temperature: 25 °C
Yield: 77 %

Procedure:
A mixture of 4-aminoisobenzofuran-1(3H)-one (894 mg, 6 mmol), isonicotinaldehyde (2.568 g, 24 mmol) and anhydrous sodium sulfate (3.6 g) in anhydrous ethanol (70 mL) was heated to reflux for two days. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to give the crude product. The crude product was washed with petroleum ether to give (E)-4-(pyridin-4-ylmethyleneamino)isobenzofuran-1(3H)-one (1.1 g, yield 77%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.44 (s, 1H), 7.40-7.42 (d, J=7.6 Hz, 1H), 7.59-7.63 (t, J=7.6 Hz, 1H), 7.77-7.79 (d, J=5.6 Hz, 2H), 7.84-7.86 (d, J=7.6 Hz, 1H), 8.54 (s, 1H), 8.81-8.82 (d, J=4.8 Hz, 1H); LC-MS (ESI) m/z: 239(M+1)+.
Reaction SMILES: [NH2:1][C@H:2]([P:6](=[O:9])([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>[OH-].[Na+].O1CCCC1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:1][C@H:2]([P:6](=[O:8])([OH:7])[OH:9])[CH:3]([CH3:5])[CH3:4])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)[C@H](N)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1)P(=O)(O)O
Temperature: 22 °C
Reaction time: 8 h

Procedure:
250 mg (1.6 mmol) of (R)-(1-amino-2-methylpropyl)phosphonic acid were dissolved in 6 ml of a 1 M NaOH and 6 ml of tetrahydrofuran. 560 mg (1.96 mmol) of 4-chlorobiphenyl-4′-sulfonyl chloride were then added and the mixture was stirred at 22° C. overnight. The reaction mixture was concentrated, acidified with 2 M HCl and extracted with ethyl acetate. The 4-chlorobiphenyl-4′-sulfonic acid resulting as a by-product precipitated and was separated off. After drying and concentrating the ethyl acetate phase, a solid was obtained.
Reaction SMILES: C([C@H](NC(=O)OC(C)(C)C)[C@H](O)CNCC(C)C)C1C=CC=CC=1.C(N(CC)CC)C.[N+](C1C=CC(S([Cl:44])(=O)=O)=CC=1)([O-])=O.[CH2:45]([C@H:52]([NH:73]C(=O)OC(C)(C)C)[C@H:53]([OH:72])[CH2:54][N:55]([CH2:68][CH:69]([CH3:71])[CH3:70])[S:56]([C:59]1[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][CH:60]=1)(=[O:58])=[O:57])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.Cl>C1(C)C=CC=CC=1>[ClH:44].[NH2:73][C@@H:52]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C@H:53]([OH:72])[CH2:54][N:55]([CH2:68][CH:69]([CH3:70])[CH3:71])[S:56]([C:59]1[CH:60]=[CH:61][C:62]([N+:65]([O-:67])=[O:66])=[CH:63][CH:64]=1)(=[O:57])=[O:58]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
(1S,2R)-tert-butyl N-[1-benzyl-2-hydroxy-3-(isobutylamino)propyl]carbamate (127.77 g, 379.7 mmol) was heated in toluene (888 ml) to 80° C. and triethylamine (42.6 g, 417.8 mmol) added. The mixture was heated to 90° C. and a solution of p-nitrobenzene sulphonyl chloride (94.3 g, 425.4 mmol) in toluene (250 ml) was added over 30 minutes then stirred for a further 2 hours. The resultant solution of the nosylated intermediate {(1S,2R)-tert-butyl N-[1-benzyl-2-hydroxy-3-(N-isobutyl- 4-nitrobenzenesulphonamido)propyl]carbamate } was then cooled to 80° C. The solution was maintained at approximately 80° C., and concentrated hydrochloric acid (31.4 ml, 376.8 mmol) was added over 20 minutes. The mixture was heated to reflux (approx 86° C.) and maintained at this temperature for an hour then a further quantity of concentrated hydrochloric acid (26.4 ml, 316.8 mmol) was added. Solvent (water and toluene mixture) was removed from the reaction mixture by azeotropic distillation (total volume of solvent removed approx 600 ml), and the resultant suspension was cooled to 70-75° C. Denatured ethanol (600 ml) was added, and the solution was cooled to 20° C. The mixture was further cooled to approximately −10° C. and the precipitate formed was isolated by filtration, washed with denatured ethanol (50 ml) and dried at approximately 50° C., under vacuum, for approximately 12 hours, to give (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzene sulphonamide hydrochloride (160 g; 73% of theory yield corrected for assay). NMR: 1H NMR (300Mhz, dmso-d6): 8.37(2H, d, J=9 Hz), 8.16(NH3+s), 8.06(2H, d, J=9 Hz), 7.31(5H, m), 5.65(1H, d, J=5 Hz), 3.95(1H, m), 3.39(2H, m), 2.95(5H, m), 1.90(1H, m), 0.77(6H, dd, J=21 Hz and 6 Hz).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][C@@:7]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH2:23])=[CH:18][CH:17]=2)[CH3:15])[CH2:9][CH2:8]1.[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:32][O:33][C:34]1[CH:30]=[CH:31][C:6]([CH2:7][O:3][CH2:4][CH2:5][CH2:6][C@@:7]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]=[CH2:23])=[CH:20][CH:21]=3)[CH3:15])[CH2:9][CH2:8]2)=[CH:5][CH:4]=1
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: C=Cc1ccc([C@H](C)N2CC[C@](CCCOCc3ccc(OC)cc3)(c3ccccc3)OC2=O)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (180 mg, 4.4 mmol) in THF (5 mL) was added a solution of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (800 mg, 2.2 mmol) in THF (10 mL) at 0° C. The resulting mixture was stirred for 30 min. Then PMBCI (520 mg, 3.3 mmol) was added to the above mixture. The mixture was stirred for 3 h. The reaction was quenched with aqueous NH4Cl solution. The organic phase was separated, and concentrated to give the crude (R)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one, which was used for the next step without purification (460 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])=[CH:5][CH:4]=1.[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])#[N:19]>>[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=1)=[O:24])#[N:19]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(OCc2ccccc2N)cc1
Product: COc1ccc(OCc2ccccc2NC(=O)c2cccc(C#N)c2)cc1

Procedure:
Using a procedure similar to Example 1B except starting from 2-[(4-methoxyphenoxy)methyl]aniline and 3-cyanobenzoyl chloride, the title compound was obtained as a solid (0.50 g, 36%); MS(FD): 359.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:24]([SH:29])[CH2:25][CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN1C(=O)CCC1>[CH3:23][N:22]1[C:18]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][O:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([S:29][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:7]=2)=[N:19][N:20]=[N:21]1
Reactant: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Reactant: CCCCCS
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: CN1CCCC1=O
Product: CCCCCSc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 120 °C
Reaction time: 0.02 h
Yield: 18.3 %

Procedure:
To a solution of N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.3 g, 0.80 mmol, 1 eq.) in 2 ml of NMP were added 1-pentanethiol (0.084 g, 0.80 mmol, 1 eq.), Cs2CO3 (0.262 g, 0.80 mmol, 1 eq.). The reaction was microwaved (30 sec prestirring, abs-normal, fixed-hold) 120° C. for 60 s. Then a mixture water/EtOAc (1/1) was added and the aqueous layer was separated and extracted with EtOAc. The organics were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 1-(1-methyl-1H-tetrazol-5-yl)-N-{[6-(pentylsulfanyl)pyridin-2-yl]methoxy}-1-phenylmethanimine (0.058 g, 17% yield) as a viscous oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C1(C)C=CC(S(O[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=O)=O)=CC=1>>[CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:4]1
Reactant: CNC1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Product: CNC1CCN(CCc2ccc(F)cc2)C1

Procedure:
3-Methylaminopyrrolidine and 2-(4-fluorophenyl)ethyl p-toluenesulfonate are reacted under the same conditions as in Starting Material Synthetic Example 4 to give 3-methylamino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine.