Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCI
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1cc(C(=O)OC)ccc1I
Yield: 99 %

Procedure:
In a manner similar to that of Example (25a), by reaction of 21.5 mL (0.189 mol, 1.5 eq) of 1-iodobutane and 35.03 g (0.126 mol, 1 eq) of methyl 3-hydroxy-4-iodobenzoate in 350 ml of methyl ethyl ketone in the presence of 52.24 g (0.378 mol, 3 eq) of potassium carbonate at 85° C. for 2 hours 30 minutes, and after washing with heptane, 41.78 g of methyl 3-butoxy-4-iodobenzoate are obtained in the form of white crystals. Yield=99%
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[C:14](O)(=O)[CH:15]([CH3:17])[CH3:16].[OH-].[NH4+]>Cl>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:14]([CH:15]([CH3:17])[CH3:16])=[N:1][C:2]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: CC(C)C(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)c1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To 50 ml of 4 N hydrochloric acid containing 11.8 g of 2-amino-4-chloro-5-sulfamylaniline was added 7.0 g of isobutyric acid and the suspension refluxed for 6 hours. The mixture was concentraded in vacuo to a solid and the solid then added with stirring to 38% ammonium hydroxide and stirred for thirty minutes at 50° C. The solid was collected by filtration, air dried, dissolved in isopropanol, and charcoal added. After boiling for five minutes, the suspension was filtered, cooled, and then filtered through Celite. Recrystallization from isopropanol provided 2.0 g of off-white crystals, mg 256°-259°.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH3+:6])[CH2:4][O:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.CCN(CC)CC.[C:25]1([CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO>C(Cl)Cl>[O:1]=[C:2]1[C@@H:5]([NH:6][C:33](=[O:34])[CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][O:3]1
Reactant: [NH3+][C@H]1COC1=O
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CCc1ccccc1)N[C@H]1COC1=O
Yield: 60 %

Procedure:
To a stirred mixture of 3 (0.4 mmol) in dry CH2Cl2 (2 mL), kept at 0° C. under N2, Et3N (1.59 mmol) and 3-phenylpropionyl chloride (0.6 mmol) were added dropwise. The mixture was reacted at 0° C. for 30 min and at room temperature for 2 h, then concentrated. Purification of the residue by flash-chromatography (cyclohexane/EtOAc 1:1 to 3:7) and recrystallization gave URB783 as a white solid. Yield 60%. Mp 104-106° C. (acetone/petroleum ether). [α]D20=−13° (c 0.5, MeOH). MS (EI): m/z 219 (M+), 91 (100). IR (Nujol) 3333, 1832, 1625, 1541 cm−1; 1H NMR (CDCl3) δ 2.57 (br s, 1H), 2.99 (t, 2H), 4.34 (t, 1H, J=5 Hz), 4.43 (dd, 1H, J1=5 Hz, J2=6.5), 5.14 (m, 1H), 5.96 (br s, 1H), 7.18-7.36 (m, 5H) ppm. 13C NMR (CDCl3): δ 31.2 (CH2), 37.7 (CH2), 58.4 (CH), 66.1 (CH2), 126.5 (CH), 128.3 (2CH), 128.7 (2CH), 140.2, 168.4 (C═O), 172.5 (C═O) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][NH:14]2)=[O:12])=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C@H:13]2[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][N:14]2[C:38](=[O:39])[NH:37][C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)=[O:12])=[CH:8][CH:9]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2C(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Into a solution of 8 (9.19 g, 33.0 mmol) in anhydrous THF (200 mL) at 0° C. was added N,N-diisopropylethylamine (DIEA) (28.7 mL, 165 mmol) and 4-chlorophenyl isocyanate (5.07 g, 33.0 mmol). The solution was stirred at RT overnight before concentrating under reduced pressure. The crude material was purified on a silica gel column eluted with 10% moving to 50% EtOAc in hexanes. Combined and concentrated pure fractions. Remaining EtOAc was azeotroped off with acetonitrile and was lyophilized from acetonitrile/water to give 9 (13.37 g, 94%) as a solid. MS: APCI (AP+): 432.1 (M)+, (AP−): 430.1 (M)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18](I)=[C:11]2[N:12]=[C:13]([CH3:17])[NH:14][C:15](=[O:16])[N:10]2[N:9]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CO.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)=[C:11]2[N:12]=[C:13]([CH3:17])[NH:14][C:15](=[O:16])[N:10]2[N:9]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1nc2c(I)c(-c3ccccc3Cl)nn2c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COCCOC
Product: Cc1nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c(=O)[nH]1

Procedure:
To a mixture of 7-(2-chlorophenyl)-8-iodo-2-methyl-3H-pyrazolo-[1,5-a][1,3,5]triazin-4-one (I-1A-1d; 141 g, 364 mmol) and 4-chlorophenylboronic acid (85.1 g, 544 mmol) in dimethoxyethane (1.4 L) was added 2 M aqueous Na2CO3 (365 ml) and then (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II), dichloromethane complex (5.80 g, 7.17 mmol). The reaction was heated at reflux for 16 hours, cooled, and the organic layer separated and then concentrated under reduced pressure. The residue was dissolved in methyltetrahydrofuran (1.4 L) and washed with 1 M aqueous NaOH (2×700 ml) and 1 M aqueous HCl (700 ml). The solvent was removed, in vacuo, to give a brown solid which was suspendend in methanol (1.2 L). The mixture was concentrated to one-third volume, the solids were collected by vacuum filtration in a course sintered glass funnel, washed with methanol (1 L) and then dried, in vacuo, to afford product I-2A-1a as a light-brown solid (103 g, 76%): +APcI MS (M+1) 371.3; 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.54-7.43 (m, 4H), 7.35-7.26 (m, 4H), 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[Br-:12].[K+].BrBr>O>[Br:12][C:8]1[CH:9]=[C:2]([F:1])[C:3]([O:10][CH3:11])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: [Br-]
Reactant: COc1cc(C=O)ccc1F
Agent: BrBr
Agent: [K+]
Solvent: O
Product: COc1cc(C=O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
A solution of 4-fluoro-3-methoxybenzaldehyde (4.3 g, 27.9 mmol), potassium bromide (16.6 g, 139.5 mmol), bromine (3.6 mL, 69.8 mmol), and water (45 mL) were stirred at room temperature for 24 hours. More bromine (1.43 mL, 27.9 mmol) was added and the reaction was stirred at room temperature overnight. The product precipitated out of solution and was collected via filtration and dried under reduced pressure to give 2-bromo-4-fluoro-5-methoxybenzaldehyde (6.01 g, 92% yield).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29](Cl)=[O:30])[CH:25]=1>C(Cl)Cl>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:29]([C:26]2[CH:25]=[C:24]([CH3:23])[O:28][N:27]=2)=[O:30])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CC(Oc3ccccc3C(C)(C)C)C2)no1
Yield: 83.5 %

Procedure:
To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.18 g, 0.80 mmol) and triethylamine (0.24 g, 2.4 mmol) in methylene chloride (4.0 mL) was added 5-methylisoxazole-3-carbonyl chloride (0.12 g, 0.80 mmol) at room temperature. After 2 h the reaction mixture was directly purified by flash column chromatography (silica gel, 80:20 heptane/ethyl acetate) to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(5-methylisoxazol-3-yl)methanone (0.21 g, 83%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11]C(=O)C)=[CH:6][C:5]=1F)(=[O:3])[CH3:2].[ClH:16].[OH-].[Na+]>C(O)C>[NH2:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([Cl:16])[CH:6]=1
Reactant: CC(=O)Nc1cc(C)c(C(C)=O)c(F)c1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1c(C)cc(N)cc1Cl
Yield: 86 %

Procedure:
An ethanol solution (51 mL) containing N-(4-acetyl-3-fluoro-5-methylphenyl)acetamide (30-2, 5.80 g, 27.7 mmol) and concentrated hydrochloric acid (20.0 mL) was heated at reflux for 15 h. The solution was added with 10% aqueous NaOH and the resultant solids were collected to give 1-(4-amino-2-chloro-6-methylphenyl)ethanone (30-3, 4.00 g, 23.9 mmol) as light yellow solids in 86% yield: 1H NMR (500 MHz, DMSO-d6) δ 6.22 (m, 2 H), 2.37 (m, 3 H), 2.22 (s, 3 H). ESI-MS: m/z 167.8 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C([O-])(O)=O.[Na+].CC(O[CH2:20][C:21]1[CH2:30][S:29][C@@H:24]2[C@H:25]([NH2:28])[C:26](=[O:27])[N:23]2[C:22]=1[C:31]([OH:33])=[O:32])=O.Cl>P([O-])([O-])([O-])=O>[NH2:28][CH:25]1[C:26](=[O:27])[N:23]2[C:22]([C:31]([OH:33])=[O:32])=[C:21]([CH2:20][S:1][C:2]3[N:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]4=[N:4][N:3]=3)[CH2:30][S:29][C@H:24]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Sc1nnc2ccccn12
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc4ccccn34)CS[C@H]12

Procedure:
To a hot (60°) solution of 3-mercapto-s-triazolo[4,3-a]pyridine [D. S. Tarhell et al., J. Am. Chem. Soc. 70, 1381 (1948)] (1.51 g., 10 mmole) and NaHCO3 (1.68 g., 20 mmole) in 0.1 M pH 7.4 phosphate buffer (50 ml.) was added portionwise 7-ACA (2.72 g., 10 mmole) and the mixture was heated at 80°-85° for 30 min. The reaction mixture being treated with carbon, the filtrate was acidified to pH 5 with dil. HCl to give 7-amino-3-(s-triazolo[4,3-a]pyridin-3-ylthiomethyl)-3-cephem-4-carboxylic acid which was collected by filtration, washed with water (10 ml.) and dried in vacuo on P2O5. Yield 1.40 g. (39%). M.p. 215°-220° (dec.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:46])[CH2:15][CH2:16][CH:17]2[CH2:24][N:23]3[C:25]4[CH:26]=[C:27]([C:38]([O:40][CH3:41])=[O:39])[CH:28]=[CH:29][C:30]=4[C:31]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[C:22]3[C:21]3[CH:42]=[CH:43][CH:44]=[CH:45][C:20]=3[O:19][CH2:18]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:32]1([C:31]2[C:30]3[CH:29]=[CH:28][C:27]([C:38]([O:40][CH3:41])=[O:39])=[CH:26][C:25]=3[N:23]3[C:22]=2[C:21]2[CH:42]=[CH:43][CH:44]=[CH:45][C:20]=2[O:19][CH2:18][CH:17]([CH2:16][CH2:15][C:14](=[O:46])[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:24]3)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COc1ccccc1-3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)N1CCNCC1)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methyl 7-{3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-3-oxopropyl}-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.04 M) in DCM was treated with TFA (170 eq) and stirred at RT overnight. The volatiles were then removed in vacuo and the residue partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product as an off-white foam (100%) that was used without further purification. (ES+) m/z 530 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[OH:7])=[CH:4][C:3]=1[F:10]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1ccc(Br)c(F)c1
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Bromo-3-fluorobenzaldehyde (as described in Example 18, Step A) (3.61 g, 17.7 mmol) was dissolved in anhydrous diethyl ether (40 mL). To this solution was added a 1.0M solution of 4-chlorophenyl-magnesium bromide (21.3 mL, 21.3 mmol). After stirring at ambient temperature for 4 hr the reaction was quenched with satd. NH4Cl and extracted with Et2O. The organic layer was washed with satd NaHCO3 solution, water, brine, dried (MgSO4), concentrated and purified by chromatography (SiO2, 10% EtOAc/hexane) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]O.P(Br)(Br)[Br:12]>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][Br:12]
Reactant: OCc1cc(F)cc(Br)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1cc(Br)cc(CBr)c1
Reaction time: 3 h

Procedure:
To a solution of 3-Bromo-5-fluorobenzyl alcohol (2.3 g, 0.011 mole) in CH2Cl2 (15 mL) was added 12.4 mL of 1.0M PBr3 (3.33 g, 0.0123 mole) in CH2Cl2, stirred for 3 hr, diluted with ether (100 mL), washed with H2O (50 mL, 3×), dried over MgSO4, concentrated, and purified by column chromatography using 1:9 ethyl acetate/hexane as an eluant solvent system. 3-Bromo-5-fluorobenzyl bromide was obtained as a white crystalline material was obtained, mp 41-43° C. 1H NMR (DMSO-d6) δ 4.69 (s, 2H), 7.52(d, 1H, J=1.76 Hz) 7.54(d, 1H, J=1.91 Hz), 7.56 (s, 1H); MS(EI): M+. m/z 266; Anal. Calc. For C7H5Br2F: C, 31.38; H, 1.88. Found: C, 31.75, H, 1.78.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Br:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15]Br>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl>[Br:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: BrC/C=C/CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: BrC/C=C/COCc1ccccc1
Reaction time: 48 h
Yield: 47.7 %

Procedure:
A solution of 10.8 ml of benzyl alcohol (103 mmol), 3.16 g of tetrabutylammonium bisulfate (58.5 mmol) and 8.63 g of sodium hydroxide (840 mmol) in water (45.6 ml) was added to a solution of 20.0 g of trans-1,4-dibromo-2-butene (94.7 mmol) in methylene chloride (80 ml) at room temperature, and the mixture was stirred for two days. The reaction mixture was diluted with 300 ml of water, followed by extraction with methylene chloride. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=20/1) to obtain 10.9 g of the title compound (yield: 48%).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([C@H:20]1[CH2:27][C:24]2([CH2:26][CH2:25]2)[CH2:23][NH:22][C@@H:21]1[C:28](O)=[O:29])=[O:19])([CH3:16])([CH3:15])[CH3:14].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:28]([C@@H:21]3[C@@H:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:27][C:24]4([CH2:25][CH2:26]4)[CH2:23][NH:22]3)=[O:29])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN[C@@H]1C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
1-Phenylpiperazine (124 mg, 0.76 mmol) was added to a mixture of (6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acid (180 mg, 0.70 mmol) and BOP (320 mg, 0.75 mmol) in DMF (4 mL) at 0° C. The mixture was stirred at 0° C. for 10 min, then N-methylmorphol (300 μL) was added. The resulting mixture was stirred at RT for overnight, diluted with 5% NaHCO3 and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated brine and dried over Na2SO4. The solution was filtered and concentrated to afford 248.4 mg of the tert-butyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Sc1sc3c(c1C(=O)N2)CCCC3
Reactant: CN1CCNCC1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)Sc1sc3c(c1C(N1CCN(C)CC1)=N2)CCCC3

Procedure:
In the same manner as in Example 80 and using 1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 1,2,3,4-tetrahydro-8-methyl-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:16]=[C:9]2[N:10]=[CH:11][C:12]([Br:15])=[C:13]([CH3:14])[C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Br:15][C:12]1[CH:11]=[N:10][C:9]2=[N:16][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=3)([C:3]#[N:4])[CH3:17])[N:7]=[C:8]2[C:13]=1[CH3:14]
Reactant: Cc1c(Br)cnc2nn(CC(C)(N)C#N)nc12
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: Cc1c(Br)cnc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1,2-amino-3-(6-bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-2-methylpropionitrile (90 mg, described in Example 153) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (65 mg, 43%). Rf=0.4 (1:1 EA/heptane). MS (ES): M/Z [M−H]=497. 1H NMR: (400 MHz, DMSO-d6): 1.76 (s, 3H), 2.56 (s, 3H), 5.40 (d, 1H), 5.54 (d, 1H), 7.82-7.94 (m, 4H), 8.86 (s, 1H) and 8.93 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[BrH:14].N([O-])=O.[Na+]>O>[Br:14][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Br
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cc(C(=O)O)c1

Procedure:
99.18 g (0.55 mol) of 5-aminoisophthalic acid, 165 mL of 48 weight % hydrobromic acid and 150 mL of distilled water were charged in a 1 L four-neck flask equipped with a thermometer, an agitator and a dropping funnel, and then agitated. The flask was cooled to 5° C. or below, and 525 mL of distilled water containing 39.4 g (0.57 mol) of sodium nitrite was added dropwise for an hour, thus obtaining diazonium aqueous solution. 94.25 g (0.66 mol) of cuprous bromide and 45 mL of 48 weight % hydrobromic acid were charged in a 3 L four-neck flask equipped with a thermometer, a Dimroth condenser, a dropping funnel and an agitator, and agitated.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]2[C@@H:27]([C:28]([OH:30])=O)[CH2:26][S:25][CH2:24]2)=[O:22])=[CH:16][CH:15]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][C:39]2=[O:44])=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([N:23]2[C@@H:27]([C:28]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][C:39]4=[O:44])=[CH:36][CH:37]=3)=[O:30])[CH2:26][S:25][CH2:24]2)=[O:22])=[CH:18][CH:19]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C(O)[C@H]1CSCN1C(=O)Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CSCN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.2 498 mg (2.60 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 573 mg (2.00 mmol) of (S)-3-(4-chlorophenylcarbamoyl)thiazolidine-4-carboxylic acid and 384 mg (2.00 mmol) of 4-(4-aminophenyl)morpholin-3-one in 4 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 18 hours. The reaction mixture is added to saturated sodium hydrogencarbonate solution, and the precipitate formed is filtered off, giving 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(S)-thiazolidine-3,4-dicarboxamide (“A3”) as a colourless solid; ESI 461.
Reaction SMILES: [Li]CCCC.[O:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[N:32]2[C:36]([CH3:37])=[C:35](I)[N:34]=[N:33]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2].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>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[N:32]2[C:36]([CH3:37])=[C:35]([C:7]3[O:6][CH:10]=[CH:9][N:8]=3)[N:34]=[N:33]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1c(I)nnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: c1cocn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ncco2)nnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of n-BuLi (0.5 mL, 2.5 M solution in hexanes) in THF (3 mL) was added oxazole (0.1 mL, 1.5 mmol) via dropwise addition and the solution was stirred for 30 minutes. ZnCl2 solution (3.9 mL, 0.5 M in THF) was then added and the reaction mixture was warmed to room temperature and stirred an additional 2 hours. Pd(PPh3)4 (20 mg, 0.015 mmol) and 4-tert-butyl-N-[4-chloro-2-(4-iodo-5-methyl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure P, 77 mg, 0.15 mmol) were then added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was subsequently diluted with EtOAc (25 mL) and the combined organics were washed with water (20 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by preparative TLC to afford the title compound: MS (ES) M+H expected 472.1, found 472.0.