Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[C:13]([C:17]1[CH:18]=[CH:19][C:20]([C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][C:25]=2[CH3:30])=C(C=1)N)([CH3:16])([CH3:15])[CH3:14].[CH3:31][NH:32][C:33]([C:35]1[CH:40]=[C:39]([O:41][C:42]2[CH:48]=CC(N)=[CH:44][CH:43]=2)[CH:38]=[CH:37][N:36]=1)=[O:34]>C(Cl)Cl.CCOC(C)=O>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][C:25]=2[CH3:30])=[C:9]([NH:8][C:6]([NH:3][C:2]2[CH:1]=[CH:48][C:42]([O:41][C:39]3[CH:38]=[CH:37][N:36]=[C:35]([C:33](=[O:34])[NH:32][CH3:31])[CH:40]=3)=[CH:43][CH:44]=2)=[O:7])[CH:10]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: Cc1cc(-c2ccc(C(C)(C)C)cc2N)c(C)[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)ccc3-c3cc(C)[nH]c3C)cc2)ccn1
Temperature: 36 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
To a stifling solution of CDI (0.21 g, 1.30 mmol) in CH2Cl2 (2 mL) was added 5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp. for 4 h, then 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.267 mmol) was then added in one portion. The resulting mixture was heated at 36° C. overnight, then cooled to room temp. and diluted with EtOAc (5 mL). The resulting mixture was sequentially washed with water (15 mL) and a 1N HCl solution (15 mL), dried (MgSO4), and filtered through a pad of silica gel (50 g) to afford N-(5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane) Rf 0.24; 1H NMR (acetone-d6) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M+H)+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=1>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1ccc2ncccc2c1)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 6-aminoquinoline (72 mg, 0.75 mmol) and 4-biphenylcarboxylic acid (149 mg, 0.75 mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.22 (d, 1H), 8.88 (dd, 1H), 8.52 (d, 1H), 8.33 (dd, 1H), 8.19 (d, 1H), 8.13 (d, 1H), 8.09 (d, 1H), 8.08 (m, 3H), 7.91 (d, 1H), 7.72 (dd, 1H), 7.52 (m, 3H), 7.43 (dd, 1H).
Reaction SMILES: C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]2N=C(N)N)[C@H]([O:25][C@@H:26]2[O:31][C@@H:30]([CH2:32][OH:33])[C@H:29]([OH:34])[C@@H:28]([OH:35])[C@@H:27]2NC)[C@@]1(O)C=O.[OH:41]S(O)(=O)=O.N[C@H](C(O)=O)CCCCN>>[O:33]=[CH:32][C@@H:30]([C@H:29]([C@@H:28]([C@@H:27]([CH2:26][OH:25])[OH:41])[OH:35])[OH:34])[OH:31]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]3N=C(N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: O=S(=O)(O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 20 h

Procedure:
196ΔcadAΔldcCΔfadR/pCABD2 strain was cultured at 37° C. for 20 hours on the LB agar medium containing 20 mg/L of streptomycin sulfate. The cells on the agar medium were scraped, inoculated into 4 mL of an L-lysine production medium containing 20 mg/L of streptomycin sulfate contained in a large diameter test tube, and cultured at a culture temperature of 37° C. for 24 hours. For the main culture, the saccharified solution of Example 4 (1) prepared from starches produced by Chlorella kessleri (1.33 g/L in terms of glucose amount), and the hydrolysis reaction mixture of Example 4 (1) prepared from starches and fat or oil were used as carbon sources. As a control, the culture was performed in a medium containing glucose at the same concentration as a carbon source.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[F:32][C:33]([F:44])([F:43])[CH2:34]OS(C(F)(F)F)(=O)=O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:34][C:33]([F:44])([F:43])[F:32])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(CC(F)(F)F)c2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reaction time: 4 h
Yield: 38.2 %

Procedure:
To a suspension of 0.50 g (0.0017 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.50 g (0.0034 mole) of potassium carbonate and 10 mL of tetrahydrofuran was added 0.46 g (0.0020 mole) of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester. After stirring at 75 degrees for four hours, the mixture was cooled and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with ethyl acetate-hexane (gradient, 100:0-30:70) gave 0.25 g of 2-chloro-9-cyclopentyl-7,7-difluoro-5-(2,2,2-trifluoro-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-150)
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:22]=2[N:23]=1.[CH3:32][O:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:32][O:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:35]1
Reactant: CO[C@@H]1CCCNC1
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
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: CO[C@@H]1CCCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(C(F)(F)F)cc4s2)n3C)C1
Yield: 30.8 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((R)-3-methoxy-piperidin-1-yl)-2-oxo-ethyl]amide (30 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (80 mg), (R)-3-methoxy-piperidine (100 mg), HBTU (200 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 546.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.54-8.53 (m, 1H), 8.28 (s, 1H), 8.12 (s, 1H), 7.83-7.81 (d, 1H), 7.71 (m, 2H), 7.56-7.54 (d, 1H), 4.24-4.18 (m, 1H), 4.12-4.08 (m, 1H), 3.73-3.71 (m, 1H), 3.70 (s, 3H), 3.52-3.47 (m, 1H), 3.38-3.34 (m, 2H), 3.31-3.25 (m, 4H), 1.88-1.81 (m, 1H), 1.71-1.62 (m, 1H), 1.45-1.36 (m, 1H), —NH proton signal was not observed.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:10]([C:24]([O:26]C(C)(C)C)=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:23])([C:19]([F:20])([F:21])[F:22])[C:15]([F:17])([F:18])[F:16])[CH:11]=[C:10]([C:24]([OH:26])=[O:25])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a DCM (7.8 mL) solution of tert-butyl 4′-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]biphenyl-3-carboxylate (0.6 g, 1.5 mmol) from step A was added trifluoroacetic acid (7.8 mL). The mixture was stirred at rt for 2 h and concentrated to dryness. The crude title compound was used in step C without further purification.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:56][C:57]1[C:61]([C:62](Cl)=[O:63])=[C:60]([CH3:65])[O:59][N:58]=1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:54][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][C:50]=1[Cl:53])[CH2:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C@H:37]2[CH2:36][O:35][C:31]3=[CH:32][C:33]4[CH2:34][C@@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]5[CH:13]=[CH:12][C:11]([C:14]6[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=6[CH3:21])=[CH:10][CH:9]=5)[C:5]([OH:4])=[O:55])=[O:24])[N:26]([C:62]([C:61]5[C:57]([CH3:56])=[N:58][O:59][C:60]=5[CH3:65])=[O:63])[CH2:27][C:28]=4[CH:29]=[C:30]3[O:38]2)=[CH:44][CH:43]=1
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3c(C)noc3C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexa hydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was dissolved in 1:1 EtOAc and saturated aqueous NaHCO3 and 3,5-dimethyl-isoxazole-4-carbonyl chloride (3 eq.) were added. After stirring at room temperature for 1 hour, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified by over silica (hexanes to 8:2 hexanes-EtOAc to 6:4 hexanes-EtOAc to 6:4 hexanes-EtOAc+2% MeOH to DCM+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (16 mg). LCMS (m/z): 862.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([O-:10])=[O:9])(=[O:3])[CH3:2].[Na+].[CH3:19][C:20]([O:23][C:24]([C:26]1[N:27]2[C@H:30]([S:31][CH2:32][C:33]=1[CH2:34]I)[C@H:29]([NH:36][C:37](=[O:46])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:28]2=[O:47])=[O:25])([CH3:22])[CH3:21].CCCCCC.CCOC(C)=O>CN(C=O)C>[CH3:22][C:20]([O:23][C:24]([C:26]1[N:27]2[CH:30]([S:31][CH2:32][C:33]=1[CH2:34][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([O:14][C:15](=[O:17])[CH3:16])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)[CH:29]([NH:36][C:37](=[O:46])[CH2:38][O:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:28]2=[O:47])=[O:25])([CH3:19])[CH3:21]
Reactant: CC(=O)Oc1ccc(C(=O)[O-])cc1OC(C)=O
Reactant: CC(C)(C)OC(=O)C1=C(CI)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)OCC2=C(C(=O)OC(C)(C)C)N3C(=O)C(NC(=O)COc4ccccc4)C3SC2)cc1OC(C)=O
Reaction time: 2 h

Procedure:
By following the procedures and conditions described in Example 4, 2.33 g (8.95 mmol) of sodium 3,4-diacetoxybenzoate in 100 mL of DMF added to 4.75 g (8.95 mmol) of (6R-trans)-3-(iodomethyl)-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 50 mL of DMF, followed by stirring for 2 hours, gave 3.36 g (58.5%) of a cream colored solid after silica gel chromatography (6:4 hexane/EtOAc).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[CH3:2].[OH-].[Na+].[S:24](=[O:28])(=O)(O)[OH:25]>>[CH2:20]([O:19][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[S:24]([C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)(=[O:28])=[O:25])[CH3:21]
Reactant: CCOC(CNCc1ccc2c(c1OC)OCO2)OCC
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
62.29 g (0.2 mol) of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde dimethylacetal (1) obtained in Example 2 was dissolved in 400 ml of 6N sulfuric acid. After stirring at 76°-78° C. for 1.5 hours, the reaction mixture was cooled and pH was adjusted to about 11 by adding 25% aqueous solution of sodium hydroxide at temperature lower than 30° C. It was extracted with 200 ml and then 100 ml of methylene chloride successively, which were combined and washed with 100 ml of water and then dried over anhydrous magnesium sulfate. The salt was filtered out and the filtrate was concentrated under vacuum. The residue was dissolved under heating by adding 120 ml of ethanol and then cooled to 5° C. to deposit crystals. The crystals were collected by filtration, washed with 30 ml of cold ethanol and then dried under vacuum to obtain 38.09 g (yield 83%) of 4-hydroxy-8-methoxy-2-methyl- 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (2), m.p. 152°-3° C. IR and NMR spectra of the resultant product are listed below. ##STR35##
Reaction SMILES: [C:1]([O:8][CH2:9]Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:11]1[CH:12]=[CH:13][C:14]2[S:19][N:18]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]4[CH:29]=[C:30]5[CH2:38][C:36](=[O:37])[NH:35][C:31]5=[CH:32][C:33]=4[Cl:34])[CH2:22][CH2:21]3)[C:15]=2[CH:16]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1.C.[Cl-].[Cl-]>[C:1]([O:8][CH2:9][N:35]1[C:31]2[C:30](=[CH:29][C:28]([CH2:27][CH2:26][N:23]3[CH2:24][CH2:25][N:20]([C:17]4[C:15]5[CH:16]=[CH:11][CH:12]=[CH:13][C:14]=5[S:19][N:18]=4)[CH2:21][CH2:22]3)=[C:33]([Cl:34])[CH:32]=2)[CH2:38][C:36]1=[O:37])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Reactant: CCCCCC(=O)OCCl
Agent: C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OCN1C(=O)Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc21
Reaction time: 24 h
Yield: 27 %

Procedure:
Chloromethyl hexanoate (3.18 g, 19.0 mmol) in dichloromethane (6 mL) was added to a suspension of Ziprasidone free base (4.0 g, 9.6 mmol), triethyl amine (4.0 mL, 27 mmol) and 4-dimethylamino pyridine (DMAP, 0.708 g, 5 mmol) in dichloride methane (240 mL) at 25-30° C. The reaction solution was stirred for 24 h at same temperature. The crude mixture was washed with water (100 mL) followed by brine solution (100 mL), upon solvent evaporation under vacuum below 40° C. provided crude title product, Compound 322, which was further purified by silica gel column chromatography. (1.4 g, 27% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.OCCC1C=C[N+:16]([O-])=[CH:15]C=1.C[Si](C#N)(C)C>>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:15]#[N:16])[CH:5]=1
Reactant: OCCc1ccncc1
Reactant: [O-][n+]1ccc(CCO)cc1
Agent: C[Si](C)(C)C#N
Product: N#Cc1cc(CCO)ccn1

Procedure:
4-(2-hydroxyethyl)-pyridine is oxidized to 4-(2-hydroxyethyl)-pyridine-N-oxide which is in turn treated with trimethylsilyl cyanide to yield 4-(2-hydroxyethyl)-2-cyanopyridine which is converted to ethyl 4-(2-hydroxyethyl)-2-pyridine carboxylate and then hydrogenated to yield ethyl 4-(2-hydroxyethyl)-piperidine-2-carboxylate.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([Br:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: BrC(Br)(Br)Br
Reactant: C=CCCCCCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 12-tridecen-1-ol (2.11 g, 10.7 mmol) and carbon tetrabromide (4.37 g, 13.1 mmol) in dichloromethane (15 ml) at 0° C. was added triphenyl phosphine (3.45 g, 13.1 mmol) in portions over 5 min. After stirring for 1.5 h at 25° C. the solvent was evaporated and the residue extracted with hexane (3×30 ml), filtering off any solids. The solvent was evaporated to afford 12-tridecenyl bromide as a clear oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc(F)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(F)c2)cc1-c1c(Br)cnn1C
Yield: 75 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.033 g, 0.12 mmol) was treated with 3-fluorophenyl isocyanate (0.017 g, 14.3 μL, 0.12 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 18 (0.040 g, 0.09 mmol, 82%) as a white solid. LCMS m/z (%)=419 (M+H79Br, 100), 421 (M+H81Br, 91). 1H NMR (400 MHz, acetone-d6) δ: 8.31 (s, 1H), 8.17 (s, 1H), 7.69 (dd, J=2.7, 9.0 Hz, 1H), 7.59 (dt, J=2.2, 12.0 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.1, 15.0 Hz, 1H), 7.11-7.19 (m, 2H), 6.73 (ddd, J=2.4, 8.4 Hz, 1H), 3.82 (s, 1H), 3.69 (s, 1H).
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN([CH:25]=[O:26])C>C1CCCCC1>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([SH:21])=[C:19]([CH:20]=1)[CH:25]=[O:26]
Reactant: Cc1ccc(S)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: Cc1ccc(S)c(C=O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
Tetramethylethylenediamine (TMEDA) (12.6 mL, 83.5 mmol) was added via syringe to n-BuLi (33 mL of 1.6 M in hexanes, 82.5 mmol) and the solution was chilled to 0° C. A solution of p-thiocresol (4.53 g, 36.5 mmol) in cyclohexane (40 mL) was added with stirring over 5 minutes. The resulting tan slurry was stirred overnight at room temperature, chilled to 0° C., and DMF (4.0 mL, 3.77 g, 51.6 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for 1.3 hours. The reaction mixture was added to 3 N HCR (150 mL). This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate-hexanes to afford 5-methyl-2-mercaptobenzaldehyde (4.47 g, 69%) as an intensely yellow solid suitable for use without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19](SC)[N:20]=[CH:21][C:10]=3[C:9]2=[O:24])=[CH:5][CH:4]=1)#[N:2].ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[CH2:43]([NH2:45])[CH3:44].C1COCC1>ClCCl>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19]([NH:45][CH2:43][CH3:44])[N:20]=[CH:21][C:10]=3[C:9]2=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCN
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(Cc1ccc(C#N)cc1)C2=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(Cc1ccc(C#N)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
(S)-5-(4-Cyanobenzyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (0.927 g, 2.54 mmol) obtained in Step 2 was dissolved in dichloromethane (10 mL), and the mixture was stirred at room temperature for 30 minutes after adding 3-chloroperbenzoic acid (65%; 1.01 g, 3.81 mmol). Thereafter, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was dissolved in THF (20 mL), and the mixture was stirred at room temperature for 3 hours after adding a 2.0 mol/L ethylamine/THF solution (12.7 mL, 25.4 mmol). The reaction mixture was concentrated under reduced pressure, purified by silica gel column chromatography, and crystallized from ethanol/diethyl ether to give the title compound (Compound 1) (0.620 g, 67%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]([C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32]O)[CH:27]=[CH:28][CH:29]=1)#[N:23].C1C=CC=CC=1>C(#N)C>[Br:20][CH2:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([C:22]#[N:23])[CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1cccc(CCCO)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccccc1
Product: N#Cc1cccc(CCCBr)c1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a mixture of 21.8 g (0.083 moles) of triphenyl phosphine stirred in 30 ml acetonitrile, 13.2 g (4.26 ml) bromine in 75 ml acetonitrile was added dropwise with stirring in an ice bath. After the addition was complete, the ice bath was removed and the mixture warmed to room temperature. Then a mixture of 12.1 g (0.075 mole) of 3-(3-cyanophenyl)-1-propanol (the product of step (b)) in 30 ml acetonitrile was added dropwise. The resulting mixture was allowed to warm to about 45°-50° C., was stirred overnight and then stripped. Benzene (50 ml) was added to the residue; the mixture was evaporated. Then, additional benzene (50 ml) was added. The mixture was stirred, and then filtered to remove the triphenyl phosphine. The filtrate was stripped to give an oil. The oil was chromatographed using a column containing 3.5 inches of 200 mesh silica gel (Merck) eluting with benzene, until TLC showed that no further product was eluted from the column. The eluates were pooled and stripped to give 17 g of an oil. The oil was distilled in a Kugelrohr apparatus, the fraction bpt. 102°-103° C. was collected to give 15.7 g of the above-identified product as an oil.
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].Cl.[NH2:13][C:14]1[CH:20]=[CH:19][C:17]([OH:18])=[CH:16][C:15]=1O.[OH-].[Na+].C1COCC1>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]1[O:5][C:15]2[CH:16]=[C:17]([OH:18])[CH:19]=[CH:20][C:14]=2[N:13]=1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2nc(-c3ccc(Cl)cc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
9.9 ml (70.5 mmol) of 2,4-dichlorobenzoyl chloride and 2.0 g (12.4 mmol) of 4-aminoresorcinol hydrochloride were introduced into a three-necked flask provided with a thermometer and a cooling condenser, and the mixture was heated at 172° to 247° C. for 1 hour, then excessive acid chloride was removed by distillation. To the residue, 6.47 g (161.8 mmol) of NaOH, 60 ml of THF, 60 μl of water and 30 ml of methanol were added, and the mixture was stirred at room temperature for about 2 hours. The reaction solution was extracted with ethyl acetate, the extract was washed with saturated sodium chloride water solution, and ethyl acetate was distilled off. Recrystallizing the residue with water/methanol/THF and drying the crystal, there was obtained 915 mg (3.27 mmol) of 2-(2,4-dichlorophenyl)-6-hydroxybenzoxazole. The yield was 26.3%.