Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].C(OC(=O)C)(=O)C>O.CC(C)=O.C(N(CC)CC)C>[C:9]1([N:8]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1C=CC(=O)N1c1ccccc1
Temperature: 40 °C

Procedure:
A reaction flask was equipped as in Example 1. To a solution of maleic anhydride (1.12 parts) in 5.6 parts acetone was added a solution of 1 part aniline, 0.375 part triethylamine, and 1.9 parts acetone over a 30-minute period. The resulting heterogeneous mixture was maintained at 40° C. for 30 minutes. Magnesium chloride hexahydrate (0.093 part) and 1.4 parts acetic anhydride were added all at once. The temperature was raised to 50° C. for 3 hours. The homogeneous mixture was cooled and 14 parts water added. The precipitated product was isolated by vacuum filtration, washed with water, and air dried. The crude product was recrystallized from ethanol/water (90/10 vol.) to yield 0.89 part N-phenyl maleimide, m.p. 84°-86° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:21])[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[O:22]C.Cl.N1C=CC=CC=1>>[OH:22][C:3]1[CH:4]=[C:5]([C:11](=[O:21])[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: COc1cc(C(=O)CCCc2ccccc2)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: c1ccncc1
Product: O=C(CCCc1ccccc1)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
1.0 g of 4'-hydroxy-3'-methoxy-5'-nitro-4-phenylbutyrophenone is held at 200° for 1 hour with 8 g of pyridine hydrochloride. The reaction mixture is poured while still warm into ice-water and extracted with ethyl acetate. The organic phase is washed with 1N hydrochloric acid and subsequently with water, dried over sodium sulfate and evaporated. The dark residue obtained is chromatographed on a 30-fold amount of silica gel with ethyl acetate. From methylene chloride/hexane there is obtained 3',4'-dihydroxy-5'-nitro-4-phenylbutyrophenone in the form of yellow crystals of m.p. 118°-119°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:34][S:35]([CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:36])=[O:37])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 7) was reacted with 1-(2-methanesulfonylethyl)-piperazine bishydrochloride in methylene chloride using the procedure as described in example 8 to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone. HR-MS (ES, m/z) calculated for C31H35N4O4SCl2 [(M+H)+] 629.1751, observed 629.1757.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)(=O)C>[CH3:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of 5-hydroxy-2-nitro-benzaldehyde (10 g, 59.8 mmol) and cesium carbonate (23 g, 70.6 mmol) in DMF (40 mL) was added iodomethane (8.8 mL, 141 mmol), and the mixture stirred at room temperature for 17 h. The resulting red-orange suspension was diluted with ethyl acetate and the mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford a thick yellow oil which solidified on standing to afford 5-methoxy-2-nitro-benzaldehyde.
Reaction SMILES: F[C:2](F)(F)[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl[C:14]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][C:15]=1[NH:21][NH2:22].[OH-].[Na+]>C(O)(=O)C.O>[C:15]1([N:21]2[C:5](=[O:7])[CH2:4][C:3]([C:2]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[N:22]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Yield: 171.5 %

Procedure:
To a mixture of ethyl trifluoroacetoacetate (5.0 g, 27.2 mmol) in acetic acid (50 mL) was added 2,4-dichlorophenylhydrazine (4.82 g, 27.2 mmol). The reaction mixture was refluxed for 22 hours and then was diluted with water (50 mL), neutralized with 2N NaOH and extracted with EtOAc (3×50 mL). The EtOAc extracts were combined, dried over Na2 SO4, filtered and concentrated to afford 5.51 g (70%) of 2,4-dihydro-2-(2,4-dichlorophenyl)-5-trifluoromethyl-3H-pyrazol-3-one (Formula III: R1 =2,4-Cl2 --Ph; R2 =CF3 ; R3 =H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)C(O)=O)=[O:4].OS(O)(=O)=O.[N-:25]=[N+]=[N-].[Na+]>>[NH2:25][C:11]1[C:10]([Cl:16])=[CH:9][C:8]([F:17])=[C:7]([CH:15]=1)[CH2:6][NH:5][C:3](=[O:4])[C:2]([F:19])([F:18])[F:1]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Yield: 64668.4 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-57 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoic acid (3.0 g), conc. H2SO4 and sodium azide (0.793 g, 0.012 mmol) to afford 2.1 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[CH:21](N)=O.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:21]=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: NC=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Reaction time: 6 h

Procedure:
To a suspension of 2.8 parts of 7-chloro-2-hydrazino 5-phenyl-3H-1,4-benzodiazepine in 40 parts by volume of formamide is added 1 part by volume of concentrated sulfuric acid. The resulting solution is left standing for 6 hours and then warmed on a boiling water bath for 30 minutes. The solution is diluted with water, neutralized with sodium bicarbonate and extracted with chloroform. The chloroform extract is washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from ethyl acetate to give 8-chloro-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine as colorless flakes. Melting point: 226° C to 227° C.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1.Cl>O1CCCC1>[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3OCCCCO)ccc21
Temperature: 40 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
2 ml (2.0 mmol) of an aqueous solution of sodium hydroxide (1M) are added to a solution of 0.20 g (0.40 mmol) of ethyl 4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 8 ml of tetrahydrofuran. The reaction mixture is stirred for 48 h while heating at 40° C. The reaction mixture is placed under a stream of nitrogen in order to eliminate the tetrahydrofuran and then 2.4 ml (2.4 mmol) of a solution of hydrochloric acid (1M) are added. The product precipitates in the form of a white solid. After filtration, the product is washed twice with 5 ml of diethyl ether and then dried in an oven under vacuum overnight. 0.17 g of 4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid is obtained (white solid, Mp 235° C., yield=90%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([OH:13])[C:5]=1[OH:14])([CH3:3])[CH3:2].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[C:16](=[O:17])([O:18][CH2:19][CH3:20])[O:13][C:6]1[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:14][C:16](=[O:17])[O:18][CH2:19][CH3:20]
Reactant: CC(C)c1cc(O)c(O)c(C(C)C)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Oc1cc(C(C)C)cc(C(C)C)c1OC(=O)OCC
Yield: 59.1 %

Procedure:
Prepared from 3,5-diisopropylbenzene-1,2-diol and ethyl chloroformate; purified by flash column chromatography on silica gel to yield a yellow oil (59.1%); 1H NMR (500 MHz, CDCl3, ppm) δ 7.02 (s, 1H), 6.98 (s, 1H), 4.32 (q, 2H, J=7.0 Hz), 4.31 (q, 2H, J=7.0 Hz), 3.11 (heptat, 1H, J=7.3 Hz), 2.89 (heptat, 1H, J=7.0 Hz), 1.38 (t, 3H, J=7.3 Hz), 1.37 (t, 3H, J=7.0 Hz), 1.24 (d, 6H, J=7.0 Hz), 1.22 (d, 6H, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][CH:11](O)[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2.S(Cl)([Cl:27])=O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][CH:11]([Cl:27])[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2
Reactant: CC1(C)C2CCC(C2)C1CCC(O)CCC1C2CCC(C2)C1(C)C
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)C2CCC(C2)C1CCC(Cl)CCC1C2CCC(C2)C1(C)C
Temperature: 25 °C

Procedure:
A solution of 16.6 gm. of 1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentanol in 25 ml. of dry pyridine is cooled to -10° C. There is then added with good agitation, 14.3 gm. of thionyl chloride over a 15 minute period. The solution is allowed to warm to room temperature and gradually heated over a period of 4 to 5 hours to 100° C. After an additional two hours at 100° C. the excess thionyl chloride is removed by vacuum stripping and the reside mixed with cracked ice. Three 100 ml. ether extractions are used to remove the halide, the diethyl ether extracts are washed with 4 × 200 ml. ice water, the ether layer separated, dried over anhydrous magnesium sulfate, filtered and stripped. The residue of di-substituted pentyl chloride may be further purified by distillation in vacuo or is suitable for further reaction as such.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.CC([O-])(C)C.[Na+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:7]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1cncc(N2CCOCC2)c1
Temperature: 120 °C
Yield: 50.8 %

Procedure:
In a sealable tube, to a mixture of 3,5-dibromo-pyridine (3.3 g, 13.8 mmol) and NaOtBu (0.051 g, 23 mmol) in toluene (70 mL), is added morpholine (1.0 g, 11.5 mmol). The mixture is bubbled with Argon for 5 min, and then BINAP (428.9 mg, 0.69 mmol) and Pd2(dba)3 (210.2 mg, 0.23 mmol) are added. The reaction mixture is bubbled with Argon for another 5 min. Then the cap is sealed and the reaction mixture is heated at 120° C. overnight and then is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is further extracted with DCM (2×). The combined DCM phases are concentrated. The crude is purified by flash chromatography on a silica gel column (EtOAc/heptane 0 to 50% gradient, then 50%) to provide 1.42 g of 4-(5-bromo-3-pyridyl)morpholine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23])([O-:14])=[O:13]>>[F:21][C:19]1[CH:18]=[CH:17][C:16]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:24])=[O:23])=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Cl
Product: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 105.6 %

Procedure:
In a similar fashion using route 14 general procedure 26, 8-aminoquinoline (500 mg, 3 mmol) and 2-nitro-4-fluorobenzenesulfonyl chloride (Intermediate 220) (914 mg, 4 mmol) gave the title compound (1.10 g, 91%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1CCO[CH:9]1[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[C:17]([CH3:26])=[CH:16][C:15]1=[O:27].C(=O)([O-])O.[Na+]>>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18]([C:17]([CH3:26])=[CH:16][C:15](=[O:27])[N:14]2[CH2:13][CH:9]=[O:8])=[CH:19][CH:20]=1
Reactant: COc1ccc2c(C)cc(=O)n(CC3OCCO3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
Into 2 mL of an 80% aqueous trifluoroacetic acid solution, 200 mg of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-4-methyl-2-oxo-1,2-dihydroquinoline was dissolved, and the mixture was stirred at room temperature for 11 hours. The reaction mixture was added with an aqueous saturated sodium hydrogen carbonate solution to be alkalified, and then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance, (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Br:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Br:30])[C:19]=1[Cl:31].CC(=O)OCC>CN(C=O)C>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Br:30])[C:19]=1[Cl:31]
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Br)c(Cl)c(Br)c1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Br)c(Cl)c(Br)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.9 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (68 mg, 0.28 mmol) in DMF was added 1,3-dibromo-2-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (132 mg, 0.36 mmol) and TEA (31 mg, 0.36 mmol) at rt. The mixture was stirred at 25° C. for 12 h, quenched with water, extracted with EA (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluted with PE:EA=5:1 to give the final title compound 5-(5-(3,5-dibromo-4-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (38 mg; yield 22%) as solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.96 (s, 2H), 7.76-7.69 (m, 3H), 4.45-4.30 (q, 2H), 1.48 (s,6H) ppm; MS: m/z=568 (M+1, ESI+).
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1.CO.C[O-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18]>O>[CH2:18]([O:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH:17]=[CH2:16]
Reactant: OCc1ncccc1O
Reactant: C=CCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCOc1cccnc1CO
Temperature: 22 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
Hydroxy-2-(hydroxymethyl)pyridine hydrochloride (50 g, 339.6 mmol) and methanol (250 mL) are combined under nitrogen and cooled to 22° C. To the vigorously stirred mixture is added 4.5 M sodium methoxide in MeOH (170.8 mL, 747.2 mmol). The mixture is stirred at room temperature for 2 h and then the solvent is evaporated. The resulting material is dissolved in DMSO (250 mL), allyl bromide (41 g, 339.6 mmoles) is added, and the mixture stirred for 18 h at room temperature. The reaction mixture is added to water (800 mL) and extracted with methylene chloride (3×80 mL). The organic portions are combined and dried over sodium sulfate, filtered, and the solvent evaporated to afford the title compound (34.4 g, 62%). LC-ES/MS m/z 166.1 [M+H]+.
Reaction SMILES: CC1CN(C(=O)C(F)(F)F)CCC2N=C(O)C=CC1=2.O=P(Cl)(Cl)Cl.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[CH:35]([CH3:36])[CH2:34][N:33](C(=O)C(F)(F)F)[CH2:32][CH2:31][C:30]=2[N:43]=1.C([O-])([O-])=O.[K+].[K+]>CO.CN(C=O)C>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[CH:35]([CH3:36])[CH2:34][NH:33][CH2:32][CH2:31][C:30]=2[N:43]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(Cl)ccc21
Agent: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: CC1CNCCc2nc(Cl)ccc21
Temperature: 100 °C
Yield: 22.3 %

Procedure:
A mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (100 mg, 365 μmol), DMF (50 μl) and POCl3 (5 ml) was heated at 100° C. for 3 h. The reaction mixture was concentrated in vacuo and purified by column chromatography rendering 101 mg (94%) of 2-chloro-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 293.2/295.2. A mixture of 2-chloro-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (40.0 mg, 137 μmol), K2CO3 (80.0 mg) and MeOH (5 ml) was heated for 2 h at 70° C. The reaction mixture was concentrated in vacuo and purified by column chromatography furnishing 6.0 mg (22%) of 2-chloro-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ. 1H-NMR (CDCl3) δ 7.48 (d, 1H), 7.91 (d, 1H), 3.58 (s, 3H), 3.55-3.20 (m, 5H), 2.93 (dd, 1H), 2.73 (dd, 1H), 1.43 (d, 3H) ppm.
Reaction SMILES: CO.[CH3:3][Si:4]([CH3:34])([CH3:33])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[CH:14]=[N:15][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:17](=[O:18])[C:12]=2[C:11]([C:27]#[C:28][Si](C)(C)C)=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>O>[C:27]([C:11]1[C:12]2[C:17](=[O:18])[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[N:15]=[CH:14][C:13]=2[N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:33])([CH3:3])[CH3:34])[CH:10]=1)#[CH:28]
Reactant: C[Si](C)(C)C#Cc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 92.9 %

Procedure:
To 150 ml of methanol solution containing 10.8 g (22.0 mmol) of 1,5-bis(2-trimethylsilylethoxymethyl)-3-trimethylsilylethynyl-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 19-(a) was added 1.00 g (7.23 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, water and a saturated aqueous solution of sodium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 8.58 g of the title compound as a pale yellowish solid. (Yield: 93%)
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]([O:18]CC2C=CC=CC=2)[CH:15]=[C:14]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C@@H:31]([OH:38])[CH2:32][CH2:33][CH2:34][C@@H:35]([OH:37])[CH3:36])[C:10]=1[C:11]([OH:13])=[O:12])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C@@H:31]([OH:38])[CH2:32][CH2:33][CH2:34][C@@H:35]([OH:37])[CH3:36])[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: [H][H]
Reactant: C[C@H](O)CCC[C@H](O)CCCCCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: C[C@H](O)CCC[C@H](O)CCCCCc1cc(O)cc(O)c1C(=O)O
Yield: 89.7 %

Procedure:
A mixture of 6.00 g of compound B from Example II and 6.03 g of 5% palladium on charcoal in 100 mL of ethanol was treated with hydrogen gas at a constant pressure of 50 psi for 5.0 hours at room temperature. The reaction was filtered through celite and concentrated under reduced pressure to provide 3.52 g of crude product. Recrystallization from aqueous ethanol furnished material with the following characteristics: mp 116°-8° C.; IR (KBr) 2993, 2860, 1660, 1540, 1225, 849 cm-1 ; 1H-NMR (DMSO-d6) δ 1.07 (d), 1.35 (brm), 6.11 (s), 6.18 (s), 7.00 (br); 13C-NMR (DMSO) δ 21.65, 23.57, 25.09, 29.36, 31.39, 35.40, 43.64, 65.88, 69.64, 100.55, 104.84, 110.04, 147.31, 161.58, 172.65.
Reaction SMILES: C(OC([NH:8][CH:9]([C:38]([OH:40])=[O:39])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[C:19]([OH:37])=[C:20]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=2[Cl:36])=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24])(=[O:17])=[O:16])=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[NH2:8][CH:9]([C:38]([OH:40])=[O:39])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[C:19]([OH:37])=[C:20]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=2[Cl:36])=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24])(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: NC(CCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O)C(=O)O
Yield: 74 %

Procedure:
Following the general procedure for Boc deprotection in example 36, N-[3-[N″-[5-(tert-butoxycarbonylamino)-5-carboxypentyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea (100 mg, 0.16 mmol) was stirred in 1 mL of trifluoroacetic acid to form the desired product (78 mg, 74%). LC-MS (m/z) 541.0 (M+).
Reaction SMILES: COC1C=CC(CSCC(C)C(Cl)=S)=CC=1.Cl.[C:18]1([C@@H:24]2[CH2:28][NH:27][C@H:26]([C:29]([OH:31])=[O:30])[CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH:24]2[CH2:28][NH:27][C@H:26]([C:29]([OH:31])=[O:30])[CH2:25]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)[C@@H]1C[C@H](c2ccccc2)CN1
Agent: COc1ccc(CSCC(C)C(=S)Cl)cc1
Agent: Cl
Product: O=C(O)[C@@H]1CC(c2ccccc2)CN1

Procedure:
The 3-[[(4-methoxy)phenylmethyl]thio]-2-methylthiopropionyl chloride from part (a) is reacted with cis-4-phenyl-L-proline, hydrochloride to yield [1(S),4R]-1-[[(4-methoxy)phenylmethyl]thio]-2-methylthio-1-oxopropyl]-4-phenyl-L-proline.