Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([F:27])=[CH:29][CH:30]=2)=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:25])([F:26])[CH:22]([F:23])[F:24])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(Cl)c(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(Cl)c(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-1-propanol (208 mg, 0.53 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (273 mg, 91%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=2)[CH:9]1[CH2:21][CH2:22][CH2:23][CH3:24])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@@H:59]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1>C(Cl)Cl>[CH2:21]([CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:18]([NH:58][C@@H:59]([CH2:73][C:74]3[CH:75]=[C:76]([F:81])[CH:77]=[C:78]([F:80])[CH:79]=3)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=3)=[O:20])[CH:11]=2)[CH2:16][CH2:17][NH:8]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCC1c2cc(C(=O)O)ccc2CCN1C(=O)OC(C)(C)C
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: ClCCl
Product: CCCCC1NCCc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1-butyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (205 mg, 0.61 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol) in methylene chloride (4.0 mL) was added HBTU (233 mg, 0.61 mmol) and the reaction mixture stirred for 0.5 h. To this was added a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (250 mg, 0.61 mmol) in methylene chloride (4.0 mL) containing N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 95:5 chloroform/methanol) gave the desired amide product. The amide was then dissolved in dioxane (5.0 mL) to which was added hydrochloric acid (20 mL, 4.0 M dioxanes, 80 mmol) and the reaction mixture stirred overnight. The reaction mixture was then concentrated to dryness and purified by flash column chromatography (silica, 90:6:3:1 ethyl acetate/chloroform/methanol/ammonium hydroxide) to yield a colorless oil. The oil was partitioned between 3:1 chloroform/2-propanol, washed with water, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated to yield a white solid. The solid was dried under high vacuum at 45° C. in the presence of P2O5 to yield 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxamide(140 mg) characterized as a mixture of diastereomers: mp 121-124° C.; ESI MS m/z 550 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10]([C:12]1[C:13]([NH2:21])=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)=[O:11].N1C=CC=CC=1.Cl>ClCCl>[CH3:8][O:9][C:10]([C:12]1[C:13]([NH:21][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)=[O:11]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1ccc2c(c1N)CCC2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1NC(=O)OC(C)C)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
Add isopropyl chloroformate (2.22 mL, 2.22 mmol, 1.0 M in toluene) dropwise to a solution of 4-Amino-indan-5-carboxylic acid methyl ester (425 mg, 2.22 mmol) and pyridine (0.44 mL, 5.5 mmol) in dichloromethane (4.4 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 24 h. Add 1M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure, to afford the title compound (576 mg, 93%): 1H NMR (MeOD) δ 1.37 (d, J=6.5 Hz, 6H), 2.16 (quintuplet, J=7.7 Hz, 2H), 2.97 (t, J=7.3 Hz, 2H), 3.05 (t, J=7.3 Hz, 2H), 3.94 (s, 3H), 4.97 (m, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H). MS (ES+): 278 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12](=[O:14])[O:11][N:10]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[NH:13][C:12](=[O:14])[O:11][N:10]=2)=[C:2]([NH:1][C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=2)=[O:25])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1-c1noc(=O)[nH]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1cc(Cl)ccc1-c1noc(=O)[nH]1
Reaction time: 16 h
Yield: 62.7 %

Procedure:
3-(2-Amino-4-chloro-phenyl)-4H-[1,2,4]oxadiazol-5-one (400 mg, 1.92 mmol) was dissolved in 20 ml dry THF and 3-trifluoromethyl-phenyl-isocyanate (450 mg, 2.40 mmol) was added and the reaction stirred for 16 hours. The solvent was reduced under vacuum and the product recrystallised from ethyl acetate and heptane to yield 480 mg (63%) of off-white crystalline solid (m.p. 246-248; decomposition).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14]([OH:16])=O>>[Br:10][C:11]1[CH:12]=[C:13]([C:14]([C:4]2[C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[S:1][C:5]=2[C:13]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[CH:11][CH:12]=2)=[O:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: c1ccc2sccc2c1
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OC)c(Br)c2)cc1
Yield: 76 %

Procedure:
The title compound was prepared in 76% yield from 2-(4-methoxyphenyl)]benzo[b]thiophene (Example 3, Part A) and 3-bromo-4-methoxybenzoic acid by essentially following the procedures detailed in Example 2, Part C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16]>>[CH3:24][O:23][C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([O:11][CH3:10])[C:20]=1[O:21][CH3:22])[C:15]([C:5]1[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1)=[O:16]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=C(O)Cc1cccs1
Product: COc1cc(C(=O)c2ccc(CC(=O)O)s2)cc(OC)c1OC

Procedure:
Using the procedure of Example 1, thiophene-2-acetic acid and 3,4,5-trimethoxybenzoyl-chloride were reacted to obtain 5-(3',4',5'-trimethoxybenzoyl)-thiophene-2-acetic acid melting at 124° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11]O)=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:32])=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][Cl:32])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Solvent: ClC(Cl)Cl
Product: CCCCc1nc(Cl)c(CCl)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
A solution of 1 g of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-methoxycarbonyl-1,1'-biphenyl-4yl)methyl]-1H-imidazole in 20 ml of CHCl3 is added with 1.44 g of thionyl chloride.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[CH3:21][CH:22]([OH:24])[CH3:23].[H-].[Na+]>O>[CH:22]([O:24][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)([CH3:23])[CH3:21]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 3 ml of 2-propanol, 52 mg of 60% sodium hydride (in oil) was added while ice-cooling. The mixture was stirred for 1.5 hours and then heated to room temperature and stirred for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.12 g of 2-(3-isopropoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 70”).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:22])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.C(O)(=O)C>C1COCC1>[CH3:22][C:15]1[CH:14]=[C:13]2[C:12](=[C:21]3[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]3)[NH:11][S:8](=[O:10])(=[O:9])[C:3]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2N)c2ncccc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2c(c3ncccc13)NS(=O)(=O)c1ccccc1-2
Reaction time: 2 h
Yield: 35.2 %

Procedure:
In a similar fashion using route 16 general procedure 31, 2-amino-N-(5-methylquinolin-8-yl)-benzenesulfonamide (Intermediate 176) (150 mg, 0.48 mmol), tert-butyl nitrite (0.12 ml, 0.88 mmol), acetic acid (28 μl, 0.48 mmol) and THF (5 ml), at 0° C. for 2 h then at room temperature for 2 h, gave the title compound (50 mg, 53%) after purification by column chromatography using silica basified with TEA with n-hexane/EtOAc (1:1) followed by DCM/MeOH (1:0-199:1) gradient elution.
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:19])=[CH:7]1)=O.Cl>[OH-].[Na+]>[OH:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:19])=[CH:7]1
Reactant: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(CCOC=O)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(CCO)c2n1

Procedure:
1,4-Dihydro-1(2-formyloxyethyl)-7-methyl-4-oxo-N(1H-tetrazol-5yl)-1,8-naphthyridine-3-carboxamide (Example 4(1)) (0.5 g) in aqueous sodium hydroxide (3.5 ml), 2N) was heated on a steam bath for 10 minutes. The solution was acidified to pH 1 with a dilute hydrochloric acid and the solid was collected and dried, m.p. 315°-316° (d), (32%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=C2C(=O)Nc3cc(Cl)ccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C2C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 40 °C

Procedure:
Sodium borohydride (0.38 g, 10 mmol) (Aldrich) was added in small portions to a solution of 4-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-piperidine-1-carboxylic acid tert-butyl ester (0.35 g, 1 mmol) (from Example 12a supra) in methanol (25 mL) and water (3 mL) at such a rate that gas evolution was not too vigorous. When addition was complete, mixture was heated at 40° C. for 1 hour. After cooling, mixture was slowly diluted with water. Precipitate formed was collected by filtration and washed with cold aqueous methanol to give rac-4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white crystalline material. (Yield 0.33 g, 94.0%).
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:39][CH2:38][C:37]1=[O:41]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][NH:26][C:37](=[O:41])[CH2:38][CH3:39])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 58 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide was prepared from (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and pyridine instead of N, N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (58% yield). HPLC: 97%, RT=4.034 min. MS: m/z=425 [M+H]+, RT=3.34 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:9][O:10][C:11](=[O:33])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH2:20][C:21]([C:29]#N)=[CH:22][N:23]2CCOCC2)=[CH:14][C:13]=1[O:31][CH3:32]>C(O)(C)C>[CH3:9][O:10][C:11](=[O:33])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH2:20][C:21]([C:22]#[N:23])=[CH:29][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]=1[O:31][CH3:32]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1c(OC)cc(CC(C#N)=CN2CCOCC2)cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)c1c(OC)cc(CC(C#N)=CNc2ccccc2)cc1OC
Reaction time: 0.5 h

Procedure:
8.6 G. of aniline were treated under cooling with 7.6 ml. of concentrated hydrochloric acid. Subsequently, 32 g. of 4-(2-cyano-3-morpholinoallyl)-2,6-dimethoxybenzoic acid methyl ester and 100 ml. of isopropanol were added. The suspension was heated at reflux with stirring for 30 minutes. About 1/3 to half of the solvent was evaporated and 20 ml. of water added. The resulting crystalline product was removed by filtration under vacuum, washed with a little cold methanol and dried. Recrystallization from methanol yielded 4-(3-anilino-2-cyanoallyl)-2,6-dimethoxybenzoic acid methyl ester of m.p. 193°-194°.
Reaction SMILES: [F:1][C:2]([F:21])([C:7]1[S:8][C:9]([C:16]([O:18]CC)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1)[C:3]([F:6])([F:5])[F:4].[OH-].[Na+].Cl>CO.O>[F:21][C:2]([F:1])([C:7]1[S:8][C:9]([C:16]([OH:18])=[O:17])=[C:10]([C:12]([F:14])([F:15])[F:13])[N:11]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CCOC(=O)c1sc(C(F)(F)C(F)(F)F)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1sc(C(F)(F)C(F)(F)F)nc1C(F)(F)F
Temperature: 60 °C

Procedure:
A solution of 540 mg (1.57 mmol) of ethyl 2-(pentafluoroethyl)-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate in 3 ml of methanol and 1 ml of water is admixed with 94.4 mg (2.36 mmol) of sodium hydroxide solution and heated at 60° C. for two hours. The reaction mixture is acidified with conc. hydrochloric acid and extracted four times with dichloromethane, and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and, after filtration, is concentrated by evaporation. This gives 417 mg (min. 50% strength, max. 82%) of 2-(pentafluoroethyl)-4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][CH2:16]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:19][CH2:16][CH2:15][CH2:14][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCSCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCSCCCBr

Procedure:
3-Dodecylthiopropanol (3.0 g) was dissolved in 60 ml of dichloromethane and 7.66 g of carbon tetrabromide and 5.44 g of triphenylphosphine were added thereto under ice-cooling. The mixture was stirred under ice-cooling for 15 minutes. The reaction mixture was concentrated, and the residue was extracted with hexane. The extract was concentrated and purified by silica gel column chromatography using hexane as an eluent to give 3.255 g of pale yellow, oily 3-bromopropyldodecyl sulfide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:20]=[C:19]([O:21]C)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:23])[CH:17]=2)[N:12]=1>O1CCOCC1.Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][C:16]([CH3:23])=[CH:15][CH:14]=2
Reactant: COc1cc(NCCCNCc2ccc(Cl)c(Cl)c2)nc2ccc(C)cc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(NCCCNCc3ccc(Cl)c(Cl)c3)cc(=O)c2c1
Yield: 237.5 %

Procedure:
2-[3-(3,4-Dichlorobenzylamino)prop-1-ylamino]-4-methoxy-6-methylquinoline (50 mg, 0.12 mmol) in 2 ml dioxane and 5 ml concentrated aq. HCl was heated at 100° C. for 18 h. Volatiles were evaporated in vacuo and the residue was triturated with CHCl3 and filtered to give the title compound as a yellow powder, (44 mg, 76%). δH (CD3OD, 400 MHz) 1.97-2.08 (m, 2H, CH2CH2CH2), 2.35 (s, 3H, Ar—CH3), 3.12 (t, J=7.8, 2H, CH2CH2CH2), 3.53 (t, J=6.7, 2H, CH2CH2CH3), 4.13 (s, 2H, ArCH2N), 6.20 (s, 1H, HCC═O), 7.36 (dd, J 8.2, 2.0, 1H, Ar—H), 7.47-7.52 (m, 2H, Ar—H), 7.57-7.66 (m, 2H, Ar—H), 7.76 (s, 1H, Ar—H); MS (ES+) 390 (MH+, 64%), 215 (100).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:23]=[CH:22][C:14]([CH2:15][O:16][C:17](=[O:21])[C:18](Cl)=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH3:24][Si:25]([CH3:45])([CH3:44])[O:26][C@@H:27]([C@@H:29]1[C@@H:32]([CH:33]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:36])[CH3:34])[NH:31][C:30]1=[O:43])[CH3:28]>C(Cl)Cl>[CH3:44][Si:25]([CH3:24])([CH3:45])[O:26][C@@H:27]([C@@H:29]1[C@@H:32]([CH:33]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:36])[CH3:34])[N:31]([C:18](=[O:19])[C:17]([O:16][CH2:15][C:14]2[CH:22]=[CH:23][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)=[O:21])[C:30]1=[O:43])[CH3:28]
Reactant: O=C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C(=S)c1ccccc1)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=S)c1ccccc1)[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N1C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: -30 °C
Reaction time: 0.58 h

Procedure:
A solution of 0.71 ml of triethylamine and 1.1 g of p-nitrobenzyloxyoxalyl chloride in 10 ml of methylene chloride was added to a solution of 0.9 g of (3S,4S)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(1RS)-1-(phenylthiocarbonyl)ethyl]-2-azetidinone in 10 ml of methylene chloride, cooled to about -30° C., and the mixture was stirred for 35 minutes at the same temperature. The reaction mixture was worked up and purified in the same manner as in Preparation 1(3), giving (3S,4S)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(1RS)-1-(phenylthiocarbonyl)ethyl]-1-(p-nitrobenzyloxyoxalyl)-2-azetidinone as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:25][CH2:26][OH:27])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:25][CH2:26][OH:27])[CH:11]=2)=[O:9])=[CH:28][CH:29]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CCO)c2ccc(C#CCO)cc2c1=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCO)c2ccc(CCCO)cc2c1=O
Reaction time: 2 h

Procedure:
To a solution of N-(4-chlorobenzyl)-1-(2-hydroxyethyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 5 (0.20 g) in a small amount of THF:methanol is added platinuim oxide (0.01 g). The mixture is placed under an atmosphere of hydrogen. After 2 hours, the mixture is filtered through Celite with THF:methanol washes. The filtrate is concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 4% to 16% methanol in dichloromethane. The product-containing fractions are concentrated under reduced pressure to afford 0.14 g of the title compound as a white solid.
Reaction SMILES: BrC1C(OC)=C(C=CC=1C[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1C)C(OCC)=O.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:35]Br)=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31].C1(S)C=CC=CC=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:35][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)c1cc(Br)ccc1CBr
Reactant: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Agent: Sc1ccccc1
Product: COC(=O)c1cc(Br)ccc1CSc1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 77, starting from methyl 5-bromo-2-bromomethylbenzoate (prepared according to Lartia et al, J Org Chem, 2008, 73, 1732) and thiophenol.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:28]>CN(C=O)C.CCOC(C)=O>[CH3:28][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Yield: 97.3 %

Procedure:
In a 100 mL round bottomed flask equipped with magnetic stirring was added tert-butyl 4-{2-[(methylsulfonyl)-amino]phenyl}-piperazinecarboxylate (Preparation III) (692 mg, 1.947 mmol) and DMF (5 mL). After stirring 5 min, NaH (60% oil dispersion) (100 mg, 2.5 mmol) (Aldrich) in DMF (10 mL) was added. The reaction was stirred 20 min, then iodomethane (190 μl, 3.05 mmol) (Aldrich) was added via syringe. After stirring 2.5 h, the reaction was diluted with 150 mL EtOAc and washed 75 mL each, satd NH4C1, H2O, 10% NaHCO3 and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-{2-[methyl(methylsulfonyl)amino]phenyl}piperazine-carboxylate (700 mg). MS (ESI, pos. ion) m/z: 370 (M+H), (ESI, neg. ion) m/z: 368 (M−H). Calc'd for C17H27N3O4S: 369.48.