Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:19][C:20]([C@@H:22]1[CH2:35][C:34]2[CH:33]=[C:32]3[C:27]([O:28][C@@H:29]([C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[C:30](=[O:37])[N:31]3[CH3:36])=[CH:26][C:25]=2[CH2:24][N:23]1[C@H:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:46][CH3:47])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:55][C:56]1[CH:57]=[C:58]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:59]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:19][C:20]([C@@H:22]1[CH2:35][C:34]2[CH:33]=[C:32]3[C:27]([O:28][C@@H:29]([C:38]4[CH:39]=[CH:40][C:41]([O:44][CH2:59][C:58]5[CH:61]=[CH:62][C:63]([Cl:64])=[C:56]([Cl:55])[CH:57]=5)=[CH:42][CH:43]=4)[C:30](=[O:37])[N:31]3[CH3:36])=[CH:26][C:25]=2[CH2:24][N:23]1[C@H:45]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:46][CH3:47])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
(S)-3-(4′-Fluoro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (27 mg, 0.078 mmol) was dissolved in 2 mL of DMF and 3,4-dichlorobenzyl bromide (0.39 mmol) and potassium carbonate (0.39 mmol) were added. The mixture was stirred at room temperature for 8 hours and was poured onto ethyl acetate and 10% sodium carbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 7-3-0.1) to provide (S)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaz a-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester (21 mg, LC/MS: m/z 889).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:23])([F:22])[CH:11]([CH3:21])[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1>C(O)C>[F:23][C:10]([F:9])([F:22])[CH:11]([CH3:21])[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:2])[CH:14]=1
Reactant: CC(Oc1ccnc(C#N)c1)C(F)(F)F
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: CC(Oc1ccnc(C(N)=O)c1)C(F)(F)F
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To 4 ml of ethanol were added 0.38 g of sodium bicarbonate and 0.32 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.49 g of 4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 8 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.5 g of 4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH2:9]([O:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:11][CH3:12]>C(Cl)Cl>[CH2:1]([O:3][C:4]([NH:6][C:7]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH2:9][CH2:10][CH2:11][CH3:12])=[S:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C=S
Reactant: CCCCOCCCN
Solvent: ClCCl
Product: CCCCOCCCNC(=S)NC(=O)OCC
Reaction time: 2 h

Procedure:
Again following the procedure of Example 1, to 1.31 parts of the ethoxycarbonyl isothiocyanate in 6 parts of methylene chloride are added 1.31 parts of butoxypropylamine. After 2 hours at room temperature, the methylene chloride is evaporated off. The viscous liquid product N-ethoxycarbonyl-N'-n-butoxypropyl thiourea (2.6 parts) gives the correct IR analysis.
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH:7][NH2:8])=[O:6])[CH2:4][CH2:3]1.[C:9](Cl)(Cl)=[O:10]>C(Cl)Cl>[O:10]=[C:9]1[N:8]=[N:7][CH:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)[O:6]1
Reactant: O=C(Cl)Cl
Reactant: CC1(C(=O)NN)CC1
Solvent: ClCCl
Product: CC1(C2N=NC(=O)O2)CC1

Procedure:
85 gm of 1-methylcyclopropane carboxylic acid hydrazide was added to methylene chloride on a 3-neck 2-liter round bottom flask. The system was first cooled to 0°-5° C. and 590.5 gm of a 12.5% solution of phosgene added dropwise over a period of time. The system was then heated at reflux for 7 hours. The methylene chloride was removed by stripping. The product was washed with petroleum ether and filtered to give 66.6 gm of 2-oxo-5-(1'-methylcyclopropyl)-1,3,4-oxadiazoline as light brown crystals, m.p. 68°-70° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc2cccnc2c1
Product: CN(C(=O)Oc1ccc2cccnc2c1)c1ccccc1

Procedure:
The title product was prepared from 7-hydroxyquinoline and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (28%, white solid). HPLC-MS: m/z=279.1 (M+1); Rt: 2.55 min.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([N:6]4[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]4=[O:7])=[N:14][CH:13]=3)=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)nc3)CC2)c(C)c1
Yield: 43.5 %

Procedure:
Using 5-methylpyrrolidin-2-one (99 mg) and (6-bromopyridin-3-yl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 127 and by the reaction and treatment in the same manner as in Example 1, the title compound (171 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:15])[CH:5]=[C:6]2[C:11]=1[CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][CH2:7]2.S(=O)(=O)(O)O.[CH3:21]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH3:15])[CH:5]=[C:6]2[C:11]=1[CH:10]([C:12]([O:14][CH3:21])=[O:13])[CH2:9][CH2:8][CH2:7]2
Reactant: Cc1cc(N)c2c(c1)CCCC2C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCCc2cc(C)cc(N)c21

Procedure:
The product from Example 140 was dissolved in methanol (50 ml) and concentrated sulfuric acid (3 ml) was added. The reaction was refluxed for 4 hours and solvent was evaporated to one-half the volume. Following the procedure of Example 136 the desired ester was obtained.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[N:11]1[CH2:12][CH:9]([O:8][C:3]2[C:2]([N:23]3[CH2:28][CH2:27][CH:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10]1
Reactant: CC(=O)C1CCNCC1
Reactant: Clc1nccnc1OC1CN(c2ccc3ccccc3n2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)C1CCN(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 160 °C
Yield: 18 %

Procedure:
To a mixture of 2-(3-((3-chloropyrazin-2-yl)oxy)azetidin-1-yl)quinoline (see PREPARATION P2.6; 312 mg, 1.0 mmol) and 1-(piperidin-4-yl)ethanone (127 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol) was added i-PrOH (3 mL) and water (1.0 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (72 mg, 0.18 mmol, 18% yield) as white solid. ESI-MS (M+1): 404 calc. for C23H25N5O2 403.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.N1C=CC=CC=1>C(OCC)C>[CH3:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cc2ccccc2[nH]1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1c(C)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of ethyl chlorooxoacetate (22.53 g, 0.165 mol) in diethyl ether (100 mL) was added over a period of 15 minutes to a cooled (0° C.) solution of 2-methylindole (19.7 g, 0.15 mol) and pyridine (14.2 g, 0.18 mol) in diethyl ether (200 mL). The reaction was stirred for two hours at 0° C. under a nitrogen atmosphere. Most of the diethyl ether had evaporated by the end of the two-hour reaction time, and a solid was present. Water (100 mL) was added, and the solid was isolated by filtration and washed with 1:1 diethyl ether/hexane. The solid (27.9 g) was then dissolved in boiling toluene (250 mL) and recrystallized upon cooling to 6° C. The crystals were isolated by filtration, washed with toluene, dried for two hours on the vacuum filter funnel, triturated with water at 75° C. for five minutes, isolated by filtration, and dried for three hours on the filter funnel to provide 17.8 g ethyl (2-methyl-1H-indol-3-yl)(oxo)acetate of as a rust-colored powder.
Reaction SMILES: CI.[C:3](=O)([O-])O.[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)=[CH:12][C:11]=1[C:21](=[O:25])[C:22]([OH:24])=[O:23]>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)=[CH:12][C:11]=1[C:21](=[O:25])[C:22]([O:24][CH3:3])=[O:23]
Reactant: O=C([O-])O
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(=O)c1cc(-n2cnnn2)ccc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
Methyl iodide (1.87 ml, 4.26 g, 30 mmol) was added to a mixture of sodium hydrogen carbonate (2.52 g, 30 mmol), and 2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoic acid (3.37 g, 13.6 mmol) in dimethylformamide (120 ml) and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 ml) and water (50 ml) were added and mixture was extracted with ethyl acetate (4×100 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×100 ml), dried (MgSO4) and evaporated under reduced pressure to give methyl 2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoate as an orange solid (3.36 g, 94%), 1H NMR (CDCl3) δ 9.02 (1H, s), 8.11 (1H, d, J=2.8 Hz), 8.03 (1H, dd, J=9.0, 2.8 Hz), 7.23 (1H, d, J=9.0 Hz), 3.99 (3H, s), and 3.96 (3H, s).
Reaction SMILES: N[C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.N[C:13]1C=CC=C(S(O)(=O)=O)[CH:14]=1>>[CH2:13]=[CH:14][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([S:8]([OH:11])(=[O:10])=[O:9])[CH:2]=1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: Nc1ccccc1S(=O)(=O)O
Product: C=Cc1cccc(S(=O)(=O)O)c1
Yield: 71 %

Procedure:
If instead of aniline-2-sulphonic acid the same amount of aniline-3-sulphonic acid was used, 11.0 g (71%) of styrene-3-sulphonic acid, Na salt, were obtained by the method indicated in Example 15.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]([O:20]C)=[O:19])[CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:22])[C:7]=1[CH:23]1[C:36]2[C:35](=[O:37])[CH2:34][C:33]([CH3:39])([CH3:38])[CH2:32][C:31]=2[O:30][C:29]2[CH2:28][C:27]([CH3:41])([CH3:40])[CH2:26][C:25](=[O:42])[C:24]1=2>O.C1COCC1>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:22])[C:7]=1[CH:23]1[C:24]2[C:25](=[O:42])[CH2:26][C:27]([CH3:40])([CH3:41])[CH2:28][C:29]=2[O:30][C:31]2[CH2:32][C:33]([CH3:39])([CH3:38])[CH2:34][C:35](=[O:37])[C:36]1=2
Reactant: COC(=O)c1cccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 3 h
Yield: 73.5 %

Procedure:
A solution of lithium hydroxide monohydrate (0.18 g, 4.36 mmol) in water (10.5 ml) was added dropwise to a solution of the methyl 6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylate produced in Example 4-3 (1.05 g, 1.98 mmol) in THF (21 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 3 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then washed with diethyl ether. Thereafter, a 1 N aqueous solution of hydrochloric acid (4.36 ml) was added to the water layer, and the mixed solution was then extracted with dichloromethane. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (0.75 g, yield: 73%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:13]1[C:12](=[O:14])[NH:11][C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)Sc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2SC(c2ccccc2)=C1Br
Reaction time: 5 h

Procedure:
A stirred solution of 25.5 g (0.1 mole) of 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one (prepared as disclosed by Krapcho et al, J. Med. Chem., 6, 544, (1963)) in 250 ml of dimethylformamide is treated with a solution of 35 g (0.2 mole) of N-bromosuccinimide in 100 ml of dimethylformamide. The mixture is stirred at 105°-110° for 5 hours, cooled, and poured into 1.8 liters of cold H2O to precipitate a solid. After cooling overnight, the latter is filtered, washed with H2O, and air-dried; wt. 29.6 g (89%); m.p. 190°-192°; s. 180°. Following crystallization from a mixture of 30 ml of hot dimethylformamide and 60 ml of MeCN, the colorless solid weighs 17.8 g (53%); m.p. 240°-242° (dec.).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[H-].[Na+].[CH3:9][S:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.Cl>O1CCOCC1>[CH:4]1([C:2](=[O:3])[CH2:1][C:15]([C:14]2[CH:20]=[CH:21][C:11]([S:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH2:6][CH2:5]1
Reactant: CC(=O)C1CC1
Reactant: CCOC(=O)c1ccc(SC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1ccc(C(=O)CC(=O)C2CC2)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
Cyclopropyl methyl ketone (0.84 g) was added to a suspension of sodium hydride (80%, 0.3 g) in dioxane. The mixture was stirred for 20 minutes and ethyl 4(methylsulphenyl)benzoate (1.0 g) was added. The mixture was stirred and heated at 45° C. for 1.5 hours and at 60° C. for 2 hours. It was left to stand at room temperature overnight. Hydrochloric acid (2M) was added and the mixture was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and hexane to give 3-cyclopropyl-1-[4-(methylsulphenyl)-phenyl]-propan-1,3-dione (0.59 g) as an orange solid, NMR (CDCl3) 1.0(m,2H), 1.2(m,2H), 1.8(m, 1H), 2.5(s,3H), 6.25(s, 1H), 7.25(d,2H), 7.8(d,2H), 16.35(bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]([CH3:46])[CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]([CH3:45])[CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(C)C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (240 mg, 0.75 mmol) and 3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K39) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (340 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[C:10](Br)=[C:9]2[C:5]([C:6]([CH2:12][CH2:13][NH2:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(O)C>C(N(CC)CC)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][CH2:13][NH2:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(CCN)c[nH]c2c1Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2c(CCN)c[nH]c2c1

Procedure:
A sample of 6-methyl-7-bromo-1H-indole-3-ethanamine was contacted with Pd/C H2 in the presence of ethanol and triethylamine. The resulting material was evaporated and partitioned between base/CHCl3. The organic phase was dried, concentrated, and dried. The resulting material was taken up into methanol and added to ethereal HCl. The resulting material was washed and vacuum dried.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.NC(N)=[S:22]>COCCO.O>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2](=[S:22])[NH:3][N:4]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC
Reactant: NC(N)=S
Solvent: COCCO
Solvent: O
Product: CCCOc1ccc(-c2ccc(=S)[nH]n2)cc1OC

Procedure:
T13.9 g of 3-chloro-6-(3-methoxy-4-n-propoxyphenyl)pyridazine are boiled under reflux with 5.5 g of thiourea in 50 ml of ethylene glycol monomethyl ether for 8 hours. After cooling, the mixture is diluted with 250 ml of water and extracted three times with chloroform. The chloroform extracts are dried over sodium sulfate and evaporated. The residue is crystallized from ethanol/ethyl acetate. 4.8 g (34.6% of theory) of the title compound of m.p. 174°-17620 are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:38]([O:40][CH3:41])=[O:39]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:38]([O:40][CH3:41])=[O:39])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.50 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide and 0.12 ml of pyridine were dissolved in 10 ml of dichloromethane and cooled to 0° C. under nitrogen. 0.12 ml of methyl chloroformate and a few crystals of 4-dimethylaminopyridine were added in succession and the mixture was left to come to room temperature and then stirred for 1 hour. The mixture was diluted with dichloromethane and then washed in succession with 5% aqueous sodium hydrogen carbonate solution, water, 2M aqueous hydrochloric acid and water and then dried over magnesium sulphate. The solvent was evaporated to give 0.54 g of methyl (E)-3-[2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]-2-isobutylcarbazate in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[O-:11][CH2:12][CH3:13].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(Cl)ccc1C#N
Yield: 57.4 %

Procedure:
To a solution of 4-chloro-2-fluoro-benzonitrile (1 g, 6.428 mmol) in ethanol (10 mL) were added sodium ethoxide solution (4.8 mL, 12.86 mmol, 21% wt in ethanol). The reaction mixture was heated at gently reflux for 12 h. The solvent was removed and the residue was partitioned between water (10 mL) and diethyl ether (20 mL). The layers were separated and the product was extracted with diethyl ether (20 mL). The organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. The solid was filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5% ethyl acetate in hexanes yielded 4-chloro-2-ethoxy-benzonitrile (670 mg, 57%).
Reaction SMILES: FC(C(F)(F)F)(C(F)(F)F)C[CH:4]([CH2:12][C:13](F)([C:18](F)(F)F)[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9].[CH2:31]([CH2:33][NH2:34])[OH:32]>ClCCl>[OH:32][CH2:31][CH2:33][NH:34][S:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:12][CH:13]([C:14]([F:15])([F:16])[F:17])[CH3:18])(=[O:9])=[O:10]
Reactant: O=S(=O)(Cl)CCCC(CC(F)(C(F)(F)F)C(F)(F)F)CC(F)(C(F)(F)F)C(F)(F)F
Reactant: NCCO
Solvent: ClCCl
Product: CC(CCCCCS(=O)(=O)NCCO)C(F)(F)F
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Referring to scheme (42) above, a solution of the 6,7,7,7-tetrafluoro-4-(2,3,3,3-tetrafluoro-2-trifluoromethyl-propyl)-6-trifluoromethyl heptane-1-sulfonyl chloride (25 grams), described above, in 125 mL dichloromethane can be added to a cooled solution (0° C.-5° C.) of ethanolamine (17.6 grams) in dichloromethane (125 mL) drop-wise to form a mixture. The mixture can be agitated, allowed to warm to room temperature, and diluted with dichloromethane (250 mL). The diluted mixture can be washed with deionized water (250 mL). 5% (wt/wt) HCl (250 mL), and saturated bicarbonate solution (250 mL). The organic layer can be separated, dried over sodium sulfate, filtered, and concentrated under vacuum to afford 6,7,7,7-tetrafluoro-4-(2,3,3,3-tetrafluoro-2-trifluoromethyl-propyl)-propyl)-6-trifluoromethyl-heptane-1-sulfonic acid (2-hydroxy-ethyl)-amide (5.0 grams) with residual dichloromethane and ethanolamine by NMR analysis.