Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.O>C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)NC(=O)CCCCl

Procedure:
A solution of 35 g 4-chlorobutyrylchloride in 100 ml of diethylether is added dropwise to a stirred solution of 19 g tert-butylamine and 28 g triethylamine in 400 ml of diethylether. After reflux for one hour the mixture is poured into water, the organic phase is separated and the water layer is extracted with diethylether. The combined organic phase is successively washed with water and saturated NaCl solution, and then dried. After evaporating the solvent, 4-chloro-N-tert-butylbutyric amide is obtained in a yield of 40.8 g. The product can be purified by recrystallization from methanol: m.p. 62.5°-64° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.CN(C)C.[CH3:24][C:25]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:26][CH2:27][CH2:28][OH:29].CN(C)CCCN>C(Cl)Cl.O>[CH3:24][C:25]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:26][CH2:27][CH2:28][O:29][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CC(=CCCO)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: CN(C)CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.49 mL (3.5 mmol) of triethylamine, 0.68 g (3.54 mmol) of p-toluenesulfonyl chloride, 15 mg (0.16 mmol) of trimethylamine hydrochloride were added to a solution of 1.0 g (3.2 mmol) of 4,8,12,16-tetramethylheptadec-3-en-1-ol in dry methylene chloride (3.2 mL) at 0° C., sequentially. After being stirred for 2 hours at room temperature, 0.080 mL (0.64 mmol) of N,N-dimethyl-1,3-propanediamine was added to the reaction mixture at 0° C. After being stirred for 15 min, water was added, and the mixture was extracted with methylene chloride. The extract was washed with 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain (4,8,12,16-tetramethylheptadec-3-enyl)tosylate as a crude product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:5]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:5]1)[CH3:2]
Reactant: COc1ccc(C2CCCN(C(C)=O)C2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1CCCC(c2ccc(OC)c(OC)c2)C1
Temperature: 5 °C
Yield: 93.2 %

Procedure:
A solution of 680 mg of N-acetyl-3-(3',4'-dimethoxyphenyl)-piperidine in 10 ml of tetrahydrofouran was slowly added with stirring at 20° C to 200 mg of lithium aluminum hydride in 10 ml of tetrahydrofuran and the mixture was stirred for an hour and then cooled to 5° C. 10 ml of ethyl acetate were slowly added thereto and the mixture was poured into water and filtered. The aqueous phase was recovered by decanting and was extracted again with ethyl acetate. The combined organic phases were washed with water, dried and evaporated to dryness to obtain 600 mg of N-ethyl-3-(3',4'-dimethoxyphenyl)-piperidine melting at about 50° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][N:25]=[C:24]([CH3:27])[C:23]=4[NH2:28])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][N:25]=[C:24]([CH3:27])[C:23]=4[NH:28][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:31]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH2:9]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5)n4)cc3)cc2)CCC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclobutanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyridine.
Reaction SMILES: [C:1]([C:4]1[C:5]([I:22])=[C:6]([C:16]([I:21])=[C:17]([NH2:20])[C:18]=1[I:19])[NH:7][C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[OH-].[Na+].S(OC)(O[CH3:29])(=O)=O>CC(C)=O>[C:1]([C:4]1[C:5]([I:22])=[C:6]([C:16]([I:21])=[C:17]([NH2:20])[C:18]=1[I:19])[N:7]([CH3:29])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: Nc1c(I)c(NC(=O)CCCC(=O)O)c(I)c(C(=O)O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(C(=O)CCCC(=O)O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reaction time: 3 h

Procedure:
To a solution of 26.0 g. of 3'-carboxy-5'-amino-2',4',6'-triiodoglutaranilic acid (Example 21, part d) in 100 ml. of 10% aqueous sodium hydroxide cooled in an ice bath was added 8 ml. of dimethyl sulfate in acetone. After 3 hours of stirring an additional 15 ml. of 10% sodium hydroxide and 2 ml. of dimethyl sulfate were added and the mixture stirred 3 hours longer. The reaction mixture was acidified, and the product collected and recrystallized from acetic acid to give 3'-carboxy-5'-amino-2',4',6'-triiodo-N-methylglutaranilic acid, pale gray catalyst, m.p. 218°-220° C. (dec.).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][CH3:17])[CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:18]([OH:22])[C:19]#[C:20][CH3:21].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:16]([CH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([C:8]2[S:7][N:6]=[C:5]([O:22][CH2:18][C:19]#[C:20][CH3:21])[N:9]=2)[CH2:11]1)[CH3:17]
Reactant: CC#CCO
Reactant: CCC1CCCC(c2nc(S(C)(=O)=O)ns2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1nsc(C2CCCC(CC)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
170 mg of 3-methylsulfonyl-5-(3-ethylcyclohexyl)-1,2,4-thiadiazole and 52 mg of 2-butyn-1-ol were dissolved in 1.5 ml of N,N-dimethylformamide, 32 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 12 hours under room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 80 mg of 5-(3-ethylcyclohexyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (14)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1C)=[O:10].ClC1C=CC2N=[C:24](C3C=CC=CC=3)[O:25]C(=O)C=2C=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:25][CH3:24])[CH:12]=1)=[O:10]
Reactant: Cc1ccccc1C(=O)c1cc(Cl)ccc1N
Reactant: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Product: COc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Yield: 64 %

Procedure:
In a manner similar to that described above for compound 1m, 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one was converted to 1s (64% yield) MS m/z=262 (M+H).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]=[C:12]([N+:14]([O-])=O)[CH3:13]>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:11][CH:12]([NH2:14])[CH3:13]
Reactant: CC(=Cc1cc(F)ccc1F)[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(N)Cc1cc(F)ccc1F
Temperature: 0 °C
Yield: 88.9 %

Procedure:
In a dry flask were placed NaBH4 (9.50 g, 0.251 mol) and 300 mL of dry THF. The flask was cooled to 0° C. under argon and 42.76 g of BF3(Et2O) was added via a syringe. After addition, a solution of 10.0 g (50.21 mmol) of 1-(2,5-difluorophenyl)-2-nitropropene was added dropwise via a syringe, and the reaction mixture was heated to reflux for 8 h. The reaction was quenched by carefully pouring the mixture to water, acidified with 2 N HCl and heated to 80° C. for 4 h. The THF was removed under reduced pressure; the residue was washed with ether twice (2×50 mL). The aqueous layer was separated, made strongly alkaline with 10% aqueous NaOH solution and extracted with ether until no product is left in aqueous layer. The extracts were dried over anhydrous MgSO4, filtered, evaporated and purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a colorless oil, 7.65 g, 88.9% yield. MS: 172.0 [M+H]+. 1H NMR (DMSO-d6, 500 MHz): δ 7.20-7.13 (m, 1H), 7.10-7.05 (m, 2H), 3.06 (sextet, 1H, J=6.5 Hz), 2.63-2.54 (m, 2H), 0.96 (d, 3H, J=6.0 Hz). Racemate status was confirmed by HPLC using a chiral column as described for compound D below.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(OC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(OC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-methoxybenzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH:7]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:8](=[O:15])[NH:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[O:5].[CH:29](OCC)(OCC)OCC.CCN(CC)CC>>[CH:17]1([CH2:16][CH:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:26]([O:27][CH3:28])[CH:25]=[CH:24][CH:23]=3)[N:1]=[CH:29]2)[C:8]([NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(OCC)OCC
Reactant: COc1cccc(C(=O)NC(CC2CCCCC2)C(=O)Nc2nccs2)c1N
Solvent: CCN(CC)CC
Product: COc1cccc2c(=O)n(C(CC3CCCCC3)C(=O)Nc3nccs3)cnc12
Temperature: 130 °C

Procedure:
2-amino-N-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-methoxybenzamide (0.5 g, 1.24 mmol) was dissolved in (EtO)3CH:Et3N (4:1, 2 mL) and the reaction was heated to 130° C. overnight. All solvents were removed. The crude product was purified via preparative HPLC. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.31 (m, 6H) 1.54-1.77 (m, 4H) 1.85 (s, 1H) 2.05-2.18 (m, 1H) 2.23-2.36 (m, 1H) 4.04 (s, 3H) 5.68-5.80 (m, 1H) 7.13 (d, J=4.29 Hz, 1H) 7.30 (d, J=8.08 Hz, 1H) 7.45-7.59 (m, 2H) 7.85 (d, J=8.08 Hz, 1H) 8.60 (s, 1H). [M+H] calc'd for C21H24N4O3S, 413; found, 413.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]2[CH2:25][CH2:24][C@@H:23]([CH2:26][O:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:22]2)[CH:20]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][O:27][CH2:26][C@@H:23]2[CH2:24][CH2:25][N:21]([C:19]3[CH:18]=[N:17][CH:16]=[C:15]([O:14][CH2:13][C@@H:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)[CH:20]=3)[CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC[C@@H](COCCCc3ccccc3)C2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1ccc(CCCOC[C@@H]2CCN(c3cncc(OC[C@@H]4CCCN4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[3(R)-[(3-phenylpropoxy)methyl]-1-pyrrolidinyl]pyridine (280 mg, 0.56 mmol) in CH2Cl2 (5 mL) was added a mixture of CF3COOH (1 mL) and water (0.1 mL) under N2. The solution was stirred overnight at room temperature. After concentration under vacuum, the crude product was purified by preparative HPLC (column: SunFire Prep C18, 150×19 mm, 5 μm particle size; UV detection at 270 nm; flow 20 mL/min; mobile phase: A, water with 0.05% TFA; B, MeOH; 0-6 min, 40% to 50% B in A; 6-7 min, 50%; 7-8 min, 100%). The eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3OH. The residue was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine and dried. After concentration in vacuo, the free base (150 mg, 67%) was obtained as a yellowish oil. 1H NMR (CDCl3, 300 MHz) δ 7.67 (d, 1H, J=2.1 Hz), 7.64 (d, 1H, J=2.1 Hz), 7.32-7.19 (m, 5H), 6.37 (t, 1H, J=2.1 Hz), 4.03-3.96 (m, 2H), 3.64-3.60 (m, 1H), 3.49-3.29 (m, 7H), 3.13-3.01 (m, 3H), 2.90 (br s, 1H), 2.74-2.63 (m, 3H), 2.19-2.13 (m, 1H), 2.04-1.88 (m, 6H), 1.69-1.57(m, 1H). LC-MS (ESI) m/z 396 (M+H+).
Reaction SMILES: [SH2:1].[C:2]1([CH3:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=[O:13])/C=C/C.P(=O)(O)(O)O>C(N(CC)CC)C>[CH:9]([C:5]1[CH:4]([CH3:3])[S:1][CH:2]([CH3:8])[CH2:7][CH:6]=1)=[O:13]
Reactant: Cc1ccccc1
Reactant: S
Reactant: C/C=C/C=O
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Product: CC1CC=C(C=O)C(C)S1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
17 g of hydrogen sulfide were passed into a mixture of 500 ml of toluene, 70 g of crotonaldehyde and 10 ml of triethylamine at 30° C. and the mixture was then stirred for 12 hours at room temperature, after which 300 ml of 37% strength by weight phosphoric acid were added. Stirring was continued for 8 hours at 90° C., after which the mixture was cooled to room temperature and the organic phase was separated off. The aqueous phase was extracted once with toluene, the combined organic phases were washed once with water and dried over sodium sulfate, the solvent was removed under reduced pressure and the residue was distilled under 0.6 mbar to give 64 g (82% of theory) of 3-formyl-5,6-dihydro-2,6-dimethyl-2H-thiopyran of boiling point 73°-76° C.
Reaction SMILES: ClC([CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.[C:11]([NH2:14])(=[S:13])[CH3:12]>CC(C)=O>[CH3:12][C:11]1[S:13][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][N:14]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(C)C(=O)Cl
Solvent: CC(C)=O
Product: CCOC(=O)c1cnc(C)s1
Temperature: 56 °C
Reaction time: 6 h
Yield: 32 %

Procedure:
Under nitrogen atmosphere, a solution of KOtBu (11.5 g) in THF (203 mL) was cooled to 0° C., and thereto were added dropwise ethyl chloroacetate (12.5 g) and ethyl formate (7.60 g) in THF (40 mL). After the addition, the mixture was stirred at 0° C. for 3 hours, and further stirred at room temperature for 16 hours. Water and a 6N aqueous hydrochloric acid solution were added to the mixture, and the mixture was extracted with Et2O, and dried over MgSO4. The solvent was evaporated under reduced pressure to give ethyl 2-chloroformyl-propionate. Under nitrogen atmosphere, to a solution of ethyl 2-chloroformylpropionate in acetone (250 mL) was added thioacetamide (7.74 g), and the mixture was stirred at 56° C. for 6 hours, and stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=12.5/1→10/1) to give ethyl 2-methyl-1,3-thiazole-5-carboxylate (5.74 g, 32%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.O.Cl>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(NCCCCCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCCCc2ccccc2)cc1

Procedure:
A mixture of 7 g. of ethyl p-[(5-phenylpentyl)amino]benzoate (prepared as described in Example 46), 7 g. of potassium hydroxide and 100 ml. of ethanol-water (9:1) is refluxed for 3 hours. The mixture is acidified with concentrated hydrochloric acid while hot, diluted with water, cooled and filtered. The solid is washed with water to give white crystals, m.p. 141°-143° C. Recrystallization from ethanol gives white crystals, m.p. 142°-144° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[O:20][C:1](=[O:2])[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][C:16]=2[CH:15]=1
Reactant: Oc1ccc(Br)cc1CNc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1Oc2ccc(Br)cc2CN1c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 99.6 %

Procedure:
Step 2 Carbonyldiimidazole (0.874 g, 5.39 mmol) and DMAP (0.088 g, 0.719 mmol) were added to a solution of 4-bromo-2-((phenylamino)methyl)phenol (1.00 g, 3.60 mmol) in DCM (100 mL) and the resulting mixture was stirred at rt for 60 h. The mixture was diluted with hexanes (100 mL), washed with NaHCO3 (aq) (2×25 mL), 1 M hydrochloric acid (25 mL) and brine (25 mL), dried and filtered through a pad of silica gel. The solids were rinsed with 1:1 EtOAc-hexane and the filtrate was concentrated to give 6-bromo-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one as a white solid (1.09 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 7.41-7.56 (3H, m), 7.30-7.41 (3H, m), 7.21-7.29 (1H, m), 7.01 (1H, d, J=8.80 Hz), 4.80 (2H, s). Mass spectrum m/z 304, 306 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])[N:9]=[CH:8][C:7]=1[C:22]#[N:23])(O)=[O:2].S(Cl)([Cl:26])=O>>[Cl:26][C:1]([CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])[N:9]=[CH:8][C:7]=1[C:22]#[N:23])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cnn(-c2ccc(C(F)(F)F)cc2Cl)c1NCC(=O)O
Product: N#Cc1cnn(-c2ccc(C(F)(F)F)cc2Cl)c1NCC(=O)Cl

Procedure:
A solution of 5-carboxymethylamino-1-(2-chloro-4-trifluoromethylphenyl)-4-cyanopyrazole (4.5 g; prepared as described in Example 26) in thionyl chloride (40 ml) was heated at reflux for 1 hour. The reaction mixture was cooled and evaporated under diminished pressure to give 5-chlorocarbonylmethylamino-1-(2-chloro-4-trifluoromethylphenyl)-4-cyanopyrazole (4.72 g), in the form of a red oil, which was used immediately in b or c below:
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].N>CO.[Ni]>[S:1]([N:11]1[C:19]2[C:14](=[C:15]([CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C#N)cccc32)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN)cccc32)cc1
Reaction time: 6 h
Yield: 88.6 %

Procedure:
A mixture of 1-tosyl-1H-indole-4-carbonitrile (0.5 g, 1.69 mmol), 5% NH3 in methanol (5.0 mL) and Raney Nickel (0.2 g) in methanol (15.0 ml) was hydrogenated at 5 Torr for 6 h at rt. After completion of the reaction, the Raney Nickel was filtered off through a pad of celite under vacuum and washed with methanol (5×2 mL). The combined filtrates were evaporated to dryness under reduced pressure. The residue was washed with 10% diethyl ether in pentane to yield the title compound as a white solid (0.45 g, 78%). [1H-NMR (CDCl3, 300 MHz): δ 7.72-7.59 (m, 3H), 7.44-7.52 (m, 1H), 7.33-6.72 (m, 5H), 4.12-4.01 (m, 2H), 2.27 (s, 3H)].
Reaction SMILES: CO[C:3]1C=C[C:6]2[C:9]([NH:11][C:12]([O:14][C:5]=2[CH:4]=1)=O)=O.[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.[CH2:26]([OH:28])[CH3:27]>CN(C)C1C=CN=CC=1>[NH2:11][C:9]1[CH:6]=[C:5]([O:14][CH3:12])[CH:4]=[CH:3][C:27]=1[C:26]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([O:18][CH2:17][CH2:16][Cl:15])=[CH:20][CH:21]=1)=[O:28]
Reactant: Nc1ccc(OCCCl)cc1
Reactant: CCO
Reactant: COc1ccc2c(=O)[nH]c(=O)oc2c1
Agent: CN(C)c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(OCCCl)cc2)c(N)c1

Procedure:
To a solution of 11.11 g (0.0575 mol) of 7-methoxyisatoic anhydride in 300 mL of ethanol was added a catalytic amount of 4-dimethylaminopyridine and 144 mL of a 1M solution containing 24.7 g (0.144 mol) of 4-(2-chloroethoxy)-aniline. The reaction mixture was sired and heated under reflux for 3 hours. One half of the solvent was evaporated in a rotary evaporator. The reaction mixture was then cooled on ice. The precipitate that formed was collected by vacuum filtration and amounted to 16.4 g. An analytical sample (mp 167-168° C.) was obtained by recrystallization from ethanol.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][Br:7].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br-:7].[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]

Procedure:
A solution of 3-trifluoromethylbenzylbromide (4.6 g, 0.019 mol) and triphenylphosphine (5.0 g, 0.019 mol) in dry toluene (200 mL) was heated to reflux for two hours. The precipitate was filtered off by suction, washed with toluene, and dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:23]([O:25][CH:26](OCC)OCC)[CH3:24].C(OC(=O)C)(=O)C>>[CH2:23]([O:25][CH:26]=[C:16]([C:15](=[O:22])[C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][C:2]=1[F:1])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:24]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1cc(CN2CCOCC2)ccc1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 3-(2-fluoro-5-(4-morpholinylmethyl)phenyl)-3-oxopropanoate (Preparation 3, 20.0 g), triethylorthoformate (21.5 ML) and acetic anhydride (21.4 mL) is heated at 150° C. in a round-bottom flask equipped with a Dean-Stark trap and condenser. After 4 h, the remaining acetic acid and triethylorthoforrnate are distilled off by heating the mixture to 100° C. at 0.2 Torr for 1 hr, leaving 22.9 g of the title compound as an amber oil. The crude product is used as is in the subsequent transformations. Physical characteristics: 1H NMR (300 MHz, DMSO-d6) δ 7.85, 7.60-7.45, 7.23, 4.36-4.17, 4.09-3.99, 3.56, 3.49, 2.34, 1.29-1.11, 1.08-0.99; MS (ESI+) m/z 366 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([NH2:22])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:23]I>N1C=CC=CC=1>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([NH:22][CH3:23])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(N)c1
Reactant: CI
Solvent: c1ccncc1
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(NC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.01 moles of ethyl α-hydroxy-γ-(3-amino-4-cyclohexylphenyl)butyrate in 100 ml. of pyridine is added 0.1 moles of methyl iodide. The reaction mixture is stirred overnight at room temperature, filtered and concentrated. The residue is distilled to obtain ethyl α-hydroxy-γ-(3-methylamino -4-cyclohexylphenyl)butyrate.