Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC)=O.[OH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]1=[O:17].C(N(CC)CC)C.[CH3:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([CH3:32])[N:27]1[CH2:33][CH2:34][NH2:35]>C(Cl)(Cl)Cl>[CH3:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([CH3:32])[N:27]1[CH2:33][CH2:34][NH:35][C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([OH:7])[C:9]1=[O:17]
Reactant: O=C(O)CN1CCC(O)C1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O
Reaction time: 0.2 h

Procedure:
1.2 ml of ethyl chloroformate are placed in 12 ml of chloroform, whereupon there are added dropwise at -30° within 30 minutes 2.0 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid and 1.74 ml of triethylamine dissolved in 50 ml of chloroform. After stirring at a temperature between -2° and -10° for 12 minutes, 2.07 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine dissolved in 10 ml of chloroform are added dropwise. The mixture is left to stand at room temperature overnight. Thereupon, the mixture is evaporated and the residue (6 g) is chromatographed on 120 g of aluminum oxide (activity grade III, neutral). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with acetonitrile and ethanol has a melting point of 128°-130° after repeated chromatography on aluminum oxide and recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11](C(OCC)=O)[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][NH:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)N1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Product: Clc1ccc(C23CNCC2C2CCC3C2)cc1Cl

Procedure:
By the method of Example 26, (-)-3a-(3,4-dichlorophenyl)octahydro-2-methyl-4,7-methano-1H-isoindole is reacted with ethyl chloroformate in toluene to give the corresponding 3a-(3,4-dichlorophenyl)octahydro-4,7-methano-2H-isoindole-2-carboxylic acid, ethyl ester. This urethane is hydrolyzed with hydrochloric acid and the solution is evaporated to give (-)-3a-(3,4-dichlorophenyl)octahydro-4,7-methano-1H-isoindole hydrochloride as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:45])[CH:4]([CH3:44])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:23]=3[O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:11]=2)[CH:6]=1.[OH-].[Na+]>CO>[CH3:44][CH:4]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:23]=3[O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:11]=2)[CH:6]=1)[C:3]([OH:45])=[O:2]
Reactant: COC(=O)C(C)c1ccc2cc(OCCCCCCc3cccc(OCc4ccccc4)c3OCc3ccccc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc2cc(OCCCCCCc3cccc(OCc4ccccc4)c3OCc3ccccc3)ccc2c1

Procedure:
A solution of 3.35 g (5.56 mmol) of rac.-alpha-methyl-6-[6[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-2-naphthaleneacetic acid methyl ester in 100 mL of methanol and 3.7 mL (22 mmol) of 6N sodium hydroxide was stirred at reflux for 4 hours. The solvent was removed at reduced pressure, the residue was acidified and the product was filtered to give (rac)-alpha-methyl-6-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-2-naphthaleneacetic acid. An analytical sample was obtained from ether-hexane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].[O-2].[Mg+2]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:15][C:14]2[CH:13]=[C:12]([CH3:11])[CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cccc(N)c1
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: Cc1cccc(Nc2ccc([N+](=O)[O-])cc2)c1
Temperature: 200 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a mixture of 4-nitro-fluorobenzene (250 mg, 1.77mmol) and 3-methyl aniline (190 mg, 1.77mmol) in 4 mL of water in a sealed tube was added magnesium oxide (86 mg, 2.126 mmol). The suspension was stirred at 200° C. for 2 days. The reaction was cooled to ambient temperature and the suspension was diluted with water and filtered to remove insoluble material. The aqueous layer was extracted 3 times with ethyl acetate (50 mL) and the combined organic layers were washed with boronic acid (5%, 50 mL) and water, dried over magnesium sulfate and concentrated in vacuo to provide (4-Nitro-phenyl)-m-tolyl-amine (190 mg, 47% yield). ). RP18-HPLC RT: 7.020 minutes; API MS: 229.20 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][CH2:3][OH:4])=[C:8]([C:13]([F:14])([F:15])[F:16])[CH:7]=1
Reactant: OCCBr
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: OCCOc1ccc(Br)cc1C(F)(F)F
Reaction time: 6 h

Procedure:
2-Bromoethanol (23.3 g) was added to a mixture of 4-bromo-2-(trifluoromethyl)-phenol (30 g) and potassium carbonate (34.4 g) in acetonitrile (200 ml). The above mixture was refluxed for 8 hours then another portion of 2-bromoethanol (8 g) was added and the reflux continued for another 6 hours. After diluting with ethyl acetate (500 ml), the mixture was washed with water (300 ml) then 0.1 M sodium hydroxide (200 ml). Organic layer was dried over magnesium sulphate, solvent removed under reduced pressure, the residue was taken into heptane by heat, 2-(4-bromo-2-(trifluoromethyl)-phenoxy)-ethanol crystalised and collected by filtration (17 g).
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[OH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].[H-].[Na+]>>[C:28]([O:27][C:26](=[O:32])[NH:25][CH2:24][CH2:23][O:22][C:12]1[CH:13]=[C:14]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (79.2 mg, 0.2 mmol) in tert-butyl N-(2-hydroxyethyl)-carbamate (Aldrich, 3 mL, 18.9 mmol) was added NaH (Aldrich, 60%, 0.2 g, 5.0 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated to 120° C. for 3.0 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 50% ethyl acetate in hexanes) to give [2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-yloxy]-ethyl]-carbamic acid tert-butyl ester as a yellow solid. (Yield 17.7 mg, 21.5%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].[C-]#N.[Na+].[C:16]1([C:22]#[C:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH2:8][C:9]#[N:10])[CH:6]=[CH:7][C:2]=1[O:1][CH2:24][C:23]#[C:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(CC#N)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC#Cc2ccccc2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC#N)ccc1OCC#Cc1ccccc1
Reaction time: 3 h

Procedure:
A mixture of (4-hydroxy-3-methoxy-phenyl)-acetonitrile (17.4 g) and sodium cyanide (6.6 g) in dimethylformamide (250 ml) is stirred under an atmosphere of nitrogen for 3 hours at +120° C. The mixture is then cooled to +60° C. and toluene-4-sulfonic acid 3-phenyl-prop-2-ynyl ester (39 g) in dimethylformamid (50 ml)is added during 5 minutes. It is stirred at +65° C. for another 4 hours. Upon cooling water (800 ml) is added. The mixture is extracted with ethyl acetate (2×500 ml). The organic phases are washed with brine (2×500 ml), dried (MgSO4) and evaporated. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexane 1:3) and recrystallised from ethyl acetate/hexane. [3-Methoxy-4-(3-phenyl-prop-2-ynyloxy)-phenyl]-acetonitrile is obtained, m.p. 74-75° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH2:22][O:23][CH3:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.Cl.[F:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[NH:35][C:34](=[O:37])[C:33]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[CH:32]2.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH2:22][O:23][CH3:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:41]3[CH2:42][CH2:43][CH:38]([C:33]4[C:34](=[O:37])[NH:35][C:36]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][C:27]=5[F:26])[CH2:39][CH2:40]3)=[O:19])[CH2:15][C:4]=2[CH:3]=1
Reactant: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)O)C1=O
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C1=O
Yield: 56 %

Procedure:
[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-acetic acid (100 mg, 0.25 mmol) and 8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (85 mg, 0.30 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 56% yield. High resolution MS m/e (M+H)+=624.1631.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH2:17])=[CH:8][CH:7]=1.CCN(CC)CC.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>C(Cl)Cl>[CH2:36]([NH:38][C:39]([NH:17][CH2:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](/[CH:5]=[CH:4]/[CH:3]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:2]([F:1])([F:27])[F:28])=[CH:7][CH:8]=1)=[O:40])[CH3:37]
Reactant: CCN=C=O
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 at 0° C. were added Et3N (0.064 mL, 0.44 mmol) and ethylisocyanate (0.023 mL, 0.33 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30% EtOAc in hexane) afforded the title compound as a solid (0.07 g, 60%): mp 84-87° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (br s, 1H), 4.24 (m, 1H), 3.21 (m, 2H), 1.2 (t, J=4.6 Hz, 3H); ESIMS m/z 515.33 ([M+H]+).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:24]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:25]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:24]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)([CH3:14])[C:4]([OH:3])=[O:23])=[CH:8][CH:9]=3)[N:34]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
A mixture of 2-(4-fluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 2, Part F) and 325 mesh K2CO3 (0.084 g, 0,60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to 3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionic acid 1H NMR (400 MHz, CDCl3) δ 8.21–8.20 (m, 1H), 7.94–7.92 (m, 1H), 7.65–7.62 (m, 2H), 7.50–7.34 (m, 4H), 7.17 (d, 2H, J=8.60 Hz), 6.93–6.77 (m, 7H), 4.21 (t, 2H, J=6.65 Hz), 3.20 (d, 1H, J=14.00 Hz), 3.13 (d, 1H, J=14.00 Hz), 3.01 (t, 2H, J=6.65 Hz) 2.40 (s, 3H), 1.37 (s, 3H); HRMS (ES+) m/z exact mass calcd for C34H31NO5F 552.2186, found 552.2175.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.[O:13]1CCOCC1>>[ClH:1].[NH2:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=1[C:8]([OH:11])=[O:13]
Reactant: O=C1NCc2ccc(Cl)cc21
Reactant: C1COCCO1
Agent: Cl
Product: NCc1ccc(Cl)cc1C(=O)O
Temperature: 110 °C
Yield: 4 %

Procedure:
A mixture of 6-chloro-2,3-dihydro-isoindol-1-one (0.115 g, 0.68 mmol) and 6M hydrochloric acid (8 ml) in dioxan (1 ml) was heated to 110° C. for 18 hours. After cooling to room temperature the solid was filtered off and dried in vacuo to give the title compound (0.0055 g, 4%) as a beige solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:13]=[C:14]([C@H:19]2[NH:24][C:23](=O)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20]2)[CH:15]=[C:16]([F:18])[CH:17]=1>C1(C)C=CC=CC=1.C1COCC1>[F:18][C:16]1[CH:15]=[C:14]([C@@H:19]2[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][NH:24]2)[CH:13]=[C:12]([F:11])[CH:17]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7.0 mL (7.0 mmol) of a 1 molar di-isobutyl-aluminium hydride solution in toluene were added to 0.48 g (2.0 mmol) (S)-6-(3,5-difluorophenyl)-3,3-dimethylpiperidin-2-one in 10 mL THF while cooling with ice and stirred for 20 h at RT. Then the reaction mixture was refluxed for 8 h. A 1M diisobutylaluminium hydride solution in toluene was added twice more and the mixture was refluxed for 8 h and 24 h in each case. After hydrolysis of the reaction mixture the precipitate formed was suction filtered and washed with THF. The filtrate was evaporated down and the residue was purified by flash chromatography (aluminium oxide).
Reaction SMILES: [OH-].[K+].O.Cl.N1CCC(=O)CC1.[F:12][C:13]1[CH:36]=[CH:35][C:16]([C:17]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:18])=[CH:15][CH:14]=1.O>CO>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[C:23]3[C:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH:30]=2)=[O:18])=[CH:35][CH:36]=1
Reactant: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2c1)c1ccc(F)cc1
Agent: Cl
Agent: O=C1CCNCC1
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc2[nH]cc(C3=CCNCC3)c2c1)c1ccc(F)cc1
Temperature: 20 °C
Yield: 46.9 %

Procedure:
To a solution of 5.8 gm (90 mMol) potassium hydroxide in 75 mL methanol were added 9.22 gm (60 mMol) 4-piperidone hydrochloride monohydrate followed by 7.8 gm (30 mMol) 5-(4-fluorobenzoyl)amino-3-(piperidin-4-yl)-1H-indole (Example 182A). This solution was stirred at reflux for 18 hours. The reaction mixture was cooled to ambient and then poured slowly into 150 mL water, maintaining the temperature of the solution at about 20° C. The resulting precipitate was filtered and recrystallized from ethanol to give 4.72 gm (47.2%) of the title compound as tan crystals. 0.725 gm of the material were crystallized again from ethanol to provide 0.241 gm light yellow crystals for analysis.
Reaction SMILES: C(=O)([O-])O.[CH3:5][N:6]([CH3:34])[C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][N+:13]2[CH:17]=[CH:16][N:15]([N:18]=[CH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:14]=2[CH:29]([CH3:31])[CH3:30])=[CH:9][CH:8]=1.[C:35]([OH:38])(=[O:37])[CH3:36]>CO>[C:35]([O-:38])(=[O:37])[CH3:36].[CH3:28][N:26]([CH3:27])[C:23]1[CH:22]=[CH:21][C:20]([CH:19]=[N:18][N+:15]2[CH:16]=[CH:17][N:13]([N:12]=[CH:11][C:10]3[CH:32]=[CH:33][C:7]([N:6]([CH3:5])[CH3:34])=[CH:8][CH:9]=3)[C:14]=2[CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1
Reactant: CC(=O)O
Agent: CC(C)c1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: O=C([O-])O
Solvent: CO
Product: CC(=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.3 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-isopropylimidazolium hydrogen carbonate are dissolved in 10 ml of methanol and 2 ml of glacial acetic acid are added thereto. After stirring at room temperature for 16 hours, the solution is concentrated and the product is crystallized by the addition of ether. After two-fold recrystallization from methanol/ether, there is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]2-isopropylimidazolium acetate of melting point 150°-151°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[Br:40][C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=1I.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:40][C:41]1[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=[CH:43][C:42]=1[C:14]1[C:13]2[C:17](=[CH:18][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=3[O:2][CH3:1])[C:29]3[S:33][N:32]=[CH:31][N:30]=3)(=[O:8])=[O:9])=[CH:11][CH:12]=2)[N:16]([CH3:19])[CH:15]=1
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c3c2)c(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)cn(C)c3c2)c(OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.500 g, 0.876 mmol), 2-bromo-1-iodo-4-(trifluoromethyl)benzene (0.769 g, 2.191 mmol), potassium phosphate (0.651 g, 3.07 mmol), and PdCl2(dppf)-CH2Cl2 (0.072 g, 0.088 mmol). DMF (5.84 ml), and the vial was flushed with argon, sealed, and stirred at 60° C. for two hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (silica gel, gradient elution 0 to 100% EtOAc:Hexanes) to afford 3-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.255 g, 0.382 mmol, 43.6% yield) as an off-white solid. m/z (ESI) 667.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH3:16])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[N:25]=[C:26]=[O:27]>COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:15]([CH3:16])[C:26]([NH:25][C:19]3[C:18]([CH3:17])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:24])=[O:27])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CNc1cc(Nc2cccc(Cl)c2)ncn1
Solvent: COCCOCCOC
Product: Cc1cccc(C)c1NC(=O)N(C)c1cc(Nc2cccc(Cl)c2)ncn1

Procedure:
A solution of N-(3-chloro-phenyl)-N′-methyl-pyrimidine-4,6-diamine (Example 124A, 94 mg, 0.4 mmol) and 2,6-dimethylphenyl isocyanate (74 mg, 0.52 mmol) in diglyme was stirred at 80° C. for 18 h. The solvent is evaporated in vacuo, and the residue is purified by column flash chromatography on silica gel (ethyl acetate/hexane 1:2) to afford title compound (29 mg, 19
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])[CH:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (3-hydroxy-phenyl)-acetic acid methyl ester (4.26 g, 25.66 mmol) and potassium carbonate (7.1 g, 51.33 mmol) in DMF (60 mL) is added 4-chloromethyl-5-methyl-2-phenyl-oxazole (5.33 g, 25.66 mmol) at RT. The reaction mixture is stirred for 16 h at 40° C. followed by 16 h at 60° C. The reaction mixture is cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 25% ethyl acetate in hexane to yield [3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acetic acid methyl ester as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1ccc(Cn2cc(Br)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
5-Bromo-1H-pyridin-2-one (1.04 g) and 4-ethylbenzyl bromide (1.43 g) were dissolved in N,N-dimethylformamide (15 ml), and thereto was added potassium carbonate (1.66 g). The mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed successively with water and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-3:1) to give 5-bromo-1-(4-ethylphenylmethyl)-1H-pyridin-2-one (1.58 g) as colorless crystals. APCI-Mass m/Z 292/294 (M+H).