Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[CH:15][CH:14]=1.CO.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccc(Oc2ccc(OCc3ccccc3)cc2)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Yield: 94 %

Procedure:
4-Benzyloxyphenyl 2-chloro-4-trifluoromethylphenyl ether (25 g., 0.066 mole), purified by recrystallization from methanol, ethyl acetate (200 ml.) and 10% palladium on charcoal (1.0 g.) are charged to a 2-liter Paar hydrogenation bottle and shaken in a hydrogen atmosphere (40-45 psi) until hydrogen uptake ceases. The catalyst is then removed by filtration and the solvent and toluene are removed in vacuo to give 17.9 g. (94% yield) of 4-(2-chloro-4-trifluoromethylphenoxy)phenol, mp 55°-6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:6]=[C:7]1[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13].[C:19]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])(=[O:22])[CH:20]=[CH2:21].[OH-].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]2[C:8](=[O:13])[N:9]([CH2:21][CH2:20][C:19]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])[C:10](=[O:12])[NH:11]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: COc1ccc(C=C2NC(=O)NC2=O)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)COC(=O)CCN1C(=O)NC(=Cc2ccc(OC)c(OC)c2)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
20 g (80.6 mmol) of 5-(3,4-dimethoxybenzylidene)-hydantoin, 17.8 g (96 mmol) of 2-ethylhexyl acrylate and 0.90 g (1.6 mmol) of potassium hydroxide were added to 150 ml of dimethylformamide, and the mixture was stirred at 110° C. for 2 hours. After cooling, the reaction solution was added with 200 ml of water and extracted with 500 ml of ethyl acetate. The extract was dried with sodium sulfate and then the solvent was distilled off under reduced pressure. The residue was recrystallized with toluene-n-hexane (1:1) and the precipitated crystals were dried to obtain 27.1 g of 2-ethylhexyl 4-(3,4-dimethoxyphenylmethylene)-2,5-dioxo-1-imidazolidinepropionate (yield: 77.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (0.5 g, 1.999 mmol) in pyridine (5 ml) was added methanesulphonyl chloride (0.309 ml, 4.00 mmol) and the mixture stirred at 20° C. for 18 hr when the solvent was removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution (10 ml) and dichloromethane (20 ml), separated by hydrophobic frit and purified by silica (70 g) cartridge on Flashmaster II using a gradient of dichloromethane and methanol to give the title compound as a brown solid (0.46 g).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[Cl:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:12]=2[Cl:11])[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Clc1cccc(CBr)c1Cl
Solvent: O
Product: Nc1cc(=O)[nH]c(SCc2cccc(Cl)c2Cl)n1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (2.22 g) with 2,3-dichlorobenzyl bromide (3.30 g) to afford the subtitle compound as a white solid. Yield: 3.25 g.
Reaction SMILES: CO.[BH4-].[Na+].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]>O>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10]
Reactant: COc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 201.6 %

Procedure:
Five milliliters of a methanol solution containing 0.6 g (16.0 mmol) of NaBH4 is added dropwise to 10 ml of a methanol solution containing 2.0 g (14 7 mmol) of 2-methoxybenzaldehyde, followed by stirring at room temperature for about 1 hour. After the progress of reaction has been confirmed by thin-layer chromatography, 100 ml of water is poured into the reaction solution to decompose excess NaBH4, followed by extraction with three 30 ml portions of ether. The ether layer is dried over anhydrous Na2SO4, and then filtered. When the solvent is removed by distillation, 1.95 g (yield: 96.1%) of 2-methoxybenzyl alcohol is obtained as an oily colorless product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[Cl:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCn1nc2ccccc2n1
Reactant: Clc1cccc(Cl)n1
Product: Clc1cccc(C#CCCn2nc3ccccc3n2)n1
Reaction time: 0.25 h
Yield: 5300 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2,6-dichloropyridine (150 mg, 1.01 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (0.17 g, 1.00 mmol, Example 109(D)). Microwave conditions: 120° C. for 15 min. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 15 mg (53 mmol, 5%) of 2-(4-(6-chloropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[CH3:15][N:16]=[C:17]=[O:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][C:17](=[O:18])[NH:16][CH3:15]
Reactant: CC(=O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Reactant: CN=C=O
Product: CNC(=O)Oc1c(Cl)cc(C(C)=O)cc1[N+](=O)[O-]

Procedure:
A mixture of 21.5 grams (0.1 mole) 3'-chloro-4'-hydroxy-5'-nitroacetophenone and 85.0 milliliters (a large excess) of methylisocyanate was refluxed for 5 hours. On cooling, a white crystalline product was formed. The product was filtered (weight 18.0 grams, melting point 115°-118° C.) and was identified by characteristic peaks in the infrared spectrum as 3'-chloro-4'-(N-methylcarbamoyloxy)-5'-nitroacetophenone.
Reaction SMILES: O.[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].O1C=CC2C([O:17][CH2:18][C@@H:19]([OH:42])[CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[S:31][C:30]5[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=5[C:28]=4[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:23][CH2:22]3)=CC=CC1=2.[O:43]1[CH2:45][C@H:44]1[CH2:46][O:47][C:48]1[C:53]2[O:54][CH:55]=[CH:56][C:52]=2[CH:51]=[CH:50][CH:49]=1>CO>[OH2:4].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[O:54]1[CH:55]=[CH:56][C:52]2[CH:51]=[CH:50][CH:49]=[C:48]([O:17][CH2:18][C@@H:19]([OH:42])[CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([C:27]4[S:31][C:30]5[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=5[C:28]=4[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:25][CH2:26]3)[C:53]1=2.[O:54]1[CH:55]=[CH:56][C:52]2[CH:51]=[CH:50][CH:49]=[C:48]([O:47][CH2:46][C@@H:44]([OH:43])[CH2:45][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[S:31][C:30]5[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=5[C:28]=4[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:23][CH2:22]3)[C:53]1=2.[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4]
Reactant: CN(C)CCCc1c(C2CCN(C[C@H](O)COc3cccc4occc34)CC2)sc2ccccc12
Reactant: c1cc(OC[C@@H]2CO2)c2occc2c1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: CN(C)CCCc1c(C2CCN(C[C@H](O)COc3cccc4ccoc34)CC2)sc2ccccc12
Yield: 39.9 %

Procedure:
A solution 4-(3-(3-dimethylaminopropyl)benzo[b]thiophen-2-yl)piperidine (0.075 g, 0.248 mmol, prepared in example 15) and (S)-(+)-7-(oxiranylmethoxy)benzo[b]furan (0.047 g, 0.248 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/10% methanol/1% ammonium hydroxide in dichloromethane gradient elution) to give the title compound as a yellow oil (0.039 g, 32%). The oxalate was prepared to give the title compound. FDMS m/e=493 (M++1 of free base). C29H36N2O3S.C2H2O4.0.5H2O
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Br:18][C:17]1[CH:16]=[N:15][N:14]2[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([C:19]([N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[O:21])[CH:11]=[N:12][C:13]=12
Reactant: c1csc(C2CCNCC2)c1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC(c2cccs2)CC1
Yield: 97.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.10 g, 0.29 mmol) obtained in Example 22, step 3 and 4-(thiophen-2-yl)piperidine hydrochloride (0.07 g, 0.35 mmol), the title compound (0.14 g, 99%) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:36])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)=[O:23])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.O>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:4][C:3]([OH:37])=[O:2])[CH2:10][CH2:9]3)=[CH:12][CH:13]=2)=[O:36])=[O:23])=[CH:29][CH:28]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3ccc(-c4ccccc4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3ccc(-c4ccccc4)cc3)cc2)CC1
Reaction time: 24 h

Procedure:
Trans-[4-(4-{3-[(biphenyl-4-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid methyl ester (60 mg, 0.120 mmol) was put into THF/water (20 mL, 3:1) solvent, and NaOH (38.51 mg, 0.963 mmol) was added thereto. The mixture was stirred for 24 hours, THF was removed, and pH of the mixture was adjusted to be 2-3 with 1N hydrochloric acid. The reaction mixture was extracted with EtOAC (3×100 mL), washed with brine and dried with anhydrous sodium sulfate, and the solvent was removed. The obtained crude material was crystallized with acetonitrile to obtain the desired compound (56 mg, 96%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8](=[O:15])[NH:7]2)([O-:3])=[O:2].[H-].[Na+].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1>CN(C)C=O>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:10]2[C:11]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=3)[NH:7][C:8](=[O:15])[C:9]2=[O:14])[CH:22]=1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2[nH]c1=O
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(=O)c(=O)[nH]c3cc([N+](=O)[O-])ccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
Under an N2 stream and exclusion of moisture, 1.03 g (5 millimoles) of 6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline is combined with 50 ml of dimethylformamide at room temperature. To this mixture is added 330 mg (11 mmol) of sodium hydride (80% strength) in 3 portions. The mixture is then stirred for one hour at room temperature. To this mixture is added dropwise 1.26 g (5.5 mmol) of 3-bromomethylbenzoic acid methyl ester in 5 ml of dimethylformamide, and the mixture is further stirred for 3 1/2 hours. After concentration, the residue is distributed in acetic water/ethyl acetate. The organic phase is separated, dried, filtered and concentrated. The residue is chromatographed over silica gel with dichloromethan ethanol=95:5, thus obtaining, besides 211 mg of 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl) benzoic acid methyl ester, which is not further purified, also 222 mg of 3-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl)benzoic acid methyl ester, mp: 265-267° C.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:41]([NH:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[F:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][NH:43][C:41](=[O:42])[C:10]2[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([C:15]3[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]4[O:22][C:21]([C:23]5[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=5)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=4[CH:34]=3)[N:11]=2)=[CH:50][CH:49]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)NCc4ccc(F)cc4)n3)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(C(=O)NCc4ccc(F)cc4)n3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 3-(benzyloxy)-N-(4-fluorobenzyl)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinamide (361 mg, 0.51 mmol) in CH3OH (5 mL) was added Pd—C under Ar. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 at RT overnight. After being filtered through celite and removal of the solvent by concentration, the residue was purified by prep-TLC (DCM:MeOH=60:1) to afford the product of N-(4-fluorobenzyl)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-hydroxypicolinamide. (220 mg, yield: 70%). 1H-NMR (CDCl3, 400 MHz) δ 12.27 (s, 1H), 8.61˜8.64 (m, 1H), 7.91˜7.96 (m, 3H), 7.64 (d, J=8.8 Hz, 1H), 7.55 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.35 (dd, J=5.6, 8.4 Hz, 2H), 7.21 (t, J=8.4 Hz, 2H), 7.01 (t, J=8.4 Hz, 2H), 5.80 (d, J=3.6 Hz, 1H), 4.59 (d, J=6.4 Hz, 2H), 3.04 (s, 3H), 2.97 (d, J=5.2 Hz, 3H), 2.91 (s, 3H). MS (M+H)+: 621.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]2[CH:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:3]12.S(Cl)([Cl:21])=O>>[Cl:21][C:16]([C:14]1[CH:15]=[C:3]2[N:4]([CH:13]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:2]2=[O:1])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2n(c1)CCc1ccccc1C2=O
Product: O=C(Cl)c1cc2n(c1)CCc1ccccc1C2=O
Yield: 89 %

Procedure:
6,11-Dihydro-11-oxo-pyrrolo[2,1-b][3]benzazepine-2-carboxylic acid (24 g., 99 mmoles) in 100 ml. of thionyl chloride was refluxed for 15 minutes. The volatiles were removed under vacuum and the residue was triturated in ether. Filtration and air-drying yielded 2-chlorocarbonyl-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one (23 g., 89%), m.p. 147°-148.5°.
Reaction SMILES: [C:1]1([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O.C1(C)C=CC=CC=1>CN(C)C=O>[C:1]1([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:20])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C=Cc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(C=Cc2ccccc2)cc1
Yield: 83.8 %

Procedure:
15.1 g (67.4 mmols) of stilbene-4-carboxylic acid, 10.0 g (84.25 mmols) of thionyl chloride, 150 ml of toluene and 0.18 ml of N,N-dimethylformamide are stirred at 70° C. for 3 hours. The reaction mixture is then evaporated and the crude product is recrystallised from n-hexane/cyclohexane. 13.7 g (84% of theory) of stilbene-4-carboxylic acid chloride are obtained in the form of white crystals; melting point 131.2° C.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:9])[CH:6]([CH3:8])[CH3:7])=[O:3].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH3:10])[O:4][CH:5]([Cl:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(Cl)OC(=O)Cl
Reactant: COCCOCCOCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOC(=O)OC(Cl)C(C)C

Procedure:
In a manner similar to the method described in Example 3, 1-chloro-2-methylpropyl chloroformate (Aldrich) was reacted with 2-(2-(2-methoxyethoxy)ethoxy)ethanol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloro-2-methylpropyl 2-(2-(2-methoxyethoxy)-ethoxy)ethyl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 15-methyl-12-oxo-2,5,8,11,13-pentaoxahexadecan-14-yl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C43H52Cl2F2N3O10: [(M+H)+]: 878, found: 878.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[C:14](=O)[CH:13]=[CH:12][NH:11][C:10]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:16])[C:9]=1[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Cc1[nH]ccc(=O)c1Cc1cccc(F)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nccc(Cl)c1Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
A solution of 3-[(3-fluorophenyl)methyl)-2-methylpyridin-4(1H)-one (0.07 g, 0.32 mmol) in phosphorous oxychloride (3 mL) was heated to 55° C. for 16 h. Then the solution was cooled to room temperature and concentrated. The remaining residue was dissolved in ethyl acetate (10 mL), washed with 5% sodium bicarbonate (2×5 mL), and saturated sodium chloride (5 mL), dried over sodium sulfate, filtered and concentrated to afford 4-chloro-3-[(3-fluorophenyl)methyl]-2-methylpyridine. 1H NMR (400 MHz, CDCl3): 8.33 (d. 1H), 7.30-7.23 (m, 2H), 6.92-6.85 (m, 2H), 6.76 (d, 1H), 4.22 (s, 2H), 2.54 (s, 3H). MS (EI) for C13H11ClF: 236.0 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6]Br.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: CCOP(=O)(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)OCC
Temperature: 160 °C
Yield: 40.5 %

Procedure:
A mixture of 3,5-bis-trifluoromethylbenzyl bromide (5.0 g, 16 mmol) and triethyl phosphite (3.4 g, 20 mmol) was heated at 160° C. for 20 hours. The reaction mixture was cooled and distilled at 83° C. (0.03 mm Hg) to give 2.36 g of the product as a colorless oil in 48% yield. D.C.I.M.S. [MH+, 365].
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH2:31][C:32](=O)[CH3:33])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH2:31][CH:32]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:4]3[C:3]([CH3:2])=[C:11]4[C:7](=[CH:6][CH:5]=3)[C:8](=[O:12])[O:9][CH2:10]4)[CH2:16][CH2:17]2)[CH3:33])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: COc1cc(CC(C)=O)ccc1C#N
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: COc1cc(CC(C)N2CCN(CCc3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]propyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxopropyl)benzonitrile. LC-MS (IE, m/z): 434.4 [M+1]+. (0.19 μM)
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.O>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CCl
Reaction time: 1.5 h
Yield: 95 %

Procedure:
In 3 l of toluene was dissolved 182 g of 2,6-xylidine, and in 1.5 l of water was dissolved 159 g of sodium carbonate. The two solutions were combined, and 203 g of chloroacetyl chloride was added thereto dropwise over 1.5 hours at an inner temperature of from 20° to 35° C., followed by stirring at that temperature for 1.5 hours. The reaction mixture was cooled with ice, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 282 g (95%) of the titled compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[N:55]1[CH2:59][CH2:58][CH:57]([C:60](O)=[O:61])[C:56]1=[O:63]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:60]([CH:57]1[CH2:58][CH2:59][N:55]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[F:48])[C:56]1=[O:63])=[O:61]
Reactant: O=C(O)C1CCN(c2ccccc2F)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccccc2F)C1=O
Yield: 43.5 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.104 g; 0.448 mmol), PyBOP (0.349 g; 0.672 mmol), N,N-diisoprpylethylamine (0.232 mL; 1.34 mmol) and 1-(2-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.448 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.078 g (44%) of the title compound as a white solid.