Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)CC)C.ClC(OCC)=O.[OH:14][CH:15]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)/[CH:16]=[CH:17]/[C@H:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[N:19]1[CH2:25][C:26]#[C:27][CH2:28][O:29][CH2:30][C:31](O)=[O:32].N.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:14][CH:15]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)/[CH:16]=[CH:17]/[C@H:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[N:19]1[CH2:25][C:26]#[C:27][CH2:28][O:29][CH2:30][C:31]([NH2:3])=[O:32]
Reactant: O=C(O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Agent: O=C([O-])O
Solvent: ClCCl
Product: NC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Triethylamine (9.4 μL, 0.067 mmol) and ethyl chloroformate (3.1 μL, 0.032 mmol) were added sequentially to a solution of {4-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid (11.8 mg, 0.032 mmol) in CH2Cl2 (0.2 mL) at 0° C. After 1 h at 0° C., ammonia (0.5 M in 1,4-dioxane, 0.32 mL, 0.16 mmol) was added and the reaction mixture was allowed to warm to rt. After 17 h at rt, the reaction mixture was treated with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford 11 mg (93%) of the title compound.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:30]([F:33])([F:32])[F:31])=[C:24]([CH2:26][C:27](O)=[O:28])[CH:25]=1.[Br:34]N1C(=O)CCC1=O>ClC1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[Br:34][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:30]([F:33])([F:32])[F:31])=[C:24]([CH2:26][CH2:27][OH:28])[CH:25]=1
Reactant: Cc1ccc(C(F)(F)F)c(CC(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: OCCc1cc(CBr)ccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Benzoyl peroxide (0.085 g) was added to a suspension of 2-(5-methyl-2-(trifluoromethyl)phenyl)acetic acid (1.12 g) and N-bromosuccinimide (1.101 g) in chlorobenzene (18 mL), and the resulting mixture was heated at 100° C. under nitrogen for 80 minutes, then allowed to cool. The resulting mixture was diluted with ethyl acetate, washed three times with water, once with brine, then dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. The oil was dissolved in tetrahydrofuran (11 mL) and treated with a 2 molar solution of borane-methyl sulfide complex in THF (5.1 mL), portionwise over 2 minutes. The resulting mixture was stirred at room temperature overnight, then cooled in ice-water and quenched by the addition of methanol. The effervescing mixture was removed from the cooling bath, stirred at room temperature for 70 minutes, then concentrated in vacuo. The residue was purified by flash chromatography on silica eluted with 15% ethyl acetate in isohexane to afford the crude product as a yellow oil. Yield 0.919 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH2:1]([O:8][C:9](=[O:10])[CH2:11][S:12](=[O:14])(=[O:13])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][C:27](=[O:30])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CS(=O)(=O)Cl)OCc1ccccc1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: O=C1CCN(c2ccc(NS(=O)(=O)CC(=O)OCc3ccccc3)cc2)CC1

Procedure:
The title compound was prepared from benzyloxycarbonylmethylsulfonylchloride (J. Antibiot., 1994, 47, 1041) and 1-(4-amino-phenyl)-piperidine-4-one (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.42 (t, J=6.0 Hz, 4H), 3.55 (t, J=6.0 Hz, 4H), 4.16 (s, 2H), 5.16 (s, 2H), 6.99 (d, J=9.0 Hz, 2H), 7.10 (d, J=9.0 Hz, 2H), 9.73 (s, 1H); MS (ES) m/z: 403.2 (MH+); HRMS Calcd. for C20H22N2O5S(M+): 402.1250. Found: 402.1237.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:15]1[C:24]2[C:19](=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH2:27][OH:28])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>ClCCl>[CH2:11]([C:15]1[C:24]2[C:19](=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:27]=[O:28])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1c(CO)ccc2c(OC)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCc1c(C=O)ccc2c(OC)cccc12
Reaction time: 0.25 h
Yield: 104.8 %

Procedure:
A solution of dimethylsulfoxide (0.54 mL) in dry dichloromethane (3 mL) was added with stirring to a chilled (<-60° C.) solution of oxalyl chloride (0.59 mL) in dry dichloromethane (15 mL) at such a rate that the reaction temperature did not exceed -60° C. After 15 minutes a solution of 1-butyl-5-methoxy-2-naphthalenemethanol (1.54 g) in dichloromethane (6 mL) was added while the reaction temperature was still maintained below -60° C. The reaction was allowed to proceed for 15 minutes then triethylamine (2.9 mL) was added to the chilled reaction and, after an additional 20 minutes the cooling bath was removed and the mixture was allowed to equilibrate to room temperature. After 2N hydrochloric acid (225 mL) was added, the layers were separated and the aqueous phase was extracted with dichloromethane (50 mL), then the combined organic extracts were dried (MgSO4) and evaporated to yield 1.6 g of 1-butyl-5 -methoxy-2-naphthalenecarboxaldehyde. Sublimation of a portion (50° C.; 0.1 mm) furnished the analytical sample, mp 61.5°-62.5° C. Anal. Calcd for C16H18O2 : C, 79.31; H, 7.49 Found: C, 79.02; H, 7.53
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:17](OC(OCC)OCC)C>>[CH3:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)[CH:17]=[N:1]2
Reactant: CCOC(OCC)OCC
Reactant: Cc1cccc(N)c1C(=O)Nc1nnn[nH]1
Product: Cc1cccc2ncn(-c3nnn[nH]3)c(=O)c12

Procedure:
A mixture of 1.3 g of 2-amino-6-methyl-N-(1H-tetrazol-5-yl)benzamide and 10 ml of triethoxymethane was heated at reflux for 1 hour. The mixture was then cooled and the solid which formed was separated by filtration, washed with ethanol and air dried to give 5-methyl-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 280°-281° C. with decomposition. This compound has the following structural formula: ##STR3##
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([N:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:27](Cl)=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1>[CH2:8]([N:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:27]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)Cl
Reactant: CN1CCNCC1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)N1CCN(C)CC1
Reaction time: 3 h

Procedure:
A mixture of 1-methylpiperazine (5 ml.), N,N-dioctadecylcarbamylchloride (5.0 g.) and benzene (50 ml.) is refluxed and stirred for three hours. The white precipitate of 1-methylpiperazine hydrochloride is removed by filtration and the filtrate concentrated in vacuo to a yellow oil (4.5 g.). The oil is then charged on a silica gel pad and eluted with benzene in 50 ml. fractions. Fractions 10-15 are combined, a large volume of methanol added and the white crystalline material which separates filtered and dried, m.p. 46°-47° C. (1.45 g.).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@H:20]([NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:53]1([C:57](Cl)=[O:58])[CH2:56][CH2:55][CH2:54]1>CC#N>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@@H:22]2[CH2:21][C@H:20]([N:45]([CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:57]([CH:53]3[CH2:56][CH2:55][CH2:54]3)=[O:58])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:43][CH2:42]1
Reactant: O=C(Cl)C1CCC1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCc3ccccc3)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Solvent: CC#N
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(Cc3ccccc3)C(=O)C3CCC3)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example 134 using (3S,5R)-3-Benzylamino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester and cyclobutanecarbonylchloride. MS: 557 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.34 min.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](I)[CH2:23][CH3:24]>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:22][CH2:23][CH3:24])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(Nc2ccc(Br)cc2)sc2ncccc12
Reactant: CCCI
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc(Br)cc2)sc2ncccc2c1=O
Yield: 80.1 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (2.69 mmol) of 2-(4-bromoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 24 mg of lithium hydride and 503 mg of propyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 811 mg of 2-[(4-bromophenyl)imino]-2,3-dihydro-3-propyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ether and hexane) as a low polarity substance and 103 mg of 2-[N-(4-bromophenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ether) as a high polarity substance.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20]([C:22]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[O:24][C:23]=3[CH3:34])=[O:21])[CH:14]=2)[CH:9]=1.O.Cl>C1COCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[O:24][C:23]([CH3:34])=[C:22]([C:20]([NH:19][CH2:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH:9]=[C:8]([O:7][CH2:6][C:5]([OH:35])=[O:4])[CH:17]=[CH:16]4)=[O:21])[CH:26]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)COc1ccc2cc(CNC(=O)c3cc(-c4ccc(Cl)cc4)oc3C)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccc(Cl)cc2)cc1C(=O)NCc1ccc2cc(OCC(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
1 N NaOH (514 μL, 0.514 mmol) was added under nitrogen to a solution of [6-({[5-(4-chloro-phenyl)-2-methyl-furan-3-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (239 mg, 0.514 mmol), prepared in the previous step, in 30 mL of THF plus 15 mL of water. After the addition the reaction was stirred at room temperature for 20 h (overnight). 1 N HCl (1 mL) was added and the reaction then concentrated under reduced pressure to remove the THF. The solid present was removed by filtration and dried under reduced pressure to give the title compound (190 mg, 83%) as a tan solid, mp 177-181° C.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:21]([N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH:27]=[C:26]([NH:28][C:2]2[N:20]=[C:5]3[C:6]([C:10]4[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:25]=[N:24]1)[CH3:22]
Reactant: FC(F)(F)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CCn1cc(N)cn1
Product: CCn1cc(Nc2nc3c(-c4ccc(C(F)(F)F)cc4)cccn3n2)cn1

Procedure:
(1-Ethyl-1H-pyrazol-4-yl)-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1.5-a]pyridine (0.100 g, 0.31 mmol) and 1-ethyl-1H-pyrazol-4-ylamine (0.046 g, 0.41 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (52 mg, 44%). MP=162-164° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.77 (d, J=6.36 Hz, 1H), 8.38 (d, J=7.76 Hz, 2H), 7.85-7.97 (m, 3H), 7.81 (s, 1H), 7.47 (s, 1H), 7.11 (t, J=6.80 Hz, 1H), 4.10 (q, J=7.12 Hz, 2H), 1.36 (t, J=6.92 Hz, 3H). MS=373 (MH)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[N:7]=1.[ClH:24]>CCOCC>[ClH:24].[ClH:24].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc(-c3cccs3)n2)CC1
Agent: Cl
Solvent: CCOCC
Product: c1csc(-c2nc(N3CCNCC3)no2)c1
Yield: 78 %

Procedure:
A solution of tert-butyl 4-(5-(2-thienyl)-1,2,4-oxadiazol-3-yl)piperazine-1-carboxylate (2.2 g) in 2M HCl in Et2O (50 mL) was stirred at RT for 6 hours. The solvent was removed under vacuum to give 1.6 g (78%) of The title compound as a solid. TLC-CHCl3/MeOH (8/2): Rf=0.2. HPLC purity>98%.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:42]([NH:41][C:38]1[CH:39]=[CH:40][C:35]([C:6]2[CH:7]=[C:8]3[C:12](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)[NH:11][N:10]=[C:9]3[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:36][CH:37]=1)(=[O:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(C(=O)OC(C)(C)C)CC4)c3c2)cc1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (55 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][C:12]3([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:11][C:10]2=[O:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][C:12]3([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=3)[N:11]([CH2:30][CH3:31])[C:10]2=[O:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1ccc(CC23CCCC=C2N(c2cc(Cl)cc(Cl)c2)C(=O)N3)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C2=CCCCC21Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[1-(3,5-Dichlorophenyl)-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (150 mg) (0.38 mmol) in DMF (5 ml) was carefully dropped on a suspension of NaH 60% (18.2 mg) (1.2 eq) in DMF (5 ml) at RT. The reaction mixture was stirred 1 h at RT, then ethyl iodide (0.046 ml) (1.5 eq) was added. After one night, the reaction mixture was poured on water and extracted with tBuOMe. The organic layer was washed with water, dried over Na2SO4 and concentrated to yield a solid which was purified by HPLC to give 4-[1-(3,5-Dichlorophenyl)-3-ethyl-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (18.2 mg) as a white solid. 1H NMR (CDCl3):. 7.55 (2H, d), 7.25 (2H, d), 7.10 (1H, m), 6.80 (2H, m), 4.95 (1H, m), 3.75 (1H, m), 3.15 (1H, m), 3.0 (2H, s), 2.5-1.7 (6H, m), 1.25 (3H, t).
Reaction SMILES: N=C=N.[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([OH:11])=O.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:32][C@@H:33]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:34][C@H:35]([OH:63])[C@@H:36]([NH:50][C:51]([C@@H:53]([NH:58][C:59](=[O:62])[O:60][CH3:61])[C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:37][C:38]1[CH:43]=[CH:42][C:41](C2C=CC=CN=2)=[CH:40][CH:39]=1>CC(N(C)C)=O.C(#N)C.CO>[CH2:37]([C@H:36]([NH:50][C:51]([C@@H:53]([NH:58][C:59](=[O:62])[O:60][CH3:61])[C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])[C@@H:35]([OH:63])[CH2:34][C@@H:33]([NH:32][C:9]([C:5]1[S:4][CH:8]=[CH:7][CH:6]=1)=[O:11])[CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)c1cccs1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)c1cccs1)C(C)(C)C
Temperature: 100 °C
Yield: 38.4 %

Procedure:
A Smith Process Vial (2-5 mL) was charged with a stir bar and PS-Carbodiimide resin (108 mg, 0.12 mmol.). To the vessel were added thiophene-2-carboxylic acid (5.6 mg, 0.044 mmol.) d in 0.2 mL dimethyl acetamide, 1-hydroxybenzotriazole hydrate (5.4 mg, 0.04 mmol.) in 0.5 mL acetonitrile (acetonitrile), diisopropylethylamine (16.7 mg, 0.12 mmol.) in 0.5 mL acetonitrile and the product of Example 23S (19.6 mg, 0.04 mmol.) in 0.7 mL acetonitrile. The reaction vessel was sealed and heated to 100° C. for 300 seconds in an Ermys Optimizer. After cooling the reaction mixture was transferred to a pre-packed 1 g column of Si-Carbonate (>4 eq. of functionalized reagent), which had been previously conditioned with methanol. The reaction products were collected, and the solvents were evaporated. The crude residue was dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC to give 8.7 mg (35%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.83 (s, 9 H), 1.55-1.76 (m, 2 H), 2.64-2.83 (m, 4 H), 3.55 (s, 3 H), 3.60 (t, J=6.26 Hz, 1 H), 3.88 (s, 1 H), 4.18 (d, J=7.63 Hz, 1 H), 4.29 (s, 1 H), 7.01-7.25 (m, 12 H), 7.54 (d, J=8.85 Hz, 1 H), 7.60 (d, J=3.66 Hz, 1 H), 7.66-7.68 (m, 1 H), 8.18 (d, J=8.85 Hz, 1 H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:20]([OH:33])[CH2:21][C@@H:22]([CH:30]([CH3:32])[CH3:31])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.[CH2:41]([C@H:48]([CH2:52][C:53]([N:55]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH3:56])=[O:54])[C:49]([OH:51])=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([C@H:48]([CH2:52][C:53]([N:55]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH3:56])=[O:54])[C:49]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C@@H:20]([OH:33])[CH2:21][C@@H:22]([CH:30]([CH3:31])[CH3:32])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:51])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)C
Reactant: CN(Cc1ccccc1)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1)C(C)C
Yield: 50.3 %

Procedure:
The procedure described in Example 2(b) was repeated, but using 280 mg (0.48 mmole) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl )-L-alanyl]amino-N-butyl-6-cyclohexyl-4-hydroxy-2-isopropylhexanamide [prepared as described in Example 2(a)] and 150 mg (0.48 mmole) of 2(R)-benzyl-3-(N-benzyl-N-methylaminocarbonyl)propionic acid, to afford 187 mg of the title compound as a white powder, melting at 155°-156° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].B(F)(F)F.CCOCC.[N+](=[C:67]([CH3:69])[CH3:68])=[N-]>CCOCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:67]([CH3:69])[CH3:68])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CC(C)=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in ether (6 ml) is added boron trifluoride etherate (10 μl) followed by freshly prepared 2-diazopropane (100 fold excess). The mixture is stirred at room temperature for 15 min and quenched with sat'd. aqueous sodium bicarbonate solution. The organic layer is separated, washed (sat'd. aqueous NaCl) and dried over anhydrous magnesium sulfate. Removal of solvent followed by preparative tlc on silica gives the title compound and its 4"-isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13].Cl[S:22]([C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][C:26]=1[O:41][CH3:42])(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:22]([C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[CH:27][C:26]=1[O:41][CH3:42])(=[O:24])=[O:23])[C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13]
Reactant: CNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)Cl
Product: CNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(C(=O)OCc3ccccc3)cc2OC)c2ccc(Cl)cc21
Yield: 86.2 %

Procedure:
This compound is prepared according to the procedure described in step A of EXAMPLE 28 from 6 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)indol-2-one and 6.66 g of benzyl 4-chlorosulfonyl-3-methoxybenzoate. 10.3 g of the expected product are obtained after crystallization from iso ether.