Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:24]1[CH2:28][C@@H:27]2[C@@H:29]([NH2:32])[CH2:30][CH2:31][C@@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:17]([N:24]1[CH2:28][C@@H:27]2[C@@H:29]([NH:32][C:14]([C@@H:9]3[CH2:10][C@@H:11]([F:13])[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:30][CH2:31][C@@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (2.87 g, 12.31 mmol) and (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Example 33 Step A (2.93 g, 13.54 mmol) in dichloromethane (16.97 mL) was added 1-hydroxybenzotriazole hydrate (2.073 g, 13.54 mmol). After 2 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (2.388 mL, 13.54 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The solvent was removed in vacuo. The crude material was purified using an 80 g silica gel cartridge eluted with a gradient of 0-5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give (2S,4R)-tert-butyl 2-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.70 (s, 1H), 7.38-7.36 (m, 2H), 7.33-7.26 (m, 2H), 7.24-7.17 (m, 1H), 5.19 (dd, J=53.5, 3.3, 1H), 4.59 (t, J=7.8, 1H), 4.31-4.22 (m, 1H), 4.04-3.92 (m, 1H), 3.68 (dd, J=12.9, 3.7, 1H), 3.62-3.57 (m, 1H), 3.60-3.45 (m, 2H), 2.83-2.76 (m, 1H), 2.56-2.58 (m, 1H), 2.52-2.43 (m, 3H), 2.35 (m, 3H), 2.10 (dq, J=12.5, 6.3, 1H), 1.92-1.82 (m, 1H), 1.67-1.57 (m, 1H), 1.49 (s, 9H), 1.46-1.36 (m, 1H); MS (ESI+) m/z 432 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:8](O)=[O:9])([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:32])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:8]([Cl:32])=[O:9])([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1C(C)(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.9 %

Procedure:
To a solution of 30.0 g of product from Example 32 in 300 ml of methylene chloride and 10 drops of dimethylformamide is added, dropwise, 14.62 g of oxalyl chloride. The reaction is stirred at room temperature for 18 hours and concentrated in vacuo. The residue is dissolved in diethyl ether, filtered through diatomaceous earth and concentrated to give 3.12 g of the desired product as yellow crystals.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1>CN(C=O)C.C(N(CC)CC)C>[C:1]([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A solution of benzoic acid (0.123 g) in DMF (5 ml) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.231 g), HOBT (0.163 g) and triethylamine (0.56 ml) and stirred at room temperature for 1 h. A solution of 3-amino-1-N-Boc-piperidine (0.3 g) in DMF (1 ml) was then added and stirring continued for 18 h. The solution was concentrated under reduced pressure to give an oil which was partitioned between ethyl acetate and water. The separated organic extracts were washed with water, hydrochloric acid (2N), saturated sodium bicarbonate solution and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.120 g) as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]#[N:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[NH2:15]/[C:14](=[N:17]\[OH:18])/[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCCCC1C#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1/C(N)=N/O
Yield: 95 %

Procedure:
In a 16 mL vial, N-boc-2-cyanopiperidine (500 mg, 2.38 mmol) was dissolved in ethanol (6.7 mL), then hydroxylamine hydrochloride (231 mg, 3.33 mmol) and triethylamine (0.56 mL, 4.05 mmol) were added. The reaction mixture was stirred at reflux for 5 h, cooled and concentrated. The residue was taken up in EtOAc and water. The two layers were separated and the aqueous phase extracted with EtOAc. The combined organics were dried on Na2SO4 and concentrated to give the product as a white solid (550 mg, 95%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1>CN(C=O)C>[F:71][C:69]1[CH:70]=[C:65]([CH:66]=[C:67]([F:72])[CH:68]=1)[CH2:64][C@H:50]([NH:49][C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH2:3][C:2]2=[O:1])=[O:13])[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC2
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc3c(c2)C(=O)CC3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-oxoindane-5-carboxylic acid (2.0 g, 11.5 mmol) in DMF (10 mL) is added diisopropylethylamine (8 mL, 46 mmol), HATU (5.5 g, 14.4 mmol), then (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (5.6 g, 13.8 mmol). The reaction is stirred 1 h at room temperature. The reaction was partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) gives the title compound. ESI MS m/z 493.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-benzoate (Compound 75, 78.0 mg, 0.20 mmol) in ethanol (3 mL) and tetrahydrofiran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 65.0 mg (89%) of the title compound as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32](O)=[O:33])[CH:31]=1)[NH:28][CH:27]=[CH:26]2.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:32]([C:30]2[CH:31]=[C:23]([Cl:22])[CH:24]=[C:25]3[C:29]=2[NH:28][CH:27]=[CH:26]3)=[O:33])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Yield: 60.5 %

Procedure:
140 mg (0.5 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine, 97 mg (0.5 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 115 mg (0.6 mmol) of EDC.HCl were stirred over night at rt in 10 ml DCM. The product was purified by column chromatography (20 silica gel; DCM) to yield 140 mg (64%) product as a colorless oil. MS (EI) 462.2 (27), 463.2 (14), 464.2 (12) (M)+.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH:29]1([CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:2][C:3]3[N:4]([CH3:28])[C:5]4[C:10]([N:11]=3)=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=[C:7]([N:18]3[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=[C:19]3[CH3:27])[N:6]=4)[CH2:35][CH2:34]2)[CH2:31][CH2:30]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: C1CN(CC2CC2)CCN1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CC4CC4)CC3)n(C)c2n1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-(cyclopropylmethyl)piperazine via General Procedure E to give 23.5 mg of 277 following reverse phase purification. MS (Q1) 502.3 (M)+
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][CH:28]=2)=[CH:18][CH:17]=1)(=O)=O>>[N:1]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:27][CH:28]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CS(=O)(=O)OCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1c[nH]cn1
Product: C(=C/c1nc(COc2ccc(CCCCCn3ccnc3)cc2)co1)\c1ccccc1
Yield: 66 %

Procedure:
In substantially the same manner as in Working Example 8, imidazole was allowed to react with 5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentyl methanesulfonate to give 4-[4-[5-(1-imidazolyl)pentyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 66%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 101-102° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: NC1CC1
Reactant: Fc1ccc(Br)cn1
Product: Brc1ccc(NC2CC2)nc1
Temperature: 80 °C
Yield: 74.7 %

Procedure:
To a sealed tube was added 5-bromo-2-fluoropyridine (1.25 g, 7.10 mmol) and cyclopropylamine (5.0 mL, 72 mmol). Upon heating at 80° C. for 48 hours the reaction was complete. The contents of the tube were transferred to a round bottom flask and concentrated in vacuo. The remaining residue was dissolved in dichloromethane and washed twice with saturated sodium bicarbonate and twice with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1.13 g, 75%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Cl)c(Cl)c3c2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3c(Cl)c(Cl)ccc31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.10 g; 0.28 mmol) in DMF (2 mL), sodium hydride (60% dispersion in mineral oil, 17 mg, 0.42 mmol) was added. After 15 min, ethyl bromoacetate (0.060 mL, 0.56 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2.5 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (3:1) to give 85 mg (70%) of a white solid: mp 136.5-138.0° C.; 1H NMR (300 MHz, CDCl3) δ 7.19 (d, J=8.7 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 4.74 (s, 2H), 4.21 (dd, J=7.1, 7.1 Hz, 2H), 3.75 (m, 4H), 3.53 (m, 2H), 2.93 (m, 2H), 1.48 (s, 9H), 1.26 (t, J=7.1 Hz, 3H); IR (diffuse reflectance) 2985, 2976, 1737, 1685, 1466, 1450, 1414, 1367, 1344, 1249, 1213, 1169, 1156, 1115, 926 cm−1; MS (EI) m/z 440 (M+), 307, 305, 301, 299, 298, 272, 225, 189, 58, 56; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.16; H, 5.98; N, 6.27.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH2:15][C@H:16]([O:20][CH2:21][CH:22]=[N:23][OH:24])[CH2:17][CH:18]=[CH2:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClN1C(=O)CCC1=O>ClCCl.S([O-])([O-])=O.[Na+].[Na+]>[CH2:7]([O:14][CH2:15][C@@H:16]1[O:20][CH2:21][C:22]2=[N:23][O:24][CH2:19][C@@H:18]2[CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC[C@H](COCc1ccccc1)OCC=NO
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Reaction time: 3 h

Procedure:
Pyridine (23.1 mL, 286 mmol) was added to a solution of 2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3) (35.6 g, 143 mmol) in dichloromethane (350 mL). N-Chlorosuccinimide (19.4 g, 145 mmol) was added in portions over roughly 2 hours. The reaction was stirred for 3 hours, then diluted with an aqueous solution of sodium sulfite (5 g in 100 mL water). The mixture was stirred for 20 minutes, and the aqueous layer was extracted with dichloromethane; the combined organic layers were washed with water, dried, and concentrated. Purification via silica gel chromatography (Eluent: 1:2 ethyl acetate/hexanes) afforded the product. Yield: 21.2 g, 85.7 mmol, 60%. 1H NMR (400 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 4.77 (d, J=13.4 Hz, 1H), 4.55-4.65 (m, 3H), 4.22 (dd, J=13.5, 1.3 Hz, 1H), 3.79 (dd, J=11.7, 8.0 Hz, 1H), 3.69-3.76 (m, 1H), 3.57 (dd, half of ABX pattern, J=10.2, 5.9 Hz, 1H), 3.49 (dd, half of ABX pattern, J=10.2, 4.3 Hz, 1H), 3.40-3.5 (m, 1H), 2.21 (ddd, J=12.9, 6.5, 1.8 Hz, 1H), 1.57 (ddd, J=13, 12, 11 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([N:13]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[C@H:15]([O:30][CH3:31])[CH2:14]2)=[N:4][CH:3]=1.[CH3:32][O:33][C:34](Cl)=[O:35]>N1C=CC=CC=1>[Cl:27][C:26]1[C:25]([Cl:28])=[C:24]([CH3:29])[NH:23][C:22]=1[C:20]([NH:19][C@H:16]1[CH2:17][CH2:18][N:13]([C:5]2[CH:6]=[C:7]([C:2]([NH:1][C:34]([O:33][CH3:32])=[O:35])=[CH:3][N:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][C@H:15]1[O:30][CH3:31])=[O:21]
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1N
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1NC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylchlorofomate (15 μl, 0.19 mmol) was added to a solution of 60 mg (0.13 mmol) of Cis(±)-ethyl 5-amino-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinate (Example 194) in 3 ml pyridine. After stirring at room temperature overnight, 7 μl more methylchloroformate was added. Solvent was removed and the residue was partitioned between EtOAc and NaHCO3 (aqueous). The EtOAc was separated and washed with water and brine. Drying (MgSO4) and removal of solvent gave 43 mg of product. NMR (d6-DMSO): 1.3 (t, 3H), 1.7 (m, 2H) 2.2 (s, 3H), 3.1 (m, 2H), 3.3 (s, 3H), 3.5 (m, 1H), 3.6 (s, 3H), 4.0-4.3 (m, 4H), 4.6 (m, 1H), 7.05 (m, 1H), 7.15 (m, 1H), 8.2 (s, 1H), 9.1 (s, 1H), 12.2 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][O:14][C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.[I:17][CH2:18][CH2:19][CH2:20]I.C(=O)([O-])[O-].[K+].[K+]>>[I:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][O:14][C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1oncc1C(=O)Nc1ccc(O)cc1
Reactant: ICCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oncc1C(=O)Nc1ccc(OCCCI)cc1
Reaction time: 4 h

Procedure:
6.5 g (0.03 mol) of 5-methylisoxazole-4-carboxylic acid (4-hydroxyphenyl)amide are dissolved in 57 ml (0.5 mol) of 1,3-diiodopropane and 26.2 g (0.19 mol) of finely ground potassium carbonate are added with intensive stirring. The reaction is complete after approximately 4 h. Working up is carried out by means of filtration, concentration and chromatography on silica gel by means of ethyl acetate/petroleum ether 1:1 with addition of 1% glacial acetic acid. The yield of the process was 6.7 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]3[C:20]4[CH2:21][N:22]([CH2:30][C:31]([NH:33][C:34]([NH2:36])=[O:35])=[O:32])[CH2:23][CH2:24][C:25]=4[C:26]([CH3:29])([CH3:28])[O:27][C:15]=3[CH:14]=2)[CH3:12])=[CH:4][CH:3]=1.[ClH:37].[O:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][C:47](O)=[O:48])[CH2:40][CH2:39]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:37].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([O:19][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][N:41]3[CH2:40][CH2:39][O:38][CH2:43][CH2:42]3)[C:16]3[C:20]4[CH2:21][N:22]([CH2:30][C:31]([NH:33][C:34]([NH2:36])=[O:35])=[O:32])[CH2:23][CH2:24][C:25]=4[C:26]([CH3:29])([CH3:28])[O:27][C:15]=3[CH:14]=2)[CH3:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CC(CCCc1ccc(F)cc1)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1

Procedure:
The above-titled compound was prepared according to the method of Example 8 by reacting equimolar quantities of {{8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridin-2-yl}acetyl}urea and 4-morpholinobutyric acid hydrochloride in the presence of dicyclohexylcarbodiimide.
Reaction SMILES: [C:1]([NH:24][CH2:25][C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:39])=[C:33]([CH:38]=1)[C:34]([O:36]C)=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].Cl>C1COCC1.[OH-].[Na+]>[C:1]([NH:24][CH2:25][C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:39])=[C:33]([CH:38]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCC(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 45.2 %

Procedure:
The methyl 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoate (0.9 g, 1.7 mmol) was dissolved in THF (15 mL) and 1 N NaOH (8 mL). The reaction was stirred (50° C., 5 h), and then acidified to pH 3 with 2 N HCl. The product was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine and dried over MgSO4. The crude material was purified by silica chromatography (0-5% MeOH/CH2Cl2) to afford 0.40 g of 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoic acid as a yellow solid. [M+H]+=521.3. Mass calculated for C31H40N2O5=520.66; found: [M−H]+=519.2.
Reaction SMILES: C1C(=O)N(O[C:9]([CH2:11][CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:14]2=[O:15])=[O:10])C(=O)C1.[NH2:20][CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>CN(C)C=O.C(Cl)Cl>[C:14]1(=[O:15])[N:13]([CH2:12][CH2:11][C:9]([NH:20][CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])=[O:10])[C:18](=[O:19])[CH:17]=[CH:16]1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCO[Si](CCCNC(=O)CCN1C(=O)C=CC1=O)(OCC)OCC
Reaction time: 22 h
Yield: 118.8 %

Procedure:
3-Maleimidopropionic acid N-hydroxysuccinimide ester (18) (4.0 g, 15.03 mmol, 1.0 equiv.) was dissolved in N,N-dimethylformamide (75 mL) and 3-aminopropyltriethoxysilane (17) (5.06 mL, 15.03 mmol, 1 equiv.) was added and the reaction mixture was allowed to stir for 22 hours. An aliquot (0.15 mL) was removed by syringe, concentrated in vacuo, and the resulting oil was analyzed by 1H NMR spectroscopy. The oil was consistent with desired product. The reaction mixture was then concentrated in vacuo at 50-55° C. and the residue obtained was dissolved in CH2Cl2 (75 mL), washed with water (3×50 mL) and brine (50 mL), filtered through granular Na2SO4, and concentrated under reduced pressure in vacuo to provide 6.65 g (>100% due to residual N,N-dimethylformamide) of the crude maleimide-silane (19) as a light yellow oil. Crude (19) was used without purification. 1H NMR (300 MHz, CDCl3) δ 6.65 (s, 2H), 6.00 (s, 1H), 3.77 (q, J=7 Hz, 6H), 3.70 (m, 2H), 3.17 (m, 2H), 2.46 (m, 2H), 1.56 (m, 2H), 1.18 (t, J=7 Hz, 9H), 0.57 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 170.36, 169.28, 134.09, 58.35, 41.77, 34.56, 34.21, 23.20, 18.20, 7.65. FB-MS (pos): [M+H]+ 373 (373.2 calcd).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[O-:13][S:14]([O-:16])=[O:15].[Na+].[Na+].O>CCO>[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([S:14]([OH:16])(=[O:15])=[O:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=S([O-])[O-]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(S(=O)(=O)O)c([N+](=O)[O-])cc1F
Yield: 73.6 %

Procedure:
In a similar fashion using route 39 general procedure 95, 1,4-difluoro-2-methyl-5-nitrobenzene (1.2 g, 6.93 mmol) in EtOH (10 ml) and Na2SO3 (1.98 g, 15.7 mmol) in EtOH:water (40 ml:25 ml) at 70° C. for 16 h gave the title compound (1.2 g, 73%) which was used in the next step without purification.