Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2.N1C=CC=CC=1.[C:23]1(=[O:37])[N:27]([CH2:28][C:29](Cl)=[O:30])[C:26](=[O:32])[C:25]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:24]12>CN(C)C1C=CN=CC=1.ClCCCl>[CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]([C:29](=[O:30])[CH2:28][N:27]2[C:23](=[O:37])[C:24]3[C:25](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:26]2=[O:32])[C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC1(C)CCCN(C(=O)CN2C(=O)c3ccccc3C2=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 55 %

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.519 g, 2.36 mmol), Pyridine (0.420 mL, 5.19 mmol), 4-Dimethylaminopyridine (21 mg, 0.17 mmol) and anhydrous 1,2-Dichloroethane (8.5 mL) were combined in a round bottom flask. α-Phthalimidoacetyl Chloride (1.105 g, 4.942 mmol) was added to the mixture and it was stirred at room temperature for 16.5 hours. The reaction was concentrated under reduced pressure and purified by normal phase chromatography to yield a yellow solid, 2-[2-(5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-2-oxo-ethyl]-isoindole-1,3-dione (55%) LCMS: m/z=408.11 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.21 (m, 2H), 7.87 (m, 2H), 7.74 (m, 3H), 4.74 (m, 1H), 4.55 (d, 1H, J=16.9), 4.55 (d, 1H, J=16.7), 2.68 (m, 1H), 2.23 (m, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.51 (m, 6H), 1.26 (m, 1H).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+].I[CH2:33][CH:34]([OH:37])[CH2:35][OH:36].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 7.34 g. of 4-(15-carbomethoxypentadecylamino)benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(15-carbomethoxypentadecylamino)benzoate.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11](CCCCN2C(=O)C3C=CC=C4C=3C(=CC=C4)C2=O)[CH2:10][CH2:9]1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:48](=[O:49])[C:47]2[CH:50]=[CH:51][CH:52]=[C:45]3[C:46]=2[C:41](=[CH:42][CH:43]=[CH:44]3)[C:40]1=[O:53].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[C:48](=[O:49])[C:47]3[CH:50]=[CH:51][CH:52]=[C:45]4[C:46]=3[C:41](=[CH:42][CH:43]=[CH:44]4)[C:40]2=[O:53])[CH2:12][CH2:13]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCN1CCN(c2ccccn2)CC1

Procedure:
Following the procedure of part (b) of example 46 but substituting 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, one obtains 2-[5-[4-(2-pyridinyl)-1-piperazinyl]pentyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2).
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].IC.[NH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:10]([C:14](O)=O)[CH:11]([CH3:13])[CH3:12].[CH2:24](N(CC)CC)C.[N+](=C)=[N-]>C1COCC1.CCOCC>[C:20]([O:19][C:17]([N:9]([CH3:24])[C@@H:10]([CH:11]([CH3:13])[CH3:12])[CH2:14][C:2]([OH:4])=[O:3])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Agent: C=[N+]=[N-]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[C@@H](CC(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Ethyl chloroformate (12.6 mL, 0.13 mol) was added dropwise to a solution of I-Me-Boc-L-Val-OH (27.3 g, 0.12 mol) and triethylamine (14.7 mL, 0.13 mol) in anhydrous THF (200 mL) at −20° C. over 15 min, and the resulting white suspension was stirred further for 30 min. A diazomethane solution (0.36 mol, prepared from 60 g of N-nitroso-N-methylurea and dried over potassium hydroxide) in ether (500 mL), was then introduced into the reaction mixture via cannula. The mixture was allowed to warm to room temperature and stirred for further 5 hours, then carefully quenched with aqueous acetic acid (10%, 250 mL). The layers were separated, and the organic layer was washed with saturated sodium bicarbonate (300 mL×3) and brine (300 mL×3), dried (Na2SO4), concentrated to about 200 mL. The residue was dissolved in THF (900 mL) and water (100 mL). The solution was heated to 40° C., and silver acetate (500 mg) was added. The suspension was stirred for 5 hours, then concentrated to about 300 mL. The residue was extracted with EtOAc (500 mL×3). The organic layer was washed with saturated sodium bicarbonate (300 mL×3) and brine (300 mL), dried (Na2SO4), concentrated to give (R)-3-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoic acid (23.8 g, 81% yield) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 10.08 (bs, 1H), 4.00 (m, 1H), 2.75 (m, 3H), 2.55 (m, 2H), 1.43 (s, 9 h), 0.85-0.84 (m, 6H).
Reaction SMILES: C(OCC)(=O)C.C(O)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:19](=[O:22])[CH2:20][Cl:21])=[O:16])([CH3:13])([CH3:12])[CH3:11].[BH4-].[Na+]>C(O)(=O)C>[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@H:19]([OH:22])[CH2:20][Cl:21])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 72.6 %

Procedure:
Ethyl acetate (4.2 ml) and ethanol (16.7 ml) were added to (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g). Sodium borohydride (133 mg) was added in portions to the obtained mixture at −10° C., and they were stirred for 1 hour 40 minutes. Acetic acid (0.40 ml) was added to the reaction mixture to terminate the reaction. The reaction mixture was slowly heated to 60° C. for the duration of 1 hour and then stirred at 60° C. for 30 minutes. The reaction mixture was slowly cooled to −10° C. for the duration of 1 hour 50 minutes and then stirred at −10° C. for 6 hours. The crystals thus formed were taken by the filtration, washed with 0° C. water and dried under reduced pressure to obtain intended (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52 g).
Reaction SMILES: [OH2:1].[NH2:2][C:3]1[C:30]([Cl:31])=[CH:29][C:6]([C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:12][C@H:11]2[O:27][CH3:28])=[O:8])=[C:5]([O:32][CH3:33])[CH:4]=1>CO>[NH2:2][C:3]1[C:30]([Cl:31])=[CH:29][C:6]([C:7]([NH:2][C:3]2[CH:4]=[C:5]([O:32][CH3:33])[C:6]([C:7]([NH:9][C@H:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:12][C@H:11]3[O:27][CH3:28])=[O:8])=[CH:29][C:30]=2[Cl:31])=[O:1])=[C:5]([O:32][CH3:33])[CH:4]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Reactant: O
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)Nc1cc(OC)c(C(=O)N[C@H]2CCN(CCCOc3ccc(F)cc3)C[C@H]2OC)cc1Cl

Procedure:
40 Parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate were boiled in 160 parts of methanol. The product was filtered off while hot and crystallized twice from a mixture of 600 parts of tetrachloromethane and 400 parts of trichloromethane. The product was filtered off, dried and recrystallized from 4-methyl-2-pentanone. The product was filtered off and dried (water-separator) yielding 18.5 parts of cis-4-amino-5-chloro-N-[2-chloro-4-[[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-aminocarbonyl]-5-methoxyphenyl]-2-methoxybenzamide; mp. 181.5° C. (compound 239).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>ClCCl>[Cl:32][CH2:8][C:6]1[O:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(C(F)(F)F)no1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(CCl)on1
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 3-trifluoromethyl-5-hydroxymethylisoxazole [(700 mg, 4.2 mmol) See K. Tanaka et al, Bull. Chem. Soc. Jpn., 57, 2184 (1984)] and triphenylphosphine (1.43 g, 5.4 mmol) in carbontetrachloride (50 ml) and dichloromethane (20 ml) is heated at reflux for 6 hours. The reaction mixture is then cooled to room temperature and passed through a silica gel plug. Concentration affords in 82% yield the desired 5-chloromethyl-3-trifluoromethylisoxazole of sufficient purity for the following step (Example 24).
Reaction SMILES: C[O:2][C:3]([CH:5]([CH3:29])[CH2:6][C:7]1[CH:8]=[C:9]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:10]=[C:11]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=1)=[O:4].[OH-].[Na+]>O1CCOCC1>[C:3]([CH:5]([CH3:29])[CH2:6][C:7]1[CH:8]=[C:9]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:10]=[C:11]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=1)([OH:4])=[O:2]
Reactant: COC(=O)C(C)Cc1cc(CCC(=O)OC(C)(C)C)cc(Cc2cccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(Cc1cc(CCC(=O)OC(C)(C)C)cc(Cc2cccnc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
A mixture of t-butyl 3-[3-(2-methoxycarbonyl-1-propyl)-5-(3-pyridylmethyl)phenyl]propanoate (Preparation 28; 2.84 g), 2N aqueous sodium hydroxide solution (4.3 ml) and 1,4-dioxane (13 ml) was stirred at room temperature for 2 hours, heated at 100° C. for 1.5 hours and then allowed to stand at room temperature for a further 18 hours. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate and water. The aqueous phase was separated, acidified with glacial acetic acid and extracted twice with dichloromethane, then the combined organic solutions dried (MgSO4) and evaporated under vacuum. The residue was chromatographed on silica gel using a dichloromethane in methanol elution gradient (0 to 7% methanol), and the product fractions combined and evaporated under vacuum to give the title compound as a gum (1.88 g); Rf 0.60 (SS 7). Found: C, 71.72; H, 7.60; N, 3.75. C23H29NO4 requires C, 72.03; H, 7.62; N, 3.65%.
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][CH2:5][C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])([C:13]#[N:14])[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].ClC1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:9]([CH:8]1[CH2:7][C:6]([C:13]#[N:14])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:5][CH2:4][C:3]1=[O:22])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(c2ccccc2Cl)CCC1=O
Yield: 95 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 39.11 gm. (0.121 mole) dimethyl-4-(o-chlorophenyl)-4-cyanopimelate (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid, and using 780 ml. of the tetrahydrofuran, 27.4 gm. (0.24 mole) of the potassium tert-butoxide, and 195 ml. of the 2.5 N acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 33.4 gm. (95% yield) of 2-carbomethoxy-4-cyano-4-(o-chlorophenyl)cyclohexanone as a crystalline solid having a melting range of 113° to 118° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([NH2:16])[CH:5]=1)(=[O:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[C:22]([CH:24]([OH:26])[CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].[CH2:33]([O:36][C:37](Cl)=[O:38])[CH:34]=[CH2:35].[Cl-].[NH4+]>N1C=CC=CC=1.[Cl-].[Na+].O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([NH:16][C:37]([O:36][CH2:33][CH:34]=[CH2:35])=[O:38])[CH:5]=1)(=[O:3])[CH3:2].[CH2:33]([O:36][C:37]([NH:17][C:18]1[CH:23]=[C:22]([CH:24]([OH:26])[CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:38])[CH:34]=[CH2:35]
Reactant: CCOC(=O)Cc1ccc(C(C)O)cc1N
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)Cc1ccc(C(C)=O)cc1N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: C=CCOC(=O)Nc1cc(C(C)=O)ccc1CC(=O)OCC
Product: C=CCOC(=O)Nc1cc(C(C)O)ccc1CC(=O)OCC
Reaction time: 0.5 h
Yield: 26 %
Yield: 50 %

Procedure:
A mixture of ethyl (4-acetyl-2-aminophenyl)acetate and ethyl [2-amino-4-(1-hydroxyethyl)phenyl]acetate (20.4 g) prepared by step d) was dissolved in pyridine (184 mL) and thereto was dropped at room temperature allyloxycarbonyl chloride (22.2 g), followed by stirring for 30 minutes. To the reaction mixture were added a saturated ammonium chloride solution (100 mL) and saturated brine (100 mL), and then pyridine was removed in vacuo. To the aqueous layer was added 2M hydrochloric acid (200 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with 2M hydrochloric acid (3×50 mL) and saturated brine (50 mL), filtered and the solvent was removed in vacuo. The residue was purified with column chromatography (SiO2 500 g, hexane/ethyl acetate 3:1˜1:1) to give ethyl (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetate (7.34 g, 26%) as a gray oil, and ethyl [2-{[(allyloxy)carbonyl]amino}-4-(1-hydroxyethyl)phenyl]acetate (14.1 g, 50%) as a purple oil.
Reaction SMILES: [CH3:1][CH2:2][N:3](C(C)C)C(C)C.[Br:10][C:11]1[C:12]([F:19])=[CH:13][C:14]([CH3:18])=[C:15]([CH:17]=1)[NH2:16].BrCC#N>C1COCC1>[Br:10][C:11]1[C:12]([F:19])=[CH:13][C:14]([CH3:18])=[C:15]([NH:16][CH2:1][C:2]#[N:3])[CH:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(F)c(Br)cc1N
Agent: N#CCBr
Solvent: C1CCOC1
Product: Cc1cc(F)c(Br)cc1NCC#N
Temperature: 25 °C

Procedure:
Hunig's Base (6.15 mL) was added to 5-bromo-4-fluoro-2-methylaniline (Example 318a, 3.59 g) in THF (50 mL) at room temperature followed by bromoacetonitrile (2.451 mL). The reaction was heated to reflux overnight. The reaction was cooled to room temperature and concentrated. 2N HCl and DCM were added. The organic layer was separated and dried (MgSO4) and concentrated to give the subtitle compound as a solid (6.61 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28]O)[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].N1C(C)=CC=CC=1C.CS([Cl:44])(=O)=O.S([O-])(=O)(=O)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][Cl:44])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CO)c2)c1
Agent: CS(=O)(=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CCl)c2)c1

Procedure:
To a solution of 3-[2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]ethyl]phenylmethanol, LiCl (1-4 equiv.), and 2,6-lutidine (1-2 equiv.) in DMF is added with stirring, cooling, and exclusion of moisture methanesulfonyl chloride (1-1.5 equiv.). The reaction mixture is stirred at ambient or elevated temperature until the alcohol and the intermediate mesylate have disappeared. The solvent is then distilled into a cooled receiver in an oil pump vacuum. The residue is diluted with EtOAc and aqueous NaHCO3 solution. The phases are separated. The organic phase is washed with brine, dried over MgSO4, and evaporated, and the residue is used directly in the subsequent step. A purer product is obtained by filtration over silica gel with EtOAc or a mixture of EtOAc with a nonpolar solvent. The product is not stable in storage and should be carried forward promptly.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:10].[NH2:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][C:26]([NH:28][CH:29]([CH3:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)=[O:27].O>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]([NH:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[CH2:25][C:26]([NH:28][CH:29]([CH3:40])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)=[O:27])=[O:10])=[CH:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)CC1CCCC1N
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(COc1ccc(C#N)cc1)NC(=O)CC1CCCC1NC(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.1 %

Procedure:
0.4 g of N-methylmorpholine, and subsequently 0.8 g of 4-chlorophenyl chloroformate were added to a suspension containing 1.2 g of 2-amino-N-[2-(4-cyanophenoxy)-1-methylethyl]cyclopentylacetic acid amide suspended in 40 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of colorless grains (yield: 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[C:16]([O:29][CH3:30])[C:17]([O:19][C:20]4(C(O)=O)[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[N:31]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][CH2:33][CH2:32]1.CN([C:42]([O:46]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[C:16]([O:29][CH3:30])[C:17]([O:19][C:20]4([CH:34]5[CH2:35][N:31]([CH2:36][CH2:37][NH:38][CH:42]=[O:46])[CH2:32][CH2:33]5)[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1cc2c(cc1OC1(C(=O)O)C=CC=CN1)nc(Nc1ccc(Cl)cc1)n2C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC1(C3CCN(CCNC=O)C3)C=CC=CN1)nc(Nc1ccc(Cl)cc1)n2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-{[4-chloropheylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4-chlorophenyl]amino-6-methoxy-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide. MS: MH+=522.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[C:29]([O:33][C:34]([N:36]1[C:40]([CH:41]2[CH2:43][CH2:42]2)=[CH:39][C:38]([NH2:44])=[N:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>ClCCl>[CH:41]1([C:40]2[N:36]([C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:35])[N:37]=[C:38]([NH:44][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:39]=2)[CH2:42][CH2:43]1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(NC(=O)C(c2ccccc2)c2ccccc2)cc1C1CC1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
To a solution of 45.6 mg (0.215 mmol) of diphenylacetic acid in 3 ml of dichloromethane at 0° C. 41.2 mg (0.215 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added. After 1 hour at the same temperature under stirring 40 mg (0.179 mmol) of tert-butyl-3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate were added. The mixture was maintained at room temperature for 16 hours, then was diluted with dichloromethane and washed with a saturated solution of sodium hydrogenocarbonate. The organic layer was dried over anhydrous sodium sulfate evaporated to dryness, to give, after column chromatography (hexane-ethylacetate) 60 mg (80% yield) of N-(5-cyclopropyl-1-terbutoxycarbonyl-pyrazol-3-yl)-2,2-diphenyl acetamide. This intermediate was submitted to hydrolysis with 15 ml of trifluoroacetic acid 10% v/v in dichloromethane for an hour. The solvent was then evaporated under vacuum, the residue redissolved with dichloromethane and washed with a saturated solution sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 42 mg (92% yield) of the title compound.
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.[NH2:6][C:7]1[CH:16]=[CH:15][C:10](C(OC)=O)=[CH:9][C:8]=1[Cl:17].C(N)=O.C[O-].[Na+]>CC(O)C>[NH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:4]([NH2:2])=[O:5])=[CH:9][C:8]=1[Cl:17]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: NC=O
Solvent: CC(C)O
Product: NC(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An anhydrous DMF solution of 1.00 g (5.39 mmol) of methyl 4-amino-3-chlorobenzoate (17-1), 728 mg (16.16 mmol) of formamide and 204 mg (3.77 mmol) of 5.5M sodium methoxide was stirred for 1 hour at 100° C. and then stirred overnight at room temperature. The reaction was poured into 2-propanol (60 mL) and then evaporated off the solvent. The resultant crude oil was purified on a silica column and eluted with DCM:MeOH:NH4OH (95:5:0.5 to 9:1:0.1). Recovered the desired product 17-2. MS (M+1): measured 171.2; theoretical 170.0. 1H NMR (DMSO): 5.86 (s, 2H), 6.75 (d, 1H), 7.01 (bs, 1H), 7.56 (dd, 1H), 7.66 (bs, 1H), 7.75 (m, 1H).