Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O.[OH-].[Li+]>O1CCOCC1.O>[CH2:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:39])=[O:2])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:32])=[CH:28][CH:29]=1)=[O:22])[CH:19]([CH3:21])[CH3:20])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2ccccc2)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(NC(=O)c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-valyl-4-(phenylcarbonylamino)-L-phenylalanine methyl ester (0.500 g, 0.94 mmol) in dioxane (30 ml) is added lithium hydroxide monohydrate (0.084 g, 2 mmol) in water (10 ml). The reaction is stirred at room temperature overnight. The mixture is taken off in water (20 ml) and washed twice with ethyl acetate (2×20 ml). The aqueous phase is acidified until pH ~2 with 1N hydrochloric acid and extracted three times with ethyl acetate (3×20 ml). The organic layer is dried over anhydrous magnesium sulphate. After filtration and remtial of the solvent invacuo the title compound is obtained as a white solid (0.400 g, 82% yield). MS: [MH]+ =518 [MNH4 ]+ =535.
Reaction SMILES: C([O:8][C:9](=[O:47])[CH2:10][CH2:11][NH:12][C:13](=[O:46])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:45])[C@H:22]([CH2:31][CH2:32][CH2:33][NH:34]C(OCC2C=CC=CC=2)=O)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:15]=1)C1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[C:9]([OH:47])(=[O:8])[CH3:10].[C:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:47])=[O:8])=[O:46])=[O:45])[CH2:31][CH2:32][CH2:33][NH2:34])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)Nc1cccc(C(=O)NCCC(=O)O)c1
Yield: 178.5 %

Procedure:
500 mg of N-[m-[[N5 -(benzyloxycarbonyl)-N2 -t-butoxycarbonyl-L-ornithyl]amino]benzoyl]-β-alanine benzyl ester, 10 ml of ethanol, 0.05 ml of acetic acid and 125 mg of Pd/C are stirred under hydrogen for 3.5 hours. The reaction mixture is filtered and the filtrate is evaporated in a vacuum. There are obtained 333 mg of N-[m-[[(S)-N2 -(t-butoxycarbonyl)-L-ornithyl]amino]benzoyl]-β-alanine acetate (1:1), [α]D =-18.1° (MeOH, c=0.44%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[OH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:33][C:32](=[O:40])[CH:31]=1>CN(C)C1C=CN=CC=1.ClCCCl>[OH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:33][C:32](=[O:40])[C:31]=1[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)c1c(O)c2ccccc2oc1=O
Reaction time: 1 h
Yield: 19.5 %

Procedure:
4-Nitrophenylacetic acid (4.5 g, 25 mmol) and then dicyclohexylcarbodiimide (5.4 g, 26 mmol) were added to a 1,2-dichloroethane (160 ml) suspension of 4-hydroxycoumarin (4.00 g, 24.6 mmol) at room temperature, after which 4-dimethylaminopyridine (0.15 g, 1.2 mmol) was added and stirring carried out for 1 hour at 60° C. and then further 4-dimethylaminopyridine (0.30 g, 2.4 mmol) added and stirring carried out for 23 hours at 85° C. The dicyclohexylurea was filtered off while the solution was still warm, then the reaction solution washed with dilute hydrochloric acid (50 ml), after which the aqueous layer was extracted with dichloromethane. After drying with anhydrous sodium sulphate, the solvent was distilled off and separation and purification performed by column chromatography. When recrystallization was performed from ethyl acetate, 4-hydroxy-3-(4-nitrophenylacetyl)-coumarin (1.56 g, 19%) was obtained as yellow crystals. Tetrahydrofuran (50 ml), methanol (18 ml) and concentrated hydrochloric acid (5 ml) were added to the compound (1.00 g, 3.1 mmol) obtained, then Pd-C (5%, containing 100% of water, 150 mg) added and the atmosphere replaced by hydrogen. The raw material was consumed in 4 hours and then the hydrogen replaced by argon.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CC=CC=1.[CH2:28]([O:35][CH2:36][CH2:37][CH2:38]O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.C1C=CC=CC=1>[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][I:20])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: II
Reactant: OCCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CO
Product: ICCCOCc1ccccc1
Reaction time: 15 h
Yield: 53 %

Procedure:
To a solution of 83.3 g. (0.318 mole) triphenylphosphine in 200 ml. benzene was added, in four portions, 80 g. (0.318 mole) of iodine. The resultant mixture was stirred 3 hours and then 50 ml. (0.618 mole) of pyridine was added followed by the slow addition of 32 g. (0.192 mole) of 3-benzyloxypropanol in 250 ml. of benzene. The reaction was stirred 15 hours longer and then diluted with 40 ml. of methanol. The mixture was filtered through diatomaceous earth and the filtrate evaporated to an oil. Distillation of the crude oil yielded 28 g. (53%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[O:11]=[C:12]([CH3:22])[CH2:13][C:14]([O:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:15]>N1CCCCC1.C(O)(=O)CCCCC.C1C=CC=CC=1>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:13]([C:12](=[O:11])[CH3:22])[C:14]([O:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:15]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)CC(=O)OC1CCCC1
Solvent: CCCCCC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC1CCCC1
Temperature: 25 °C
Yield: 109 %

Procedure:
A solution of 2,3-dichlorobenzaldehyde (2.5 g, 14.3 mmoles), cyclopentyl 3-oxobutanoate (2.42 g, 14.3 mmoles), piperidine (8 drops) and hexanoic acid (11 drops) in dry benzene (80 ml) was heated at reflux for 4 hours using a Dean and Stark apparatus. The solution was allowed to cool to room temperature and the solvent removed in vacuo to leave the sub-title compound as an oil 5.1 g.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:10]=2[N+:22]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C1COCC1.[Pd]>[CH:1]1([CH2:7][NH:8][C:9]2[C:10]([NH2:22])=[CH:11][C:12]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1NCC1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccccc2)ccc1NCC1CCCCC1
Reaction time: 0.05 h
Yield: 99.8 %

Procedure:
To a solution of cyclohexylmethyl-(2-nitro-4-phenoxy-phenyl)-amine (0.55 g, 1.69 mmol) in THF (50 mL) was added palladium, 10% on activated carbon (0.55 g). The reaction flask was equipped with a septum and was placed under vacuum for 3 min. This flask was placed under hydrogen atmosphere (balloon inflated with hydrogen) and the reaction mixture was stirred for 18 h. The palladium was filtered off through a plug of diatomaceous earth and washed with EtOAc. The solvent was removed via rotary evaporation providing N1-cyclohexylmethyl-4-phenoxy-benzene-1,2-diamine (0.50 g, 99% yield) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.C(N(C(C)C)CC)(C)C.CS([Cl:24])(=O)=O>ClCCl>[Cl:24][CH2:8][C:7]1[C:2]([F:1])=[CH:3][N:4]=[CH:5][C:6]=1[F:10]
Reactant: OCc1c(F)cncc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1cncc(F)c1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under argon, 5.0 g of (3,5-difluoropyridine-4-yl)methanol (Example 114A, 34.5 mmol, 1 equivalent) were initially charged in 100 ml of dichloromethane at −20° C., and 5.7 ml of diisopropylethylamine (34.5 mmol, 1 equivalent) and 2.95 ml of methanesulphonyl chloride (37.9 mmol, 1.1 equivalent) were added in succession. The mixture was warmed to RT and stirred at RT for 16 h and then at 40° C. for 3 h. The reaction solution was then concentrated, and twice 50 ml of toluene were added and the mixture was re-concentrated. This gave 13 g (230% of theory) as a crude product which were reacted further without purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:45]=[CH:44][C:9]2[N:10]=[C:11]([NH:13][C:14]([N:16]([C:32]3[CH:37]=[CH:36][C:35]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:34][CH:33]=3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:31])[NH:25][C:26]4[N:27]=[N:28][NH:29][N:30]=4)=[CH:20][CH:19]=3)=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH:38]1([C:35]2[CH:34]=[CH:33][C:32]([N:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24](=[O:31])[NH:25][C:26]4[N:27]=[N:28][NH:29][N:30]=4)=[CH:22][CH:23]=3)[C:14](=[O:15])[NH:13][C:11]3[S:12][C:8]4[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:45]=[CH:44][C:9]=4[N:10]=3)=[CH:37][CH:36]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCOC(=O)c1ccc2nc(NC(=O)N(Cc3ccc(C(=O)Nc4nn[nH]n4)cc3)c3ccc(C4CCCCC4)cc3)sc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2nc(NC(=O)N(Cc3ccc(C(=O)Nc4nn[nH]n4)cc3)c3ccc(C4CCCCC4)cc3)sc2c1
Reaction time: 16 h

Procedure:
2-{3-(4-Cyclohexylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}benzothiazole-6-carboxylic acid ethyl ester (16 mg, 0.025 mmol) was dissolved in ethanol (4 mL). Sodium hydroxide (1 mL, 4 N) was added and the reaction mixture was left at room temperature for 16 hours. Hydrochloric acid (4 mL, 1 N) was added, and the resulting precipitate was subsequently collected by filtration to afford the title compound.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Cl:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2([OH:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1>>[ClH:12].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]2([OH:24])[CH2:19][CH2:20][N:21]([CH2:3][CH:2]([OH:1])[CH2:4][C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[CH2:22][CH2:23]2)=[CH:25][CH:26]=1
Reactant: OC1(Cc2ccc(Cl)cc2)CCNCC1
Reactant: Oc1ccc(CC2CO2)cc1
Product: Cl
Product: Oc1ccc(CC(O)CN2CCC(O)(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
The title compound, m.p. 172°-174° C. and MS: m/e=376.4 (M+H+), was prepared from (RS)-4-Oxiranylmethyl-phenol and 4-(4-Chloro-benzyl)-piperidin-4-ol.
Reaction SMILES: [CH:1]1([C:8]2[C:13]([C:14]3[C:32]([F:33])=[CH:31][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][C:15]=3[F:34])=[C:12](O)[N:11]=[C:10]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:44])=O.N1C(C)=CC=CC=1C>>[Cl:44][C:12]1[N:11]=[C:10]([C:36]2[CH:41]=[N:40][CH:39]=[CH:38][N:37]=2)[N:9]=[C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]=1[C:14]1[C:32]([F:33])=[CH:31][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][C:15]=1[F:34]
Reactant: CN(CCCOc1cc(F)c(-c2c(O)nc(-c3cnccn3)nc2C2CCCCCC2)c(F)c1)C(=O)OC(C)(C)C
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CN(CCCOc1cc(F)c(-c2c(Cl)nc(-c3cnccn3)nc2C2CCCCCC2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 110 °C

Procedure:
To tert-butyl {3-[4-(4-cycloheptyl-6-hydroxy-2-pyrazin-2-ylpyrimidin-5-yl)-3,5-difluorophenoxy]propyl}methylcarbamate (130 mg, 0.23 mmol) is added 2.0 mL of phosphorous oxychloride and 1.0 mL of 2,6-lutidine, and the mixture is heated at 110° C. for 12 h. The excess phosphorous oxychloride is removed in vaccuo, and the resulting residue is chromatographed over silica gel, eluting with 30% ethyl acetate in hexanes. Concentration provides tert-butyl {3-[4-(6-chloro-4-cycloheptyl-2-pyrazin-2-ylpyrimidin-5-yl)-3,5-difluorophenoxy]propyl}methylcarbamate as a light yellow semi-solid (23 mg). MS: m/z 588.0 (M+H). This product is dissolved in 2 mL of methylene chloride, and 2.3 mL of trifluoroacetic acid is added. The mixture is stirred at 40° C. for 20 h, and concentrated in vaccuo, yielding N-{3-[4-(4-chloro-6-cycloheptyl-2-pyrazin-2-ylpyrimidin-5-yl)-3,5-difluorophenoxy]propyl}-N-methylamine as a trifluoroacetic acid salt as a light yellow semi-solid (24 mg). MS: m/z 488.2 (M+H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[N:13]1([C:19]2[S:20][C:21]3[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CI>C1COCC1>[CH3:1][CH:26]1[CH2:25][CH2:24][C:22]2[N:23]=[C:19]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:20][C:21]=2[C:27]1=[O:28]
Reactant: CC(C)NC(C)C
Reactant: O=C1CCCc2nc(N3CCOCC3)sc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1CCc2nc(N3CCOCC3)sc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13.4 %

Procedure:
A solution of N,N-diisopropylamine (0.60 g, 0.83 mL, 5.9 mmol) in dry THF (5 mL) was cooled to −78° C. and n-butyllithium (2.36 mL, 2.5M in hexane, 5.9 mmol) was added dropwise. The reaction mixture was allowed to warm to 0° C., stirred for 15 minutes and cooled to −78° C. A suspension of Example 6 (1.4 g, 5.9 mmol) in THF (5 mL) was added slowly. The reaction mixture was warmed to 0° C. and stirred for 10 min at 0° C. before dropwise addition of methyl iodide (0.84 g, 0.37 mL, 5.9 mmol). A solid formed immediately. The reaction mixture was allowed to warm slowly to r.t. The solid was filtered, washed with THF and then purified by column chromatography (SiO2, 1:3 EtOAc/hexane) to give the title compound (0.20 g, 13%) as a white solid. δH (DMSO-d6) 3.70 (4H, t, J 4.9 Hz), 3.54 (4H, t, J 4.9 Hz), 2.80-2.72 (2H, m), 2.55-2.45 (1H, m), 2.15-2.09 (1H, m), 1.82-1.72 (1H, m), 1.10 (3H, d, J 6.9 Hz). LCMS (ES+) 253.0 (M+H)+.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37]([CH:42]=O)=[CH:36]2>C(Cl)Cl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37](/[CH:42]=[CH:20]/[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[CH:36]2
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: COc1ccc2[nH]c(C=O)cc2c1
Solvent: ClCCl
Product: COc1ccc2[nH]c(/C=C/C(=O)OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
Benzyl (triphenylphosphoranylidene)acetate (49.2 g, 0.120 mol) was added to a stirred solution of 5-methoxy-1H-indole-2-carbaldehyde (1) (20.0 g, 0.114 mol) in CH2Cl2 (500 mL) and the solution was stirred at room temperature for 4 h. The solvent was removed in vacuo and the residue slurried with methanol (200 mL), whereupon crystallisation of the product occurred. The mixture was filtered, washed with several portions of cold methanol, and dried to give benzyl (2E)-3-(5-methoxy-1H-indol-2-yl)-2-propenoate (2) in a 30.46 g, 87% yield as pale yellow plates; mp 155–157° C. 1H NMR δ (CDCl3) 8.28 (s, 1H), 7.69 (d, J=16.1 Hz, 1H), 7.43–7.32 (m, 5H), 7.23 (d, J=9.1 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.92 (dd, J=9.1, 2.3 Hz, 1H), 6.74 (d, J=1.8 Hz, 1H), 6.24 (d, J=16.1 Hz, 1H), 5.26 (s, 2H), 3.84 (s, 3H).Found: C, 74.45; H, 5.62; N, 4.58. C19H17NO3 requires C, 74.25; H, 5.57; N, 4.56.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(Br)n2)CC1
Temperature: 20 °C
Yield: 92.8 %

Procedure:
2-bromothiazole-4carboxylic acid (1.31 g, 6.3 mmol) was combined with tert-butyl piperazine-1-carboxylate (1.2 g, 6.3 mmol) in DCM (15 mL), and then stirred at 20° C. until it formed a clear solution. N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.2 g, 6.3 mmol) was then added, and the reaction was stirred at 20° C. for 2 hours. The reaction was concentrated in vacuum, before transferring it to a separation funnel with ethyl acetate. The organic layer was washed with saturated NaHCO3, water, NH4Cl, and then with brine. After drying the organic layer with MgSO4, it was concentrated in vacuum to yield compound 72 (2.2 g, 91%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.16 (1H, s), 3.61 (4H, m), 3.38 (4H, m), 1.42 (9H, s) ppm; LCMS-ESI (POS), M/Z, M+1-C3H9: Found 320.0.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CC1(C)C2CC[C@@]1(CS([O:23][CH2:24][CH2:25][CH2:26][C@@:27]1([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1)(=O)=O)C(=O)C2.[C:42]1([C:48](Cl)=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[Cl:40][C:35]1[CH:34]=[C:33]([C:27]2([CH2:26][CH2:25][CH2:24][OH:23])[CH2:32][CH2:31][CH2:30][N:29]([C:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:49])[CH2:28]2)[CH:38]=[CH:37][C:36]=1[Cl:39]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)OCCC[C@@]1(c3ccc(Cl)c(Cl)c3)CCCNC1)C(=O)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCCC(CCCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Diisopropylethylamine(5.7 mL, 3.27 mmol, 5.0 eq) was added to a mixture of camphorsulfonate salt (9) (3.4 g, 6.53 mmol) in CH2Cl2 (21 mL, 0.3 M) and followed by dropwise addition of PhCOCl (0.83 mL, 7.19 mmol, 1.1 eq). The solution was stirred at room temperature for 1 hour. The reacting mixture was diluted with CH2Cl2 (200 mL) and washed with brine, 1 M KHSO4, and saturated NaHCO3 then dried over MgSO4. The concentrated crude oil was purified by flash chromatography (CH2Cl2-MeOH/95:5) to give white solid (2.30 g, 89.8%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.Cl.[O:28]1[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]1.CCN(CC)CC>CS(C)=O.CCOC(C)=O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:33][C@@H:30]2[CH2:31][CH2:32][O:28][CH2:29]2)[CH2:13][CH2:14]1
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Reactant: N[C@@H]1CCOC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1ccc(CN2CCN(c3nc4ccncc4nc3N[C@@H]3CCOC3)CC2)c(F)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 87.1 %

Procedure:
To a mixture of 3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine (5.06 g, 13.46 mmol) in DMSO (40 mL) was added (R)-tetrahydrofuran-3-amine hydrochloride (4.16 g, 33.7 mmol) and Et3N (24.40 mL, 175 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 14 h then cooled to room temperature and diluted with EtOAc (80 mL), washed with water (30 mL) and brine (2×30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo, then the residue was purified by column chromatography (petroleum ether:EtOAc from 10:1 to 1:1) on silica gel to give the title compound as a yellow solid (5.0 g). ESI-MS m/z [M+H]+ 427.1.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:38])=[O:26])=[CH:28][CH:29]=1)[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COc1ccc2oc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(Br)c2c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2Br)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a mixture of 4-{[(3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid (125 mg) synthesized above, β-alanine ethyl ester hydrochloride (63.0 mg), 1-hydroxybenzotriazole monohydrate (62.9 mg), triethylamine (114 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.6 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (134 mg, 88%) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=2[S:15]([N:18]2[CH2:24][CH:23]([OH:25])[CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH2:3][CH2:2]1.Cl>C1COCC1.O>[CH:1]1([O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=2[S:15]([N:18]2[CH2:24][CH:23]([OH:25])[CH2:22][O:21][CH2:20][CH2:19]2)(=[O:16])=[O:17])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC2CC2)c(S(=O)(=O)N2CCOCC(O)C2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC2CC2)c(S(=O)(=O)N2CCOCC(O)C2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a solution of methyl 4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoate (620.00 mg, 1.67 mmol, 1.00 eq) in THF (5.00 mL) and H2O (1.00 mL). The formed mixture was stirred at 50° C. for 3 hr. The reaction mixture was neutralized with 1N HCl solution and extracted with EA, the combined organic layer was dried over Na2SO4, concentrated to afford crude product 4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoic acid (510.00 mg, 1.43 mmol, 85.45% yield) as white solid.