Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:46])[CH2:30][CH2:31][N:32]([S:40]([CH2:43][CH2:44][CH3:45])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:46][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[S:40]([CH2:43][CH2:44][CH3:45])(=[O:42])=[O:41]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCCS(=O)(=O)N(CCN(C)C)c1ccc(N)cc1
Product: CCCS(=O)(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-propylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H34N4O5S
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.[H-].[Na+].[CH3:26]I.O>CN(C=O)C>[CH3:26][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:5]2=[N:4][N:3]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[C:2](=[O:1])[C:6]2=[CH:7]1
Reactant: CI
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc2c(=O)n(-c3ccc(C(=O)O)cc3)nc-2c2ccccc21
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A suspension of 4-(3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (0.050 g, 0.16 mmol) in DMF (1 ml) was added in small portions to a suspension of NaH (55%) (0.017 g, 0.39 mmol) in DMF (0.5 ml) under N2. The reaction was stirred at room temperature. After 1 h MeI (0.053 g, 0.38 mmol) was added. After additional 24 h water was added and the solid material (mainly consisting of ester product) was removed by filtration. The filtrate was acidified with 2M HCl. The precipitate was collected, washed with water and dried to yield 4-(5-methyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (0.018 g). This material contained approx. 10% of ester product: 1H NMR (400 MHz, DMSO-d6) δ 8.89 (1H, s), 8.34 (2H, d), 8.29 (1H, d), 7.99 (2H, d), 7.85 (1H, d), 7.76 (1H, t), 7.62 (1H, t), 4.00 (3H, s); ESI MS m/z 320 (M+H+).
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](I)=[CH:11][C:10]=2F)=[C:5](F)[C:4]=1F.C([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)CC.OCC(C)(CO)C.CC(C)=O>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:6]1([C:9]2[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: C[Si](C)(C)c1ccc(-c2ccc(I)cc2F)c(F)c1F
Reactant: CCCc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(CO)CO
Solvent: CC(C)=O
Solvent: CC(C)O
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 89 %

Procedure:
A solution of (2 mmol) of 8, (2.2 mmol) of 4-propylphenylboronic acid, 250 mg (2.40 mmol) of neopentyl glycol, 1.53 g (4.84 mmol) of Ba(OH)2 8 H2O, 1.35 ml (0.103 mmol, 5 mol %) of a 76 mM acetone solution of Pd(OAc)2 in 20 ml of 95% i—PrOH is stirred at 80° C. for 12 hours. The solvent is subsequently removed under reduced pressure. 5 ml of 2 M HCl are added to the residue, and the mixture is extracted with dichloromethane (3×5 ml). The combined organic phases are dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, and the residue is converted into 10 (yield: 89%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:40][C:39]2=[CH:41][CH:42]=[C:36]([CH:37]=[CH:38]2)[O:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:45])[CH3:44])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([O:16]C(C)(C)C)=[O:15])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:40][C:39]2=[CH:38][CH:37]=[C:36]([CH:42]=[CH:41]2)[O:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:44])[CH3:45])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([OH:16])=[O:15]
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCN)C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
0.71 g (1.10 mmol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1 (17),14(18),15-trien-12-yl)ureido]hexanoate was dissolved in 11 ml of dichloromethane, and the same volume of trifluoroacetic acid was added. Stirring at RT for 4 h was followed by concentration and fractionation of the residue by preparative HPLC. The required fractions were combined and, after evaporation of acetonitrile, mixed with dilute hydrochloric acid, concentrated further and finally freeze dried. 0.42 g of the title compound was obtained as hydrochloride.
Reaction SMILES: C(OO)(=[O:3])C.[C:6]([O:9][C@@H:10]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([O:20][C:21](=[O:23])[CH3:22])[C@@H:13]([S:24][CH3:25])[O:12][C@H:11]1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:36][CH:35]=2)[CH:27]=1)(=[O:8])[CH3:7]>CC(O)=O.CC#N>[C:6]([O:9][C@@H:10]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([O:20][C:21](=[O:23])[CH3:22])[C@@H:13]([S@:24]([CH3:25])=[O:3])[O:12][C@H:11]1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:39]=2)[CH:27]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OO
Reactant: COC(=O)CCCc1ccc(Cc2cc([C@@H]3O[C@H](SC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)CCCc1ccc(Cc2cc([C@@H]3O[C@H]([S@](C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
Peracetic acid (32% in dilute HOAc, 0.12 mL, 0.512 mmol) was added to a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(4-methoxy-4-oxobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (9, 100 mg, 0.170 mmol) in 1 mL of HOAc and 2 mL of CH3CN at 0° C. The reaction was stirred for 20 min at 0° C. The reaction was quenched with 1N aqueous NaOH, then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvents were removed in vacuo to provide a 2:1 diastereomeric mixture of sulfoxides 60 (60 mg, 58% yield) that was carried to the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d, 2:1 mixture of diastereomers at S, designated as major Ha and minor Hb) δ ppm 7.11-7.17 (m, 2 H), 7.05-7.09 (m, 2 H), 6.97-7.02 (m, 3 H), 5.59 (t, J=9.3 Hz, 1 Hb), 5.46 (t, J=9.3 Hz, 1 Hb), 5.41 (t, J=9.6 Hz, 1 Ha), 5.21 (t, J=9.9 Hz, 1 Ha), 5.17 (t, J=9.3 Hz, 1 Hb), 5.13 (t, J=9.9 Hz, 1 Ha), 4.50 (t, J=10.4 Hz, 1 Ha), 4.48 (d, J=9.9 Hz, 1 Ha), 4.46 (d, J=10.1 Hz, 1 Hb), 4.31 (d, J=10.1 Hz, 1 Hb), 3.93 (m, 2 Hb), 3.92 (m, 2 Ha), 3.66 (s, 3 H), 2.67 (s, 3 Ha), 2.64 (s, 3 Hb), 2.61 (t, J=7.8 Hz, 2 H), 2.33 (t, J=7.3 Hz, 2 H), 2.23 (s, 3 H), 2.09 (s, 3 Ha), 2.08 (s, 3 Hb), 2.02 (s, 3 Hb), 2.01 (s, 3 Ha), 1.93 (quin, J=7.3 Hz, 2 H), 1.75 (s, 3 Ha), 1.74 (s, 3 Hb). MS (ES+) [M+H]+=603.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH:20]=[O:21])=[CH:16][CH:17]=1
Reactant: OCCCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 51.6 %

Procedure:
A solution of oxalyl chloride (1.32 mL, 15.1 mmol) in dichloromethane (40 mL) was stirred at −78° C. and treated dropwise with dimethyl sulfoxide (2.21 mL, 31.1 mL) over 5 minutes. The resulting solution was stirred for 35 minutes at −78° C. A solution of 3-(4-fluorophenyl)-propan-1-ol (1.50 g, 9.73 mmol) in dichloromethane (12 mL) was added over 5 minutes, and stirring continued at the same temperature for 50 minutes. Triethylamine (4.41 mL, 31.6 mmol) was added, and the cooling bath was replaced by an ice-water bath. The resulting slurry was stirred for one hour, then was diluted with dichloromethane. The resulting mixture was washed with half-saturated aqueous ammonium chloride, then with saturated sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The resulting orange oil was distilled in a short-path apparatus at 50° C. and 0.2 Torr pressure to provide a colorless liquid (764 mg, 50%). 1H NMR (300 MHz, CDCl3) δ9.83 (t, J=1 Hz, 1H), 7.17 (m, 2H), 6.99 (t, J=9 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 2.79 (tt, J=7, 1 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].C(OC([C@@H]1C[C@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1)=O)C.Cl[C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: Clc1ncccn1
Agent: CCOC(=O)[C@@H]1C[C@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ncccn1

Procedure:
In analogy to the procedure described in example 335a, (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (prepared as described for the corresponding (2S,4S)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester in example 192e) was reacted with 2-chloro-pyrimidine (CAS Reg. No. 1722-12-9) in a shaking reactor at 150° C. for 48 h to give the title compound as yellow oil. MS (ESI): m/z=416.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][CH3:22].[CH2:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>ClC1C=CC=CC=1>[CH2:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7](=[O:17])[C:6]=3[C:5]([NH:18][C:7](=[O:17])[C:6]3[CH:15]=[CH:2][C:3]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:4][CH:5]=3)=[CH:4][C:3]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: CCCCc1cc(N)c2c(c1N)C(=O)c1ccccc1C2=O
Solvent: Clc1ccccc1
Product: CCCCc1ccc(C(=O)Nc2cc(CCCC)c(NC(=O)c3ccc(CCCC)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Temperature: 20 °C

Procedure:
1,4-Diamino-2-butylanthraquinone (0.30 g, 0.001 mole) and p-butylbenzoic acid chloride (0.48 g, 0.0024 mole) are refluxed in 20 ml chlorobenzene for 0.5 hrs. The reaction mass is cooled to 20° C. and chromatographed with chloroform on Silica gel. 1,4-Bis(4-butylbenzamido)-2-butylanthraquinone is obtained in amount 0.36 g (60%). Found, %: C 76.74, H 8.31, N 4.53; C40H52N2O4. Calculated, %: C 76.89, H 8.39, N 4.48; λmax =475 nm, S=-0.22. M.p.=180°-181.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=2)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]C)=[O:34].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=2)[CH2:9][CH2:10][CH2:11][C:12]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:13])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCN
Reactant: COc1ccc(CCN(CCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CCN(CCCC(=O)NCCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-homoveratrylaminobutyric acid and methyl 4-aminobutyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-(homoveratrylamino)butyryl]-4-aminobutyric acid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:20])=[O:19]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2Cl)c1Br
Yield: 66 %

Procedure:
2,3,4-Trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,3,4-trichlorobenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p.110°-113° C., yield 66%.
Reaction SMILES: CN([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)C.C([O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[NH:29])[NH2:28])[CH:22]=1)(C)(C)C>C(O)(=O)C>[C:10]1([CH3:13])[CH:11]=[CH:12][C:7]([C:6]2[N:5]=[CH:4][N:28]=[C:27]([C:23]3[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=3)[C:20]([OH:19])=[O:30])[N:29]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)N=CN(C)C)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=N)N)c1
Solvent: CC(=O)O
Product: Cc1ccc(-c2ncnc(-c3cccc(C(=O)O)c3)n2)cc1
Temperature: 115 °C
Yield: 8.9 %

Procedure:
Part D. A mixture of N-dimethylaminomethylene-4-methyl-benzamide (221.9 mg, 1.15 mmol) and 3-carbamimidoyl-benzoic acid tert-butyl ester (196.0 mg, 0.89 mmol) in anhydrous acetic acid (8 mL) is heated to 115° C. at 150 W, 250 psi in a microwave reactor for 30 min. until complete consumption of the starting material is determined by TLC. A white solid is precipitated by addition of 1 N HCl, and collected by filtration, followed by washing with water and hexanes. The obtained solid is further purified by flash column chromatography, eluting with methanol/methylene chloride (1:20) to afford the title product (23.1 mg, 5.3% yield), m.p. 298-300° C. 1H NMR (300 MHz, DMSO-d6): δ 9.40 (1H, s), 8.63 (2H, d, J=8.3 Hz), 8.48 (2H, d, J=8.0 Hz), 8.13 (2H, d, J=8.0 Hz), 7.41 (2H, m), 2.41 (3H, s). MS (ES+): m/e 292.30.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH2:16]([O:15][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:20][C:21]1[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=3)[O:24][C:25]=1[CH3:26])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:18])[CH3:17]
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3ccc(F)c(C)c3)oc2C)c1)C(=O)O
Yield: 58 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole, the title compound was obtained in 58% yield as a pale yellow solid. MS: (M−H)− 435.2.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][C:33]3[CH:61]=[CH:60][C:36]([CH2:37][N:38]([CH2:46][C@H:47]([OH:59])[C:48]4[C:56]5[S:55][C:54](=[O:57])[NH:53][C:52]=5[C:51]([OH:58])=[CH:50][CH:49]=4)C(=O)OC(C)(C)C)=[CH:35][CH:34]=3)[CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18].C1(C)C=CC=CC=1>C(Cl)Cl>[CH:3]([OH:5])=[O:4].[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][C:33]3[CH:61]=[CH:60][C:36]([CH2:37][NH:38][CH2:46][C@@H:47]([C:48]4[C:56]5[S:55][C:54](=[O:57])[NH:53][C:52]=5[C:51]([OH:58])=[CH:50][CH:49]=4)[OH:59])=[CH:35][CH:34]=3)[CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)c2nc4ccccc4s2)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1nc2ccccc2s1)N1CCOC2(CCN(CCOc3ccc(CNC[C@H](O)c4ccc(O)c5[nH]c(=O)sc45)cc3)CC2)C1
Product: O=CO
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (1.25 mL) was added to a solution of (R)-tert-butyl 4-(2-(4-(benzo[d]thiazole-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethoxy)benzyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate (example 106, step c) (0.33 g) in DCM (4 mL) and the resulting mixture stirred for 10 minutes. Toluene (20 mL) was added and the mixture was evaporated in vacuo. The residue was azeotroped with toluene (3×20 mL). Purification was by preparative HPLC (Phenomenex Gemini®, Gradient: 5-40% acetonitrile in 0.1% aqueous formic acid). The fractions containing product were combined and freeze-dried to give the titled compound as a white solid. Yield 0.096 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)[CH:33]=4)[CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)[CH:33]=4)[CH:28]=3)=[CH:25][CH:26]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Agent: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Yield: 58 %

Procedure:
This compound was prepared following the procedure for [1-(2-{5-[4-(6-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (R)-methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) to provide [1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 58%) as a white powder. LCMS-ESI+: calc'd for C47H50N8O6: 822.4 (M+). Found: 823.8 (M+H+). 1H-NMR: 400 MHz, (CDCl3) 5: (Mixture of rotomers) 7.62-7.87 (m, 9H), 7.29-7.43 (m, 6H), 7.18 (s, 2H), 6.09 (m, 1H), 5.46 (m, 2H), 5.33 (s, 1H), 5.27 (s, 1H), 4.33 (t, 1H), 3.84 (m, 1H), 3.71 (m, 1H), 3.68 (s, 3H), 3.61 (s, 3H), 3.24 (m, 1H), 2.83-2.93 (m, 3H), 2.35 (m, 1H), 1.92-2.23 (m, 6H), 0.86-0.97 (m, 6H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)=[O:16]>>[C:46]([O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:44][CH:43]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 52 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[NH2:14][S:11]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:4]1[C:3]([N:2]([CH3:10])[CH3:1])=[O:9])(=[O:13])=[O:12]
Reactant: NS(N)(=O)=O
Reactant: CN(C)C(=O)[C@H]1CCCN1
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@H]1CCCN1S(N)(=O)=O

Procedure:
To a solution of the subtitle compound of step ii) (2.20 g) in dioxane (25 ml) was added sulfamide (7.20 g) and the mixture heated at reflux for 45 h. The reaction mixture was cooled and adsorbed on to silica gel and then purified by column chromatography (5% methanol/EtOAc) to afford the subtitle compound as an oil. Yield: 1.6 g.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.O>C(Cl)Cl>[Si:14]([O:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1)([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Yield: 43.6 %

Procedure:
A solution of 4-(methylamino)phenol (5.0 g, 29 mmol), TBDMSCl (4.8 g, 32 mmol) and imidazole (9.9 g, 0.15 mol) in DCM was stirred at r.t. for 1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated and purified by silica gel chromatography (PE:EtOAc=10:1) to give 3.0 g (43%) of the title compound as a dark green oil. [M+H] Calc'd for C13H23NOSi, 238. Found, 238.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>O>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:17]2[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]2=[O:9])=[CH:14][CH:13]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: COc1ccc(Cn2c(C)cc(O)cc2=O)cc1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
4-Hydroxy-6-methyl-2-pyrone (4.60 g, 36.45 mmol) and 4-methoxybenzylamine (5.00 g, 36.45 mmol) in H2O (100 mL) were heated to reflux. After 15 hours at reflux the reaction was allowed to cool to room temperature. The precipitate was collected by filtration washing with H2O to give a pale yellow solid (8.00 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 7.2 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 5.74 (d, J=2.0 Hz, 1H), 5.56 (d, J=2.5 Hz, 1H), 5.08 (s, 2H), 3.68 (s, 3H), 2.14 (s, 3H).