Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:65][O:66][C:67](=[O:75])[CH2:68][CH:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1>C(Cl)Cl>[CH3:65][O:66][C:67](=[O:75])[CH2:68][CH:69]1[CH2:70][CH2:71][N:72]([C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:30])[CH2:73][CH2:74]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)CC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC1CCN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (581 mg, 1 mmol) in methylene chloride (10 mL), HATU (Aldrich, 500 mg, 1.3 mmol) was added followed by the addition of DIPEA (0.35 mL, 2.2 mmol) and piperidin-4-yl-acetic acid methyl ester (Oakwood, 205 mg, 1.3 mmol). The mixture was stirred at rt for 3 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12 g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 586 mg.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][O-:14].[Na+]>O1CCOCC1.O>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:14][CH3:13])[CH:11]=1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(F)cc1OC
Temperature: 100 °C
Reaction time: 48 h
Yield: 93.6 %

Procedure:
To a solution of methyl 2,4-difluorobenzoate (50 g, 290 mmol) in dioxane (300 mL) was added sodium methoxide (18.0 g, 333.21 mmol) and the reaction was stirred for 48 hours at 100° C. in an oil bath. The reaction mixture was cooled to room temperature and diluted with H2O (200 mL). The mixture was extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 4-fluoro-2-methoxybenzoate as colorless oil (50.0 g, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:28])[S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:28])[S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:40][C:37]3[S:38][CH:39]=[C:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)[N:36]=3)=[O:24])=[CH:26][CH:27]=2)(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: CN(c1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-(4-(benzyloxy)phenyl)sulfamoyl)benzoic acid (15) (493 mg, 1.24 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (200 mg, 1.13 mmol) using method C. The residue was purified using flash chromatography eluting with 0-8% MeOH in dichloromethane. The resulting solid was triturated with diethyl ether to give 4-(N-(4-(benzyloxy)phenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off white solid. Yield: 289 mg (46%). 1H-NMR: 8.62 (d, J=5.0 Hz, 1H), 8.29 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.46-7.31 (m, 6H), 7.04-6.96 (m, 4H), 5.10 (s, 2H), 3.16 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH2:11][O:8][C:7]2[C:2]([CH3:1])=[C:3]([OH:9])[CH:4]=[CH:5][CH:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCC1CCCCC1
Reactant: Cc1c(O)cccc1O
Product: Cc1c(O)cccc1OCC1CCCCC1

Procedure:
Alkylation of 2-methylbenzene-1,3-diol using (bromomethyl)cyclo hexane following the method used in Example 154 gave 3-(cyclohexylmethoxy)-2-methylphenol. Yield (0.58 g, 37%): 1H NMR (400 MHz, CDCl3) δ 6.98 (t, J=8.0 Hz, 1H), 6.42 (t, J=7.6 Hz, 2H), 4.60 (bs, 1H), 3.72 (d, J=6.4 Hz, 2H), 2.12 (s, 3H), 1.68-1.89 (m, 6H), 1.16-1.35 (m, 3H), 1.01-1.11 (m, 2H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:22]1([CH2:21][NH:20][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCC1CC1
Product: c1ccc2c(c1)ncn2-c1ccnc(NCC2CC2)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with aminomethylcyclopropane according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): 266.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.65 (s, 1H); 8.38 (br s, 1H); 8.23 (d, J=7.8 Hz, 1H); 7.88 (d, J=7.8 Hz, 1H); 7.42 (m, 2H); 6.82 (d, J=5.5 Hz, 1H); 5.30-6.25 (br, 1H); 3.42 (br s, 2H); 1.19 (br s, 1H); 0.62 (m, 2H); 0.35 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=1.C=O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16](S(O)(=O)=O)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]=1[CH2:1][C:2]1[CH2:23][C:13]2[C:18]([C:3]=1[CH3:4])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=CCc2ccccc21
Agent: C=O
Solvent: Cc1ccccc1
Product: CC1=C(CC2=C(C)c3ccccc3C2)Cc2ccccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 247.4 %

Procedure:
In a 500 mL flask equipped with magnetic stirring bar were introduced 14.8 g (0.114 moles) of 3-methyl-indene, 2.3 g (0.077 moles) of para-formaldehyde and 4.37 g (0.023 moles) of para-toluenesulphonic acid in 200 ml of toluene; the mixture was heated to 80° C. and was maintained under stirring for 1 hour at 80° C. Then the reaction was quenched with water/NaHCO3; the organic layer was separated, washed with water and brought to dryness under reduced pressure. The crude product was crystallized upon standing at room temperature, and then was further purified by washing with pentane or MeOH, thus isolating 15.5 g of bis(3-methyl-2-indenyl)methane (purity of 89.8% by G.C.; yield=89.8%).
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([C:28]5[CH:29]=[C:30]([C:36]6[CH:41]=[CH:40][C:39]([C:42]([O:44]C)=[O:43])=[CH:38][C:37]=6[CH3:46])[CH:31]=[CH:32][C:33]=5[O:34][CH3:35])=[CH:26][C:25]([CH:47]([CH3:49])[CH3:48])=[C:24]([N:50]([CH3:52])[CH3:51])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Li+]>C1COCC1>[F:53][C:2]([F:1])([F:54])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([C:28]5[CH:29]=[C:30]([C:36]6[CH:41]=[CH:40][C:39]([C:42]([OH:44])=[O:43])=[CH:38][C:37]=6[CH3:46])[CH:31]=[CH:32][C:33]=5[O:34][CH3:35])=[CH:26][C:25]([CH:47]([CH3:49])[CH3:48])=[C:24]([N:50]([CH3:51])[CH3:52])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3cc(C(C)C)c(N(C)C)nc3[C@@H]3CC[C@H]4[C@@H](c5cc(C(F)(F)F)cc(C(F)(F)F)c5)OC(=O)N34)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1cc(C(C)C)c(N(C)C)nc1[C@@H]1CC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To methyl 3′-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)-5-(propan-2-yl)pyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (24 mg, 0.033 mmol) in THF (1 mL) was added lithium hydroxide (9.51 mg, 0.397 mmol). The reaction was stirred overnight at room temperature. Reaction was incomplete. More lithium hydroxide (4.76 mg, 1.99 mmol) was added, and the reaction was heated to 50° C. for 5 hours. The reaction was purified by HPLC to yield 3′-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)-5-(propan-2-yl)pyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylic acid (10 mg, 0.012 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 1.6:1 ratio. 1H NMR (500 MHz, CDCl3) δ7.94-8.10 (m, 2H), 7.90 (s, 1H), 7.84 (s, 2H), 7.48 (m, 2H), 7.42 (dd, J=8.5 Hz, J=2.0 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H, minor rotamer), 7.30 (d, 1H, merged with solvent peak, major rotamer), 7.14 (d, J=8.5 Hz, 1H, minor rotamer), 7.07 (d, J=8.5 Hz, 1H, major rotamer), 5.98 (d, J=8.0 Hz, 1H, minor rotamer), 5.93 (d, J=8.0 Hz, 1H, major rotamer), 5.09 (t, J=7.5 Hz, 1H, minor rotamer), 5.01 (t, J=7.5 Hz, 1H, major rotamer), 4.76 (m, 1H), 3.93 (s, 3H, minor rotamer), 3.83 (s, 3H, major rotamer), 3.40 (m, 1H), 3.07 (s, 6H), 2.47 (s, 3H, major rotamer), 2.40 (s, 3H, minor rotamer), 2.35 (m, 1H), 2.05 (m, 1H), 1.60 (m, 1H), 1.29 (t, J=6.5 Hz, 6H), 1.08 (m, 1H). MS ESI calc'd. for C39H38F6N3O5 [M+H]+ 742.3, found 742.5. RTA (95% HS): 182 nM
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([CH3:33])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(OCC)(=O)C>[CH:18]1([CH2:17][C@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:25]([CH3:33])[CH:24]=2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:34])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)ccc1S(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
In a flask containing N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (300 mg, 0.56 mmol) was added ethanol (10 mL) and concentrated hydrochloric acid (seven drops) and was stirred at 25° C. for 2 h. It was then diluted with ethyl acetate (100 mL) and washed with water (1×30 mL) and saturated aqueous brine solution (1×30 mL). The organic layer was then dried over sodium sulfate and absorbed onto silica gel (2.5 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 5% methanol/ethyl acetate) afforded 3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (194 mg, 83%) as a white foam: [α]28589=−19.0° (c=0.20, methanol); ES-HRMS m/e calcd for C21H29N3O4S (M+H)+ 420.1952, observed 420.1949; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.18 (m, 2H, CH2), 1.37-1.80 (m, 8H, 4×CH2), 2.06-2.17 (m, 1H, CH) ArCH3), 3.16 (s, 3H, SO2CH3), 3.66 (q, J=5.6 Hz, 2H, OCH2), 3.85 (dd, J=8.8 Hz, J=5.7 Hz, 1H, ArCH), 3.98 (t, J=5.6 Hz, 2H, NCH2), 4.82 (t, J=5.6 Hz, 1H, OH), 6.40 (d, J=2.2 Hz, 1H, Ar), 7.41-7.46 (m, 2H, Ar), 7.52 (d, J=2.2 Hz, 1H, Ar), 7.83 (d, Jo=8.5 Hz, 1H, Ar), 10.72 (s, 1H, NH).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][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][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28].[P:37]([O:44]CC)([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40]>>[CH2:39]([O:38][P:37]([CH2:2][CH2:3][CH2:4][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][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])([O:41][CH2:42][CH3:43])=[O:44])[CH3:40]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCCCCCCCCCCCCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCCCCCCCCCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Temperature: 150 °C
Reaction time: 18 h
Yield: 101.7 %

Procedure:
A mixture of 0.98 g of 1-bromo-22-(nonafluorobutyl)docosane and 4.00 g of triethyl phosphite was heated at 150° C. After 18 hr, diethyl ethylphosphonate and other volatiles were distilled, b.p. 30-50° C. at 0.05 torr (7 Pa), leaving 1.09 g of 1-(diethylphosphono)-22-(nonafluorobutyl)docosane as an off-white solid, which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])O.[Na+].O>CN(C)C=O>[C:21]1(=[O:30])[N:20]([CH2:19][CH2:18][CH2:17][N:13]2[CH2:14][CH2:15][CH:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:11][CH2:12]2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 70 °C
Yield: 40.3 %

Procedure:
A mixture of 4-(3-indolyl)piperidine (7.47 g), N-(3-bromopropyl)phthalimide (10.0 g) and sodium hydrogen carbonate (3.45 g) in dry N, N-dimethylformamide (88 ml) was heated at 70° C. for 2 hours. After cooling, the reaction mixture was poured into water (880 ml) and extracted with a mixture of chloroform and methanol (10:1 V/V). The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (290 g) and eluted with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with diethyl ether to give pale yellow crystals of 1-(3-phthalimidopropyl)-4-(3-indolyl)piperidine (5.83 g).
Reaction SMILES: C([O:5][C:6](/[CH:8]=[CH:9]/[C:10]1[C:20]2[O:19][CH2:18][CH2:17][C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[C:6](/[CH:8]=[CH:9]/[C:10]1[C:20]2[O:19][CH2:18][CH2:17][C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)C1=Cc2cccc(/C=C/C(=O)OC(C)(C)C)c2OCC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=Cc2cccc(/C=C/C(=O)O)c2OCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of ethyl 9-[(E)-(2-tert-butoxycarbonylvinyl)]-2,3-dihydro-1-benzoxepin-4-carboxylate (0.56 g) was added trifluoroacetic acid (0.63 ml) at 0° C. The reaction mixture was stirred overnight at ambient temperature and evaporated in vacuo. The residue was triturated with diisopropyl ether to give a solid of ethyl 9-[(E)-(2-carboxyvinyl)]-2,3-dihydro-1-benzoxepin-4-carboxylate (0.3 g).
Reaction SMILES: [OH-].[Na+].[CH3:3]/[C:4](/[CH:11]=[CH:12]/[CH:13]=[C:14](/[C:16]1[CH2:17][O:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:21][CH:20]=2)\[CH3:15])=[CH:5]\[C:6]([O:8]CC)=[O:7].Cl>C(O)C.O>[CH3:3]/[C:4](/[CH:11]=[CH:12]/[CH:13]=[C:14](/[C:16]1[CH2:17][O:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[CH:21][CH:20]=2)\[CH3:15])=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(\C)C1=Cc2cc(-c3ccccc3)ccc2OC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(/C=C/C=C(\C)C1=Cc2cc(-c3ccccc3)ccc2OC1)=C\C(=O)O
Reaction time: 1 h
Yield: 67.5 %

Procedure:
44 ml of 35% sodium hydroxide are added to a solution of 7.34 g (19 mmol) of the ester obtained in Example 25 in a mixture of 310 ml of ethanol and 140 ml of distilled water. The reaction mixture is then refluxed for 2 hours. The solution, cooled to +10° C., is acidified to pH 4 by means of a 4N hydrochloric acid solution. After the addition of 80 ml of water, the mixture is stirred at +10° C. for one hour. After filtration, the solid is rinsed with water and dried in a vacuum oven at 70° C. over phosphoric acid. Recrystallisation from ethanol yields 4.6 g of a yellow solid.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[C:6]([C:18]([OH:20])=O)=[CH:5][N:4]=1)#[N:2].[C:21]1([CH2:27][C@@H:28]([NH2:35])[CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:21]1([CH2:27][C@@H:28]([NH:35][C:18]([C:6]2[C:7]([CH2:9][CH:10]3[CH2:11][CH2:12][C:13]4([CH2:14][CH2:15]4)[CH2:16][CH2:17]3)=[N:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[O:20])[CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N#Cc1ncc(C(=O)O)c(CC2CCC3(CC2)CC3)n1
Reactant: N[C@H](Cc1ccccc1)CN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncc(C(=O)N[C@H](Cc2ccccc2)CN2CCCC2)c(CC2CCC3(CC2)CC3)n1
Reaction time: 24 h

Procedure:
To a solution of the crude 2-cyano-4-(spiro[2.5]oct-6-ylmethyl)pyrimidine-5-carboxylic acid (22 mg, step 74.5) in DMF (1.5 mL) are added (R)-2-phenyl-1-pyrrolidin-1-ylmethylethylamine (0.083 mmol), EDCl—H2O (0.11 mmol), and HOAt (0.11 mmol) at room temperature. The reaction mixture is stirred for 24 h and the reaction is quenched by the addition of H2O. The mixture is extracted with AcOEt, and the organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by RP-HPLC to give the title compound; MS (M+1)+: 474, Rf (solvent): 0.63 (CH2Cl2:MeOH=10:1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH2:29])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:4][CH:3]1[CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34].ClC(Cl)(Cl)C[O:45][C:46](=O)[NH:47][C:48]1[N:49]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[N:50]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:52]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:53]([C:51]1[CH:52]=[C:48]([NH:47][C:46]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH:3]([CH2:30][O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:4]5)=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:45])[N:49]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[N:50]=1)([CH3:56])([CH3:54])[CH3:55]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OCC1CN(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCN1C)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCN(C)C(CO[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 51.1 %

Procedure:
A mixture of Intermediate 56e (87.0 mg, 0.15 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 66.8 mg, 0.17 mmol), DIPEA (39.2 μL, 0.23 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo and the residue purified by FCC, using 0-10% MeOH in DCM, to provide the title compound as a pale yellow foam (64 mg, 51%). LCMS (Method 3): Rt 3.63 min, m/z 834 [M+].
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][C:22]([F:26])([F:25])[CH2:23][SH:24].Cl>CN(C)C=O>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([S:24][CH2:23][C:22]([F:26])([F:25])[F:21])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: FC(F)(F)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(SCC(F)(F)F)c(C(=O)O)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) in 6 ml N,N-dimethylformamide were added 13.8 mol cesium carbonate and 9.16 mmol 2,2,2-trifluoro-ethanethiol and the mixture was stirred at 90° C. for 30 min. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a red-brown solid which was used in the next step without further purification (yield 99%). MS (m/e): 312.9 ([M−H]−, 100%).
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:34](O)=[O:35])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:59][CH2:60][CH2:61][C:62]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[NH:64][CH:63]=1>CN(C=O)C>[NH:64]1[C:65]2[C:70](=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:62]([CH2:61][CH2:60][NH:59][C:34](=[O:35])[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[NH:18][C:1]([O:3][CH2:4][CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]3[C:17]2=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:2])=[CH:63]1
Reactant: O=C(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCc1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1c[nH]c2ccccc12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Commercially available Nα-Fmoc-Nδ-Cbz-L-ornithine (528.0 mg) was dissolved in DMF (10.6 ml), and HOBt (235 mg), WSCI hydrochloride (334 mg), and tryptamine (0.165 ml) were added to the solution. The mixture was stirred for 16 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in chloroform and extracted with 1 mol/l aqueous solution of hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate. The solvent was removed by distillation and the residue was purified by silica gel column chromatography (50 g, chloroform/ethyl acetate=1/1) to obtain the title compound (690 mg) as a white solid.