Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC2N(C(CC3N(C)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH:41]=O)=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1.[CH3:43][C:44]1[O:45][CH:46]=[N:47][N:48]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH2:41][C:46]3[O:45][C:44]([CH3:43])=[N:48][N:47]=3)=[C:33]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:34]=2)[CH:31]=1
Reactant: Cc1nnco1
Reactant: O=Cc1c(-c2ccccc2)nc2ccc(Cl)cn12
Agent: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Product: Cc1nnc(Cc2c(-c3ccccc3)nc3ccc(Cl)cn23)o1

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 6-chloro-2-phenylimidazo[1,2-a]pyridine-3-carbaldehyde and 2-methyl-1,3,4-oxadiazole. M/e+ 325 for C17H14ClN4O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.25 (d, J=1.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.61 (d, J=9.5 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.43 (d, J=7.3 Hz, 1H), 7.22 (dd, J=9.5, 1.8 Hz, 1H), 4.58 (s, 2H), 2.52 (s, 3H) ppm.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[BrH:9]>ClCCl>[Br:9][CH2:7][CH2:8][CH:2]([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC1CCOC(=O)C1
Reactant: Br
Solvent: ClCCl
Product: CC(CCBr)CC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of β-methyl-δ-valerolactone (3.0 g) in anhydrous dichloromethane (30 ml), cooled to 0-5° C., was saturated with hydrogen bromide gas and the mixture was stirred for three days at room temperature. The mixture was diluted with dichloromethane (100 ml) and the resulting solution was washed with 10-% NaCl (3×30 ml). Next the solution was dried with anhydrous MgSO4 and the solvent was distilled under reduced pressure, Yield: 4.6 g. NMR ˜100% pure product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[CH:24]=1>>[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]=1[C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:29])[CH:24]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)NC3CCOCC3)c2)cn1
Yield: 42 %

Procedure:
As described for Example 71, tetrahydro-pyran-4-ylamine was converted, using 3-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (52 mg, 42%) which was obtained as an off-white solid. MS: m/e=413.0 [M+H]+.
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]=[C:30]=[O:31])[CH:23]=1>O>[F:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[CH2:28][NH:29][C:30](=[O:31])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=NCc1cccc(F)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C(=O)c1csc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
An N-methylpyrrolidinone (5 mL) solution of ethyl 2-(2-aminothiazol-4-yl)-2-oxoacetate (commercial, 1.00 g, 5.0 mmol) and 1-fluoro-3-(isocyanatomethyl)benzene (831 mg, 5.5 mmol) was heated in a microwave reactor at 120 C for 30 minutes. Upon cooling, water (50 mL) was added with vigorous stiffing. Filtration of the precipitate afforded ethyl 2-(2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)-2-oxoacetate. M/Z 352 (M+H)+. The filtrate was dissolved in EtOH (100 mL) then hydroxylamine hydrochloride (700 mg, 10 mmol) and sodium acetate (1.07 g, 13 mmol) were added to the mix. The solution was stirred at 75 C for 4 hours and filtered while hot. Evaporation of the mixture and Flash chromatography afforded ethyl 2-(2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)-2-(hydroxyimino)acetate as a mixture of isomers. M/Z 367 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1.CN1CCOCC1>C(#N)C.C([O-])(O)=O.[Na+]>[N:12]1([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Benzyl chloroformate (11.0 mL, 0.0768 mol) was added into a solution of methyl piperidine-4-carboxylate (10.0 g, 0.0698 mol) and 4-methylmorpholine (15.4 mL, 0.140 mol) in acetonitrile (20.0 mL). After 30 min, the mixture was diluted with NaHCO3 (7.5%), extracted with ethyl acetate (AcOEt) (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to afford 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (12 gram) which was directly used in next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1)=O.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[CH3:26].[OH-].[K+].Cl>CO.O>[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])/[CH:24]=[CH:1]/[C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:14][CH:15]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: CCOC(=O)COc1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)/C=C/c2ccc(OCC(=O)O)cc2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Commercially available ethyl 2-(4-formylphenoxy)acetate (20.0 g, 0.1 mol) and commercially available 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol) were dissolved in 200 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (22.0 g, 0.392 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, and extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with water and brine (200 mL each), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained yellow oil was dried under high-vacuum, 10 g (33%) of yellowish solid was obtained. MS (EI): 313 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:5][O:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:25][C:26]([F:49])([F:48])[CH2:27][CH2:28][C@@H:29](OS(C(F)(F)F)(=O)=O)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([C@H:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:29]([CH2:28][CH2:27][C:26]([F:25])([F:48])[F:49])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:5][O:4][N:3]=1
Reactant: Cc1nocc1CC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nocc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
In a 250 mL round-bottomed flask, a solution of tert-butyl 2-(3-methylisoxazol-4-yl)acetate (1.75 g, 8.87 mmol) in THF (56 mL) and toluene (27 mL) was cooled in a −78° C. bath and treated with a solution of 1M KHMDS (11.09 mL, 11.09 mmol) in THF dropwise over 2 minutes via syringe. After stirring for 15 minutes at −78° C., the reaction mixture was placed in a room temperature water bath for 15 minutes and then placed in a −78° C. bath for another 15 minutes before a solution of Intermediate S5D, (R)-benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate (4.55 g, 11.53 mmol) in 6 mL THF and 3 mL toluene was added over 2 minutes. The reaction mixture was stirred in −78° C. bath for 2 hours before being quenched with saturated aqueous NH4Cl and then warmed to room temperature. The mixture was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO4 filtered and concentrated. The residue was purified on silica gel column (330 g ISCO) eluting with a gradient of 0-30% EtOAc/CH2Cl2. Tubes were collected containing the product, which was concentrated to afford Intermediate S6A (2.394 g, 61% yield) containing about 30% of the (2R,3S) isomer.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH3:18])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:19])[CH:4]=1.[CH:22]1(C=O)C[CH2:23]1>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH:18]4[CH2:23][CH2:22]4)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:19])[CH:4]=1
Reactant: O=CC1CC1
Reactant: CCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21
Product: O=c1cc(C(F)(F)F)c2cc3c(cc2[nH]1)CCCN3CC1CC1

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1=H, n=1) and cyclopropanecarboxaldehyde. 1H NMR (400 MHz, CDCl3) 11.44 (br. s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.92 (s, 1H), 3.40 (t, 2H, J=5.6), 3.21 (d, 2H, J=6.2), 2.90 (t, 2H, J=6.3), 1.99 (m, 2H), 1.07 (m, 1H), 0.58 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=C(C=CC=1)CBr.[N+:28]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br)([O-:30])=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([N+:28]([O-:30])=[O:29])[CH:32]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: Cc1cccc(CBr)c1
Product: CCOC(=O)C1(Cc2cccc([N+](=O)[O-])c2)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared using the protocol described in Example 61, Step A substituting methyl N-tert-butoxycarbonyl-piperidine-4-carboxylate with ethyl N-tert-butoxycarbonyl-piperidine-4-carboxylate (Example 30, Step A), and 3-methylbenzyl bromide with 3-nitrobenzyl bromide.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]([OH:16])=O)[CH:7]=1.[O:20]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14](=[O:16])[NH:33][C:30]2[CH:29]=[CH:28][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:32][CH:31]=2)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)C(Cc1cccc(OCC(=O)O)c1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCC(=O)Nc2ccc(Oc3ccccc3)cc2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-(3-carboxymethoxy-phenyl)-2-methoxy-propionic acid methyl ester (PREPARATION 4, step 2) and 4-phenoxy-phenylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H23NO6 [M+H]+: 322.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[I:12]I>FC(F)(F)C([O-])=O.[Ag+].C(Cl)(Cl)Cl>[I:12][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1
Reactant: II
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Reaction time: 1 h

Procedure:
8.4 g (39.5 mmol) of 2-trichloroacetylpyrrole and 100 ml of chloroform were introduced into a three-necked flask under a stream of nitrogen and 8.6 g (39.5 mmol) of silver trifluoroacetate and 10.16 g (39.5 mmol) of iodine were added successively. Stirring was carried out at room temperature for one hour and the reaction mixture was poured into ice and extracted with dichloromethane. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was triturated in hexane and filtered. 8.2 g (61%) of the expected compound, with a melting point of 118°-119° C., were recovered.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:7]=2[N:8]=1.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][N:2]([CH3:18])[C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([NH:12][C:13]3[O:31][C@:23]4([CH2:22][N:21]=3)[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]4)[S:9][C:7]=2[N:8]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1nc2cnc(N(C)C)nc2s1)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ncc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
A mixture of dimethyl 5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (90 mg, 0.301 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (83 mg, 0.361 mmol) and cesium carbonate (196 mg, 0.60 mmol) in DMF (1.0 mL) was heated to 100° C. for 1.5 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by silica gel chromatography (2-40% 9:1 methanol: ammonium hydroxide-chloroform) to afford (R)—N5,N5-dimethyl-N2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-yl)thiazolo[5,4-d]pyrimidine-2,5-diamine (81 mg, 71% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.07 (br. s., 1H) 8.50 (s, 1H) 4.01 (d, J=9.54 Hz, 1H) 3.67 (d, J=9.54 Hz, 1H) 3.39 (dd, J=14.93, 1.63 Hz, 1H) 3.23 (s, 6H) 2.71-3.10 (m, 5H) 2.10-2.24 (m, 2H) 1.68-1.84 (m, 1H) 1.46-1.68 (m, 2H). MS (LC/MS) R.T.=0.87; [M+H]+=360.23.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32].C(N(CC)CC)C>C(O)CCC>[OH:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:32][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: NCc1cccc(O)c1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Oc1cccc(CNc2ncnc3c2ncn3C2CCCCO2)c1
Yield: 90 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) 3-hydroxybenzylamine, and 5 mL of triethylamine was refluxed in n-butanol for 3 hours. After removal of the n-butanol by vacuum evaporation water was added to remove the n-butanol residues. The resulting material was treated with water and partitioned into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of diethylether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 90%, white solid. TLC (EtOAc:hexane (1:1) (v:v): single spot; HPLC: purity >99%. 1H-NMR (400 MHZ, DMSO): 1.57m (2H); 1.70m (1H); 1.95m (2H); 2.27qq (1H, Ja=11.7 Hz, Jb=4.0 Hz); 3.66m (1H); 4.0d (1H); 4.63bs (2H); 5.67dd (1H, Ja=11.3 Hz, Jb=1.8 Hz); 6.58dd (1H, Ja=8.2 Hz, Jb=1.5 Hz); 6.73 (d, 1H, J=7.7 Hz); 7.07t (1H, J=7.7 Hz); 8.21 s (1H); 8.33bs (1H); 8.36bs (1H); 9.26 (1H). MS (ES): [M+H]+=326 (100).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[C:6]([CH3:14])=[CH:5][C:4]1([CH3:16])[CH3:15])[CH3:2].[Cl:17][C:18]1[C:19]([Cl:31])=[C:20]([Cl:30])[C:21]([Cl:29])=[C:22]2[C:27](=[O:28])[O:26][C:24](=[O:25])[C:23]=12>ClCCCl>[C:27]([C:22]1[C:21]([Cl:29])=[C:20]([Cl:30])[C:19]([Cl:31])=[C:18]([Cl:17])[C:23]=1[C:24]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[OH:13])[N:3]([CH2:1][CH3:2])[C:4]([CH3:15])([CH3:16])[CH:5]=[C:6]2[CH3:14])=[O:25])([OH:28])=[O:26]
Reactant: CCN1c2cc(O)ccc2C(C)=CC1(C)C
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: ClCCCl
Product: CCN1c2cc(O)c(C(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c3C(=O)O)cc2C(C)=CC1(C)C

Procedure:
24 g (0.11 mol) N-ethyl-7-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline and 31.6 g (0.11 mol) tetrachloro-phthalic acid anhydride were dissolved in 200 ml 1,2-dichloroethane and refluxed for 3 h. After cooling, the solution was filtered and evaporated to dryness in a rotary evaporator. The residue was suspended in ca. 500 ml chloroform and heated to boiling. The solid (=product) was filtered. In order to increase the yield, the mother liquor was rotary evaporated to dryness and purified by column chromatography. For this ca. 100 g silica gel (ICN silica 32-63, 60A) was used as a separation material for ca. 3 g crude product. A mixture of chloroform +5% ethanol serve as a flow agent. The filtered solid was dissolved in ca. 1 l diethyl ether. After filtering the solvent was removed by distillation and the residue was dried to form a yellow solid.
Reaction SMILES: [F:1][C:2]1([F:40])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@H:28]4[CH2:32][O:31]C(C)(C)[O:29]4)[C:21]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[F:40][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@H:28]([OH:29])[CH2:32][OH:31])[C:21]([C:35]([CH3:38])([CH3:39])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)OC[C@H](Cn2c(C(C)(C)CO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1C[C@H](O)CO
Temperature: 80 °C

Procedure:
(S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (290 g, 0.5 mmol) was dissolved in methanol (5 mL). Water (0.5 mL) was added followed by p-TsOH.H2O (20 mg, 0.1 mmol). The reaction was heated at 80° C. for 45 minutes. The solution was then partitioned between ethyl acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100% ethyl acetate-hexanes) to yield the product as a cream colored foamy solid. (146 mg, 54%, ee>97% by SFC). ESI-MS m/z calc. 520.5, found 521.5 (M+1)+. Retention time 1.67 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (d, J=1.1 Hz, 1H), 7.42-7.37 (m, 2H), 7.33-7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J=5.0 Hz, 1H), 4.91 (t, J=5.5 Hz, 1H), 4.75 (t, J=5.8 Hz, 1H), 4.42-4.38 (m, 1H), 4.10 (dd, J=8.8, 15.1 Hz, 1H), 3.90 (s, 1H), 3.64-3.54 (m, 2H), 3.48-3.33 (m, 2H), 1.48-1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14-1.11 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:36])[CH:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][N:12]1[CH:29]=[N:28][C:14]([CH2:15][C@@H:16]([C:25]([OH:27])=[O:26])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:47]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:47][C:10]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:36])[CH2:11][N:12]1[CH:29]=[N:28][C:14]([CH2:15][C@@H:16]([C:25]([OH:27])=[O:26])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(CC(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(CC(Cl)(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)C(=O)O
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A portion of the 1-[3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (5.5 g) in dry tetrahydrofuran (50 ml) was added dropwise to a stirred solution of lithium hexamethyldisilazide in tetrahydrofuran (33 ml, 1M solution in tetrahydrofuran) at -78° C. under an atmosphere of nitrogen. After 30 minutes the resulting solution was rapidly transferred, under an atmosphere of nitrogen, into a stirred solution of N-chlorosuccinimide (1.6 g) in dry tetrahydrofuran (50 ml). The resulting mixture was cooled in an ice bath under an atmosphere of nitrogen. The mixture was allowed to warm to room temperature over a period of 20 minutes and was quenched upon an addition of an excess of saturated aqueous potassium dihydrogen orthophosphate. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield a residue. The residue was dissolved in ethyl acetate, washed with water and then brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield a foam which was chromatographed on silica gel using a mixture of methanol:dichloromethane (2:23) as an eluent to yield 1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[ (1,1-dimethylethoxy)carbonyl]-L-histidine (2.85 g) as a mixture of diastereoisomers, (δ (CDCl3) 1.45 (9H, s), 1.48 (9H, s), 3.01 (2H, bd, J=15Hz), 3.23 (2H, bd, J=15Hz), 4.35 (2H, bs), 4.62 (2H, bt, J=17Hz), 4.86 (2H, bt, J=17Hz), 5.48 (2H, m, 4 lines), 6.38 (1H, bs), 6.57 (3H, m), 6.98 (2H, dd, J=9Hz and 2Hz), 7.42 (2H, m), 7.46 (5H, s), 7.49 (5H, s), 7.56 (1H, bs) and 7.60 (1H, bs)), having the formula: ##STR33##
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@:5]([C:9]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])([CH2:7][CH3:8])[CH:4]=[CH:3]1.[H][H]>[Pd].CO>[NH2:1][C@@H:2]1[CH2:3][CH2:4][C@@:5]([C:9]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[O:10])([CH2:7][CH3:8])[CH2:6]1
Reactant: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)C=C[C@@H](N)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)CC[C@@H](N)C1

Procedure:
A mixture of tert-butyl (1S,4S)-5-{[(1R,4S)-4-amino-1-ethylcyclopent-2-en-1-yl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.12 g, 6.32 mmol) and 5% palladium on carbon in methanol (35 ml) was stirred at room temperature under 48 psi of hydrogen for 21 hours. The reaction was filtered through celite and the filter cake washed with methanol. The filtrate and washings were concentrated under reduced pressure to give tert-butyl (1S,4S)-5-{[(1S,3R)-3-amino-1-ethylcyclopentyl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as a brown oil/foam (2.46 g, theoretical yield 2.13 g) which was used without further purification in the next step.