Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH:10]([CH2:23][OH:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH:10]([CH2:23][O:24][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc3ccccc32)C(CO)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3ccccc32)C(CO[Si](C)(C)C(C)(C)C)C1
Yield: 100.9 %

Procedure:
Dissolve 3-Hydroxymethyl-4-indol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.3 mmol) in dichloromethane (20 ml). Add imidazole (340 mg, 5.0 mmol) and tert-butyldimethylsilyl chloride (754 mg, 5.0 mmol) and stir at ambient temperature for 72 hours. Dilute with dichloromethane, wash with 1N HCl, water, brine. Dry with sodium sulfate, filter, and concentrate to an oil. Purify by flash chromatography (10% ethyl acetate:hexanes) to yield the title compound (1.48 g, 100%). ES (M++1): 389.2
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)NO
Reactant: O=Cc1cccc(F)c1O
Product: CC(C)(C)[N+]([O-])=Cc1cccc(F)c1O

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 3-fluoro-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 92.7% yield as a yellow crystalline solid, m.p. 70.3° C. (Rf=0.25 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>>[N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:19][CH:21]2[O:23][CH2:22]2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: Oc1ccccc1-n1cccc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-n2cccc2)c(OCC2CO2)c1
Reaction time: 6 h

Procedure:
95.7 g of o-(pyrrol-1-yl)-phenol, 245 g of potassium carbonate and 167 g of epichlorohydrin are heated to the boil in a nitrogen atmosphere, whilst stirring. After 6 hours, the reaction mixture is cooled and filtered and the filtrate is evaporated in vacuo, ultimately at a bath temperature of 120° C. The oil which remains is dissolved in 300 ml of ether and the solution is extracted with 300 ml of 2 N sodium hydroxide solution and washed with 100 ml of water. The oil which remains after evaporating off the solvent is distilled in a high vacuum and gives 1-[o-(pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane of boiling point 103°-105° C/0.001 mm Hg.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Cl:9][C:10]1[C:16]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:15][C:13]([NH2:14])=[C:12]([F:23])[CH:11]=1>C(OCC)(=O)C>[Cl:9][C:10]1[C:16]([C:17]([O:19][CH:20]([CH3:21])[CH3:22])=[O:18])=[CH:15][C:13]([N:14]=[C:2]=[O:3])=[C:12]([F:23])[CH:11]=1
Reactant: CC(C)OC(=O)c1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Temperature: 0 °C
Yield: 133.3 %

Procedure:
5.4 ml (0.045 mol) of trichloromethyl chloroformate were added to 30 ml of ethyl acetate. The resulting solution was cooled to 0° C. A solution of 13.9 g (0.06 mol) of 4-chloro-2-fluoro-5-isopropoxycarbonylaniline in 25 ml of ethyl acetate were added dropwise to the above cooled solution over a period of 15 minutes. The mixture was stirred at a temperature of 0° to 10° C. for an hour, and then refluxed for two hours. The reaction mixture was concentrated to give 15.45 g (yield 99.9%) of the desired product as nearly white crystals with a melting point of 41°-43° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(CC)CC.[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CCOC(C)=O>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of morpholine (12.04 g, 0.14 mol) and Et3N (13.97 g, 0.14 mol) in EtOAc was added 3,4-difluoronitrobenzene (20.0 g, 0.13 mol) dropwise in an ice bath. The reaction mixture was warmed to rt slowly, stirred at rt overnight, and then filtered. The filter cake was washed with water, dried in vacuo to obtain the 1st crop of product. The organic phase was separated from the filtrate, and the water phase was washed with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the 2nd crop of product. The solids of 1st crop and 2nd crop were combined to give the title compound as a yellow solid (28.0 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10](O)=[O:11].[Cl:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:27]=1[C:21]1([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:20][CH:19]2[CH2:28][C:29]([O:31]CC)=[O:30]>>[Cl:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:27]=1[C:21]1([CH2:22][CH2:23][N:24]([C:10](=[O:11])[CH2:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:25][CH2:26]1)[CH2:20][CH:19]2[CH2:28][C:29]([OH:31])=[O:30]
Reactant: O=C(O)CCc1ccccc1Cl
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Product: O=C(O)CC1CC2(CCN(C(=O)CCc3ccccc3Cl)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-chlorophenyl)propanoic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate followed by a procedure analogous to that in Example 2. LC-MS Method 1 tR=1.87, min, m/z=446
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH2:21]>CO>[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]1[O:22][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:11]([O-:13])=[O:12])[N:21]=1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CCCC(N)=O
Solvent: CO
Product: COC(=O)CCCc1nc(-c2ccccc2[N+](=O)[O-])co1

Procedure:
Combine 2-bromo-2′-nitroacetophenone (10.4 g, 42.6 mmol) with 4-carbamoyl-butyric acid methyl ester (12.2 g, 84.1 mmol) and heat the neat mixture in a sealed vessel at 120-150° C. for about 4-6 h. Cool the mixture, transfer to a round bottom flask with methanol and concentrate. Partition the residue between water and EtOAc. Dry the combined EtOAc extracts over Na2SO4 and concentrate. Initial chromatography over silica gel (EtOAc/CH2Cl2) followed by a second chromatography over silica gel (Hex/EtOAc) allowed for recovery of 4-[4-(2-nitro-phenyl)-oxazol-2-yl]-butyric acid methyl ester (3.05 g, 25%). MS (ES): (M+1)+ 291.1, 292.2 m/z.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][C:4]([CH3:7])=[C:3]1[CH:8]=[CH:9][C:10](=[O:13])[CH2:11][CH3:12].[OH:15]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:15][C:4]1([CH3:7])[CH2:5][CH2:6][C:2]([CH3:1])([CH3:14])[CH:3]1[CH:8]=[CH:9][CH:10]([OH:13])[CH2:11][CH3:12]
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Reactant: CCC(=O)C=CC1=C(C)CCC1(C)C
Product: CCC(O)C=CC1C(C)(C)CCC1(C)O

Procedure:
The entitled compound was obtained from 1-(2,2,5-trimethylcyclopent-5-enyl)pent-1-en-3-one in the same manner as in Example 1-(4), (5), and (6).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([N:5]([CH2:11][CH:12]=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH3:4].[CH2:14]([NH:21][CH2:22]C(O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1>[CH2:14]([N:21]1[CH2:22][CH2:1][CH:2]2[CH:12]1[CH2:11][N:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH:3]2[CH3:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CC(C)N(CC=O)C(=O)OCC
Reactant: O=C(O)CNCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2C(CCN2Cc2ccccc2)C1C

Procedure:
11.6 g (62.6 mmol) of ethyl N-(1-buten-3-yl)-N -(2-oxoethyl)-carbamate and 10.4 g (62.6 mmol) of N -benzylglycine in 170 ml of toluene are heated under reflux overnight in a water separator. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[C:22](C=O)=[C:21]([F:25])[C:20]([F:26])=[C:19]([F:27])[C:18]=1[F:28]>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:22]2[C:21]([F:25])=[C:20]([F:26])[C:19]([F:27])=[C:18]([F:28])[C:17]=2[F:16])[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2c(F)c(F)c(F)c(F)c2F)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 3.4 mL of pentafluorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 176°-178° C.). 1H NMR (CDCl3) δ 2.89 (dd, 1 H), 3.15 (dd, 1 H), 3.70 (dd, 2 H), 6.02 (dd, 1 H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:4]1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29]O.CCN(CC)CC>>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][N:3]([CH3:2])[CH2:4]2)=[CH:16][CH:15]=1
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCCC(COc2ccc(NC=C3C(=O)Nc4ccc(F)cc43)cc2)C1
Yield: 77.2 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine hydrochloride (688 mg, 1.2 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.23 mmol, 1 equiv.) with the addition of anhydrous Et3N (2.25 equiv.) are reacted to give the named compound as a yellow solid (657 mg, 77%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C@@H:22]([CH2:25][CH3:26])[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:23])[CH2:25][CH3:26])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[C@H](C)CO
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A 0° C. solution of (R)-Methyl 2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetate (2.8 g, 10 mmol), (S)-2-methyl-1-butanol (1.1 mL, 10 mmol), triphenylphosphine (2.6 g, 10 mmol), and tetrahydrofuran (100 mL) was treated dropwise with diisopropylazodicarboxylate (1.9 mL, 10 mmol) via syringe. The resulting reaction mixture was allowed to warm to room temperature and maintained overnight. The reaction was concentrated and the residue was purified by column chromatography on silica gel (5%→10% ethyl acetate in hexanes) to afford (2R)-methyl 2-(tert-butoxycarbonylamino)-(4-((S)-2-methyl-butoxy)-phenyl)acetate (2.8 g, 80% yield) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J=7.3 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 5.49 (d, J=6.6 Hz, 1H), 5.26 (d, J=7.3 Hz, 1H), 3.81 (dd, J=9.1, 6.1 Hz, 1H), 3.73 (s, 3H), 3.69-3.76 (m, 1H), 1.86 (dq, J=13.1, 6.5 Hz, 1H), 1.52-1.61 (m, 1H), 1.45 (s, 9H), 1.22-1.33 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 352.2 [(M+H)+, calcd for C19H30NO5 352.5].
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:4]2[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=2)=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Cc1ccoc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccc(Br)cc2)oc1C
Yield: 41.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using commercial 2,3-dimethylfuran (5.00 g, 52.0 mmol), commercial 4-bromobenzylbromide (13.0 g, 52.0 mmol) and 2.5M n-BuLi/hexanes (20.8 mL, 52.0 mmol) in THF. Purification on Biotage KP-Sil eluting with 1% EtOAc/pet. ether gave 5.72 g (41%) of the title compound. 1H NMR (DMSO-d6) δ1.84 (s, 3H), 2.09 (s, 3H), 3.83 (s, 2H), 5.87 (s, 1H), 7.17 (d, 2H), 7.49 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([CH3:18])[C:16](I)=[C:12]3[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][OH:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:16]2[C:15]([CH3:18])=[N:14][N:13]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][OH:25])=[N:11][C:12]=23)=[CH:30][CH:29]=1
Reactant: Cc1nn2c(-c3ccc(F)cc3)cc(N3CCC[C@H]3CO)nc2c1I
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C)nn3c(-c4ccc(F)cc4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
(S)-(1-(7-(4-Fluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (56 mg), 4-methoxyphenylboronic acid (30 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (10 mL), ethanol (5 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight at 90° C. under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (27 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH:33]([CH3:35])[CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:36](Cl)([Cl:38])=[O:37]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:36]([Cl:38])=[O:37])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH:33]([CH3:35])[CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([O:13][C:14](=O)[C:15]([C:27]#[N:28])=[CH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[O:25][CH3:26])C>>[C:27]([CH:15]1[C:16]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[O:25][CH3:26])=[C:10]2[C:2](=[C:3]3[CH:4]=[CH:5][N:6]=[C:7]3[CH:8]=[CH:9]2)[O:1][C:14]1=[O:13])#[N:28]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)ccc1OC
Product: COc1ccc(OC)c(C2=c3ccc4c(c3OC(=O)C2C#N)C=CN=4)c1
Yield: 2.6 %

Procedure:
The title compound was prepared from 4-hydroxyindole and 3-(2,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 2.6% yield. 1H NMR (CDCl3): 8.64 (s, 1H), 7.33-7.31 (m, 1H), 7.29-7.24 (m, 1H), 7.10-7.01 (m, 4H), 6.83-6.82 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1(C(OCC)=O)[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6]1C(=O)C)[CH3:2].[BrH:27]>CC(O)=O>[BrH:27].[OH:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][NH:6][C@@H:5]2[C:4]([O:3][CH2:1][CH3:2])=[O:26])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1(C(=O)OCC)C(c2ccc(OC)cc2)CCN1C(C)=O
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1NCCC1c1ccc(O)cc1

Procedure:
A solution of N-acetyl-2-ethoxycarbonyl-3-(4-methoxyphenyl)proline ethyl ester (10 g, 27 mmol) in aqueous HBr (48%, 40 mL) and HOAc (10 mL) was heated at 120° C. under a nitrogen atmosphere overnight. The reaction mixture was concentrated in vacuo, and the residue was azeotroped with acetonitrile (2×) and Et2O/toluene (1×) to yield 3-(4-hydroxyphenyl)proline, ethyl ester hydrobromide as a mixture of diastereomers.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: NCCCOCCO
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCCOCCO)ccc21
Yield: 40.1 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [3-(2-hydroxy-ethoxy)-propyl]-amide (41 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (82 mg), 2-(3-amino-propoxy)-ethanol (49 mg), HBTU (91 mg), and DIEA (52 uL). LC/MS: m/z 509.8.
Reaction SMILES: ClCCCCO[C:7]1[C:12]2[C:13]([CH2:20][CH3:21])([CH2:18][CH3:19])[O:14][C:15](=[O:17])[NH:16][C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([S:28][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH2:18][CH3:19])([CH2:20][CH3:21])[C:12]=3[CH:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Sc1ccccc1
Reactant: CCC1(CC)OC(=O)Nc2cccc(OCCCCCl)c21
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccccc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy-4,4-diethyl-4H-3,1-benzoxazin-2-one and thiophenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH:23]=[CH:27][CH:26]=[CH:25]2)[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: Nc1cc(F)cc2c1OC(COC1CCCCO1)CC2
Reactant: COC1CCC(OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Fc1cc2c(c(-n3cccc3)c1)OC(COC1CCCCO1)CC2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
A mixture of intermediate 16-b (0.036 mol), 2,5-dimethoxytetrahydrofuran (0.22 mol) and PTSA (catalytic quantity) in DMF (140 ml) was stirred for 90 min at 100° C. The solvent was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed once with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2). The pure fractions were collected and the solvent was evaporated, yielding 6.6 g (55.3%) of (±)-6-fluoro-3,4-dihydro-8-(1H-pyrrol-1-yl)-2-[[(tetrahydro-2H-pyran-2-yl)oxy]-methyl]-2H-1-benzopyran (interm. 17-b).
Reaction SMILES: [C:1]([N:4]1[C@H:12]([C:13]([O-:15])=O)[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2].C([N:44]1[C@H:52]([C:53]([O-:55])=[O:54])CC(=O)C2C=CC=CC=2N(CC2C=CC=CC=2)C(=O)[C@H]1CC12CC3CC(CC(C3)C1)C2)(=O)C>>[C:1]([N:4]1[C@H:12]([C:13]([NH:44][CH2:52][C:53]([OH:55])=[O:54])=[O:15])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2Cl)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2Cl)c2ccccc2C(=O)C[C@H]1C(=O)NCC(=O)O

Procedure:
The compound was prepared by an identical route to that used to prepare example 22 except that (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-(2-chlorobenzyl)-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate was used in step a in place of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(=O)=O.[CH3:43][C@H:44]1[O:49][C@@H:48]([CH3:50])[CH2:47][NH:46][CH2:45]1.[I-].[Na+]>O1CCCC1>[CH3:50][C@H:48]1[O:49][C@@H:44]([CH3:43])[CH2:45][N:46]([CH2:6][CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:47]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCOS(C)(=O)=O)CC2)c2ncnn12
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCN3C[C@@H](C)O[C@@H](C)C3)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethyl methanesulfonate (0.3 g), cis-2,6-dimethylmorpholine (1.2 g), sodium iodide (0.015 g) and tetrahydrofuran (10 mL) was stirred at 70° C. for 5 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.3 g, 96%).