Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:12][CH2:13][CH3:14])(=[O:11])[C:8]#[C:9][CH3:10].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:28][N+:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:37][CH2:36]2)=[CH:31][C:30]=1[O:38][CH2:39][C:40]1[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=1[F:47].O>CN(C=O)C>[CH2:13]([O:12][C:7]([C:8]1[C:9]([CH3:10])=[N:28][N:29]2[C:30]([O:38][CH2:39][C:40]3[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=3[F:47])=[CH:31][C:32]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:34]=12)=[O:11])[CH3:14]
Reactant: N[n+]1ccc(C2CC2)cc1OCc1c(F)cccc1F
Reactant: CC#CC(=O)OCC
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
468 mg (3.4 mmol) of potassium carbonate were added to a mixture of 264 μl (2.3 mmol) of ethyl but-2-ynoate and 540 mg (1.1 mmol) of 1-amino-4-cyclopropyl-2-[(2,6-difluorobenzyl)oxy]pyridinium 2,4,6-trimethylbenzenesulphonate (Example 147A) in 10 ml of DMF. The reaction mixture was stirred at room temperature for 2 h and then poured into 25 ml of water precooled to 5° C. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:11]2[CH2:16][CH2:15][CH:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl>[C:17]([CH:14]1[CH2:15][CH2:16][CH:11]([C:5]2[CH:10]=[CH:9][C:8]([C:20](=[O:22])[CH3:21])=[CH:7][CH:6]=2)[CH2:12][CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)C1CCC(c2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(C2CCC(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a suspension of AlCl3 (5.9 g, 54 mmol) in DCM (200 mL) at 0° C. was added 1-(4-phenylcyclohexyl)ethanone (9 g in DCM), and acetyl chloride (10.4 mL, 146 mmol) dropwise over 30 min. The mixture was stirred to rt for 15 min. and heated at 45° C. for 4 h. After being cooled to rt, the mixture was poured it into ice-HCl (1N). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were combined, concentrated and purified on column (hexane:ethyl acetate, 8:2) to give 1-(4-(4-acetylcyclohexyl)phenyl)ethanone (A2) as a mixture of two isomers (5 g, 46% yield).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+].O>CO>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:10][CH3:9])[CH:7]=1
Reactant: C[O-]
Reactant: Fc1cc(I)ccn1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(I)ccn1
Yield: 95.4 %

Procedure:
500 ml of methanol was added to 59.4 g (253 mmol) of crude 2-fluoro-4-iodopyridine obtained in Step (b) so that it was dissolved in methanol, and 21.5 g (398 mmol) of sodium methoxide was added, followed by reflux with heating for 3 hours. 300 ml of water was added to terminate the reaction, and methanol was distilled off under reduced pressure. After extraction with ethyl ether, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 56.7 g (crude yield: 91%) of crude 4-iodo-2-methoxypyridine.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]C)=[O:9])[CH:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1>[OH-].[Na+]>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: COC(=O)C1CCC(C)=CC1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC1=CC(NC(=O)OC(C)(C)C)C(C(=O)O)CC1
Temperature: 50 °C
Yield: 73.7 %

Procedure:
5 g (18.6 mmol) of tert-butyl (3-methyl-6-carbomethoxy-2-cyclohexen-1-yl)-carbamate are introduced into 40 ml of 1N sodium hydroxide solution, and the mixture is stirred at 50° C. until a clear solution has formed. The solution is extracted once using diethyl ether, and a pH of 1 is then established at 0° C. using concentrated hydrochloric acid. After the mixture has been extracted using diethyl ether and evaporated, 3.5 g (74% of theory) of tert-butyl 3-methyl-6-carboxy -2-cyclohexen-1-yl-carbamate of melting point 132°-136° C. are obtained. ##STR77## (Process B/a)
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[S:32]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:38][CH2:37][C:34]1[CH:35]=[CH:36][S:32][CH:33]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1ccsc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccsc1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 35.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), thiophen-3-ylmethanamine (11.8 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(thiophen-3-ylmethyl)acetamide (12.9 mg, 0.025 mmol, 35.2% yield): LCMS=527.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.53 Hz), 7.52-7.76 (7 H, m), 7.26 (1 H, dd, J=5.02, 1.25 Hz), 6.85-7.01 (2 H, m), 5.16 (1 H, s), 4.60 (2 H, s); HPLC peak RT=3.0 min (Method E).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.P(Br)(Br)[Br:12]>C(Cl)(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([Br:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: BrP(Br)Br
Reactant: CC(O)c1cccc(F)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(Br)c1cccc(F)c1
Yield: 78.6 %

Procedure:
Dissolve (±)-1-(3-fluorophenyl)ethanol (250 mg, 1.786 mmol) in carbon tetrachloride (10 mL). Add phosphorus tribromide (0.1 mL, 1.786 mmol) at 0° C. and stir the solution at room temperature overnight. Dilute the reaction mixture with dichloromethane and wash with brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to obtain the title compound (285 mg) that was used without any further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH2:27]([P:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>C1(C)C=CC=CC=1>[Cl-:1].[CH2:36]([P+:31]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCP(CCCC)CCCC
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Solvent: Cc1ccccc1
Product: CCCC[P+](CCCC)(CCCC)Cc1ccc(NC(=O)/C=C/c2cccc(-c3ccc(C)cc3)c2)cc1
Product: [Cl-]
Temperature: 80 °C
Reaction time: 72 h

Procedure:
In toluene(10 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (300 mg), and to the mixture was added tributylphosphine (248 μl). The mixture was stirred at 80° C. for 3 days and cooled to room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give (E)tributyl[4-[3-(4-methylphenyl)cinnamamido]benzyl]phosphonium chloride (Compound 78) (389 mg) as colorless crystals.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1)(=O)=O.[F:13][C:14]1[CH:15]=[C:16]([NH:32][C:33]([C:35]2[C:36](=[O:48])[N:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:38]([CH3:41])[C:39]=2[CH3:40])=[O:34])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[F:13][C:14]1[CH:15]=[C:16]([NH:32][C:33]([C:35]2[C:36](=[O:48])[N:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:38]([CH3:41])[C:39]=2[CH3:40])=[O:34])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:5][CH2:6][CH2:7][CH2:8][C:9]3([OH:12])[CH2:11][CH2:10]3)=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.8 %

Procedure:
To a mixture of 3-(1-hydroxycyclopropyl)propyl methanesulfonate (240 mg, 1.2 mmol) and N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.62 mmol) in 5 mL of N,N-dimethylacetamide was added cesium carbonate (470 mg, 2.4 mmol). After stirring at rt for 12 hrs, then the mixture was warmed up to 40° C. and stirred for 6 hrs. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (40 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (5:1 (v/v) EtOAc/n-hexane) to afford the desired compound as a white solid (68 mg, 19%).
Reaction SMILES: [O:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])S(C(F)(F)F)(=O)=O.[CH3:16][O:17][C:18](=[O:25])[C:19](CO)([CH3:22])[CH2:20][OH:21]>ClCCl.N1C(C)=CC=CC=1C>[CH3:16][O:17][C:18](=[O:25])[C:19]([CH3:22])([O:1][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH2:20][O:21][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:1]
Reactant: COC(=O)C(C)(CO)CO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)C(C)(COS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
Add Tf2O (80 mL) dropwise to a cool solution (−78° C.) of 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid methyl ester (Preparation 5, 32.5 g) in dichloromethane (400 mL) and 2,6-lutidine (80 mL). Allow the reaction to reach room temperature. and stir for about 2 hours. Dilute with dichloromethane (400 mL) and wash with HCl (3% aqueous solution). Dry the organic layer over MgSO4, filter and concentrate. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate 5%, to give 2-methyl-2,3-bis-trifluoromethanesulfonyloxy-propionic acid methyl ester as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ ppm 4.7 (d, 2H, J=10.3 Hz), 4.5 (d, 2H, J=10.3 Hz), 3.8 (s, 3H), 1.4 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:32](OC(C)(C)C)=O)[NH:24]C(OC(C)(C)C)=O.[C:39]([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:32]([CH3:39])=[N:23][N:24]=3)[C:11]=2[CH:10]=[C:9]1[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2c(cc(-c3cncs3)n2Cc2ccccc2)n1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nnc2ccc3c(cc(-c4cncs4)n3Cc3ccccc3)n12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1-Benzyl-5-chloro-2-(1,3-thiazol-5-yl)-1H-pyrrolo[3,2-b]pyridine (67 mg, 0.20 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (72 mg, 0.31 mmol) and Cs2CO3 (100 mg, 0.31 mmol) were combined in toluene (7.2 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (16 mg, 0.020 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was stirred at 110° C. overnight, then was cooled, diluted with DCM, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes afforded intermediate di-tert-butyl 1-[1-benzyl-2-(1,3-thiazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate. This intermediate was heated in the microwave as a solution in AcOH (3.0 mL) to 180° C. for 6 minutes. AcOH was removed in vacuo, the residue was reconstituted, and the product was concentrated and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (12.5 mg, 18%).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[C:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>C(O)(=O)C.[Zn]>[C:13]1(=[CH:12][C:11]2[CH:2]=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Clc1nc2ccccc2cc1C=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: C(=C1CCCC1)c1cnc2ccccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 2-chloro-3-cyclopentylidenemethylquinoline (7.6 g, 31.3 mmol) in glacial acetic acid (80 ml) at 60° C. was treated with zinc powder (4.0 g, 62.6 mmol). After stirring at 60° C. for 3 hours, the reaction mixture was cooled and then treated dropwise with aqueous sodium hydroxide solution (2M, 330 ml); the temperature being kept below 20° C. throughout. The resulting mixture was then extracted with ethyl acetate (2×250 ml). The combined organic extracts were dried over sodium sulphate then concentrated in vacuo (30° C., 14 mmHg) to give a crude red oil (8 g) which was extracted with hot pentane (2×200 ml). Concentration of the combined extracts in vacuo (20° C.; 14 mmHg) afforded 3-cyclopentylidenemethylquinoline (4 g, 31 mmol) which was used without further purification;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12].O.O.[Sn](Cl)Cl>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12])[NH2:8]
Reactant: Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cc(N)cc1Cl
Yield: 79.9 %

Procedure:
Dissolve 1,3-dichloro-2-methyl-5-nitrobenzene (0.50 g, 2.43 mmol) in DMF and treat with tin (II) chloride dihydrate (2.74 g, 12.1 mmol) in a single portion. Stir the reaction for 1 hour, dilute with ethyl acetate, and filter through celite. Wash the filtrate four times with water and twice with brine, dry over MgSO4, filter and concentrate to a dark oil. Purify the residue by silica gel chromatography eluting with a gradient of 5% to 10% ethyl acetate in hexanes to give 342 mg (80%) of the titled product as white flakes.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][N:25]=2)=[O:34])=[O:8])[N:6]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2n[nH]c3ccccc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 1H-Indazole-3-carboxylic acid. LC-MS (basic): tR=0.77 min; [M+H]+=477.3.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[F:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[F:12][C:6]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1cccc(F)c1F
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1cccc(F)c1F
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A solution of 2-bromo-1-(2,3-difluorophenyl)ethanone (7.20 g, 30.6 mmol) and potassium thiocyanate (3.01 g, 30.6 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (85 ml) was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 5.67 g (86.8%) of the desired product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[Cl:27][C:23]1[CH:22]=[C:21]([C@@H:19]([OH:20])[CH2:18][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:30])=[CH:3][CH:4]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CNc1ccc(CCN(C[C@H](O)c2cccc(Cl)c2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a solution of tert-butyl [2-(4-aminophenyl)-ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (1.75 g) and formaldehyde (37% w/w solution in water, 390 μl) in 1,2-dichloroethane (20 ml) was added sodium triacetoxyborohydride (1.23 g), and the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. The resulting mixture was poured into a mixture of 1N sodium hydroxide and chloroform, and the mixture was stirred for 20 minutes. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl](2-[4-(methylamino)phenyl]ethyl]carbamate (550 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.Cl.[CH2:14]([NH:21][C:22]1[C:23]([NH2:29])=[CH:24][CH:25]=[C:26]([F:28])[CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:30](N(CC)CC)C>C(Cl)Cl>[CH2:14]([NH:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:10]([C:4]1[CH:5]=[C:6]([CH3:9])[C:7](=[CH2:30])[N:2]([CH3:1])[CH:3]=1)=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(F)cc1NCc1ccccc1
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: C=C1C(C)=CC(C(=O)Nc2ccc(F)cc2NCc2ccccc2)=CN1C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl chloride D1′ (100.000 mg; 0.598 mmol) in dry DCM (2.000 ml) is added dropwise to a solution of N2-benzyl-4-fluoro-benzene-1,2-diamine hydrochloride E-1.4 (151.180 mg; 0.598 mmol) in DCM (2.000 ml) and triethylamin (0.249 ml; 1.795 mmol). The mixture is stirred for 1 h. Precipitation occurs; the residue is filtered off and washed with DCM (2 ml). The precipitate is then dried under vacuum (Yield: 85%, 186 mg; 0.509 mmol)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][CH:36]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([CH:34]=[CH:33][CH:32]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1cccc(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3cccc(Cl)c3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-chlorophenol: ESMS m/e: 509.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]C(C2C=CC(C3C=CC(F)=CC=3)=CC=2)=O)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[C:30]([O:34][C:35](=[O:38])[NH:36][NH2:37])([CH3:33])([CH3:32])[CH3:31]>C(O)C.C(OCC)(=O)C>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:37][NH:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])=[C:3]([N+:27]([O-:29])=[O:28])[CH:4]=1)(=[O:9])=[O:10]
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A solution of Example 1D (212 mg, 0.49 mmol) and tert-butylcarbazate (976 mg, 2.3 mmol) in ethanol (5 mL) was heated to reflux, stirred for 16 hours, diluted with ethyl acetate (50 mL), washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:0.5:98.5/methanol:acetic acid:dichloromethane, then 2:0.5:97.5/methanol:acetic acid:dichloromethane to provide the desired product. MS (ESI(−)) m/e 331 (M−H)−.
Reaction SMILES: [CH2:1]([O:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:19])[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][CH3:16].[CH2:27]([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:27]([O:35][C:36]1[CH:37]=[CH:38][C:39]([C:40]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH:18]([O:17][CH2:1][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][CH3:16])[CH3:19])=[CH:21][CH:22]=2)=[O:41])=[CH:43][CH:44]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCOC(C)c1ccc(O)cc1
Product: CCCCCCCCCCCCCCCCOC(C)c1ccc(OC(=O)c2ccc(OCCCCCCCC)cc2)cc1

Procedure:
The procedure of Example 26 was followed except for use of (+)-4-(1-hexadecyloxyethyl)phenol in place of (+)-4-(1-methoxyethyl)phenol and 4-octyloxybenzoic acid chloride in place of 4'-octyloxy-4-biphenylcarboxylic acid chloride to obtain (+)-4-(1-hexadecyloxyethyl)phenyl 4-octyloxy-benzoate. [α]D20 =+35.9° (c=1, CHCl3).