Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D83 starting from [4-(trifluoromethyl)phenyl]boronic acid and 4-bromobenzaldehyde. LC-MS (ESI): m/z 251 [M+H]+; 3.63 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:12][C:9]1[CH:8]=[C:4]([C:5]([N:16]2[C@@H:17]3[C@@H:22]([C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18]3)[CH2:13][CH2:14][CH2:15]2)=[O:7])[CH:3]=[C:2]([Cl:1])[C:10]=1[OH:11]
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1cc(Cl)c(O)c(Cl)c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 26 %

Procedure:
The title compound is prepared from 3,5-dichloro-4-hydroxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 26% of theory; LC (method 4): tR=2.03 min; Mass spectrum (ESI+): m/z=376/378/380 (2 Cl) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)c1cc(Cl)cn1N
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccc(F)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and 4-fluoro benzaldehyde in refluxing methanol for 12 h. ESI (m/z): 281 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([CH2:25][N+:26]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>CN(C=O)C.CC(O)(C)C.COCCOC.O>[C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([C:25]#[N:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: N#CC1CCCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 112 %

Procedure:
A mixture of hexahydro-1-(phenylmethyl)-4H-azepin-4-one (0.2 mol) and 4-toluene-sulfonylmethyl isocyanide (0.25 mol) in DMF (200 ml) was stirred at 0° C. A solution of potassium tert-butoxide (0.4 mol) in a mixture of 2-methyl-2-propanol (200 ml) and 1,2-dimethoxyethane (200 ml) was added dropwise at 0° C. The mixture was allowed to reach room temperature and stirring was continued for 1 hour. The mixture was stirred in water and this mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated, yielding 48 g of (±)-hexahydro-1-(phenylmethyl)-1H-azepine-4-carbonitrile (intermediate 1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Product: COc1cc2ncnc(Nc3nc4ccc([N+](=O)[O-])cc4s3)c2cc1OC

Procedure:
(6,7-Dimethoxyquinazolin-4-yl)-(6-nitrobenzothiazol-2-yl)amine was prepared from 2-amino-6-nitrobenzothiazole (Sigma-Aldrich, 976 mg, 5 mmol) and 4-chloro-6,7-di-methoxyquinazoline (Fluorochem, 1.12 g, 5 mmol) according to GP 1. After filtration, the residue was washed thoroughly with dioxane, water and methanol. After drying in vacuo, crude (6,7-dimethoxy-quinazolin-4-yl)-(6-nitrobenzothiazol-2-yl)amine was obtained as an ochre solid (2.25 g) which was used without further purification. LC/ESI-MS: m/z=384 [M+H]+; m/z=382 [M−H]−; Rt=3.67 min.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]1[C:27]2[C:28]3[C:33]([NH:34][C:26]=2[CH2:25][NH:24][CH2:23]1)=[CH:32][CH:31]=[CH:30][CH:29]=3>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:24]4[CH2:23][CH2:22][C:27]5[C:28]6[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=6)[NH:34][C:26]=5[CH2:25]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCc2c([nH]c3ccccc23)C1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and noreleagnine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=458.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])/[CH:12]=[CH:13]/[CH2:14][CH3:15])=[CH:4][CH:3]=1.[C:17]([CH2:19][C:20]([O:22]CC)=O)#[N:18].CC(C)([O-])C.[K+].O1CCCC1.Cl>C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:11](=[O:16])[CH2:12][CH:13]([CH2:14][CH3:15])[CH:19]([C:17]#[N:18])[C:20]2=[O:22])=[CH:6][CH:7]=1
Reactant: CC/C=C/C(=O)NCCc1ccc(F)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCC1CC(=O)N(CCc2ccc(F)cc2)C(=O)C1C#N
Temperature: 80 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
A solution of trans 2-pentenoic acid [2-(4-fluorophenyl)ethyl]amide (2.0 g, 9.05 mmol) and ethyl cyanoacetate (1.93 mL, 18.1 mmol) in tert-butanol (30 mL) was treated with a solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 18.1 mL, 18.1 mmol) and heated at 80° C. After 18 hours, the solution was cooled to room temperature and treated with 1.0 N aqueous hydrochloric acid. The mixture was concentrated under vacuum and the residue was recrystallized from ethanol to provide a pale pink solid (2.0 g, 77%). 1H NMR (300 MHz, CDCl3) δ7.19 (m, 2H), 7.00 (t, J=9 Hz, 2H), 4.01 (m, 2H), 3.50 (d, J=11 Hz, 1H), 2.97 (dd, J=17, 3 Hz, 1H), 2.83 (t, J=8 Hz, 2H), 2.4-2.2 (m, 2H), 1.88 (m, 1H), 1.44 (m, 1H), 1.02 (t, J=7 Hz, 3H). Mass spec (ES−) m/z 287.2 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
4-Chloroaniline (2.0 g) was dissolved in acetonitrile (20 ml), and ethyl bromoacetate (2.1 g) and potassium carbonate (2.2 g) were added to stir the mixture at 60° C. for 2 days. The reaction mixture was filtered through Celite pad, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel (hexane:chloroform=2:1) to obtain the title compound (2.3 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[CH3:21][N:19]([CH3:20])[C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:18][CH:13]([N:12]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[C:28](=[O:30])[CH3:29])[CH2:14][CH2:15]1
Reactant: CN(C)C1(c2ccccn2)CCC(NCCc2c[nH]c3ccccc23)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(CCc1c[nH]c2ccccc12)C1CCC(c2ccccn2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-yl cyclohexane-1,4-diamine (250 mg) was dissolved in dry pyridine (5 ml), acetic anhydride (0.64 ml) was added and the mixture was stirred for 22 hours at room temperature. Some ice was added to the reaction mixture and it was then concentrated to low volume. The residue was taken up in 1M sodium hydroxide solution (20 ml) and ethyl acetate (20 ml) and stirred. A white solid was left behind, which could be suction filtered (86 mg). The aqueous phase of the filtrate was extracted with ethyl acetate (2×20 ml). The combined organic extracts were concentrated to low volume after drying. The residue obtained in this way was identical to the solid obtained earlier. Both substances were combined. 219 mg N-(4-dimethylamino-4-pyridin-2-yl cyclohexyl)-N-[2-(1H-indol-3-yl)ethyl] acetamide were obtained (mp 209–210° C.), of which 195 mg were dissolved in 2-butanone (25 ml) with gentle heating to 40° C. and converted into the corresponding dihydrochloride with chlorotrimethyl silane (0.303 ml) (white solid; 219 mg; mp 244–247° C.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccc(F)cc1)OCC
Agent: Cl
Product: NCC(CP(O)O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 4.4 g of ethyl 3-amino-2-(4-fluorophenyl)propyl(diethoxymethyl)phosphinate in 40 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 2 h. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 20 ml of water under reduced pressure. The crude product is dissolved in 20 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-(4-fluorophenyl)propylphosphonous acid (1/3M H2O), m.p. 225°-235° C., 31P=+24.1 ppm (D2O).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](=[O:10])[CH2:8][Br:9])[O:4][N:3]=1.B.C1COCC1>>[Br:9][CH2:8][C@@H:7]([C:5]1[O:4][N:3]=[C:2]([Br:1])[CH:6]=1)[OH:10]
Reactant: O=C(CBr)c1cc(Br)no1
Agent: B
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1cc(Br)no1

Procedure:
The title compound was prepared from 3-bromo-5-(bromoacetyl)isoxazole (which was obtained in Example 118), (R)-2-methyl-CBS-oxaborolidine monohydrate, and 1 M BH3/THF solution in substantially the same manner, as described in Example 103 with one change; the crude product was purified by flash chromatography and reverse phase chromatography to give a colorless oil (1.45 g, 16% yield): 1H NMR (300 MHz, CDCl3) δ 3.67–3.81(m, 2H), 5.16. (m, 1H), 6.49 (s, 1H).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[C:21]([OH:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH2:24]>C(O)(=O)C>[C:21]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[N:24]1[C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:18][CH2:19][C:10]=2[CH:1]=[C:2]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([OH:30])=[O:29]
Reactant: O=C(CC1CCc2ccccc2C1=O)c1ccccc1
Reactant: Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1-n1c(-c2ccccc2)cc2c1-c1ccccc1CC2

Procedure:
A mixture of 20.0 g. (0.076 mole) of 2-phenacyl-1-tetralone, 9.86 g. (0.072 mole) of anthranilic acid, and 70 ml. of glacial acetic acid was heated under reflux for 501/2 hours and concentrated to an oil, which crystallized from isopropyl alcohol to provide 10.7 g. (41%) of solid, m.p. 170°-185°. Recrystallization from ethanol-water, isopropyl alcohol, and cyclohexane-methanol gave 4.0 g. of yellow crystals, m.p. 223.5°-224.5°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=O)[CH:26]=[N:27][C:28]=1[CH2:29][OH:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:31][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]2)[CH:26]=[N:27][C:28]=1[CH2:29][OH:30]
Reactant: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Reactant: O=Cc1cnc(CO)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cnc(CO)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-1,5-naphthyridin-2(1H)-one (Intermediate 21: 38.9 mg, 0.134 mmol) and 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 39: 23 mg, 0.134 mmol) in 1,2-Dichloroethane (2.5 ml) was stirred under N2 at room temperature for 1 h. Then, sodium triacetoxy borohydride (85 mg, 0.402 mmol) was added and the mixture was stirred at RT overnight. LCMS showed desired compound and imine. An excess of sodium triacetoxy borohydride (85 mg, 0.401 mmol) was added and the mixture was stirred at rt 6 h. LCMS showed desired compound and imine. An excess of sodium triacetoxy borohydride (85 mg, 0.401 mmol) was added. The mixture was stirred at room temperature overnight. LCMS showed desired compound and imine. An excess of sodium triacetoxy borohydride (85 mg, 0.401 mmol) was added and the mixture was stirred at room temperature overnight. LCMS did not show imine and showed desired compound. NaHCO3 sat. was added and the aqueous phase was extracted twice with DCM. The combined organic phases were washed with sat. NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Flash-Master chromatography on a 2 g silica gel cartridge using DCM/MeOH 95:5 as eluent to obtain two fractions. The first was 9 mg of white solid consistent with the desired compound by HNMR. The second was 4 mg white solid consistent with desired compound but not enough pure by HNMR and LCMS. This second fraction was discarded.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.[H-].[Na+].[C:20]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]>CN(C=O)C>[C:20]([C:22]1[CH:23]=[C:24]([S:28]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(S(=O)(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 300 mg, 1.37 mmol) at 0° C. in DMF (12 mL) is added 60% sodium hydride (82 mg, 2.06 mmol) and the mixture stirred for 10 min at 0° C. The reaction mixture is then warmed to room temperature and stirred for 30 min. 3-Cyanobenzenesulfonyl chloride (552 mg, 2.74 mmol) in DMF (2 mL) is added dropwise at 0° C. and the reaction is stirred at room temperature for 1 h. The reaction is quenched by adding water (1 mL). The resulting mixture is purified by HPLC X-bridge RP18 using acetonitrile-0.1% ammonia hydroxide as an eluent to yield 1-(3-cyano-benzenesulfonyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 7.11 (s, 1H), 7.54 (dd, J=7.8, 4.8 Hz, 1H), 7.66 (dd, J=8.1, 2.0 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.86 (dd, J=8.7, 1.6 Hz, 1H), 7.94 (t, J=1.5 Hz, 1H), 7.98 (dt, J=8.2, 2.0, 1.8 Hz, 1H), 8.16 (dd, J=7.6, 1.3 Hz, 1H), 8.19 (d, J=1.0 Hz, 1H), 8.34 (d, J=8.6 Hz, 1H), 8.67 (d, J=2.8 Hz, 1H), 8.71 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 385.0763 [(M+H)+ Calcd for C21H13N4O2S: 385.0759].
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28]O)=[CH:23][C:22]=3[F:30])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)[NH:54]C(=O)C2=CC=CC=C12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][NH2:54])=[CH:23][C:22]=3[F:30])[CH2:19][CH2:20]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CO)cc3F)CC2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CN)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 10-1 (30 mg, 0.07 mmol), triphenylphosphine (19 mg), phthalimide (11 mg) and DEAD (12 μL) in THF (1 mL) was stirred at room temperature for 3 days. The mixture was concentrated under a stream of nitrogen and combined with DCM (0.2 mL), ethanol (0.5 mL) and hydrazine (50 μL). The mixture was stirred at room temperature for 20 h, filtered and concentrated under a stream of nitrogen. The crude mixture was taken up with methanol and purified by preparative HPLC to afford 16a as a brown oil: LC-MS 408.2 (MH+-17).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([C:31]([O:33]C)=[O:32])[CH:25]=[CH:24]5)=[CH:17][CH:16]=3)=[C:11]([CH:35]([CH3:37])[CH3:36])[O:10][N:9]=2)=[C:6]([CH3:38])[CH:5]=[CH:4][N:3]=1.CO.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1[C:7]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]5)=[CH:17][CH:16]=3)=[C:11]([CH:35]([CH3:36])[CH3:37])[O:10][N:9]=2)=[C:6]([CH3:38])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(C)ccnc5C)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccnc(C)c1-c1noc(C(C)C)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 100 °C
Yield: 86.1 %

Procedure:
A solution of methyl 6-[4-({[3-(2,4-dimethyl-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (20 mg, 0.04 mmol) in THF (0.4 mL) was placed in a microwave reaction tube followed by methanol (0.20 mL) followed by a 1 N solution of sodium hydroxide (0.08 mL, 0.08 mmol). The tube was sealed and heated to 100° C. for 10 minutes. The solution was neutralized with 1 N HCl and concentrated. The residue was diluted with water and filtered. The resulting solid was dried with P2O5 in a 45° C. vacuum oven under reduced pressure to yield 6-[4-({[3-(2,4-dimethyl-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (17 mg, 86%). 1H NMR (400 MHz, DMSO-d6): δ 13.5-13.2 (br s, 1H), 8.53 (d, J=9 Hz, 1H), 8.38 (d, J=5 Hz, 1H), 8.27 (s, 1H), 8.17-8.08 (m, 3H), 7.74 (d, J=9 Hz, 2H), 7.22 (d, J=5 Hz, 1H), 7.22 (d, J=9 Hz, 2H), 4.79 (s, 2H), 3.47 (septet, J=7 Hz, 1H), 2.24 (s, 3H), 2.08 (s, 3H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 494 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].FC1C=C(C2C3CN(C([O:51][C:52](C)([CH3:54])[CH3:53])=O)CCC=3NN=2)C=CC=1F>>[F:27][C:25]1[CH:26]=[C:21]([C:13]2[C:14]3[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][C:19]=3[N:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:30])([CH3:31])[CH3:1])[C:4]([N:6]3[CH2:7][CH2:54][C@H:52]([OH:51])[CH2:53]3)=[O:5])=[O:10])[N:12]=2)[CH:22]=[CH:23][C:24]=1[F:28]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Product: CN1CCc2c(c(-c3ccc(F)c(F)c3)nn2C(=O)N[C@H](C(=O)N2CC[C@H](O)C2)C(C)(C)C)C1

Procedure:
Compound 47 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with intermediate 25. LCMS (+ESI) m/z=476.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1>[OH-].[Na+].C(O)C>[O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1ccc(N2CCOCC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
20.2 g (76.8 mmol) of ethyl [4-(3-oxomorpholin-4-yl)phenyl]acetate are dissolved in a solution of 3.37 g of sodium hydroxide in 40 ml of ethanol, and the reaction solution is stirred at room temperature for 18 hours. The reaction mixture is evaporated, and the residue is dissolved in water and acidified to a pH of 3 using 1N hydrochloric acid. The mixture is extracted with ethyl acetate, and the organic phase is dried over sodium sulfate and evaporated, giving 4-(3-oxomorpholin-4-yl)phenylacetic acid as a yellowish solid; ESI 236.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:37]I>CCOCC.CCOCC.CC#N>[I:37][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: II
Reactant: OCCCc1ccc(F)c(F)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: Fc1ccc(CCCI)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of 2.00 g (11.6 mmol) of 3-(3,4difluorophenyl)propanol (from EXAMPLE 199, Step A), 3.96 g (15.1 mmol) of triphenylphosphine and 1.03 g (15.1 mmol) of imidazole in 2:1 v/v ether/CH3CN at 0° C. was treated with 4.10 g (16.3 mmol) of iodine. The resulting mixture was warmed to rt and stirred for 1 h. The mixture was diluted with 200 mL ether, and washed with sat'd Na2S2O3 (2×30 mL) and sat'd CuSO4 (30 mL). The organic phase was dried over MgSO4 and concentrated. The residue was partially dissolved in ether and filtered to remove triphenylphosphine oxide. The filtrate was concentrated. Flash chromatography on silica gel using 4:1 v/v hexanes/EtOAc afforded 3.25 g (99%) of the title compound.
Reaction SMILES: Br.[NH+]1C=CC=CC=1.[Br:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][N:12]=[C:11]([O:17]C)[CH:10]=1>CN(C)C=O>[Br:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][NH:12][C:11](=[O:17])[CH:10]=1
Reactant: COc1cc(Br)c(OC)cn1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: COc1c[nH]c(=O)cc1Br
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2.82 g (176 mmol, 20 eq.) of pyridinium hydrobromide were added to a solution of 1.94 g (8.81 mmol) of 4-bromo-2,5-dimethoxypyridine in 80 ml of dimethylformamide, the mixture was stirred at 100° C. for 3 h and concentrated under reduced pressure. The residue was triturated with 50 ml of water, filtered off, washed with water and dried under reduced pressure. The filtrate was extracted twice with dichloromethane/methanol (10:1). The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield: 771 mg (43% of theory) and 465 mg (purity 88%, 23% of theory)