Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH:14]2[C:26]([NH2:28])=[O:27])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[C:26]([NH2:28])=[O:27])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: NC(=O)C1CN(Cc2ccccc2)CCN1CCCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1CNCCN1CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 76.3 %

Procedure:
A solution of 56.9 parts of 1-[5,5-bis(4-fluorophenyl)-4-pentenyl]-4-(phenylmethyl)-2-piperazinecarboxamide in 400 parts of methanol was hydrogenated in a Parr apparatus and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in 2-propanone and the whole was acidified with a mixture of hydrochloric acid and 2-propanol. After the addition of 2,2'-oxybispropane, the supernatant liquid was decanted and the precipitate was stirred in 2,2'-oxybispropane. The precipitated product was filtered off and dissolved in water. After washing with 2,2'-oxybispropane, the aqueous layer was treated with ammonium hydroxide and the product was extracted with trichloromethane. The extract was washed with a sodium chloride solution, dried, filtered and evaporated (under trichloromethane), yielding 35.2 parts (76.3%) of 1-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide as a residue (int. 34).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]2[N:37]=[CH:36][C:35](O)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]2[N:37]=[CH:36][C:35]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=3)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: COc1ccc(COc2ccc(O)cn2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(COc2ccc(OCCN(CC(F)(F)F)c3ccc(C#N)c(C(F)(F)F)c3)cn2)cc1

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 6-({[4-(methyloxy)phenyl]methyl}oxy)-3-pyridinol (step B above) with the following exceptions: PPh3 was used instead of PBu3, and the reaction was started at 0° C., then allowed to proceed at rt: 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=3.3 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.37 (m, 2H; AA′XX′), 7.18 (d, J=2.7 Hz, 1H), 7.15 (dd, J=8.9, 3.1 Hz, 1H), 7.00 (dd, J=8.9, 2.7 Hz, 1H), 6.90 (m, 2H; AA′XX′), 6.72 (d, J=8.9 Hz, 1H), 5.23 (s, 2H), 4.20 (t, J=5.1 Hz, 2H; overlapping 4.19), 4.19 (q, J=8.6 Hz, 2H; overlapping 4.20), 3.99 (t, J=5.2 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:28]=1)[CH:24]=O>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:28]=1)[CH2:24][N:1]1[CH:2]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]1=[O:8]
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cc(Cl)cc(-c2ccccn2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc(Cl)cc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 3-chloro-5-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 437.10 g/mol.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:11]1
Reactant: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Yield: 78.5 %

Procedure:
Dissolve 3-{4-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (924 μmol, 500 mg) in dichloromethane (10 mL), add trifluoroacetic acid (5 mL), and stir the reaction at room temperature for 2 h. Concentrate the material in vacuo and partition the residue between 1N NaOH (10 mL) and CH2Cl2 (15 mL). Separate the organic portion and extract the aqueous portion with CH2Cl2 (3×10 mL). Dry the combined organics over Na2SO4, filter, and concentrate to dryness to afford 320 mg of 6-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[Cl:10].[OH:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:15]=[CH:16][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:11][C:12]2[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:15]=[CH:16][CH:17]=2)=[CH:4][C:3]=1[Cl:10]
Reactant: Clc1cc(CBr)ccc1Br
Reactant: COC(=O)CCc1cccc(O)c1
Product: COC(=O)CCc1cccc(OCc2ccc(Br)c(Cl)c2)c1

Procedure:
Compound 39.3 was synthesized using the procedure described above for preparing 1.1 using 1-bromo-4-(bromomethyl)-2-chlorobenzene 39.1 (available from Metina AB) and methyl 3-(3-hydroxyphenyl)propanoate 39.2 (available from Aagile Labs Division of Tyger Scientific). 1H NMR (400 MHz, CDCl3) δ ppm 7.63 (1H, d, J=8.2 Hz), 7.55 (1H, d, J=2.0 Hz), 7.17-7.24 (2H, m), 6.78-6.85 (3H, m), 4.99 (2H, s), 3.68 (3H, s) 2.94 (2H, t, J=7.8 Hz), 2.64 (2H, t, J=7.8 Hz).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][N:10]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25](=[O:27])[CH3:26])[CH2:20][CH2:19]1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].O>CS(C)=O>[CH3:9][N:10]([CH:18]1[CH2:19][CH2:20][N:21]([CH2:24][C:25]2([CH3:2])[CH2:26][O:27]2)[CH2:22][CH2:23]1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15]
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)CN1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(CC2(C)CO2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
Trimethylsulfoxonium iodide (1.96 g, 8.89 mmol) was gradually added to a suspension of sodium hydride (372 mg, 9.32 mmol) in dimethylsulfoxide (20 ml), and the mixture was stirred at room temperature for 1.5 hours. To which a solution of tert-butyl N-methyl-[1-(2-oxopropyl)piperidin-4-yl]carbamate (2.3 g, 8.5 mmol) in dimethylsulfoxide (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into iced water, and extracted with diethyl ether. The extract was washed with a saturated saline solution, dried over magnesium sulfate, and then filtered. The resultant filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl N-methyl-[1-(2-methyl-2-oxiranylmethyl)piperidin-4-yl]carbamate (2.1 g, yield 86%) as a light yellow oily material.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.[N+:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)([O-:41])=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(Cl)Cl>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:17]3[N:18]=[C:19]4[C:11]([C:9]([NH:8][CH:6]([C@H:4]5[CH2:3][C@H:2]([O:1][C:46](=[O:47])[C:45]6[CH:44]=[CH:43][C:42]([N+:39]([O-:41])=[O:40])=[CH:50][CH:49]=6)[CH2:5]5)[CH3:7])=[O:10])=[CH:12][N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:14]4=[N:15][CH:16]=3)=[N:21][N:22]2[CH3:30])=[CH:27][CH:26]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide (200 mg, 0.37 mmol) in THF (4 mL) was added 4-nitrobenzoic acid (124 mg, 0.74 mmol) and triphenylphosphine (204 mg, 0.78 mmol). Then the reaction mixture was cooled to 0° C. and diethyl azodicarboxylate (123 μL, 0.78 mmol) was added dropwise. The reaction was stirred at room temperature overnight then diluted with CH2Cl2 (25 mL) and washed with 1.0 M aqueous NaOH. The aqueous phase was back-extracted with CH2Cl2 then the combined organics were dried over MgSO4 and concentrated. The residue was absorbed onto SiO2 and purified via chromatography with 20% to 80% EtOAc/hexanes to provide 250 mg (98%) of 4-nitrobenzoic acid trans-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Sc1ncccn1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ncc(Sc2ncccn2)s1
Temperature: 150 °C
Yield: 60.2 %

Procedure:
A mixture of 2-acetamido-5-chlorothiazole (14.3 g), 2-mercaptopyrimidine (10 g) and potassium carbonate anhydrous (22.4 g) in N,N-dimethylformamide (280 ml) was stirred at 150° C. an hour. The reaction mixture was poured into water with stirring under ice cooling. The mixture was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to give solid. The solid was triturated with water, and the precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetamido-5-(2-pyrimidinylthio)thiazole (12.30 g, yield: 60.2%). mp: 225° C. (dec.) IR (Nujol): 3170, 1645, 1555, 1310 cm-1
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[CH:7]=[CH:8][C:9]2([CH2:22]/1)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)C.[CH:24]([NH:27][NH2:28])([CH3:26])[CH3:25].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:24]([N:27]1[C:6]2[CH:7]=[CH:8][C:9]3([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]3)[CH2:22][C:5]=2[CH:4]=[N:28]1)([CH3:26])[CH3:25]
Reactant: CN(C)/C=C1\CC2(C=CC1=O)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)NN
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)n1ncc2c1C=CC1(CCN(C(=O)OC(C)(C)C)CC1)C2
Temperature: 25 °C
Yield: 98.5 %

Procedure:
(E)-tert-Butyl 10-((dimethylamino)methylene)-9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (107 g) was taken up in toluene (700 mL) and isopropyl hydrazine (44.4 g) was added. The reaction was stirred at reflux for 4 hours. The reaction was cooled to room temperature and ethyl acetate was added (500 mL). The reaction solution was washed with citric acid (2×300 mL, 10% aqueous), and water (400 mL). The organic layer concentrated in vacuo to afford tert-butyl 1-isopropyl-1,4-dihydrospiro[indazole-5,4′-piperidine]-1′-carboxylate as a yellow solid (109 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.25 (s, 1H) 6.42 (dd, J=10.05, 0.49 Hz, 1H) 5.84 (d, J=9.95 Hz, 1H) 4.42-4.52 (m, 1H) 3.36-3.53 (m, 4H) 2.62 (s, 2H) 1.56-1.68 (m, 2H) 1.45-1.55 (m, 17H).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:24]([N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCI
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of trans-4-hydroxy-L-proline, methyl ester, hydrochloride (4.0 g, 22.02 mmol) and 1-iodododecane (3.04 g, 44.04 mmol) in methanol (30 ml) was treated with potassium carbonate. The mixture was stirred and refluxed for 7 h, cooled to r.t., diluted with ethyl acetate (700 ml), washed with water (400 ml), brine (200 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (petroleum ether/ethyl acetate 60:40 to 40:60) to afford the title compound (3.72 g, 54%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C@@:9]12[C@H:18]3[CH2:19][CH2:20][C@:21]4([CH3:32])[C:25]([C:26]5[CH:27]=[CH:28][CH:29]=[N:30][CH:31]=5)=[CH:24][CH2:23][C@H:22]4[C@@H:17]3[CH2:16][CH:15]=[C:14]1[CH2:13][C@@H](O)C[CH2:10]2.CO.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:6][C:5]([O:4][C@@H:1]1[CH2:13][C:14]2[C@@:9]([CH3:10])([C@@H:18]3[C@@H:17]([CH2:16][CH:15]=2)[C@@H:22]2[CH2:23][CH:24]=[C:25]([C:26]4[CH:27]=[CH:28][CH:29]=[N:30][CH:31]=4)[C@@:21]2([CH3:32])[CH2:20][CH2:19]3)[CH2:8][CH2:2]1)=[O:7]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (70 g) is added to a suspension of Abiraterone (16 g) in ethyl acetate (48 mL) The mixture is heated to 70° C. until the reaction is complete (about 20 h); the temperature is then reduced to about 50° C. and methanol (28 mL) is added. The resulting mixture is maintained under stirring for 2 h, cooled to room temperature, and ethyl acetate (110 mL) and an aqueous solution of sodium carbonate (450 mL) are added. The phases are separated and the organic phase is treated with decolourising carbon. The organic phase is then concentrated under vacuum and the concentrate is taken up with acetonitrile (about 80 mL) to obtain a sandy solid, which is isolated by filtration (at 0-5° C.) and dried under vacuum at 40° C. for 8 h (about 15 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:14]([CH3:15])=[C:13]([O:16][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Yield: 93.8 %

Procedure:
To a mixture of 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester (8.0 g, 34.2 mmol) and potassium carbonate (9.45 g, 68.4 mmol) was added benzyl bromide (4.5 mL, 37.6 mmol) in acetone (100 mL). The resulting mixture was vigorously stirred at reflux for 10 hours under a nitrogen atmosphere. The mixture was cooled, then filtered, and concentrated in vacuo to give 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (10.4 g, 94%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]([C@H:38]2[CH2:43][CH2:42][C@H:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:40][CH2:39]2)[N:25]=1.[F-].[K+].O>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.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:24]([CH3:23])=[N:25][N:26]([C@H:38]4[CH2:39][CH2:40][C@H:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42][CH2:43]4)[CH:27]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)c(C)n2)CC1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](n2cc(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c(C)n2)CC1

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (57.8 mg, 0.150 mmol), ethyl trans-4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (60.0 mg, 0.166 mmol), Pd(PPh3)4 (8.70 mg, 0.00753 mmol), potassium fluoride (26.2 mg, 0.452 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=539.18/541.20 (100/50) [MH+]. HPLC: tR=1.70 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].CCOC(C)=O.CO>CO.[Hg]=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[O:7][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:15][C:14]=1[C:22]([F:23])([F:24])[F:25]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Agent: O=[Hg]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)o2)cc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
Mercury (II) oxide (yellow) (4.55 g, 21.0 mmol) was suspended in 60 mL of anhydrous MeOH under Ar. A bright-orange suspension was formed. To this suspension was added 4-hydroxybenzoic acid hydrazide (3.20 g, 21.0 mmol) and 4-chloro-3-trifluoromethyl-phenylisothiocyanate (5.0 g, 21.0 mmol). The reaction mixture was refluxed for 2 hours. The solvent was removed in vacuo. The black residue was redissolved in 100 mL of EtOAc and the resulting black suspension was filtered through a short pad of silica gel. The filtrate was mixed with 10 g of dry silica gel and solvent was removed in vacuo. The impregnated silica gel was loaded on silica gel column and the product was separated using a gradient of hexane:ethyl acetate mixture starting from 50:50 ratio and finishing at 0:100. All fractions containing the product were combined; solvent was removed in vacuo to give a grey solid. The solid was heated in 50 mL of 4:1 mixture of EtOAc/MeOH. The formed suspension was cooled down to ambient temperature and filtered to give the title product as a white crystalline solid (4.54 g, 60.7% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:20]C)=[CH:16][CH:17]=2)[C:12]1=[O:22])([OH:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].[NH4+].[Cl-].[C:29]1(C)C=CC=CC=1>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:20])=[CH:16][CH:17]=2)[C:12]1=[O:22])([O:3][CH3:29])=[O:2]
Reactant: COc1ccc2c(c1)C(=O)C(Cc1ccccc1C(=O)O)C2
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Product: COC(=O)c1ccccc1CC1Cc2ccc(O)cc2C1=O
Temperature: 60 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
To a solution of the product of Step 2 (25 g, 84.5 mmol) in toluene (1.2 L) at 60° C. was added AlCl3 (45 g, 338 mmol) in portions. The mixture was stirred at 60° C. for 14 hrs. NH4Cl solution was added and the mixture was extracted with EtOAc. The crude concentrated extract was treated with excess CH2N2 in Et2O. Chromatography of the resulting product on silica gel (eluted with 30% EtOAc/hexane) gave 17.5 g (70%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH3:19].O.[C-:21]#[N:22].[Na+]>CN(C)C=O>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:21]#[N:22])=[C:4]([O:18][CH3:19])[CH:5]=1
Reactant: [C-]#N
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nc3ccccc3o2)ccc1CC#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (318 mg, 1 mmol), dimethylformamide (7.5 mL) and deionzed water (2.5 mL) was stirred at rt. Sodium cyanide (150 mg, 3.0 mmol) was added to reaction. After 3 h, dimethylformamide (10 mL) was added to help dissolve solids in reaction mixture. Let reaction mixture stir overnight at rt. Workup was done by washing reaction with brine (3×30 mL), extraction with EtOAc, combined organic extracts, dried (Na2SO4), filtered and removed solvent in vacuo. Flash chromatography of resulting orange solid on silica gel using a gradient elution of 1:9 EtOAc:hexanes to 1:3 EtOAc:hexanes afforded the desired intermediate, [4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]acetonitrile as a yellow solid. 1H NMR(CDCl3, 300 MHz) δ 7.86–7.36 (m, 7H), 3.99 (s, 3H), 3.74 (s, 2H), 2.59–1.91 (m, 8H). MS (ESI) 265 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@H:37]4[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Product: Cc1c(C(=O)N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c1) and commercially available tert-butyl(3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow foam.