Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][CH:8]=2.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:15]([N:22]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[N:5][C:4]=2[CH:3]=[CH:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: ClCCc1nnc2ccccc2c1Cl
Solvent: ClC(Cl)Cl
Solvent: Oc1ccccc1
Product: c1ccc(Cn2ccc3nnc4ccccc4c32)cc1

Procedure:
3-(2-Chloroethyl)-4-chlorocinnoline (2 g, 0.0088 mol), benzylamine (4 g, 0.037 mol) and phenol (2 g, 0.0212 mol) were heated in an oil bath at 160° for 20 hours. The reaction had not gone to completion so the temperature was raised to 190° for a further 6 hours. The reaction mixture was dissolved in chloroform (300 ml) and extracted with 2N sodium hydroxide (3×100 ml). The chloroform extracts were washed with water (100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by chromatography using chloroform as eluant. The fractions containing the product were combined and evaporated to dryness to give a brown solid. Recrystallization from isopropyl alcohol gave the title compound, 0.5 g, m.p. 190-192°.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]3[N:14]=[CH:15][CH:16]=[C:12]3[N:11]=[C:10]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH2:3]1.F[C:31](F)(F)[C:32]([O-])=[O:33].C(Cl)(=O)C.O>N1C=CC=CC=1>[C:32]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]3[N:14]=[CH:15][CH:16]=[C:12]3[N:11]=[C:10]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=3)[CH:9]=2)[CH2:3]1)(=[O:33])[CH3:31]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](N)C3)n3nccc3n2)cc1
Reactant: O=C([O-])C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: CC(=O)N[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
As crude product mixture of (R)—N-(7-(3-aminopiperidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (Compound 309 in Example 323) and trifluoroacetate salt (65 mg, 0.165 mmol) was dissolved in pyridine (2 ml). At 0° C. acetyl chloride (0.025 ml, 0.353 mmol) was added and the mixture was stirred for 2 hours at room temperature. Afterwards an additional amount of acetyl chloride (0.009 ml) was added to drive the reaction to completion. Water (2 ml) was then added to quench the reaction. The mixture was concentrated in vacuo, and the crude product was purified by preparatory HPLC (25-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the collected fractions gave the titled compound (35 mg, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ=10.90 (s, 1H), 8.08 (d, J=2.3 Hz, 1H), 8.03-7.94 (m, 4H), 7.64-7.56 (m, 2H), 7.36 (s, 1H), 6.35 (d, J=2.3 Hz, 1H), 4.26-4.17 (m, 1H), 4.13 (d, J=11.9 Hz, 1H), 3.86 (br. s., 1H), 3.14 (s, 1H), 3.07 (dd, J=9.5, 11.7 Hz, 1H), 1.90 (br. s., 2H), 1.81 (s, 3H), 1.75 (br. s., 1H), 1.59-1.47 (m, 1H), 1.45 (s, 5H); ESI-MS: m/z 437.5 (M+H)+.
Reaction SMILES: Cl.C[O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].[C:9](Cl)(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[C:9]([NH:6][CH:5]([CH3:7])[C:4]([OH:3])=[O:8])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)C(C)N
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Product: CCCCCCCCCC(=O)NC(C)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of example 4A using 19.0 g (184 mmol) of D,L-alanine methyl ester hydrochloride and 35.14 g (184 mmol) of decanoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([O:19]C)=[CH:17][CH:16]=[CH:15][C:14]=2[F:21])[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:14]([F:21])=[CH:15][CH:16]=[CH:17][C:18]=2[OH:19])[N:3]=1
Reactant: COc1cccc(F)c1-c1nc(Cl)c2ccc(C)cc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 65.5 %

Procedure:
Under an N2 atmosphere, 4-chloro-2-(2-fluoro-6-methoxyphenyl)-7-methylquinazolin (7.0 g, 23.12 mmol) was dissolved in CH2Cl2 (110 mL) and cooled to −50° C. internal temperature using a dry ice/acetone bath. A 1.0 M solution of BBr3 in CH2Cl2 (115.6 mL, 115.6 mmol) was added dropwise via an addition funnel while maintaining the internal temperature at −50° C. The reaction mixture was warmed to 0° C., and the reaction was complete after 1.5 h. It was then slowly quenched with saturated aqueous NaHCO3 solution to pH 7. After partitioning between CH2Cl2 and H2O, the mixture was separated and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a brown solid. Purification via silica gel chromatography using 75% CH2Cl2/25% hexanes gave 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol as a yellow solid (4.37 g, 66%). LC/MS: m/z 289.1 (M+H)+ at 3.71 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:20]([CH3:21])[CH2:19][CH2:18][C:17]([C:22](O)=[O:23])=[CH:16][C:15]=3[CH:25]=2)=[CH:7][CH:6]=1)[CH3:3].S(Cl)(Cl)=O.[CH3:30][N:31]([CH3:34])[CH:32]=O>>[CH2:2]([O:4][CH2:5][CH2:6][CH2:30][N:31]([CH2:32][C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:22]([C:17]2[CH2:18][CH2:19][N:20]([CH3:21])[C:14]3[CH:13]=[CH:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH2:2][CH3:3])=[CH:10][CH:9]=4)=[CH:25][C:15]=3[CH:16]=2)=[O:23])=[CH:15][CH:25]=1)[CH3:34])[CH3:3]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCOCCCN(C)Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCC)cc4)ccc3N(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In dimethylformamide (5 ml) was dissolved 7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylic acid hydrochloride (0.5 g), and to the mixture was added, under ice-cooling, thionyl chloride (0.25 ml). The mixture was stirred at room temperature for 45 minutes, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml), and the mixture was added dropwise to a suspension of 4-((N-(3-ethoxypropyl)-N-methylamino)methyl)aniline dihydrochloride (0.41 g) and triethylamine (1.2 ml) in tetrahydrofuran (10 ml), under ice-cooling. Under nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-((N-(3-ethoxypropyl)-N-methylamino)methyl)phenyl)-7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 319) (0.39 g) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:16])[CH:7]=[C:8]([O:13][CH2:14][CH3:15])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH:17]([N:20]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1)([CH3:19])[CH3:18].Cl>N1C(C)=CC(C)=CC=1C>[CH:30]1([N:20]([CH:17]([CH3:19])[CH3:18])[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([O:16][C:6]3[CH:7]=[C:8]([O:13][CH2:14][CH3:15])[C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:24][CH:23]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: CCOc1cc(O)cc(OCC)c1OCC
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOc1cc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OCC)c1OCC
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-triethoxyphenol (777 mg, 4.0 mmol) and p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.30 g, 4.0 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH:14]=O)[CH:6]=[CH:5]2.[F:16][C:17]([F:41])([F:40])[C@H:18]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28]1)[C:19]1[CH:20]=[N:21][C:22]([NH:25][NH2:26])=[CH:23][CH:24]=1>C(O)C>[F:40][C:17]([F:16])([F:41])[C@H:18]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])[CH2:28]1)[C:19]1[CH:20]=[N:21][C:22]([NH:25]/[N:26]=[CH:14]/[C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([F:1])[CH:3]=3)[N:8]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COc1cc2nc(C=O)ccc2cc1F
Solvent: CCO
Product: COc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 6-fluoro-7-methoxyquinoline-2-carbaldehyde (54.7 mg, 0.266 mmol) in ethanol (5 mL) was added tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (100 mg, 0.266 mmol) and the reaction was stirred for 24 hours at ambient temperature. The reaction was concentrated to dryness and used as is in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]23[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[C:8]3=[O:25])=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.CCN(C(C)C)C(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:14][C@@H:13]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:8]3=[O:25])=[CH:26][CH:27]=1
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@@H](O)CN12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Reaction time: 1 h

Procedure:
To a solution of (5S,7R)-5-(4-bromobenzyl)-3-(3,5-dichloro-phenyl)-7-hydroxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.81 g) in CH2Cl2 (5 mL) and DIEA (0.50 mL) at 0° C. was added methanesulfonyl chloride (0.19 mL). After 1 hour at 0° C., the mixture was diluted with CH2Cl2, washed with satd. NaHCO3 and brine, dried (Na2SO4) and concentrated to give (5S, 7R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-7-methylsulfonyloxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione. MS (m/z) 494 (MH+). (2) To a solution of the compound obtained above in DMF (4 mL) at 75° C. was added sodium azide (0.54 g). After heating for 2 hours the mixture was diluted with Et2O and water. The organic solution was collected, washed with water and brine, dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel: 2% methanol/CH2Cl2, Chromatotron) afforded the titled compound (0.82 g). MS (m/z) 494 (MH+), mp 58.9° C.
Reaction SMILES: C(N(CC)CC)C.C[Si]([C:12]#[N:13])(C)C.[CH3:14][C:15]1[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(#N)C>[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:12]#[N:13])[CH:16]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1cc[n+]([O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccnc(C#N)c1
Yield: 64.6 %

Procedure:
Triethylamine (13.4 mL, 91.9 mmol) and trimethylsilyl cyanide (25 mL, 187.5 mmol) were added sequentially to a solution comprising 4-methylpyridine N-oxide (5 g, 45.8 mmol) and acetonitrile (20 mL). The mixture was heated at reflux for 24 hours, cooled and diluted with methylene chloride (150 mL). Saturated sodium bicarbonate solution (100 mL) was added slowly to the mixture and then the aqueous layer was separated and extracted with methylene chloride (100 mL). The combined organic layers were washed with water (2×150 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexanes to provide 4-methylpyridine-2-carbonitrile (3.5 g, 29.6 mmol) as a dark solid, 1H-NMR (300 Mhz, DMSO-d6): 2.4 (s, 3H), 7.6 (d, 1H, J=5 Hz), 7.8 (s, 1H), 8.6 (d, 1H, J=5 Hz), MS (ESI), Calculated for C7H6N2 : 228.24, Found (MH+): 119.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[N:13]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>CO.O1CCCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][C:12]3[N:13]=[C:9]([S:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:31])=[O:3])[S:10][CH:11]=3)=[CH:23][CH:22]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(-c3ccc(F)cc3)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Sc1nc(CCOCc2ccc(-c3ccc(F)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.2 %

Procedure:
2-[(4-{2-[(4′-Fluorobiphenyl-4-yl)methoxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid ethyl ester (400 mg) synthesized in Example 155-3 was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL), aqueous sodium hydroxide solution (1 mol/L, 2 mL) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, aqueous 10% citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 1:1) to give the title compound (245 mg) as a white solid.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.Cl>>[F:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][CH2:38][C:32]2([OH:31])[CH2:33][CH2:34][N:35]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:36][CH2:37]2)=[CH:46][CH:45]=1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Reactant: OC1(CCCc2ccc(F)cc2)CCNCC1
Agent: Cl
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-Formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 4-hydroxy-4-(3-(4-fluorophenyl)propyl) piperidine.HCl (from EXAMPLE 110, Step A) using procedures analogous to those described in EXAMPLE 1, Steps J and K. For the title compound: ESI-MS 537 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][C@@:9]([CH3:19])([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1.[C:20]1(B(O)O)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1.[F-].[Cs+]>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.C1COCC1>[C:20]1([C:2]2[CH:3]=[N:4][N:5]([CH2:7][CH2:8][C@@:9]([CH3:19])([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(I)cn1)S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1cc(C2=CCCCC2)cn1)S(C)(=O)=O
Temperature: 60 °C
Yield: 83.5 %

Procedure:
To a vial containing ethyl (2R)-4-(4-iodo-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoate (500 mg, 1.25 mmol, 1.0 eq), cyclohex-1-en-1-ylboronic acid (205 mg, 1.62 mmol, 1.3 eq), cesium fluoride (759 mg, 5.00 mmol, 4 eq) and Pd(PPh3)4 (100 mg 0.087 mmol, 0.07 eq) was added THF (5 mL). The vial was sealed and the mixture was heated at 60° C. overnight. The mixture was filtered through celite, and eluted with EtOAc. The filtrate was absorbed onto silica gel and purified by flash chromatography, eluting with 0-20% EtOAc/Hpt then 5% MeOH/EtOAc to give ethyl (2R)-4-[4-(cyclohex-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate (370 mg, 83.6% yield). LC-MS M+H+355.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: Cc1ccc(Br)cc1
Product: Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
The title compound was prepared by Suzuki coupling of 1-bromo4-nitrobenzene and 1-bromo-4-methylbenzene.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:12]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.ClCC(OCC)=O.Cl>O1CCCC1>[O:12]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[C:9](=[O:11])[CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:29]2=[O:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: O=C=NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(=O)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CN(c2ccccc2)C(=O)N1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.2 %

Procedure:
To a solution of 1.25 g (8.29 mmol) of N-phenylaminoacetic acid in 100 ml of tetrahydrofuran, 2.0 g (8.29 mmol) of 4-phenoxybenzenesulfonyl isocyanate were added at room temperature, and the resultant mixture was stirred for 16 hours. After completion of the reaction, the liquid reaction mixture was cooled to 0° C. and added with 2.09 g (20.7 mmol) of triethylamine and 900 mg (8.29 mmol) of ethyl chloroacetate, followed by stirring at 0° C. for 1 hour. After completion of the reaction, the liquid reaction mixture was added with 40 ml of 1N hydrochloric acid and 60 ml of saturated saline and subjected to extraction with ethyl acetate. After washing the resultant extract with water, it was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The thus-obtained crude product was purified by column chromatography on silica gel (hexane/ethyl acetate=3:1) and subjected to crystallization from hexane/ethyl acetate, thereby obtaining 310 mg (yield: 9.2%) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH2:21][CH3:22])[CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH3:8]>O1CCCC1>[CH2:21]([N:9]([CH2:7][CH3:8])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH2:18])=[CH:19][CH:20]=1)[CH3:22]
Reactant: CCN(CC)CCOc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A 1M solution of lithium aluminium hydride (5 ml; 5 mmol) was added dropwise to a stirred solution of 1.01 g (5 mmol) of 4-(2-diethylaminoethoxy)benzonitrile in 5 ml of dry tetrahydrofuran at 0° C. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the cautious addition of a saturated solution of 5 ml of Rochelle's salt and then evaporated. The residue was partitioned between 25 ml of diethyl ether and 25 ml of water and the organic phase was separated, dried over magnesium sulfate and evaporated. The crude product was purified by flash column chromatography on silica gel using dichloromethane/methanol/water/acetic acid (60:18:2:3) for the elution. Product-containing fractions were combined and evaporated to give 785 mg (71%) of 4-(2-diethylaminoethoxy)benzylamine as a colorless oil. [Mass spectrum (ESI) MH+ =223].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[O:18][N:17]=[C:16]([CH3:19])[CH:15]=1)=[C:6]2OS(C(F)(F)F)(=O)=O)#[N:2].[C:28]1(B(O)O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.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.O>[C:28]1([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:9][C:8](=[O:13])[C:7]=2[C:14]2[O:18][N:17]=[C:16]([CH3:19])[CH:15]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: OB(O)C1=CCCCCC1
Reactant: Cc1cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc(C#N)ccc3[nH]c2=O)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2c(C3=CCCCCC3)c3cc(C#N)ccc3[nH]c2=O)on1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 6-cyano-3-(3-methyl-isoxazol-5-yl)-2-oxo-1,2-dihydro-quinolin-4-yl ester (30 mg, 0.075 mmol), cyclohepten-1-ylboronic acid (12.6 mg, 0.090 mmol), Pd(PPh3)4 (8.7 mg, 0.0075 mmol) and Na2CO3 (375 ul, 0.75 mmol, 2.0 M) in 1 ml of 1,4-dioxane was stirred at 80° C. for 1 h, then cooled to rt. Treated with 20 ml of H2O, the mixture was acidified to PH=7 with 1N HCl and then extracted with EtOAc (3×15 ml). The combined organic layers were washed with H2O (20 ml), brine (15 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (10-20% EtOAc/DCM) gave 15.1 mg (58%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) δ 12.3 (s, 1H), 8.08 (d, 1H, J=1.7 Hz), 7.77 (dd, 1H, J=8.6, 1.7 Hz), 7.43 (d, 1H, J=8.6 Hz), 6.70 (s, 1H), 5.79 (t, 1H, J=6.1 Hz), 2.44 (s, 3H), 2.26-2.52 (m, 4H), 1.62-1.94 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H19N3O2, 346.2 (M+H), found 346.1.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.N1C=CC=CC=1.[C:21](Cl)(Cl)=[O:22]>ClCCl>[F:1][C:2]1[C:3]([N:9]2[CH2:10][C:11]([CH3:14])([CH3:12])[O:13][C:21]2=[O:22])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: CC(C)(O)CNc1ncc(I)cc1F
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CN(c2ncc(I)cc2F)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
(580 mg, 1.87 mmol) 1-(3-Fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (Example 1, step 1) was dissolved in dichloromethane (10 ml) and pyridine (300 μl, 3.74 mmol, 2 equiv.) was added at room temperature. The mixture was cooled to 0-5° C. and phosgene (20% in toluene) (1.19 ml, 2.24 mmol, 1.2 equiv.) was added dropwise over a period of 15 min at 0-5° C. The mixture was stirred for 1 hour at 0-5° C. The reaction mixture was extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with a heptane:ethyl acetate gradient 100:0 to 50:50. The desired 3-(3-fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one (500 mg, 1.49 mmol, 79.5% yield) was obtained as a white solid, MS: m/e=337.0 (M+H+).