Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:21][CH2:20][C:12]3([S:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[NH:13]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>C(Cl)Cl>[C:31]([N:13]1[C:12]2([CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:23][CH:22]=3)[CH2:21][CH2:20]2)[S:16][CH2:15][C@H:14]1[C:17]([OH:19])=[O:18])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)c1ccc(OC2CCC3(CC2)N[C@H](C(=O)O)CS3)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
In 50 ml of methylene chloride were dissolved 2.40 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid and 2.23 ml of triethylamine. To the solution thus obtained was dropwise added 1.41 g of benzoyl chloride at 0-5° C., and the resulting mixture was stirred at the same temperature as above for 3 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl ether was added to the residue thus obtained, and the deposited crystal was collected by filtration. Thus, 2.10 g of (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid was obtained as a colorless crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH2:22]([Li])[CH2:23][CH2:24][CH3:25].C(B(C(CC)C)C(CC)C)(CC)C.BrBr.[OH-].[Na+].OO>C1(C)C=CC=CC=1.C(OCC)C>[CH3:22][CH:23]([C:11]1[S:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:12]=1)[CH2:24][CH3:25]
Reactant: [Li]CCCC
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Agent: BrBr
Agent: CCC(C)B(C(C)CC)C(C)CC
Agent: OO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC(C)c1cc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) in toluene (40 ml)/diethyl ether (130 ml) was treated with 1.6M n-butyl lithium (14 ml, 1.1 equiv.) and heated at reflux for 1.5 hours. The reaction mixture was cooled to -76° and treated dropwise with 1M tri-s-butylboron (22 ml, 1.1 equiv.). After 0.5 hours at -76°, the reaction mixture was stirred at 0° for 0.5 hours, recooled to -76° and treated with bromine (1 ml, 20 mmole) in 20 ml diethyl ether. The mixture was allowed to warm to room temperature, and then after 2 hours was treated sequentially with 50% (w/w) sodium hydroxide (2.3 ml) and 30% hydrogen peroxide (8 ml). The mixture was stirred overnight, and then extracted with ethyl acetate. The organic extracts were washed with water and brine, dried and concentrated in vacuo. Chromatography on a Waters Prep 500 (hexane/ethyl acetate, 9:1) provided the title compound (2.9 g, 41%) as an oil. Proton NMR was consistent with the assigned structure. Mass Spec. (MS): m/z 352 (M+), 323 (M--C2H5).
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[NH2:50]>C(Cl)Cl>[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[NH:50][C:13](=[O:15])[C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH3:17])[CH3:16]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC1(C)CCC(C)(C)C1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)NC1C(C)(C)CCC1(C)C
Reaction time: 48 h

Procedure:
To a stirred solution of N-Cbz-2-aminoisobutyric acid in dry CH2Cl2 containing dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP), all at 0° C., is added, via an addition funnel, 2,2,5,5-tetramethyl-1-cyclopentyl amine dissolved in CH2Cl2. After stirring for 48 hours, the mixture is filtered, and the filtrate is washed with 5% HCl (1×50 ml), saturated NaHCO3 (1×50 ml), and water (1×50 ml). The organic layer is separated, dried over MgSO4 and is evaporated to yield N-Cbz-2-aminoisobutyric acid 2,2,5,5-tetramethylcyclopentyl amide.
Reaction SMILES: C(OC([N:8]1[CH:12]([CH:13]=[CH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10][CH:9]1[C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[N:30])=[O:23])=O)(C)(C)C>C(O)C.[Pd]>[CH3:21][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH:12]2[NH:8][C@H:9]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]#[N:30])=[O:23])[CH2:10][CH2:11]2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(C=CC2CCC(C(=O)N3CCC[C@H]3C#N)N2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(CCC2CC[C@@H](C(=O)N3CCC[C@H]3C#N)N2)c1

Procedure:
A solution of 2-(2-(S)-cyano-pyrrolidine-1-carbonyl)-5-(R/S)-(2-m-tolyl-vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 23) (50 mg) and 10% Pd/C(10 mg) in ethanol (5mL) was stirred under H2 balloon overnight. The catalyst was removed by filtration, and the filtrate was concentrated to provide the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>C1COCC1>[C:17]1([CH:10]2[CH2:9][NH:8][CH2:13][CH2:12][N:11]2[C:14](=[O:16])[CH3:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)N1CCNCC1c1ccccc1
Reaction time: 2 h
Yield: 119.4 %

Procedure:
To a solution of 4-acetyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.82 mmol) in THF (3 mL) at 0° C. was added 50% TFA/dichloromethane (1 mL). After stirred for 2 h, the reaction mixture was concentrated in vacuo. The residue was diluted with dichloromethane and silica-bound carbonate (2 g, 0.77 mmol/g, Silicycle, Inc.) was added. The reaction mixture was stirred overnight, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (10/1 dichloromethane/methanol with 1% triethyl amine) to provide 1-(2-phenyl-piperazin-1-yl)-ethanone (200 mg, 119%). (M+H)+=205 m/e.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.[CH:38]12[N:44]([C:45](=O)[CH2:46]Br)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2>>[CH:38]12[N:44]([CH2:45][CH2:46][O:37][C:36]3[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]4[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=4[CH:17]4[CH2:26][CH2:25][C:24]5[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=5[CH2:18]4)=[CH:3][C:2]=3[F:1])[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2
Reactant: O=C(CBr)N1C2CCC1CC2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3C4CCC3CC4)c(F)c2)c1
Yield: 52.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([C@@H:19]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@@:20]3([CH3:28])[OH:21])[C:4]=2[N:5]=[C:6]([NH:8]C(=O)C(C)(C)C)[N:7]=1.[NH3:29]>>[NH2:8][C:6]1[N:7]=[C:2]([NH2:29])[C:3]2[C:17]([I:18])=[CH:16][N:15]([C@@H:19]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@@:20]3([CH3:28])[OH:21])[C:4]=2[N:5]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)cn([C@@H]3O[C@H](CO)[C@@H](O)[C@@]3(C)O)c2n1
Reactant: N
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c2c(N)nc(N)nc21

Procedure:
A mixture of the compound from Step B (2.92 g 5.6 mmol) and anhydrous liquid ammonia (50 mL) was heated in a stainless steel autoclave at 110° C. for 1 d, then cooled and the solvent evaporated. The residue was treated with MeOH to yield 0.30 g of 15.4. The filtrate was evaporated and purified on silica gel column with CH2Cl2/MeOH (20/1) to furnish additional 1.52 g of the target compound (total yield 77%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.[CH3:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:29])[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=2)[CH2:12][CH2:11]1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CC(CC(C)C)=O>[CH3:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([NH:16][C:17](=[O:29])[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:22]([O:27][CH3:28])[CH:21]=2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: CCOC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
20.7 g of potassium carbonate and 5 ml of methanol were added to a solution of 28.9 g of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 131) in 600 ml of methylisobutylketone. The solution was reacted for 30 minutes, while it was refluxed. Next, 27.7 ml of ethyl bromoacetate was added dropwise into the solution over about 20 minutes by means of a dropping funnel. Thereafter, the solution was stirred for 4 hours. After reaction, the solution was allowed to cool to room temperature. After the potassium carbonate has been filtered out from the filtrate, the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 35.2 g of N-(trans-4-methylcyclohexyl)-4-(ethoxycarbonylmethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCc2ccc(Br)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-bromobenzylamine hydrochloride and DBU in DME. ES-MS m/e (%): 372 (M{81Br}+H+, 95), 370 (M{79Br}+H+, 100).
Reaction SMILES: [CH3:1][Si:2]([C:5]1[CH:6]([Si](C)(C)C)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].C(=O)=O.[B:21](Cl)([Cl:23])[Cl:22]>>[CH3:1][Si:2]([C:5]1[CH:6]([B:21]([Cl:23])[Cl:22])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3]
Reactant: ClB(Cl)Cl
Reactant: C[Si](C)(C)C1=Cc2ccccc2C1[Si](C)(C)C
Agent: O=C=O
Product: C[Si](C)(C)C1=Cc2ccccc2C1B(Cl)Cl
Temperature: -30 °C
Reaction time: 3 h

Procedure:
In a manner similar to the preparation of compound 2, 12.3 g (0.047 mol) of compound 13 were introduced into a round-bottomed flask which was cooled to −30° C. and had a reflux condenser cooled with dry ice. 5.6 g (0.046 mol) of BCl3 were added to this. When the addition was complete, the cooling bath was removed and the reaction mixture warmed to room temperature and was stirred for 3 hours. The temperature was then raised to 55° C. for 6 hours. After cooling and removal of the volatile contents in vacuo, the crude product was obtained. Distillation under a high vacuum gave the purified product, the main isomer of which was identified as follows:
Reaction SMILES: CO[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]#[N:13].[H-].[Na+]>C1COCC1>[O:10]=[C:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:11][C:12]#[N:13]
Reactant: COC(=O)c1ccccc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of benzoic acid methyl ester (1.0 equiv.) and methyl cyanide (2.0 equiv.) in anhydrous THF (1.0 M) was added sodium hydride (60% in mineral oil, 2 equiv.) under nitrogen. After the resulting reaction mixture was stirred at 70° C. overnight, the reaction mixture was quenched with ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under vacuum afforded the crude product as a brown solid. 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.94-7.92 (m, 2H), 7.69-7.65 (m, 1H), 7.55-7.54 (m, 2H), 4.08 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[O:9][C:8](C(O)=O)=[CH:7][C:6]=2[CH:13]=1.[B-](F)(F)(F)[F:16].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(=O)(O)[O-].[Na+]>O.CC(=O)OCC>[Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[O:9][C:8]([F:16])=[CH:7][C:6]=2[CH:13]=1
Reactant: F[B-](F)(F)F
Reactant: Cc1cc2oc(C(=O)O)cc2cc1Br
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2oc(F)cc2cc1Br
Yield: 36.1 %

Procedure:
A mixture of 5-bromo-6-methyl-benzofuran-2-carboxylic acid (229, 243 mg, 0.95 mmol), Selectfluor (481 mg, 1.36 mmol) and sodium bicarbonate (228 mg, 2.72 mmol) in 3 ml water and 3 ml EA was stirred vigorously at r.t. for 60 h before addition of another 240 mg of Selectfluor. After further 20 h the reaction mixture was diluted with EA, washed twice with 1N NaOH. Org phase was washed with brine, dried over sodium sulfate, concentrated to dryness to give 78.5 mg of title compound as light brown wax (yield: 36.1%, purity>95%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)=[C:14]=[O:15]>C1COCC1.CN(C=O)C>[C@H:16]1([NH:13][C:14]([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[NH:8]2)=[O:15])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Reactant: O=C=N[C@@H]1CCc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@@H]3CCc4ccccc43)c(=O)c12

Procedure:
In analogy to example 1c, 200 mg (1.089 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 208.1 mg (1.2 mmol) of (R)-1-isocyanatoindane in THF/DMF at RT. Yield: 154 mg (41%), M+H+: 343.32.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15]2)=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:15]2[CH3:26])=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c(Cl)cc(OCc3ccccc3)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(OCc3ccccc3)cc2n1C
Temperature: 25 °C

Procedure:
After 3.70 g (11.2 mmol) of ethyl 6-benzyloxy-4-chloro-2-indolecarboxylate was added to a suspension of 0.45 g (11.2 mmol) of 60% sodium hydride in 70 ml of dimethylformamide, the mixture was stirred at room temperature. After the mixture became an almost transparent solution, a solution of 3.18 g (22.4 mmol) of methyl iodide in 10 ml of dimethylformamide was dropwise added to the transparent solution at room temperature followed by stirring for 5 hours at the same temperature. The reaction solution was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate and the combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was isolated and purified by silica gel column chromatography to give 3.72 (96.4%) of ethyl 6-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[C:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[N:20]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[C:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:20]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A mixture of 4-cyanobenzeneboronic acid (7.35 g, 50 mmol), (6-bromo-pyridin-2-yl)carbamic acid tert-butyl ester (13.8 g, 50 mmol), Pd(Ph3P)4 (5.8 g, 0.15 mmol) and K2CO3 (10.4 g, 75 mmol) in DMF/H2O (1:1, 250 mL) was stirred under argon at 80° C. overnight. DMF was evaporated off under reduced pressure and the residue was dissolved in EtOAc (200 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by column (Petroleum Ether/EtOAc 50:1) on silica gel to give [6-(4-cyano-phenyl)-pyridin-2-yl]carbamic acid tert-butyl ester (7.0 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.02-8.07 (m, 2 H), 7.95 (d, J=8.4 Hz, 1 H), 7.71-7.79 (m, 3 H), 7.37-7.44 (m, 2 H), 1.53 (s, 9 H).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1.[OH:15][C:16]([CH3:31])([CH3:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[O:28][CH3:29]>C(Cl)Cl.CO>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([OH:15])([CH3:31])[CH3:30])=[C:20]([O:28][CH3:29])[CH:21]=2)[C:10](=[O:14])[CH:9]=1
Reactant: O=c1cc(Cl)cc[nH]1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 21 h
Yield: 62.8 %

Procedure:
Pyridine (1.2 mL, 15.4 mmol) was added to a stirred solution of commercially available 4-chloropyridin-2(1H)-one (100 mg, 0.77 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part C (278 mg, 1.16 mmol), and copper (II) acetate, monohydrate (154 mg, 0.77 mmol) in CH2Cl2 (7 mL) and MeOH (0.7 mL). The reaction mixture stirred at RT under the presence of air overnight (21 hours). The reaction mixture was diluted with CH2Cl2, washed with IN HCl, sat. NaHCO3, dried (Na2SO4), and concentrated. The crude product was purified using preparative HPLC (C18 column/10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 4-chloro-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one 9D (169 mg, 0.49 mmol, 62.8% yield) as a brown gum. LC/MS 324 (M+H)+, tR 0.75 min (method 5)
Reaction SMILES: C(O)=O.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@:13]([C:18]#[C:19][CH2:20][OH:21])([OH:17])[C@@H:12]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C1(C)C=CC=CC=1P.C(N(CCCC)CCCC)CCC.I[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[O:56][CH3:57]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@:13](/[CH:18]=[C:19](/[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[O:56][CH3:57])\[CH2:20][OH:21])([OH:17])[C@@H:12]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COc1ccccc1I
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P
Solvent: O=CO
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: COc1ccccc1/C(=C/[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)CO
Temperature: 70 °C
Yield: 35 %

Procedure:
Formic acid (138 ml, 3.77 mmol) was added to a stirred, degassed solution of (2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3-ol (Description 7, 473 mg, 1.43 mmol), palladium (II) acetate (33 mg, 0.14 mmol), trio-o-tolylphosphine (85 mg, 0.28 mmol), tributylamine (1.12 ml, 4.87 mmol) and 2-iodoanisole (446 ml, 3.44 mmol) in N,N-dimethylformamide (3 ml) at room temperature and the resulting mixture was heated at 70° C. for 5 h. The mixture was cooled, filtered, diluted with ethyl acetate (50 ml), washed with water (100 ml), hydrochloric acid (2M, 50 ml) and saturated aqueous sodium chloride (50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (60:40) to give the title compound as a yellow glass (220 mg, 35%). 1H NMR (360 MHz, CDCl3) δ7.41 (2H, d, J 7.6 Hz), 7.22-7.34 (4H, m), 7.12 (1H, dd, J 1.7, 7.4 Hz), 6.94 (1H, t, J 7.5 Hz), 6.89 (1H, d, J 8.2 Hz), 5.84 (1H, s), 5.00 (1H, s), 4.40 (1H, d, J 12.7 Hz), 4.15 (1H, dd, J 6.0, 13.1 Hz), 4.05 (1H, d, J 12.5 Hz), 3.86 (3H, s), 3.44 (1H, dt, J 5.6, 12.3 Hz), 2.04-2.18 (1H, m), 1.80-1.96 (3H, m), 1.28 (9H, s), and 1.64-1.84 (3H, m). m/z (ES+) 440 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(N(C(C)C)CC)(C)C.[NH2:55][CH:56]([CH2:59][OH:60])[CH2:57][OH:58]>C(O)(C)C>[OH:44][C@H:43]([CH2:45][NH:55][CH:56]([CH2:59][OH:60])[CH2:57][OH:58])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])[NH:13]2)=[O:11])=[N:5]1
Reactant: NC(CO)CO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H](O)CNC(CO)CO)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 28.6 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (43.6 mg, 0.066 mmol), isopropyl alcohol (2 mL), diisopropylethyl amine (0.1 mL, 0.56 mmol) and serinol (0.1 mL, 1.09 mmol) was microwaved at 130° C. for 15 min. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-{2-[(R)-2-hydroxy-3-(2-hydroxy-1-hydroxymethyl-ethylamino)-propoxy]-2-methyl-propyl}-1H-pyrazol-3-yl)-amide (14.2 mg, 28.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C36H46Cl2F2N6O5S+H [(M+H)+]: 751.2948. found: 751.2943.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([Cl:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Br)c2ccccc12
Temperature: 40 °C
Reaction time: 16 h

Procedure:
4-Bromonaphthalene-1-carboxylic acid (9.80 g) was suspended in thionyl chloride (80 mL) and stirred at 40° C. for 16 hours and evaporated under vacuum. Solid was dissolved in DCM (20 mL) and evaporated under vacuum, giving 4-bromonaphthalene-1-carbonyl chloride (13.8 g, crude) as a white solid.