Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C(NC(C)C(N2CCCC2C(O)=O)=O)=O)=CC=1Cl.[O:24]=[C:25]1[O:29][CH:28]([O:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=CC=2)[CH:27]([NH:39][C:40]([CH:42]2[CH2:46][CH2:45][CH2:44][N:43]2[C:47](=[O:61])[CH:48]([NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[C:54]([Cl:59])[CH:53]=2)[CH3:49])=[O:41])[CH2:26]1>>[CH:32]1([CH2:31][O:30][CH:28]2[CH:27]([NH:39][C:40]([CH:42]3[CH2:46][CH2:45][CH2:44][N:43]3[C:47](=[O:61])[CH:48]([NH:50][C:51](=[O:60])[C:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[C:54]([Cl:59])[CH:53]=3)[CH3:49])=[O:41])[CH2:26][C:25](=[O:24])[O:29]2)[CH2:33][CH2:38][CH2:37][CH2:36]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCC1CCCC1
Yield: 51 %

Procedure:
Prepared from 97a and syn-(2-cyclopentylmethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 195 mg of title compound (51% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.15-1.90 (m, 1H), 1.90-2.40 (m, 5H), 2.55-2.78 (m, 2H), 3.50-3.90 (m, 4H), 4.38-4.92 (m, 3H), 5.53 (d, 0.8H), 5.57 (d, 0.2H), 6.78 (d, 1H), 7.50-8.15 (m, 2H). Analytical HPLC: 10.48 min. LC-MS (ES+): m/e=521.2 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][CH2:23]2)=[O:11])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: NN1CCN(Cc2ccccc2)CC1
Solvent: O=S(Cl)Cl
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NN1CCN(Cc2ccccc2)CC1
Reaction time: 6 h
Yield: 5.8 %

Procedure:
4-Acetylamino-5-chloro-methoxybenzoic acid (3.50 g, 0.144 mole) was treated with thionyl chloride (25 ml) at 50° for 1/2 hour. The mixture was evaporated in vacuo and the residue azeotroped twice with anhydrous benzene (100 ml) and redissolved in anhydrous benzene (100 ml). Triethylamine (1.45 g) was added followed by 1-amino-4-benzylpiperazine (2.75 g 0.144 mole) and the reaction left for 6 hours at room temperature. The mixture was evaporated in vacuo, taken up in water (50 ml) basified with dilute sodium hydroxide (10%) and extracted with chloroform. Evaporation of the dried (MgSO4) chloroform extract gave 4-acetylamino-5-chloro-2-methoxy-N-[4-benzyl-1-piperazinyl]benzamide (3.50 g; 58%) as colourless microcrystals m.p. 211°-213° C. A sample recrystallised from benzene gave m.p. 212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH2:21]C(=O)C)=[CH:15][C:14]=3[CH3:26])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:28]=1.[OH-:29].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH2:21][OH:29])=[CH:15][C:14]=3[CH3:26])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:28]=1
Reactant: [OH-]
Reactant: CC(=O)CC(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)c(C)c1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)CO)ccc1C(=O)N1CCCCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Chloro-1-[2-methyl-4-(2-acetylacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.48 g) is dissolved in tetrahydrofuran (7 ml), and thereto is added a 5 N aqueous sodium hydroxide solution (0.5 ml), and the mixture is stirred at room temperature for two hours. The reaction solution is neutralized with a 2 N hydrochloric acid, and extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered, and concentrated. To the resulting residue is added n-hexane/ethyl acetate (1:1), and the mixture is washed, filtered, and the obtained powder is dried to give 7-chloro-1-[2-methyl-4-(2-hydroxyacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as white powder.
Reaction SMILES: C(N(CC)CC)C.C(Cl)Cl.[CH2:11]([N:15]1[C:23]([N:24]2[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:30])[CH2:25]2)=[N:22][C:21]2[C:16]1=[N:17][C:18]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1)=[N:19][C:20]=2[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH:12]([CH3:14])[CH3:13].[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CO>[C:44]([N:27]1[CH2:28][CH2:29][N:24]([C:23]2[N:15]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:16]3[C:21]([N:22]=2)=[C:20]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:19]=[C:18]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:17]=3)[CH2:25][C@@H:26]1[CH3:30])(=[O:46])[CH3:45]
Reactant: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 83.3 %

Procedure:
Triethylamine (86.3 μl, 0.62 mmol) was added to a methylene chloride solution (3.0 ml) of 5-{9-isobutyl-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (116.8 mg, 0.26 mmol) at room temperature followed by the addition of acetic anhydride (29.2 μl, 0.31 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 70 minutes and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (107.1 mg, 84%) as a pale yellow solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH:11](Br)([CH3:13])[CH3:12].[OH-].[K+].Cl>C(O)C>[CH:11]([S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)Br
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Sc1ccccc1C(=O)O
Reaction time: 6 h

Procedure:
To a suspension of thiosalicylic acid (16.7 g; 109 mmol; Fluka) and isopropyl bromide (20.0 g; 163 mmol) in ethanol (125 ml) were added slowly, with vigorous stirring, KOH pellets (17.3 g; 433 mmol). After stirring for 6 h, the reaction mixture was poured into water-ice mixture (1200 ml) and acidified with concentrated hydrochloric acid (approx. 50 ml). The precipitated product was filtered off, washed with 50% aqueous ethanol (2×100 ml) and dried under reduced pressure. Yield 6.4 g (30%).
Reaction SMILES: [H-].[Na+].CS(C)=O.[CH3:7][C:8]([CH3:14])([CH2:11][CH:12]=[CH2:13])[CH2:9][OH:10].[CH3:15]I>CCOCC.O>[CH3:15][O:10][CH2:9][C:8]([CH3:14])([CH3:7])[CH2:11][CH:12]=[CH2:13]
Reactant: CI
Reactant: C=CCC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: C=CCC(C)(C)COC
Yield: 25.4 %

Procedure:
Under nitrogen, 2.211 g NaH was suspended in 50 mL dry ether in a three-necked round bottom flask. Anhydrous (CH3)2SO (5.0 mL) was added. The flask was cooled with ice. 2,2-Dimethyl-4-penten-1-ol(7.0 g) in 13 mL anhydrous ether was added dropwise through an addition funnel. The solution was then refluxed overnight. Upon cooling in ice, 43.56 g CH3I (5 eq) was added through an addition funnel. Soon a white precipitate was seen. The slurry was refluxed for 4 h. Upon cooling, water and ether were added to the mixture. The ether layer was separated, washed with water twice and dried with Na2SO4. Careful evaporation of ether (the product has a low b.p.) gave 2.0 g pure product. 1H NMR (CDCl3): δ 0.86 (s, 6H, —CMe2-); 2.00 (d, 2H, CH2═CH—CH2—); 3.05 (s, 2H, —CH2OMe); 3.33 (s, 3H, —CH2OMe); 5.00 (m, 2H, CH2═CH—); 5.80 (m, 1H, CH2═CH—).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:18])([CH3:17])[CH:9]([C:11](=[O:16])[NH:12][CH:13]1[CH2:15][CH2:14]1)[OH:10])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]([CH3:18])([CH3:17])[CH:9]([OH:10])[C:11]([NH:12][CH:13]1[CH2:14][CH2:15]1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(O)C(=O)NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C(O)C(=O)NC1CC1

Procedure:
A solution of (2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethylethyl)-carbamic acid tert-butyl ester in CH2Cl2 (10 mL) and TFA (5 mL) was stirred at room temperature for 4 h. The reaction mixture was then concentrated and chased with toluene to yield 3-amino-N-cyclopropyl-2-hydroxy-3-methylbutyramide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C:14](=[O:31])[CH2:15][NH:16][C:17](=[O:30])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[N+:32]([O-:34])=[O:33].S(Cl)(Cl)=O.[CH2:39](O)[CH3:40]>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C:14](=[O:31])[CH2:15][NH:16][C:17](=[O:30])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=2)[CH2:9][C:10]([O:12][CH2:39][CH3:40])=[O:11])=[CH:4][C:3]=1[N+:32]([O-:34])=[O:33]
Reactant: Cc1ccnc(NCCCCC(=O)NCC(=O)NC(CC(=O)O)c2ccc(Cl)c([N+](=O)[O-])c2)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC(NC(=O)CNC(=O)CCCCNc1cc(C)ccn1)c1ccc(Cl)c([N+](=O)[O-])c1
Product: Cl

Procedure:
Esterification of 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid by activation with thionyl chloride and reaction with ethanol under standard conditions produces ethyl 3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionate hydrochloride, RT 27.95, FAB-MS (M+H)+ 520.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:17])([C:13]#[C:14][CH2:15][CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:26][C:27](Br)=[O:28]>CCOCC>[C:13]([C:8]1([C:9]([F:10])([F:11])[F:12])[C:7]2[CH:6]=[C:5]([Cl:18])[CH:4]=[CH:3][C:2]=2[NH:1][C:27](=[O:28])[CH2:26][O:17]1)#[C:14][CH2:15][CH3:16]
Reactant: O=C(Br)CBr
Reactant: CCC#CC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC#CC1(C(F)(F)F)OCC(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 167 mg of 6-amino-3-chloro-α-(1-butynyl)-α-(trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of dry pyridine and 0.066 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF and was treated at room temperature with 25 mg of 100% sodium hydride for 1.5 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried and evaporated. The crude product was purified by preparative silica gel TLC (elution with ethyl acetate/hexanes 1:2) affording after crystallization from ethyl acetate/hexanes 106 mg of the title compound as colorless crystals: mp 167-168°; Anal. Calcd. for C14H11NO2ClF3: C, 52.93; H, 3.49; N, 4.42. Found: C, 52.73; H, 3.64; N, 4.13.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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:9]1([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccnc(Cl)c1
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: COCCOC
Solvent: O
Product: Clc1ccnc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
2,4-dichloropyridine (10 g, 67.57 mmol), phenylboronic acid (9.0 g, 74.32 mmol), and potassium carbonate (28 g, 202.70 mmol), 300 mL dimethoxyethane and 30 mL of water was placed in a 1 L round-bottom flask. Nitrogen was bubbled directly into the mixture for 30 min. Tetrakis(triphenylphosphine)palladium(0) (780 mg, 0.675 mmol) was added and nitrogen was bubbled into the reaction mixture for a another 15 min. The reaction mixture was then heated to reflux under nitrogen for 16 h. The reaction was then allowed to cool to room temperature and diluted with ethyl acetate and water. The organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with a saturated brine solution. The organic layer was then dried over magnesium sulfate, filtered, and the solvent was removed under vacuum to give an off-white solid as crude. The crude was purified by column chromatography using silica gel as the stationary phase and 2% ethyl acetate in hexanes as the mobile phase. 8.0 g of desired product was obtained after purification (54% yield). 11.5 g of desired product was obtained after purification (89.77% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[CH:20]([CH:22]=[CH2:23])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]([C:12]([CH2:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])([CH2:21]/[CH:20]=[CH:22]/[CH3:23])[CH:13]=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: C=CC(C)O
Reactant: CCCCC(C=O)CS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C/C=C/CC(C=O)(CCCC)CS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-(((4-methylphenyl)-sulfonyl)methyl)hexanal (5.63 g, 21 mmol) in 35 ml of toluene in a RBF fitted with a Dean-Stark trap is added 2-hydroxy-3-butene (10 mL, 115 mmol), followed by p-toluenesulfonic acid (0.13 g) at room temperature under nitrogen. The mixture is heated to reflux overnight. After cooling to room temperature, the toluene solution is washed with saturated NaHCO3 solution (2×10 mL), water (2×20 mL), brine (1×20 mL), and dried with MgSO4. After removing solvents, the product is obtained as a brownish oil in quantitative yield with a GC purity of 89%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=O.[C:13]([Si:17]([CH3:32])([CH3:31])[O:18][CH2:19][CH2:20]OC1C=CC(I)=CC=1C=O)(C)(C)C.C[Si]([NH:37][Si](C)(C)C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.C(N(CC)CC)C.C(Cl)(=O)C>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]=[N:37][C:19]([O:18][Si:17]([CH3:32])([CH3:31])[CH3:13])=[CH2:20])[CH:9]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Reactant: O=Cc1cc(I)ccc1[N+](=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(N=Cc1cc(I)ccc1[N+](=O)[O-])O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 1d, 5-iodo-2-nitrobenzaldehyde prepared in Example 9a (4.2 g, 15 mmol) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (2.4 g, 15 mmol), n-butyllithium (2.5 M, 6 mL, 15 mmol), trimethylsilyl chloride (1.6 g, 15 mmol), triethylamine (2.1 g, 20 mmol) and acetyl chloride (1.5 g, 20 mmol) to give crude 1-(5-Iodo-2-nitrophenyl)-3-trimethylsilyoxy -2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.
Reaction SMILES: N[C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[C:9](=O)([O-])[O-].[Na+].[Na+].O.[C:16]1([C:22]2[N:27]=[C:26]([C:28](Cl)=[O:29])[CH:25]=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[OH:4][C@H:3]([CH3:5])[C@H:2]([CH2:9][C:28](=[O:29])[C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:27]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1cccc(-c2ccccc2)n1
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)[C@H](CC(=O)c1cccc(-c2ccccc2)n1)C(=O)O
Temperature: 10 °C
Yield: 94 %

Procedure:
A 3-L three neck round bottomed flask was equipped with an overhead stirrer, thermocouple, pressure equalizing dropping funnel, nitrogen inlet/outlet and ice/water cooling bath. L-threonine, 62.8 g (0.53 mol) was added, followed by 117 g (1.1 mol) of sodium carbonate and 1500 mL of deionized water. The aqueous solution was cooled to 10.0° C. During this time the addition funnel was charged with the acid chloride/toluene solution prepared in Step A. This toluene solution was added dropwise to the aqueous reaction over approximately 10 minutes at ˜10° C. Once the addition was complete, the reaction was warmed to room temperature (˜22-25° C.) and vigorously stirred until it was shown to be complete by HPLC analysis (typically ˜3 hr). The reaction mixture was then transferred to a separatory funnel and the two layers were separated. The lower aqueous phase was then recharged to the reaction flask. Methanol (800 mL) was then added to the mixture followed by pH adjustment (target pH=1-2) with 2.5M HCl (˜850 mL), keeping the temperature at 15-20° C. Some off-gassing occurred at ˜pH=5, followed by precipitation of the product at pH=3. The slurry was allowed to stir at room temperature for 30 minutes post pH adjustment. The white solid was collected by vacuum filtration, (mother liquor losses <2 mg/mL), washed with deionized water (2×500 ml) then dried in a vacuum oven at 40° C. with a nitrogen sweep to a constant weight to provide 141 g (0.471 mol, 94%) of the title compound with an HPLC purity of 99 A % (95 wt %). 1H NMR (d6-DMSO, 400 MHz) δ 12.9 (s, 1H, b), 8.71 (d, 1H, J=9.16 Hz), 8.23 (d, 1H, J=7.24 Hz), 8.1 (m, 3H), 8.03 (d, 1H, J=7.0 Hz), 7.55 (m, 3H), 5.34 (s, 1H, b), 4.46 (dd, 1H, J=2.52, 9.16 Hz), 4.34 (dd, 1H, J=1.92, 6.24 Hz), 1.15 (d, 3H, J=6.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1Br>>[F:1][C:2]1[CH:7]=[C:6]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][C:25]([F:24])([F:35])[F:34])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: FC(F)(F)Oc1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3OC(F)(F)F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-(trifluoromethoxy)bromobenzene. MS (ESI): mass calcd. for C17H11F4N3O, 349.08; m/z found, 350.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.02 (s, 1H), 7.96 (m, 1H), 7.65-7.47 (m, 4H), 7.42 (d, J=5.1, 1H), 7.39 (s, 1H), 6.73 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33]([N:35]([CH2:39][C:40]2[CH:41]=[C:42]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=2)[O:43][CH2:44][C@@H:45]2[CH2:47][C@H:46]2[C:48]([OH:50])=[O:49])[CH:36]2[CH2:38][CH2:37]2)=[O:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:66][C:67]([N:69]([CH3:71])[CH3:70])=[O:68]>CN(C=O)C.CCOCC>[CH:36]1([N:35]([CH2:39][C:40]2[CH:53]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:51]=[C:42]([O:43][CH2:44][C@@H:45]3[CH2:47][C@H:46]3[C:48]([O:50][CH2:66][C:67]([N:69]([CH3:71])[CH3:70])=[O:68])=[O:49])[CH:41]=2)[C:33]([C@@H:10]2[C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]4[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[Cl:32])=[CH:16][CH:15]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]2)=[O:34])[CH2:37][CH2:38]1
Reactant: CN(C)C(=O)CCl
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)OCC(=O)N(C)C)c1
Temperature: 80 °C

Procedure:
To a solution of (1R,2R)-2-{[3-{[[((3R,4S)-1-(tert-butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl](cyclopropyl)-amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic acid (1 eq.) from the previous step in DMF (0.1 M) was added cesium carbonate (2 eq.) and 2-chloro-N,N-dimethylacetamide (1.8 eq.). The reaction was heated to 80° C. for 2 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified was flash column chromatography (SiO2, 90% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3].C[Si](C)(C)[C:32]([F:35])([F:34])[F:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]([OH:26])[C:32]([F:35])([F:34])[F:33])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)C(F)(F)F)C1=O
Reaction time: 1 h

Procedure:
A solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal (80 mg, 0.186 mmol) and trimethyl(trifluoromethyl)silane (82 μL, 0.558 mmol) in THF (929 μL) was treated at 0° C. with 1 M tetrabutylammonium fluoride in THF (93 μL, 0.093 mmol). After being stirred for 1 h, three additional equivalents of trimethyl(trifluoromethyl)silane (82 μL, 0.558 mmol) and 1 M tetrabutylammonium fluoride in THF (93 μL, 0.093 mmol) were added to the reaction at 0° C. and the reaction was stirred for 14 h. The reaction mixture was diluted (EtOAc), washed (1×H2O and 1×sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure. Purification by reverse phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 60 to 90% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution) provided two compounds which are diastereomers at the secondary alcohol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([OH:16])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]3)[C:21]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([NH:31][C@H:28]3[CH2:29][CH2:30][N:26]([C:22]4[C:21]5[N:20]([CH:19]=[CH:18][N:17]=5)[CH:25]=[CH:24][N:23]=4)[CH2:27]3)=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1ncn(-c2ccc(F)c(F)c2)n1
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1ncn(-c2ccc(F)c(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of 1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (0.10 g, 0.44 mmol, 1 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.12 g, 0.44 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.19 mL, 0.49 mmol, 1.1 eq) and HATU (0.19 g, 1.3 mmol, 3 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)-1-(3,4-difluorophenyl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide (0.046 g, 0.11 mmol, 25%).