Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[O:4]1)[CH3:2].[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH2:17]([C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:21])[C:5](=[O:16])[O:4]1)[CH3:18]
Reactant: CI
Reactant: CCC1(CC)OC(=O)Nc2ccc([N+](=O)[O-])cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(CC)OC(=O)N(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4,4-diethyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one (5.00 g, 19.98 mmol) in DMF (30 mL) at 0° C. was added sodium hydride (1.20 g-60%, 29.97 mmol). After 20 minutes, methyl iodide (3.8 mL, 61.00 mmol) was added and the reaction was warmed to room temperature. After stirring for one hour, the reaction was quenched with ammonium chloride (sat.) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine repeatedly and dried over magnesium sulfate. Solvent was removed and the residue was triturated with ether to give 4,4-diethyl-1-methyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one a yellowish-white solid (3.74 g, 71%). 1H NMR (DMSO-d6): δ 8.27 (dd, J=9.0, 2.6 Hz, 1H), 8.05 (d, J=2.6 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 3.37 (s, 3H), 2.15 (m, 4H), 0.80 (t, J=7.3 Hz, 6H); MS (ESI) m/z 265 ([M+H]+); Anal. calcd for C13H16N2O4: C, 59.08; H, 6.10; N, 10.60. Found: C, 59.62; H, 6.20; N, 10.48.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:11](=[O:14])[CH2:12][CH3:13])[CH2:8]C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](O)(=O)[CH2:22][C:23]([OH:25])=[O:24]>N1C=CC=CC=1>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:11](=[O:14])[CH2:12][CH3:13])[CH:8]=[CH:21][CH2:22][C:23]([OH:25])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(=O)C(CC=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: CCC(=O)C(C=CCC(=O)O)(c1ccccc1)c1ccccc1
Yield: 72.9 %

Procedure:
A mixture of 3,3-diphenyl-4-oxo-hexanal (45 mg)[from Example 2], malonic acid (40 mg) and pyridine (1.5 ml) was heated at 80°-90° C. for 18 hours, with stirring. The volatiles were removed in vacuo and the residue was partitioned between water and chloroform (3×). The combined extracts were washed with water and dried (Na2SO4). Rotary evaporation of the solution gave a crude material which was purified by PTLC. Development with hexane/ethyl acetate (2:1) produced two bands. The lower band which was near the origin was scraped off the plate and eluted with methanol. Rotary evaporation of the solution yielded 38 mg of 5,5-diphenyl-6-oxo-3-octenoic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:36]1[CH2:41][CH2:40][N:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:22][C:2]([CH3:1])([CH3:21])[CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:24]2[CH:25]=[C:26]3[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=2)[NH:29][CH:28]=[C:27]3[CH:36]2[CH2:37][CH2:38][N:39]([S:42]([CH2:45][CH3:46])(=[O:43])=[O:44])[CH2:40][CH2:41]2)[CH:9]=[N:8][CH:7]=1
Reactant: CC(C)(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC(C)(C)C)c4)cc23)CC1
Yield: 34 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), (2,2-dimethylpropyl)amine (0.015 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.7 mg of the title compound (34%).
Reaction SMILES: O1CCOCC1.Cl[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9].[NH2:15][CH2:16][C:17]([OH:19])=[O:18]>[OH-].[Na+]>[CH2:11]([O:10][C:8]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:9])[CH:12]([CH3:14])[CH3:13]
Reactant: NCC(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)COC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 ml of dioxane and 872 μl (6.66 mmol) of isobutyl chloroformate are added to a solution of 500 mg (6.66 mmol) of glycine in 14 ml of 2N NaOH solution. The mixture is stirred overnight at RT and then extracted with methylene chloride. The aqueous phase is acidified with 4N HCl solution and extracted twice with methylene chloride. Drying (Na2SO4) and concentration of the extracts by evaporation yield N-isobutyloxycarbonyl-glycine; FAB-MS: (M+H)+=176; 1H-NMR (CDCl3) 8.0 (sb), 6.93 and 5.21 (2m, 1H), 4.02 and 3.88 (2m, each 2H), 1.93 (m, 1H), 0.94 (d, J=7, 6H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:23]O)[CH:19]=[CH:20][C:21]=1[CH3:22]>>[F:15][C:16]1[CH:17]=[C:18]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cc1ccc(CO)cc1F
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1F

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-fluoro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.28 (3H, s), 5.19 (2H, s), 5.72 (1H, d, J=2.0 Hz), 7.18-7.20 (1H, m), 7.07-7.11 (2H, m), 7.41 (1H, dd, J=1.2, 4.8 Hz), 7.56 (1H, d, J=1.6 Hz), 8.03 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H13FN4O, 309; Found, 309.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH:14]=3)=[C:9]([CH2:23][CH2:24][CH3:25])[CH:8]=2)=[CH:4][CH:3]=1.[C:28]([O:33]C)(=[O:32])[C@@H:29]([CH3:31])O>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([O:22][C@@H:29]([CH3:31])[C:28]([OH:33])=[O:32])[CH:20]=[CH:21][C:16]=4[O:15][CH:14]=3)=[C:9]([CH2:23][CH2:24][CH3:25])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1coc2ccc(O)cc12
Reactant: COC(=O)[C@@H](C)O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1coc2ccc(O[C@@H](C)C(=O)O)cc12

Procedure:
The title compound was prepared according to the following general procedure using the phenol from Step 11 and methyl (R)-lactate as the substrates.
Reaction SMILES: C(O)C.[CH:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])OCC.[CH3:14][C:15]([CH3:19])=[CH:16]C=O.C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.[K+]>[CH2:12]([O:11][CH:4]([O:8][CH2:9][CH3:10])[CH:14]=[C:15]([CH3:19])[CH3:16])[CH3:13]
Reactant: CC(C)=CC=O
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: CCOC(C=C(C)C)OCC
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
Under an argon atmosphere, a 250-mL, round-bottomed flask equipped with a stir bar was charged with abs. ethanol (52 mL, 892 mmol, 5.0 eq). The flask was cooled to 4° C. (internal) in an ice bath. Triethyl orthoformate (29.7 mL, 178 mmol, 1.0 eq) was added followed by 3-methyl-2-butenal (17.2 mL, 178 mmol, 1.0 eq). The resulting clear, colorless solution was further cooled to 2° C. (internal). Potassium hydrogen sulfate (1.277 g, 9.38 mmol, 0.05 eq) was then added in one portion, resulting in an immediate exotherm to 10° C. The heterogeneous mixture was allowed to warm to 21° C. (internal) over 45 minutes (within 20 minutes, the mixture became slightly cloudy) and then stirred for an additional 15 minutes. The reaction mixture was then filtered and the remaining solid rinsed with abs. ethanol (5 mL). To the resulting clear, colorless solution was added anhydrous potassium carbonate (2.615 g, 18.92 mmol). The mixture was stirred for one hour before filtering off the potassium carbonate. The solid was rinsed with abs. ethanol (5 mL) and the filtrate was vacuum distilled (172 mm Hg) through a Vigereux column (13.5 cm) to produce 24.14 g (85% yield) of the title compound (boiling point 115°-119° C.).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].[C:23](Cl)(=[O:33])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:28]1[O:29][C:30]2[CH:31]=[CH:32][C:24]([C:23]([O:20][CH2:19][N:15]3[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]4[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:23](=[O:33])[C:24]5[CH:32]=[CH:31][C:30]6[O:29][CH2:28][O:27][C:26]=6[CH:25]=5)[C:4](=[O:22])[CH2:5]4)[CH2:17][C:16]3=[O:18])=[O:33])=[CH:25][C:26]=2[O:27]1
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)c3ccc4c(c3)OCO4)C(=O)C2)CC1=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.7 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (0.94 g, 3.0 m mol) and pyridine (10 ml), piperonyloyl chloride (1.00 g, 6.0 m mol) dissolved in pyridine (10 ml) was added, and then the mixture was stirred for 20 hours at room temperature. To the reaction mixture, chloroform (250 ml) was added and the solution was washed with 10% sulfuric acid solution and successively with water, further was washed with aqueous sodium bicarbonate solution and successively with water. Then, the solvent was removed under reduced pressure to give the titled compound (1.12 g; yield 61%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[N:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=[C:2]([C:18]2[CH:19]=[N:20][CH:21]=[C:16]([F:15])[CH:17]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ccc(F)cc2c1Cl
Reactant: OB(O)c1cncc(F)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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cncc(F)c2)nc2ccc(F)cc2c1Cl

Procedure:
Prepared according to general Procedure F using 2,4-dichloro-6-fluoro-3-methylquinoline (300 mg, 1.3 mmol), 5-fluoropyridin-3-ylboronic acid (160 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium(0) (151 mg, 0.13 mmol), sodium carbonate (242 mg, 2.28 mmol) in toluene:water (5 mL:2 mL) and heating at 130° C. overnight. After purification 4-chloro-6-fluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=291.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=1.[C:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)#[CH:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:36]#[C:35][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccncc1
Reactant: O=S(=O)(Oc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1)C(F)(F)F
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4ccncc4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)-benzene and 4-ethynyl-pyridine.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17][NH2:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>CCCCCCC>[C:1]([NH:18][CH2:17][CH:16]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCCCCCCCCCC(CN)CCCCCCCC
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CCCCCCCCCCC(CCCCCCCC)CNC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
62 ml of pivaloyl chloride were dissolved in 180 ml of heptane and then added to 150 g of 2-octyldodecylamine at a temperature of 60° C. After addition of 70 ml of triethylamine, the reaction medium was stirred for 2 hours and then purified on silica. 118 g of the desired amide were thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.Cl.[CH3:28][NH2:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:29][CH3:28])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CN
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Agent: Cl
Product: CNC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to methylamine hydrochloride via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-methylterephthalamide. MS (Q1) 401 (M)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:21][CH:22]=[O:23])=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccnc2ccccc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-quinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=[CH:11][C:4]=12.C([Li])(CC)C.C(Br)(Br)(Br)[Br:30]>O1CCCC1>[Br:30][C:8]1[C:3]([C:2]([F:23])([F:22])[F:1])=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(F)(F)F)ccnc21
Reactant: BrC(Br)(Br)Br
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: FC(F)(F)c1c(Br)cnc2[nH]ccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
4-Trifluoromethyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (1.54 g, 4.5 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −78° C. Sec-butyllithium (1.4 M in cyclohexane, 10 mL, 14 mmol) was added dropwise and the mixture was stirred at −78° C. for 1 h. A solution of carbontetrabromide (4.5 g, 13.5 mmol) in tetrahydrofuran (20 mL) was added quickly at −78° C. and the mixture was stirred for 15 min. The reaction was quenched with saturated ammonium chloride solution. The mixture was warmed to ambient temperature and the layers were separated. The organic layer was dried with magnesium and concentrated. Purification by flash silica gel chromatography using a gradient of (ethyl acetate and methanol 9:1) in hexanes afforded 5-Bromo-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (170 mg, 0.64 mmol, 9% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.49 (bs, 1H), 8.54 (s, 1H), 7.82 (m, 1H), 6.61 (m, 1H). MS: m/z 264.9/266.9 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17](Br)=[N:18][CH:19]=3)[CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH:23]1[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=1C.[H-].[Na+].N#N>CN(C=O)C>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:29][C:28]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:5]4[CH:6]=[CH:21][CH:22]=[C:3]([CH3:1])[CH:4]=4)=[N:18][CH:19]=3)[CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cccc(O)c1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccc(Br)nc2)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccccc2Oc2ccc(Cn3cncc3Cc3ccc(C#N)cc3)cn2)c1
Temperature: 110 °C

Procedure:
The compound from Example 1 Step 3 (0.11 g 0.20 mmol), m-cresol (0.064 g, 0.59 mmol) and sodium hydride (60% dispersion in oil, 4.0 equiv, 0.032 g) were suspended in DMF (0.5 mL) in an N2 purged sealed tube and heated at 110° C. for 24 hr. The residue was dissolved in methanol and purified on a C18 preperative hplc column. Lyophilized from dioxane/HCl to provide the title compound. FAB-MS: calc: 380.4 found: 381.0. 2 1H-NMR (CD3OD): 2.4 ppm (s, 3H); 4.2 ppm (s, 2H); 5.4 ppm (s, 2H); 6.8-7.6 ppm (11H); 7.9 ppm (s, 1H); 9.1 ppm (s,1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:44][C@H:45]([CH3:53])[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=3)=[CH:27][N:28]=2)=[CH:19][CH:18]=1)[C:13]([NH:44][C@@H:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH3:53])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)O)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Prepared using General Procedure 7. To a stirred solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid (1000 mg, 1.762 mmol) and (R)-tert-butyl 2-aminopropanoate HCl (352 mg, 1.938 mmol) in DMF (8 mL). The solution was cooled to 0° C. and TEA (737 μl, 5.28 mmol) was added. To this mixture was slowly added HATU (804 mg, 2.114 mmol) over 5 mins then the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with EA (150 mL) and washed with 1M HCl (100 mL) then brine (100 mL). The organic layer was isolated and dried over MgSO4. The solvents were removed to give a white solid and ACN (50 mL) was added and the suspension was sonicated. The fine suspension was stirred for 30 mins then filtered and washed with iso-hexanes to afford 881 mg (70.5%) of tert-butyl ((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-23 as a white powder. LCMS-ESI (m/z) calculated for C41H50N4O6: 694.4; no m/z observed, tR=3.39 min (Method 11). The chiral purity was calculated at >99% e.e. (Chiral Method).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([OH:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CN(C=O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O[C@H]1CCCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(O[C@H]2CCCN(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a suspension of NaH (0.83 g, 37 mmol) in DMF (10 mL) was added 1-benzyl-(3S)-3-hydroxypiperidine (4.1 g, 21.5 mmol), and the resulting reaction mixture was stirred at ambient temperature for 2 hours. 4-Fluoronitrobenzene (2.5 mL, 23.6 mmol) in DMF (10 mL) was then added to the mixture dropwise. The resulting reaction mixture was stirred at ambient temperature for 2 hours. After removal of DMF in vacuo, the crude mixture was dissolved in ethyl acetate (200 mL), washed with water (100 mL×3), brine (100 mL), to give a yellow oil. Purification using silical gel chromatography column afforded 1-benzyl-(3S)-3-(4-nitrophenoxy)piperidine (6.5 g, 97% yield) as a yellow oil.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1)=[O:32]>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=2)=[O:32])[N:10]=[CH:9]1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: O=C(COCCCc1c[nH]cn1)c1cccc([N+](=O)[O-])c1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of 2-bromo-1-(3-nitrophenyl)ethanone are treated as described in Example 74.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C(#N)C>[CH3:27][C:15]([NH:14][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4])([CH3:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: CC(C)(N)COc1ccc(C#N)cn1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)COc1ccc(C#N)cn1
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.05 g, 0.25 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen, was added 6-(2-amino-2-methyl-propoxy)-nicotinonitrile (0.1 g, 0.508 mmol). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the desired compound as a white solid. MS (DCI) m/z 352 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.01-2.04 (2H, m), 2.05 (2H, s), 2.07 (2H, s), 3.03 (1H, m), 3.04 (6H, s), 3.5-4.57 (2H, m), 4.57-4.58 (1H, m), 4.58-5.59 (1H, m), 7.0-7.08 (3H, m).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>CC(O)=O>[NH2:3][C:4]1[N:13]=[CH:12][C:11]([Br:1])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrBr
Reactant: COC(=O)c1cccnc1N
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Bromine (0.7 mL, 14 mmole) was added dropwise to a stirred solution of methyl 2-aminonicotinate (2.0 g, 13 mmole) in HOAc (50 mL). A suspension formed within 30 min. The reaction was allowed to stir at room temperature for 2 h, then was concentrated under vacuum. The residue was triturated with 1.0 N Na2CO3 (50 mL) and the solid was collected by suction filtration. The solid was washed with H2O (50 mL) and dried under vacuum to give the title compound (2.95 g, 98%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=2.5 Hz, 1 H), 8.23 (d, J=2.5 Hz, 1 H), 6.40 (br s, 2 H), 3.90 (s,3 H).