Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:15]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)[C:16]([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.O>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH:5][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:21][CH:22]=1
Reactant: CC(C)(C)CCN
Reactant: CC(C)(C)Cc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CCNC(=O)c1ccc(CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cold solution of 5.26, g of 3,3-dimethylbutylamine and 21.0 ml of triethylamine in 180 ml of methylene chloride was added dropwise a solution of p-neopentylbenzoylchloride in 20 ml of methylene chloride. The resulting mixture was stirred at room temperature for 5 hours and diluted with water. The organic layer was washed with 3N hydrochloric acid, water, 1N sodium hydroxide, brine, dried, and evaporated to yield a solid. The solid was recrystallized from ethylacetate:hexane to yield N-(3,3-dimethylbutyl)-4-(2,2-dimethylpropyl)benzamide as a beige solid, mp 124°-126° C.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21](O)=[O:22])=[C:8]2[CH3:25])=[CH:4][CH:3]=1.C[N:29](C=O)C.C(Cl)(=O)C(Cl)=O.N>C1C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21]([NH2:29])=[O:22])=[C:8]2[CH3:25])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)c(CC(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(C)CC(N)=O)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the acid of Example 7, Step 6, (600 mg, 1.39 mmol) in benzene (10.0 mL) was added at 0° C. DMF (50 mL) and oxalyl chloride. After a period of 30 min at 0° /C., THF (10.0 mL) was added to the resulting mixture and ammonia gas was bubbled until saturation. The mixture was stirred for 4 h at r.t. The reaction was poured over water, extracted with EtOAc, dried over Na2SO4, evaporated in vacuo and filtered over silica gel (50% EtOAc in THF) to provide the desired amide (530 mg).
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1)[O:12][C@H:13]1[CH2:21][CH2:20][C@H:19]2[C@@H:15]([CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18]2)[C@@H:14]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[C:1]([O:9][CH2:10][C@H:11]([C:36]1[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1)[O:12][C@H:13]1[CH2:21][CH2:20][C@H:19]2[C@@H:15]([CH2:16][NH:17][CH2:18]2)[C@@H:14]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CC[C@@H]1O[C@H](COC(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1[C@H]1[C@@H]2CNC[C@H]2CC[C@@H]1O[C@H](COC(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The intermediate from step A (8.6 g, 12.43 mmol) was added to 4 N HCl in dioxane (200 mL) at 0° C. The solution was then stirred at room temperature for 1 h. The volatiles were removed in vacuo. The residue was dissolved in 750 mL ether, washed with 2N sodium hydroxide aqueous, brine and saturated sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a foam solid (8.12 g crude). M++1: 592.49.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:15]=[CH:16][CH:17]=1>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[CH2:22]([NH:21][C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:13]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: Nc1cccc(NC(=O)NCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(NCc1ccccc1)Nc1cccc(Nc2ncnc3cc[nH]c23)c1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 41.6 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in 1-methyl-2-pyrrolidone (1.3 mL), was added N-(3-aminophenyl)-N′-benzylurea (220 mg), and the mixture was heated to 140° C. and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL), and extracted with a mixed solvent (30 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=100/0→85/15). The object fraction was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (97 mg) as pale-yellow powder crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[NH:21][C:14]=23)[CH2:3][CH2:2]1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:14]=23)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3ccc(F)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a2) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][C:24](=[O:26])[CH3:25])[CH:19]=2)[CH:14]=1)=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O1CCCC1.[OH-].[Na+]>O>[CH2:2]([C:1]1[S:36][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][C:24](=[O:26])[CH3:25])[CH:19]=3)[CH:14]=2)=[N:10][N:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCCC(=O)NNC(=O)c1ccc2cc(OC(C)=O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCc1nnc(-c2ccc3cc(OC(C)=O)ccc3c2)s1
Yield: 97.9 %

Procedure:
In a 100 ml-round-bottomed flask, 3.00 g (8.42 mM) of N-heptanoyl-N'-(6-acetoxy-2-naphthoyl)hydrazine, 3.83 g (9.47 mM) of Lawesson's reagent and 40 ml of tetrahydrofuran were placed, followed by refluxing for 1 hour under stirring. After the reaction, the reaction mixture was cooled on an iced water bath and poured into a solution of 3.00 g of sodium hydroxide in 250 ml of iced water to precipitate a crystal. The crystal was recovered by filtration and washed with water to obtain 2.92 g of 2-hexyl-5-(6-acetoxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 97.9 %).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:14]=[C:13](Br)[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C[C:26]([N:28](C)C)=O>[C-]#N.[C-]#N.[Zn+2].[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:14]=[C:13]([C:26]#[N:28])[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(cc(Br)n2Cc2cccc(F)c2)c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1ncc2c(cc(C#N)n2Cc2cccc(F)c2)c1O
Temperature: 120 °C

Procedure:
A mixture of 2-bromo-1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (1000 mg), Zn(CN)2 (150 mg), Zn dust (17 mg), Pd2(dba)3 (59 mg), dppf (71 mg) in DMA (8 mL) was heated to 120° C. for 90 min; then the mixture was partitioned between EtOAc and water, the organic phase was then washed with sat. NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated sequentially to give a residue, which was purified with column to give desired title compound (270 mg). The title compound, ESI MS (m/z): 340 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)(=[O:3])[CH3:2].[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([NH:12][C@@H:13]([CH3:29])[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=3)=[N:16]2)=[O:11])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)no1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Yield: 30.5 %

Procedure:
(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from 5-acetylisoxazole-3-carboxylic acid (2.142 g, 13.81 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3 g, 2.142 g). The product was purified by Flash-chromatography with yield of 30.5%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.66 (s, 3H), 4.26 (dd, 1H), 4.47 (dd, 1H), 4.56-4.66 (m, 1H), 4.65 (d, 1H), 7.30 (s, 1H), 7.50 (d, 1H), 7.71 (d, 1H), 7.84 (dd, 1H), 7.08 (d, 1H), 7.17 (d, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12](Cl)=[O:13])[CH:9]=[N:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[C:29]1([C:27]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([NH:15][C:12]([C:8]3[CH:9]=[N:10][CH:11]=[C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)[CH:7]=3)=[O:13])[CH:28]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)c1cncc(-n2cccc2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cncc(-n2cccc2)c1
Reaction time: 2 h

Procedure:
0.062 mL of triethylamine and 69 mg of 5-(1H-pyrrol-1-yl)pyridine-3-carbonyl chloride were added to 5.0 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenylbenzoate at room temperature sequentially and stirred at the same temperature for 2 hours. 0.031 mL of triethylamine and 23 mg of 5-(1H-pyrrol-1-yl)pyridine-3-carbonyl chloride were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour. 0.62 g of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 4-phenyl-2-(5-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoate.
Reaction SMILES: [CH2:1]([N:3]([CH2:58][CH3:59])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:36]=[CH:37][CH:38]=2)[C:16]([N:18]([CH2:20][CH2:21][N:22]2[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[CH3:19])=[O:17])=[O:12])=[C:6]([C:39]2[CH:44]=[C:43]([C:45](=[O:57])[NH:46][C@@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[CH2:50][CH2:49][CH2:48]3)[CH:42]=[CH:41][N:40]=2)[CH:5]=1)[CH3:2].Cl>O1CCOCC1>[N:22]1([CH2:21][CH2:20][N:18]([CH3:19])[C:16](=[O:17])[C:15]2[CH:36]=[CH:37][CH:38]=[C:13]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:58][CH3:59])=[CH:5][C:6]=3[C:39]3[CH:44]=[C:43]([C:45](=[O:57])[NH:46][C@@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:50][CH2:49][CH2:48]4)[CH:42]=[CH:41][N:40]=3)=[O:12])[CH:14]=2)[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCCN(C(=O)OC(C)(C)C)CC3)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCCNCC3)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (S)-tert-butyl 4-(2-(3-((4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)-N-methylbenzamido)ethyl)-1,4-diazepane-1-carboxylate was added 4M HCl in dioxane (3 mL). The mixture was stirred at room temperature for 2 h, concentrated to give a light yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[CH3:34]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][C:25]([F:24])=[C:26]([CH3:34])[CH:27]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: Cc1cc(C(=O)Cl)ccc1F
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc(F)c(C)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-4-fluoro-3-methyl-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 4-fluoro-3-methylbenzoyl chloride (125 μl, 0.89 mmol). The title compound was obtained as yellow powder (220 mg, 61%).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=2[C:24]#[N:25])[CH:17]=1.FC1C=CC(B2OC(C)(C)C(C)(C)O2)=C(C=1)C#N.ClC1C=C(Cl)C=CN=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]([C:18]2[CH:17]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:21]=[CH:20][N:19]=2)=[C:23]([CH:26]=1)[C:24]#[N:25]
Reactant: N#Cc1cc(F)ccc1-c1cc(Cl)ccn1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Agent: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Agent: Clc1ccnc(Cl)c1
Product: CC(C)(O)c1ccn2c(-c3ccnc(-c4ccc(F)cc4C#N)c3)cnc2c1F

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 2-(4-chloropyridin-2-yl)-5-fluorobenzonitrile (prepared from 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile and 2,4-dichloropyridine by an analogous procedure to that described in WO 02/076983), by the method of Example 23, to give 5-fluoro-2-{4-[8-fluoro-7-(2-hydroxyprop-2-yl)imidazo[1,2-α]pyridin-3-yl]pyridin-2-yl}benzonitrile: δH (500 MHz, CDCl3) 1.75 (6H, s), 2.08 (1H, s), 7.32 (1H, t, J 7.0), 7.45-7.49 (1H, m), 7.53-7.56 (2H, m), 7.92 (1H, s), 7.98 (1H, t, J 0.7), 7.99 (1H, dd, J 3.4, 5.4), 8.50 (1H, d, J 7.3), 8.87 (1H, d, J 5.1); m/z (ES+) 391. Also isolated from the above reaction was 5-fluoro-2-{4-[8-fluoro-7-(2-hydroxyprop-2-yl)imidazo[1,2-α]pyridin-3-yl]pyridin-2-yl}benzamide: δH (500 MHz, DMSO) 1.59 (6H, s), 7.35-7.44 (3H, m), 7.60 (1H, t, J 0.6), 7.66 (1H, dd, J 0.5, 0.7), 7.82-7.84 (1H, m), 7.85 (1H, s), 7.95 (1H, s), 8.05 (1H, s), 8.60 (1H, d, J 7.1), 8.73 (1H, d, J 5.4); m/z (ES+) 409.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:15]=[C:16]([C:33]2([CH:39]([C:41]3[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][CH:42]=3)[OH:40])SCCCS2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].BrN1C(=[O:54])CCC1=O.ClCCl>CC(C)=O.O.CC(C)=O>[CH2:1]([O:13][C:14]1[CH:15]=[C:16]([C:33](=[O:54])[C:39]([C:41]2[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][CH:42]=2)=[O:40])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCOc1ccc(C2(C(O)c3ccc(Br)cc3)SCCCS2)cc1OCCCCCCCCCCCC
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C(=O)C(=O)c2ccc(Br)cc2)cc1OCCCCCCCCCCCC
Temperature: 0 °C

Procedure:
A solution of [2-(3,4-bis-dodecyloxy-phenyl)-[1,3]dithian-2-yl]-(4-bromo-phenyl)-methanol (JYC-I-049-A). (10.99 g, 0.015 mol) in 400 mL of acetone was added dropwise to a solution of N-bromosuccinimide (NBS) (45.4 g, 0.255 mol) in 300 mL of 3% water/acetone (v/v) at 0° C. in an ice bath. The reaction mixture was stirred at 0° C. and gradually warmed up to room temperature over 30 min. The mixture was then poured into a saturated aqueous NaSO3 solution (400 mL) and dichloromethane (400 mL). The mixture was stirred for an additional 10 min. The organic layer was washed with water several times and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give a pale yellow solid. Purification was carried out by first recrystallization from hexanes, followed by column chromatography (silica gel, hexanes:dichloromethane=1:1 (v/v)) to afford two products. The major product, 1-(3,4-bis-dodecyloxy-phenyl)-2-(4-bromo-phenyl)-ethane-1,2-dione (JYC-I-053-B), was isolated as a yellow solid. (3.21 g, 33%). 1H NMR (200 MHz, CDCl3, δ): 7.81 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.54 (d, J=2.0 Hz, 1H), 7.39 (dd, J=2.0 Hz, 8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 1.82 (m, 4H), 1.20-1.52 (m, 40H), 0.85 (t, J=6.2 Hz, 6H). 13C{(H} NMR (50 MHz, CDCl3, δ): 193.60, 192.64, 155.37, 149.46, 132.30, 132.08, 131.24, 130.17, 126.22, 125.60, 112.13, 111.58, 69.23, 69.15, 31.91, 29.61, 29.36, 29.03, 28.88, 25.97, 25.90, 22.68, 14.10. HRMS-FAB (m/z): [M+H]+ calcd for C38H58BrO4, 657.3518; found, 657.3515. Anal. Calcd for C39H57BrO4: C, 69.39; H, 8.73. Found: C, 69.27; H, 8.71. The minor product, 1-(2-bromo-4,5-bis-dodecyloxy-phenyl)-2-(4-bromo-phenyl)-ethane-1,2-dione (JYC-I-053-A), was isolated as a white solid (0.31 g). 1H NMR (200 MHz, CDCl3, δ): 7.85 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 7.39 (s, 1H), 6.98 (s, 1H), 4.02 (t, J=6.6 Hz, 2H), 4.01 (t, J=6.6 Hz, 2H), 1.82 (m, 4H), 1.20-1.52 (m, 36H), 0.86 (t, J=6.4 Hz, 6H). HRMS-FAB (m/z): [M+H]+ calcd for C38H57Br2O4, 735.2624; found, 735.2638.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl.CCN(CC)CC.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:20](=[O:21])[CH2:19][Cl:18]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of L-proline methyl ester.HCl (8.04 g, 43 mmol) in CH2Cl2 (86.0 ml) at 0° C. was added NEt3 (12.0 mL, 86 mmol), followed by chloroacetyl chloride (1.1 equiv, 3.72 g, 47 mmol) dropwise via syringe. The reaction mixture was allowed to warm to room temperature with stirring. After 16 h, the mixture was diluted with sat. aqueous NaHCO3 and the organic layer was removed. The aqueous portion was extracted with CH2Cl2 (25 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford N-chloroacetyl-L-proline methyl ester as a light brown oil (7.85 g, 38 mmol). A portion of the resulting oil (5.25 g, 26 mmol) was dissolved in butanone (51 mL) at RT and NaN3 (3.67 g, 51 mmol) was added in one portion. The reaction vessel was fitted with a reflux condenser and the heterogenous mixture was heated at 80° C. for 20 h. The resulting mixture was cooled to room temperature, filtered and concentrated in vacuo to afford N-azidoacetyl-L-proline methyl ester as a light red oil (5.37 g, 25 mmol). A portion of the oil (1.97 g, 9 mmol) was dissolved in anhydrous PhMe (38 mL) and PPh3 (2.55 g, 10 mmol) was added in one portion. After gas evolution steadied, the reaction mixture was heated at 90° C. for 20 h. The reaction mixture was concentrated in vacuo and triturated with a 1:1 mixture of Et2O/hexanes in order to remove the desired diketopiperazine product from the bulk of phosphine oxide byproduct. The trituration solution was concentrated and the resulting residue was purified by flash column chromatography on silica gel (elution: 1% MeOH to 10% MeOH in 1:1 EtOAc/PhMe+1% NEt3). The resulting diketopiperazine lactim ether product, (S)-1-methoxy-6,7,8,8a-tetrahydropyrrolo[1,2-a]pyrazin-4(3H)-one (13), (1.43 g, 8 mmol, 80% yield, 3 steps) was obtained as a light yellow oil: TLC (60% EtOAc in hexane), Rf: 0.20 (CAM); [α]D25=+102 (c 2.07, CH2Cl2); IR (film): 2951, 2984, 2889, 2360, 2107, 1685, 1457, 1322, 1263, 1022, 751, 673, 625, 573 cm−1; 1H NMR (400 MHz, CDCl3) 4.21 (dd, J=9.5 Hz, 1.6 Hz, 1H), 4.11 (d, J=4.9 Hz, 1H) 4.03 (m, 1H), 3.68 (s, 3H), 3.65 (m, 1H) 3.47 (m, 1H), 2.25 (m, 1H), 2.03 (m, 1H), 1.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4, 161.8, 56.5, 53.3, 52.3, 44.2, 29.3, 22.2; Exact mass calcd for C8H12N2O2 [M+Na+], 191.0791. Found 191.0790.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[O:19][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Al](C)C>CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([CH3:20])[C@@H:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Al](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H]2O[C@H]12
Solvent: CCCCCC
Product: C[C@@H]1c2ccccc2C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O

Procedure:
Under argon to a solution of (±)-(1S,2R,3R)-3-tert-butoxycarbonylamino -1,2-epoxy-1,2,3,4-tetrahydro-naphthalene (108 mg) in hexane (10 ml) was added a 2 M solution of trimethylaluminum in hexane (0.30 ml), the mixture was heated under reflux for 31/2 hours and was quenched by addition of a 2 M aqueous solution of ammonium chloride adjusted to pH 8 with ammonium hydroxide. The resulting suspension was extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate and evaporated under vacuum to give a colorless oil which was purified by preparative thin layer chromatography on silica gel (elution with ethyl acetate:cyclohexane, 3:8) to afford the title compound as a solid (32 g).