Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl[C:23]([O:25][CH:26]1[CH:33]2[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:35][CH:27]1[CH2:28]3)[CH2:32]2)=[O:24]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:23]([O:25][CH:26]3[CH:27]4[CH2:35][CH:31]5[CH2:30][CH:29]([CH2:34][CH:33]3[CH2:32]5)[CH2:28]4)=[O:24])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Solvent: ClCCl
Product: CCOC(=O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A 100-mL flask was charged with (±)-ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (457 mg, 1.3 mmol) dissolved in dry CH2Cl2 (10 mL). TEA (394 mg, 3.9 mmol) was added at 0° C. and stirred for 1 h. 2-adamantyl chloroformate (301 mg, 1.4 mmol) was added and the mixture was stirred overnight. The mixture was concentrated to give a residue was purified by column chromatography to give (±)-(2-adamantyl) 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (270 mg, 39%). The enantiomers were separated by chiral HPLC to give isomer 1 (100 mg, 14%) and isomer 2 (100 mg, 14%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[O:16][C:15](=[O:17])[C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccc(F)cc2)=NC12CCCCC2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
After a suspension of 13.3 g (50 mmol) of 1-[(4-fluorobenzoyl)amino]cyclohexanecarboxylic acid in 30 ml of acetic anhydride was stirred at 100° C. for 30 minutes, the reaction solution was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was washed with water, a saturated aqueous sodium hydrogencarbonate solution, and then saturated brine. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 8.5 g (69%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH2:15])=O)(C)(C)C.Cl>C(O)CCC>[F:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([C:14]([NH2:15])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Agent: Cl
Solvent: CCCCO
Product: NC(=O)[C@@H]1C[C@H](F)CN1
Temperature: 50 °C
Reaction time: 60 h

Procedure:
A mixture of (2S,4S)-2-carbamoyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g), conc. Hydrochoric acid (0.6 ml) and 1-butanol (10 ml) is heated for 48 hours at 50° C. The reaction mixture is evaporated and partitioned dichloromethane and aqueous sodium bicarbonate, the dichloromethane layers are dried over sodium sulphate and evaporated. A solution of 7M ammonia in methanol (10 ml) is added to the residue and the mixture is stood for 60 hours at room temperature in a sealed vessel. Evaporation and trituration with ethanol gives the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]([OH:20])=O)=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(CC)CC.[N:52]1([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:56][CH2:55][CH2:54][CH2:53]1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:18]([N:60]2[CH2:61][CH2:62][CH:57]([N:52]3[CH2:56][CH2:55][CH2:54][CH2:53]3)[CH2:58][CH2:59]2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH:7]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of 0.42 g (1.5 mmol) of 3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (intermediate 1B) in 15 ml of DMF was added 0.60 g (1.6 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and 0.62 ml=0.45 g (4.5 mmol) of Et3N; after 30 min, 0.24 g (1.6 mmol) of 4-pyrrolidin-1-yl-piperidine was added. 1 hour later, the reaction mixture was poured into crashed ice and extracted three times with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 95:5 to 4:1) to give 0.56 g (89%) of the title compound as light brown oil. MS: 418.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][NH:11][C:12]1[C:15](=[O:16])[C:14](=[O:17])[C:13]=1[NH:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH3:21])[C:5]#[N:6].[H-].[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]([C:12]1[C:15](=[O:16])[C:14](=[O:17])[C:13]=1[NH:18][C:19]([CH3:22])([CH3:23])[CH2:20][CH3:21])[C:26](=[O:28])[CH3:27]
Reactant: CCC(C)(C)Nc1c(NCc2ccc(C#N)cc2Cl)c(=O)c1=O
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(N(Cc2ccc(C#N)cc2Cl)C(C)=O)c(=O)c1=O
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
A solution of 3-chloro-4-{[2-(1,1-dimethyl-propylamino)-3,4-dioxo-cyclobut-1-enylamino]-methyl}-benzonitrile (0.829 g, 2.50 mmol, Example 76) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (5 mL) was treated with sodium hydride (0.066 g, 2.75 mmol) and stirring was continued for 15 minutes. Acetic anhydride (0.281 g, 2.75 mmol) was added. After stirring 40 minutes at room temperature, solvent was removed and the residue was partitioned between ethyl acetate and brine, and the brine fraction was extracted with ethyl acetate. The combined ethyl acetate fractions were washed with dilute, aqueous sodium carbonate solution, with brine and dried (anhydrous sodium sulfate). Removal of solvent gave a yellow solid that was chromatographed (gravity, chloroform) on silica. The appropriate fractions were freed of solvent and the foamy residue was solidified by addition-rotoevaporation of hexane (twice). Recrystallization (twice) of the solid from acetone-hexane gave 513 mg of the title compound as a white solid: mp 150.5°-151.0° C. (softens 149.5° C.); 1H NMR (DMSO-d6) δ7.90-9.22 (broad hump, 1H), 8.10 (s, 1H), 7.84 (m, 1H), 7.51 (d, 1H), 5.29 (br s, 2H), 2.16 (s, 3H), 1.71 (q, 2H), 1.35 (s, 6H), 0.85 (t, 3H) ppm. IR (KBr): 3300, 3080, 2230, 1790, 1720, 1680 cm-1. MS (m/z) 373/375 (M+). HPLC indicates a major component (>99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]2[C:29]([O:31][C:32](=O)[C:22]=2[CH:21]=1)=[O:30]>>[Br:19][C:16]1[CH:17]=[CH:18][C:12]2[O:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([N:1]4[C:29](=[O:30])[C:23]5[C:22](=[CH:21][CH:20]=[C:25]([C:26]([OH:28])=[O:27])[CH:24]=5)[C:32]4=[O:31])[CH:3]=3)=[N:14][C:13]=2[CH:15]=1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole (166 mg, 0.5 mmol) and 1,2,4-benzenetricarboxylic anhydride (100 mg, 0.5 mmol) the title compound was obtained (238 mg, 93%). 1H NMR (DMSO) δ 8.44(dd, 1H), 8.32(m, 3H), 8.10(d, 1H), 8.02(d, 1H), 7.77(d, 1H), 7.57(dd, 1H), 7.48(d, 1H). MS 490.9 m/z (M−H)−.
Reaction SMILES: [Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].FC(F)(F)S(O[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])(=O)=O.CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][O:5][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: C=C(Br)CCO
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(Br)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 3-bromobut-3-en-1-ol (5.2 g, 34.4 mmol) in dichloromethane (69 mL) at rt was added tert-Butyldimethylsilyl trifluoromethanesulfonate (10 g. 37.9 mmol) and DIEA (7.22 mL, 41.3 mmol) and the mixture was stirred at rt for 30 min. The reaction mixture was partitioned between dichloromethane and water, and the crude product obtained from the dichloromethane layer was purified by chromatography eluting with 5-30% EtOAc/Hexanes to give the title compound as a colorless liquid (8.72 g, 95%). 1H NMR (400 MHz, CDCl3) δ 5.66 (1H, s), 5.48 (1H, s), 3.81 (2H, t, J=6.0 Hz), 2.64 (2H, t, J=6.0 Hz), 0.91 (9H, s), and 0.09 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl.C(=O)([O-])[O-]>O1CCOCC1.CO.COCCO>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]([CH2:13][CH3:14])[C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCNC(=O)c2ccc(N)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1CCNC(=O)c2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Temperature: 25 °C

Procedure:
Into a microwave vial, 8-amino-1-ethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (75 mg, 0.00036 mol), N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (113 mg, 0.332 mmol), 4 M of hydrogen chloride in dioxane (0.2 mL), and 2-methoxyethanol (2.3 mL) were added. The reaction was then heated in microwave at 120 degree Celsius for one hour. MP-carbonate (3.16 mmol/g loading; 263 mg, 0.83 mmole) and methanol (10 mL) were added. The mixture was stirred at room temperature over night. The solid was filtered and washed with methanol. The desired product was isolated via column chromatography with DCM and methanol as eluant. The collected fractions afforded N-{(1R,2R)-2-[5-Chloro-2-(1-ethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a yellow solid (35 mg, 19%). 1H-NMR (DMSO-D6, 400 MHz): δ 9.19 (s, 1H), 7.94 (s, 1H), 7.51 (d, 1H), 7.12 (d, 1H), 7.07 (d, 1H), 6.97 (s, 1H), 6.75 (d, 1H), 5.99 (bs, 1H), 3.70-3.88 (m, 1H), 3.25-3.52 (m, 7H), 2.92 (s, 3H), 1.97-2.10 (m, 2H), 1.69 (bs, 2H), 1.15-1.48 (m, 4H), 1.08 (t, 3H) LCMS (ESI+) 508.26 (M+H). MP 216-220° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:46])([F:45])[C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:12][N:13]([CH3:37])[C:14](=[O:36])[C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[CH:19][C:18]([CH:28]([OH:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:28]([C:18]1[CH:19]=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:15]([C:14]([N:13]([CH2:12][C:11]2[CH:10]=[C:9]([C:8]([F:45])([F:7])[F:46])[CH:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=2)[CH3:37])=[O:36])=[CH:16][N:17]=1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccccc1-c1cc(C(O)c2ccccc2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1-c1cc(C(=O)c2ccccc2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 0.018 ml (0.21 mmol) oxalyl chloride in 2.5 ml dichloromethane 0.03 ml (0.4 mmol) dimethylsulfoxide were added at −78° C. After 5 min a solution of 100 mg (0.179 mmol) (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(hydroxy-phenyl-methyl)-N-methyl-4-o-tolyl-nicotinamide (Example 76) in 2.5 ml dichloromethane were added dropwise at −78° C. After stirring for another 30 min at −78° C. 0.15 ml (0.90 mmol) triethylamine were added. The reaction mixture was allowed to warm to room temperature. Dilution with dichloromethane was followed by washing with three portions of 1 M aqueous hydrochloric acid solution and one portion of a saturated aqueous solution of sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Column chromatography afforded 69 mg (70%) of the title compound as a light-yellow foam.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCOCC1.O>[OH:3][CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C#N)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)c1ccc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.1 g (0.01 mole) of p-(5-acetyl-2-furyl)benzonitrile and 40 ml of 95% dioxane/water was added portionwise 0.37 g (0.10 mole) of NaBH4 while maintaining the temperature at 15°-20° by means of an ice bath. The reaction was stirred at room temperature for 3 hours and then added to ice/water with a precipitate forming. The precipitate was filtered and dried in vacuum pistol at room temperature to yield 1.6 g (75%), n.p. 79°-82°, of title compound.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=1>C(O)C>[C:15]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2-c2ccccc2)[nH]c1=O
Temperature: 80 °C

Procedure:
The mixture of ethyl 2-(methylthio)-6-oxo-1,6-dihyropyrimidine-5-carboxylate (319 mg, 1.491 mmol) and [1,1′-biphenyl]-2-amine (252 mg, 1.491 mmol) were dissolved in 10 mL of ethanol and heated at 80° C. overnight. After heating, the solution was run on thin layer chromatography and filtered. The precipitate was collected and stored. 1H-NMR confirmed the product.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](=[O:28])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccccc1Oc1ccccc1

Procedure:
Using the same method as in Example 1-(ii), 2-phenoxyaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-oxo-2-[(2-phenoxyphenyl)amino]ethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 89%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:11]([Cl:15])=[N:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[N+:23]([C:26]1[CH:43]=[CH:42][C:29]([C:30]([O:32][C:33]([CH2:40][CH3:41])([C:36]([F:39])([F:38])[F:37])[C:34]#[CH:35])=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][C@@:33]([C:34]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=5)=[CH:10][C:11]([Cl:15])=[N:12]4)=[CH:7][CH:6]=3)[CH:35]=2)([C:36]([F:37])([F:38])[F:39])[CH2:40][CH3:41])=[O:31])=[CH:42][CH:43]=1)([O-:25])=[O:24]
Reactant: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: [N-]=[N+]=NCc1ccc2c(-c3ccc(F)cc3)cc(Cl)nc2c1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(azidomethyl)-2-chloro-4-(4-fluorophenyl)quinoline (500 mg, 1.60 mmol), 1-ethyl-1-(trifluoromethyl)prop-2-yn-1-yl 4-nitrobenzoate (529 mg, 1.76 mmol), copper iodide (456 mg, 2.4 mmol) and diisopropylethylamine (1.4 mL, 8.04 mmol) in THF (10 mL) was stirred at rt for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with EtOAc/hexanes, 4:6) gave the title compound. MS (+ESI): 614 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:3]=1.[CH2:16]([C:18]1[C:26]2[C:21](=[N:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([NH2:28])[CH:19]=1)[CH3:17].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:16]([C:18]1[C:26]2[C:21](=[N:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([NH:28][C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[N:5][CH:6]=2)=[O:10])[CH:19]=1)[CH3:17]
Reactant: Cc1nc(-c2nccs2)ncc1C(=O)O
Reactant: CCc1cn(N)c2ncc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3nccs3)nc2C)c2ncc(F)cc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A solution of 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (509 mg, 2.28 mmol) and 3-ethyl-5-fluoropyrrolo[2,3-b]pyridin-1-ylamine (340 mg, 1.9 mmol) in DMF (6 mL) is stirred at 40° C. for 1 h. The mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at 40° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 5 min. The precipitate is collected by filtration and dried in vacuo to afford 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (3-ethyl-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide (481 mg, 66%). MS: 383 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 11.95 (s, NH, 1H), 9.10 (s, 1H), 8.29 (s, 1H), 8.14 (d, 1H), 8.08 (d, 1H), 8.00 (m, 1H), 7.57 (s, 1H), 2.79 (s, 3H), 2.75 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][NH2:15])=[CH:11][CH:10]=1>CO>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][NH:15][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[CH:11][CH:10]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CCN)cc1
Solvent: CO
Product: COC(=O)CCNCCc1ccc(OC)cc1
Yield: 97.9 %

Procedure:
A mixture of methyl acrylate (6.0 g, 69.7 mmol) and p-methoxyphenethyl amine (10.5 g, 69.7 mmol) in anhydrous methanol (88 mL) was refluxed for 3 days and then was concentrated to give methyl 3-[(4-methoxyphenethyl)amino]-propionate (16.2 g).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][C:8]=1[NH2:9])([CH3:6])([CH3:5])[CH3:4].C(Cl)(Cl)Cl.[OH-].[Na+]>CO>[Br:1][C:12]1[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][C:8]([NH2:9])=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:13]=1
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(Br)c(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Bromine (271 μL, 5.29 mmol) was added dropwise via syringe to a solution of 2,5-di-tert-butylaniline (1.09 g, 5.29 mmol) in methanol (80 mL). The solution was stirred at room temperature for 10 min. Chloroform and 0.1 N NaOH were added and the organic layer was dried (Na2SO4), filtered and concentrated to a pale yellow solid (1.46 g, 97%): mp 89-90° C.; 1H NMR δ1.38 (s, 9H), 1.45 (s, 9H), 3.77 (brs, 2H), 6.68 (s, 1H), 7.35 (s, 1H); 13C NMR δ29.4, 29.7, 33.7, 35.8, 111.0, 117.4, 133.1, 133.8, 143.3, 145.9; FAB-MS obsd 283.0936; calcd 283.0937; Anal calcd for C14H22BrN: C, 59.16; H, 7.80; Br, 28.11; Found, C, 59.33; H, 7.78; Br, 27.86.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21]([O:23]C)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1.[OH-].[Li+].OS(O)(=O)=O>O1CCOCC1.O>[OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21]([OH:23])=[O:22])[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=1
Reactant: COC(=O)c1cc(OC2COCC2O)cc(-c2ccc(C)cc2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(OC3COCC3O)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 5-(4-hydroxytetrahydrofuran-3-yloxy)-4′-methylbiphenyl-3-carboxylate (140 mg, 0.40 mmol) in 1,4-dioxane (2.8 mL) and water (2.8 mL) was added lithium hydroxide (50 mg, 2.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then acidifized with 2N aq. H2SO4 to pH 4-5 and concentrated in vacuo. The residue was treated with water and extracted with EtOAc (10 mL×2). The combined organic layers were dried (MgSO4) and concentrated to afford the title compound. 1H NMR (CD3OD, 400 MHz): 7.87 (t, J=1.6 Hz, 1H), 7.55-7.51 (m, 3H), 7.42 (t, J=2.0 Hz, 1H), 7.28 (d, J=7.6 Hz, 2H), 4.84 (d, J=4.4 Hz, 1H), 4.38 (d, J=4.0 Hz, 1H), 4.23 (dd, J=10.4, 4.4 Hz, 1H), 4.05 (dd, J=9.6, 4.4 Hz, 1H), 3.94 (dd, J=10.4, 1.6 Hz, 1H), 3.77 (dd, J=9.6, 1.6 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]1([C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc2ccccc2nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1cc2ccccc2nc1-c1ccccc1
Yield: 99.2 %

Procedure:
3-methyl-2-chloroquinoline (29.71 g, 167 mmol), phenylboronic acid (24.4 g, 200 mmol), triphenylphosphine (4.388 g, 16.7 mmole) and 2M K2CO3 aqueous soln. (225 mL) were dissolved in the 264 mL of ethylene glycol dimethyl ether. To the stirred solution was added palladium acetate (0.94 g, 4.18 mmole) and the mixture was refluxed under N2 for 20 hours. The reaction mixture was cooled and the water was extracted with methylene chloride three times. The combined organic phase was washed with portions of brine. The organic layer was then dried with anhydrous sodium sulfate, filtered, and evaporated of solvent. The crude material was purified by kegelrohr distillation to give 1 (36.31 g, 98.6%).