Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][OH:28])=[C:23]([CH3:31])[CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][S:2]([O:28][CH2:27][CH2:26][O:25][C:24]1[CH:29]=[CH:30][C:21]([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:22][C:23]=1[CH3:31])(=[O:4])=[O:3]
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.74 mL (35.29 mmol) of methanesulfonic acid chloride was added dropwise at 0° C. to a solution of 10.70 g (29.41 mmol) of 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethanol and 4.08 mL (29.41 mmol) of triethylamine in 500 mL of THF and the mixture was then stirred for 2 hours at RT. The reaction mixture was filtered and the filtrate was evaporated down in vacuo. The residue was stirred with diethyl ether and water, and the precipitate was filtered off and dried in vacuo. Yield: 11.00 g (85% of theoretical); C23H20ClNO4S (M=441.928); calc.: molpeak (M+H)+: 442/444 (Cl); found: molpeak (M+H)+: 442/444 (Cl); HPLC-MS: 6.36 minutes (method C).
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:11])[C:9]#[CH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CCCCCC.C([Li])CCC.[Cl:23]N1C(=O)CCC1=O>C1COCC1.O.C(OCC)(=O)C>[CH2:1]([NH:7][C:8](=[O:11])[C:9]#[C:10][Cl:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CC(=O)NCCCCCC
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCNC(=O)C#CCl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
2.45 g of N-(n-hexyl)propiolamide was dissolved in 40 ml of dry THF, which was cooled to -78° C. 20 ml of n-butyllithium hexane solution (1.6 mol/1) was added thereto, and the mixture was stirred for 10 minutes. 4.28 g of N-chlorosuccinimide was added thereto, and the resultant mixture was stirred at -78° C. for 2 hours. The mixture was allowed to be warmed to -30° C., to which 10 ml of water was added. The mixture was then stirred overnight at a room temperature. Ethyl acetate and water were added to the reaction solution for separation. An organic phase was concentrated under reduced pressure. A residue was purified by the silica gel column chromatography (eluent: ethyl acetate/hexane=1/9). N-(n-hexyl)-3-chloropropiolamide (2.50 g) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:17][Si](CC)(CC)CC)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:25][CH2:26][CH3:27].CCN(C(C)C)C(C)C.[C:37]1([CH2:43][CH2:44][C:45](Cl)=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:9]([F:11])([F:12])[F:10])[C:13]([F:14])([F:15])[F:16])[CH:5]=[CH:4][C:3]=1[N:25]([CH2:26][CH3:27])[C:45](=[O:46])[CH2:44][CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCNc1ccc(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)CCc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 67.1 %

Procedure:
A solution of 100 mg (0.23 mmol) of [2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-amine in CH2Cl2 was treated with 0.08 mL (0.46 mmol) of DIPEA and 0.07 mL (0.46 mmol) of 3-phenylpropionylchloride. The mixture was stirred at RT for 10 hours and treated with 0.4 mL of a 1 M TBAF-solution in THF. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 4:1 yielded 70 mg (67%) of N-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-3-phenyl-propionamide, light yellow oil, MS: 454 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.O.[C:34](=O)(O)[O-:35].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[C:16]([CH:34]=[O:35])[CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccccc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(C=O)cc1CC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
1.0 g of N-[4-(trifluoromethyl)phenyl]-2-(2-methoxyphenyl)acetamide was dissolved in 10 mg trifluoroacetic acid, and 0.46 g hexamethylene tetramine was added, and the mixture was reacted at 85° C. for 3 hours. The reaction solution was returned to room temperature, water and ethyl acetate were added, and sodium bicarbonate was further added until the pH reached 8. The reaction solution was extracted with ethyl acetate, washed with brine and dried over anhdydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 0.7 g of N-[4-(trifluoromethyl)phenyl]-2-(5-formyl-2-methoxyphenyl)acetamide as a colorless oil from fractions eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: C(O[C:4](=[O:30])[N:5]([C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:16]=[C:15]([NH2:26])[C:14]=1[N+:27]([O-])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>C(O)(=O)C.CO.[Zn]>[NH2:26][C:15]1[C:14]2[NH:27][C:4](=[O:30])[N:5]([CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:13]=2[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:16]=1
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(-c2ccccc2F)nc(N)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(-c2ccccc2F)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
[2-Amino-6-(2-fluoro-phenyl)-3-nitro-pyridin-4-yl]-benzyl-carbamic acid ethyl ester (31 mg) was dissolved in acetic acid (1 ml). Zinc powder (Aldrich, 99%, 20 mg) was added and the mixture left to stir at room temperature under nitrogen for 2 hours. Additional zinc powder (30 mg) was added and mixture left to stir for a further 1 hour. The reaction mixture was diluted with methanol (2 ml) then filtered directly onto a cation exchange cartridge (Bakerbond SCX, sulphonic acid bonded-phase, 1 g). The SCX cartridge was washed with methanol (2×5 ml) to remove impurities and then the product was released with ammonia in methanol (2 M, 5 ml). The desired fraction was evaporated to a pale brown solid. This was triturated with ethyl acetate then filtered and washed with more ethyl acetate to yield the title compound (8 mg) as a pale purple solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 2 H) 5.82 (s, 2 H) 6.87 (d, J=1.95 Hz, 1 H) 7.15-7.29 (m, 3 H) 7.29-7.39 (m, 5 H) 7.81 (td, J=8.01, 1.95 Hz, 1 H) 10.51 (s, 1 H), LCMS Rt=2.21 m/z 335 [MH]+
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[CH3:16])[CH:6]=1>C(OCC)(=O)C.C(O)C>[CH3:16][C:8]1[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2C)cn1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(N)cc2C)cn1
Yield: 99.4 %

Procedure:
A mixture of 4-methyl-1-(2-methyl-4-nitro-phenyl)-1H-imidazole (1.26 g, 5.8 mmol) and of stannous chloride dihydrate (6.81 g, 30.2 mmol) in ethyl acetate (40 mL) and ethanol (20 mL) was stirred for 1 hour at 70° C. The reaction mixture was quenched by addition of water, neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude title compound (1.08 g, 99%) as a yellowish gum. MS ISP (m/e): 188.4 (100) [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:13]=2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[CH:13]=4)[C:5]4[S:10][CH2:9][CH2:8][C:6]=4[N:7]=3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Clc1nc2c(c(Nc3cccc(CN4CCOCC4)c3)n1)SCC2
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCN(c3nc4c(c(Nc5cccc(CN6CCOCC6)c5)n3)SCC4)CC2)cc1
Temperature: 160 °C
Yield: 74.5 %

Procedure:
1.09 g (2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl)-(3-morpholin-4-ylmethyl-phenyl)-amine, 1.77 g 1-(4-chloro-phenyl)-piperazine and 1.03 ml diisopropylethylamine are placed in 12 ml dioxane, then heated in the microwave for 1 hour at 160° C. Then water is added and the mixture is extracted with dichloromethane. The organic phase is separated off using a phase transfer cartridge and evaporated to dryness. The residue is crystallised with methanol. 1.17 g of the product are obtained as a powder (m.p 177°-178° C.).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]([CH:17]([NH:26][CH:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[NH:29][C:28]1=[O:38])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].O>O1CCCC1>[CH2:7]([O:14][C:15]([CH:17]([NH:26][CH:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:28]1=[O:38])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1Nc2ccccc2CCC1NC(CCc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCc2ccccc2)CCc2ccccc21
Temperature: 25 °C

Procedure:
Potassium t-butoxide (1.2 g) was added to a solution of 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (3.0 g) and t-butyl bromoacetate (2.2 g) in tetrahydrofuran (100 ml) stirring at room temperature under an atmosphere of dry nitrogen. The reaction mixture was stirred for 20 hours at room temperature, then poured into water (250 ml) and extracted with dichloromethane (2×150 ml). The combined dichloromethane solutions were washed with water (100 ml) and dried over magnesium sulfate. Evaporation of the solvent gave 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:47]([OH:49])=[O:48])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36]C(OCC1C=CC=CC=1)=O)=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br>C(O)(=O)C>[C:1]([O:18][CH:19]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:47]([OH:49])=[O:48])[CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O)C(C)C
Agent: Br
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To Nα -[N-(3-hexadecanoyloxyoctadecanoyl)-L-valyl]-Nε -benzyloxycarbonyl-L-lysine (650 mg) in acetic acid (5 ml) was added 30% hydrogen bromide solution in acetic acid (4 ml), and the mixture was stirred at room temperature for 2 hours. Excess solvent was removed off by evaporation under reduced pressure. The residue was taken up in benzene, and the solvent was distilled off. This operation was repeated twice to give powder of N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-valyl]-L-lysine.hydrogen bromide (550 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.Br[C:25]1[CH:26]=[C:27]2[C:31](=[C:32]([Cl:34])[CH:33]=1)[C:30](=[O:35])[N:29]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=1)[CH2:28]2.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>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.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:25]2[CH:26]=[C:27]3[C:31](=[C:32]([Cl:34])[CH:33]=2)[C:30](=[O:35])[N:29]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]([F:46])([F:47])[F:45])=[CH:39][CH:38]=2)[CH2:28]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a purged (argon) sample of 4-methylene-piperidine-1-carboxylic acid tert-butyl ester (51.6 mg, 0.26 mmol) was added 9-BBN. The mixture was stirred at 60° C. for one hour. After cooling to room temperature this solution was added to 5-bromo-7-chloro-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one (100.0 mg, 0.24 mmol), Pd(dppf)Cl2 (5.9 mg, 0.0072 mmol), DMF (2.0 mL), potassium carbonate 943.1 mg, 0.31 mmol) and water (0.2 mL). The mixture was allowed to stir at 75° C. overnight. The mixture was then cooled to room temperature and poured into water (3 mL). The pH was adjusted to 11 with aqueous sodium hydroxide (3N). The product was extracted with ethyl acetate. The combined organic layers were washed with water three times, brine, dried over sodium sulphate, filtered and concentrated. Column chromatography (30% Ethyl acetate/hexanes) provided the title compound (54.9 mg, 44%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([O:22][CH2:23]C=O)=[CH:18][CH:17]=1>CCCCCC.O1CCCC1>[C:16]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:20][CH:21]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=CCOc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(COc2ccc(-c3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound was prepared as described in General Method 1 using 4.76 g of methyl acetoacetate, 1.97 g of NaH 50% dispersion in oil, 19.5 mL of 2.1M n-butyl lithium in hexane, 8.7 g of [[1,1'-biphenyl]-4-yloxy]-acetaldehyde and 200 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 60 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 152°-154° C.). 'H NMR (CDCl3) δ2.83 (dd, 1H), 2.95 (dd, 1H) 3.61 (dd, 2H), 4.23 (dd, 1H), 4.38 (dd, 1H), 5.03-5.07 (m, 1H), 6.94-6.98 (m, 2H), 7.30-7.57 (m, 7H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[N+:12]([O-:14])=[O:13].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:11][C:7]1[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([N:3]([O:2][CH3:1])[CH3:16])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CON(C)C(=O)c1cccc(C)c1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CON(C)C(=O)c1cccc(CBr)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of Intermediate 37A (5.5 g, 24.53 mmol), NBS (5.24 g, 29.4 mmol) and benzoyl peroxide (0.594 g, 2.453 mmol) in CCl4 (80 mL) was purged with nitrogen and then heated to 80° C. for 4.5 h. The reaction mixture was cooled to room temperature and then quenched with water. The mixture was extracted with DCM and the combined extracts were washed with saturated NaHCO3 and brine and then dried (Na2SO4), filtered and concentrated to dryness. The crude material was purified by flash chromatography (SiO2, 80 g column, EtOAc/hexane=0-100%) to afford Intermediate 37B.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ncc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
N-tert-Butyl-2-(2-methoxypyrimidin-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 212 μmol) was dissolved in dichloromethane and treated with trifluoroacetic acid (484 mg, 327 μL, 4.24 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.45 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(2-methoxypyrimidin-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (64 mg, 187 μmol, 88%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.35 (s, 1H), 9.48 (s, 1H), 8.86 (s, 2H), 8.01 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 3.88 (s, 3H), 1.38 (s, 9H); MS (EI/CI) m/z: 342.1 [M+H].
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:13]([C:6]=2[CH:5]=[CH:4][N:3]=1)[CH2:12][CH2:11][C:10]3=[O:14].[C:15]1([As](C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=CC=C[CH:16]=1.C([Sn](CCCC)(CCCC)C(C)=C)CCC>CN(C=O)C.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]>[C:15]([C:2]1[C:7]2[CH:8]=[C:9]3[N:13]([C:6]=2[CH:5]=[CH:4][N:3]=1)[CH2:12][CH2:11][C:10]3=[O:14])([CH3:20])=[CH2:16]
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCn2c1cc1c(Cl)nccc12
Agent: [Pd]
Agent: C=C(C)[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)c1nccc2c1cc1n2CCC1=O
Temperature: 78 °C

Procedure:
To a mixture of 1-chloro-6,7-dihydro-8H-pyrido[3,4-b]pyrrolizin-8-one (5.0 g, 24.3 mmol), tris (dibenzylidene acetone)dipalladium (0) (1.0 g, 1.09 mmol) and triphenylarsine (2.70 g, 8.82 mmol) in DMF (100 mL) was added tributylisopropenyl stannane (9.60 g, 29.00 mmol). The resulting mixture was degassed and heated at 78° C. for a period of 18 h. The solvant was evaporated under reduced pressure. CH2Cl2 and celite were added to the resulting mixture which was then filtered over celite. The title compound was purified by flash chromatography (50% to 100% EtOAc in Hexane).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)=[N:16][C:15]=12>O1CCCC1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:25][CH2:26][C:27]([OH:30])([CH3:1])[CH2:28][CH2:29]3)=[N:16][C:15]=12
Reactant: O=C1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reactant: C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC1(O)CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reaction time: 2 h
Yield: 46.8 %

Procedure:
Methylmagnesium bromide (3M in diethyl ether, 0.24 ml, 0.72 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-5-(4-oxopiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (Example 22) (0.107 g, 0.3 mmol) in dry tetrahydrofuran (2 ml) at room temperature under nitrogen. After stirring for 2 h, the mixture was diluted with water (20 ml) and 1M aqueous citric acid (5 ml). The mixture was extracted with dichloromethane (20 ml) and the organic extract was dried (Na2SO4), filtered and concentrated. Preparative thin layer chromatography on silica, eluting with 2% methanol:dichloromethane, gave 3-(2-fluorophenyl)-5-(4-hydroxy-4-methylpiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.053 g, 47%). δH (360 MHz; CDCl3) 1.38 (3H, s), 1.75-1.85 (2H, m), 1.90-2.00 (2H, m), 3.56-3.64 (2H, m), 3.83-3.89 (2H, m), 7.20-7.30 (2H, m), 7.30-7.40 (1H, m), 7.60 (1H, dd, J=7 and 7), 7.88 (1H, dd, J=7 and 7), 8.02 (1H, d, J=7), 8.15 (1H, dd, J=7 and 7), 8.68 (1H, d, J=7); m/z (ES+) 378 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14].Cl>CC(O)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of diethyl (2,5-difluoro-4-nitrophenyl)propanedioate (700 mg, 2.2 mmol) with HOAc (10 mL) and HCl (6 N, 10 mL) was heated under N2 at 120° C. for 2.5 hours and then allowed to cool and stirred overnight. Most of the solvent was removed by evaporation and then water was added. The mixture was extracted with EtOAc. The organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated to give (2,5-difluoro-4-nitrophenyl)acetic acid.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[CH2:24]([O:11][C:10]([C:7]1([C:4]2[CH:5]=[CH:6][C:1]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:2][CH:3]=2)[CH2:9][CH2:8]1)=[O:12])[CH3:25]
Reactant: CCO
Reactant: O=C(O)C1(c2ccc(-c3ccccc3)cc2)CC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(c2ccc(-c3ccccc3)cc2)CC1

Procedure:
1-(Biphenyl-4-yl)cyclopropanecarboxylic acid (10 g, 42 mmol), ethanol (100 mL) and sulfuric acid (40 mL) were heated to 65° C. for 4 hours. The product was extracted with CH2Cl2 and water (2×), dried and evaporated to yield 9.5 g of 1-(biphenyl-4-yl)cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1[F:40]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1[F:40])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CBr)c(F)c1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)c1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(F)c1

Procedure:
The title compound was prepared from 3-(3-Benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 4-Bromomethyl-3-fluoro-benzoic acid following the procedure of Example 478: MS m/z 532; MS m/z 530; HRMS: calcd for C31H21F4NO3+H+, 532.15303; found (ESI, [M+H]+), 532.153;