Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][C:14]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[CH2:1]([N:8]([C:9]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:20])[C:15]=2[C:16]([F:19])=[CH:17][CH:18]=1)[S:28]([CH3:27])(=[O:30])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2c(NCc3ccccc3)ccc(F)c21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccccc1)c1ccc(F)c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Example 44C (0.40 g, 1.5 mmol) in dichloromethane (9 mL) was treated with pyridine (0.36 mL, 4.4 mmol), treated with methanesulfonyl chloride (0.13 mL, 1.6 mmol), stirred for 4 hours, treated with pyridine (0.2 mL, 2.5 mmol), treated with methanesulfonyl chloride (0.10 mL, 1.3 mmol), stirred for 16 hours,refluxed for 9 hours, cooled to ambient temperature, treated with water (25 mL) and extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were washed with brine, dried (Na2SO4) and concentrated. Purification of the residue on silica gel with 1:1 ethyl acetate:hexanes provided the desired product.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[O:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1>CCOCC>[OH:15][C:16]1([C:7]2[CH:12]=[N:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:20][CH2:21]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 52.2 %

Procedure:
n-Butyllithium (1.6M in hexanes, 6.65 mL, 10.64 mmol) was added dropwise to 5-bromo-2-methoxypyridine (2.0 g, 10.64 mmol) in ether (30 mL) cooled to −78° C. over a period of 15 minutes. The resulting solution was stirred at −78° C. for 40 minutes then a solution of benzyl 4-oxo-1-piperidinecarboxylate (2.48 g, 10.64 mmol) in ether (10 mL) was added dropwise. The reaction was allowed to warm slowly to room temperature then quenched with ammonium chloride solution (50 mL) and extracted with EtOAc. The extract was washed sequentially with water and saturated brine, dried over MgSO4 and concentrated by evaporation then purified by flash silica chromatography, elution gradient 50 to 80% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford benzyl 4-hydroxy-4-(6-methoxypyridin-3-yl)piperidine-1-carboxylate (1.90 g, 52%) as a pale orange oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:22][CH2:23][Br:24])[C:5]1[C:6]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11].[OH-].[K+].Br>O1CCOCC1.CO>[Br:1][CH2:2][CH2:3][N:4]([CH2:22][CH2:23][Br:24])[C:5]1[C:6]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(N(CCBr)CCBr)c(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(C(=O)O)cc1N(CCBr)CCBr
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
A solution of 6 (1.00 g, 2.05 mmol) in a dioxane/MeOH (1:1, 20 mL) was treated at 10° C. with 4N aqueous KOH (5 mL), and stirred at 10° C. for 45 min. The mixture was acidified to pH 2 with1 N aqueous HBr, concentrated to a small volume under reduced pressure, and then diluted with saturated aqueous NaBr (20 mL). The resulting semi-solid was isolated and crystallized twice from MeOH/H2O to give 5-[bis(2-bromoethyl)amino]-4-(methylsulfonyl)-2-nitrobenzoic acid (7) (0.70 g, 72%): mp 174-176° C.; 1H NMR [(CD3)2SO] δ 8.50 (s, 1 H), 7.88 (s, 1 H), 3.79 (t, J=7.0 Hz, 4 H), 3.62 (t, J=7.0 Hz, 4 H), 3.48 (s, 3 H). Anal. (C12H14Br2N2O6S) C, H, N.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Br:19]C1C=C(C=CC=1)N.N1C=CC=CC=1C=O>>[Br:19][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: Brc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-bromoaniline (223 mg, 1.3 mmol) and pyridine-2-carboxaldehyde (135 mg, 1.3 mmol) were employed to obtain 2-[2-(3-bromophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]([C:20]([OH:22])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si](C=[N+]=[N-])(C)C.CCCCCC>CO.C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]([C:20]([O:22][CH3:23])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To O-benzyl-N-(tert-butoxycarbonyl)homoserine (5.8 g, 18.9 mmol) in 20% methanol/benzene (72 mL) is added 2M trimethylsilyldiazomethane in hexane (12.3 mL, 24.5 mmol), and the reaction stirred at room temperature 1.5 h. The solution is concentrated under reduced pressure to give the title compound in pure form. ESI MS m/z 324.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]C1CC(=O)NC1=O>CN(C)C=O>[Br:21][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=C1CC(Br)C(=O)N1
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Yield: 89.3 %

Procedure:
An amount of 13.65 (53.7 mmol) of 9-phenylanthracene was dissolved in 100 ml of N,N dimethylformamide. An amount of 10.5 g (59 mmol) of N bromosuccinimide was added and allowed to react for six hours. Then, distilled water was added to stop the reaction and the deposit was filtered. The recovered deposit was purified by column chromatography to obtain 15.97 g (48 mmol) of 9-bromo-10-phenylanthracene. The yield was 89.3%.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].CS([C:16]1[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[N:17]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[O:10][C:16]1[N:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[N:21]=1
Reactant: CS(=O)(=O)c1nc(C(F)(F)F)cc(C(F)(F)F)n1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Oc2nc(C(F)(F)F)cc(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 55.8 %

Procedure:
4-Nitro-m-cresol (0.77 g), 2-methanesulfonyl-4,6-bistrifluoromethyl-pyrimidine (1.77 g) and potassium carbonate (1.04 g) were refluxed in acetonitrile (15 ml) for 5 hours. After finishing the reaction, the reaction mixture was poured into ice to separate out crystals. The obtained crystals were filtered and dried to obtain 2-(3-methyl-4-nitrophenoxy)-4,6-bistrifluoromethyl-pyrimidine (1.03 g).
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]1([C:26](Cl)=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:27])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: O=C(Cl)c1cccc2ccccc12
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1C(=O)c1cccc2ccccc12

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 1-naphtoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a colorless oil.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C@H:31]3[CH2:33][C@@H:32]3[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:27][CH:26]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CO.Cl>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C@H:31]3[CH2:33][C@@H:32]3[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:29][CH:30]=2)[N:22]=[CH:21]1
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2c[nH]cn2)cc1
Yield: 66.4 %

Procedure:
Ethyl (1S,2S)-2-[4-(1-trityl-1H-imidazol-4-yl)phenyl]cyclopropanecarboxylate (4.1 g, from Step 1) was suspended in 30 mL of methanol and 30 mL of 1N HCl. The reaction mixture was heated at reflux for 2 hours. The solvent was evaporated in vacuo and the residue was triturated with ether (100 mL). The liquid organic layer was discarded. The solid was the desired product HCl salt. To the solid were added 100 mL EtOAc and 13 mL of 1N NaOH to release the free base. The aqueous/organic mixture was shaken in a separation funnel. The aqueous layer was discarded, and the organic layer was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to give the title compound (1.4 g, 66.4%). 1H NMR (500 MHz, (CD3OD): 7.98 (s, 1H), 7.58 (d, 2H), 7.39 (s, 1H), 7.17 (d, 2H), 4.18 (q, 2H), 2.43 (m, 1H), 1.86 (m, 1H), 1.57 (m, 1H), 1.37 (m, 1H), 1.24 (t, 3H). LCMS: ink 257 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C([Li])CCC.C[O:25]B(OC)OC>O1CCCC1>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:3]3[C:2]([OH:25])=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: COB(OC)OC
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1c(-c2nonc2N)nc2cncc(O)c21
Reaction time: 0.75 h
Yield: 57.9 %

Procedure:
A solution of the product from Example 100 (2.6 g, 8.41 mmol) in tetrahydrofuran (180 ml) at −78° C. was treated with a 2.5M solution of n-butyllithium (8.41 ml, 21.03 mmol) in hexanes. After the addition was complete the mixture was treated with trimethylborate (2.62 g, 25.23 mmol) and allowed to reach room temperature. After 1.5 hours at room temperature the reaction was carefully quenched with 3M aq. NaOH (12.5 ml) followed by a 30% aqueous hydrogen peroxide solution (4.3 ml). After 45 minutes the reaction was acidified with 2M hydrochloric acid and then applied to a SCX ion exchange column and eluted with methanol and then a mixture of methanol/0.880 ammonia (9:1). The basic fractions were then reduced and the solid residue was triturated with dichloromethane and filtered to afford the title compound, (1.2 g, 58%); MS (ES+) m/e 247 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]2[C@@H:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([O:24][CH3:25])[CH:23]=3)[C:14](=[O:15])[O:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9].[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]2[C@@H:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([O:24][CH3:25])[CH:23]=3)[C:14](=[O:15])[O:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9].[S:27]([O-:2])(=[O:29])(=[O:28])[CH3:30]
Reactant: CS(=O)(=O)Cl
Agent: COc1cc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(O)c(OC)c2)ccc1O
Solvent: c1ccncc1
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
Matairesinol (500 mg, 1.4 mmol) was dissolved in 50 ml pyridine. To the solution stirred at room temperature, mesyl chloride (Methanesulfonyl chloride, 642 mg, 5.6 mmol) was added dropwise. The mixture was heated and stirred at 50° C. for 3 h. The solvent was then removed under reduced pressure and the residue extracted with dichloromethane (50 ml) and water (2×25 ml). The organic phase was dried over NaSO4 and the solvent removed. The residue was chromatographed on a silica column using CHCl3:EtOAc (1:1) as eluent. Yield 543 mg, 75.5%, slightly yellow-brown oil, purity>90% (NMR).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([N:14]([CH3:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:26]([O:28]CC)=O)=[O:7])=[CH:4][CH:3]=1.[NH3:33].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([N:14]([CH3:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:26]([NH2:33])=[O:28])=[O:7])=[CH:31][CH:32]=1
Reactant: N
Reactant: CCOC(=O)c1nc(N(C)c2ccc3ncccc3c2)sc1NC(=O)c1ccc(F)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1ccc2ncccc2c1)c1nc(C(N)=O)c(NC(=O)c2ccc(F)cc2)s1
Temperature: 80 °C
Yield: 84 %

Procedure:
To a solution of ethyl 5-(4-fluorobenzamido)-2-[methyl(quinolin-6-yl)-amino]thiazole-4-carboxylate (0.14 g, 0.31 mmol) in THF (5 mL) was added 7N NH3-MeOH (5mL), and the mixture was heated at 80° C. for 16 hrs in a sealed tube. The solvent was evaporated in vacuo, and the resulting solids were purified by silica gel chromatography eluted with EtOAc to give 110 mg (84% yield) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:19]=2[CH3:35])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C1COCC1.Cl.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:19]=2[CH3:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)NCCNc2cc(C)nc(Oc3c(C)cc(C)cc3C)c2C)cc1OC
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(CCNCCNc2cc(C)nc(Oc3c(C)cc(C)cc3C)c2C)cc1OC

Procedure:
Add BH3 in THF (1 M solution, 0.3 mmol, 0.3 mL) to a solution of the crude 2-(3,4-dimethoxyphenyl)-N-(2-{[3,6-dimethyl-2-(2,4,6-trimethylphenoxy)(4-pyridyl)]amino}ethyl) acetamide in THF (2.0 mL) at ambient temperature. Heat the reaction mixture under reflux for 15 h, dilute with a solution of 10% aq HCl/MeOH (1:1, 2 mL) and heat again under reflux (1 h). Dilute the reaction mixture with CHCl3 (10 mL), wash with saturated aq NaHCO3 (1×5 mL), dry and concentrate in vacuo. Chromatograph the crude residue on SiO2-gel using a gradient of 100% EtOAc to 10% Et2NH/EtOAc to obtain the title compound as a colorless oil. Immediately dissolve the product in Et2O (1 mL), treat with excess 4 M HCl/dioxane and concentrate in vacuo to obtain the hydrochloride salt of the title compound as a colorless solid. 1H NMR (d4-MeOH, Unity 400): d 6.99-6.77 (6H, m), 3.81 (3H, s), 3.78 (3H, s), 3.62 (2H, m), 2.98 (2H, t), 2.39 (3H, s), 2.29 (3H, s), 2.16 (3H, s), 2.07 (6H, s). M+1: 464.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([O:22]CC)=[CH2:21])[CH:14]=[N:13]2>C1COCC1.O.CO>[Br:8][CH2:22][C:20]([C:15]1[CH:14]=[N:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([Br:9])[CH:11]=2)[N:16]=1)=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1cnc2cc(Br)ccc2n1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CBr)c1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
NBS (55.1 mg, 0.310 mmol) was added to a solution of 6-bromo-2-(1-ethoxyvinyl)quinoxaline (72 mg, 0.26 mmol) in THF (2 mL) and water (0.500 mL) and the mixture was stirred at rt for 2 h. The reaction was diluted with MeOH and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield 2-bromo-1-(6-bromoquinoxalin-2-yl)ethanone (50 mg, 0.15 mmol, 59% yield) as white solid. LC-MS retention time 2.40 min; m/z 329 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([NH:39][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:29])([F:30])[F:31])[C:9]=3[CH:17]=2)[CH:19]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=536.96 (M+H+); retention time=0.92 minutes.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH:14]=2)=[CH:5][CH:4]=1)[NH2:2].N(C1C=CC=CC=1)=[C:19]=[S:20]>CN1C(=O)CCC1.C(Cl)Cl>[SH:20][C:19]1[N:8]2[CH:7]=[C:6]([C:9]3[CH:10]=[CH:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH:14]=3)[CH:5]=[CH:4][C:3]2=[N:1][N:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: CCn1cc(-c2ccc(NN)nc2)ccc1=O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCn1cc(-c2ccc3nnc(S)n3c2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
A mixture of 5-(6-hydrazinylpyridin-3-yl)-1-ethylpyridin-2(1 H)-one (1.2 g, 5.22 mmol) and isothiocyanatobenzene (775 mg, 5.74 mmol) in NMP(3 ml) and DCM (10 ml) was stirred at room temperature for 30 min. The DCM was removed via rotary evaporation and the reaction was diluted with 1,3-dichlorobenzene (7 mL). The mixture was then heated in a microwave at 160° C. for 1 hr. Ether (10 ml) was added to the reaction and the resulting solid was collected by filtration and washed with ether to provide the title compound, 5-(3-mercapto-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-ethylpyridin-2(1 H)-one (600 mg, 42.3% yield).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([CH3:20])=[N:9][N:10]([C:12]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=2N)[CH:11]=1.Cl.N([O-])=O.[Na+].[I-:26].[K+]>O.CCOC(C)=O>[Cl:6][C:7]1[C:8]([CH3:20])=[N:9][N:10]([C:12]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=2[I:26])[CH:11]=1
Reactant: [I-]
Reactant: Cc1cccc(-n2cc(Cl)c(C)n2)c1N
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(-n2cc(Cl)c(C)n2)c1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (7.77 mL, 146 mmol) was added to a solution of 2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylaniline (1.9 g, 8.57 mmol) in concentrated hydrogen chloride (2.056 mL, 25.7 mmol) at 0° C. The solution was stirred and after cooling back to 0° C., sodium nitrite (0.591 g, 8.57 mmol) in water (3.5 mL) was added dropwise. The reaction was stirred 40 min at 0° C. before potassium iodide (2.85 g, 17.14 mmol) in water (3.5 mL) was added dropwise and then the solution was stirred at RT. After 1 h, the reaction is poured into ice with EtOAc and separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with 1N HCl, water, saturated sodium bicarbonate, 1N sodium sulfite, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography by eluting with 1:4 EtOAc in hexane to provide 4-chloro-1-(2-iodo-3-methylphenyl)-3-methyl-1H-pyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH2:14].[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCc1c(Br)ccc2c1CCO2
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCCCc1c(Br)ccc2c1CCO2
Reaction time: 8 h

Procedure:
A solution of 3-(5-bromo-2,3-dihydro-benzofuran-4-yl)-propylamine (256 mg) in pyridine (3 ml) at 40 was treated with acetic anhydride (0.11 ml) and the solution stored overnight at 4°. The cold solution was acidified with 2N hydrochloric acid and the mixture extracted with ethyl acetate. The extracts were dried and evaporated and the residue chromatographed on silica (20 g) using dichloromethane:methanol:ammonia (100:8:1) to give the title compound as an oil which slowly solidified (175 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCO>[Cl:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Agent: Cl
Solvent: CCO
Product: Clc1cccc(CNc2nccc(-c3n[nH]c4nc(NC5CCNCC5)ncc34)n2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.15 mmol) in EtOH (4 mL) was added conc. HCl (4 mL). The reaction mixture was stirred at room temperature for 15 hours. The solvent was then removed and the residue was purified by prep-HPLC to afford {3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-piperidin-4-yl-amine; hydrochloride. (Yield 20 mg, 26.3%).
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]([CH3:28])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH:23]([NH:25][CH3:26])[CH2:22][C:21]4=[O:27])=[CH:16][CH:15]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([CH2:26][NH:25][CH:23]1[CH2:24][N:20]([C:17]2[CH:18]=[CH:19][C:14]([N:13]([CH3:28])[C:11](=[O:12])[C:10]3[CH:29]=[CH:30][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=3)=[CH:15][CH:16]=2)[C:21](=[O:27])[CH2:22]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CNC1CC(=O)N(c2ccc(N(C)C(=O)c3ccc(C4CCCCC4)cc3)cc2)C1
Solvent: c1ccncc1
Product: CC(=O)CNC1CC(=O)N(c2ccc(N(C)C(=O)c3ccc(C4CCCCC4)cc3)cc2)C1

Procedure:
4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide (101 mg) was mixed with pyridine (20 mg) and acetic anhydride (25 mg) and, after 3 hours, volatile fractions were removed in vacuo. This resulted in the product with the molecular weight of 447.58 (C27H33N3O3); MS (ESI): 448 (M+H+).
Reaction SMILES: C(O)C.[OH-].[Na+].[CH3:6][S:7][C:8]([CH3:25])([CH3:24])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:23])[CH2:13][CH:14]=[CH:15][C:16]([CH3:22])=[CH:17][C:18]([O:20]C)=[O:19]>O>[CH3:6][S:7][C:8]([CH3:24])([CH3:25])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:23])[CH2:13][CH:14]=[CH:15][C:16]([CH3:22])=[CH:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)C=C(C)C=CCC(C)CCCC(C)(C)SC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O

Procedure:
To 350 ml. of ethanol, 105 ml. of water and 70 ml. of 50% aqueous sodium hydroxide is added 46.5 g. of methyl 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoate. The mixture is refluxed for about 18 hours. After cooling, alcohol is removed in vacuo. Water is added followed by acidification and then extraction with ether to yield 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoic acid.