Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([N:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([N:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-n3cccc3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-n3cccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-pyrrol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.23 g, 0.5 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the obtained crystals were recrystallized from methanol-diethyl ether to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-(1H-pyrrol-1-yl)-1(2H)-isoquinolinone dihydrochloride (0.19 g, 95.0%) as crystals.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.Cl>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: COCCC(=O)c1cccc(Br)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCC(O)c1cccc(Br)n1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 1-(6-bromo-2-pyridinyl)-3-(methyloxy)-1-propanone (547 mg, 2.24 mmol) in anhydrous MeOH (15 mL) under nitrogen at 0° C. was treated portion-wise with sodium borohydride (127 mg, 3.36 mmol) over 10 min. The resulting solution was stirred under nitrogen and gradually allowed to warm to room temperature over 2 h. The reaction mixture was then diluted with aqueous HCl (0.5M, 20 mL) and the resulting mixture extracted with EtOAc (2×50 mL). The combined organic layer was dried (MgSO4) and reduced under vacuum to afford the title compound as an off-white gum (551 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1cccc(F)c1
Product: Fc1cccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-fluoro-phenylboronic acid to give [1-(3-fluoro-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 305(MH+).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[CH3:11][C:12]1[C:17]([O:18][C:19]2[N:24]=[CH:23][N:22]=[C:21]3[N:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:26]=[CH:27][C:20]=23)=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(C(C)C)CC)(C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH:5]1([O:4][C:2]([N:31]2[CH2:30][CH2:29][CH:28]([N:25]3[C:21]4=[N:22][CH:23]=[N:24][C:19]([O:18][C:17]5[C:12]([CH3:11])=[N:13][CH:14]=[CH:15][CH:16]=5)=[C:20]4[CH:27]=[N:26]3)[CH2:33][CH2:32]2)=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCNCC1
Reactant: O=C(Cl)OC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 12.9 %

Procedure:
A solution of cyclohexyl chloroformate (Waterstone Technology, LLC, Carmel, Ind., USA; 42 mg, 0.26 mmol) in dichloromethane (150 μL) was added to a cooled (˜0° C.) solution of 4-(2-methyl-pyridin-3-yloxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 28; 52 mg, 0.17 mmol), diisopropylethylamine (77 μL, 0.80 mmol) and 4-dimethylaminopyridine (1 mg) in anhydrous dichloromethane (2 mL) over 30 sec. The mixture was stirred at 0° C. for 5 min, then warmed to room temperature and stirred for 1 h. Water (5 mL) was added. The layers were separated and the organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, and purified on an Isco 4 g column eluting with 0-4% methanol/dichloromethane. Fractions containing the product were pooled, concentrated and lyophilized to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclohexyl ester (9.6 mg, 13%). Mass spectrum (ES) MH+=437.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13](=O)[CH2:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[NH2:24][C:25]1[C:29]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)=[CH:28][NH:27][N:26]=1>>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[N:26]3[N:27]=[CH:28][C:29]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)=[C:25]3[N:24]=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(C(F)(F)F)c4)nc23)ccn1
Yield: 37.9 %

Procedure:
Reaction of 1-(3,4-bis-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (176 mg, 0.5 mmol), prepared from commercially available 3,4-bis-trifluoromethyl-acetophenone [CAS No. 129604-25-7] according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (93 mg, 38%). MS (ISP) 491.3 [(M+H)+]; mp 223° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:35]1[NH:40][CH2:39][CH2:38][N:37]2[CH:41]=[CH:42][CH:43]=[C:36]12>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:40]4[CH2:39][CH2:38][N:37]5[CH:41]=[CH:42][CH:43]=[C:36]5[CH2:35]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: c1cc2n(c1)CCNC2
Product: O=C1N=C(N2CCn3cccc3C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,2,3,4-Tetrahydro-pyrrolo[1,2-a]pyrazine following General Procedure B.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C[O-].[Na+].[CH2:16](I)[CH2:17][CH2:18][CH3:19].CS(C)=O>C(OCC)(=O)C>[CH2:16]([O:6][C:5]1[C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[O:8][C:2](=[O:1])[C:3]=1[OH:4])[CH2:17][CH2:18][CH3:19]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CCCCI
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A reaction mixture was prepared containing the following ingredients: 33 g. of L-ascorbic acid, 10.2 g. of sodium methylate, 34.5 g. of n-butyl iodide and 250 ml. of DMSO. The reaction mixture was stirred at ambient temperature and the progress of the reaction monitored by thin layer chromatography. After 24 hours, the reaction mixture was added to 500 ml. of ethyl acetate. 3-O-n-Butyl-L-ascorbic acid formed in the above reaction precipitated and was separated by filtration. Further precipitation was caused by adding 300 ml. of toluene to the filtrate. These crystals were also collected and the combined crystals dissolved in 500 ml. of methanol. (weight=about 20 g.) 45 g. of silica gel was added to this solution. The solution was evaporated to dryness in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=O>O>[F:1][C:2]1[C:3]2[O:4][CH2:5][CH2:6][C:7](=[O:9])[C:10]=2[C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: Cc1ccc(F)c(OCCC(=O)O)c1
Solvent: O
Product: Cc1ccc(F)c2c1C(=O)CCO2
Temperature: 100 °C
Reaction time: 2 h
Yield: 68534.5 %

Procedure:
A mixture of 3-(2-fluoro-5-methylphenoxy)propanoic acid (10a) (860 mg, 4.64 mmol) in polyphosphoric acid (12.8 g, 130.3 mmol) was stirred at 100° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water (90 mL), and extracted with ethyl acetate (2×60 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 8-fluoro-5-methyl-3,4-dihydro-2H-1-benzopyran-4-one (10b) (573 mg, 3.18 mol, 73%) which was used without further purification. Ms m/z ([M+H]+) 181.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: ClCCCBr
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCCCl
Temperature: 32.5 °C
Reaction time: 7 h

Procedure:
A mixture of 186.5 g (0.94 mol) of N—(2-hydroxy-5-nitrophenyl)acetamide and 142.7 g (1.03 mol) of potassium carbonate in 570 ml of dimethylformamide was heated to 30-35° C. with stirring; 444.0 g (2.82 mol) of 1-bromo-3-chloropropane were then added and heating was continued at 40° C. for 7 hours (orange-coloured suspension).
Reaction SMILES: CS([C:4]1[N:13]2[C:7]([CH2:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]=[CH:12]2)=[N:6][N:5]=1)=O.CS(C1N2C(CC3C=CC=CC=3C=C2)=NN=1)(=O)=O.[O-:36][CH2:37][CH3:38].[Na+].C(O)C>C(O)C>[CH2:37]([O:36][C:4]1[N:13]2[C:7]([CH2:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]=[CH:12]2)=[N:6][N:5]=1)[CH3:38]
Reactant: CS(=O)c1nnc2n1C=Cc1ccccc1C2
Reactant: CC[O-]
Agent: CS(=O)(=O)c1nnc2n1C=Cc1ccccc1C2
Agent: [Na+]
Solvent: CCO
Product: CCOc1nnc2n1C=Cc1ccccc1C2

Procedure:
By a procedure similar to that described in Example 35, 0.245 g of 3-methylsulfinyl-11H-s-triazolo [3,4-b][3]benzazepine, in lieu of 3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine, was reacted with 1.2 ml of 1 N-sodium ethoxide/ethanol in 2 ml of ethanol to obtain 3-ethoxy-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from acetone yielded colorless needles, melting point 143°-144° C. The infrared absorption spectrum of this product was identical with that of the compound obtained in Example 35.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.C(O[C:13](=[S:15])[S-:14])C.[K+].CN1C(=O)CCC1.O>C(O)(=O)C>[Cl:9][C:4]1[N:3]=[C:2]2[S:14][C:13]([SH:15])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(Cl)nc1Cl
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: Sc1nc2ccc(Cl)nc2s1
Temperature: 170 °C
Reaction time: 3.5 h

Procedure:
To a round bottom flask was added 2,6-dichloropyridin-3-amine (21.4 g, 131 mmol), potassium ethoxy(thioxo)methanethiolate (42.1 g, 262 mmol), and anhydrous NMP (300 mL). The reaction mixture was then heated to 170° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 3.5 hours. The crude reaction mixture was then allowed to cool to room temperature, and acidified to pH 5 with glacial acetic acid, which led to a precipitate which was collected by filtration. This precipitate was then suspended in ethyl acetate and washed with water, then brine, dried over sodium sulfate, filtered, and concentrated to give 5-chloro[1,3]thiazolo[5,4-b]pyridine-2-thiol (1-1) as a tan solid. HRMS (M+H)+: observed=202.9502, calculated=202.9499.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[Na+].[C:16](OCC)(=[O:18])[CH3:17]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11](=[O:13])[CH2:12][C:16](=[O:18])[CH3:17])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cccc2c1OCCO2
Agent: [H-]
Agent: [Na+]
Product: CC(=O)CC(=O)c1cccc2c1OCCO2
Temperature: 80 °C

Procedure:
1-(2,3-Dihydro-1,4-benzodioxin-5-yl)-ethanone (1.2 g) was dissolved in 20 mL of ethyl acetate, and sodium hydride (0.33 g, 60% oil dispersion) was added. The reaction mixture was heated to 80° C. overnight, quenched with water, and neutralized with carbon dioxide to give an oily product of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)butan-1,3-dione (0.37 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.O>CS(C)=O>[N:10]1([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1cnccc1Cl
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cnccc1-n1cncn1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
A mixture of known 4-chloro-nicotinonitrile (3.325 g, 24 mmol) (Tetrahedron Lett. 46:135-137, 2005), 1H-[1,2,4]triazole (1.99 g, 28.8 mmol), and CsCO3 (9.30 g, 28.5 mmol) in DMSO (5.0 mL) was stirred at 55° C. for 1.5 h. The resulting thin light brown slurry was shaken with water (50 mL) and extracted with DCM (1×50 mL, 2×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated under vacuum at 90° C. to afford the title compound as a beige solid (3.38 g, 82%).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])[N:8]([CH3:21])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH2:23]>O1CCOCC1.[Ag]>[CH3:21][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]3[C:5]([CH:6]=[O:23])=[CH:4][CH:3]=[CH:11][CH:7]=3)[C:11]=2[N:10]=[C:9]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: O
Reactant: Cn1c(-c2ccccc2[N+](=O)[O-])nc2c(C(Br)Br)cccc21
Agent: [Ag]
Solvent: C1COCCO1
Product: Cn1c(-c2ccccc2[N+](=O)[O-])nc2c(-c3ccccc3C=O)cccc21
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of silver hyperchlorate (57 mg, 0.27 mmol) in water (2 mL) was added to a solution of 4-dibromomethyl-N-methyl-2-(2-nitrophenyl)-benzimidazole (39 mg, 0.9 mmol) in 1,4-dioxane (2 mL). The mixture was refluxed for 5 h to afford a grey suspension. After cooling to room temperature, the precipitate was filtered off through a pad of celite and washed with ethyl acetate. The filtrate was washed with water and brine, dried over Na2SO4. Concentration using a rotary evaporator and subsequent column chromatography on silica gel using hexane/ethyl acetate (1:3) as the eluent to give N-methyl-2-(2-nitrophenyl)-benzimidazole-4-benzaldehyde (24 g, 93%) as a light-yellow solid. Rf=0.23 (hexane/ethyl acetate=1:3); 1H NMR (250 MHz, CDCl3) δ 3.68 (s, 3H), 7.47 (t, J=7.8 Hz, 1H), 7.66-7.74 (m, 2H), 7.77-7.86 (m, 2H). 7.90 (d, J=7.6 Hz, 1H), 8.28 (dd, J,=7.9 Hz, J2 =1.5 Hz, 1H), 10.81 (s, 1H). HRMS: Calcd for C1H11N3O3 281.0800, found 281.0814.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH:13]O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N+:11]=1[O-:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: OO
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)[n+]([O-])c(Cl)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 15.3 g (0.073 mole) of methyl 2,6-dichloroisonicotinate in 180 ml of trifluoroacetic acid was heated at 90° C. During a six hour period 34 ml of 30% hydrogen peroxide was added to the hot reaction mixture in four to five ml aliquots. After complete addition the reaction mixture was stirred at 90° C. for two hours. The solvent was distilled from the mixture under reduced pressure to leave a solid. The solid was triturated with water, and the mixture was then filtered. The filter cake was recrystallized from acetone to yield 8.75 g of methyl 2,6-dichloroisonicotinate N-oxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[CH:9]=[C:10](I)[C:3]=12.[CH3:13][N:14]1[CH2:19][CH2:18][O:17][C:16]2[CH:20]=[CH:21][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:23][C:15]1=2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[CH:9]=[C:10]([C:22]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][CH2:19][N:14]([CH3:13])[C:15]=4[CH:23]=3)[C:3]=12
Reactant: CN1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Cn1cc(I)c2c(Br)ccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: CN1CCOc2ccc(-c3cn(C)c4nccc(Br)c34)cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
Alternatively, to a mixture of 4-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (D7) (1 g, 2.97 mmol), 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.857 g, 3.12 mmol) in DME (18 mL) and MeOH (2.0 mL) was added bis(triphenylphosphine)palladium(II) chloride (0.208 g, 0.297 mmol) and 2M sodium carbonate aq. solution (14.84 mL, 29.7 mmol). The mixture was stirred at 60° C. for 1 hour. The mixture was cooled to RT and filtered. The solid was washed with excess ethyl acetate and the filtrate concentrated in vacuo. The residue aqueous was extracted with ethyl acetate (4×200 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified on normal phase chromatography eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give the title compound (344 mg). LCMS (A): m/z (M+H)+ 358/360, C17H16BrN3O requires 357/359 (acidic).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16](=[O:22])[NH:17]4)[CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:21]=[CH:20][N:19]=[C:18]5[C:13]=4[C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16](=[O:22])[NH:17]5)=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:33])=[C:30]([C:37]([F:38])([F:39])[F:40])[CH:29]=1
Reactant: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1C(F)(F)F)N1CCOc2cc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
Compound 218 (50 mg, 0.14 mmol), 4-fluoro-2-trifluoromethyl-benzoyl chloride (49 mg, 0.22 mmol), and DIEA (0.07 mL, 0.43 mmol) were dissolved in dioxane (2 mL) and stirred for 1 h at room temperature. The reaction was quenched with H2O, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 100% EtOAc in hexanes to provide 219 (28 mg, 36% yield) as a tan solid. LC-MS (M+H=536, obsd.=536).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:11]=1
Reactant: Brc1cccnc1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cccnc1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-bromopyridine (Fluka), the title compound was obtained as an off-white solid after purification by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][S:12]([O-:14])=[O:13].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+].N>CS(C)=O.[Cu]I>[CH3:11][S:12]([C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1)(=[O:14])=[O:13]
Reactant: CS(=O)[O-]
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Cu]I
Agent: N
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cnc2[nH]ccc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To 5-bromo-7-azaindole (1, 1.00 g, 5.08 mmol) in dimethyl sulfoxide (15.0 mL) were added sodium methanesulfinate (0.622 g, 6.09 mmol), L-proline (0.117 g, 1.02 mmol), copper(I) iodide (0.200 g, 1.05 mmol), and sodium hydroxide (0.0406 g, 1.02 mmol). The reaction was stirred at 120° C. overnight. The reaction was poured into aqueous ammonia, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound as a white solid (207, 0.50 g, 50.2%). MS (ESI) [M−H+]−=195.1.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[ClH:37].[Cl:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>CN(C)C=O>[ClH:38].[ClH:37].[CH2:1]([C@@H:8]1[CH2:13][N:12]([CH2:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccccc1
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2cccnc2)C[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled mixture of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3 g) and triethylamine (0.39 ml) in dimethylformamide (8 ml) was added 3-(chloromethyl)pyridine hydrochloride (0.12 g). The reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. Additional triethylamine (0.39 ml) and 3-(chloromethyl)pyridine hydrochloride (0.12 g) were added and the resulting mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated and subjected to a chromatography on a silica gel eluting with a mixture of toluene and ethyl acetate (5:1). The eluent was treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(pyridin-3-yl-methyl)piperazine dihydrochloride.