Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([OH:24])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=1[S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C.O>C(Cl)Cl.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([O:24][S:35]([C:28]2[C:29]([CH3:34])=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=2[CH3:26])(=[O:37])=[O:36])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1cc(F)c(OS(=O)(=O)c2c(C)cc(C)cc2C)nc1Nc1ccc(F)cc1F
Yield: 85.8 %

Procedure:
In 4 ml of methylene chloride was dissolved 400 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate, and 300 mg of 2,4,6-trimethylbenzenesulfonyl chloride and 150 mg of triethylamine were added thereto with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 2 hours. Subsequently, to the reaction mixture were added 4 ml of methylene chloride and 4 ml of water, and the organic layer was separated, washed successively with 4 ml of water and 4 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diethyl ether, after which crystals were collected by filtration to obtained 520 mg (yield 85.8%) of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinoyl]acetate. The physical properties of this compound were identical with those of the compound obtained in Example 19.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=2[CH2:13][CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:4][CH:3]=1.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:30].[Na+].C(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:29]([N:10]([CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:30]
Reactant: Oc1ccc(CCNc2ccccc2CC2CCc3cc(O)ccc3C2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(CCc1ccc(O)cc1)c1ccccc1CC1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of 6-{2-[2-(4-hydroxyphenyl)ethylamino]benzyl}-5,6,7,8-tetrahydronaphthalen-2-ol (1.0 g) in tetrahydrofuran (15 ml) were sequentially added acetic acid (in catalytic amounts), sodium triacetoxyborohydride (2.8 g) and acetaldehyde (572 mg), and the solution was stirred overnight at room temperature. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (730 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[C:17]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[NH:19][C:18]1=[O:27]>ClCCl>[Cl:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)([C:12]3[CH:13]=[CH:14][C:9]([N:8]([CH3:15])[CH3:7])=[CH:10][CH:11]=3)[C:18](=[O:27])[NH:19]2)=[CH:24][CH:23]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: CN(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CN(C)c1ccc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the suspension of cesium carbonate (0.147 g, 0.45 mmol) (Aldrich) in dichloromethane (2 mL) was added N,N-dimethylaniline (27.4 mg, 0.23 mmol) (Aldrich), followed by the addition of 3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (70 mg, 0.19 mmol) (from Example 60a supra) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with water, extracted with dichloromethane three times. The combined organic layer was washed with water, brine, dried over MgSO4. After filtration, the solvent was removed. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-(4-dimethylamino-phenyl)-1,3-dihydro-indol-2-one as a white solid. (Yield: 35 mg, 45%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1COc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of 3-acetamidophenol (1.0 g, 6.6 mmol) in dimethylformamide (10 ml) was added cesium carbonate (1.3 g, 3.9 mmol), followed by stirring at room temperature for 30 minutes. To the resulting mixture was added methyl 2-bromomethylbenzoate (1.8 g, 7.9 mmol), and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was poured into a5% aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), followed by trituration with hexane to give methyl 2-(3-acetamidophenoxymethyl)benzoate as a white solid (1.21 g, 61%).
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1.Br[C:11]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([CH:23]([CH3:27])[C:24]([OH:26])=[O:25])=[CH:16]2.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)(Cl)Cl>[CH3:27][C@H:23]([C:24]([OH:26])=[O:25])[C:15]1[CH:14]=[CH:13][C:12]2[CH:11]=[C:20]([O:21][CH3:22])[CH:19]=[CH:18][C:17]=2[CH:16]=1
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1cc(C)cc(C)c1
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
20.8 Ml (0.15 moles) of mesitylene and 30.9 g (0.10 moles) of (+)-2-(5-bromo-6-methoxy-2-naphthyl)propionic acid are added to 150 ml of chloroform and the mixture is cooled to 0° C. 20 Grams (0.15 moles) of anhydrous aluminum chloride are added portionwise under strong stirring to the mixture while going on with the cooling so that temperature does not exceed 20° C. The reaction mixture is kept at this temperature for 3 hours and then is poured into a mixture made of 100 g of ice and 10 ml of 32% hydrochloric acid. The reaction mixture is heated to 45° C., the layers are separated, the organic layer is twice washed with 50 ml of 1M hydrochloric acid and then with 100 ml of water. The organic layer is concentrated under vacuum and the residue is crystallized from 75 ml of toluene. The product is filtered and dried obtaining 21 g of the title compound, which corresponds to the drug known as naproxen, having [α]D 20 =+66.5° (C=1% in chloroform), with a yield of 91%.
Reaction SMILES: [CH3:1][C:2](=[O:9])[C:3](=[N:7]O)[C:4](=O)[CH3:5].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH2:17]>C(#N)C>[CH3:5][C:4]1[NH:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)=[N:7][C:3]=1[C:2](=[O:9])[CH3:1]
Reactant: NCc1ccccn1
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: CC(=O)c1nc(-c2ccccn2)[nH]c1C
Temperature: -10 °C
Yield: 35.8 %

Procedure:
A mixture of 6.5 g (0.05 mole) of 2,3,4-pentanetrione 3-oxime and 6.0 g (0.055 mole) of 2-pyridylmethylamine in 125 ml of acetonitrile was stirred and refluxed as described in Example 1. Cooling at -10° C. gave a precipitate which was recrystallized from acetonitrile to give 3.6 g of the product of the Example as a yellow solid, mp 145°-147° C.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([N:16]3[C:24](=[O:25])[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[C:17]3=[O:26])[C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:27])(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([N:16]3[C:17](=[O:26])[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=4[C:24]3=[O:25])[C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:27])#[N:2]
Reactant: NC(=O)CN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#CCN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 78.8 %

Procedure:
N,N-dimethylformamide (3 drops) was added to a mixture consisting of 2-[4-carbamoylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.2 g), toluene (30 ml) and thionyl chloride (0.2 g), and then the mixture was refluxed under heating for 3 hours. After the solvent was concentrated, toluene (50 ml) was added and fully mixed therewith, and then toluene was distilled off. The resulting solid was recrystalled from ethanol to give the desired 2-[4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.15 g). mp. 225°-229° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>N1C=CC=CC=1.Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[S:39]([C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)(=[O:41])=[O:40])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)S(=O)(=O)c3cccs3)cc2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 56.1 %

Procedure:
To a cold solution (0° C.) of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-phenoxy}acetate (40 mg, 0.091 mmol) in anhydrous pyridine (2 ml) was added 2-thiophenesulfonyl chloride (Aldrich, 82 mg, 0.45 mmol) and the reaction mixture was stirred at 0° C. for 4 hrs and at rt for an additional 15 hours. The reaction mixture was diluted with an aqueous solution of HCl (1N) and extracted with DCM (3×). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure to give 30 mg (56%) of the title compound as a yellow oil. HPLC, Rt: 5.9 un purity: 92.5%). 1H NMR (CDCl3) δ: 7.61 (dd, J=5.3, 1.5 Hz, 1H), 7.58 (dd, J=3.8, 1.5 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.39 (d, J=7.9 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 7.12 (dd, J=5.3, 3.8 Hz, 1H), 7.04 (m, 4H), 6.78 (d, J=8.7 Hz, 2H), 4.61 (s, 2H), 4.33 (s, 2H), 4.30 (s, 2H), 3.81 (s, 3H), 2.63 (t, J=7.7 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=2[CH2:15][O:14]1)CCC)[C:2]1C=CC=C[CH:3]=1.CC(O)=O>[Pd].CCO>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[CH2:15][O:14][CH:13]([CH2:12][NH:8][CH2:1][CH2:2][CH3:3])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: CCCN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 68 %

Procedure:
(−)-N-benzyl-N-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methyl}propan-1-amine (0.25 g, 0.67 mmol), palladium on carbon (10%, 30 mg), concentrated AcOH (0.1 ml) and EtOH (15 ml) was hydrogenated at 40 psi for 1 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to dryness. The crude product was dissolved in EtOAc (100 ml) and basified with Na2CO3 (10%, 50 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2×75 ml). The combined organic layers were collected, dried (Na2SO4), filtered and evaporated to dryness (0.32 g). Purification by flash chromatography (EtOAc/MeOH 10:1) afforded the pure title compound (0.13 g, 71%, >95% e.e.). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/MeOH/DEE. M.p. 235° C. [α]DMeOH=−80°. 1H-NMR (400 MHz, MeOH): δ 7.49 (1H, dd, J1 8.0 Hz J2 2.0 Hz), δ 7.41 (1H, d, 2.0 Hz), δ 7.30 (1H, d, J 8 Hz), δ 5.25 (1H, t, J 5.2 Hz), δ 5.02 (2H, dd, J1 50 Hz, J2 16 Hz), δ 3.1 (3H, s), δ 2.97 (2H, m), δ 2.65 (2H, t, J 7.2 Hz), δ 1.56 (2H, m), δ 0.95 (3H, t, J 7.6 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:19]([C:20](O)=[O:21])=[CH:18][N:17]=[C:16]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:15]=1.[CH2:29]([NH:36][CH:37]1[CH2:40][CH2:39][CH2:38]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH2:29]([N:36]([CH:37]1[CH2:38][CH2:39][CH2:40]1)[C:20]([C:19]1[C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[F:7])=[N:15][C:16]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[N:17][CH:18]=1)=[O:21])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(CNC2CCC2)cc1
Reactant: O=C(O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1cnc(N2CCOCC2)nc1-c1ccccc1F)N(Cc1ccccc1)C1CCC1
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
A solution of 2M oxalyl chloride in CH2Cl2 (0.062 mL, 0.125 mmol) was added to a stirred solution of 4-(2-fluorophenyl)-2-morpholinopyrimidine-5-carboxylic acid (Example 1; 0.03 g, 0.1 mmol) in CH2Cl2(2 mL) and DMF (0.030 mL) at room temperature, and stirring continued for 15 min. A solution of N-benzylcyclobutanamine (0.016 g, 0.1 mmol) in CH2Cl2(1 mL) and diisopropylethylamine (0.044 mL, 0.25 mmol) were added and stirred for 3 h. The solvent was removed under reduced pressure, and the residue was purified by Biotage SP1 on packed silica gel column (10%-80% EtOAc/Hexanes gradient) to give N-benzyl-N-cyclobutyl-4-(2-fluorophenyl)-2-morpholinopyrimidine-5-carboxamide (0.032 g, 72%). Mass Spec. FIA MS 447 (M+1), 1H NMR (DMSO-d6, 500 MHz) δ 8.43 (brs, 1H), 7.52-7.55 (m, 2H), 6.99-7.31 (m, 7H), 4.62 (brm, 2H), 3.78 (brm, 4H0, 3.68 (brm, 4H), 2.15 (brm, 2H), 1.85 (brm, 2H), 1.17 (brm, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[CH:21]1[CH2:30][C:29]([CH3:32])([CH3:31])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=2)[NH:22]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[CH:21]1[CH2:30][C:29]([CH3:31])([CH3:32])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[CH:27]=2)[NH:22]1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cc(N3CCOCC3)ccc2Cl)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cc(N3CCOCC3)ccc2Cl)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a suspension of 60% sodium hydride (650 mg, 16 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (1.53 g, 16 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A23. A solution of 2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (900 mg, 2.3 mmol) and 1,1′-carbonyldiimidazole (730 mg, 4.5 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B23. Solution B23 was added to Solution A23 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (190 mg, 17%) as a white solid: MS (ESI) M+1=478.0.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20](Cl)=[O:21].[CH3:23][N:24](C)[CH:25]=O>>[CH3:23][N:24]([CH3:25])[C:20](=[O:21])[CH2:19][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Cl:1]
Reactant: CN(C)C=O
Reactant: O=C(Cl)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Product: CN(C)C(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl

Procedure:
A solution of 3.5 g of {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chloride in 35 ml dimethylformamide is heated at 100° C. for 4 hr. The reaction mixture is then poured into ice, acidified and extracted with ether (4×200 ml). The organic extracts are washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to afford an oil which crystallizes on trituration with ether/petroleum ether. Chromatography on silica gel affords N,N-dimethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide mp 116° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][N:44]1[C:52]2[CH:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][NH:62][CH2:63][CH3:64])=[C:55]([C:65]([F:68])([F:67])[F:66])[CH:54]=3)[N:49]=[C:48]([C:69]#[N:70])[C:47]=2[N:46]=[CH:45]1>ClCCl>[C:69]([C:48]1[C:47]2[N:46]=[CH:45][N:44]([CH3:43])[C:52]=2[CH:51]=[C:50]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][N:62]([CH2:63][CH3:64])[C:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])=[O:9])=[C:55]([C:65]([F:68])([F:66])[F:67])[CH:54]=2)[N:49]=1)#[N:70]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CCNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 64.5 %

Procedure:
To a solution of (S)-1-methylpyrrolidine-2-carboxylic acid (16 mg), DIPEA (60 ul) and HBTU (51.7 mg) in dichloromethane (2 ml) was added 1-methyl-6-(4-(2-(ethylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (55 mg). The reaction was left stirring at room temperature for 60 hrs. Reaction mixture was diluted with dichloromethane, washed with sodium bicarbarbonate and water. Organic layer was dried over magnesium sulphate and solvent removed under reduced pressure. The residue was purified by acidic prep HPLC and cationic ion exchange column to yield (S)—N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-ethyl-1-methyl-pyrrolidine-2-carboxamide (40 mg).
Reaction SMILES: [C:1]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:23][CH2:24]I>CC#N>[C:1]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:23][CH3:24])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=C(O)c1ccsc1C(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccsc1C(=O)c1ccncc1
Temperature: 30 °C
Reaction time: 48 h
Yield: 85.5 %

Procedure:
To a solution of 2-isonicotinoylthiophene-3-carboxylic acid (2.2 g, 9.4 mmol) from example 2.1 and Cs2CO3 (6.2 g, 18.9 mmol) in CH3CN (500 mL) was added CH3CH2I (2.9 g, 18.9 mmol) dropwise. The mixture was stirred at 30° C. for 48 h. The mixture was filtered and concentrated to give the title compound (2.1 g, 85.5% yield) as yellow oil. LC-MS (Method A): m/z 340 (M+H)+, Rt: 0.81 min.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.6 mmol) and 3-(chloro)phenylboronic acid (1.35 g, 8.6 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (2.4 g, 17.2 mmol) and Pd(PPh3)4 (0.19 g, 0.172 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated, partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) for 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (1.2 g, 4.54 mmol, 53% yield) as a brown solid.
Reaction SMILES: [O:1]1[C:9]2[C:4](=N[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.BrBr.[C:12](O)(=O)C>>[O:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:12][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(=O)O
Reactant: c1cnc2ccoc2c1
Agent: BrBr
Product: c1ccc2occc2c1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
For furo[3,2-b]pyridine compounds of formula xii(a) the reaction may be performed by first reacting a furo[3,2-b]pyridine of formula xvi where R7 is amino or preferably nitro with bromine in acetic acid. The reaction is typically performed at about 50° C. for about 4 hours. After the bromination is substantially complete, the volatiles are then removed under reduced pressure and the residue is subjected to an extractive work-up under basic conditions. The resulting 3-bromofuro[3,2-b]pyridine in diethyl ether is then treated with an alkyl lithium, typically-n-butyl lithium, in the same solvent, below −100° C. to affect a metal-halogen exchange. After stirring at this temperature for about 1 hour, the reaction mixture is treated with an equivalent of an appropriate compound of formula xvii. Once the addition of the compound of formula xvii is complete, the reaction mixture is stirred below −78° C. for an additional 3 to 5 hours. It is critical, when R1 is hydrogen, to maintain the reaction mixture at this temperature to avoid equilibration of the anion to the 2-position of the benzofuran ring. The reaction mixture is then allowed to warm to −20° C. over about 50 minutes. An excess of an appropriate base, preferably sodium or potassium hydroxide, in a lower alkanol, typically methanol or ethanol is then added and the reaction refluxed for 0.25 to 24 hours to provide a benzofuran compound of formula xii(a) where R7 is amino or nitro.