Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[C:19]([NH2:25])[CH:18]=2)=[N:15][NH:14][C:13](=[O:26])[CH2:12]1.C1COCC1>C(O)(=O)C>[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]3[N:23]([CH3:24])[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[N:25][C:19]=3[CH:18]=2)=[N:15][NH:14][C:13](=[O:26])[CH2:12]1
Reactant: CNc1ccc(C2=NNC(=O)CC2C)cc1N
Reactant: O=C(O)c1ccncc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc2c(c1)nc(-c1ccncc1)n2C
Reaction time: 16 h

Procedure:
A mixture of 12.3 g of isonicotinic acid, 23.2 g of 5-methyl-6-(3-amino-4-methylaminophenyl)-4,5-dihydropyridazin-3-one, 16.2 g of N,N'-carbonyldiimidazole and 600 ml of THF is stirred at 25° for 16 hours. After the usual working up, an oily mixture of 5-methyl-6-(3-amino-4-N-methylisonicotinamidophenyl)- and 5-methyl-6-(3-isonicotinamido-4-methylaminophenyl)-4,5-dihydropyridazin-3-one is obtained and is dissolved in 400 ml of acetic acid. After the solution has been boiled for 3 hours, then cooled and submitted to the usual working up, 5-methyl-6-[1-methyl-2-(4-pyridyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one is obtained; dihydrochloride, decomposition above 298°.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:12](=O)[CH2:13][CH3:14]>>[CH2:13]([CH:12]1[NH:9][C:3]2[C:4](=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])[N:5]2[CH:1]=[CH:2][CH:8]=[C:7]12)[CH3:14]
Reactant: CCC=O
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Product: CCC1Nc2c(C)cccc2-n2cccc21

Procedure:
The title compound was prepared 3-methyl-2-nitro aniline according to the sequence of Examples 1 and 2, and the resulting oil treated with proprionaldehyde according to the procedure of Example 3 to yield a brown solid, mp 65-68° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:15][OH:16].O.O.O.C([O-])(=O)C.[Na+]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[N:15][OH:16])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NO
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1cccc(C(F)(F)F)c1
Yield: 90.1 %

Procedure:
7.5 g of 3'-trifluoromethylacetophenone, 6.25 g of hydroxylamine hydrochloride, and 8.8 g of sodium acetate trihydrate were heated in 125 ml of methanol under reflux for one hour. After completion of the reaction, the methanol was distilled off under reduced pressure. 190 ml of water was added to the resulting residue, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and stripped of the solvent by distillation under reduced pressure to obtain 7.3 g of 3'-trifluoromethylacetophenone oxime having a melting point of 63° to 65° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][Cl:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ccnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-chloro-6-methoxyquinolin-7-ol (5.7 g, 0.027 mole) and 1-bromo-3-chloropropane (13.2 mL, 0.14 mole) in DMF (150 mL), was added potassium carbonate (30 g, 0.27 mole). The mixture was stirred at RT for 20 h. The mixture was concentrated in vacuo then diluted with H2O (100 mL). The mixture was extracted with EtOAc (3×50 mL) and the organic extracts were washed with H2O and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (5% MeOH/CH2Cl2) to yield the title compounds as a light yellow solid. MS (ESI, pos. ion) m/z: 286 (M+1). Mass Calc'd for C13H13Cl2NO2: 285.0.
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.[H-].[Na+].Br[CH2:12][C:13]([C:15]1[N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[C:23](=[O:24])[C:18]2=[C:17]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:14]>CN(C=O)C>[CH2:27]([O:26][C:17]1[C:16]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:15]([C:13](=[O:14])[CH2:12][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6][S:1]2(=[O:8])=[O:7])[N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[C:23](=[O:24])[C:18]=12)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(=O)CBr)CCN(C)C2=O
Reactant: O=S1(=O)CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(=O)CN1CCCCS1(=O)=O)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,2-thiazinane 1,1-dioxide (70 mg, 0.51 mmol) and sodium hydride (0.51 mmol) in anhydrous DMF (2 mL) was stirred at room temperature for 30 minutes. The mixture was treated with a solution of ethyl 6-(bromoacetyl)-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.23 g, 0.51 mmol) in DMF. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 20 to 100% ethyl acetate in hexane gradient to afford the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[N:18][N:17]4[CH2:27][CH2:28][CH2:29][C:16]=34)[CH:11]=2)[N:6]=[CH:5]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:26][C:22]1[N:21]=[C:20]([C:19]2[C:15]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[N:6]=[CH:5][N:4]([CH2:3][CH2:2][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:13]4=[O:14])=[C:16]3[CH2:29][CH2:28][CH2:27][N:17]3[N:18]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCCl)c(=O)c4c2)CCC3)n1
Reactant: C1COCCN1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCN5CCOCC5)c(=O)c4c2)CCC3)n1
Temperature: 140 °C
Yield: 74 %

Procedure:
Combine 3-(2-chloro-ethyl)-6-[2-[6-methyl-(pyridin-2-yl)]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-3H-quinazolin-4-one (Example 6; 30 mg, 0.07 mmol) and morpholine (1 mL) in a pressure tube. Seal the tube and place in a microwave reactor. Radiate the mixture and heat at 140° C. for 1 h. The crude product is purified with silica gel chromatography, using dichloromethane to 10:1 dichloromethane/methanol as eluting solvents to give 25 mg (74%) of the target compound. MS ES+ m/e 457.5 (M+1). 1H NMR (400 MHz, CD2Cl2) δ 8.3 (d, J=2.0 Hz, 1H), 8.0 (s, 1H), 7.7 (dd, J=8.0, 2 Hz, 1H), 7.6 (m, 2H), 7.5(d, J=7.6 Hz, 1H), 7.0 (d, J=8 Hz, 1H), 4.3 (t, J=7.2 Hz, 2H), 4.1 (t, J=5.6 Hz, 2H), 3.6 (m, 4H), 3.1 (t, J=6.8 Hz, 2H), 2.7 (m, 4H), 2.5 (m, 4H), 2.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=O)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[N:33]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([NH2:33])=[O:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(CC)N1C(=O)[C@@](C)(CC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 1.15 g (2.49 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic acid (Example 71, Step F) in THF (12.5 mL) was added 383 μL (3.48 mmol) of N-methylmorpholine and 392 μL (2.98 mmol) of isobutyl chloroformate. The resulting off-white slurry was stirred at 0° C. for 2 h, and then 336 μL (28% ammonia in water, 4.97 mmol) of ammonium hydroxide was added. After an additional 3 h at 0° C., the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])C)=[O:4].[CH3:13][O:14][C@H](C)[C@@H](C(O)=O)N>>[CH3:13][O:14][C@H:7]([CH3:9])[C@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CO[C@H](C)[C@H](N)C(=O)O
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC

Procedure:
(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using O-Methyl-L-Threonine instead of L-Valine. Dichloromethane extraction was carried out 10 times instead of 3 times.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1(O)[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].O>ClCCCl.[I-].[Zn+2].[I-]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.3 %

Procedure:
To a solution of 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-4-hydroxy-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (5.40 g, 9.49 mmol) in 1,2-dichloroethane (150 ml) were added zinc iodide (4.54 g, 14.23 mmol) and sodium cyanoborohydride (4.47 g, 71.17 mmol), which was then stirred at room temperature for 12 hours. After the reaction was completed, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=9:1) to give the title compound (2.64 g, yield 50%, 3RS/4RS:3RS/4SR=6:1) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[C:13]([CH3:17])[C:14]([CH3:16])=[CH:15][C:7]=2[S:6]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(OCC)(=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH:5]3[C:10](=[O:11])[NH:9][C:8]4[CH:12]=[C:13]([CH3:17])[C:14]([CH3:16])=[CH:15][C:7]=4[S:6]3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Cc1cc2c(cc1C)SC(CCCBr)C(=O)N2
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C)SC(CCCN1CCN(c3ccc(F)cc3)CC1)C(=O)N2
Temperature: 110 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
In 10 ml of ethyl acetate were dissolved 628 mg of 2-(3-bromopropyl)-6,7-dimethyl-2H-1,4-benzothiazin-3(4H)-one and 721 mg of 1-(4-fluorophenyl)piperazine. The solution was concentrated and the concentrate was stirred at 110° C. for one hour, diluted with water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and concentrated to give 2-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-6,7-dimethyl-2H-1,4-benzothiazin-3(4H)-one (650 mg, 78.6%). Recrystallization from methanol gave colorless prisms, m.p. 161°-162° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].O=[C:8]1[N:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]2[CH2:24][CH2:25][C:26](=[O:27])[C:11]=2[CH:10]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[NH:9]1.CI>CN(C)C=O>[CH3:8][N:9]1[CH:10]([C:28]2[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[CH:34][CH:35]=2)[C:11]2[C:26](=[O:27])[CH2:25][CH2:24][C:12]=2[N:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=2)[C:1]1=[O:4]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(C2NC(=O)N(c3ccnc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (82 mg, 0.25 mmol) is added to a solution of 4-(2,5-Dioxo-1-(2-(tri-fluoromethyl)pyridin-4-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 15.5, 50 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL). Methyl iodide (28 mg, 0.20 mmol) is added, and the mixture is stirred at room temperature for 1 h and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 43 mg; ESI mass spectrum [M+H]+=413; Retention time HPLC: 0.78 min (005_CA01).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27](O)=[O:28])=[CH:20][C:19]=3[CH:30]=2)=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH3:2].S(Cl)(Cl)=O.[CH3:35][N:36]([CH:38]=O)[CH3:37]>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:30]=[CH:19][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:6][C:9]4[CH:14]=[CH:13][C:12]([CH2:38][N:36]([CH3:35])[CH:37]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:11][CH:10]=4)=[O:28])=[CH:20][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1)[CH2:7][CH3:8])[CH3:2]
Reactant: CCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1

Procedure:
In DMF (5 ml) was dissolved 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2 g). To the solution was added, under ice-cooling, thionyl chloride (0.09 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (25 ml). The solution was added dropwise a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.20 g) and triethylamine (0.35 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere stirred at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 5) (0.23 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH:15]=[CH:14]2.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH:15]=[CH:14]3)=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OCc3ccc(Cl)nc3)ccc2[nH]1
Temperature: 40 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
2-chloro-5-(chloromethyl)pyridine (0.995 g, 6.14 mmol) was added slowly to a well-stirred mixture of 6-hydroxyquinolin-2(1H)-one (0.9 g, 5.58 mmol), K2CO3 (1.158 g, 8.38 mmol) and potassium iodide (0.927 g, 5.58 mmol) in DMF (18 mL) at 40° C. The reaction mixture was stirred at 40° C. for 18 h and poured into ice/water. The suspension was filtered and the filter cake taken up in methanol/DCM and purified by flash chromatography on silica gel using 1-5% (10% ammonium hydroxide in methanol)/DCM. The desired fractions were concentrated to give 6-((6-chloropyridin-3-yl)methoxy)quinolin-2(1H)-one as a beige solid (1.0 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (1H, s), 8.55 (1H, d, J=2.01 Hz), 7.98 (1H, dd, J=8.03, 2.51 Hz), 7.85 (1H, d, J=9.54 Hz), 7.58 (1H, d, J=8.03 Hz), 7.18-7.32 (2H, m), 6.51 (1H, d, J=9.54 Hz), 5.19 (2H, s). LCMS: R.T.=3.07; [M+H]+=287.01.
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[CH2:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[N:26](C(OC(C)(C)C)=O)[CH:25]=1)=[O:12])[CH3:2].CO.Cl>>[ClH:9].[O:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[CH2:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:12])[CH3:2]
Reactant: COc1ccc(Cl)cc1NC(=O)Nc1cccc2c1ccn2Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Agent: Cl
Solvent: CO
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc2c1ccn2Cc1c[nH]c2ncccc12
Reaction time: 8 h
Yield: 185.7 %

Procedure:
To 1-(2-methoxyl-5-chlorophenyl)-3-{1-[1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1H-indol-4-yl}urea (500 mg, 0.92 mmol) was added hydrogen chloride methanol solution (25%), and the resulting mixture was stirred overnight, then concentrated to give the product 1-(2-Methoxyl-5-chlorophenyl)-3-[1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-indol-4-yl]urea hydrochloride (412 mg, 93%).
Reaction SMILES: [CH2:1]([C:8]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>ClCCl>[CH2:31]([O:30][C:28]([N:10]1[CH2:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:11]1)=[O:29])[CH3:32]
Reactant: COc1cccc(C2(Cc3ccccc3)CNC2)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCOC(=O)N1CC(Cc2ccccc2)(c2cccc(OC)c2)C1
Temperature: 25 °C

Procedure:
To a stirred and cooled solution of 3-benzyl-3-(3-methoxyphenyl)azetidine (0.45 g, 1.776 mmol) under argon in dichloromethane containing diisopropylamine (0.465 ml, 2.66 mmol) was added dropwise ethyl chloroformate (0.26 ml, 2.7 mmol). The reaction was stirred over night while it was allowed to warm up to room temperature. Hydrochloric acid (1N) was added and the mixture diluted with dichloromethane. The organic layer was separated and the aqueous layer extracted twice with dichloromethane. The combined organic layers were washed subsequently with water, sodium bicarbonate and brine, dried over sodium bicarbonate, filtered and the solvent evaporated to obtain desired product. m=546 mg (61%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[Cl:18].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])[C:24](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:9]=2[Cl:18])=[CH:6][C:5]2[NH:19][C:24]([C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[F:21])=[N:20][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2Cl)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)c(Cl)c1
Yield: 74 %

Procedure:
A solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]benzene-1,2-diamine (120 mg, 0.37 mmol), pentafluoropropanoic acid (5 ml) was stirred overnight at 80° C. in an oil bath. Then the mixture was quenched with water (100 ml), pH adjusted to 7 with saturated aqueous sodium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenyl]-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (124.4 mg, 74%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:17][C:15]=2[N:16]=1.[CH2:25](O)[CH2:26][OH:27]>C1C=CC=CC=1>[O:24]1[CH2:25][CH2:26][O:27][CH:23]1[CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:16][C:15]=2[CH:17]=1
Reactant: OCCO
Reactant: O=CCCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Solvent: c1ccccc1
Product: c1ccc2cc(Cc3nc4cc(CCC5OCCO5)ccc4o3)ccc2c1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionaldehyde (2.9 g), ethylene glycol (0.685 g), P-toluenesulfonic acid monohydrate (0.175 g) and benzene (50 ml) was stirred for 3 hours under reflux. The reaction mixture was successively washed with aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate (MgSO4). The solvent was distilled off, whereby 5-[2-(1,3-dioxolan-2-yl)ethyl]-2-(2-naphthylmethyl)benzoxazole (2.95 g, 89%) was obtained. Recrystallization from dichloromethane- isopropyl ether gave colorless prisms. Melting point: 85-86° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([CH2:19][O:20][CH2:21][C:22]3([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:27][CH2:26][N:25]([C:28](OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[CH3:28][N:25]1[CH2:26][CH2:27][C:22]([CH2:21][O:20][CH2:19][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=2)([C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccncc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A flask was charged with tert-butyl 4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(pyridin-4-yl)piperidine-1-carboxylate (50 mg, 0.091 mmol) and trifluoroacetic acid (1 mL, 13.0 mmol) in dichloromethane (5 mL) at 0° C. under nitrogen. After 20 min the solvent was evaporated under reduced pressure and the resulting residue dried overnight. The resulting oil was dissolved in dichloromethane (5 mL) and treated with formaldehyde (37 wt. % solution in water, 1.0 mL) at 0° C. After 20 min, the reaction was treated with sodium triacetoxyborohydride (77 mg, 0.363 mmol). The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting residue purified via preparative HPLC. The solvent was evaporated to afford 21 mg (50%). Mass Spec: 466.10 (MH)+. LC tr=2.325 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).