Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7]O)=[N:3]1.S(Cl)(Cl)=O.[I:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:23]([O-:25])=[O:24])[NH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[I:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:23]([O-:25])=[O:24])[N:16]([CH2:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[N:15]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: Cn1ccc(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To (1-methyl-1H-pyrazol-3-yl)methanol (2.01 g, 17.93 mmol) in DCM (80 mL) at 0° C. was cautiously added thionyl chloride (10.43 mL, 143.4 mmol). The cold bath was removed and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residual yellow solid was diluted with DMF (30 mL). 3-Iodo-4-nitro-1H-indazole (5.181 g, 17.93 mmol) and K2CO3 (7.432 g, 53.78 mmol) were added to the DMF solution. The reaction mixture was stirred for 20 hours, and concentrated under reduced pressure to remove most of the DMF. The residue was diluted with DCM (100 mL) and washed with H2O. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/Hexane 1:3) to provide the product (5.11 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:23][N:24]1[C:29](=[O:30])[CH:28]=[CH:27][NH:26][C:25]1=[O:31].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:26]4[CH:27]=[CH:28][C:29](=[O:30])[N:24]([CH3:23])[C:25]4=[O:31])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: Cn1c(=O)cc[nH]c1=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c(=O)ccn(-c2ccc(-n3cnc(CNC(=O)c4ccc(Cl)s4)c3)cc2)c1=O
Temperature: 130 °C
Yield: 22.6 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (66 mg, 0.15 mmol), 3-methyluracil (60 mg, 0.48 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (60 mg, 0.43 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (15 mg). MS 442.2 and 444.2 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[NH2:11][OH:12].O>C(O)(=O)C.O1CCOCC1.C(Cl)(Cl)Cl.C(O)(C)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[N:11][OH:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: NO
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(=NO)c1ccc(Cl)nc1
Temperature: 150 °C
Yield: 94 %

Procedure:
Combine 1-(6-chloropyridin-3-yl)ethanone (3.4 g, 22.8 mmol), hydroxylamine (50%) in water (5.77 g, 87.4 mmol) and 0.75 mL of acetic acid in 15 mL of dioxane in a pressure vessel. Seal the vessel and heat the mixture in an oil bath for 3 h at 150° C. Cool the mixture to RT. Dilute with chloroform/IPA (3/1), wash with water, and aqueous saturated sodium chloride. Separate the layers and dry the organic layer over sodium sulfate. Concentrate in vacuo to afford the title compound (3.52 g, 94%). MS (ES) m/z 171 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:14][N:13]([C:15](=[O:26])[NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:15]([N:13]1[CH2:14][C:10]2([CH2:11][NH:8][CH2:9]2)[CH2:12]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC2(CN(C(=O)NCc3ccc(Cl)cc3Cl)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(CNC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-(2,4-Dichloro-benzylcarbamoyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (20 mg, 50 μmol) and trifluoroacetic acid (740 mg, 6.49 mmol) were dissolved in dichloromethane (2 mL) and the reaction mixture was stirred for 30 min at ambient temperature. Concentration of the reaction mixture in vacuo afforded the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:24])[N:11]([CH3:23])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:25][O:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][N:32]2[C:36]3=[N:37][CH:38]=[CH:39][C:40](Cl)=[C:35]3[C:34]([CH3:42])=[N:33]2)=[CH:29][CH:28]=1.CC([O-])(C)C.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:24])[N:11]([CH3:23])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:40]1[CH:39]=[CH:38][N:37]=[C:36]2[N:32]([CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:44][CH:43]=3)[N:33]=[C:34]([CH3:42])[C:35]=12
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)c(F)c2)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cnc(Nc6ccc(F)cc6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a mixture of 5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)-3-methylpyrimidin-4(3H)-one (25.2 mg, 0.077 mmol) and 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (20 mg, 0.070 mmol) dissolved in DMF (0.5 mL), added KOtBu (0.077 ml, 0.077 mmol) 1M solution in THF, and potassium carbonate (10.6 mg, 0.077 mmol). The mixture was stirred at 110° C. overnight. Cooled to room temperature and partitioned between EtOAc (15 mL) and water (20 mL). The organic layer was dried with brine, Na2SO4, and evaporated to afford 27 mg of crude product. Purified by silica gel column chromatography (Biotage 12M) eluting with 5% MeOH/EtOAc to afford desired product as white solid (4.6 mg, 11%). LRMS (APCI pos) m/e 581.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH:27]=[N:26][NH:25][C:24]1=[O:28]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:25]1[C:24](=[O:28])[N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([F:15])([F:30])[F:29])[CH:27]=[N:26]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccccc1C(F)(F)F
Product: C[C@@H](n1ncn(-c2ccccc2C(F)(F)F)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 20.3 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.0 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.1 g of 4-(2-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(2-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone (0.4 g) was obtained as a colorless powder.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:20]([C:23]1[CH:28]=[C:27]([CH2:29][O:30][CH3:31])[N:26]=[CH:25][N:24]=1)=[C:21]=S.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH3:31][O:30][CH2:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:20][C:21]2[O:13][C@:5]3([CH2:4][N:3]=2)[CH:10]2[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]2)[CH2:6]3)[CH:28]=1
Reactant: COCc1cc(N=C=S)ncn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COCc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ncn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.39 g, 1.71 mmol) in dimethylformamide was added cesium carbonate (1.39 g, 4.28 mmol) and 4-isothiocyanato-6-(methoxymethyl)pyrimidine (0.31 g, 1.71 mmol). The suspension was stirred at ambient temperature for 15 min. To the reaction mixture was added N,N′-diisopropylcarbodiimide (0.80 mL, 5.13 mmol) and the mixture was stirred overnight then concentrated. The residue was purified by column chromatography (5-25% 9:1 methanol/ammonium hydroxide in ethyl acetate) to afford (R)—N-(6-(methoxymethyl)pyrimidin-4-yl)-4 H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.18 g, 0.58 mmol, 34% yield) as a yellow solid. 1H NMR (400 MHz, MeOD-d4) δ ppm 8.65 (1 H, d, J=1.01 Hz), 6.92 (1 H, br. s.), 4.40 (3 H, s), 4.03 (1 H, d, J=10.32 Hz), 3.72 (1 H, d, J=10.32 Hz), 3.44 (2 H, s), 3.18-3.26 (1 H, m), 3.06-3.13 (1 H, m), 2.69-2.96 (4 H, m), 1.94-2.19 (2 H, m), 1.45-1.86 (3 H, m). MS (LC/MS) R.T.=0.76; [M+H]+=304.30.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH:5]=1)[CH3:14]
Reactant: COc1ccc(CCl)cc1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C=O)c(OCc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
To a suspension of 4-diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol), potassium carbonate (428 mg, 3.10 mmol), and tetrabutylammonium iodide (57 mg, 0.15 mmol) in 1.6 mL of dry N,N-dimethylformamide was added 4-methoxybenzyl chloride (0.31 mL, 2.3 mmol) at 0° C. After being stirred at room temperature for 2 h, the reaction mixture was filtered to remove inorganic salts. The filtrate was diluted with diethyl ether, and the solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound as a colorless oil (493 mg, quant.).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]([CH3:12])[CH3:11])[S:7][CH:8]=1.Cl.[NH2:14][CH2:15][CH2:16][SH:17]>>[NH2:14][CH2:15][CH2:16][S:17][CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]([CH3:12])[CH3:11])[S:7][CH:8]=1
Reactant: CN(C)Cc1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Product: CN(C)Cc1nc(CSCCN)cs1

Procedure:
To the solution from Example 13 above was added 56.7 g. of 2-aminoethanethiol, hydrochloride. The mixture was then heated and stirred, and distilled. The distillation was stopped when the pot temperature reached 133°, after 22 ml. of organic and 115 ml. of aqueous distillate had been received. To the residue remaining in the distillation flask was added 100 ml. of deionized water, 100 ml. of dichloromethane, and 100 ml. of 50% aqueous sodium hydroxide, dropwise with ice bath cooling. The mixture was then filtered, and the filter cake was washed with dichloromethane. The aqueous layer of the filtrate was extracted twice with 100 ml. portions of dichloromethane, and then the organic layers were combined, dried over sodium sulfate and filtered. The filtrate was evaporated to dryness under vacuum to obtain 97.7 g. of the desired product, which was identified as being 79.8% pure by gas chromatography, using a 2 mm. by 6-foot column of Gaschrom-Q (Applied Science Co.) containing 10% of OV-210 (Ohio Valley Chemical Co.) using 25 ml./min. of helium as the carrier at 170° isothermal.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:42]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([S:8][CH:9]([CH2:42][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(CN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of N-[2-(benzylthio)-3-oxopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (0.90 g) and morpholine (0.15 mL) in tetrahydrofuran (20 mL) was stirred at room temperature for 30 min, and ice-cooled. Sodium triacetoxyborohydride (0.39 g) was added to this solution, and the mixture was stirred from under ice-cooling to room temperature for 16 hr. The reaction solution was acidified with aqueous citric acid solution, basified with aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=6:4-10:0) to give the title compound (0.89 g, yield: 89%) as a colorless amorphous solid. MS: 716 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[CH:8][C:9]=1I)=[O:4].C([Mg]Cl)(C)C.CC1OCCC1.Br[C:24]1[CH:52]=[CH:51][C:27]([C:28]([N:30]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2)=[O:29])=[CH:26][CH:25]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[CH:8][C:9]=1[C:24]1[CH:52]=[CH:51][C:27]([C:28]([N:30]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:32]2)=[O:29])=[CH:26][CH:25]=1)=[O:4]
Reactant: COC(=O)c1c(I)cnn1C
Reactant: Cc1cccnc1N(C(=O)c1ccc(Br)cc1)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccc(C(=O)N(c3ncccc3C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 4-iodo-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (8.1 g, 30.45 mmol) in THF (anhydrous, 60 mL) was added isopropyl magnesium chloride (16.5 mL, 16.5 mmol) at −45° C. The solution turned from clear to light green-yellowish. Stirred at this temperature for 30 min, GC-MS (sample in CD3OD) indicated all halogen-metal exchange completed. To the mixture was added 1.9 N ZnCl2 in 2-MeTHF (9.62 mL, 18.3 mmol) dropwise and the reaction was warmed to room temperature. The mixture was stirred for 2 h, over which time it turned from clear yellowish to an opaque yellowish mixture. To this reaction was added Preparation 2 tert-butyl 3-[(4-bromobenzoyl)(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate (12.04 g, 25.37 mmol) as a solid in one batch. The reaction temperature was then raised to 50° C., 1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (166 mg, 0.254 mmol) was added. The reaction was then stirred at 60° C. for 2 h then cooled to room temperature. The reaction was quenched with water and extracted 3× EtOAc. The organic layer was dried and concentrated. Purification was performed by Combiflash ISCO column (220 g) 0-75% EtOAc/heptane to isolate the desired title compound (12.8 g, 78%).
Reaction SMILES: CO[CH2:3][C:4]1[S:5][CH:6]=[N:7][N:8]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].Br>>[S:5]1[CH:6]=[N:7][N:8]=[C:4]1[CH2:3][S:13][CH2:12][CH2:11][NH2:10]
Reactant: COCc1nncs1
Reactant: NCCS
Agent: Br
Agent: Cl
Product: NCCSCc1nncs1

Procedure:
Equimolar quantities of 2-methoxymethyl(1,3,4)thiadiazole and cysteamine hydrochloride were refluxed under nitrogen for 42 hours in a three-fold excess of hydrobromic acid (48%). The mixture was evaporated to dryness and the residue was dissolved in water. The solution was adjusted to pH 11 by the addition of IRA 400(OH-) and applied to a column of CG50(H+) which was eluted with dilute acetic acid. The eluate was evaporated to give 2-(2-(1,3,4)thiadiazolylmethythio)ethylamine as an oil.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[I-].[K+].C(N(CC)CC)C.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[CH3:25]>C1(C)C=CC=CC=1.O>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])=[CH:20][C:19]=1[CH3:25]
Reactant: Cc1cc(N)ccc1Br
Reactant: CN(C)CCCl
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(NCCN(C)C)ccc1Br
Temperature: 110 °C
Reaction time: 17 h
Yield: 18.1 %

Procedure:
2-Chloro-N,N-dimethylethylamine hydrochloride (372 mg, 2.58 mmol), potassium iodide (428 mg, 2.58 mmol) and triethylamine (0.719 ml, 5.16 mmol) were added to a solution of 4-bromo-3-methylaniline (400 mg, 2.15 mmol) in toluene (5.0 ml), and the mixture was heated with stirring at 110° C. for 17 hours. The reaction mixture was cooled and water was then added, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give N′-(4-bromo-3-methyl-phenyl)-N,N-dimethyl-ethane-1,2-diamine (100 mg, 18%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:29]=[CH:28][C:19]4[C:20]([C:24]([O:26]C)=[O:25])=[C:21]([CH3:23])[O:22][C:18]=4[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C=O)C>[CH3:23][C:21]1[O:22][C:18]2[CH:17]=[C:16]([O:15][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:6][CH:7]=4)[N:12]=[CH:11][CH:10]=3)[CH:29]=[CH:28][C:19]=2[C:20]=1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCCBr)ccc34)ccc12
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Cc1oc2cc(Oc3ccnc4cc(OCCN5CCCC5)ccc34)ccc2c1C(=O)O
Yield: 14.1 %

Procedure:
To a solution of methyl 6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxylate 121-D (2.4 g, 7.2 mmol) in DMF (20 ml) was added K2CO3 (5 g, 35.8 mmol) a dibromoethane (2.7 g, 14.3 mmol). The reaction mixture was stirred at room temperature overnight. Column chromatography gave methyl 6-{[7-(2-bromoethoxy)quinolin-4-yl]oxy}-2-methyl-1-benzofuran-3-carboxylate 121-E (1.5 g). A solution of compound 121-E (750 mg) and pyrrolidine (351 mg) in DMF (3 ml) was heated to 60° C. for 45 min. The reaction mixture was extracted with EtOAc. Methyl 2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}benzofuran-3-carboxylate 121-F (110 mg) was purified by silica gel chromatography using 5-10% MeOH/CH2Cl2. Compound 121-F (110 mg) was treated with 20% NaOH (1 ml) in MeOH (1 ml) overnight. The reaction mixture was acidified with AcOH and extracted with EtOAc. The residue was purified by silica gel chromatography using 0-10% MeOH in CH2Cl2 to give 2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxylic acid 121-G (100 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C.Cl>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:19]1[CH2:22][CH2:21][CH2:20]1)=[O:7]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(F)c1)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
Commercially available 3,4-difluorobenzoic acid (3.00 g, 19.0 mmol) was dissolved in dichloromethane (50 mL), and N,N-dimethylformamide (0.10 mL) was added, followed by dropwise addition of oxalyl chloride (1.98 mL, 22.8 mmol) and stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in dichloromethane (100 mL), and azetidine hydrochloride (2.27 g, 24.2 mmol) and triethylamine (6.60 mL, 47.4 mmol) were added, followed by stirring at room temperature for 4.5 hours under nitrogen atmosphere. 0.5N hydrochloric acid (100 mL) was added, and extraction was carried out with dichloromethane (100 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-50%) to afford the desired compound (600 mg, yield 16%) as a colorless liquid.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](O)=[O:12])=[CH:6][CH:5]=1.S(Cl)([Cl:20])=O>>[F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([Cl:20])=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1

Procedure:
20 g of 4-difluoromethoxy-α-isopropyl-phenylacetic acid were dissolved in 100 ml of thionyl chloride and the solution was heated to the boil for 1 hour. After distilling off excess thionyl chloride, the residue was distilled under a high vacuum. 4-Difluoromethoxy-α-isopropylphenylacetic acid chloride of boiling point 93°-99° C./0.2 mm Hg was obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[O:21][CH:22]=[CH:23][N:24]=1)CCC>COCCOC.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>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cccc2cc(C=O)c(-c3ncco3)nc12
Temperature: 100 °C
Yield: 34.3 %

Procedure:
To a solution of 2-chloro-8-methylquinoline-3-carboxaldehyde (250 mg, 1.21 mmol) in DME (3 mL) was added 2-(tributylstannyl)oxazole (0.31 mL, 1.76 mmol) and Pd(PPh3)4 (70 mg, 0.06 mmol). The reaction mixture was heated in a microwave at 100° C. for 45 minutes. More Pd(PPh3)4 (50 mg, 0.04 mmol) was added to the mixture, which was heated at 100° C. for 2 h. Purification by column chromatography (SiO2, 0-100% EtOAc in heptane) gave the title compound as a cream solid (99 mg, 34%). δH (DMSO-d6) 10.85 (s, 1H), 8.91 (s, 1H), 8.52 (d, J 0.6 Hz, 1H), 8.12 (d, J 8.1 Hz, 1H), 7.86 (d, J 7.0 Hz, 1H), 7.64-7.72 (m, 2H), 2.81 (s, 3H). LCMS (ES+) 239 (M+H)+, RT 3.65 minutes (Method 3).