Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:20][C:19]([N:36]=[C:37]=[O:38])=[C:18]([F:39])[CH:17]=1.Cl>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([F:39])[C:19]([N:36]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:37]2=[O:38])=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)COc1ccccc1Oc1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 0 °C

Procedure:
To ethyl 3-amino-4,4,4-trifluorocrotonate are added N,N-dimethylformamide and sodium hydride and the mixture is stirred at 0° C. Thereafter, to the reaction solution is added a mixture of 4-chloro-2-fluoro-5-{2-(ethoxycarbonylmethoxy)phenoxy}phenyl isocyanate [Intermediate compound A12-23] and N,N-dimethylformamide, and the mixture is stirred at room temperature. The reaction solution is poured into a mixture of hydrochloric acid and ice water, and the deposited crystal is collected by filtration to obtain ethyl [2-{2-chloro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-4-fluorophenoxy}phenoxy]acetate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)=[O:18])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:24][CH:21]1[CH2:22][CH2:23][N:19]([C:17](=[O:18])[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)=[CH:16][CH:15]=2)[CH2:20]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(Cc2nc3ccccc3[nH]2)cc1)N1CCC(O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(C(=O)c2ccc(Cc3nc4ccccc4[nH]3)cc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A portion of [4-(1H-benzoimidazol-2-ylmethyl)-phenyl]-(3-hydroxy-pyrrolidin-1-yl)-methanone (1.00 g, 3.1 mmol) was dissolved in dichloromethane, treated with diisopropylethylamine (0.60 g, 4.6 mmol), cooled to 0° C., treated dropwise with a solution of methanesulfonyl chloride (0.49 g, 4.3 mmol) in dichloromethane, stirred at 0° C. for 10 min. and concentrated under vacuum to provide a solid residue. Purification of this residue by column chromatography (silica, chloroform:methanol 0→5%) gave the title product as a yellow solid (62%). 1H NMR (400 MHz, CDCl3): 7.58 (m, 2H), 7.56 (m, 4H), 7.22 (m, 2H), 5.27 (d, J=5.4 Hz 1H), 4.35 (s, 2H), 3.93 (s, 1H), 3.80 (s, 1H), 3.63 (m, 4H), 3.09 (m, 3H), 2.31 (m, 2H). [M+H] 400.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:33][C@@H:34]2[CH2:38][CH2:37][C:36](=[O:39])[NH:35]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[I-].C([N+](CC)(CC)CC)C.C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:33][C@@H:34]2[CH2:38][CH2:37][C:36](=[O:39])[NH:35]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)N2)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCC(=O)N1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of Example 4C (810 mg, 2.49 mmol), (S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (Aldrich, 807 mg, 3 mmol), potassium carbonate (828 mg, 6 mmol), tetrabutylammonium iodide (20 mg, 0.05 mmol), tetrabutylammonium hydrogensulfate (20 mg, 0.06 mmol) and tetraethylammonium iodide (20 mg, 0.07 mmol) in anhydrous toluene (100 mL) was refluxed for 15 h. The mixture was cooled to room temperature, washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was chromatographed (SiO2, ethyl acetate-ethanol 9:1) to afford 510 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.32 (s, 9H), 1.83 (m, 1H), 2.07 (m, 3H), 3.78 (s, 3H), 4.09 (m, 2H), 4.30 (m, 1H), 7.10 (d, J=9 Hz, 1H), 7.27 (s, 1H), 7.45 (dd, J=9 Hz, 3 Hz, 1H), 7.62 (d, J=3 Hz, 1H), 7.82 (broad s, 1H); MS (DCI/NH3) m/z 422 (M+H)+. Anal. calcd for C20H24ClN3O3S.0.25H2O: C, 56.33; H, 5.79; N, 9.85. Found: C, 56.42; H, 5.55; N, 9.25.
Reaction SMILES: Cl.[CH2:2]([NH:9][CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:12]=2[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:23]([CH2:30][C@H:31]1[O:33][CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(NC1CCCC2C=C(OC)C=CC=2C1)C1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C1(C)C=CC=CC=1>[CH2:2]([N:9]([CH2:32][C@H:31]([OH:33])[CH2:30][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:12]=2[CH2:11]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)CCCC(NCc1ccccc1)C2
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-Benzyl-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine hydrochloride was converted to the corresponding free base in a usual manner. A mixture of (2S)-3-phenoxy-1,2-epoxypropane (75 mg), N-benzyl-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amine (140 mg), and ytterbium(III) trifluoromethanesulfonate (93 mg) in toluene (2.6 ml) was stirred at room temperature for 3 days and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (dichloromethane-methanol) over silica gel to afford (2S)-1-[N-benzyl-N-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (200 mg).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[CH:50][N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[N:51]1[CH:50]=[CH:49][N:48]2[C:43]([C:11]3[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]4[S:28][C:27]([CH2:29][N:30]5[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]5)=[CH:26][C:9]=4[N:10]=3)=[CH:44][CH:45]=[CH:46][C:47]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Brc1cccc2nccn12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cccc5nccn45)nc(N4CCOCC4)c3s2)CC1
Yield: 44.1 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (0.35 g, 0.51 mmol), 5-bromoimidazo[1,2-a]pyridine (0.11 g, 0.56 mmol), copper(I) 2-thiophene carboxylate (0.019 g, 0.1 mmol) and Pd(PPh3)4 (0.059 g, 0.05 mmol) in dioxane (5 mL) was subjected to microwave irradiation at 140° C. for 20 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90). The residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The solution was concentrated in vacuo and the residue was purified by reverse phase HPLC (Phenomenex Gemini 5u C 18, 20 mM triethylamine in water on a gradient of acetonitrile 75:25 to 2:98) to give 697 as a white powder (0.117 g, 45%). LCMS: RT=4.35 min, [M+H]+ 521.2. 1H NMR (400 MHz, DMSO-d6): δ 9.33 (d, J=1.1 Hz, 1 H); 8.04 (dd, J=7.5, 1.2 Hz, 1 H); 7.78 (dd, J=8.9, 1.1 Hz, 1 H); 7.74 (d, J=1.2 Hz, 1 H); 7.54 (s, 1 H); 7.41 (dd, J=8.9, 7.5 Hz, 1 H); 7.07 (d, J=3.5 Hz, 1 H); 6.95 (d, J=3.5 Hz, 1 H); 4.00 (t, J=4.7 Hz, 4 H); 3.89 (s, 2 H); 3.82 (t, J=4.7 Hz, 4 H); 2.56-2.54 (m, 4 H); 2.49-2.44 (m, 4 H); 1.08 (s, 6 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18]C)[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:32]([N:29]1[CH2:28][CH2:27][CH:26]([C:23]2[CH:24]=[CH:25][C:20]([C:11]3[C:12]4[C:13](=[O:18])[NH:14][CH:15]=[CH:16][C:17]=4[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[N:10]=3)=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)(=[O:34])[CH3:33]
Reactant: COc1nccc2c1c(-c1ccc(C3CCN(C(C)=O)CC3)cc1)nn2-c1c(F)cccc1F
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CC(=O)N1CCC(c2ccc(-c3nn(-c4c(F)cccc4F)c4cc[nH]c(=O)c34)cc2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution of 1-(4-(4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)piperidin-1-yl)ethanone (112 mg) in acetonitrile (3 mL) were added sodium iodide (73 mg) and chloro(trimethyl)silane (0.155 mL), and the mixture was stirred at 60° C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, hexane/ethyl acetate to ethyl acetate/methanol). The obtained fraction was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 10 mM ammonium carbonate)) to give the title compound (51 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:44])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[C:29]4[CH:37]=[C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[N:35]=[CH:34][C:30]=4[N:31]=[CH:32][N:33]=3)=[CH:23][C:22]=2[CH3:43])[CH:15]=1)(C)(C)C>C(Cl)Cl>[CH3:43][C:22]1[CH:23]=[C:24]([NH:27][C:28]2[C:29]3[CH:37]=[C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[N:35]=[CH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:25]=[CH:26][C:21]=1[O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([OH:44])=[O:12]
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)O)c1
Yield: 99.4 %

Procedure:
Trifluoro acetic acid (10 mL) was added to a solution of 3-[2-Methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-benzoic acid tert-butyl ester (0.40 g, 0.82 mmol) in CH2Cl2 (10 mL). After 12 h the reaction was concentrated to give a red solid (0.36 g, 100%). LRMS: 4.42 (MH+), HPLC Rf: 8.34 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.[NH2:40][C@@H:41]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([NH:44][CH3:45])=[O:43]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:40][C@@H:41]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([NH:44][CH3:45])=[O:43])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=418.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH2:34][CH3:35])[CH:30]=[CH:29][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH:16]([C:24]([O:26]CC)=[O:25])[C:14]2=[O:15])[CH2:9][CH2:8]1)=[O:6].[OH-].[Na+].C(O)C>O>[CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH2:34][CH3:35])[CH:30]=[CH:29][C:4]=1[C:5]([N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH:16]([C:24]([OH:26])=[O:25])[C:14]2=[O:15])[CH2:11][CH2:12]1)=[O:6]
Reactant: CCOC(=O)C1Cc2ccccc2N(C2CCN(C(=O)c3ccc(OCC)cc3OC)CC2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C(=O)N2CCC(N3C(=O)C(C(=O)O)Cc4ccccc43)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To 1-[1-(2-methoxy-4-ethoxybenzoyl)-4-piperidinyl]-3-ethoxycarbonyl-3,4-dihydrocarbostyril (0.48 g) are added sodium hydroxide (0.2 g), water (4 ml) and ethanol (10 ml) and the mixture is stirred at room temperature for 30 minutes. Water is added to the reaction mixture and the mixture is extracted with ethyl acetate. The aqueous layer is neutiralized with acetic acid and extracted with dichloromethane. The extract is concentrated to give 1-[1-(2-methoxy-4-ethoxybenzoyl)-4-piperidinyl]-3-carboxy-3,4-dihydrocarbostyril (0.38 g) as white amorphous form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)(O)[O-].[Na+].[CH3:23][C:24](CC(C)C)=O.O.ClCC(Cl)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[O:12][CH2:24][CH2:23][N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10]=2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1
Reactant: CC(=O)CC(C)C
Reactant: CCCCNc1cc(C(=O)OC)cc(Br)c1O
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCN1CCOc2c(Br)cc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold, stirred solution of Methyl 3-bromo-5-(butylamino)-4-hydroxybenzoate (440 mg) and sodium bicarbonate (280 mg) in 1:1 isobutyl methyl ketone/water (10 mL) was added chloroacetyl chloride (226 mg). The mixture was stirred for 1 h, warmed to room temperature, and heated at reflux for 14 h. The mixture was cooled to room temperature, diluted with chloroform, and the layer separated. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give a white solid: 1H NMR (300 MHz, CDCl3) δ 7.94, 7.62, 4.76, 3.98, 3.93, 1.65, 1.43, 0.97, which was used in the next step without further purification or characterization.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:43])[CH2:10][C:11]1[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]3)[CH:27]=2)[N:16]=1>C(Cl)Cl>[NH:30]1[CH2:29][CH:28]([N:26]2[CH:27]=[C:23]([NH:22][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:39]=[CH:40][CH:41]=[CH:42][C:11]=4[CH2:10][C:9]([NH2:8])=[O:43])[C:20]([CH3:21])=[CH:19][N:18]=3)[CH:24]=[N:25]2)[CH2:31]1
Reactant: Cc1cnc(Nc2cnn(C3CN(C(=O)OC(C)(C)C)C3)c2)nc1CCc1ccccc1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2cnn(C3CNC3)c2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate (A120) (0.050 g, 0.102 mmol) in DCM (3 mL) and the resulting mixture stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure then 2 M aqueous K2CO3 (5 mL) and water (15 mL) were added to the residue. The resulting aqueous solution was extracted with EtOAc (3×15 mL) then the combined organic extracts were dried (MgSO4), filtered, evaporated in vacuo and adsorbed onto silica gel. The product was purified using column chromatography (CombiFlash Rf, 4 g SiO2 Cartridge, 5-50% MeOH in DCM) to give the title compound 30 as a yellow oil (0.6 mg, 1.5%); 1H NMR (300 MHz, d4-MeOH) δ 8.08 (d, J=2.0 Hz, 2H), 7.66 (s, 1H), 7.18-7.26 (m, 4H), 5.19-5.26 (m, 1H), 4.67 (t, J=9.0 Hz, 1H), 4.54 (dd, J=9.4, 5.3 Hz, 1H), 4.56 (t, J=9.8 Hz, 1H), 4.30 (dd, J=10.4, 5.5 Hz, 1H), 3.65 (s, 2H), 3.14 (t, J=2.9 Hz, 2H), 2.98-3.01 (m, 2H), 1.93 (s, 3H). LCMS-B: rt 4.426 min; m/z 392 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:8](=[S:10])=[S:9]>C(O)(C)C>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:8](=[S:9])[SH:10])([CH3:3])[CH3:2]
Reactant: S=C=S
Reactant: CC(C)NC(C)C
Solvent: CC(C)O
Product: CC(C)N(C(=S)S)C(C)C
Reaction time: 1 h

Procedure:
5′-(Diisopropyldithiocarbamyl)-2,5-dimercapto-1,3,4-thiadiazole (i.e., formula (I) where X is hydrogen and R1 and R2 are isopropyl radicals) was prepared in the following manner. In 100 grams of isopropyl alcohol 20.5 grams of diisopropylamine was combined with 16 grams of carbon disulfide (CS2) and held at a temperature of about 27° C. for about 1 hour to yield a diisopropyl dithiocarbamic acid intermediate. Subsequently, 30 g of a 2,5-dimercapto-1,3,4-thiadiazole was added to the mixture along of 20 g of 35 wt. % hydrogen peroxide. The mixture was reacted for about 1 hour at a temperature of about 28° C. to yield the solid end product 5′-(diisopropyldithiocarbamyl)-2,5-dimercapto-1,3,4-thiadiazole. The isopropyl alcohol was filtered off and saved for recovery.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11]1.Cl>ClCCl>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:18][C:13]=2[CH2:12][CH2:11]1
Reactant: c1ccc2c(c1)CCO2
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc2c(c1)CCO2
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
To a solution of propionyl chloride (0.72 mL, 8.30 mmol) in dichloromethane (10 mL), aluminum chloride (835 mg, 6.25 mmol) was added at 0° C. under an argon atmosphere and stirred for 10 minutes, then a solution of 1,2-dihydrobenzofuran (500 mg, 4.15 mmol) in dichloromethane (11 mL) was added dropwisely at the same temperature. After stirring for 5 minutes, the resultant mixture was added with 1N HCl at 0° C. and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (n-hexane/ethyl acetate), and 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (716 mg, yield 98%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])(O)=O.[C:12](=O)([O-:14])[O-:13].[K+].[K+].CI>CC(C)=O>[C:12]([CH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccccc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: O=Cc1ccccc1CC(=O)O
Temperature: 56 °C
Reaction time: 72 h
Yield: 99.5 %

Procedure:
2-Carboxybenzaldehyde (4.53 g, 30 mmoles) was dissolved in acetone (100 mls) and anhydrous potassium carbonate (4.14 g, 30 mmoles) was added. After stirring methyl iodide (5.6 mls, 90 mmoles) was added and the reaction was heated (56° C.) for 30 minutes. The reaction became very thick so further acetone was added (50 mls) and stirring continued at room temperature for a further 72 hours. The reaction mixture was filtered through Celite and then evaporated to leave a viscous oil. The oil was then partitioned between water (30 ml) and ethyl acetate (30 ml). The aqueous layer was washed with further ethyl acetate (2×30 mls) and all the ethyl acetate extracts combined and washed with brine (30 mls) and then water (30 mls) dried over anhydrous magnesium sulphate and evaporated to leave a clear light yellow oil (4.9 g, 100% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38](C4C(C#N)=CSC=4)=[CH:37][CH:36]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[O:48]1[CH2:53][CH2:52][N:51](C2C=CC(O)=CC=2)[CH2:50][CH2:49]1>>[S:1]1[C:5]2[CH:4]=[CH:9][CH:8]=[CH:7][C:6]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([N:51]4[CH2:52][CH2:53][O:48][CH2:49][CH2:50]4)=[CH:37][CH:36]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Oc1ccc(N2CCOCC2)cc1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(N4CCOCC4)cc3)s1)CC2

Procedure:
The title compound was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with 4-morpholinophenol in step 2 of Example 51: 1H NMR (DMSO-d6): δ 7.96 (d, J=7.67 Hz, 1H), 7.72 (d, J=7.98 Hz, 1H), 7.60 (d, J=7.06 Hz, 1H), 7.27-7.42 (m, 4H), 6.88 (d, J=8.9 Hz, 2H), 6.75-6.79 (m, 2H), 4.76 (s, 2H), 3.85 (t, J=6.29 Hz, 2H), 3.64-3.68 (m, 6H), 3.07-3.11 (m, 2H), 2.95-2.98 (m, 6H), 1.87-1.94 (m, 2H). ESI (+)/MS: 656 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)c2cccs2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (60.9 mg, 0.21 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.6 mL of dry CH2Cl2 was added 2-thiophenecarbonyl chloride (97%, 39.2 mg, 1.2 eq.) at room temperature. After being shaken at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded thiophene-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 15 (82.1 mg, 98%). LRMS 300 (M−100)+.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH3:20][C:3]([NH:2][C:28](=[O:31])[CH2:29][CH3:30])([CH:17]([CH3:18])[CH3:19])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5]
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2-Amino-2,3-dimethyl-N-(p-tolylsulfonyl)butyramide hydrochloride (1.2 g, 5.3 mol) is dissolved in 25 mL of toluene under N2. Then triethylamine (1.9 mL, 2.5 equivalents) is added, followed by immediate addition of propionyl chloride (0.55 mL, 6.36 mol). The reaction mixture is heated for one hour, and then solvents are removed under reduced pressure. The yellowish residue is recrystallized from EtOH/water, to yield the title product as a white solid having mp 166°-168° C.