Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]([F:26])([F:25])[C:19]([F:24])([F:23])[C:20](O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:20]([C:19]([F:23])([F:24])[C:18]([F:25])([F:26])[C:17]([F:28])([F:27])[F:16])[NH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Product: FC(F)(F)C(F)(F)C(F)(F)c1nc2ccc(-c3ccc(Cl)cc3)cc2[nH]1
Yield: 18 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (2 g, 11.59 mmol) in dioxane (100 ml) and water (10 ml) was added (4-chlorophenyl)boronic acid (3.6 g, 23.02 mmol), K3PO4 (5.01 g, 23.18 mmol) and Pd(PPh3)4 (0.7 g, 0.58 mmol) with stirring for 4 h at 95° C. maintained with an inert atmosphere of nitrogen. Then the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 5% ethyl acetate in petroleum ether to afford 4-(4-chlorophenyl)-2-nitroaniline as a yellow solid (2.0 g, 69%). Next, to a solution of 5-(4-chlorophenyl)-2-nitroaniline (300 mg, 1.21 mmol) in ethanol (10 ml) was added hydrogen chloride (0.5 ml, 3.63 mmol) and Zn powder (800 mg, 12.3 mmol) in portions at room temperature and stirred for 2 h at 85° C. The resulting mixture was concentrated under vacuum to give a residue and dissolved in water (100 ml), adjusted to pH 8 with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 ml) and dried and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% to 20% ethyl acetate in petroleum ether to produce 4-(4-chlorophenyl)benzene-1,2-diamine as an off-white solid (200 mg, 76%). Finally, a solution of 4-(4-chlorophenyl)benzene-1,2-diamine (150 mg, 0.69 mmol) in heptafluorobutanoic acid (2 ml) was stirred for 8 h at 120° C. Then the reaction was quenched with water (50 ml), adjusted to pH 7 with sodium bicarbonate and extracted with ethyl acetate(3×100 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% to 10% ethyl acetate in petroleum ether to produce 6-(4-chlorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (49.5 mg, 18%).
Reaction SMILES: N1C=CC=CC=1.[OH:7][C@H:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1>C(Cl)Cl>[O:7]=[C:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81.1 %

Procedure:
CrO3 (194 g, 1.94 mol) was added slowly with stirring over 30 min to a solution of pyridine (340 mL) in DCM (900 mL) at 0° C. The mixture was warmed to rt and (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (56 g, 0.216 mol) in DCM (700 mL) was added. The reaction was stirred vigorously for 4 hs at rt. The formed dark solid was decanted and washed with DCM. The organic phases were washed with aq. NaHCO3, 10% aqueous critic acid, and brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and purified by silica gel column chromatography (PE: EtOAc=50:1 to 10:1) to afford (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (42.6 g, 81%) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4]Br.[C-:12]#[N:13].[Na+]>C1(C)C=CC=CC=1.O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][C:12]#[N:13]
Reactant: COc1cccc(Cl)c1CBr
Reactant: [C-]#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(Cl)c1CC#N
Yield: 87.3 %

Procedure:
483 g of 2-chloro-6-methoxybenzyl bromide in 410 ml of toluene are reacted with 131 g of sodium cyanide in 132 ml of water and 3.28 g of Aliquat 336. 325 g of colorless oil are obtained (b.p. 103° C./0.08 mbar).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].Cl[C:37]1[N:41]([CH2:42][C:43]2[O:47][C:46]([CH3:48])=[N:45][CH:44]=2)[C:40]2[CH:49]=[CH:50][CH:51]=[CH:52][C:39]=2[N:38]=1>C(Cl)Cl>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([C:37]3[N:41]([CH2:42][C:43]4[O:47][C:46]([CH3:48])=[N:45][CH:44]=4)[C:40]4[CH:49]=[CH:50][CH:51]=[CH:52][C:39]=4[N:38]=3)[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Reactant: Cc1ncc(Cn2c(Cl)nc3ccccc32)o1
Solvent: ClCCl
Product: Cc1ncc(Cn2c(N3CCN([C@H]4CCN(C(=O)c5cc(C(F)(F)F)cc(C(F)(F)F)c5)[C@@H](Cc5ccccc5)C4)CC3)nc3ccccc32)o1
Yield: 40 %

Procedure:
Compound 15 (0.005 mol), 2-chloro-1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazole (0.005 mol) and Cupper (0.005 mol) were stirred at 140° C. for 2 hours. The mixture was cooled, dissolved in CH2Cl2, filtered and washed with CH2Cl2 and a diluted NH4OH solution. The organic layer was separated, washed with a diluted NH4OH solution, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99.5/0.5, 99/1, 98.5/1.5 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 1.42 g (40%) (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 70).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][C@@H:9]1[CH2:15][CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][N:18]2[C:22](=[O:23])[C:21]3[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]2=[O:28])[CH2:10][C@@H:9]1[CH2:15][CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC[C@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC[C@H]1C[C@@H](ON2C(=O)c3ccccc3C2=O)CCN1C(=O)OC(C)(C)C

Procedure:
A suspension of 0.74 g (0.003227 mol) of trans-N-BOC-2-ethyl-4-hydroxypiperidine (cf. Example 3b), 0.526 g (0.003227 mol) of N-hydroxyphthalimide and 0.846 g (0.003227 mol) of triphenylphosphine in 10 ml of benzene is reacted in accordance with the general procedure of Example 3a with a solution of 0.566 ml (0.003385 mol) of diethyl azodicarboxylate (93%) in 2 ml of benzene, to give the title compound as a colourless resin; Rf =0.60 (silica gel/ethyl acetate:hexane (2:1)).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4][N:3]1[C:14]1[C:15](OS(C(F)(F)F)(=O)=O)=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)OB([C:48]2[CH:49]=[C:50]3[C:54](=[CH:55][CH:56]=2)[N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[N:52]=[CH:51]3)OC1(C)C>COCCOC.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>[C:60]([O:59][C:57]([N:53]1[C:54]2[C:50](=[CH:49][C:48]([C:15]3[C:14]([N:3]4[CH2:4][CH2:5][N:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=5)[CH2:7][C@@H:2]4[CH3:1])=[N:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=4)[N:16]=3)=[CH:56][CH:55]=2)[CH:51]=[N:52]1)=[O:58])([CH3:63])([CH3:61])[CH3:62]
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
To a solution of (S)-methyl 3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (240 mg, 0.38 mmol) in ethylene glycol dimethyl ether (20 ml) was added Pd(PPh3)4 (27 mg, 0.02 mmol), sodium carbonate (74.3 mg, 0.69 mmol) in water (6 ml), and tert-butyl 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (300 mg, 0.87 mmol). After stirring 90 minutes at 90° C. in an oil bath, the reaction was then quenched by the addition of water (200 ml), extracted with dichloromethane (3×30 ml), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford a residue, which was purified via silica gel chromatography (20% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(1-(tert-butoxycarbonyl)-1H-indazol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid (134 mg, 60%).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Br:75][C:76]1[CH:81]=[CH:80][CH:79]=[C:78](/[CH:82]=[CH:83]/[C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=2[F:90])[N:77]=1>C(O)CC.O>[Br:75][C:76]1[N:77]=[C:78]([C@@H:82]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:83]([C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=2[F:90])[OH:12])[CH:79]=[CH:80][CH:81]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OCl
Reactant: Fc1ccccc1/C=C/c1cccc(Br)n1
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CC(C)(C)OC(=O)N[C@H](c1cccc(Br)n1)[C@H](O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl carbamate (270 mg, 2.31 mmol) in propanol (3 mL) was added sodium hydroxide (91 mg, 2.27 mmol) in water (6 mL) followed by tert-butyl hypochlorite (0.256 mL, 2.27 mmol). The solution was cooled to 0° C. and (DHQD)2PHAL (34.8 mg, 0.045 mmol) was added in propanol (3 mL) followed by (E)-2-bromo-6-(2-fluorostyryl)pyridine (207 mg, 0.744 mmol) in propanol (6 mL). To this was added potassium osmate dihydrate (10.97 mg, 0.030 mmol) as a solid in one portion. The reaction was allowed to gradually warm to room temperature in the dewar overnight. The reaction was cooled to 0° C. and quenched by addition of sodiumthiosulfate (300 mg) in water (3 mL). The reaction was stirred at room temperature for 30 min. The reaction was diluted with ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (15%→30% EtOAc/Hex) gave 375 mg (quant.). Mass spec.: 411.2 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]=[O:13]>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:12][OH:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C=O
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1CCO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromo-1-methyl-2-nitro-benzene (f-1) (0.01134 mol) and paraformaldehyde (0.009 mol) in DMSO (5 ml) and Triton-B (035 ml) was stirred at 50° C. for 2 hours, then cooled to room temperature and purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98.5/1.5; 35-70 μm). The pure fractions were collected and the solvent was evaporated. Yield: 1.18 g of 2-(4-Bromo-2-nitro-phenyl)-ethanol (f-2) (42%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:42])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[N:27]=[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])[O:29][C:30]=3[C:31]([F:34])([F:33])[F:32])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[F:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:28]1[O:29][C:30]([C:31]([F:34])([F:32])[F:33])=[C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([C@H:10]3[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:43])=[O:4])[CH2:12][CH2:11]3)=[CH:18][CH:17]=2)=[O:42])=[O:25])[N:27]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4F)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4F)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
NaOH (22.6 mg, 0.57 mmol) was added to trans-{4-[4-(3-{[2-(2-fluoro-phenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (65 mg, 0.11 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 15 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH of 2, stirred for 30 minutes, and filtered. The filtrate was eluted with a gradient of methanol/DCM (5-10%) on a silica gel by column chromatography and purified to obtain the desired compound (60 mg, 94%) as a white solid.
Reaction SMILES: CS([Br:5])(=O)=O.[CH3:6][O:7][C:8](=[O:35])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33]O)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8](=[O:35])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33][Br:5])[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: CS(=O)(=O)Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CO)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylsulfonyl bromide (0.96 mL) is added to a solution of {(S)-6-[(R)-4-hydroxymethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (2.00 g) and triethylamine (1.98 mL) in dichloromethane (20 mL) chilled in an ice bath. The cooling bath is removed, and the solution is stirred at room temperature overnight. More dichloromethane is added, and the resulting solution is washed with aqueous NaHCO3 solution and brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 2): tR=1.24 min.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:20]([CH:16]3[CH2:19][CH2:18][CH2:17]3)=[O:21])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)c1ccc(-c2csc(N)n2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1ccc(-c2csc(NC(=O)C3CCC3)n2)cc1
Yield: 77.1 %

Procedure:
4-(4-Isopropyl-phenyl)-thiazol-2-yl amine (90 mg, 0.41 mmol) was acylated in CH2Cl2 using cyclobutane carbonyl chloride (60 μL, 0.52 mmol, 1.25 eq.) in the presence of excess pyridine. The reaction was quenched with sat. NH4Cl, extracted with EtOAc and dried over MgSO4. Purification by silica gel chromatography (10% EtOAc in hexanes) afforded 95 mg (80%) of cyclobutanecarboxylic acid [4-(4-isopropyl-phenyl)-thiazol-2-yl]-amide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1.I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:11][CH3:12])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: CCI
Reactant: Cc1cscc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cscc1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Methyl-3-thiophenecarboxylic acid (1.42 g) (synthesized in accordance with the method described in J. Org. Chem., 51, 230 (1986)) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (0.8 ml) and potassium carbonate (1.38 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water. and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 4-methyl-3-thiophenecarboxylate (1.7 g). Ethyl 4-methyl-3-thiophenecarboxylate (1.7 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.2 ml) in acetonitrile (20 ml) was added. The mixture was stirred at room temperature for 1 hour, and then 10% aqueous sodium thiosulfate (100 ml) was added and stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and ethyl 2,5-dichloro-4-methyl-3-thiophenecarboxylate. The mixture of ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and 2,5-dichloro-4-methyl-3-thiophenecarboxylate was dissolved in ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (20 ml) was added. The mixture was stirred at room temperature for 2 hours, and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 5-chloro-4-methyl-3-thiophenecarboxylic acid and 2,5-dichloro-4-methyl-3-thiophenecarboxylic acid. The mixture was suspended in toluene (15 ml). Oxalyl chloride (1.31 ml) was added dropwise and then N,N-dimethylformamide (1 drop) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and added dropwise into a mixture of 25% aqueous ammonia solution (16 ml) and ethyl acetate (50 ml) with stirring under ice-cooling. The resulting mixture was stirred at room temperature for 10 minutes. The organic layer was collected and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-4-methyl-3-thiophenecarboxamide (0.83 g) and 2,5-dichloro-4-methyl-3-thiophenecarboxamide (0.61 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=2)=[CH:5][CH:4]=1.CO.C1COCC1.[Li+].[OH-]>O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1coc(-c2ccc(CO)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1coc(-c2ccc(CO)cc2)n1
Yield: 91 %

Procedure:
A solution of ethyl 2-[4-(hydroxymethyl)phenyl]-1,3-oxazole-4-carboxylate (2.5 g, 10.1 mmol) in 1:1 MeOH:THF was treated with 1.0 M LiOH:H2O and stirred at room temperature overnight and concentrated in in vacuo. The resulting residue was diluted with water, treated with 1.0 M HCl and filtered to afford the title product 91% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 219 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[O:7][C:6]2=[O:17].[C:18]1([C:24]2[N:25]=[CH:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][N:11]([C:31]([NH:30][C:27]3[CH:26]=[N:25][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:29][N:28]=3)=[O:32])[CH2:10][CH2:9]1)[O:7][C:6]2=[O:17]
Reactant: O=C1OC2(CCNCC2)c2ccc(F)cc21
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2ccc(F)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A mixture of 5-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (64 mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (73 mg) and triethylamine (174 μL) in chloroform (5 mL) was stirred at 80° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20 mL), then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) and recrystallized from ethyl ether-hexane to give the subject compound (100 mg) as colorless crystals (melting point 236-238° C.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][CH:23]2[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].CO>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH:25]1[CH2:24][CH:23]([NH:22][C:3]2[C:2]([CH3:1])=[N:11][C:10]3[C:5]([N:4]=2)=[C:6]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:7]=[CH:8][CH:9]=3)[CH2:26]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CN(C(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CNC1
Yield: 40.8 %

Procedure:
A solution of tert-butyl 3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)azetidine-1-carboxylate (98.0 mg, 0.218 mmol) and TFA (1.0 mL, 12.98 mmol) in DCM (2.0 mL) was stirred at 25° C. for 1 h. MeOH (2 mL) was added, and the mixture was concentrated in vacuo. The residue was partitioned between 5% MeOH/DCM (80 mL) and saturated aq. NaHCO3 (50 mL). The aq. layer was separated and concentrated in vacuo. Sonication of the residue with 5% MeOH/DCM (80 mL, then 2×40 mL) and concentration of the combined organic layers provided a yellow-orange oil. This oil was triturated with Et2O, the supernatant was drawn off, and the precipitated residue was taken up in 5% MeOH/DCM, filtered, and dried in vacuo to provide a yellow foam. Purification of this foam by reversed-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) furnished 2-(3-(azetidin-3-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (41.0 mg, 0.089 mmol, 41% yield) as a red-brown solid: 1H NMR (400 MHz, MeOH-d4) δ ppm 11.47 (1H, br. s.), 7.78 (1H, d, J=7.2 Hz), 7.69 (1H, d, J=8.0 Hz), 7.45 (1H, t, J=8.0 Hz), 7.34 (1H, d, J=2.0 Hz), 5.21 (1H, quin, J=7.5 Hz), 4.43-4.51 (2H, m), 4.18-4.28 (2H, m), 3.63 (2H, t, J=7.0 Hz), 3.01 (2H, t, J=7.0 Hz), 2.64 (3H, s). 19F NMR (376 MHz, MeOH-d4) δ ppm −77.58 (3F, s). m/z (ESI, +ve) 349.1 (M+H)+.