Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([CH2:19][C@H:20]([OH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:4]=2[CH:3]=1.[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:32][N:33]([CH3:38])[S:34]([NH:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([CH2:19][C@H:20]([OH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:4]=2[CH:3]=1)(=[O:36])=[O:35]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2

Procedure:
Under nitrogen, a solution of (2S)-1-[N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (150 mg), dimethylaminosulfonyl chloride (43 μl) and pyridine (31 μl)in toluent (5 ml) was stirred at 80° C. for 24 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give (2S)-1-[N-(3-dimethylaminosulfonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (156 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:28][C:29]([F:32])([F:31])[F:30])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].Cl.C[N:35](C)CCCN=C=NCC.CN(C)C=O>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:28][C:29]([F:32])([F:31])[F:30])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([NH2:35])=[O:27])[CH2:22][N:23]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: O=C(O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.5 %

Procedure:
A mixture of {2-[7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (410 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (240 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (310 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-90:10, volume ratio), and the obtained solid was washed with hexane to give the title compound (260 mg, yield 63%) as brown crystals. The crystals were recrystallized from acetone-hexane to give pale-yellow prism crystals. melting point 239-240° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:63]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@H:64]([C:81](O)=[O:82])[CH2:65][CH2:66][CH2:67][CH2:68][NH:69][C:70]([O:72][CH2:73][C:74]1[CH:80]=[CH:79][CH:78]=[CH:77][C:75]=1[Cl:76])=[O:71].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:63]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@H:64]([C:81]([NH:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:82])[CH2:65][CH2:66][CH2:67][CH2:68][NH:69][C:70]([O:72][CH2:73][C:74]1[CH:80]=[CH:79][CH:78]=[CH:77][C:75]=1[Cl:76])=[O:71]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2Cl)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
At 0° C. the solution of 746 mg (0.81 mmol) of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 50 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 340 mg (0.82 mmol) of Boc-Lys(ClZ)-OH, 110 mg (0.82 mmol) of 1-hydroxybenzotriazole and 170 mg (0.82 mmol) of dicyclohexylcarbodiimide in 40 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 16 h and TLC (chloroform/methanol, 10:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 100 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 50 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated. The residue was purified on sinica gel chromatography (CHCl3/CH3OH, 30/1) to provide 850 mg (81%) of the title compound as a glassy mass. Mp 78–88° C., FAB-MS (m/e) 1111.3[M+H]+, 1132.5[M+Na]+, 1010.0[M-Boc]+.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH:8]1([NH:11][C:12]([C:14]2[C:22]3[CH:21]=[C:20]([C:23]4[C:28]([Cl:29])=[CH:27][N:26]=[C:25]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)[N:24]=4)[S:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9]1>CN(C=O)C.C(OCC)(=O)C>[Cl:29][C:28]1[C:23]([C:20]2[S:19][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:12](=[O:13])[NH:11][CH:8]4[CH2:9][CH2:10]4)[C:22]=3[CH:21]=2)=[N:24][C:25]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]2[CH2:35][CH2:36][N:37]([C:6]([NH2:5])=[O:7])[CH2:38][CH2:39]2)=[N:26][CH:27]=1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Cl)cc12
Reactant: C[Si](C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)N1CCC(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reaction time: 2 h
Yield: 76.2 %

Procedure:
Trimethylsilyl isocyanate (26 mg, 0.22 mmol) is added to a stirred suspension of 2-[5-chloro-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (50 mg, 0.11 mmol) in DMF (1 mL) and stirred for 2 hours. The mixture is diluted with ethyl acetate (1 mL) then filtered to give the title compound as a yellow solid (43 mg). ES+(m/z) 513 (35Cl) and 515 (37Cl) [M+H].
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:38][O:39][C:40]1[C:41]2[N:54]=[C:53]([NH2:55])[S:52][C:42]=2[C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[N:44][CH:45]=1>C1COCC1>[CH3:1][O:2][CH2:3][C:4]([NH:55][C:53]1[S:52][C:42]2[C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:44][CH:45]=[C:40]([O:39][CH3:38])[C:41]=2[N:54]=1)=[O:6]
Reactant: COCC(=O)O
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCC(=O)Nc1nc2c(OC)cnc(N3CCOCC3)c2s1

Procedure:
From methoxyacetic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 339 (M+H+, 100).
Reaction SMILES: C(N1C2C(=CC(C)=CC=2)C(O)([CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)C1=O)C.C([O:36][CH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([CH3:46])[CH:44]=2)[N:39]([CH2:47][CH:48]([CH3:50])[CH3:49])[C:38]1=[O:51])(=O)C1C=CC=CC=1>>[OH:36][C:37]1([CH2:13][C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([CH3:46])[CH:44]=2)[N:39]([CH2:47][CH:48]([CH3:49])[CH3:50])[C:38]1=[O:51]
Reactant: CCN1C(=O)C(O)(Cc2cc(OC)c(OC)c(OC)c2)c2cc(C)ccc21
Reactant: Cc1ccc2c(c1)C(OC(=O)c1ccccc1)C(=O)N2CC(C)C
Product: COc1cc(CC2(O)C(=O)N(CC(C)C)c3ccc(C)cc32)cc(OC)c1OC

Procedure:
This compound was made in an analogous fashion to 1-ethyl-3-hydroxy-5-methyl-3-(3,4,5-trimethoxybenzyl)indolin-2-one using 5-methyl-1-isobutyl-2-oxoindolin-3-yl benzoate. 1H-NMR δ 7.22 (s, 1H), 7.08 (d, 1H), 6.58 (d, 2H), 6.1 (s, 2H), 3.74 (s, 3H), 3.63 (s, 6H), 3.48 (m, 1H), 3.29 (d, 1H), 3.11 (m, 1H), 3.06 (bs, OH), 2.35 (s, 3H), 1.85 (m, 1H), 0.70 (dd, 6H).
Reaction SMILES: Cl[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[NH:7][C:6]2=[O:14].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>C(#N)C>[C:15]1([CH:2]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[NH:7][C:6]3=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1[nH]c(=O)c2cc(C(Cl)c3ccccc3)ccc2[nH]1
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: O=c1[nH]c(=O)c2cc(C(c3ccccc3)n3cncn3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
A mixture of 5.8 parts of 6-(chlorophenylmethyl)-2,4(1H,3H)-quinazolinedione, 10 parts of 1H-1,2,4-triazole and 158 parts of acetonitrile was stirred for 1 hour at room temperature and for 2 hours at reflux temperature. The solvent was evaporated and the residue was washed with water. The precipitate was filtered off and purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the first fraction was evaporated and the residue was washed with ethyl acetate and dried, yielding 2.2 parts (34.1%) of 6-[phenyl(1H-1,2,4-triazol-1-yl)methyl]-2,4(1H,3H)-quinazolinedione; mp. 280.9° C. (comp. 40).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([N+:15]([O-])=O)=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:9]=2[NH2:15])[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc(N)c2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2cccc(N)c2N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 3-(4-methyl-piperazin-1-yl)-2-nitro-phenylamine (139 mg, 0.59 mmol) in MeOH (20 mL) were added Pd/C (10%, 14 mg) and the mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 1 h. The reaction mixture was filter over Celite to afford the title compound (120 mg, 99%). 1H NMR (MeOH-d4) δ 2.34 (s, 3H), 2.62 (br, 4H), 2.99 (m, 4H), 6.51-6.65 (3H). ESI-MS m/z 207.1 (MH+).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[C:22]4[O:27][C:28](Cl)=[C:29]([CH3:30])[C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CC1(C)C(C)(C)OB([C:40]2[C:48]3[S:47][N:46]=[N:45][C:44]=3[CH:43]=[CH:42][CH:41]=2)O1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:18]2[CH:17]=[N:16][N:15]([C@H:12]3[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]3)[CH:19]=2)=[C:21]2[C:29]([CH3:30])=[C:28]([C:40]3[C:48]4[S:47][N:46]=[N:45][C:44]=4[CH:43]=[CH:42][CH:41]=3)[O:27][C:22]=12
Reactant: Cc1c(Cl)oc2c(N)ncc(-c3cnn([C@H]4CC[C@H](O[Si](C)(C)C(C)(C)C)CC4)c3)c12
Reactant: CC1(C)OB(c2cccc3nnsc23)OC1(C)C
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: C1COCCO1
Product: Cc1c(-c2cccc3nnsc23)oc2c(N)ncc(-c3cnn([C@H]4CC[C@H](O)CC4)c3)c12

Procedure:
A solution of 4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-chloro-3-methylfuro[2,3-c]pyridin-7-amine (20 mg, 0.043 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3-benzothiadiazole (12.5 mg, 0.0477 mmol), and Pd(PPh3)4 (5.0 mg, 0.0043 mmol) in 1,4-dioxane (0.2 mL) and 1.0 M aqueous sodium carbonate (0.2 mL) was heated to 120° C. in a microwave for 60 min. The organic phase was separated, treated with 12 M aqueous HCl (0.071 mL) at 40° C. for 1 h, and then concentrated. Purification by ISCO chromatography (0 to 15% 7 N NH3/MeOH:DCM) followed by trituration from DCM:hexanes (˜5 mL, 1:1) and filtration afforded 5.3 mg (27%) of the title compound as an orange solid. 1H NMR (400 MHz, DMSO-d6): δ 8.83 (d, J=7.8 Hz, 1 H), 8.19 (d, J=6.8 Hz, 1 H), 7.90-8.03 (m, 2 H), 7.67 (s, 1 H), 7.58 (d, J=0.5 Hz, 1 H), 6.38 (s, 2 H), 4.67 (d, J=4.3 Hz, 1 H), 4.09-4.27 (m, 1 H), 3.42-3.60 (m, 1 H), 2.27 (s, 3 H), 2.06 (d, J=12.1 Hz, 2 H), 1.90-1.98 (m, 2 H), 1.77-1.90 (m, 2 H), 1.28-1.48 (m, 2 H); MS (ESI): 446.85, 448.96 [M+H]+; HPLC tR=2.51 min (ZQ3: polar—4 min).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[F:42][C:43]([F:53])([F:52])[C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH2:46][NH2:47]>C1COCC1>[F:42][C:43]([F:52])([F:53])[C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH2:46][NH:47][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31]
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1C(F)(F)F)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 2-trifluoromethyl-benzylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 600.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH2:13])[CH:5]=1.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
3-amino-5-nitro-benzoic acid methyl ester (25 g; 0.13 mol) was dissolved in to dichloromethane (300 ml) and treated at 0° C. with 11 ml of pyridine. Methanesulfonylchloride (11 ml; 0.14 mol) was added and the reaction mixture was stirred overnight at room temperature. Water was added and the precipitate filtered and washed with dichloromethane/diethylether. 32 g (0.11 mmol; 89% yield) of 3-methylsulfonylamino-5-nitro-benzoic acid methyl ester were obtained as a solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]([F:26])[CH:14]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:19][C:18]1[C:13]([NH:12][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=3[N:6]=2)=[CH:14][C:15]([F:26])=[C:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=1
Reactant: Fc1ccc2sc(Br)nc2c1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc(Cl)c(Nc2nc3cc(F)ccc3s2)cc1F
Yield: 33 %

Procedure:
In xylene (5 ml), 2-bromo-5-fluorobenzothiazole (548 mg, 2.36 mmol), ethyl 4-amino-5-chloro-2-fluorophenylacetate (547 mg, 2.36 mmol), and pyridinium p-toluenesulfonate (PPTS) (178 mg, 0.71 mmol) were heated under reflux for 3 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (7:1, v/v) eluate fractions, ethyl (5-chloro-4-(5-fluoro-2-benzothiazolyl)amino-2-fluorophenyl)acetate (298 mg, 33%) was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[F-:12].[K+]>CS(C)=O>[Cl:1][C:2]1[N:9]=[C:8]([F:12])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: [F-]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(F)c(F)nc1Cl
Temperature: 20 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To 2,6-dichloro-5-fluoronicotinonitrile (50 g, 262 mmol) was added spray-dried potassium fluoride (30 g, 516 mmol) followed immediately by the addition of anhydrous DMSO (125 mL). The reaction mixture was stirred at 20° C. for 16-20 hours. The progress of the reaction was closely monitored by HPLC. When the product concentration reached maximum (˜79%), the reaction was worked up immediately. Ethyl acetate (1000 mL) was added to the reaction mixture followed by the addition of ice (50 g). Water (500 mL) was then slowly added with cooling to ensure the temperature did not exceed 25° C. The organic phase and the aqueous phase were separated. The organic phase was washed with water (400 mL). Active carbon (12 g, Darco G-60, 100 mesh) was added and the mixture was stirred for 2 hours. The mixture was filtered through a pad of Celite. The filtrate was washed with water (400 mL) and concentrated by rotary evaporation to a volume of about 120 mL. The concentrate was diluted with heptane (150 mL) and the resulting solution was concentrated to a volume of about 150 mL, which resulted in precipitation of solid product. The mixture was stirred for 30 minutes at room temperature and filtered. The filter cake was washed with heptane (100 mL) and dried to afford the title compound (29.5 g, 65%). 1H NMR (500 MHz, CDCl3) δ ppm 7.92-7.96 (m, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([OH:30])=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.[H-].[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>CN(C)C=O>[CH2:36]([O:30][C:20]1[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][N:18]([CH2:17][C:16]2[CH:31]=[CH:32][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:33])=[CH:14][CH:15]=2)[N:19]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-hydroxy-1H-pyrazol-4-yl]propionate (452 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Benzyl bromide (0.178 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-benzyloxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (383 mg, yield: 71%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1)=O.Cl.[CH3:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[NH2:8][CH2:7][C:6]1[CH:16]=[CH:17][C:3]([CH2:1][NH:27][C:26]2[CH:28]=[CH:29][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:24][CH:25]=2)=[CH:4][CH:5]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)c1ccc(NCc2ccc(CN)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of tert-butyl N-(4-formylbenzyl)carbamate (45 mg, 0.2 mmol) and 4-methanesulfonylaniline hydrochloride (41 mg, 0.2 mmol) in 1 mL of methanol was stirred at room temperature for 30 min, then 0.15 mL of acetic acid was added, followed by 16 mg (0.24 mmol) of sodium cyanoborohydride. The reaction was complete in 5 h. The mixture was treated with saturated sodium bicarbonate solution until pH=8, then extracted with ethyl acetate twice. The combined organics were dried over MgSO4, filtered, and concentrated. The solid was dissolved in 1 mL of methylene chloride, followed by the addition of 0.1 mL of trifluoroacetic acid. The mixture was stirred at room temperature overnight, then concentrated to afford the titled compound as an oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8]O)[N:7]=1.P(Br)(Br)[Br:13]>C(Cl)Cl>[Br:13][CH2:8][C:6]1[N:7]=[C:3]([C:2]([F:11])([F:10])[F:1])[S:4][CH:5]=1
Reactant: OCc1csc(C(F)(F)F)n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: FC(F)(F)c1nc(CBr)cs1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a stirring solution of (2-(trifluoromethyl)thiazol-4-yl)methanol (550 mg, 3.00 mmol) in DCM (5 ml) was added PBr3 (0.283 ml, 3.00 mmol) at 0-5° C. in 5-10 min. and stirring continued for 1 h. Reaction mixture was diluted with DCM and washed with water. Organic layer was separated and distilled out to get crude product which was column purified using 0-2% EtOAC in hexane to get title compound in 36% yield.