Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1[N:5]([C@@H:6]2[O:10][C@@H:9]3COP(O)(O[C@H]3[C@H:7]2O)=O)[C:4]2NC(N)=N[C:21](=O)[C:3]=2N=1.[C:24]([S:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([OH:38])[CH:36]=2)[N:31]([CH2:39][C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[C:30]=1[CH2:55][C:56]([CH3:63])([CH3:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58])([CH3:27])([CH3:26])[CH3:25]>>[CH2:60]([O:59][C:57](=[O:58])[C:56]([CH3:62])([CH3:63])[CH2:55][C:30]1[N:31]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([C:3]3[CH:21]=[CH:7][C:6]([O:10][CH3:9])=[N:5][CH:4]=3)=[CH:44][CH:45]=2)[C:32]2[C:37]([C:29]=1[S:28][C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH3:61]
Reactant: Nc1nc(=O)c2ncn([C@@H]3O[C@@H]4COP(=O)(O)O[C@H]4[C@H]3O)c2[nH]1
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Yield: 86 %

Procedure:
The cGMP starting material used for the process was ethyl 3-(3-(tert-butylthio)-5-hydroxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-indol-2-yl)-2,2-dimethylpropionate from Example 3. Ethyl 3-(3-(tert-butylthio)-5-hydroxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-indol-2-yl)-2,2-dimethylpropionate from Example 3, was scaled up to 2.0 kg. In order to ensure optimal Suzuki coupling conditions, the amount of time needed to deoxygenate the mixture was increased from about 5-10 minutes to about 30-45 minutes. Workup and isolation of the product proceeded as described above to yield 1.49 kg of 3-[5-hydroxy-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionic acid ethyl ester in about 86% yield.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][CH:13]=2)[C:10]=1[Cl:11])=[O:5])C.[CH2:23]([NH2:25])[CH3:24]>O1CCCC1.O>[CH2:23]([NH:25][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:12]2[S:16][C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:14][CH:13]=2)[C:10]=1[Cl:11])=[O:5])[CH3:24]
Reactant: CCN
Reactant: CCOC(=O)c1[nH]nc(-c2cnc(-c3ccccc3)s2)c1Cl
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1[nH]nc(-c2cnc(-c3ccccc3)s2)c1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To 15 mg (0.045 mmol) of the above-prepared 4-chloro-5-(2-phenyl-thiazol-5-yl)-2H-pyrazole-3-carboxylic acid ethyl ester was added 45 mg (1.0 mmol) of 2M ethylamine in tetrahydrofuran followed by the addition of 2 drops of water. The mixture was heated to 60° C. in a sealed tube and allowed to stir overnight. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 2:5 ethyl acetate:hexanes as eluant to give 5 mg of the title compound (33%). 1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H) 8.00 (d, 2H) 7.47 (m, 3H) 6.78 (m, 1H) 3.58 (m, 2H) 1.32 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[CH3:12][C:11]1([CH3:13])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[N:32]1[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]1
Reactant: CC1(C)C(Cl)=Nc2ccccc2C1(O)c1ccccc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN1CCN(C2=Nc3ccccc3C(O)(c3ccccc3)C2(C)C)CC1
Reaction time: 4 h
Yield: 68.7 %

Procedure:
2-Chloro-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (0.7g., 0.0025 mole) was dissolved in dry dioxan (10 ml.). Triethylamine (0.5g) followed by N-methylpiperazine (1.92g.) were added and the mixture stirred for 4 hours. The mixture was then evaporated down to a white solid residue which was recrystallised from isopropyl alcohol to give the title compound (0.60g., m.p. 268° - 269° C) [Found: C, 75.6; H, 8.1; N, 12.15% C22H27N3O requires C, 75.6; H, 7.8; N, 12.0%].
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O>>[CH:18]([N:13]1[C:12]([C:30]2[S:29][CH:33]=[CH:32][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1cccs1
Product: CC(C)n1nc2c(c1-c1cccs1)CCNCC2
Yield: 36.2 %

Procedure:
The title compound (46 mg) was prepared according to Example 189 using 208 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 187 mg of 2-thiopheneboronic acid. MS (ESI): exact mass calculated for C14H19N3S, 261.13; found, m/z 262.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.70-7.69 (m, 1H), 7.25-7.23 (m, 1H), 7.15-7.14 (m, 1H), 4.65 (br s, 2H), 4.55-4.49 (m, 1H), 3.8-3.6 (m, 2H), 3.23-3.10 (m, 2H), 2.93-2.83 (m, 2H), 1.44-1.36 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([NH:14][C@H:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][CH3:17])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:1][C:2]1[C:3]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([NH:14][C@H:15]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH3:17])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[C@H](NC(=O)c1c(C)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC[C@H](NC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 24.3 %

Procedure:
3-methyl-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (9.8 g, 26 mmol) was dissolved in 200 mL hot CCl4 (with stirring) under N2 and heated at a gentle reflux. NBS (6.9 g, 39 mmol) was added and solution irradiated with long wave UV light for 0.5 h. Additional NBS (1.9 g, 11 mmol) was added and solution irradiated and refluxed for another 0.5 h. It was then allowed to cool and concentrated under reduced pressure to remove most of the CCl4. The residue was then dissolved in CH2Cl2 and washed with aqueous NaHCO3 containing a few crystals of sodium thiosulfate. The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was then purified using silica gel chromatography (0-15% EtOAc/CH2Cl2) to give 2.9 g of desired product (24%) as a yellow-white solid. 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.11 (d, J=8.1 Hz, 1H), 7.81-7.67 (m, 2H), 7.67-7.58 (m, 2H), 7.55-7.26 (m, 9H), 6.39 (d, J=7.8 Hz, 1H), 5.28 (q, J=7.6 Hz, 1H), 4.74-4.50 (m, 2H), 2.23-1.91 (m, 2H), 1.03 (t, J=7.4 Hz, 3H); LCMS: m/z 459 (MH+).
Reaction SMILES: [CH2:1]([CH:3]1[C:18](=[O:19])[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]2[C:4]1=[O:20])[CH3:2].[C:21]([S:24][CH2:25][CH2:26]Br)(=[O:23])[CH3:22]>>[C:21]([S:24][CH2:25][CH2:26][C:3]1([CH2:1][CH3:2])[C:18](=[O:19])[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[N:5]2[C:4]1=[O:20])(=[O:23])[CH3:22]
Reactant: CCC1C(=O)N2CCCC(C(=O)OC(C)(C)C)N2C1=O
Reactant: CC(=O)SCCBr
Product: CCC1(CCSC(C)=O)C(=O)N2CCCC(C(=O)OC(C)(C)C)N2C1=O

Procedure:
In a manner analogous to that described in Example 1(D)(c), from 4 g of tert.butyl 2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate and 5.43 g of S-(2-bromoethyl) thioacetate there was obtained tert.butyl 2-(2-acetylthioethyl)-2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate as a mixture of diastereomers. Chromatography gave 1.1 g (20%) of diastereomer A having a melting point of 82°-84° C. (from diethyl ether/hexane) and 0.4 g (7%) of diastereomer B in the form of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[NH:16][C:15](=[S:18])[N:14]([CH2:19][CH2:20][CH2:21][OH:22])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]I>C(#N)C>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([S:18][CH3:23])[N:14]([CH2:19][CH2:20][CH2:21][OH:22])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCn1c(=S)[nH]c2c(OCc3ccccc3)cccc21
Reactant: CI
Solvent: CC#N
Product: CSc1nc2c(OCc3ccccc3)cccc2n1CCCO
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 4-benzyloxy-1-(3-hydroxypropyl)-2-thioxo-2,3-dihydro-1H-benzimidazole (70 mg) in acetonitrile (2 ml) was added methyl iodide (37.9 mg), and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo. The residue was purified by preparative thin layer chromatography and pulverized with diisopropyl ether to give 4-benzyloxy-1-(3-hydroxypropyl)-2-methylthio-1H-benzimidazole (67 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:22](=[O:23])[N:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[N:20]4[CH:32]=[CH:33][CH:34]=[C:19]4[C:18]=3[OH:35])=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1.[H][H].C(OCC)C>CN(C)C=O.[Pd]>[O:38]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:22](=[O:23])[N:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[N:20]4[CH:32]=[CH:33][CH:34]=[C:19]4[C:18]=3[OH:35])=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1
Reactant: [H][H]
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=c1c(C2=NS(=O)(=O)c3cc(C4CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 27.8 %

Procedure:
3-[7-(1,1-Dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (Example 11b, 0.100 g, 0.180 mmol) was dissolved in N,N-dimethylformamide (15 mL) at 25° C. Palladium on carbon (5%, 0.250 g) was added and the atmosphere in the reaction flask replaced with hydrogen from a balloon. After stirring for 1 h under a hydrogen balloon, the mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→3% methanol in dichloromethane) to afford a yellow solid. Trituration of this material with diethyl ether afforded the desired product, 3-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (0.028 g, 0.050 mmol, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ: 2.08-2.18 (1H, m), 2.23-2.29 (1H, m), 2.32-2.43 (1H, m), 3.20-3.28 (1H, m), 3.31-3.37 (1H, m), 4.56-4.61 (1H, m), 5.65 (2H, s), 6.60 (2H, d, J=7.0 Hz), 6.59-6.61 (1H, m), 7.02-7.03 (1H, m), 7.14-7.18 (2H, m), 7.42-7.46 (1H, m), 7.67-7.75 (2H, m), 7.87 (1H, bs), 13.73 (1H, s). LC-MS (ESI) calcd for C25H21FN4O6S2 556.09. found 557.15 [M+H+].
Reaction SMILES: COC1C=CC=CC=1C([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=O.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=O)=[N:26][CH:27]=1>>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[C@@H:8]([NH:7][C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:32])[F:31])=[CH:27][N:26]=1)=[O:30])[CH2:9]2
Reactant: COc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(C(F)(F)F)cn1

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 19S, using 5-(trifluoromethyl)picolinic acid in place of o-methoxybenzoic acid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.98 (s, 1H), 8.22 (dd, J=8 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 6.36 (s, 1H), 4.11 (m, 1H), 3.39 (dd, J=16 Hz, 1H), 2.83-2.77 (m, 4H), 2.56 (ddd, J=16 Hz, 1H), 2.00 (m, 1H), 1.66 (m, 3H), 1.50 (m, 1H). C14H16F3N3O=299.12 LCMS (M+H): m/z 300
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1.C(Cl)(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 36 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.33 (dd, 2H, J=5.8, 3.6 Hz,), 7.29–7.26 (m, 2H), 7.25–7.20 (m, 1H), 7.02–6.95 (m, 2H), 6.93 (d, 1H, J=7.1 Hz), 6.54–6.49 (m, 1H), 3.26 (q, 2H, J=6.5 Hz), 3.22–3.14 (m, 1H), 2.90 (d, 1H, J=12.0 Hz), 2.55–2.37 (m, 4H), 2.29 (t, 2H, J=6.5 Hz), 2.06 (s, 4H), 2.00–1.90 (m, 3H), 1.82–1.75 (m, 4H), 1.73–1.66 (m, 3H), 1.65–1.57 (m, 4H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 494.3 (M+H)+; Anal. Calc. for C30H40FN3O2.0.10 CHCl3.0.650 DMF: C, 70.92; H, 8.27; N, 8.64. Found: C, 70.83; H, 8.11; N, 8.93.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[C:7]3[N:8]=[CH:9][NH:10][C:6]=3[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nccc2[nH]cnc12
Product: COc1ccc(CNc2nccc3[nH]cnc23)cc1

Procedure:
In step (5) of Reaction Scheme X, a 4-chloro-1H-imidazo[4,5-c]pyridine of Formula LVIII is reacted with 4-methoxybenzylamine to provide an N-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine of Formula LIX. The reaction can be carried out by combining a compound of Formula LVIII with excess N-(4-methoxybenzyl)amine and excess pyridine hydrochloride in a suitable solvent such as 2,2,2-trifluoroethanol and heating (150° C.) in a microwave reactor.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[C:16]([O:19][CH2:20][CH2:21][CH:22]1[NH:25][C:24](=[O:26])[CH2:23]1)(=[O:18])[CH3:17]>>[Si:8]([N:25]1[CH:22]([CH2:21][CH2:20][O:19][C:16](=[O:18])[CH3:17])[CH2:23][C:24]1=[O:26])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(=O)OCCC1CC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
Triethylamine (Et3N) (2.96 ml, 21.2 mmol) and t-butyldimethylsilyl chloride (3.059 g, 20.3 mmol) are added to an ice-cold stirring solution of 4-(2-acetoxyethyl)-azetidin-2-one (3.098 g, 19.3 mmol) in anhydrous dimethylformamide(DMF) (20 ml). A white precipitate appears immediately. The cooling bath is removed and the mixture is stirred at 25° C. (room temperature) for 5 mins. The mixture is diluted with benzene (200 ml), washed with H2O (5×80 ml) and brine, dired with MgSO4, filtered, and evaporated under reduced pressure to afford N-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-azetidin-2-one (5.078 g) as an off white solid: ir(neat) 5.75, 8.08, 8.41, 11.92, and 12.18 cm-1 ; nmr (CDCl3)δ 0.25 (s, 6), 0.98 (s, 9), 1.97 (m, 2), 2.05 (s, 3), 2.67 (dd, 1), 3.20 (dd, 1) 3.62 (m, 1), and 4.12 (t,2); mass spectrum m/e 214 (M+ -57) and 172.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[N:28]([CH3:29])[CH3:30])[CH:10]=1
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.0 g) in methanol (10 ml) was added a solution of 2-(aminomethyl)-4-fluoro-N,N-dimethylbenzenesulfonamide hydrochloride obtained in Step 1 (1.37 g) and triethylamine (1.6 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.11 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH2:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH:33][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: NC(c1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(c2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, 1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine, TBTU and DIPEA in THF.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@@H:7]2[C:12]([CH3:14])([CH3:13])[O:11][C:10]([NH:15][C:16]34[CH2:23][CH:22]5[CH2:24][C:18]([C:25]([NH2:27])=[O:26])([CH2:19][CH:20]3[CH2:21]5)[CH2:17]4)=[N:9][S:8]2(=[O:29])=[O:28])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH2:6]([C@@H:7]1[C:12]([CH3:14])([CH3:13])[O:11][C:10]([NH:15][C:16]23[CH2:23][CH:22]4[CH2:24][C:18]([C:25]([NH2:27])=[O:26])([CH2:19][CH:20]2[CH2:21]4)[CH2:17]3)=[N:9][S:8]1(=[O:28])=[O:29])[C:5]1[CH:30]=[CH:31][CH:2]=[CH:3][CH:4]=1
Reactant: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1Cc1ccc(Br)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1Cc1ccccc1
Yield: 48.8 %

Procedure:
3a-[(R)-5-(4-bromobenzyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino]hexahydro-2,5-methanopentalene-2-carboxamide (80 mg) was dissolved in ethanol and stirred in a hydrogen atmosphere (5 bar) in the presence of palladium on charcoal (10%) for 30 min. The solution was filtered and concentrated. Purification was effected by preparative HPLC. This gave the product (33 mg) with a molecular weight of 431.5 g/mol (C22H29N3O4S), MS (ESI): (M+H+) 432.5 g/mol.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OC=C)(=O)[CH3:11]>>[C:1]([O:9][CH:10]=[CH2:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C=COC(C)=O
Product: C=COC(=O)c1ccccc1
Temperature: 65 °C

Procedure:
The catalyst is suspended once more in the mixture of benzoic acid and vinyl acetate and the batch is heated to 65° C., affording again about 7 g of vinyl benzoate after 30 hours.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[I:11]I.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: II
Reactant: Clc1cc2[nH]ncc2cn1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc2[nH]nc(I)c2cn1
Temperature: 40 °C

Procedure:
A flask was charged with 6-chloro-1H-pyrazolo[4,3-c]pyridine (3.0 g, 19.54 mmol), iodine (13.11 g, 51.7 mmol), KOH (3.29 g, 58.6 mmol), and DMF (60 mL). The mixture was heated at 40° C. for 16 h and then additional iodine (7.8 g, 30.7 mmol) and KOH (1.6 g, 28.4 mmol) were added. The mixture was heated at 70° C. for 3 h then quenched with 1 N Na2S2O3 and extracted with EtOAc. The organic phase was washed with water, brine, and dried over Na2SO4. After evaporation of volatiles DCM was added. A solid precipitated and was collected by filtration to yield 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. for C6H4ClIN3 [M+1]+ 280. found 280.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH2:28][NH:27][N:26]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:33])=[O:32])[C:25]=3[CH2:24]2)[CH2:11][O:10]1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH2:28][NH:27][N:26]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:32])=[O:33])[C:25]=3[CH2:24]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (52 mg, 0.099 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (1 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated and purified on reverse phase HPLC using H2O/acetonitrile containing 0.05 TFAv/v, to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.21-1.27 (m, 2H); 1.38-1.43 (m, 2H); 2.06 (q, 1H, J=14 Hz); 2.73-2.79 (m, 1H); 2.29-3.06 (m, 1H); 3.57-3.64 (m, 1H); 3.74 (t, 1H, J=12 Hz); 3.81-3.90 (m, 1H); 4.44-4.54 (m, 3H); 4.69 (d, 1H, J=12 Hz); 4.71-4.81 (m, 2H); 7.18-7.26 (m, 2H); 7.27-7.32 (m, 1H); 7.74 (s, 1H). LC-MS: 425.21 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:18].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:31]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:31][C:13]1[C:8]2[NH:7][C:6](=[O:18])[N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:9]=2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc2[nH]c(=O)n(CCCCl)c12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)c2[nH]c(=O)n(CCCCl)c12
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 7.6 %

Procedure:
A mixture of methyl 3-(3-chloropropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (5.00 g, 18.6 mmol) and 2,2′-azobis(isobutyronitrile) (3.06 g, 18.6 mmol) in ethyl acetate (90 mL) was stirred at 70° C. for 40 min. N-Bromosuccinimide (3.31 g, 18.6 mmol) was added portionwise to the reaction mixture and the resultant mixture was stirred 70° C. for 5 h. The reaction mixture was washed with aqueous saturated sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (490 mg, 1.41 mmol, 7.6%).