Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]([C@@H:4]1[C@@H:15]2[C@H:11]([O:12]C(C)(C)[O:14]2)[C@@H:10]2[C@@H:6]([S:7][C:8]([N:18]([CH3:20])[CH3:19])=[N:9]2)[O:5]1)[CH3:3].Cl.[NH4+].[OH-]>CO>[CH3:20][N:18]([CH3:19])[C:8]1[S:7][C@H:6]2[O:5][C@H:4]([C@H:2]([F:1])[CH3:3])[C@@H:15]([OH:14])[C@H:11]([OH:12])[C@H:10]2[N:9]=1
Reactant: C[C@@H](F)[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@H]2OC(C)(C)O[C@@H]21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](F)[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](O)[C@@H]1O
Yield: 118.5 %

Procedure:
A solution of 159 (150 mg, 0.16 mmol) in methanol (10 mL) was treated with concentrated aqueous HCl (1 mL) for 1 hour at room temperature, then the resulting solution was concentrated under vacuum to give a residue, which was dissolved into methanol (5 mL) and neutralized with concentrated NH4OH (1 mL). After removal of all the solvent, the residue was purified by flash column chromatography with 10% methanol in dichloromethane to afford the title compound as a white solid (50.1 mg, 38%). (ES, m/z); [M+H]+ 265.0; 1H NMR (300 MHz, D2O) δ 6.23 (d, J=6.6 Hz, 1H), 4.97-4.70 (m, 1H), 4.22-4.19 (m, 1H), 4.02-3.99 (m, 1H), 3.67-3.62 (m, 2H), 2.91 (s, 6H), 1.26 (dd, J=6.6 Hz, 26.1 Hz, 3H).
Reaction SMILES: [OH:1][C@@H:2]([CH3:38])[C@H:3]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[CH2:4][O:5][CH3:6].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[OH:1][C@@H:2]([CH3:38])[C@H:3]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[CH2:4][O:5][CH3:6]
Reactant: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H](C)O
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H](C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.9 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2S)-2-hydroxy-1-methoxymethyl-propyl)-amide (44 mg, 0.081 mmol) and TFA (0.3 ml, 3.9 mmol) were combined with dichloromethane (1 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.15 ml, 2.2 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 15 mg (46%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2S)-2-hydroxy-1-methoxymethyl-propyl)-amide as an off-white solid. MS: [M+H]+=413; 1H NMR (300 MHz, DMSO-d6) δ: 12.83 (br. s., 1H), 9.14 (s, 1H), 8.62 (dd, J=8.8, 5.3 Hz, 1H), 8.44 (s, 1H), 8.30 (d, J=9.6 Hz, 1H), 7.68 (dd, J=9.6, 1.8 Hz, 1H), 7.13 (td, J=9.1, 2.0 Hz, 1H), 4.94 (d, J=5.6 Hz, 1H), 4.17-4.23 (m, 1H), 4.15 (s, 3H), 3.85-3.96 (m, 1H), 3.75 (dd, J=9.6, 5.6 Hz, 1H), 3.57 (dd, J=9.6, 3.5 Hz, 1H), 3.25 (s, 3H), 1.17 (d, J=6.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=O)[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:37]([F:40])([F:39])[F:38])([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[S:50])[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:37]([F:40])([F:39])[F:38])([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CCN1CCC(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Product: O=[N+]([O-])c1ccc(NC2CCN(C(=S)CCN3CCC(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F

Procedure:
1-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-3-[4-(4-trifluoromethyl-phenyl)-piperidin-1-yl]-propan-1-one (20 mg; 0.035 mmol, prepared in accordance with Example 14) is reacted with Lawesson's reagent (7 mg; 0.018 mmol according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (6 mg; 0.010 mmol). The structure was confirmed using Protocol 1-B. Calculated mass=589; observed mass=589; HPLC retention time=4.74 min.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:45][C:46]1[C:47]([N:66]2[CH2:71][CH2:70][N:69]([C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=3[CH3:78])[CH2:68][CH2:67]2)=[CH:48][C:49]([O:64][CH3:65])=[C:50]([CH:63]=1)[C:51]([NH:53][CH2:54][CH2:55][CH2:56][N:57]1[CH2:61][CH2:60][CH2:59][C:58]1=[O:62])=[O:52].[Cl-].[Li+]>CN(C=O)C>[CH3:65][O:64][C:49]1[C:50]([C:51](=[O:52])[NH:53][CH2:54][CH2:55][CH2:56][N:57]2[CH2:61][CH2:60][CH2:59][C:58]2=[O:62])=[CH:63][C:46]([NH:45][C:9]([C:7]2[N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[O:5][CH:6]=2)=[O:11])=[C:47]([N:66]2[CH2:67][CH2:68][N:69]([C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=3[CH3:78])[CH2:70][CH2:71]2)[CH:48]=1
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: COc1cc(N2CCN(c3ccccc3C)CC2)c(N)cc1C(=O)NCCCN1CCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2coc(C3CC3)n2)cc1C(=O)NCCCN1CCCC1=O
Reaction time: 0.05 h

Procedure:
2-Cyclopropyl-oxazole-4-carboxylic acid 1h (74.8 mg, 0.489 mmol) was taken in DMF (5.0 ml) and HATU (212.3 mg, 0.558 mmol) was added to this and stirred for 3 min. N,N-diisopropylethylamine (0.243 mL, 1.396 mmol) was added to this and the mixture was stirred again for 3 min. 5-Amino-2-methoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 2b (130.0 mg, 0.279 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. A saturated solution of lithium chloride was added and the product was extracted with ethyl acetate. Organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated to give the crude product 2c which was purified on preparative HPLC using water/methanol as eluent.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Br[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][C:2]1[N:3]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:4]2[CH:10]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[N:6]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: BrCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A mixture of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate (4.125 g), 1-(bromomethyl)naphthalene (5 g) and K2CO3 (6.2 g) was stirred at 80° C. for 3 h. When TLC showed no starting material remaining, the mixture was cooled to room temperature and then poured into water (500 mL). It was extracted with EtOAc (500 mL×3) and the combined organic layers were washed with brine (500 mL×3) and then concentrated in-vacuo. The residue was purified by silica gel chromatography eluted with MeOH:DCM=1:100 to afford the desired product as a yellow solid (4.6 g, 74%). 1H NMR (300 MHz, DMSO-d6): δ ppm 2.42 (s, 3H), 3.04 (t, 4H, J=4.8 Hz), 3.68 (t, 4H, J=4.8 Hz), 3.90 (s, 3H,), 6.02 (s, 1H), 6.28 (d, 1H, J=7.5 Hz), 7.29 (d, 1H, J=2.4 Hz), 7.32 (d, 1H, J=7.5 Hz), 7.39 (d, 1H, J=2.4), 7.60-7.71 (m, 2H), 7.84 (d, 1H, J=8.4 Hz), 8.01 (d, 1H, J=7.5 Hz), 8.24 (d, 1H, J=7.5 Hz); LC-MS: m/e=416 [M+1]+.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[CH2:11][CH:10]2[CH:7]([C:8](=[O:12])[CH2:9]2)[CH:6]1[C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH3:3].S(Cl)(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([S:4][C:5]1[CH2:11][CH:10]2[CH:7]([C:8](=[O:12])[CH2:9]2)[C:6]=1[C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH3:3]
Reactant: CCCSC1CC2CC(=O)C2C1C(=O)OC
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCSC1=C(C(=O)OC)C2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 33 mg of crude methyl 3-(1-propylthio)-7-oxobicyclo[3.2.0]heptan-2-carboxylate, prepared by the procedure of Paragraph A, in 2 mL of methylene chloride at -40° under argon was added 24 mg of sulfuryl chloride. This solution was stirred for 15 min at -40° and then cooled to -70°. Triethylamine was added until the solution was basic to pH paper, and the solution was allowed to warm slowly to room temperature. The reaction mixture was partitioned between methylene chloride and brine, and the organic layer was dried over sodium sulfate and concentrated to dryness. The crude product was purified by preparative thin layer chromatography on three 20×10×0.05 cm silica gel plates, eluting with ether-petroleum ether (1:1), to afford after crystallization from ether 7.5 mg (23%) of methyl 3-(1-propylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylate: NMR (220 MHz; CDCl3): δ 1.05 (3 H, t, J=7), 1.68 (2H, m), 2.87 (2H, t, J=7), 2.9-3.0 (3H, m), 3.3-3.45 (2H, m), 3.78 (3H, s), and 4.51 (1H, m); HRMS: Calcd for C12H16O3S, 240.0819; found, 240.0807.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.C(O)C>C(OCC)(=O)C>[ClH:17].[Cl:18][C:13]1[CH:12]=[C:11]([CH:10]2[O:9][CH2:8][CH2:7][NH:6][CH2:5][CH:4]2[CH2:3][C:1]#[N:2])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CC#N)C1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 171.5 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(cyanomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (88 mg) in ethyl acetate (0.5 mL) was added 2 N hydrogen chloride-ethanol solution (3 ml), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was crystallized from ethyl acetate and diisopropyl ether to give the title compound (63 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][N:25]=2)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1n[nH]c2ccccc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2n[nH]c3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1H-Indazole-3-carboxylic acid.
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]Br.P([O-])([O-])[O-]>>[CH2:9]([O:8][P:4]([CH2:15][C:14]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:12]([Cl:11])[CH:13]=1)(=[O:3])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOP(OCC)OCC
Agent: [O-]P([O-])[O-]
Product: CCOP(=O)(Cc1ccc(Cl)c(Cl)c1)OCC
Temperature: 80 °C

Procedure:
Triethylphosphite (4.28 ml) was added dropwise to 3,4-dichlorobenzylbromide (6.0 g, 25 mmol) at rt with stirring. After 1 ml of triethylphosphite was added, the mixture was heated to 80° C. until an exothermic reaction was started. The remaining phosphite was added at a rate sufficient to maintain the reflux. After the addition was completed, the mixture was heated to reflux for 1 h and allowed to cool. The crude product was distilled under vacuum at 155–158° C./1–2 torr to afford (3,4-dichlorobenzyl)-phosphonic acid diethyl ester (6.5 g).
Reaction SMILES: [C-]#N.[K+].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:14]1.[CH3:36][N:37](C=[O:40])C>O.C(OCC)(=O)C.CCCCCC.C(N(CC)CC)C>[OH2:40].[C:30]1([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:36]#[N:37])[N:14]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[C:30]1([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:36]#[N:37])[N:14]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN(C)C=O
Reactant: BrCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCN(CC)CC
Product: N#CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: 70 °C
Reaction time: 58 h
Yield: 52 %

Procedure:
A stirred mixture of potassium cyanide (0.4 g, 6.1 mmol), 1-(8-bromooctyl)-3,4,5-triphenyl-lH-pyrazole (2.70 g, 5.5 mmol) and DMF (30 mL was heated at 70° C. under an atmosphere of nitrogen. After 58 hours, the reaction mixture was diluted with water and extracted with dichloromethane (3 x). The combined extracts were washed with water, saturated sodium chloride solution, dried over sodium sulfate and concentrated to leave an oil. Chromatography on a column of silica gel using a mixture ethyl acetate, hexane and triethylamine (20:79:1) as eluent gave 3,4,5-triphenyl-lH-pyrazole-1-nonanenitrile hemihydrate (1.27 g, 52%) as a beige solid. An analytical sample, recrystallized from a mixture of dichloromethane and hexane, had m.p.=79.5°-80.5° C. MS(CI): m/e =434 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:19][S:20]([C:23]1[C:31]2[C:26](=[CH:27][N+:28]([O-:32])=[CH:29][CH:30]=2)[NH:25][N:24]=1)(=[O:22])=[O:21].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]3)[C:7]([CH2:9][N:25]3[C:26]4=[CH:27][N+:28]([O-:32])=[CH:29][CH:30]=[C:31]4[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[N:24]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2c[n+]([O-])ccc12
Reactant: OC1CCC(n2c(CCl)nc3cc(Cl)ccc32)C1
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCC(O)C2)c2c[n+]([O-])ccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 3-(5-chloro-2-chloromethyl-benzoimidazol-1-yl)-cyclopentanol and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine 6-oxide instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:22])([CH3:23])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccccc1COc1ccc(C(C)(C)C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C(=O)O)c1ccc(OCc2ccccc2C(=O)O)cc1

Procedure:
Reaction of ethyl 4-(2-ethoxycarbonylbenzyloxy)-α,α-dimethylphenylacetate with potassium hydroxide as described in Example 1c provides 4-(2-carboxybenzyloxy)-α,α-dimethylphenylacetic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23]>CN(C=O)C>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH2:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(C)cc3c2ccc2nnc(C)n23)c1
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.043 g, 1.1 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (200.0 mg, 1.074 mmol, from Example 2, Step 5) in DMF (20 mL). After 10 minutes, methyl 3-(bromomethyl)benzoate (0.25 g, 1.1 mmol, Alfa Aesar) was added. After 45 minutes, the reaction mixture was poured into pH 7 buffer and the product was extracted with three portions of EtOAc. The combined organic extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated and used without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[Cl:19])(=O)=O.B([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(O)O>>[Cl:19][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Product: COc1ccc2c(Cl)c(-c3ccc(C(=O)O)cc3)ccc2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Followed the coupling procedure described for Example 3, starting from 1-chloro-6-methoxynaphthalen-2-yl trifluoromethanesulfonate (Intermediate 4, 1 equiv) and 4-boronobenzoic acid (1.2 equiv), where the mixture was stirred at 80° C. for 2 hours. The crude product was obtained after workup and was taken on without purification.
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:20][S:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])=[N:5][CH:6]=[CH:7][C:8]=1OCCC1(CCC)OCCO1.ClC1C=C[N+]([O-])=C(C)C=1C.[CH2:42]([C:44]1([CH2:50][OH:51])[O:49][CH2:48][CH2:47][CH2:46][O:45]1)[CH3:43]>>[Na:1].[CH2:42]([C:44]1([CH2:50][O:51][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:20][S:21]([C:23]3[NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)=[O:22])[C:3]=2[CH3:2])[O:49][CH2:48][CH2:47][CH2:46][O:45]1)[CH3:43]
Reactant: CCCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCO1
Reactant: CCC1(CO)OCCCO1
Agent: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na]
Product: CCC1(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCCO1
Yield: 9.6 %

Procedure:
The same procedure as in the steps (3c) to (3h) of Example 3 was repeated using 4-chloro-2,3-dimethylpyridine 1-oxide and (2-ethyl-1,3-dioxan-2-yl)methanol to obtain the title compound (305 mg, 6 steps: 9.6%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[CH:15]=2)[CH:10]=[C:9]1[C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[C:36]([CH3:38])[C:35]([OH:39])=[C:34]([CH3:40])[CH:33]=2)[N:29]=[N:28][C:27]=1[O:41][CH3:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[CH:10]=[C:9]1[C:26]1[CH:31]=[C:30]([C:32]2[CH:33]=[C:34]([CH3:40])[C:35]([OH:39])=[C:36]([CH3:38])[CH:37]=2)[N:29]=[N:28][C:27]=1[O:41][CH3:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(CO[Si](C)(C)C(C)(C)C)cc2n1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(CO)cc2n1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
3.06 g 6-(tert-Butyldimethylsiloxymethyl)-2-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester is dissolved in 50 mL THF. After addition of 4.1 g tetrabutylammonium fluoride trihydrate, the red solution is stirred for 2 hours. The reaction mixture is diluted with EtOAc, washed with saturated aqueous ammonium chloride, water, and brine, dried with MgSO4 and concentrated in vacuo. Purification on silica affords 2.04 g (82%) 6-hydroxymethyl-2-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[N+:12]([C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[Cl:21])([O-:14])=[O:13].Cl>C(#N)C.O>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[S:22]([C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)(=[O:23])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCCN(CCCC)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To 565 g of dibutylamine were added 2.5 liters of water and 230 g of sodium hydroxide and the mixture was cooled to 0° C. To the mixture was added dropwise 1400 ml of an acetonitrile solution containing 1120 g of 3-nitro-4-chlorobenzenesulfonyl chloride while maintaining at 10° C. or lower. After the completion of the reaction, 100 ml of concentrated hydrochloric acid was added thereto. The crystals thus deposited were collected by filtration, washed with water and dried. Yield: 1208 g (79.2%). Melting point: 67° to 68° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([N:15]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[CH2:16][C:17]([OH:19])=O)[C:11]2=[O:35])[CH:6]=[CH:5][N:4]=1)#[N:2].[CH2:36]([NH2:44])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([N:15]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=4)[CH:24]=3)(=[O:21])=[O:22])[CH2:16][C:17]([NH:44][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:19])[C:11]2=[O:35])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1
Reactant: NCCc1ccccc1
Product: COc1ccc2ccc(S(=O)(=O)N(CC(=O)NCCc3ccccc3)[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 127, Part C using 2-[[1-(2-cyan-pyridine-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxy-naphthalene-2-sulfonyl)amino]acetic acid in place of 2-[[1-(5-cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxynaphthalene-2-sulfonyl)amino-]acetic acid and with phenethylamine instead of NH4OH. The crude product is purified by column chromatography eluting with gradient of 50% EtOAc/CH2Cl2 to 2% MeOH/50% EtOAc/CH2Cl2 to afford the title compound as a white solid.