Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16]C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:18].CO>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([NH2:18])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: N
Solvent: CO
Product: NC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate (50 g, 0.21 mol) was stirred in a solution of ammonia in methanol (7 M, 400 mL, 2.8 mol). After 2 days, the solution was concentrated with heating (50° C.) to about 300 mL at which point all solids remained dissolved. The reaction was then allowed to cool down and the resulting solid was filtered, washed with ether and dried to give 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid amide as colorless crystals (40 g).
Reaction SMILES: ClC1C(F)=C(C2CNC(=O)C2)C(OCC)=C(C(Cl)C)C=1.CC1C2C(=NC=NC=2N)NN=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:51]([C:53]3[C:54]([O:67][CH2:68][CH3:69])=[C:55]([C@@H:61]4[CH2:65][NH:64][C:63](=[O:66])[CH2:62]4)[C:56]([F:60])=[C:57]([Cl:59])[CH:58]=3)[CH3:52])[N:48]=[C:49]([CH3:50])[C:42]=12.NC1N=CN=C2N([C@@H](C3C(OCC)=C([C@H]4CNC(=O)C4)C(F)=C(Cl)C=3)C)N=C(C)C=12.NC1N=CN=C2N([C@@H](C3C(OCC)=C([C@@H]4CNC(=O)C4)C(F)=C(Cl)C=3)C)N=C(C)C=12>CN(C)C=O.O>[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([CH:51]([C:53]3[C:54]([O:67][CH2:68][CH3:69])=[C:55]([CH:61]4[CH2:65][NH:64][C:63](=[O:66])[CH2:62]4)[C:56]([F:60])=[C:57]([Cl:59])[CH:58]=3)[CH3:52])[N:48]=[C:49]([CH3:50])[C:42]=12
Reactant: CCOc1c([C@H](C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1[C@@H]1CNC(=O)C1
Agent: CCOc1c(C(C)Cl)cc(Cl)c(F)c1C1CNC(=O)C1
Agent: CCOc1c([C@@H](C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1[C@@H]1CNC(=O)C1
Agent: CCOc1c([C@@H](C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1[C@H]1CNC(=O)C1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC(=O)C1
Temperature: 100 °C

Procedure:
The mixture of diastereoisomers from step 7 were each processed individually to the final products. A mixture of 4-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]pyrrolidin-2-one (0.36 g, 1.1 mmol) (from Step 7), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.19 g, 1.3 mmol), cesium carbonate (0.54 g, 1.7 mmol) and potassium iodide (18 mg, 0.11 mmol) in N,N-dimethylformamide (7.4 mL) was heated at 100° C. for 4.5 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (3×50 mL) to give a mixture of diastereoisomer ((S)-4-(34(S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; (S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; and (R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one). The mixture of diastereoisomers were purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired products [from peak 1 were isolated peak A (compound 345) (0.13 g, 54%) and peak B (compound 346) (0.11 g, 46%); from peak 2 were isolated peak A (compound 347) (0.15 g, 63%) and peak B (compound 348) (0.14 g, 55%)]. Compound 346: 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.82 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.30 (br s, 1H), 6.23 (q, J=7.0 Hz, 1H), 4.05-3.90 (m, 1H), 3.88-3.78 (m, 2H), 3.63-3.53 (m, 1H), 3.29-3.20 (m, 1H), 2.54 (s, 3H), 2.38-2.21 (m, 1H), 1.70 (d, J=7.1 Hz, 3H), 1.39 (t, J=6.9 Hz, 3H). LCMS for C20H23ClFN6O2 (M+H)+: m/z=433.2; Found: 433.1. Compound 347:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[N:13]=2)=[O:9])[CH:5]=[C:4]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:3]=1.[Cl:27]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[N:13]=2)=[O:9])[C:5]([Cl:27])=[C:4]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:3]=1
Reactant: COCc1cccc(CNC(=O)c2cc(-c3ccc(C)o3)nc(N)n2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: COCc1cccc(CNC(=O)c2nc(N)nc(-c3ccc(C)o3)c2Cl)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A solution of 2-amino-N-(6-methoxymethyl-2-pyridylmethyl)-6-(5-methyl-2-furyl)pyrimidine-4-carboxamide (50 mg, 0.142 mmol) in acetic acid (10 mL) at room temperature was treated with N-chlorosuccinimide (24 mg, 0.156 mmol), stirred at 100° C. for 2 h, cooled to room temperature, concentrated in vacuo and partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was dried (MgSO4), concentrated in vacuo and the resulting solid was triturated with diethyl ether and filtered to give the title compound (30 mg, 54%) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][OH:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(CO)ccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C=O)ccc12
Reaction time: 0.75 h

Procedure:
Step 1 A partial solution of 4-bromo-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-2, 1.00 g, 3.13 mmol) in THF (75 mL) was stirred at rt and treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1 H)-one (Dess-Martin periodinane, 1.993 g, 4.70 mmol). After 45 min, the solution was diluted with EtOAc and washed with 5% aqueous sodium sulfite, NaHCO3 (aq), and brine, then was dried and concentrated. The residue was triturated with methanol, and the precipitate was collected by filtration, washed with methanol and dried to provide 4-bromo-7-formyl-9H-carbazole-1-carboxamide as a tan powder (ca. 85% purity, 948 mg, 81%) used without purification. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (1 H, s), 10.14 (1 H, s), 8.80 (1 H, d, J=8.1 Hz), 8.38 (1 H, d, J=0.9 Hz), 8.28 (1 H, br. s.), 7.97 (1 H, d, J=8.1 Hz), 7.83 (1 H, dd, J=8.3, 1.4 Hz), 7.64 (1 H, br. s.), 7.54 (1 H, d, J=8.1 Hz). Mass spectrum m/z 317, 319 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:33]([O:32][C:30](=[O:31])[NH:21][C:17]1[CH:16]=[C:15]([C:13]2[O:14][C:10]([CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:11][N:12]=2)[CH:20]=[CH:19][N:18]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Nc1cc(-c2nnc(CCc3cccc(F)c3)o2)ccn1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(-c2nnc(CCc3cccc(F)c3)o2)ccn1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
To a solution of 4-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]pyridin-2-amine (280 mg, 0.985 mmol), triethylamine (0.82 mL, 5.92 mmol) and 4-dimethylaminopyridine (12 mg, 0.0985 mmol) in tetrahydrofuran (10 mL) was added benzyl chloroformate (0.70 mL, 4.92 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) and recrystallized from hexane/ethyl acetate to give the title compound (30 mg, yield 7%) as colorless crystals.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:32][C:33]([O:35][CH:36](I)[CH3:37])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:36]([O:35][C:33]([O:32][CH2:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH3:37])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(I)OC(=O)OCC(C)(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(OC(=O)OCC(C)(C)C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 46.8 %

Procedure:
In the same manner as in Example 81, 100 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 170 mg of 1-(neopentyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([N:12]([CH:21]([C:25]2[CH:34]=[CH:33][C:28]3OC[CH2:31][O:32][C:27]=3[CH:26]=2)[C:22]([NH2:24])=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.COC1C=C(C=CC=1)C=O>>[Cl:1][C:2]1[C:3]([C:10]([N:12]([CH:21]([C:25]2[CH:34]=[CH:33][CH:28]=[C:27]([O:32][CH3:31])[CH:26]=2)[C:22]([NH2:24])=[O:23])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Cl)c(C(=O)N(Cc2ccc(C)cc2)C(C(N)=O)c2ccc3c(c2)OCCO3)n1
Agent: COc1cccc(C=O)c1
Product: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(SC)ncc2Cl)c1

Procedure:
This was prepared in the same manner as the product from example 242, using 3-methoxybenzaldehyde as the aldehyde component, to return the title compound as a solid, 1.74 g, (76%).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21].O>C1COCC1>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:20]([CH3:21])[CH3:19])=[N:7][CH:6]=3)[S:9][C:10]=2[CH:16]=1
Reactant: CNC
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc(-c3ccc(N(C)C)nc3)sc2c1

Procedure:
2-(6-Fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (0.201 g) and 2 M dimethylamine in THF (5 mL) were heated in a microwave oven at 100° C. for 5 min. Water was added and the precipitated product was filtered off, washed with water and dried in a desicator over P2O5 to yield 0.193 g of the product as a pale beige solid. 1H NMR δ ppm 8.71 (d, 1H) 8.07 (dd, 1H) 7.84 (d, 1H) 7.65 (d, 1H) 7.08 (dd, 1H) 6.77 (d, 1H) 3.84 (s, 3H) 3.12 (s, 6H); MS m/z (M+H) 286.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[CH3:7][O:8][C:9]1[CH:20]=[C:19]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:20]=[C:19]2[C:12](=[CH:11][CH:10]=1)[NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH:18][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: CCCN=C=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCNC(=O)NCCc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
0.851 g of propyl isocyanate is added to a suspension of 1.902 g of 5-methoxytryptamine in 4 cm3 of pyridine at +5° C. The mixture is stirred at room temperature for 2 hours and then the reaction medium is poured onto ice-water. The mixture is acidified slightly with a 1N hydrochloric acid solution. The resulting precipitate is isolated by filtration, washed with water, dried and then recrystallised in toluene, yielding 2.34 g (85%) of N-[2-(5-methoxyindol-3-yl)ethyl]-N'-propylurea.
Reaction SMILES: C([O:5][C:6]([C:8]1([C:26]2[O:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH:27]=2)[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])(C)(C)C.C(OCC1CCCCN(S(C2C=CC(OC)=CC=2)(=O)=O)C1C(O)=O)(=O)C>>[O:30]1[C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=[C:26]1[C:8]1([C:6]([OH:7])=[O:5])[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCCC2(C(=O)OC(C)(C)C)c2cc3ccccc3o2)cc1
Agent: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)O)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCCC2(C(=O)O)c2cc3ccccc3o2)cc1

Procedure:
3-Benzofuran-2-yl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid was synthesized from 3-Benzofuran-2-yl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester in the same manner as the procedures used for the preparation of 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid: MS (M-H)30 426.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:18][C:19](=[O:29])[O:20][C@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)O1.Br[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=1>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:18][C:19](=[O:29])[O:20][C@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)[CH2:16][CH2:17]3)=[CH:11][CH:10]=2)=[N:33][CH:34]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc(C3(NC(=O)O[C@@H]4CN5CCC4CC5)CC3)cc2)OC1(C)C
Product: O=C(NC1(c2ccc(-c3ccc(F)cn3)cc2)CC1)O[C@@H]1CN2CCC1CC2
Yield: 34 %

Procedure:
Using general procedure E, (S)-quinuclidin-3-yl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl)cyclopropyl)carbamate, 2-bromo-5-fluoropyridine and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (34%). 1H NMR (500 MHz, CDCl3) δ 8.51-8.52 (d, J=3.5 Hz, 1H), 7.87-7.85 (d, J=10.5 Hz, 2H), 7.69-7.67 (m, 1H), 7.47-7.42 (m, 1H), 7.32-7.27 (m, 2H), 5.79-5.66 (d, 1H), 4.73-4.71 (t, J=5.0 Hz, 1H), 3.22-3.19 (m, 1H), 2.87-2.61 (m, 5H), 2.01-1.22 (m, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ 160.8, 157.4, 156.1, 153.5, 144.4, 137.8, 136.3, 126.7, 125.7, 124.9, 123.6, 121.1, 71.6, 55.7, 47.4, 46.5, 35.3, 29.7, 25.4, 24.8, 19.4, 18.2 ppm. Purity: >99% LCMS (214 nm & 254 nm); retention time 1.41 min; (M+1) 382.2.
Reaction SMILES: [C:1]([C:4]1[C:9]2[C:10]([CH3:39])=[C:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]([C:36]([OH:38])=[O:37])[CH:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[O:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C2C(C)=C(C(NC3C=CC(C4C=CC(S(N[C@H](C(OC)=O)C(C)C)(=O)=O)=CC=4)=CC=3)=O)OC=2C=CC=1)(=O)C.[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[C:9]2[C:10]([CH3:39])=[C:11]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]([C:36]([OH:38])=[O:37])[CH:33]([CH3:34])[CH3:35])(=[O:29])=[O:30])=[CH:24][CH:23]=4)=[CH:20][CH:21]=3)=[O:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Agent: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(C(C)=O)c4c3C)cc2)cc1)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(C(C)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of 0.05 g of N-[(4′-{[(4-acetyl-3-methyl-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine, the product of Example 94, Step 3, in 18 mL of ethanol was added 0.01 g of sodium borohydride and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with 1N HCl, adjusting to ˜pH3. The reaction mixture was concentrated in vacuo and the residue was then extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated to provide 0.037 g of N-{[4′-({[4-(1-hydroxyethyl)-3-methyl-1-benzofuran-2-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valine. Yield 74%. m.p. 148° C.(d); MS: 549.1(M−H)−.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[N:28]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:28])=[O:13])=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (1.60 g), 1H-1,2,3-benzotriazol-1-ol (0.77 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.09 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hr. 28% Aqueous ammonia (320 mg) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was washed with hexane to give the title compound (1.25 g, yield 79%) as pale-brown crystals. The crystals were recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 228-229° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)=NOS(=O)(=O)c2ccc(Cl)cc2)cc1OC

Procedure:
As described under 1.2, 10.3 g (0.05 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 12.2 g (0.055 mol) of 4-chlorobenzenesulfonic acid chloride in the presence of triethylamine. After recrystallisation of the crude product from ethyl acetate/hexane, 15.9 g (84%) of α-(4-chlorophenyl-sulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of yellowish crystals having a melting point of 145.5-148.5° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 350 nm (ε=11660) that extends to 437 nm. Elemental analysis: C16H13ClN2O5S (380.80)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([S:27][C:28]4[CH:29]=[CH:30][C:31]5[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]6[CH2:42][CH2:41]6)=[O:39])[N:36]=5)[N:33]=4)=[N:25][N:26]=3)[CH:23]=2)[CH:6]=[N:7][C:8]=1[O:9]COCC[Si](C)(C)C)#[N:2].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44].C(Cl)Cl>>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([S:27][C:28]4[CH:29]=[CH:30][C:31]5[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]6[CH2:42][CH2:41]6)=[O:39])[N:36]=5)[N:33]=4)=[N:25][N:26]=3)[CH:23]=2)[CH:6]=[N:7][C:8]=1[OH:9])#[N:2].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]
Reactant: C[Si](C)(C)CCOCOc1ncc(-c2ccc3nnc(Sc4ccc5nc(NC(=O)C6CC6)cn5n4)n3c2)cc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(-c2ccc3nnc(Sc4ccc5nc(NC(=O)C6CC6)cn5n4)n3c2)cnc1O

Procedure:
As a crude reaction mixture, N-(6-(6-(5-cyano-6-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]-pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide was refluxed in TFA:DCM (1:1, 5 mL) for 30 min. The reaction was then concentrated and purified by preparative LCMS to provide the title compound, N-(6-(6-(5-cyano-6-hydroxypyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide as a TFA salt. The product was then dissolved in MeOH, treated 4M HCl in dioxane, and concentrated to dryness to provide the HCl salt of the title compound. 1H NMR (METHANOL-d4, 400 MHz): δ=8.80 (br. s., 1 H), 8.51 (d, J=2.5 Hz, 1 H), 8.13 (d, J=2.8 Hz, 1 H), 8.04 (d, J=9.6 Hz, 1 H), 7.79-7.96 (m, 3 H), 7.27 (d, J=7.8 Hz, 1 H), 1.83 (br. s., 1 H), 0.91 ppm (d, J=16.7 Hz, 4 H). ESI-MS:m/z 513.4 (M+H)+.
Reaction SMILES: [C-]#N.[Na+].[CH3:4][S:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1.O>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([C:10]([C:9]2[CH:12]=[CH:13][C:6]([S:5][CH3:4])=[CH:7][CH:8]=2)=[O:11])[CH2:22][C:23](=[O:25])[CH3:24])=[CH:19][CH:20]=1
Reactant: CC(=O)C=Cc1ccc(Cl)cc1
Reactant: CSc1ccc(C=O)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(C(=O)C(CC(C)=O)c2ccc(Cl)cc2)cc1
Temperature: 35 °C
Yield: 48.3 %

Procedure:
Sodium cyanide (90 mg, 1.87 mmol) was added to a solution of 4-(methylthio)benzaldehyde (300 mg, 1.97 mmol) in N,N-dimethylformamide (2 ml). While stirring the resulting mixture at 30-40° C., a solution of 4-(4-chlorophenyl)-3-buten-2-one (370 mg, 1.97 mmol) in N,N-dimethylformamide (3 ml) was dropped. The thus-obtained mixture was then stirred at the same temperature for 90 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off and the thus-obtained brown oil (762 mg) was separated and purified by preparative thin-layer chromatography on silica gel [developing solvent: hexane/diethyl ether (2/1)], whereby the title compound was obtained as a pale yellow oil (317 mg, 48.3%).