Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:33])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:9]=2[N:10]=1)(=[O:3])[CH3:2].[CH:34]([C:37]1[CH:42]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:40]=[C:39]([CH:46]([CH3:48])[CH3:47])[C:38]=1[S:49](Cl)(=[O:51])=[O:50])([CH3:36])[CH3:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:33][S:49]([C:38]2[C:39]([CH:46]([CH3:47])[CH3:48])=[CH:40][C:41]([CH:43]([CH3:45])[CH3:44])=[CH:42][C:37]=2[CH:34]([CH3:36])[CH3:35])(=[O:51])=[O:50])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(OS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)c2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Reaction time: 1 h
Yield: 92 %

Procedure:
The intermediate from Step 1 above (500 mg, 0.98 mmol) was dissolved in DCM (15 mL) at ambient temperature. DMAP (7.3 mg, 0.06 mmol), and TEA (16 ml, 11 mmol) were added to the solution, followed by 2,4,6-triisopropylbenzenesulfonyl chloride (454 mg, 1.5 mmol). After 1 h the reaction had gone to completion, the crude mixture was concentrated, and then purified by flash chromatography (SiO2, 10% EtOAc—CHCl3), affording 690 mg (92%) of 5-acetylamino-7-(2,4,6-triisopropyl-benzenesulfonyloxy)-3-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidin-2-one as a foaming white solid 17: 74.5-76.3° C.; Rf=0.7 (SiO2, 20% EtOAc—CHCl3); 1H (400 MHz, d6-DMSO) δ 10.83 (s, 1H), 7.39 (s, 2H), 6.03 (d, J=4.0, 1H), 5.91-5.96 (m, 1H), 5.69 (t, J=6.4, 1H), 4.30-4.70 (m, 1H), 4.22-4.26 (m, 1H), 4.16-4.20 (m, 1H), 3.90-4.00 (m, 2H), 2.97-3.01 (m, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 1.88 (s, 3H), 1.17-1.25 (m, 18H).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C@H:7]1[C@@H:12]([OH:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[CH:16]=2)[CH2:8]1)=[O:6])[CH3:3].[C:25](OC(=O)C)(=[O:27])[CH3:26].[OH-].[Na+]>C1(C)C=CC=CC=1>[ClH:1].[CH2:2]([O:4][C:5]([C@H:7]1[C@@H:12]([O:13][C:25](=[O:27])[CH3:26])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[CH:16]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@@H]1CN(CC2=Cc3ccc(OC)cc32)CC[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CN(CC2=Cc3ccc(OC)cc32)CC[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2 g (5.6 mmol) of cis-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride and 20 ml of acetic anhydride are heated under reflux in 100 ml of toluene for 18 hours. 200 ml of ice-water are then added to the cooled reaction mixture and the whole is stirred for 30 minutes. The reaction mixture is rendered alkaline to pH 10 with 2N sodium hydroxide solution and the toluene phase is then separated off. The aqueous phase is extracted twice with dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated by evaporation. The crude product so obtained is purified by chromatography over the 10-fold amount of silica gel with diethyl ether as eluant. The purified product is converted into the hydrochloride and crystallised from ethanol/diethyl ether. Cis-4-acetoxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride of m.p. 202°-203° is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([CH3:17])[C:12](=[O:18])[N:11]([C@@H](C1C=CC=CC=1)C)[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([CH3:17])[C:12](=[O:18])[NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(NC(=O)OC(C)(C)C)CCC[C@]2(C)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@]12CCC[C@]1(C)C(=O)NC2
Yield: 89.4 %

Procedure:
(1S,5S)-1-(tert-Butoxycarbonylamino)-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (77 mg, 0.22 mmol) was dissolved in ethanol (6.0 mL). 10% palladium-carbon (50% wet) (69 mg) was added, and the mixture was stirred in a hydrogen atmosphere at 45° C. for 19.5 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 50 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Se](=O)=[O:16]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH:14]=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: O=[Se]=O
Reactant: Cc1cccc(-c2ccccc2C)n1
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cccc(C=O)n1

Procedure:
2.8 g of 6-(2-methylphenyl)-2-methylpyridine was dissolved in 180 ml 1,4-dioxane, 1.4 g of selenium dioxide (Aldrich Gold Label) was added and the mixture refluxed for 36 hours. The solids were removed by filtration. Ether was added and the organic extracts washed five times with 100 ml water. After drying over magnesium sulfate and evaporation, 6-(2-methylphenyl)-2-pyridinecarboxaldehyde was afforded as a pale yellow oil (1.4 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CSCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCSCC2)nc1
Temperature: 25 °C

Procedure:
To a solution of 20 g (126 mmol) of 2-chloro-5-nitropyridine in 200 ml tetrahydrofuran were added dropwise 32.5 ml (315 mmol) thiomorpholine within 10 min. The reaction mixture was refluxed for additional 2 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was re-dissolved in 200 ml ethyl acetate. The organic phase was washed with 200 ml 1 N sodium bicarbonate solution, dried (magnesium sulfate) and evaporated to give 29.3 g (quantitative) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:39]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:40])[CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N1CCOCC1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.20 mmol) (from Example 25a supra) in tetrahydrofuran (3 mL) was added triethylamine (32 mg, 0.3 mmol), followed by the addition of morpholine-4-carbonyl chloride (38 mg, 0.24 mmol) (Aldrich). The mixture was stirred at 45° C. for 3 hours, then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue were triturated with dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-[1-(morpholine-4-carbonyl)-piperidin-3-yl]-1,3-dihydro-indol-2-one as a white solid. (Yield 60 mg, 60%).
Reaction SMILES: [C:1]([O:9][CH:10]([O:14][C:15]([NH:17][CH2:18][C:19]1([CH2:25][C:26]([OH:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH:11]([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[C:1]([O:9][CH:10]([O:14][C:15]([NH:17][CH2:18][C:19]1([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH:11]([CH3:12])[CH3:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccccc1
Reactant: CC(C)C(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)C(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 1-{[(α-benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid (84) (150 mg, 0.38 mmol), benzene (18 mL), and methanol (2 mL) was cooled to 0° C. Trimethylsilyldiazomethane was added slowly at 0° C. until the yellow color persisted. The mixture was stirred at 0° C. for 30 min until the reaction was complete (monitored by TLC). After removing the solvent under reduced pressure, chromatography of the residue on silica gel, eluting with 5% ethyl acetate/hexane gave 98 mg (64%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.02 (d, J=6.4 Hz, 3H), 1.03 (d, J=6.4 Hz, 3H), 1.32-1.52 (m, 10H), 2.14 (m, 1H), 2.27 (s, 2H), 3.17 (m, 2H), 3.62 (s, 3H), 5.40 (t, 1H), 6.81 (d, J=4.8 Hz, 1H), 7.40 (m, 2H), 7.54 (m, 1H), 8.12 (m, 2H). MS (ESI) m/z 406.29 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[CH:9][N:8]([S:21]([C:18]3[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1c[nH]c2ncc(Br)cc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.1 %

Procedure:
To a solution of 5-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (B-6-1) (1.2 g, 5.68 mmol) in THF (30 mL) was added NaH (0.34 g, 8.5 mmol) under N2 at 0° C., 4-bromophenylsulfonyl chloride (1.2 g, 6.8 mmol) was added 30 minutes later. The mixture was stirred at room temperature for 1.5 h. TLC (Petroleum ether: EtOAc=5:1) showed that the reaction was complete. Saturated aqueous NaCl (10 mL) was added, and the mixture was filtered to give 5-bromo-3-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (B-6-2) (0.8 g) as a white solid. The organic layer was separated from the filtrate, concentrated to 8 mL, then filtered to give 5-bromo-1-(4-bromophenylsulfonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine (0.5 g). Two batches were combined to give 5-bromo-3-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (B-6-2) (1.3 g, 65.2%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][C:7]1=[C:6]2[CH:16]=O.C([O-])(=O)C.[NH4+].[N+:23]([CH2:26][CH3:27])([O-:25])=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][C:7]1=[C:6]2[CH:16]=[C:26]([N+:23]([O-:25])=[O:24])[CH3:27]
Reactant: COc1ccc2c(c1)c(C=O)c1n2CCCC1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc2c(c1)c(C=C(C)[N+](=O)[O-])c1n2CCCC1
Temperature: 25 °C

Procedure:
A stirred solution of 2-methoxy-6,7,8,9-tetrahydro-pyrido[1,2-a]indole-10-carboxaldehyde and ammonium acetate in nitroethane is heated to 100° C. for 1 h, cooled to room temperature and partitioned between ethyl acetate and water. The combined organic extracts are washed (water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]([OH:20])([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.Cl[CH2:22][CH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)=[O:26]>>[CH3:36][C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:25]([CH2:24][CH2:23][CH2:22][N:17]2[CH2:16][CH2:15][CH:14]([C:7]([OH:20])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[CH2:19][CH2:18]2)=[O:26])=[CH:28][CH:29]=1)([CH3:34])[CH3:35]
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
reacting azacyclonol with 4 -chloro-1-[4-(1,1-dimethylethyl)phenyl]-1-butanone to yield terfenadone free-base;
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
First, 0.15 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61) was dissolved in 0.50 ml of N,N-dimethylformamide, to which 97 mg of potassium carbonate and 48 μl of methyl bromoacetate were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 97 mg (yield, 53%) of 3-{4-chloro-2-fluoro-5-[(methoxycarbonyl)methoxy]phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-165; m.p., 116.6° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:31]OS(C)(=O)=O)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:43][CH2:42][CH2:41][C@@H:38]1[CH2:39][OH:40].CN(C=O)C>CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([CH2:30][CH2:31][N:37]3[CH2:43][CH2:42][CH2:41][C@@H:38]3[CH2:39][OH:40])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:28])([F:29])[F:27])[CH:20]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC[C@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCOS(C)(=O)=O)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC[C@@H]2CO)CC1
Yield: 100.8 %

Procedure:
Add 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-methanesulfonyloxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg; 1 equiv; 933 μmol); D-prolinol (3.00 equiv; 2.80 mmol; 283 mg); DMF (1 mL) and heat at 50° C. for 18 h in a sealed vessel. Dilute with EA, wash with saturated sodium bicarbonate, brine, dry MgSO4, filter and purify on 40 g silica gel with 1-10% MeOH/DCM to provide the title compound (506.9 mg; 0.94 mmol; 100%). MS (ES+): m/z=541 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:43][CH2:44][C:45]([NH:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[O:46].[Br:53][C:54]1[CH:62]=[C:61](/[CH:63]=[CH:64]/[CH:65]([C:70]2[CH:75]=[C:74]([Cl:76])[C:73]([OH:77])=[C:72]([Cl:78])[CH:71]=2)[C:66]([F:69])([F:68])[F:67])[CH:60]=[CH:59][C:55]=1[C:56](O)=[O:57]>C(Cl)Cl>[Br:53][C:54]1[CH:62]=[C:61](/[CH:63]=[CH:64]/[CH:65]([C:70]2[CH:71]=[C:72]([Cl:78])[C:73]([OH:77])=[C:74]([Cl:76])[CH:75]=2)[C:66]([F:69])([F:68])[F:67])[CH:60]=[CH:59][C:55]=1[C:56]([NH:43][CH2:44][C:45](=[O:46])[NH:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[O:57]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(O)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: NCC(=O)NCC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(O)c(Cl)c2)C(F)(F)F)cc1Br)NCC(F)(F)F
Reaction time: 12 h
Yield: 50.9 %

Procedure:
DIPEA (0.20 mL, 1.26 mmol), PyBOP (245 mg, 0.47 mmol) and 2-amino-N-(2,2,2-trifluoroethyl)acetamide (90 mg, 0.47 mmol) were added to a stirred solution of (E)-2-bromo-4-(3-(3,5-dichloro-4-hydroxyphenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (200 mg, 0.42 mmol, 66% purity) in CH2Cl2 (5 mL) at ambient temperature. The resulting mixture was then stirred for 12 h. The reaction mixture was diluted with CH2Cl2, washed with 1N HCl, followed by saturated sodium bicarbonate solution, brine solution and water. The organic layer was dried (Na2SO4), filtered, concentrated under vacuum. The residue was purified by column chromatography on silica (100-200 mesh) eluting with 30% EtOAc in petroleum ether to give the title compound as light green solid (130 mg, 52%).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1>CC(C)=O>[I:1][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: [I-]
Reactant: N#Cc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccc(CI)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
Sodium iodide (99 mg, 0.660 mmol) and 4-(chloromethyl)benzonitrile (100 mg, 0.660 mmol) were dissolved in Acetone (Volume: 2.199 mL) and allowed to stir at room temperature for 4 hours. The resulting solid was filtered and the filtrate concentrated to obtain 4-(iodomethyl)benzonitrile (130 mg, 0.535 mmol, 81% yield) as an orange oil. It was taken directly to the next step without characterization and purification. N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) was dissolved in 1.0 mL of DMF and added to a suspension of sodium hydride (12.78 mg, 0.320 mmol) in 2.0 of DMF. The reaction was stirred at 80° C. for 10 minutes before adding 4-(iodomethyl)benzonitrile (129 mg, 0.533 mmol) dissolved in 2.0 mL of DMF. The reaction was allowed to stir overnight. After 18 hours, the reaction was cooled to room temperature before diluting with water and ethyl acetate. The organic phase was washed with water followed by saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified via column chromatography using 50% ethyl acetate/hexanes to 100% ethyl acetate. The purification provided product as a white solid. (Yield: 50 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.78-7.67, 7.66-7.57, 7.49, 7.43-7.01, 6.80-6.68, 5.65-5.51, 4.62, 4.54-3.83, 3.16-2.83, 2.75, 2.35-2.26, 1.80-1.24
Reaction SMILES: [F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12](=O)[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[NH2:26][O:27][CH2:28][CH2:29][OH:30]>CO>[OH:30][CH2:29][CH2:28][O:27]/[N:26]=[C:12](/[C:9]1[CH:10]=[CH:11][C:6]2[N:7]([C:3]([C:2]([F:25])([F:1])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:4][N:5]=2)[N:8]=1)\[CH3:13]
Reactant: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Reactant: NOCCO
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 55.3 %

Procedure:
A solution of 1-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (54 mg, 0.159 mmol) and 2-(aminooxy)ethanol (intermediate S) (36.1 mg, 0.318 mmol) in 8 mL of MeOH was stirred at it overnight. Solvent was evaporated and the residue was partitioned between water and EtOAc. Aqueous layer was extracted with EtOAc twice. Organic layers were combined, washed with brine and dried over Na2SO4. Solvent was evaporated and the crude was purified by HPLC (basic with 0.05% NH4OH) to give 35 mg (55%) of the title compound as a white solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.98 (d, 1H), 8.52 (d, 1H), 8.43 (s, 1H), 8.23 (d, 1H), 8.19 (d, 1H), 8.06 (d, 1H), 8.04 (d, 1H), 7.66 (m, 1H), 4.36 (m, 2H), 3.84 (m, 2H), 2.18 (s, 3H). LCMS (method B): [MH]+=398.9, tR=2.29 min.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:15]=[CH:14][C:13]=1[OH:25])[CH:10]=[CH2:11]>>[CH2:9]([C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:15]=[CH:14][C:13]=1[O:25][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:10]=[CH2:11]
Reactant: C=CCc1cc(-c2ccccc2C)ccc1O
Reactant: BrCc1ccccc1
Product: C=CCc1cc(-c2ccccc2C)ccc1OCc1ccccc1

Procedure:
Following the procedure of step B but using benzyl bromide, the phenol from step C was converted into the title compound
Reaction SMILES: C[N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:12]=1)[C:3](=O)OC(C)(C)C.[H-].[Na+].[CH2:24]([S:28](Cl)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([S:28]([N:13]1[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][C:11]([CH2:10][NH:2][CH3:3])=[CH:12]1)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CCCCS(=O)(=O)n1cc(CNC)cc1-c1ccccc1
Yield: 24 %

Procedure:
Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (70 mg), sodium hydride (60% in oil, 98 mg) and butane-1-sulfonyl chloride (230 mg), a procedure as in Example 38 was performed to give the title compound as pale-purplish red crystals (yield 18 mg, 21%).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1O>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][C:22]=1[O:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(C(F)(F)F)ccc1Cl

Procedure:
The title compound was prepared according to the method of Example 2 step (b) but using (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester and 2-chloro-5-(trifluoromethyl)phenol.
Reaction SMILES: NO.[CH2:3]([OH:5])[CH3:4].[OH:6][NH:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]1[C:20]([OH:31])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1)=[NH:9].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:3]([O:6][NH:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]1[C:20]([OH:31])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1)=[NH:9])(=[O:5])[CH3:4]
Reactant: CCO
Reactant: N=C(NO)n1c(-c2cccc(-c3ccccc3)c2O)cc2ccccc21
Agent: NO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)ONC(=N)n1c(-c2cccc(-c3ccccc3)c2O)cc2ccccc21

Procedure:
The cyano group in compound 15 is then converted into the carbamimidoyl group by first treating 15 with hydrogen chloride gas in an anhydrous alcoholic solvent such as methanol, ethanol and the like, and then treating the resulting (5-methoxycarbonimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole 16 with an inorganic base such as ammonium carbonate, and the like in an alcoholic solvent such as methanol, ethanol, or with excess ammonia to give resulting (5-carbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole of Formula I. Alternatively, compound 15 can be converted to a compound of Formula I by first refluxing it with hydroxylamine in an alcoholic solvent such as ethanol and then treating the resulting (N-hydroxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole with acetic anhydride in acetic acid to give (N-acetoxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole. The acetoxy group is then removed under hydrogenation reaction conditions by treating (N-acetoxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole with 10% palladium in an alcoholic solvent such as methanol, ethanol, and the like.