Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][OH:16].[OH-].[Na+].[I-].[Na+]>O>[OH:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1ccc(O)cc1
Reactant: OCCBr
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CCc1ccc(OCCO)cc1

Procedure:
A mixture of 4-[4-hydroxyphenyl]butan-2-one (16.4 g], 2-bromoethanol (16.9 g), sodium hydroxide (7.5 g), sodium iodide (7.5 g) and water (200 ml) was heated under reflux for 4 hours, cooled and extracted with dichloromethane. The extract was washed with brine, dried (MgSO4) and evaporated to dryness. The residual oil was distilled to give the title compound as a colourless liquid, bp 170°-1°/0.8 mm. P τ(CDCl3) 7.85 (3H, s), 7.15-7.35 (4H, complex), 7.4-7.6 (1H, t), 5.85-6.25 (4H, complex), 2.8-3.4 (4H, dd).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Product: O=Cc1ccc(OCCCCc2ccccc2)cc1
Yield: 63 %

Procedure:
Following the process described in example 18 (point A), starting from 4-hydroxybenzaldehyde and 4-phenyl-1-butanol, the title compound was prepared (63% yield).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([O:8]S(C)(=O)=O)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH2:20]([C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[C:34](O)[CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:29][N:30]=[C:24]2[CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[C:34]([O:8][C@@H:7]5[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]5[F:1])[CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:29][N:30]=[C:24]2[CH:23]=1)[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H](F)C1
Reactant: CCc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Product: CCc1ccn2c(-c3ccc4cccc(O[C@@H]5CCNC[C@H]5F)c4n3)cnc2c1

Procedure:
Prepared according to the procedure for Example 16, using (cis)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate in place of tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate and 2-(7-ethylimidazo[1,2-a]pyridin-3-yl)quinolin-8-ol in place of 2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol. MS APCI (+) m/z 391.2 (M+1) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=2)[N:16]([CH2:26][CH3:27])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]>O1CCCC1.[Pd]>[NH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:26][CH3:27])[CH:15]=[C:14]2[CH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(N)ccc21
Yield: 100.5 %

Procedure:
A solution of ester (G) (4.80 g) in tetrahydrofuran (75 ml) was hydrogenated in the presence of palladium-on-carbon (10% w/w; 0.25 g), at 3.45 bar for 2 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residual oil was purified by flash chromatography to give methyl 4-(5-amino-1-ethylindol-3-ylmethyl)-3-methoxybenzoate (H) as an amber oil (4.43 g, 100%); TLC, silica gel, Rf =0.23, hexane:ethyl acetate (6:4 v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](COCC[Si](C)(C)C)[N:13]=2)=[CH:4][CH:3]=1.C(Cl)Cl.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Cc2ccc(Cl)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Cc2cc(-c3ccncc3)sc2-c2nnc[nH]2)cc1
Yield: 97 %

Procedure:
The 4-[4-(4-chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine (58 mg, 0.12 mmol) and methylene chloride (4.0 mL, 62 mmol) were combined in a round bottomed flask equipped with a stirbar. The mixture was stirred and trifluoroacetic acid (1.1 mL, 14 mmol) was added in one portion. The resulting yellow solution was stirred overnight at rt under an atmosphere of nitrogen. Excess solvent was removed on the rotovap and the residue was digested in a mixture of EtOAc and aqueous sodium bicarbonate solution. The mixture was stirred then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted twice more with EtOAc. The organics were combined, washed with bicarbonate solution, then saline, and then dried over sodium sulfate. The mixture was filtered then evaporated in vacuo and the residue was purified by column chromatography on silica, elution 100% DCM to 100% EtOAc to afford the title compound as an off-white powder. Yield 41 mg (97% yield). LCMS: (FA) ES+, 353, 355. 1H NMR (400 MHz, d6-DMSO) δ: 14.31 (1H, br s), 8.67 (1H, br s), 8.55 (2H, d, J=6.3 Hz), 7.69 (1H, s), 7.63 (2H, d, J=6.3 Hz), 7.36-7.30 (4H, m), 4.47 (2H, s).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[C:11]([OH:13])=[O:12].[CH2:14](O)[CH3:15]>>[CH2:14]([O:12][C:11]([C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2]1)=[O:13])[CH3:15]
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1
Reaction time: 16 h

Procedure:
HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([CH3:18])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)=[O:7])C.[OH-].[Li+]>C(O)C.O>[F:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([F:17])[CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[CH:5]([CH3:18])[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(C)C(=O)NCc1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
To a solution of 4.0 g (14.75 mmol) N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid ethyl ester in 300 ml of ethanol, 15 ml of water and 1.41 g (59 mmol) of lithium hydroxide were added and the mixture was refluxed for 5 hours. After concentration in vacuo water (50 ml) was added and the mixture was extracted with dichloromethane (three times 30 ml). The aqueous phase was acidified with 8 N hydrochloric acid and extracted with dichloromethane (four times 30 ml).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:21]=[CH:20][C:19]=1[O:30][CH2:31][CH2:32][CH2:33]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH:21]=[CH:20][C:19]=1[O:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)COc1ccc(OCCCBr)c(Cl)c1
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(OCC(F)(F)F)cc3Cl)cc2O1
Temperature: 70 °C
Yield: 81.1 %

Procedure:
To a 40 ml DMF solution of ethyl 7-hydroxy-chromane-2-carboxylate (1.81 g, 8.15 mmol) and 3-bromopropyl 2-chloro-4-(2,2,2-trifluoroethoxy)phenyl ether (3.4 g, 9.8 mmol) was added cesium carbonate (3.2 g, 9.8 mmol). The resulting suspension was heated to 70° C. for 5 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on slica gel eluting with 20% AcOEt/hexanes to give the title compound 3.23 g (81%).
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.CN.[NH2:9][C:10]1[C:11]([F:36])=[CH:12][C:13]([F:35])=[C:14]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23](F)[C:24]=3[CH3:26])[C:19](=[O:31])[C:18]([C:32]([OH:34])=[O:33])=[CH:17]2)[CH:15]=1>C(OCC)C>[NH2:9][C:10]1[C:11]([F:36])=[CH:12][C:13]([F:35])=[C:14]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([NH:1][CH3:2])[C:24]=3[CH3:26])[C:19](=[O:31])[C:18]([C:32]([OH:34])=[O:33])=[CH:17]2)[CH:15]=1
Reactant: Cc1c(F)c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: c1ccncc1
Agent: CN
Solvent: CCOCC
Product: CNc1c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
Pyridine (500 mg) and a 40% aqueous solution (300 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-8-methyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (220 mg), and the mixture was stirred for 3 hours at 40° C. and for 2 days at room temperature. Diethyl ether was added to the reaction mixture, followed by stirring. A supernatant liquid was removed, and acetic acid (3 drops) was added to the residue, followed by stirring. Solids deposited were recrystallized from ethanol and N,N-dimethylformamide to obtain the title compound (190 mg) as a reddish brown powder.
Reaction SMILES: [CH2:1]([C:3]1([CH3:13])[CH:8]([CH3:9])[CH2:7][CH2:6][C:5]([CH2:11][CH3:12])([CH3:10])[NH:4]1)[CH3:2].[CH2:14](Br)[CH:15]=[CH2:16].[OH-].[Na+]>C(C1(C)N=C(CCC)CC(CCC)(C)N1)CC>[CH2:16]([N:4]1[C:5]([CH2:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:13])[CH:15]=[CH2:14]
Reactant: CCC1(C)CCC(C)C(C)(CC)N1
Reactant: C=CCBr
Agent: CCCC1=NC(C)(CCC)NC(C)(CCC)C1
Agent: [Na+]
Agent: [OH-]
Product: C=CCN1C(C)(CC)CCC(C)C1(C)CC
Temperature: 75 °C

Procedure:
36.7 g of 2,6-diethyl-2,3,6-trimethylpiperidine and 30 g of allyl bromide are stirred for 7 days with heating at about 75° C. The reaction mixture is made alkaline by addition of 200 ml of 2 n sodium hydroxide and is extracted with ether. The ethereal solution is dried over K2CO3 and evaporated. The residue is purified by fractional distillation yielding 1-allyl-2,6-diethyl-2,3,6-trimethylpiperidine (Compound No. 4) which distills at 132°-135° C./16 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH3:34][CH:35]([CH3:48])[CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:42]3[CH:41]=[CH:40][C:39]([CH2:38][CH2:37][CH2:36][CH:35]([CH3:48])[CH3:34])=[CH:44][CH:43]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CC(C)CCCc1ccc(B(O)O)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(CCCC(C)C)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (500 mg, 0.91 mmol) was coupled with 4-(4-methylpentyl)phenyl boronic acid according to general procedure G to give (4-{4-(2,4-dichloro-phenyl)-2-[4′-(4-methyl-pentyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenylamino)-acetic acid methyl ester.
Reaction SMILES: O=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.C[O+](C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1)[C:27]([NH:29][NH2:30])=O>C(#N)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:27]2[N:3]3[CH2:4][CH2:5][CH2:6][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]3=[N:30][N:29]=2)[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1
Reactant: COc1cc(C(=O)NN)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C1CCCNC1=O
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)c3)nnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a mixture of ethyl 2-oxopiperidine-3-carboxylate (1.86 g) in acetonitrile (20 mL) was added trimethyloxonium tetrafluoroborate (1.61 g) at room temperature, and the mixture was stirred at room temperature for 2 hr. 3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)benzohydrazide (2.23 g) was added to the reaction mixture at room temperature, and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was collected by filtration, and washed with ethyl acetate to give the title compound (1.32 g).
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[CH2:16][CH2:15][C:6]2=[C:7]([C:12]([OH:14])=O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[CH2:4]1)[CH3:2].[CH3:19][Li]>C(OCC)C>[CH2:17]([C:3]1([CH2:1][CH3:2])[CH2:16][CH2:15][C:6]2=[C:7]([C:12](=[O:14])[CH3:19])[S:8][C:9]([S:10][CH3:11])=[C:5]2[CH2:4]1)[CH3:18]
Reactant: CCC1(CC)CCc2c(C(=O)O)sc(SC)c2C1
Reactant: [Li]C
Solvent: CCOCC
Product: CCC1(CC)CCc2c(C(C)=O)sc(SC)c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5,5-diethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (669 mg, 2.35 mmol) in diethyl ether (20 mL), a solution of methyllithium (2.6 mL, 1.6 M in diethyl ether) is added at rt. The reaction mixture is stirred at rt for 4 h, diluted with diethyl ether, washed with 1 N aq. K2HPO4 solution followed by 1 N aq. NaOH, dried over Na2SO4 and evaporated to give 1-(5,5-diethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (458 mg) as a yellow oil, LC-MS: tR=1.15 min, [M+1]=283.1; 1H NMR (CDCl3): δ 2.96 (t, J=7.0 Hz, 2H), 2.53 (s, 3H), 2.45 (s, 3H), 2.32 (s, 2H), 1.56 (t, J=7.0 Hz, 2H), 1.35-1.20 (m, 4H), 0.83 (t, J=7.6 Hz, 6H).
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[N+:5]([C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[CH:10]=[CH:11][S:12](Cl)(=[O:14])=[O:13])([O-:7])=[O:6]>>[N+:5]([C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[CH:10]=[CH:11][S:12]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:14])=[O:13])([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccccc1C=CS(=O)(=O)Cl
Reactant: CC(=N)N
Product: CC(=N)NS(=O)(=O)C=Cc1ccccc1[N+](=O)[O-]

Procedure:
Reaction of acetamidine with 2-nitrostyrylsulfonyl chloride according to the above procedure affords N-(2-NITROSTYRYLSULFONYL)ACETAMIDINE, m.p. 175°-178° C.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:50])[CH2:21][C:22]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[C:29]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:28]=2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C(=O)(O)[O-].[Na+]>O.C(#N)C.CN1C(=O)CCC1.N1C=CC=CC=1>[C:15]([O:19][C:20](=[O:50])[CH2:21][C:22]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([O:33][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:14][CH:13]=3)[CH:30]=[C:29]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH:28]=2)[CH2:23]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CCc1cc(O)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CCc1cc(OC(=O)c2ccc(NC(=N)N)cc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (77 mg) was added to a mixture of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(3-(3-tert-butoxy-3-oxopropyl)-5-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (167 mg), pyridine (0.16 mL), and NMP (0.16 mL) at 50 C, and the obtained mixture was stirred at 50 C for 30 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (77 mg) was added thereto, and the obtained mixture was stirred at 50 C for 3 hours. Pyridine (0.16 mL) and NMP (0.16 mL) were added thereto, then 4-carbamimidamidobenzoyl chloride hydrochloride (77 mg) was added, and then, the obtained mixture was stirred at 50 C for 30 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (77 mg) was added thereto, and the obtained mixture was stirred overnight at 50 C. The reaction mixture was fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). To the obtained fraction, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (104 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:34])[CH:7]=[C:8]([O:32][CH3:33])[C:9]=2[CH:11]([OH:31])[C:12]2[N:16](COCC[Si](C)(C)C)[C:15]3[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:14]=3[N:13]=2)[NH:4][CH:3]=1.ClC1C2C(=C(C)C=C(OC)C=2C(O)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)NC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:34])[CH:7]=[C:8]([O:32][CH3:33])[C:9]=2[CH:11]([OH:31])[C:12]2[NH:16][C:15]3[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:14]=3[N:13]=2)[NH:4][CH:3]=1
Reactant: COc1cc(C)c2[nH]cc(Cl)c2c1C(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cc(C)c2[nH]cc(Cl)c2c1C(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: [Cl-]
Solvent: NCCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C)c2[nH]cc(Cl)c2c1C(O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 60 °C

Procedure:
A mixture of (±)-2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.2 g, 0.402 mmol) was dissolved in THF (4.02 mL) and treated with TBAF (1M in THF, 4.02 mL, 4.02 mmol) and ethylenediamine (0.272 mL, 4.02 mmol) and heated at 60° C. The reaction was cooled to room temperature, and treated with 10 mL of a saturated aq. solution of ammonium chloride and then diluted with EtOAc. The layers were separated and the organic layer was washed with water (3×100 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified via FCC (0-100% EtOAc in heptanes) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (d, J=6.57 Hz, 1H) 11.28 (br. s., 1H) 7.87 (d, J=6.19 Hz, 1H) 7.61 (m) 7.40-7.50 (m, 2H) 6.94-7.12 (m, 1H) 6.79 (s, 1H) 6.02-6.20 (m, 1H) 3.42-3.50 (m, 3H) 2.45 (s, 3H). HRMS calcd. for C19H16ClN4O2 (M+H)+ 367.0957. found 367.096.
Reaction SMILES: Cl[C:2]1[C:3]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:5](=[O:20])[N:6]([CH2:8][C:9]2[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:7]=1.O.[NH2:35][NH2:36]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:3]2[C:2]([NH:35][NH2:36])=[N:7][N:6]([CH2:8][C:9]3[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=3)[C:5](=[O:20])[C:4]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:28][CH:29]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(Cl)c(-c2ccc(Cl)cc2)c(-c2ccncc2)c1=O
Reactant: NN
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccncc2)c1=O
Temperature: 130 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added 6-chloro-5-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (900 mg, 1.833 mmol), 1-BuOH (2 ml) and hydrazine hydrate (5 ml). The reaction was heated to 130° C. and stirred at that temperature for 8 hrs. After this time the reaction was cooled to rt and concentrated under reduced pressure. The reaction was poured into a separatory funnel and partitioned between EtOAc (50 ml) and water (20 ml). The layers were separated and the organic layer was washed with water (20 ml) and saturated aqueous NaCl (20 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the product 5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one as yellow solid. HPLC retention time (method A) 1.138 min; LCMS (M+H)=487.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Li].C([N-]C(C)C)(C)C.[I:17]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.O.O1CCCC1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([I:17])[C:5]([F:8])=[CH:4][N:3]=1
Reactant: II
Reactant: Fc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cnc(Cl)cc1I
Temperature: -75 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
A tetrahydrofuran (5 ml) solution containing 2-chloro-5-fluoropyridine (500 mg) was added to a tetrahydrofuran (20 ml) solution containing lithium-N,N-diisopropylamide (2M tetrahydrofuran/ethylbenzene/heptane solution) (2.9 ml) at −75° C. in a nitrogen atmosphere, followed by stirring at −75° C. for 3 hours. Subsequently, a tetrahydrofuran (5 ml) solution containing iodine (1.16 g) was added, followed by stirring at −75° C. for 1 hour. Then, water/tetrahydrofuran (2 ml/8 ml), water (10 ml), and 3M aqueous sodium thiosulfate were slowly added at −75° C., −50° C., and −35° C., respectively, to the reaction solution. The reaction solution was adjusted to room temperature, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=20:1 to 10:1), and a white solid of 2-chloro-5-fluoro-4-iodopyridine (457 mg) was thus obtained.
Reaction SMILES: Cl[CH:2]([CH3:15])[CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[CH2:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:16]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:2]([CH3:15])[CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:17]
Reactant: CC(Cl)CC(=O)NCCc1ccccc1
Reactant: CCCCCCCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCN(CC)C(C)CC(=O)NCCc1ccccc1

Procedure:
Reflux 5.0 g (21 mmol) of 3-chloro-N-[2-phenylethyl]butanamide, 3.0 gm (21 mmol) N-ethylheptanamine and 3.0 g (21 mmol) of potassium carbonate in 100 mL of methanol. Follow the progress of the reaction by thin layer chromatography on silica gel. At the completion of the reaction remove the solvent in vacuo and add 100 mL of H2O. Extract the aqueous mixture with 3×100 mL of methylene chloride. Dry the organic extracts over anhydrous sodium sulfate. Remove the drying agent and evaporate the solvent to obtain the title compound.