Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9]([CH3:19])([CH3:18])[C:10](=N)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].O.[OH:21]S(O)(=O)=O>>[OH:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9]([CH3:19])([CH3:18])[C:10](=[O:21])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=N
Solvent: O
Product: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
To a mixture of ethyl 5-hydroxy-7-imino-8,8-dimethyl-7,8-dihydroquinoline-6-carboxylate (100 mg, 384 μmol) and water (3 mL, 166525 μmol), was added H2SO4 (0.02 mL, 384 μmol). The resulting mixture was then heated to 80° C. After 30 minutes, 0.1 mL of H2SO4 was added. After 90 minutes, the reaction was cooled to room temperature and extracted with EtOAc. The organic phase was washed with water and then with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give a light-yellow solid. The aqueous layer was concentrated in vacuo to give a white solid/yellow liquid. The solid was washed with EtOH and a white solid was filtered away. The filtrate was concentrated in vacuo to give a yellow solid. The solid was washed with DCM and the supernatant was decanted off. The solid was dissolved in MeOH and concentrated in vacuo to give a light-yellow solid which was washed once more with DCM and the supernatant was decanted away. The solid was placed under high-vacuum to leave a light-yellow solid which was purified by silica flash chromatography (0-10% MeOH/DCM) to give the title compound as a white crystalline solid (24 mg, 24%). MS (m/z)=262 (M+H)+. Calculated for C14H15NO4 261.3.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[N:11]=[CH:12][N:13]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH:14]=2)C=CC=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][N:25]=[CH:26]2>O1CCOCC1.CN(C=O)C>[CH:15]1([N:13]2[CH:14]=[C:10]([NH:9][C:8]([NH:20][C:21]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:22]=3[CH:23]=[CH:24][N:25]=[CH:26]4)=[O:19])[N:11]=[CH:12]2)[CH2:16][CH2:17][CH2:18]1
Reactant: O=C(Nc1cn(C2CCC2)cn1)Oc1ccccc1
Reactant: Nc1cccc2cnccc12
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(Nc1cn(C2CCC2)cn1)Nc1cccc2cnccc12
Temperature: 70 °C
Yield: 51.4 %

Procedure:
To a 1 dram vial with septa screw cap was added (1-cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester (Example 4, 50 mg, 0.19 mmol), 5-aminoisoquinoline (30 mg, 0.21 mmol), and 1:1 dioxane-DMF (1 mL). The reaction mixture was heated at 70° C. for 2 h. The reaction mixture was adsorbed onto silica gel and was purified by silica gel chromatography (40:1 chloroform-methanol) to afford 30 mg (52% yield) of 1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-yl-urea; 1H NMR (400 MHz, CD3OD) δ9.21 (d, J=1.7 Hz, 1H), 8.45 (d, J=6.2 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 7.98 (d, J=5.4 Hz, 1H), 7.84 (dd, J=2.3, 8.3 Hz, 1H), 7.66 (m, 1H), 7.54 (s, 1H), 7.12 (brs, 1H), 4.66 (m, 1H), 2.5-2.3 (m, 4H), 1.9 (m, 2H); MS (AP/Cl): 308.0 (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=O)[CH3:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:34][CH2:35][C@@H:36]([OH:53])[C@@H:37]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C>ClCCl>[OH:53][C@H:36]([CH2:35][NH:34][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([C:2]([CH3:3])=[CH2:1])[CH:5]=[N:6][CH:7]=1)[C@@H:37]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:49])[CH3:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Reactant: C=C(C)c1cncc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)c1cncc(C(=O)NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.5 %

Procedure:
To 5-(prop-1-en-2-yl)nicotinic acid (200 mg, 1.23 mmol) in dichlormethane (10 ml) at rt, EDCI (330 mg, 1.72 mmol) and HOBT (200 mg, 1.48 mmol) were added. After stirring at rt for 10 minutes, tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (344 mg, 1.23 mmol) was added followed by DIPEA (0.2 ml). After stirring overnight at rt, reaction mixture was worked up as usual and residue was column purified (90% ethylacetate/10% hexanes) to yield 280 mg of tert-butyl (2S,3R)-3-hydroxy-1-phenyl-4-(5-(prop-1-en-2-yl)nicotinamido)butan-2-ylcarbamate, which on stirring with 4N HCl in dioxane for 4 h yields the HCl salt of N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-5-(prop-1-en-2-yl)nicotinamide.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>C(O)(=O)C>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:22]=[CH:21][NH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: CC(C)(C)C1=CC(=Nc2cc[nH]n2)C=C(C(C)(C)C)C1=O
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A mixture of 5.3 g of 2,6-di-tert-butyl-1,4-benzoquinone, 2.1 g of 3-aminopyrazole and 16 drops of acetic acid was heated with stirring at 110° C for 15 minutes. The reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (eluent: diethyl ether-chloroform=1:20), giving 5.5 g of 2,6-di-tert-butyl-4-(3-pyrazolylimino)-2,5-cyclohexadien-1-one (Compound 34a) as a pale red solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([O:11][CH3:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].N1C=CN=C1.Cl[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([O:11][CH3:12])[C:5]=1[O:13][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:2]=[CH2:3]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=CCc1cc(Br)cc(OC)c1O
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1cc(Br)cc(OC)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
After dissolving 3 g of 2-allyl-4-bromo-6-methoxyphenol in 10 ml of DMF, 1.3 g of imidazole and 2 g of chlorotriisopropylsilane were added and the mixture was stirred at 50° C. for 4 hours. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give (2-allyl-4-bromo-6-methoxyphenoxy)triisopropylsilane.
Reaction SMILES: C(B(CC)OC)C.[BH4-].[Na+].[Cl:10][CH2:11][C@@H:12]([OH:22])[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1.CO>[Cl:10][CH2:11][C@@H:12]([OH:22])[CH2:13][C@@H:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(=O)C[C@H](O)CCl
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C[C@H](O)C[C@H](O)CCl
Reaction time: 2 h

Procedure:
Diethyl methoxy borane (88 ml) followed by sodium borohydride (16 grams) was added to a pre-cooled mixture of (S)-ethyl 6-chloro-5-hydroxy-3-oxohexanoate (110 grams) in tetrahydrofuran (550 ml) and methanol (220 ml) at −75° C. under nitrogen atmosphere and stirred for 2 hrs. The reaction mixture was quenched with 50% hydrogen peroxide at 0° C. The reaction mixture was extracted into methylene chloride and washed it with 10% sodium bicarbonate followed by saturated sodium chloride solution. The methylene chloride layer was dried with sodium sulfate and distilled off under reduced pressure to get the title compound.
Reaction SMILES: C(O[C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:13](=[O:32])[CH2:14][C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)[C@H:10]2[CH2:41][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[O-]CC.[Na+].Cl>C(O)C.C(OCC)(=O)C>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:12]2[C:13](=[O:32])[C:14]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][C:18]=4[S:17](=[O:31])(=[O:30])[N:16]=3)=[C:4]([OH:5])[C@H:6]3[C@@H:11]2[C@H:10]2[CH2:41][C@@H:7]3[CH2:8][CH2:9]2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 60 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of the crude (1S,2R,3S,4R)-3-{(4-fluorobenzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester in absolute ethanol (3 mL) was added a 21 wt. % solution of sodium ethoxide in ethanol (0.51 mL, 1.37 mmol). After stirring at 60° C. for 2 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 100% ethyl acetate in hexanes) to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (131.5 mg, 0.235 mmol, 68% over two steps), as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 1.28 (2H, d, J=11.0 Hz), 1.47 (1H, t, J=10.8 Hz), 1.57-1.74 (3H, m), 2.56 (1H, d, J=3.2 Hz), 2.75 (1H, d, J=2.3 Hz), 2.96 (1H, d, J=9.2 Hz), 3.02 (3H, s), 3.58 (1H, d, J=9.2 Hz), 4.42 (1H, d, J=15.5 Hz), 5.03 (1H, d, J=15.7 Hz), 7.04 (2H, t, J=8.5 Hz), 7.31 (2H, dd, J1=7.9 Hz, J2=5.5 Hz), 7.37 (1H, d, J=8.8 Hz), 7.54 (1H, dd, J1=8.3 Hz, J2=2.3 Hz), 7.69 (1H, d, J=2.3 Hz). LC-MS (ESI) calcd for C25H25FN4O6S2 560.12, found 561.4 [M+H+]. ee=98.5% [HPLC-analysis: Chiralpak AS-RH 2.1×150 mm, 5 micron at r.t., Solvent A-Solvent B (see table for gradient), 0.3 mL/min, 312 nm, t1=7.58 min (major), t2=8.95 min].
Reaction SMILES: [C:1]1(=[O:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.[BH4-].[Na+].O>CO>[CH:1]1([OH:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: O=C1CC2CCCc3cccc1c32
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1CC2CCCc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2a,3,4,5-Tetrahydro-2H-acenaphthylen-1-one (4.85 g) was dissolved in methanol (70 ml). Sodium borohydride (1.07 g) was added to the solution under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to give 2a,3,4,5-tetrahydro-2H-acenaphthylen-1-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:22][PH:23]([O-])([O-:27])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@:10]([NH:9][C@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:3]=[C:2]([P:23]([CH3:22])(=[O:27])[O:24][CH2:25][CH3:26])[CH:7]=[CH:6][CH:5]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccccc1)c1cccc(Br)c1
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1cccc([C@H](N[S@](=O)C(C)(C)C)c2ccccc2)c1
Reaction time: 8 h

Procedure:
To (R)—N—((R)-(3-bromophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, 24-c, (11.8 g, 32.3 mmol), ethyl methylphosphite (6.5 g, 64.6 mmol) and Et3N (9.09 g, 96.9 mmol) in THF (100 ml) was added PdCl2(dppf) (2.1 g, 3.23 mmol). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum to provide the crude product, 24-d, (15 g). The crude product was used to the next step directly.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[N:13][N+:14]([O-:16])=[O:15])[S:11][CH3:12])=[CH:4][CH:3]=1.C(#N)C.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10](=[N:13][N+:14]([O-:16])=[O:15])[S:11][CH3:12])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CSC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CSC(=N[N+](=O)[O-])N(Cc1ccc(Cl)nc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
To a mixture of N-(6-chloro-3-pyridylmethyl)-S-methyl-N'-nitroisothiourea (1.3 g) and acetonitrile (10 ml) was added pyridine (1.6 g) and further dropwise acetyl chloride (0.79 g) under ice-cooling. After stirring for 1 hour under ice-cooling, the mixture was warmed to room temperature and stirred at the same temperature for 2 hours. The reaction mixture was concentrated and 50 ml of ether and 5 ml of 2N hydrochloric acid were added to the mixture which was then partitioned. The resultant organic layers were dried over anhydrous magnesium sulfate and concentrated to afford 1.6 g of N-acetyl-N-(6-chloro-3-pyridylmethyl)-S-methyl-N'-nitroisothiourea as a red oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:20](B(O)O)[CH:21]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:20]([C:2]2[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=2)[CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: COCCOCOc1ccc(C(C)(C)C)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COCCOCOc1ccc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)nn1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
A mixture of 3-chloro-6-trifluoromethylpyridazine [purchased from Combi-Blocks] (250 mg, 1.37 mmol), (5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)phenyl)boronic acid [Intermediate 7] (463.8 mg, 1.64 mmol) and potassium carbonate (284.5 mg, 2.06 mmol) in dimethoxyethane (7.5 mL) and water (2.5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (79.1 mg, 0.068 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 22 hours. The cooled reaction mixture was partitioned between ethyl acetate (50 mL) and 10% aqueous sodium carbonate solution (50 mL), the organic phase separated, washed with water (50 mL) and saturated brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a brown syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 30% ethyl acetate in hexanes to give 3-(5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)phenyl)-6-(trifluoromethyl)pyridazine (0.462 g, 88% yield) as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7](OS(C(F)(F)F)(=O)=O)[C:6]([C:21]#[N:22])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:6]([C:21]#[N:22])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1CCNCC1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc2c(F)cc(Cl)cc2c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(N2CCCCC2)nc2c(F)cc(Cl)cc2c1-c1ccccc1
Temperature: 70 °C
Yield: 37.4 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 6-chloro-3-cyano-8-fluoro-4-phenyl-quinolin-2-yl ester (189 mg, 0.439 mmol), piperidine (150 mg, 174 μl, 1.76 mmol) and potassium carbonate (121 mg, 0.878 mmol) in THF (6 ml) was heated to 70° C. for 60 min. The yellow suspension was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was triturated with dichloromethane and the off-white solid was filtered off. The filtrate was evaporated and the remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 98:2-95:5) to afford the title compound (60 mg, 37%) as yellow solid. MS (ESI): 366.4 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=3[N:9]=2)[CH2:4][C@H:3]1[O:21][CH3:22].[Cl:23][C:24]1[N:25]=[C:26]([C:31](O)=[O:32])[NH:27][C:28]=1[CH2:29][CH3:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:23][C:24]1[N:25]=[C:26]([C:31]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=4[N:9]=3)[CH2:4][C@H:3]2[O:21][CH3:22])=[O:32])[NH:27][C:28]=1[CH2:29][CH3:30]
Reactant: COC(=O)c1cccc2[nH]c(N3CC[C@H](N)[C@H](OC)C3)nc12
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4c(C(=O)OC)cccc4[nH]3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-1H-benzimidazole-4-carboxylate obtained in Example (187c) (220 mg, 0.75 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (130 mg, 0.75 mmol) were dissolved in DMA (5 ml). WSC hydrochloride (580 mg, 3 mmol) and HOBt (100 mg, 0.75 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/hexane solvent to obtain the title compound as crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=O)=[CH:10][CH:9]=2)[CH:2]=1.I.CS[C:21](=[NH:34])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=1>N1C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:21]2[NH:34][C:12]([C:11]3[CH:16]=[CH:17][C:8]([O:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:9][CH:10]=3)=[N:14][N:15]=2)=[CH:24][C:25]=1[C:30]([F:31])([F:32])[F:33]
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NNC(=O)c1ccc(Oc2cccnc2)cc1
Agent: I
Solvent: c1ccncc1
Product: FC(F)(F)c1cc(Nc2nnc(-c3ccc(Oc4cccnc4)cc3)[nH]2)ccc1Cl
Yield: 12.7 %

Procedure:
4-(pyridine-3-yloxy)benzohydrazide (2.33 g, 10.2 mmol) was dissolved in ca. 70 mL of anhydrous pyridine and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl] isothiourea hydroiodide (4.04 g, 10.2 mmol) was added. The reaction mixture was refluxed for 18 hrs under Ar. The pyridine was removed in vacuo and the resulting residue was purified by silica gel chromatography using EtOAc as eluent to give the title product (0.56 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:27]=O)[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH2:33])[CH2:31][CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([O:8][C:9](=[O:29])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH2:27][NH:33][CH2:30][CH2:31][CH3:32])[CH:19]=2)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: O=Cc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 8 h

Procedure:
A mixture of [3-(3-formyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzyl ester (0.038 mol) in DCE (300 mL) was cooled in an ice bath to 15° C., then propylamine (0.042 mol), followed by NaBH(OAc)3 (0.057 mol) which was added portionwise. The reaction mixture was stirred overnight at room temperature and the mixture was washed with a saturated NaHCO3 solution. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: 90:10 CH2Cl2:CH3OH). The product fractions were collected and the solvent was evaporated, then co-evaporated with toluene to yield the title compound as a residue.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2OC(=O)C=Cc2ccccc2)c(O)c(C(C)(C)C)c1
Yield: 86 %

Procedure:
To the same flask as used in Example 6 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 151.18 g (1.0 mole) of cinnamic acid, 500 g of toluene and 118.65 g (1.5 moles) of pyridine. After replacing the air in the container with nitrogen, 286.43 g (1.5 moles) of p-toluenesulfonyl chloride was added little by little with stirring. After completion of the addition, temperature maintenance and after-treatment were carried out in the same manner as in Example 6, and the residue was recrytallized from toluene to obtain 404.8 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monocinnamoate having a melting point of 164° to 169° C. Yield, 86%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[N:25][O:26][CH2:27][CH3:28])[CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O.NN.O>C(O)C>[CH2:27]([O:26][N:25]=[C:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1)[CH2:13][NH2:14])[CH3:28]
Reactant: CCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCON=C(CN)c1ncc(C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To 111 mg of N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(ethoxyimino)ethyl]phthalimide in 3 ml of ethanol, 86 mg of hydrazine monohydrate was added, and the mixture was stirred at 80° C. for 1 hour. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3). The resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using methanol-chloroform (1:10) as the eluent to obtain 47 mg of the desired product as a yellow oil. The oil was used in the next step without further purification.