Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-])=O.C(N(CC)CC)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33](Cl)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1.Cl>C1COCC1.CO>[CH:7]([C:6]1[CH:5]=[C:4]([NH:1][C:33]([C:28]2[C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:22][CH:23]=3)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH:11]=[CH:10][CH:9]=1)=[O:8]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=Cc1cccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 mL round bottom flask was charged with 3-nitrobenzaldehyde (5.20 g, 34.4 mmol), 100 mL methanol, and Dowex® sulfonic acid resin (e.g., Dowex 50WX4-400, Aldrich catalogue number 21-784-4) in its H+ form (0.57 g), washed with two 5 mL portions of methanol and added as a slurry in 5 mL of methanol. The resulting slurry was heated at reflux for 90 minutes, then stirred overnight at ambient temperature (1H NMR analysis of an aliquot showed a 95:5 ratio of the dimethyl acetal to starting aldehyde). The resin was removed by filtration, and the filtrate concentrated to a pale yellow oil. The acetal was dissolved in 100 mL THF and 10% Pd/C was added (0.52 g). The mixture was placed in a Parr® hydrogenator under 276 kPa (40 psi) hydrogen pressure). After 90 minutes, and three recharges of hydrogen, the pressure of hydrogen held steady and the reaction vessel mixture was purged with nitrogen. The catalyst was removed by filtration through Celite®, and rinsed with four 50 mL portions of THF. The filtrate was treated with triethylamine (10.6 mL, 76 mmol) followed by 4'-trifluoromethyl-biphenyl-2-carboxylic acid chloride (9.8 g, 34 mmol) added, as a solution in 10 mL THF, dropwise over 15 minutes. The resulting slurry was stirred for 20 hours at ambient temperature. 1 N HCl (aqueous) (100 mL) was then added and the mixture was stirred vigorously for 2 hours. The bulk of the THF was then removed on a rotary evaporator. The aqueous layer was extracted with three 50 mL portions of isopropyl ether/ethyl acetate (3:1 v/v). The combined organic extracts were washed twice with 1 N HCl [aq], two times with saturated aqueous NaHCO3 and once with brine, and then dried over MgSO4, filtered, and concentrated to give a white solid. Recrystallization from 4:1 hexanes ethyl acetate (250 mL) provided the title product as a powdery, white solid (10.5 g, 83% yield). 1H NMR: (CDCl3): δ 9.92 (s, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.69-7.67 (m, 3H), 7.62-7.52 (m, 5H), 7.46-7.42 (m, 3H), 7.06 (br s, 1H). MS (electron impact): 369 (M+, 20), 249 (100).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[NH:37])[NH2:36])=[CH:31][CH:30]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35](=[NH:36])[NH2:37])=[CH:33][CH:34]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[(4-amidinophenyl)-oxymethyl]-5-[N-(ethoxycarbonylmethyl)-benzenesulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][C:36]1([CH3:45])[CH2:41][CH:40]([NH2:42])[CH2:39][C:38]([CH3:44])([CH3:43])[NH:37]1>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH:40]3[CH2:41][C:36]([CH3:45])([CH3:35])[NH:37][C:38]([CH3:44])([CH3:43])[CH2:39]3)[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Yield: 29 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) and 2,2,6,6-tetramethyl-4-piperidinamine (0.30 g, 1.9 mmol) the title compound was obtained (0.035 g, 0.054 mmol, 29% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 8.95-8.72 (m, 1H), 8.20 (d, J=4.9 Hz, 1H), 7.95-7.72 (m, 1H), 7.72-7.20 (m, 6H), 6.43-6.20 (m, 1H), 2.05 (d, J=12.8 Hz, 2H), 1.75-1.27 (m, 22H). MS (ESI): 645 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[NH:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:7](=[S:30])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)Nc1cc(OC)c(OC)c(OC)c1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(=S)Nc1cc(OC)c(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Ethyl 3,4,5-trimethoxyoxanilate (3.0 g) was dissolved in benzene (20 mL), and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.14 g) was added to the solution. The reaction mixture was stirred at 80° C. for 1 hour, and water was added thereto. After conducting extraction with ethyl acetate, the resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH:7]=[CH:8][CH3:9])[OH:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH3:9])[CH:10]=[C:1]([O:11][CH3:12])[C:2]=1[OH:3])(=[O:15])[CH3:14]
Reactant: CC=Cc1ccc(O)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC=Cc1cc(OC)c(O)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of isoeugenol (344 g., 2.1 moles) in 420 ml. of pyridine under nitrogen atmosphere is added 428 ml. of acetic anhydride over a period of 30 minutes. The resulting solution is stirred at room temperature overnight followed by treatment with ice-water (1400 ml.). After stirring for three hours, the resulting precipitate is filtered, washed with water (3×500 ml.) and dried in vacuo to give 381.7 g. of crude product. Acetyl isoeugenol (269 g., 62%) is obtained from washing the crude product with n-hexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:19]#[N:20])([N:12](CC=C)CC=C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CC(=O)N(C)C1=O.C(=O)(O)[O-].[Na+]>ClCCl.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:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([NH2:12])([C:19]#[N:20])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCN(CC=C)C1(C#N)CN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(N)(C#N)C1
Yield: 96 %

Procedure:
A solution of 3-cyano-3-diallylamino-azetidine 1-carboxylic acid tert-butyl ester (143.5 mg, 0.5174 mmol), 1,3-dimethylbarbituric acid (242.5 mg, 1.553 mmol) and tetrakis(triphenylphosphine)palladium(0) (30.3 mg, 0.0262 mmol) in dichloromethane (1.3 ml) was stirred at 40° C. for five hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-amino-3-cyano-azetidine-1-carboxylic acid tert-butyl ester (98 mg, 96%).
Reaction SMILES: [N+:1]([C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:5][CH2:6][OH:7])([O-:3])=[O:2].C(N(CC)CC)C.[F:21][C:22]([F:45])([C:26]([F:44])([F:43])[C:27]([F:42])([F:41])[C:28]([F:40])([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:23](Cl)=[O:24]>C1(C)C=CC=CC=1.CCOCC.C(O)C>[F:21][C:22]([F:45])([C:26]([F:43])([F:44])[C:27]([F:41])([F:42])[C:28]([F:39])([F:40])[C:29]([F:37])([F:38])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:23]([O:7][CH2:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:24]
Reactant: O=[N+]([O-])C(=CCO)c1ccccc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(OCC=C(c1ccccc1)[N+](=O)[O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
βNitrocinnamyl alcohol (5.4 g, 0.03 mol) and one equivalent of triethylamine (3.03 g, 0.03 mol) were dissolved in 100 ml of toluene. The solution was cooled in an ice bath and perfluorooctanoyl chloride (12.6 g, 0.03 mol) was added dropwise with stirring. The reaction was stirred an additional two hours and diluted with ether. The reaction was extracted with water and the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily product was crystallized from petroleum ether to give yellow prisms, mp 79°-81°, IR 1785, 1655, 1535, 1325, and 1200 cm-1. A solution of the material in 95% ethanol showed an absorption of λmax at 302 nm, epsilon=10,800 which rapidly decreased on exposure to the GE H3T7 source. This loss of the 302 nm absorption was accompanied by a decrease in the pH (increased acidity) of the solution as as indicated by methyl red pH indicator.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([OH:13])=[O:12])[NH:2]1.[OH-].[Na+].[C:16]([S:24][CH2:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CCOCC>[C:16]([S:24][CH2:25][CH:26]([CH3:30])[C:27]([N:2]1[CH:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(CSC(=O)c1ccccc1)C(=O)N1Cc2ccccc2CC1C(=O)O
Temperature: 5 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of (-)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (7.0 g., 0.04 M) and sodium hydroxide (1.6 g., 0.04 M) in water (160 ml.) at 10° C. was slowly added (-)-3-benzoylthio-2-methylpropionyl chloride (9.7 g., 0.04 M). At the same time, from a separate dropping funnel, was added a solution of sodium hydroxide (1.6 g., 0.04 M) in water (15 ml), at such a rate that the solution was maintained at a pH between 9.5 and 7.5 pH units (final pH 7.5). After stirring overnight at 5° C., the reaction mixture was filtered and the clear filtrate acidified with dilute hydrochloric acid. The product was extracted into methylene chichloride, washed and dried over sodium sulfate. After filtration the solvent was removed by evaporation at reduced pressure, leaving a residue (14 g.). This material was separated on an HPLC preparative column (Prep Pak C18 column, Waters) using a mobile phase of 50 parts methanol, 50 parts water and 0.5 parts acetic acid. Two main fractions were obtained, 15% and 84%. The residue from the major fraction was dissolved in ether, washed and dried over sodium sulfate. After filtration the solvent was removed by evaporation at reduced pressure, leaving a white solid, the title compound (10 g.), m.p. 61-63, [α]D25 =-76.39 (C=1.55% EtOH.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C>C1COCC1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([B:24]([OH:25])[OH:23])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(Oc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To a solution of 4-phenoxybromobenzene (98.2 g, 0.39 mol) in dry THF (800 mL) under nitrogen at −78° C. was added n-BuLi (2.5M solution in hexanes) (172 mL, 0.43 mol) dropwise. A temperature rise to −65° C. was observed. On complete addition, the mixture was allowed to stir at −78° C. for 15 min. Triisopropylborate (109.2 mL, 0.473 mol) was added dropwise over 30 min. On complete addition, a suspension was observed. The mixture was allowed to warm to 0° C. over 1 hr, stirred at 0° C. for 4 hrs. The reaction was quenched by the dropwise addition of water (300 mL) such that the internal temperature <20° C. (ice-cooling required). The mixture was allowed to warm to room temperature overnight then evaporated to dryness. The residue was suspended in water (600 mL) and acidified by the cautious addition of conc. HCl. The resulting precipitate was collected by filtration and dried in vacuo at 45° C. The solid was ground to a fine powder and triturated with petroleum ether (40-60° C.). The pale solid was filtered and dried to give 4-phenoxyphenylboronic acid(68.8 g, 83%). 1H NMR (250 MHz, d6-DMSO):7.99 (1H, m), 7.91 (1H, t), 7.83 (1H, d), 7.4 (2H, m), 7.14 (1H, m), 6.92-7.07 (5H, m). Microanalysis:Req. C(71.4%), H(5.45%), Found C(70.25%), H(4.7%)
Reaction SMILES: [OH:1][CH:2]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:31]([O:35]CC)(=O)[CH2:32][OH:33]>C1(C)C=CC=CC=1>[CH2:19]([N:18]([CH2:17][CH:2]([OH:1])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:32](=[O:33])[CH2:31][OH:35])[C:32](=[O:33])[CH2:31][OH:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCNCC(O)CNCCCCCCCCCCCC
Reactant: CCOC(=O)CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN(CC(O)CN(CCCCCCCCCCCC)C(=O)CO)C(=O)CO
Temperature: 100 °C
Reaction time: 7.5 h
Yield: 79.8 %

Procedure:
A reactor was charged with 10.7 g (0.03 mole) of 15-hydroxy-13,17-diazanonacosan, 50 ml of toluene and 7.1 ml (0.07 mole) of ethyl glycolate, and the contents were heated to 100° C. and continuously stirred for 7.5 hours while purging ethanol formed with a nitrogen stream. After completion of a reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (on 200 g of silica gel, developing solvent: chloroform/methanol=100/1), thereby obtaining 13 g (yield: 96%) of the title compound as a viscous liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25](O)=[O:26])=[N:17]1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:25]([C:18]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:16][N:17]=2)=[O:26])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: O=C(O)c1noc2ccccc12
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2noc3ccccc23)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with benzo[d]isoxazole-3-carboxylic acid. LC-MS (acidic): tR=0.92 min; [M+H]+=358.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>C(Cl)Cl.CN(C=O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([NH:37][CH2:36][C:35]1[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:40])[F:41])=[CH:39][CH:38]=1)=[O:7])(=[O:14])[CH3:13]
Reactant: COc1ccc(C(C)=O)cc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(C(C)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-Methoxy-5-acetylbenzoic acid (Step B, 2.5 g, 12.8 mmol), HOBt.H2O (2.08 g, 15.4 mmol), and EDC (3.70 g, 19.3 mmol) in CH2Cl2 (20 ml) and DMF (5 ml) was added 4-(Trifluoromethyl)benzylamine (2.48 g, 14.1 mmol), and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and then redissolved in ethyl acetate. The organic layer was washed with 3% K2CO3, 1 N HCl, and brine, dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on silica gel column (chloroform:methanol 95:5) to provide the title compound as white solid.
Reaction SMILES: C([O-])=O.[NH4+:4].[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)[CH3:6].C(O)(=O)C>[Ir].CO>[CH3:6][CH:5]([NH2:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccccc1
Reactant: [NH4+]
Agent: [Ir]
Agent: O=C[O-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)c1ccccc1
Temperature: 60 °C

Procedure:
946 mg (15.0 mmol) of ammonium formate (MW: 63.06) was introduced in a 20-mL Schlenk tube and subjected to argon-gas replacement. To this, 5 mL of dehydrated methanol, 582 μL (5.0 mmol) of acetophenone (MW: 120.15), 582 μL (5.0 mmol) of acetic acid, and 12.1 mg (0.025 mmol, S/C=200) of the iridium catalyst Ir-1 (MW: 484.01) were added, and the mixture was stirred while heating at 60° C. for 5 hr. After distillation of the solvent, a saturated sodium hydrogen carbonate solution was added, then a product was extracted with methylene chloride, the organic layer was washed with water, and the product was dried with sodium sulfate. The drying agent was removed by filtration and the methylene chloride was distilled away to give a crude product DL-1-phenylethylamine. Its conversion rate was 100% based on NMR measurement, with 92.8% of DL-1-phenylethylamine, 0.4% of 1-phenylethanol, and 6.8% of other by-products.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH3:35])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH3:35])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(4-methyl-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (27 mg, 55.6 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (127 mg, 85.7 μL, 1.11 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo and then the residue was diluted with dichloromethane and 25% aqueous NH4OH. The mixture was washed with water (2×), then the organic phase was collected, concentrated in vacuo, and purified by chromatography (silica, 1 to 10% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (7 mg, 18.2 μmol, 33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.61 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 6.98 (d, J=5.8 Hz, 1H), 6.71 (s, 1H), 6.61 (s, 1H), 4.08 (q, J=5.5 Hz, 1H), 3.92 (d, J=9.9 Hz, 1H), 3.81 (d, J=12.2 Hz, 1H), 3.59 (d, J=11.7 Hz, 1H), 3.47 (t, J=11.8 Hz, 1H), 3.28 (s, 1H), 3.17 (d, J=5.0 Hz, 2H), 2.67 (t, J=7.8 Hz, 1H), 2.33 (s, 1H), 2.26 (s, 3H), 1.72 (m, 3H), 1.23 (s, 1H), 0.93 (t, J=7.4 Hz, 3H); MS (EI/CI) m/z: 386.2 [M+H].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[N:19]=[CH:18][C:17]=2[N:31]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32]2)[CH2:9]1)=O)(C)(C)C>CO>[C:29]([C:26]1[N:27]=[CH:28][C:23]([NH:22][C:20]2[N:19]=[CH:18][C:17]([N:31]3[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32]3)=[C:16]([NH:15][CH2:14][CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:21]=2)=[N:24][CH:25]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C(=O)O)c2)C1
Solvent: CO
Product: N#Cc1cnc(Nc2cc(NCC3CCCNC3)c(-n3ccc(C(=O)O)c3)cn2)cn1

Procedure:
1-(4-((1-(tert-Butoxycarbonyl)piperidin-3-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (7 mg, 0.013 mmol) was dissolved in methanol (1 mL) and absorbed onto a TsOH solid phase extraction cartridge cartridge. After 1.5 h the cartridge was eluted with 7M ammonia in methanol. The eluent was evaporated to dryness to give 1-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([F:19])[CH:21]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(B(O)O)cc1F
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)c(F)c3)cccc2c1N
Yield: 78.5 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 3-fluoro-4-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (135 mg, 78% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.57 (br, 1H), 7.88-7.66 (m, 3H), 7.52-7.41 (m, 2H), 7.10(m, 1H), 3.96 (s, 3H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 1.67 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H). HPLC 1.76 min.