Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[Cl:9].[CH3:10][S-:11].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:11][CH3:10])=[CH:4][C:3]=1[Cl:9]
Reactant: C[S-]
Reactant: Fc1ccc(Br)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(Br)c(Cl)c1
Yield: 109.2 %

Procedure:
A solution of 1-bromo-2-chloro-4-fluorobenzene (7, 0.50 g, 2.39 mmol) and sodium thiomethoxide (0.17 g, 2.42 mmol) in DMSO (2.5 mL) was stirred at 100° C. for 1 h. The reaction mixture was added to 20 mL water with stirring, the aqueous mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo. The title compound (0.62 g) was obtained as a colorless oil and was used in the next step without further purification.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C[O-].[Na+].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH2:23][NH:24][C:25](=[O:28])[CH2:26]Cl)[CH:20]=[CH:21][CH:22]=1.C(O)(=O)C>CO.O>[OH:10][C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:26]=1[C:25]([NH:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=1)=[O:28]
Reactant: O=C(CCl)NCc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccccc1S
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1sc2ccccc2c1O
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a solution of methyl thiosalicylate (0.67 g; 0.004M) in 20 ml of methanol is added solid sodium methoxide (0.65 g; 0.012M; 3 eqv.) followed by N-[(3-trifluoromethylphenyl)methyl]-chloroacetamide (1.0 g; 0.004M) and the mixture is refluxed under a nitrogen atmosphere for 30 minutes. The mixture is cooled to room temperature and added to a solution of 1.5 ml of glacial acetic acid in 25 ml of water and cooled to 0° C. The cream colored solid is collected, washed with 50% methanol-water, air dried, and recrystallized from nitromethane to give 1.05 g (78% yield) of the title compound; m.p. 139°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:38])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]=2[C:34](Cl)=[O:35])=[C:19]([Cl:37])[CH:18]=1.O>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15](=[O:38])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]=2[C:34](=[O:35])[NH:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])=[C:19]([Cl:37])[CH:18]=1
Reactant: COC(=O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)Cl)c(Cl)c1
Reactant: NCCOc1ccc(Cl)cc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(2,4-Dichloro-phenoxy)-ethylamine 29 (19 mg, 0.09 mmol) in toluene (0.2 mL) is cooled to 0° C. The above solution of intermediate 61 (0.06 mmol) is added and the solution is warmed to room temperature. After stirring at room temperature for 1 hour the mixture is poured into H2O and extracted three times with DCM. The organic layers are combined, dried (MgSO4), filtered, and concentrated to afford crude (3-Chloro-4-{4-[2-(2,4-dichloro-phenoxy)-ethyl-carbamoyl]-3-phenyl-isoxazol-5-yl}-phenyl)-acetic acid methyl ester 62.
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][C@@:11]([CH3:37])([OH:36])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[CH3:37][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[O:36][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCN(C2CCN(c3ccc(OC(F)(F)F)cc3)CC2)CC1)Cn1cc([N+](=O)[O-])nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@]1(CN2CCN(C3CCN(c4ccc(OC(F)(F)F)cc4)CC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
(S)-1-(2-bromo-4-nitroimidazol-1-yl)-2-methyl-3-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazin-1-yl}propan-2-ol (790 mg, 1.34 mmol) was dissolved in N,N-dimethylformamide (4 ml), sodium hydride (69 mg, 1.74 mmol) was added while cooling on ice, and the solution was stirred at the same temperature for 1 hour. To the reaction mixture, ethyl acetate (1.3 ml) and water (10 ml) were added in this order, and the precipitated crystals were filtered off and washed with water. The crystals were purified by silica gel column chromatography (methylene chloride/methanol=10/1) and recrystallized from ethyl acetate/isopropyl ether to obtain (S)-2-methyl-6-nitro-2-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazin-1-ylmethyl}-2,3-dihydroimidazo[2,1-b]oxazole (270 mg, yield 40%) as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[O:11].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].CN([CH:30]=[O:31])C>>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:10]([C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH:30]=[O:31])=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])[CH2:17][CH2:16]1
Reactant: CN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C(=O)c2[nH]c3ccccc3c2C=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 4, 0.206 g) in DMF (1.5 mL) at 0° C. was treated with phosphorus oxychloride (0.1 mL) over 10 min. The reaction mixture was warmed to ambient temperature and stirred for 16 h. The reaction mixture was poured into water and adjusted to neutral pH by addition of 1 M sodium hydroxide. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane afforded the title compound (0.108 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15]([O:17]CC)=[O:16])[CH2:7][C:6]12[CH2:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20]1.[OH-:28].[K+].[CH2:30]([OH:33])[CH2:31][CH3:32]>O>[C:15]([OH:17])(=[O:16])/[CH:32]=[CH:31]\[C:30]([OH:28])=[O:33].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][C:6]12[CH2:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20]1
Reactant: [OH-]
Reactant: CCOC(=O)N1Cc2cc(OC)c(OC)cc2C2(Cc3ccccc3O2)C1
Reactant: CCCO
Agent: [K+]
Solvent: O
Product: COc1cc2c(cc1OC)C1(CNC2)Cc2ccccc2O1
Product: O=C(O)/C=C\C(=O)O
Yield: 81 %

Procedure:
A mixture of 6',7'-dimethoxy-2'-ethoxycarbonylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (4.2 g), potassium hydroxide (7.0 g) and water (7.0 ml) in n-propanol (150 ml) is heated under reflux for four hours. Removal of the solvent under reduced pressure yields an oil which is stirred in water (300 ml) and then extracted with chloroform. The combined organic phases are washed with water, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is removed to yield 3.1 g (81%) of product as an oil which is dissolved in ether and converted to the maleate salt (1.9 g), mp 165°-167°. The material is twice recrystallized from ethyl acetate/methanol to yield a white solid (1.4 g), mp 180°-181° (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]=O)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([CH3:24])([CH3:23])[NH2:22])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([NH:22][CH2:10][CH:8]([OH:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([CH3:23])[CH3:24])=[CH:15][CH:14]=1
Reactant: O=CC(=O)c1cccc(Cl)c1
Reactant: Cc1ccc(CCC(C)(C)N)cc1
Product: Cc1ccc(CCC(C)(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using 3-chlorophenylglyoxal and 3-(4-methylphenyl)-1,1-dimethylpropanamine. The chromatographed material was recrystallized from cyclohexane to give the title compound m.p. 136. τ(CDCL3 +d6DMSO) 8.9 (6H, s), 8.2-8.4 (2H, m), 7.7 (3H, s), 7.0-7.6 (4H, m), 5.35 (1H, dd), 2.9 (4H, s), 2.5-2.7 (5H, m).
Reaction SMILES: P(=O)(O)(O)O.C([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])CCC.Cl[C:20]1C=CC(C([C@@]2(O)[C@](C(=O)C3C=CC(Cl)=CC=3)(O)[C@@H](COC(=O)C3C=CC(Cl)=CC=3)O[C@@H]2Cl)=O)=C[CH:21]=1.[CH2:56](C(C)=O)[CH:57](C)C>>[CH:15]1([NH:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:57][CH2:56]2)[CH2:16][CH2:17][CH2:18][CH2:21][CH2:20]1
Reactant: CCCCN(CCCC)CCCC
Reactant: O=C(OC[C@H]1O[C@H](Cl)[C@@](O)(C(=O)c2ccc(Cl)cc2)[C@@]1(O)C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(=O)CC(C)C
Agent: O=P(O)(O)O
Product: C1CCC(NC2CCCCC2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a mixture of 3.32 g of orthophosphoric acid in 67 mL of methyl isobutyl ketone were added 2.11 g of tri-n-butylamine and 6.6 g of molecular sieves 4A, and the mixture was cooled to 5° C. with stirring. To the mixture was added 6.66 g of 2,3,5-O-tris(4-chlorobenzoyl)-α-D-ribosyl chloride. After 1 hour, precipitation of crystals initiated and then a thick suspension was provided. After 10 hours, the ratio of α-form/β-form for compound (19) in the reaction suspension was 10:1. To the suspension was added 6.33 g of tri-n-butylamine to dissolve the precipitated crystals and molecular sieves were removed by filtration. The filtrate was washed with 55 mL of water. The organic layer was ice-cooled. To the mixture was added 2.4 g of cyclohexylamine for crystallization with stirring. After 1 hour, the precipitated crystals were collected by filtration and dried in vacuo at room temperature to provide 7.02 g of a dicyclohexylamine salt of compound (21) as a colorless powder (Yield: 73.0%; α-form:β-form =99:1).
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.N=O.[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18]>>[OH:3][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([O:12][CH2:18][C:17]([OH:21])([CH3:20])[CH3:19])[C:6]([CH3:14])([CH3:13])[CH2:5]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: N=O
Agent: OO
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 50 °C

Procedure:
A solution of 50.7 g (0.75 mol) of 50% aqueous hydrogen peroxide mixed with 25 mL of tert-butyl alcohol is added over two hours to a mixture of 25.8 g (0.15 mol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 8.95 g (0.045 mol) of ferrous chloride tetrahydrate and 110 mL of tert-butyl alcohol at 50° C. The reaction mixture is then maintained at 50° C. for six hours and monitored by gas chromatography. Another 17.7 g (0.26 mol) of 50% hydrogen peroxide is added and the reaction mixture is heated at 50° C. for two more hours to bring about complete reaction of the starting nitroxyl compound. The reaction mixture is filtered to remove solids, and the filtrate is diluted with water. The tert-butyl alcohol-water solution is extracted three times with methylene chloride and the aqueous layer is thoroughly extracted with ethyl acetate to afford 7.4 g of the title compound. The combined organic layers are washed once with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give 21.7 g of an orange oil. The orange oil is purified by flash chromatography on silica gel with 3:2 heptane:ethyl acetate to afford another 12.4 g of the title compound and 4.2 g of a compound which has the same retention time by gas chromatography as an authenic sample of 1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidin-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:11]1([S:14](Cl)(=[O:16])=[O:15])[CH2:13][CH2:12]1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][S:14]([CH:11]2[CH2:13][CH2:12]2)(=[O:16])=[O:15])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1ncc(Br)cc1N
Agent: Cl
Solvent: c1ccncc1
Product: COc1ncc(Br)cc1NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
5-Bromo-2-(methyloxy)-3-pyridinamine (1.05 g, 5.17 mmol, available from Asymchem) was dissolved in pyridine (10 ml) and cyclopropanesulfonyl chloride (1.818 g, 12.93 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight, then acidified to ca. pH 2 with 2M HCl (aq) and extracted into DCM. The DCM was passed through a hydrophobic frit and the filtrate was evaporated to dryness to afford the title compound (1.48 g).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]=[O:7].[N+:13]([CH3:16])([O-:15])=[O:14].C(O)(=O)C>CO.C(OCC)C>[F:3][C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]([OH:7])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc(F)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])CC(O)c1cc(F)ccc1F

Procedure:
To sodium hydroxide (1N, 3 L) and methanol (1500 mL) at 5° C. was added a solution of 2,5-difluorobenzaldehyde (350 g, 2.46 mol) and nitromethane (157 mL, 2.9 mol) in methanol (350 mL) dropwise over a period of 1 h. The reaction mixture was then neutralized with glacial acetic acid (165 mL). Diethyl ether (1500 mL) was added and the layers separated. The organic layer was washed successively with saturated aqueous sodium carbonate solution (1000 mL), and saturated aqueous brine (1000 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to afford 1-(2,5-difluorophenyl)-2-nitroethanol that was used without further purification in Step B.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)([CH3:4])([CH3:3])[CH3:2].[C:12](O)(=O)C.[CH:16]([NH2:18])=[NH:17]>C(O)CCC>[C:1]([CH:5]1[C:6]2[N:18]=[CH:16][N:17]=[CH:12][C:7]=2[CH2:8][CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCCCC1=O
Reactant: N=CN
Reactant: CC(=O)O
Solvent: CCCCO
Product: CC(C)(C)C1CCCc2cncnc21
Temperature: 130 °C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
A 100 mL reaction flask is charged with 2-tert-butyl-cyclohexanone (10 g, 0.07 mol), formamidine acetate (40 g, 0.4 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 8-tert-butyl-5,6,7,8-tetrahydro-quinazoline (˜5 g) is obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](ON3C(=O)CCC3=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:26][CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1.Cl>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:26][CH2:27][C@H:28]3[CH2:29][CH2:30][C@H:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
A solution of N-(9-fluorenylmethoxycarbonyloxy)succinimide (4.4 g; 14.0 mmol) in 1,4-dioxane (40 mL) was added dropwise to a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (2.0 g; 12.7 mmol) in 10% Na2CO3 (30 mL) cooled to 0° C. The mixture was then allowed to warm to ambient temperature and after 1 h stirring at room temperature was treated with 1 N HCl (32 mL) until the final pH was 2. The resulting solution was extracted with n-BuOH (100 mL); the volatiles were removed and the crude residue was purified by flash chromatography to give D as a white solid (1.6 g; 4.2 mmol). Yield 33%.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C@@H:2]2[CH2:7][CH2:6][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[NH:10][C:9]3=[O:17])[CH2:4][CH2:3]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN([C@H]2CC[C@@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.3 %

Procedure:
A mixture of 1.5 g of 1,3-dihydro-1-(4-oxocyclohexyl)-2H-benzimidazol-2-one, 1.21 g of tert-butyl-1-piperazinecarboxylate, 20 mL of 1,2-dichloroethane, 0.4 mL of acetic acid and 1.8 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×250 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with 90:10 CHCl3 : MeOH gave 0.631 g of cis-1,3-dihydro-1-{4-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as white solid: mp=228°-30° C.; 1H NMR (400 MHz, CDCl3) 7.45 (m, 1H), 7.14 (m, 1H), 7.05 (m, 2H), 3.55 (br s, 4H), 2.49 (br s, 6H), 2.27 (s, 1H), 2.15 (br d, J=15.1, 2H), 1.58 (br d, J=10.6, 4H), 1.49 (s, 9H); followed by 0.52 g of trans-1,3-dihydro-1-{4-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as white solid: mp=195°-6° C.; 1H NMR (400 MHz, CDCl3) 7.14 (m, 2H), 7.12-7.04 (m, 2H), 4.28 (m, 1H), 3.46 (br s, 4H), 2.56 (br s, 5H), 2.49 (m, 1H), 2.29 (q, 2H), 2.06 (d, J=6.4, 2H), 2.0 (d, J=9, 2H), 1.52 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[C:25]([C:32]#[N:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(=N[OH:39])C.[Cl-].[In+3].[Cl-].[Cl-].CCOC(C)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[C:25]([C:32]([NH2:33])=[O:39])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5cccnc54)c3CO)ncc2c1
Reactant: CC=NO
Agent: [Cl-]
Agent: [In+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5cccnc54)c3CO)ncc2c1
Reaction time: 3 h
Yield: 17.4 %

Procedure:
A stirred solution of 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (610 mg, 783 μmol, Eq: 1.00), acetaldoxime (139 mg, 143 μl, 2.35 mmol, Eq: 3) and indium (III) chloride (8.66 mg, 39.1 μmol, Eq: 0.05) in toluene (25.2 ml) was heated to 110° C. and stirred for 3 h. The reaction mixture was poured into 15 mL EtOAc and extracted with sat NH4Cl (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. After removal of solvent and residue was separated by flash chromatography (silica gel, 12 g, 80% to 100% EtOAc in hexanes) gave 66 mgs of desired product with impurity. This material was re-purified by preparative reverphase HPLC in TFA. The desired product was neutralized with NaHCO3 (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo., extracted with ethyl acetate/methanol (9:1) to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (43 mgs, 12%) as white solid. 1H NMR (DMSO-d6) δ: 8.64 (dd, J=7.9, 1.6 Hz, 1H), 8.60 (d, J=2.5 Hz, 1H), 8.45 (s, 1H), 8.36 (dd, J=4.8, 1.8 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.82 (dd, J=13.2, 1.6 Hz, 1H), 7.66-7.78 (m, 3H), 7.63 (dd, J=7.3, 2.3 Hz, 1H), 7.36 (dd, J=8.0, 4.8 Hz, 1H), 7.18 (br. s., 1H), 4.72 (t, J=5.4 Hz, 1H), 4.11-4.34 (m, 2H), 1.44 (s, 9H). MS m/e 486.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH2:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[N:3]=1.[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31]>C1COCC1>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:4]1[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[C:7]2[CH2:8][NH:9][C:30](=[O:31])[NH:1][C:2]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc(N)c2CN)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc3c2CNC(=O)N3)C1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
To a cold (0° C.) solution of tert-butyl 3-[2-amino-3-(aminomethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate (0.020 g, 0.050 mmol) in THF (2.0 mL) under an argon atmosphere was added 1,1′-carbonyldiimidazole (0.009 g, 0.055 mmol). After stirred for 15 min, the mixture was quenched with saturated sodium bicarbonate solution. The resulting mixture was partitioned between ethyl acetate and saturated ammonium chloride solution. The separated organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2.0 mL). The mixture was heated at 60° C. for 1 hr and allowed to cool to room temperature. The resulting precipitates were collected by filtration, washed with ethyl acetate and dried under reduced pressure to give tert-Butyl 3-[7-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]-1-piperidinecarboxylate. (0.007 g, yield; 33%)