Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=4)[CH2:18][CH2:17][NH:16]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:26]1([C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[CH:30]=[CH:29][N:28]=[CH:27]1.CC([O-])=O.[Na+].C([BH3-])#N.[Na+]>CO>[N:26]1([C:31]2[CH:38]=[CH:37][C:34]([CH2:35][N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=4)[CH:15]3[C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[CH:33][CH:32]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: Oc1ccc2c(c1)CCNC2c1ccc(OCCN2CCCC2)cc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Oc1ccc2c(c1)CCN(Cc1ccc(-n3ccnc3)cc1)C2c1ccc(OCCN2CCCC2)cc1
Yield: 112.3 %

Procedure:
A solution of 1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol (0.023 g, 0.067 mmol), 4-imidazol-1-yl-benzaldehyde (0.011 g, 0.063 mmol), NaOAc (0.011 g, 0.14 mmol), and sodium cyanoborohydride (0.004 g, 0.063 mmol) in MeOH (2.0 ml) was stirred at rt for 18 hr. The reaction mixture was evaporated in vacuo to a yellow residue that was dissolved in EtOAc (5 ml) and washed first with sat. NaHCO3 solution (5 ml) and then with H2O (5 ml). The organic solution was dried over MgSO4 and evaporated to give 0.035 g of yellow residue. Purification by preparative TLC, eluting with EtOAc:MeOH (7:3), gave 0.007 g (23% yield) of white solid.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19]C(O)=O)[CH:16]=[CH:17][CH:18]=1.C([O-])(=O)C.[Na+]>C(O)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH:19]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:6]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OC(=Cc2cccc(Br)c2)c2ccccc21
Temperature: 220 °C
Yield: 81 %

Procedure:
A mixture of phthalic acid anhydride (43 g, 0.291 mol), 3-bromophenyl acetic acid (62.5 g, 0.291 mol) and sodium acetate (2 g, 0.015 mol) was heated at 220° C. for 2 h under an atmosphere of nitrogen. The reaction mixture was cooled to about 80° C. and ethanol (75 ml) was added. The precipitate was filtered off, washed with a mixture of heptane and ethanol (9:1) and dried in vacuo at 50° C. which afforded 71 g (81%) of 3-(3-bromobenzylidene)-3H-isobenzofuran-1-one as a solid.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>N1C=CC=CC=1.C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[Si:29]([O:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][C:4]([O:6][CH3:7])=[O:5])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(O)CC(=O)OC
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(CC(=O)OC)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
The alcohol (11Z,14Z)-methyl 3-hydroxyicosa-11,14-dienoate (3) (1.40 g, 4.14 mmol) in pyridine:THF (2:1, 30 mL) was treated with silver nitrate (913 mg, 5.40 mmol), t-butylchlorodimethyl silane (814 mg, 5.40 mmol) and stirred (60 min) The mixture was filtered through Celite and the filter cake rinsed with pyridine. The filtrate was concentrated and the residue was taken-up in CH2Cl2, washed with HCl (5%, aq.) and brine, dried, filtered and concentrated. The crude material was subjected to chromatography to yield (11Z,14Z)-methyl 3-((tert-butyldimethylsilyl)oxy)icosa-11,14-dienoate (4) (1.70 g, 91%) as a clear colorless oil. Rf 0.8 (10% EtOAc-hexanes), FW 452.79, C27H52O3Si.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1)[CH3:14].[CH2:25]([NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1)[C:26]#[CH:27].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C.C(OCC)(=O)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:16][CH2:17][CH:18](/[CH:21]=[C:33]2/[C:29]([NH:28][CH2:25][C:26]#[CH:27])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:19][CH2:20]1)[CH3:14]
Reactant: CC(c1ccc(C(F)(F)F)cc1C(F)(F)F)N1CCC(C=O)CC1
Reactant: C#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(C)c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 1-{1-[2,4-bis(trifluoromethyl)phenyl]ethyl}piperidine-4-carbaldehyde (1.15 g) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (1.00 g) in 2-propanol (16.3 mL) was added piperidinium acetate (0.473 g). The reaction mixture was stirred at 60° C. overnight, allowed to cool to room temperature, and diluted with ethyl acetate. The mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), further purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (1.13 g).
Reaction SMILES: FC(F)(C(F)(F)F)COC(=O)OCC(F)(F)C(F)(F)F.FC(F)(C(F)(F)F)C[NH:24][C:25](=[O:47])[O:26][CH2:27][CH:28]1[CH:33]=[CH:32][CH2:31][CH:30]([CH2:34][O:35][C:36](=[O:46])[NH:37]CC(F)(F)C(F)(F)F)[CH2:29]1>>[C:36](=[O:46])([O:35][CH2:34][CH:30]1[CH:31]=[CH:32][CH2:33][CH:28]([CH2:27][O:26][C:25](=[O:47])[NH2:24])[CH2:29]1)[NH2:37]
Reactant: O=C(NCC(F)(F)C(F)(F)F)OCC1C=CCC(COC(=O)NCC(F)(F)C(F)(F)F)C1
Agent: O=C(OCC(F)(F)C(F)(F)F)OCC(F)(F)C(F)(F)F
Product: NC(=O)OCC1C=CCC(COC(N)=O)C1
Yield: 95.5 %

Procedure:
The reaction was carried out in the same manner as Example 7 except for using 53.5 g (0.1642 mol) of bis(2,2,3,3,3-pentafluoropropyl)carbonate (to be referred to as “BPFC” hereinafter) synthesized in the above Synthesis Example 3 in place of BTFC, and it was confirmed that tetrahydro-m-xylylene bis(2,2,3,3,3-pentafluoropropyl carbamate) (to be referred to as H-XDC-3 hereinafter) was generated as the main product (H-XDA base yield 95.5%). Structural assignment of the product H-XDC-3 was carried out by 19F-NMR and GC-Mass analyses as well as 1H-NMR. Analytical Results of mass fragments of H-XDC-3, 1H-NMR and 19F-NMR were shown in the following.
Reaction SMILES: CN1CCC[C@H]1C(O)=O.C[O:11][C:12](=[O:35])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[C:29]([C:30](=[O:34])[NH:31][C:32]=2[CH:33]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:19].[OH-].[Na+].Cl>C(Cl)Cl.O1CCOCC1>[O:34]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[CH:22]=[CH:21][C:20]([C:18]([N:14]3[CH2:15][CH2:16][CH2:17][C@H:13]3[C:12]([OH:35])=[O:11])=[O:19])=[CH:33][C:32]=2[NH:31]1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1ccc2c(c1)[nH]c(=O)c1ccccc12
Agent: CN1CCC[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN1C(=O)c1ccc2c(c1)[nH]c(=O)c1ccccc12

Procedure:
Prepared from to 3-[6(5H)Phenanthridinone]-carbonyl chloride 7 and (S)-methylproline in methylene chloride according to General Procedure A. The resulting 1-[(5,6-dihydro-6-oxo-3-phenanthridinyl)carbonyl]-proline methyl ester was hydrolyzed with 1N sodium hydroxide in dioxane. After neutralizing the mixture with HCl, the desired compound was collected as a white solid precipitate (60% yield), mp 250-253° C. 1H-NMR (400 MHz, DMSO-d6), 12.60 (bs, 1H), 11.79 (s, 1H), 8.55 9d, 1H, J=8 Hz), 8.47 (d, 1H, J=8 Hz), 8.34 (d, 1H, J=8 Hz), 7.90 (t, 1H, J=8 Hz), 7.70 (t, 1H, J=8Hz), 7.54 (s, 1H), 7.40 (d, 1H, J=8 Hz), 4.44 (m, 1H), 3.56 (m, 2H, 2.37 (m, 1H), 1.90 (m, 3H) Anal. (C19H16N2O2), C H N.
Reaction SMILES: [O:1]=O.[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.[OH-].[NH4+].[NH4+].[NH4+].[NH4+].[OH-].[OH-].[OH-].[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:3][C:4]1[C:5](=[O:1])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=1)[CH:7]=2
Reactant: O=O
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Yield: 89.6 %

Procedure:
Into a three-necked, 300-mL flask equipped with a stirrer, a molecular-oxygen-containing gas (air) inlet tube and a gas outlet tube (fitted with a condenser), 2,7-dibromofluorene (9.30 g, 0.029 mol) was charged, followed by its dissolution with toluene (100 g). Subsequent to addition of a 25% aqueous solution of tetraammonium hydroxide (0.77 g) and a 48% aqueous solution of sodium hydroxide (2.66 g), the resulting mixture was vigorously stirred at 60° C. for 3 hours while introducing air at a flow rate of 0.1 L/min. After completion of the stirring, the reaction mixture was allowed to stand, and the resulting toluene layer was collected. The toluene layer was then subjected to acid washing, followed by water washing until its pH arose to 7. Toluene was then distilled off to recover crude crystals of 2,7-dibromofluorenone. The content of 2,7-dibromofluorene in the crude crystals at that time was 0%. Those crude crystals were recrystallized from N,N′-dimethylformamide (15 g) to afford 2,7-dibromofluorenone as yellow crystals (8.26 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([S:11](Cl)(=O)=O)=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1.BrC1C(C(CC)C)=CC(S(Cl)(=O)=O)=C(C(CC)C)C=1>>[Cl:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[CH:6][C:5]([SH:11])=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1
Reactant: CC(C)c1cc(S(=O)(=O)Cl)c(C(C)C)cc1Cl
Agent: CCC(C)c1cc(S(=O)(=O)Cl)c(C(C)CC)cc1Br
Product: CC(C)c1cc(Cl)c(C(C)C)cc1S

Procedure:
4-Chloro-2,5-diisopropylbenzenethiol was prepared by the procedure of Example 2B except that 4-chloro-2,5-diisopropylbenzenesulfonyl chloride was substituted for the 4-bromo-2,5-di-sec-butylbenzenesulfonyl chloride. The resulting product had a boiling point of 93°-95°C at 0.3 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:39][O:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[C:9]([NH:11][CH:12]2[C:37](=[O:38])[N:14]3[C:15]([C:21]([O:23]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:22])=[C:16]([CH2:19][CH3:20])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:39][O:40][CH2:41][C:42]([OH:44])=[O:43])[C:9]([NH:11][CH:12]2[C:37](=[O:38])[N:14]3[C:15]([C:21]([OH:23])=[S:22])=[C:16]([CH2:19][CH3:20])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(N)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: CCC1=C(C(O)=S)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3cccc(N)n3)[C@H]2SC1
Yield: 55.9 %

Procedure:
The solution of benzhydryl 7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.3 g) in trifluoroacetic acid (10 ml) and anisole (2 ml) was stirred for 2 hours at ambient temperature. The resultant solution was poured into diisopropyl ether (300 ml) and the precipitates were collected by filtration. The precipitates were dissolved in an aqueous solution of sodium bicarbonate (pH 7.5). The aqueous solution was washed with ethyl acetate and was adjusted to pH 2.3 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(6-aminopyridin-2-yl)-2-carboxymethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylic acid (syn isomer, 0.87 g), mp. 164° to 167° C. (dec.).
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1.[OH-].[Li+]>O1CCOCC1.O>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:34])([F:35])[F:36])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]4[CH2:17][CH2:18][N:13]([C:11]([N:8]5[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:43])=[O:2])[CH2:10][CH2:9]5)=[O:12])[CH2:14][CH2:15]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)CC1CCN(C(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1CCN(C(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1
Temperature: 25 °C

Procedure:
To a mixture of [1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-acetic acid methyl ester (70 mg, 0.117 mmol) in dioxane (3 mL) and water (3 mL) at room temperature was added lithium hydroxide (0.01 g, 0.24 mmol). The mixture was stirred at room temperature for about an hour. The mixture was acidified to pH of about 2 and then blown to dryness. Purification by reversed-phase HPLC gave [1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-acetic acid. LCMS calcd for C30H31F3N4O5 (m/e) 584, obsd 585 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:27]\[OH:28])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCCCC2)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)C2CCCCC2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-cyclohexyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=417.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:10]1[C:5]2[C:6](=[N:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:8]([CH3:11])[CH:9]=1
Reactant: Cn1ccc2ccc(F)nc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cn1cc(Br)c2ccc(F)nc21
Yield: 99.4 %

Procedure:
To a solution of 6-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine (257.3 g, 1.71 mol) in DCM (3.86 L) is added N-bromosuccinimide (320.3 g; 1.80 mol) in five portions over 30 minutes. The mixture is stirred without heating or cooling overnight, then filtered and concentrated to about 1 L. This is purified by column chromatography on silica, eluting with 0 to 30% EtOAc in isohexane. The appropriate fractions are evaporated to give the product as an off white solid (391.3 g, 1.7 mol). 1H-NMR (400 MHz, CDCl3): δ 7.91-7.87 (m, 1H), 7.15 (s, 1H), 6.77 (d, 1H), 3.81 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[N:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1.C[C@H]1CO1.CCN(C(C)C)C(C)C.C(O)C.[ClH:68]>CCOCC>[ClH:68].[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:22][N:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cnc32)cc1
Agent: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCNCC5)cn4)cnc32)cc1
Yield: 63.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)piperazine-1-carboxylate (400 mg, 0.56 mmol) was deprotected in HCl in ether (10 ml) to afford crude compound. Using similar reaction conditions as described in Step-i of example-82A, above crude was alkylated using (S)-2-methyloxirane (163 mg, 2.8 mmol), DIPEA (217 mg, 1.68 mmol) and ethanol (10 mL) to get 240 mg (63.7% yield) of the titled compound. MS: m/z=667.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@@H:6]1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:28][CH2:29][C:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:15]1([C@H:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH2:14][N:5]2[C:3](=[O:4])[CH2:2][NH:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(CCl)N1CCc2ccccc2[C@@H]1C1CCCCC1
Reactant: NCC1(O)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: O=C(CNCC1(O)CCCCC1)N1CCc2ccccc2[C@@H]1C1CCCCC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
(1S)-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (4.496 g) was dissolved in acetonitrile (100 mL). To the mixture were added potassium carbonate (6.25 g), tetra-n-butylammoniumiodide (679 mg), and 1-(aminomethyl)cyclohexanol hydrochloride (4.50 g), followed by stirring at 60° C. for 6 hours. Thereafter, the solvent was evaporated and water was added to the reaction mixture, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to obtain 1-[({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol (3.02 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:7]=1
Reactant: C1CNCCN1
Reactant: Clc1cc(N2CCCC2)nc(Cl)n1
Solvent: CCO
Product: Clc1cc(N2CCCC2)nc(N2CCNCC2)n1

Procedure:
A solution containing 2.0 g (9.17 mmoles) of 2,4-dichloro-6-pyrrolidinopyrimidine and 3.95 (45.9 mmoles) of piperazine in ethanol is boiled under reflux for 1 hour and then evaporated. The evaporation residue is distributed between 100 ml of chloroform and 100 ml of 1% sodium hydroxide solution. After separation the organic phase is washed twice with 50 ml of water each, then dried and evaporated. The evaporation residue is subjected to chromatography on a silica gel column. By using a 9:1 mixture of chloroform/methanol as eluent and recrystallizing the obtained product from hexane, the title compound is obtained in a yield of 1.66 g (67.6%), m.p.: 77°-92° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH:22]=[CH2:23])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:24])[CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH2:22][CH3:23])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:24])[CH:3]=1
Reactant: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Yield: 93 %

Procedure:
A solution of 0.255 (0.79 mmol) of the product of Example 7, Step G in 10 mL ethanol was placed in a small Parr hydrogenation flask and 50 mg of a 10% palladium on carbon catalyst was added. The reaction mixture was then shaken in a Parr apparatus under a 45 psig hydrogen atmosphere for 1 hour at room temperature. The reaction mixture was then removed from the flask, filtered, evaporated and dried in vacuo to afford 0.239g (93%) of the title compound which was used in the next step without further purification.
Reaction SMILES: [C:1]([CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[ClH:16]>C(O)C.[Pd]>[ClH:16].[NH2:2][CH2:1][CH:3]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C#N)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(CN)c1ccccc1

Procedure:
To a solution of ethyl 3-cyano-3-phenylpropanoate 2 (9.27 g, 45.6 mmol) in ethanol (70 mL) was added concentrated hydrochloric acid (2.4 mL) followed by 10% palladium on carbon (1.0 g) and the reaction hydrogenated at 80 psi for 18 h. The mixture was filtered through celite and concentrated in vacuo. The residue was triturated in ether and filtered to give 2 (4.97 g in 2 crops, 45%) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:8]([CH2:22][CH3:23])[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][N:14]=1)[CH3:7].[OH-:24].[K+].Cl>O>[CH2:22]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=2)[NH:15][N:14]=1)[CH3:23]
Reactant: CCN(CC)CCCNc1n[nH]c2ccccc12
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCN(CC)CCCNc1n[nH]c2ccc(O)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To 4.3 g of 95% sulfuric acid was added 9.25 g of the 3-(3-diethylaminopropylamino)indazole, and the mixture was stirred for 3 hours at 80° C. To the mixture was added 13 ml of water, and the pH of the mixture was adjusted to 14 with potassium hydroxide. The mixture was washed twice with 20 ml of chloroform, and water was removed under reduced pressure. To the residue thus obtained were added 12.5 g of potassium hydroxide and 0.6 ml of water, and the mixture was stirred for 8 hours at 250° C. After cooling, to the mixture was added hydrochloric acid to separate crystals. Then the crystals were obtained by filtration and dried to give 4.39 g of 3-(3-diethylaminopropylamino)-5-hydroxyindazole having the following analytical values in a yield of 40%.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: O=[N+]([O-])c1ccc(Br)cc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2cccc3c2oc2ccccc23)cc1
Temperature: 0 °C
Yield: 62.6 %

Procedure:
To a mixture of dibenzofuran-4-boronic acid (30 g, 0.14 mol), 4-bromonitrobenzene (25.7 g, 0.127 mol), sodium carbonate (150 g) in toluene/water (500 mL/500 mL) was added tetrakis(triphenylphosphine)palladium(0) (8.2 g, 0.7 mol %) and the resulting reaction mixture was refluxed for 20 h under N2 atmosphere. The toluene layer was separated and concentrated to 200 mL. The concentrated solution was cooled to 0° C. and filtered off. The collected solid was dried and dissolved in chloroform and the obtained solution was filtered through celite bed to remove insoluble materials. The filtrate was concentrated under vacuum to give the title compound (23 g, 58%).