Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a solution of N-tert-butyl-2-(5-methylpyrazin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (72 mg, 158 mol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (360 mg, 243 μL, 3.16 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (2.5 mL), methanol (1.2 mL) and ammonium hydroxide (0.35 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give N-tert-butyl-2-(5-methylpyrazin-2-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (26 mg, 79.9 mol, 51%) as a light green solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.45 (s, 1H), 10.12 (s, 1H), 9.17 (d, J=1.5, 1 H), 8.40 (s, 1H), 8.21 (s, 1H), 8.10 (d, J=3.2, 1 H), 7.73 (s, 1H), 2.42 (s, 3H), 1.46 (s, 9H); MS (EI/CI) m/z: 326.1 [M+H].
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][CH2:7][CH2:8][CH:9]1[CH2:14][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[CH:16]=2)[CH2:12][CH2:11][N:10]1[CH3:28]>CO.[Pd]>[CH3:5][O:6][CH2:7][CH2:8][CH:9]1[N:10]([CH3:28])[CH2:11][CH2:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[CH:16]=2)[CH2:14]1
Reactant: COCCC1CN(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CCN1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COCCC1CN(c2ccc(N)c(OC(C)C)c2)CCN1C
Temperature: 80 °C
Yield: 87.8 %

Procedure:
112 mg of ammonium formate and 10 mg of Pd/C (10%) are added to a solution of 100 mg of 2-(2-methoxyethyl)-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazine in 2 ml of methanol. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure. The residue is taken up with 10 ml of ethyl acetate and 2 ml of water. The two phases are separated, and the aqueous phase is washed with twice 10 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated, so as to obtain 80 mg of 4-[3-(2-methoxyethyl)-4-methylpiperazin-1-yl]-2-(propan-2-yloxy)aniline in the form of a brown oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[CH3:18].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1.C(OCC)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:19]([C:20]#[N:21])([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: Cc1ccc(CC#N)cc1C
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cool a solution of sodium bis(trimethylsilyl)amide (723 mL, 1M in tetrahydrofuran, 723 mmol) to 0° C. in an ice bath. Add a solution of 3,4-dimethylphenylacetonitrile (50.0 mmol) in tetrahydrofuran (130 mL) over about 1.5 hours. When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir. After 2 hours, transfer the above solution via cannula into a cooled (-50° C.) solution of ethyl bromoacetate (126 g, 757 mmol) in tetrahydrofuran (250 mL). After the transfer is complete, allow the reaction mixture to warm to ambient temperature. After 18 hours, dilute with diethyl ether (500 mL) and extract with water, 1M hydrochloric acid solution, saturated aqueous solution of sodium bicarbonate, and then brine. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give a residue. Recrystallize the residue from diethyl ether to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([N:24]([CH2:39][CH3:40])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:23]>>[CH2:39]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=[C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH:13]=3)[NH:17][C:16]2=[O:21])[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:40]
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccc(Cl)c3)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)Nc4cccc(Cl)c4)cc32)c1C
Yield: 37.2 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)amide (120 mg, 3.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (100 mg) to give 80 mg (37%) of the title compound as a yellow solid.
Reaction SMILES: B(O)(O)O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15](=[O:29])[CH:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)C(OC)=O)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1>CC(OC)(C)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15](=[O:29])[CH2:16][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: COC(=O)C(C(=O)c1cc(OC)cc(OC)c1)c1ccc(OC)cc1
Agent: OB(O)O
Solvent: COC(C)(C)C
Product: COc1ccc(CC(=O)c2cc(OC)cc(OC)c2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
26.7 g of boric acid (0.43 mol) and 74.4 g of crude methyl 3-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)-3-oxopropionate (0.216 mol) prepared according to Example 1 are introduced into a round-bottomed flask equipped with a distillation head. Heating is carried out, the temperature being brought gradually to 100° C. for 1 h, 120° C. for 1 h, 140° C. for 1 h and then 160° C. for 4 h while distilling off light products. The mixture is cooled to 80° C., 250 ml of water and then 200 ml of toluene are added, the mixture is kept stirred at 60° C. for 1 h, separation by settling is then carried out and the toluene phase is recovered, washed with 100 ml of a saturated aqueous sodium bicarbonate solution and concentrated on a rotary evaporator. The crude oily product obtained is taken up in 200 ml of MTBE to precipitate the product, which is filtered off and dried. Thus, after drying, 33.6 g of 1-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanone are obtained in the form of a cream-white solid, i.e. a yield of 54.4% with respect to the crude starting β-ketoester. M.p.: 93-4° C.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1.[C:19]([C:23]([CH2:25][C:26](OCC)=[O:27])=O)([F:22])([F:21])[F:20].CS(O)(=O)=O.[OH-].[Na+]>O>[O:27]=[C:26]1[CH:25]=[C:23]([C:19]([F:22])([F:21])[F:20])[C:18]2[C:2](=[CH:3][CH:4]=[C:5]([CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:13][C:14](=[O:16])[CH3:15])[CH:17]=2)[O:1]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC(=O)Nc1ccccc1Cc1ccc(O)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccccc1Cc1ccc2oc(=O)cc(C(F)(F)F)c2c1
Temperature: 20 °C
Yield: 26 %

Procedure:
A solution of N-[2-(4-hydroxybenzyl)phenyl]acetamide (200 mg, 0.83 mmol) in CF3COCH2CO2Et (305 mg, 1.66 mmol) & MeSO3H (750 μL, 11.55 mmol) was heated at 75° C. for 2 d. On cooling to 20° C., the mixture was treated with H2O (20 mL), then the pH was adjusted to 12 with NaOH. The mixture was extracted with EtOAc (150 mL), then the extracts were washed with 0.5 M NaOH (2×50 mL), before being dried (MgSO4). Filtration, solvent evaporation, & column chromatography (1:2 PE-EtOAc) yielded N-[2-(2-oxo-4-trifluoromethyl-2H-chromen-6-ylmethyl)-phenyl]acetamide (78 mg, 26%): m/z (ES+)=362.2 [M+H]+. A solution of this compound in AcOH-12 M HCl (1:6, 3.5 mL) was heated at 95° C. for 6 h. On cooling to 20° C., H2O (8 mL) was added, then the mixture was treated with NaOH then Na2CO3 to adjust the pH to 10. Extraction with EtOAc (10 mL) & solvent evaporation furnished a residue which was subjected to column chromatography (2:1 PE-EtOAc) to give the title compound (8 mg, 12%): δH (CDCl3)=3.50 (br s, 2H), 4.00 (s, 2H), 6.70 (d, 1H), 6.80 (m, 2H), 7.00 (d, 1H), 7.10 (t, 1H), 7.35 (d, 1H), 7.40 (d, 1H), 7.55 (s, 1H); m/z (ES+)=320.1 [M+H]+. Compounds of Formula I
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH:13]([CH3:15])[NH:12][CH:11]([CH3:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH:11]([CH3:16])[CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=3)[CH2:14][CH:13]2[CH3:15])[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1cccc(N2CC(C)NC(C)C2)n1
Product: COc1cccc(N2CC(C)N(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)C(C)C2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methoxy-pyridin-2-yl)-3,5-dimethyl-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]3)[O:3]1.I[CH2:22][CH3:23]>>[CH2:22]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([B:4]3[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)[C:15]1=[O:19])[CH3:23]
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Reactant: CCI
Product: CCN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 9, Step 1 starting from 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one and iodoethane. LCMS (M+H)+=302.1.
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[N:4][N:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=12.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.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>[F:21][C:17]1[CH:16]=[C:15]([C:3]2[C:2]([C:29]3[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=3)=[C:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][N:5]3[N:4]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Fc1cccc(-c2nn3cc(C(F)(F)F)ccc3c2Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Yield: 44.7 %

Procedure:
To a solution of the 3-bromo-2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine (50 mg, 0.139 mmol) in DMF (5 ml) was added 4-methanesulfonylphenylboronic acid (37 mg, 1.3 eq), ground potassium phosphate (83 mg) and tetrakis(triphenylphosphine)palladium(0) (10 mg) and the mixture heated to 90° for 18 h under N2. The cooled mixture was poured into water (10 ml) and extracted into ethyl acetate (4×10 ml). The combined organic phases were washed sequentially with water, brine, 2N sodium hydroxide and brine, dried and concentrated in vacuo to give the title compound as an off-white solid (27 mg, 45%). MH+ 435
Reaction SMILES: S=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:15][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc2oc(=S)[nH]c2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2oc(Cl)nc2c1
Temperature: 67.5 °C
Yield: 65 %

Procedure:
To a mixture of 2-thioxo-2,3-dihydrobenzooxazole-5-carbonitrile (2.56 g, 14.5 mmol) and thionylchloride (14.1 mL) was added two drops of DMF. The mixture was heated at 65-70° C. for 1 h. Then the mixture was cooled to rt and diluted with CH2Cl2. The solvent and excess thionylchloride were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 20% EtOAc in Petroleum ether) to give 2-chlorobenzooxazole-5-carbonitrile 1.69 g (65%).
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=1[C:11](OC)=O>O1CCCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:9]([NH2:8])=[C:10]([C:11]2[O:7][N:6]=[C:3]([CH3:4])[N:5]=2)[CH:15]=1
Reactant: COC(=O)c1cc(OC)ccc1N
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N)c(-c2nc(C)no2)c1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
Sodium hydride (594 mg) was added to a stirred suspension of acetamide oxime (1.0 g) and 4 molecular sieves (4 g) in dry tetrahydrofuran (50 ml) under nitrogen. The mixture was heated at 60° for 30 min then allowed to cool to room temperature. A solution of 2-amino-5-methoxybenzoic acid, methyl ester (2.0 g) in dry tetrahydrofuran (20 ml) was added and the mixture stirred at reflux for 2.5 h. The suspension was allowed to cool, filtered and the filtrate evaporated to give the title compound as a yellow solid (1.64 g)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:2]1=2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32](Cl)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:10][C:7]4[CH:8]=[CH:9][C:2]5[S:1][CH:5]=[CH:4][C:3]=5[CH:6]=4)=[C:27]3[CH:26]=[N:25]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc5sccc5c4)ncnc32)CC1
Temperature: 80 °C

Procedure:
A mixture of benzo[b]thiophen-5-ol (MCAT GmbH, Konstanz, Germany; 300 mg, 2 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 607 mg, 1.8 mmol), and potassium carbonate (414 mg, 3 mmol) in dimethylformamide (20 mL) was heated at 80° C. for 3 h. The mixture was cooled and then poured into saturated aqueous ammonium chloride solution, and the resulting mixture was extracted three times with ethyl acetate. The combined organic layers were washed twice with water and once with brine, dried (magnesium sulfate), filtered, evaporated and chromatographed, eluting with 50% ethyl acetate/hexanes to give 4-[4-(benzo[b]thio-phen-5-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow foam.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].ClC1C=CC=C(C(OO)=[O:22])C=1.S([O-])([O-])=O.[Na+].[Na+].C1C(C(O[O-])=O)=CC=CC=1>C(Cl)Cl>[C:1]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]2[O:22][CH:10]2[CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O[O-])c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C)C(=O)OCC1CCC2OC2C1
Reaction time: 3 h
Yield: 94.6 %

Procedure:
A 8 liter, 4 necked flask equipped with a thermometer, cooling jacket, stirring means and drip funnel was charged with 200 g of cyclohexen-4-ylmethyl methacrylate produced in Step A and 1200 ml of methylene chloride. The reactants were cooled to a temperature below 10° C. A solution of 263.6 g of m-chloroperbenzoic acid (80% purity, Kishida Chemicals) in 2800 ml of methylene chloride was added thereto dropwise over 3 hours and then allowed to react for additional 3 hours with stirring. After the reaction, an amount of 10% aqueous solution of sodium sulfite was added to the reaction mixture and allowed to react at room temperature for 1 hour to decompose unreacted perbenzoate. After having confirmed the absence of perbenzoate using starch-iodine indicator paper, the reaction mixture was washed with 1000 ml of an aqueous solution containing 81 g of sodium carbonate and then with an amount of saline successively. Thereafter the mixture was dried over magnesium sulfate and evaporated under reduced pressure with addition of 40 mg of p-methoxyquinone as a polymerization inhibitor to remove the solvent. 206 g of crude product of the titled compound was obtained. Yied: 95% of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:38])[C:15]([O:30]CC2C=CC=CC=2)=[C:16]2[C:21](=[O:22])[N:20]3[CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][N:25]4[C@H:19]3[CH2:18][N:17]2[CH:29]=1)=[O:12]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:38])[C:15]([OH:30])=[C:16]2[C:21](=[O:22])[N:20]3[CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][N:25]4[C@H:19]3[CH2:18][N:17]2[CH:29]=1)=[O:12]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C[C@@H]3CCCN3[C@H]1C2
Agent: [Pd]
Solvent: CO
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C[C@@H]3CCCN3[C@H]1C2
Yield: 34.9 %

Procedure:
To a solution of (4aR,13aS)—N-[(2,4-difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (19 mg, 0.04 mmol) in methanol (8 mL) was added 10% Pd/C (10 mg). Hydrogen was bubbled through the reaction mixture via a balloon for 2 h. The resultant mixture was filtered through Celite with methanol and dichloromethane. The filtrate was concentrated in vacuo to give the title compound (6 mg, 38%) as a white solid. 1H NMR (CDCl3) δ 11.73 (m, 1H), 10.36 (m, 1H), 8.31 (s, 1H), 7.33 (m, 1H), 6.78 (m, 2H), 4.62 (m, 2H), 4.50 (m, 1H), 4.27-4.19 (m, 2H), 3.87-3.77 (m, 2H), 3.16-3.08 (m, 2H), 2.83 (m, 1H): 2.11-1.65 (m, 4H); ES+ MS: 431 (M+1).
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36]N>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:31]=1[NH:36][CH:2]=[C:6]2[CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])[CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCCO3)CC2)c1
Reactant: COc1ccccc1NN
Agent: Cl
Product: COc1cccc2c(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c[nH]c12

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 420.2 (M+H)+.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[CH:3][CH:2]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=4)=[N:11][C:10]=13)=[O:18])[CH2:24]2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.7 %

Procedure:
A mixture of 2-p-tolylbenzoxazole-4-carboxylic acid (62 mg, 0.24 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (66 mg, 0.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg, 0.49 mmol) and 1-hydroxybenzotriazole (66 mg, 0.49 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (0.16 mL, 0.98 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-p-tolylbenzoxazole-4-carboxamide (25 mg, 27%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.10 (d, J=7.0 Hz, 1H), 8.20 (dd, J=7.5, 0.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 2H), 7.68 (dd, J=8.0, 1.0 Hz, 1H), 7.45 (t, J=7.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 4.64-4.55 (m, 1H), 3.17-3.11 (m, 2H), 2.70-2.60 (m, 2H) 2.56 (s, 3H), 2.48 (s, 3H), 2.08-1.98 (m, 2H), 1.75-1.50 (m, 3H), 1.25-1.17 (m, 3H); MS (ESI+) m/z 390 (M+H); HPLC>99% (AUC), tR=13.37 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[S:12][CH:13]=1.C([Li])CCC.CN(C)[CH:31]=[O:32].O>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[S:12][C:13]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Under a nitrogen atmosphere at −78° C., to a solution (100 mL) of the compound (8.0 g, 23 mmol) obtained in Example 89a in tetrahydrofuran was added n-butyllithium (1.6M hexane solution, 18 mL, 28 mmol), and the mixture was stirred at the same temperature for 1 hr. Anhydrous N,N-dimethylformamide (2.3 mL, 30 mmol) was added to the reaction mixture, and the mixture was stirred at −78° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound (5.5 g, 64%) as a pale-yellow solid.