Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:10]=2)=[CH:5][CH:4]=1.[N:27]([C:38]([C:45]#[N:46])([CH3:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[N:28][C:29]([C:36]#[N:37])([CH3:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+].O>CC(C)=O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:42][C:41](=[O:43])[CH2:40][CH2:39][C:38]([N:27]=[N:28][C:29]([C:36]#[N:37])([CH3:35])[CH2:30][CH2:31][C:32]([O:34][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:9]4[CH:10]=[C:11]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[N:12]=[C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)[CH:14]=4)=[CH:7][CH:8]=3)=[O:33])([C:45]#[N:46])[CH3:44])=[CH:4][CH:5]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:12]=1
Reactant: CC(C#N)(CCC(=O)O)N=NC(C)(C#N)CCC(=O)O
Reactant: BrCc1ccc(-c2cc(-c3ccccn3)nc(-c3ccccn3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C#N)(CCC(=O)OCc1ccc(-c2cc(-c3ccccn3)nc(-c3ccccn3)c2)cc1)N=NC(C)(C#N)CCC(=O)OCc1ccc(-c2cc(-c3ccccn3)nc(-c3ccccn3)c2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 46.3 %

Procedure:
A reaction mixture of 4′-(4-bromomethylphenyl)-2,2′:6′,2″-terpyridine (1.500 g, 3.729 mmol), 4,4′-azobis(4-cyanopentanoic acid) (500 mg, 1.7839 mmol), Cs2CO3 (750 mg, 2.302 mmol), 1.0 ml of water and 100 ml of acetone was stirred vigorously at room temperature for 5 days. The solvents were removed under vacuum, and CH2Cl2 was added. The precipitate was filtered off. The filtrate was evaporated to dryness under vacuum, and then 300 ml of CH2Cl2-hexane mixture solvents (1:12, v/v) was added. The precipitate was filtered, and dried, and further purified by column chromatography (Al2O3) using ethyl acetate-hexane (3:2, v/v) as eluent to give pure product (0.763 g, 46%). 1H-NMR (CDCl3): δ=8.64 (m, 12H), 7.85 (m, 8H), 7.47 (m, 4H), 7.30 (m, 4H), 5.20 (s, 4H, —CH2—O—C(O)—), 2.65-2.48(m,8H, —OOC—CH2CH2—), 1.69(m, 6H, =N—C(CN)—CH3). HRMS (TOF): calculated for C56H47N10O4[(M+H)+] m/z=923.3782, found m/z=923.3759 Fluorescent Spectral Properties: λex=320 nm, λem=380 nm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15]1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].CO.O.[OH-].[K+].CO>O>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[O:13])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of benzyl 4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorobenzyl)carbamoyl)piperazine-1-carboxylate (200 mg, 0.38 mmol) in a KOH/MeOH/H2O (10 mL; prepared as a stock solution using 10 g KOH, 50 mL MeOH and 25 mL H2O) solution of was stirred for 2 hours at 80° C. The reaction was extracted with EtOAc, dried over NaSO4 and concentrated under reduced pressure to yield tert-butyl 2-(N-(4-chlorobenzyl)piperazine-1-carboxamido)ethylcarbamate (132 mg, 89%). MS (ESI) m/e (M+H+) 397.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][N:12]([CH2:17][CH2:18][N:19]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH3:20])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[C:30]([C:27]1[CH:28]=[CH:29][C:24]([S:21]([N:19]([CH3:20])[CH2:18][CH2:17][N:12]2[CH2:13][CH:14]3[O:16][CH:10]([CH2:9][NH:8][CH2:15]3)[CH2:11]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1)#[N:31]
Reactant: CN(CCN1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(CCN1CC2CNCC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1

Procedure:
Step (iii) product 7-{2-[(4-Cyano-benzenesulfonyl)-methyl-amino]-ethyl}-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (2.2 g) was dissolved in dioxane (10 ml) and to which HCl in dioxane (saturated, 20 ml) was added drop by drop at RT under nitrogen atmosphere. Solvent was decanted, the precipitated solid was washed with dry diethyl ether (three times) and dried under vacuum to yield the title compound (2 g) as white powder.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Br)[C:15]([F:22])=[CH:14][N:13]=1>C1COCC1>[Br:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:10][CH:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]2)[C:15]([F:22])=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1c(Br)ncc(F)c1Br
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2c(F)cnc(Br)c2[N+](=O)[O-])CC1
Reaction time: 0.25 h

Procedure:
NaH (86.67 mg, 2.167 mmol) was added portionwise to a solution of 1-methylpiperidin-4-ol (192.0 mg, 1.667 mmol) in THF (5.000 mL) at 0° C. and the resulting solution stirred for 15 min and then 2,4-dibromo-5-fluoro-3-nitro-pyridine (500 mg, 1.667 mmol) in THF (5.000 mL) was added and the reaction mixture stirred at RT overnight. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). Combined organic extracts was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatograph on silica eluting with ethyl acetate/petroleum ether (24 g column, 0-100% EtOAc) using the ISCO column companion system. Product fractions were combined and concentrated in vacuo to leave the product as a yellow oil that solidified on standing. (125 mg). MS (ES+) 334.0 336.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-bromoaniline (4.11 g) was treated in the same manner as described in Example 37 to give white crystalline powder of the title compound.
Reaction SMILES: [ClH:1].[O:2](CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=C[CH:4]=1.Cl.[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47](C(C)(C)C)=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([O:2][CH2:3][CH3:4])=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: CCOc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 358 (M−15,0.1), 253 (17), 252 (100), 163 (6), 121 (21), 114 (8), 108 (8).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C.C(OCC)C>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][S:4][N:3]=1
Reactant: Sc1ccccc1
Reactant: O=c1c(Cl)nsnc1Cl
Agent: CN(C)C
Solvent: CCOCC
Product: O=c1c(Cl)nsnc1Sc1ccccc1
Reaction time: 3 h

Procedure:
In one portion 2.5 g of trimethylamine was added to a solution of 4.6 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one in 75 ml of ethyl ether in a 250 ml flask. A solution of 2.8 g of thiophenol in 25 ml of ethyl ether was then added dropwise to the flask during a 15 minute period. The reaction was allowed to stir for 3 hrs. after which it was filtered. The filter cake was washed with ether, and the filter cake was discarded. Successively, the ether solution was washed twice with 50 ml of water and once with 50 ml of saturated sodium chloride solution. The ether solution was then dried over anhydrous sodium sulfate. The ether was evaporated, leaving a solid residue which was recrystallized from 75 ml of cyclohexane. The yellow-orange 3-chloro-5-phenylthio-4H-1,2,6-thiadiazin-4-one weighed 3.6 g, mp 99.5°-101.5° C. (Lit. mp 102.5°-103.5° C., J. Geevers and W. P. Trompen, supra.) The ir spectrum was consistent with the assigned structure.
Reaction SMILES: ClC(Cl)(Cl)[C:3]1[O:7][N:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[N:4]=1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:20][CH:21]([C:3]1[O:7][N:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[N:4]=1)[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCCN1CCCCC1
Reactant: Cn1cc(-c2noc(C(Cl)(Cl)Cl)n2)c2ccccc21
Product: Cn1cc(-c2noc(C(N)CN3CCCCC3)n2)c2ccccc21
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
5-Trichloromethyl-3-[1-methyl-1H-indol-3-yl]-1,2,4-oxadiazole (0.100 g, 0.316 mmol) (D8) was dissolved with stirring in 1-(2-aminoethyl) piperidine (0.8 ml) and heated to 120° C. After 0.5 h, the reaction mixture was allowed to cool and was partitioned between EtOAc and water. The organic layer was then washed with water (1×), dried (Na2SO4) and evaporated under reduced pressure to give a yellow oil which was purified by silica gel chromatography (10% MeOH in EtOAc as eluant) to give the title compound as a colourless oil that crystallised on standing (0.095 g, 93%).
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccccc2)CCN(C)C1
Temperature: 80 °C
Yield: 4.4 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (171 mg, 0.76 mmol), bromo benzene (100 mg, 0.6 mmol), dichlorobistriphenylphosphine palladium(II) (12 mg, 0.018 mmol) and TBAF.3H2O (567 mg, 1.8 mmol) were heated 80° C. for 5 min by microwave. After completion of reaction (monitored by TLC), the mixture was poured into water (10 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum and the crude product purified by column chromatography using silica gel (100-200 mesh) and 1% MeOH in DCM as eluent, followed by reverse phase chromatography to obtain 8 mg of 2,8-dimethyl-5-phenylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.55 (d, 2H), 7.50 (d, 1H), 7.40-7.31 (m, 3H), 7.20 (s, 1H), 7.10 (d, 1H), 3.70 (s, 2H), 3.0 (t, 2H), 2.90 (t, 2H), 2.60 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1cccc(Cl)c1
Solvent: Nc1cccc(Cl)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1cccc(Cl)c1
Yield: 14 %

Procedure:
This compound was prepared using 102 mg (0.5 mmol) of 2-[(3-chlorophenyl)-hydrazono]malononitrile, which was derived from 3-chloroaniline (106 μL, 1.0 mmol) and malononitrile (1.5 mmol) as, described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, precipitated from an ethyl acetate solution by the addition of hexanes, and dried to yield 17 mg (14%) of the title compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 5.98 (br, s, 2H), 6.38 (br, s, 2H), 7.18 (d, 1H), 7.40 (t, 1H), 7.60 (d, 1H), 7.69 (s, 1H), 10.78 (s,1H).
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][C:4]([O:6][CH:7]([CH3:12])[C:8]([F:11])([F:10])[F:9])=[O:5].C([O-])(=O)C.[NH4+:18].C(O)(=O)C>O>[NH2:18][C:2]([CH3:13])=[CH:3][C:4]([O:6][CH:7]([CH3:12])[C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: [NH4+]
Reactant: CC(=O)CC(=O)OC(C)C(F)(F)F
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(N)=CC(=O)OC(C)C(F)(F)F
Temperature: 25 °C

Procedure:
2.4 g (12 mmol) of 2,2,2-trifluoro-1-methylethyl 3-oxobutanoate are heated with 1.8 g (24.6 mmol) of ammonium acetate and 0.6 g (11 mmol) of acetic acid with the addition of molecular sieves at 110° C. for 5 h. After cooling to room temperature, the reaction mixture is mixed with water and extracted with ethyl acetate. Washing of the organic phase with water and saturated sodium chloride solution is followed by drying over magnesium sulfate. After filtration, the solvent is removed in vacuo. The resulting crude product (1.5 g, 77% purity, 77% of theory) is employed without further purification in the next stage.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([NH:17][CH3:18])=[CH:10][CH:9]=3.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:19](=[O:21])[CH3:20])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([NH:17][CH3:18])=[CH:10][CH:9]=3
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc2c(c1)Sc1cc(NC)ccc1N2
Solvent: c1ccncc1
Product: CNc1ccc2c(c1)Sc1cc(NC)ccc1N2C(C)=O
Temperature: 100 °C
Yield: 49 %

Procedure:
The 3,7-dimethylamino-10H-phenothiazine obtained in Synthesis 7 was placed in a 250 cm3 round bottom flask and acetic anhydride ((H3CCO)2O, 40 cm3) and pyridine (10 cm3) were added, and the resulting solution was heated at 100° C. for 18 hours with stirring. The reaction mixture was cooled to room temperature and then poured carefully into ice-water while stirring to give a light brown solid, which was filtered using a standard Buchner funnel apparatus with a water aspirator, washed once with water (100 cm3), and dried in an oven at 60° C. for 3 hours to yield the title compound, which was recrystallised from ethanol by dissolving it in hot ethanol (100 cm3), adding activated charcoal (1 g), filtering to remove the charcoal, cooling the solution to 5° C. using an ice-water bath so that a precipitate formed (colourless crystals), and filtering using a standard Buchner filter with a water aspirator in order to collect the crystals. The crystals where then dried in an oven at 60° C. for 3 hours (MW 327.45, 4.25 g, 13.0 mmol, yield 49%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C>[Cl:1][CH2:2][CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)CC(O)CCl
Temperature: 100 °C
Yield: 96.9 %

Procedure:
In a 200 ml-volume stainless steel-made autoclave whose atmosphere had been replaced with nitrogen were charged 8.23 g (50 mmoles) of ethyl 4-chloroacetoacetate and 20 ml of ethanol. To the mixture was added 84 mg (0.05 mmole) of Ru2Cl4 ((-)-BINAP)2 (C2H5)3N, and the mixture was heated to 100° C. When the temperature reached 100° C., 100 kg/cm2 of hydrogen was introduced into the autoclave, and the mixture was stirred under heating. After cooling to room temperature, the reaction mixture was taken out, and the ethanol was removed by distillation. Distillation of the residue gave 8.07 g (97) of ethyl 4-chloro-3-hydroxybutyrate having a boiling point of 74°-75° C./l mmHg).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:10]3[C:12]([CH3:15])=[N:13][CH:14]=[C:9]3[CH:8]=[N:7][C:6]=2[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([CH3:35])OCC[O:31]2)=[CH:26][CH:25]=1)[CH3:2].Cl>CC(C)=O>[CH2:1]([C:3]1[C:11]2[N:10]3[C:12]([CH3:15])=[N:13][CH:14]=[C:9]3[CH:8]=[N:7][C:6]=2[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30](=[O:31])[CH3:35])=[CH:28][CH:29]=1)[CH3:2]
Reactant: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc3cnc(C)n3c12
Agent: Cl
Solvent: CC(C)=O
Product: CCc1c(-c2ccc(C(C)=O)cc2)n(COCC[Si](C)(C)C)c2ncc3cnc(C)n3c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
8-Ethyl-1-methyl-7-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.147 g, 0.298 mmol, prepared using D from Preparation #5 with (E)-styreneboronic acid, E, F, G, I, J.2 with Ac2O and L.1 with mercury(II) trifluoracetate) was dissolved in acetone (10 mL) then HCl (5.0 N aqueous, 3.0 mL, 15 mmol) was added. The mixture was stirred at rt for about 1 h. The mixture was concentrated under reduced pressure then treated with saturated aqueous NaHCO3 (5 mL) and water (10 mL). The layers were separated then the aqueous mixture was extracted with DCM (25 mL then 2×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 1-(4-(8-ethyl-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-7-yl)phenyl)ethanone (0.092 g, 69%): LC/MS (Table 2, Method a) Rt=3.30 min; MS m/z 449 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-(tert-butoxy carbonyl)piperazine according to conditions described in general procedure C. Mp: 175-177° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.36 (s, 9 H), 1.58-1.59 (m, 6 H), 3.24-3.31 (m, 8 H), 3.47 (s, 4 H), 6.22 (d, J=5.5 Hz, 1H), 6.96 (d, J=12.4 Hz, 1 H), 7.15 (d, J=9.1Hz, 1 H), 7.41 (d, J=8.0 Hz, 1 H), 7.47 (s, 1 H), 7.50-7.62 (m, 3 H), 7.82-7.84 (m, 1 H), 7.98 (d, J=7.7 Hz, 1 H), 8.27 (d, J=5.5 Hz, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([NH2:28])=[N:25][C:24]=1[CH3:29])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([NH:28][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:25][C:24]=1[CH3:29])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)CCCc2ccccc2)sc1C(=O)NCc1ccccc1
Yield: 47 %

Procedure:
Following the procedure as described in Example 11, making variations only as required to use 4-phenylbutanoic acid in place of 5-phenylpentanoic acid to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 47% yield; m.p. 45-46° C.; 1H NMR (CDCl3, 300 MHz) δ 11.13 (s, br, 1H), 7.35-7.09 (m, 10H), 6.24 (t, J=5.0 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.52 (s, 3H), 2.41 (t, J=7.5 Hz, 2H), 2.00 (q, J=7.5 Hz, 2H); MS (ES+) m/z 397.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH:14]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:15]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred solution of methyl 5-chloro-2-(3-hydroxyazetidin-1-yl)nicotinate (D62) (50 mg, 0.206 mmol) and triethylamine (0.057 ml, 0.412 mmol) in dimethylformamide (0.26 ml) cooled at 0° C., methansulfonyl chloride (0.016 ml, 0.206 mmole) was added dropwise and the reaction mixture stirred at the same temperature for 1 h. After solvent evaporation the obtained residue was purified by SPE-Si (5 g) eluting with a mixture petroleum ether/ethyl acetate from 90/10 to 70/30. Collected fractions, after solvent evaporation, afforded the title compound (D63) (53 mg)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13](=[O:24])[N:14]2C(OC(C)(C)C)=O)=[CH:10][CH:9]=1.I[CH2:26][CH2:27][N:28]([CH2:33][CH2:34]I)[S:29]([CH3:32])(=[O:31])=[O:30].C(O)(=O)C>CN(C=O)C.O.C(OCC)(=O)C>[Br:7][C:8]1[CH:16]=[C:15]2[NH:14][C:13](=[O:24])[C:12]3([CH2:34][CH2:33][N:28]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:26]3)[C:11]2=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)Cc2ccc(Br)cc21
Reactant: CS(=O)(=O)N(CCI)CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
Cesium carbonate (3.4 g, 10.6 mmol) was added portionwise over a 20 minute period to a stirred solution of tert-butyl 6-bromo-2-oxoindoline-1-carboxylate (preparation 8a, 1.0 g, 3.2 mmol) and N,N-bis(2-iodoethyl)methanesulfonamide (preparation 12b, 1.42 g, 3.5 mmol) in N,N′-dimethylformamide (50 mL) under an argon atmosphere. After the addition the mixture was warmed to room temperature and stirred overnight. Acetic acid (0.2 mL) followed by ethyl acetate and water were added to the reaction mixture and the organic layer was separated, washed with water, dried (MgSO4) and evaporated. The residue was treated with a 5M solution of hydrogen chloride in 1,4-dioxane (25 mL) and the mixture was stirred and heated to 70° C. After 30 minutes, the mixture was concentrated in vacuo and the residue was purified by flash chromatography (98:2 dichloromethane/methanol) to give the title compound (0.33 g, 29%) as a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][C:6]=2[S:5][CH:4]=1)=[CH2:2]>C1COCC1.CO.[Pd]>[CH2:1]([C:3]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:7][C:6]=2[S:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of tert-butyl 8-ethenyl-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (231 mg) in THF-MeOH (2:1, 15 mL) was added 10% palladium on carbon (50 mg), and the mixture was stirred for 1 hr under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→15% ethyl acetate/hexane) to give the title compound (195 mg, 84%) as a colorless oil.