Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]#[N:14])=[CH:10][C:9]=2[C:15]#[N:16])=[CH:4][CH:3]=1.[Br:17]Br.O>O1CCOCC1>[Br:17][C:10]1[C:9]([C:15]#[N:16])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:12][C:11]=1[C:13]#[N:14]
Reactant: N#Cc1cc(C#N)c(-c2ccc(Cl)cc2)[nH]1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1[nH]c(-c2ccc(Cl)cc2)c(C#N)c1Br
Temperature: 25 °C

Procedure:
A sample of 5-(p-chlorophenyl)pyrrole-2,4-dicarbonitrile (1.0 g, 0.004 mole) is dissolved in 20 mL of dioxane and-a solution of bromine (0.8 g, 0.005 mole) in dioxane (10 mL) is then added thereto. The solution is stirred several hours at room temperature and then poured into water precipitating a white solid (1.2 g, 100%). The solid has a m.p. >225° C. and a mass spectrum of a sample gives a pattern consistent with the desired structure.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH-].[Na+].Br[CH2:15][CH2:16][CH2:17][Cl:18]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][CH2:4][O:3][CH3:2])[CH2:7][CH2:8]1
Reactant: ClCCCBr
Reactant: COCCC1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COCCC1CCN(CCCCl)CC1
Yield: 86.7 %

Procedure:
4-(2-Methoxy-ethyl)-piperidine hydrochloride (1.5 g, 8.4 mmol), acetone (30 ml, 20 vol), 5M NaOH solution (6.03 ml, 3.6 eq.) and 1-bromo-3-chloropropane (3.96 g, 25.1 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (1.6 g, 88%) as a pale yellow oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:38][NH2:39]>>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:39][CH3:38])[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Solvent: C1CCOC1
Product: CNCCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Yield: 19.4 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.340 g, 0.720 mmol) in 2.0 M methylamine in THF (8 mL, 16 mmol) was stirred at 70° C. in a sealed tube for about 15.5 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in chloroform and aqueous sodium bicarbonate. The organic phase was then washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 10% methanol in chloroform and 1.0% ammonium hydroxide/10% methanol in chloroform. After drying at 57° C. in vacuo for 20 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-methyl-amine as a light yellow semi-solid (0.0461 g, 19.4%) was obtained. This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 73° C. for 20 hours to yield the hydrochloride as a tan foam (0.0422 g). Mass Spectrum (+EI, [M+H]+) m/z 332. 1HNMR (500 MHz, DMSO-d6): δ14.24 (s, 1H), 8.89 (s, 2H), 7.96-7.99 (m, 2H), 7.53-7.68 (m, 4H), 7.40 (d, 1H, J=2.19 Hz), 7.25 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.30-4.32 (m, 2H), 3.33-3.35 (m, 2H), 2.60-2.63 ppm (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Br-:8].[NH2:1][C:2]1[CH:7]=[CH:6][N+:5]([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccncc1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: Nc1cc[n+](C(c2ccccc2)c2ccccc2)cc1
Product: [Br-]

Procedure:
A mixture of 38 parts of 4-aminopyridine, 100 parts of bromodiphenylmethane and 500 parts by volume of acetonitrile is heated at reflux temperature for about three hours with stirring. The reaction mixture is filtered, the solid obtained washed with 125 parts by volume of hot acetonitrile and air-dried overnight at room temperature. The obtained solid is recrystallized from 500 parts by volume of ethanol to yield 4-amino-1-(diphenylmethyl)pyridinium bromide, as a colorless crystalline solid melting at about 260°-262° C. This compound has the following formula. ##STR19##
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OC(=O)c2c(O)cccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1OC(=O)c2c(OCc3ccccc3)cccc21
Reaction time: 72 h
Yield: 68.7 %

Procedure:
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (0.51 g, 3.09 mmol) in anhydrous N,N-dimethylformamide (7 ml) under nitrogen was added sodium hydride (130 mg, 3.25 mmol). Immediate evolution of gas and bright yellow color was observed. The mixture was stirred for 5 minutes after which benzyl bromide (1.8 ml, 15.45 mmol) was added. The reaction was stirred for 72 h. Saturated sodium bicarbonate (2 ml) was added and the mixture stirred for 2 minutes, diluted in ethyl acetate (35 ml) and washed with saturated sodium bicarbonate (5 ml), 1N hydrochloric acid (5 ml), and brine (2×5 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. To the crude material was added hexane and the formed precipitate was filtered off, washed further with hexane and dried in vacuo to give 0.54 g (69%) of 4-(benzyloxy)-isobenzofuran-1,3-dione as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(N2CCN(Cc3ccc(N)cc3)CC2)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: CCc1ccc(N2CCN(Cc3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 1-(p-ethylphenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(p-ethylphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[N:14]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15](=[O:18])[N:16]([CH3:17])[C:12]=3[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:26]1([Mg]Cl)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:22][C:20]([CH3:21])([CH3:23])[CH2:19][N:14]1[C:13]2[CH:24]=[CH:25][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:2])[CH:5]=3)=[CH:11][C:12]=2[N:16]([CH3:17])[C:15]1=[O:18]
Reactant: CC(=O)c1cccc(-c2ccc3c(c2)n(C)c(=O)n3CC(C)(C)C)c1
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(C(C)(O)c4ccccc4)c3)cc21
Reaction time: 1 h

Procedure:
A solution of 5-(3-acetylphenyl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-17, 170 mg, 0.51 mmol) in anhydrous THF (5 ml) was cooled to −78 deg C. and treated with Phenyl magnesium chloride (1.8 M in THF, 365 μL, 0.66 mmol, 1.3 eq). The reaction mixture was warmed to 0 deg C. and stirred for 1 h. The reaction was only ˜30% complete, so more of the Grignard reagent (1.8 M in THF, 365 μL, 0.66 mmol, 1.3 eq) was added at 0 deg C. and the reaction was maintained there for 30 min. The completed reaction was partitioned between EtOAc (50 ml) and water (55 ml) and the cloudy, white precipitate present which was removed via filtration. The filtrate was separated in a separatory funnel and the aqueous layer was re-extracted with EtOAc (50 ml). The combined organic layers were dried over Na2SO4, concentrated, then purified via flash column chromatography (SiO2: 100% Hex to 50:50 Hex/EtOAc), affording the title compound, 1-(2,2-dimethylpropyl)-5-[3-(1-hydroxy-1-phenylethyl)phenyl]-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (10-1) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.48-7.45 (m, 3H), 7.40-7.31 (m, 4H), 7.27-7.24 (m, 2H), 7.12 (s, 1H), 7.05 (d, 1H, J=8.15 Hz), 3.67 (s, 2H), 3.45 (s, 3H), 2.02 (s, 3H), 1.05 (s, 9H). LRMS m/z: Calc'd for C27H30N2O2(M+H) 415.2, found 415.5.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]2[NH:21][C:22]([C:27]3[C:28](=[O:43])[N:29]([NH:38][CH:39]4[CH2:42][CH2:41][CH2:40]4)[C:30]4[C:35]([C:36]=3[OH:37])=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:23][S:24](=[O:26])(=[O:25])[C:19]=2[CH:18]=1.C(N(CC)CC)C>ClCCl>[CH:39]1([NH:38][N:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]([OH:37])=[C:27]([C:22]3[NH:21][C:20]4[CH:44]=[CH:45][C:17]([NH:16][S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:15][CH2:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)=[O:7])=[CH:18][C:19]=4[S:24](=[O:26])(=[O:25])[N:23]=3)[C:28]2=[O:43])[CH2:40][CH2:41][CH2:42]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 662.8 %

Procedure:
A solution of chlorosulfonyl isocyanate (0.051 g, 0.36 mmol) in dichloromethane (2 mL) was treated dropwise with benzyl alcohol (0.039 g, 0.36 mmol) at 0° C., stirred at 25° C. for 30 minutes and treated with a solution of the product of Example 464B (0.127 g, 0.03 mmol) and triethylamine (0.12 g, 1.2 mmol) in dichloromethane (4 mL). The reaction mixture was stirred for 2 hours at 25° C. and partitioned between dichloromethane (10 mL) and 1N aqueous hydrochloric acid (10 mL). The resulting organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 3% methanol in dichloromethane to provide the title compound (0.127 g, 66% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.57 (m, 1 H) 1.70 (m, 1 H) 2.04 (m, 4 H) 3.78 (m, 1 H) 5.12 (s, 2 H) 6.57 (s, 1 H) 7.30 (m, 5 H) 7.44 (t, J=7.54 Hz, 1 H) 7.50 (m, 1 H) 7.66 (m, 2 H) 7.89 (t, J=7.91 Hz, 1 H) 8.07 (d, J=8.09 Hz, 1 H) 8.17 (d, J=8.46 Hz, 1 H) 11.13 (s, 1 H) 12.16 (s, 1 H) 14.15 (s, 1 H) 15.06 (s, 1 H). MS (ESI−) m/z 637 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([OH:30])=O)=[CH:25][C:24]=4[CH:31]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.C([O:59][C:60](=[O:64])[CH2:61][NH:62][CH3:63])C>>[CH3:34][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([N:62]([CH2:61][C:60]([OH:64])=[O:59])[CH3:63])=[O:30])=[CH:25][C:24]=4[CH:31]=3)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33]
Reactant: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)N(C)CC(=O)O)cc2c1

Procedure:
A solution of 5-{1-[4-(3,3-Dimethyl-2-oxo-cyclohexyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid (153 mg, 0.331 mmol) (from example R2), EDC (94 mg, 0.496 mmol), HOBT (47 mg, 0.347 mmol), triethylamine (0.2 ml, 1.3 mmol), and sarcosine ethyl ester hydrochloride (76 mg, 0.496 mmol) were reacted followed by base hydrolysis as in Example 74 to yield (55 mg, 34%) MS (ES) m/e: 532.3 (M−1)
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[C:18]([O:22][C:23](=[O:30])[NH:24][C@H:25]1[CH2:28][C@H:27]([NH2:29])[CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.CC(C)([O-])C.[Na+]>ClCCl>[C:18]([O:22][C:23](=[O:30])[NH:24][C@H:25]1[CH2:28][C@H:27]([N:29]2[C:2]3=[N:7][CH:6]=[CH:5][N:4]=[C:3]3[C:8]([CH3:13])([CH3:12])[C:9]2=[O:11])[CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3nccnc32)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-(3-Chloropyrazin-2-yl)-2-methylpropanoic acid (intermediate 29, 0.302 g, 1.505 mmol) was dissolved in dichloromethane (20 mL) and treated with thionyl chloride (5.0 ml, 68.5 mmol). The solution was heated at reflux for 30 minutes then evaporated to dryness under reduced pressure. Carbon tetrachloride (20 ml) was added to the crude residue and it was evaporated to dryness once more. It was dried under high vacuum for 20 minutes. The crude acid chloride was dissolved in dichloromethane (6 mL) and added slowly to an ice cooled solution of tert-butyl(trans-3-aminocyclobutyl)carbamate (0.280 g, 1.505 mmol) and diisopropylethylamine (2.5 ml, 14.37 mmol) in dichloromethane (10 mL). The solution was stirred for 15 minutes after which the mixture was evaporated to dryness under reduced pressure and the crude dissolved in dry tetrahydrofuran (10 mL). Sodium t-butoxide (1.45 g, 15.09 mmol) was added and the reaction stirred at room temperature. After 30 minutes the reaction was partitioned between water (300 mL) and ethyl acetate (300 mL). The organic was washed with 20% saturated ammonium chloride (200 mL) then dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired tert-butyl(trans-3-(7,7-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)cyclobutyl)carbamate (0.462 g, 1.390 mmol, 92% yield). It was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (5 mL). The solution was stirred for 15 minutes. The dark solution was evaporated to dryness under reduced pressure and further dried under high vac. The crude amine was combined with purified using silica chromatography (1-20% (2N ammonia in methanol) in dichloromethane gradient) to give 5-(trans-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.294 g, 1.27 mmol, 91% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8]/[CH:9]=[C:10](/[F:13])\[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:12][CH2:11]/[C:10](/[F:13])=[CH:9]\[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC/C=C(/F)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC/C=C(/F)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of (E)-tert-butyl-N-(3-fluoro-4-hydroxybut-2-enyl)carbamate (1.65 g, 8 mmol) in CH2Cl2 (30 mL) at 0° C. under nitrogen was added triethylamine (1.67 mL, 12 mmol) followed by methanesulfonyl chloride (0.74 mL, 9.6 mmol). The reaction was left to stir at 0° C. for 1 hr. All volatiles were removed under reduced pressure and the crude yellow residue was taken up in acetone (30 mL). The insoluble white precipitate (triethylammonium chloride) was filtered off and washed with acetone (10 mL). The filtrate containing the crude mesylate was used immediately for Procedure E.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18](O)=[O:19])[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:44][C@@H:45]([C:48]1[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[C:50]([Cl:56])[CH:49]=1)[CH2:46][CH3:47].C(N(CC)CC)C>CN(C)C=O>[Cl:56][C:50]1[CH:49]=[C:48]([C@H:45]([NH:44][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:19])[CH2:46][CH3:47])[CH:55]=[CH:54][C:51]=1[C:52]#[N:53]
Reactant: CC[C@@H](N)c1ccc(C#N)c(Cl)c1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C#N)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (75 mg, 0.270 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol). The mixture was stirred for 2 h at 50° C., then 4-((R)-1-amino-propyl)-2-chloro-benzonitrile hydrochloride (68 mg, 0.3 mmol) and triethylamine (60 mg, 0.6 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 82 mg (67%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(3-chloro-4-cyano-phenyl)-propyl]-amide as white solid. LC/MS (method 2): Rt=1.24 min; m/z=455.08 (M+H+). 1H-NMR: δ (ppm)=8.20 (1H, d), 7.94 (1H, d), 7.70 (1H, s), 7.50 (1H, d), 7.24 (1H, s), 4.95 (1H, d), 4.82-4.92 (2H, m), 4.20-4.29 (2H, m), 3.70-4.00 (5H, m), 2.07 (1H, m), 1.97 (1H, m), 1.74-1.85 (3H, m), 1.57 (1H, m), 1.19 (3H, d), 0.89 (3H, t).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].N1C=CC=C[CH:25]=1>ClCCl>[CH:17]([O:22][CH:14]([CH3:13])[CH3:9])([CH3:18])[CH3:25].[C:17]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][CH2:6]1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: c1ccncc1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCC(NC(=O)c2ccc(F)cc2)CC1
Product: CC(C)OC(C)C
Reaction time: 24 h

Procedure:
To a suspension of N-(piperidin-4-yl)-4-fluorobenzamide (556 mg) in dichloromethane (5 ml) were added pivaloyl chloride (0.37 ml), pyridine (0.24 ml) and N,N-dimethylaminopyridine (25 mg) at ambient temperature. After stirring for 1 day, the mixture was diluted with dichloromethane, and washed with water and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. After trituration with diisopropyl ether, N-(1-pivaloylpiperidin-4-yl)-4-fluorobenzamide (305 mg) was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17].B(Br)(Br)Br.BrC1C=C2C(C=CN=C2)=CC=1O>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C:16]([F:19])([F:17])[F:18]
Reactant: COc1ccc2cncc(CCCC(F)(F)F)c2c1
Agent: BrB(Br)Br
Agent: Oc1cc2ccncc2cc1Br
Product: Oc1ccc2cncc(CCCC(F)(F)F)c2c1
Yield: 42.4 %

Procedure:
1.02 g of 6-Methoxy-4-(4,4,4-trifluoro-butyl)-isoquinoline (87) were treated with boron tribromide as described for the synthesis of compound 1 to give 410 mg of the desired product 88. LCMS Method #1, retention time 1.04 min, detected mass 256.00 [M+H]+
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[CH3:26][C:27]1([C:51]([NH2:53])=[O:52])[C:32]([CH3:34])([CH3:33])[S:31][CH2:30][CH2:29][N:28]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]#[C:47][CH2:48][CH2:49]O)=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(Br)(Br)(Br)[Br:55]>C1COCC1>[CH3:26][C:27]1([C:51]([NH2:53])=[O:52])[C:32]([CH3:34])([CH3:33])[S:31][CH2:30][CH2:29][N:28]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]#[C:47][CH2:48][CH2:49][Br:55])=[CH:40][CH:39]=1)(=[O:37])=[O:36]
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCO)cc2)C1(C)C(N)=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCBr)cc2)C1(C)C(N)=O
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of 2.123 g (8.093 mmol) of triphenylphosphine and 0.373 mL (4.61 mmol) of pyridine in 40 mL of dry THF under nitrogen was added 1.73 g (4.046 mmol) of methyl 4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide. The solution was cooled in a water bath and 1.34 g (4.046 mmol) of carbon tetrabromide was added and the resulting mixture was stirred for 3 h. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:8) to provide 1.726 g (87%) of methyl 4-({4-[(5-bromo-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide as a pale yellow oil. Electrospray Mass Spec: 492.0 (M+H)+
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]C(=O)OC(C)(C)C)=[C:14]([NH:26][C:27]2[N:35]=[C:34]3[C:30]([NH:31][C:32](=[O:47])[N:33]3[C@H:36]3[C:45]4[C:40](=[C:41]([F:46])[CH:42]=[CH:43][CH:44]=4)[O:39][CH2:38][CH2:37]3)=[CH:29][N:28]=2)[CH:13]=1>>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=1[NH:26][C:27]1[N:35]=[C:34]2[C:30]([NH:31][C:32](=[O:47])[N:33]2[C@H:36]2[C:45]3[C:40](=[C:41]([F:46])[CH:42]=[CH:43][CH:44]=3)[O:39][CH2:38][CH2:37]2)=[CH:29][N:28]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(F)cc1Nc1ncc2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A freshly prepared solution of 30% TFA/DCM (5 mL) was added to (R)-tert-butyl 4-fluoro-2-(9-(8-fluorochroman-4-yl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino)phenylcarbamate and the solution was stirred at room temperature for 60 min then the solvents were removed in vacuo to yield (R)-2-(2-amino-5-fluorophenylamino)-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one that was used as such MH+=411.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:33])[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=2[CH3:22])[CH:12]=[CH:11][C:10]=1[O:29]C(=O)C.C(=O)([O-])O.[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:33])[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=2[CH3:22])[CH:12]=[CH:11][C:10]=1[OH:29]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccn3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccccn3)c2)=C(C)C1=O
Yield: 50.8 %

Procedure:
N-(Pyridin-2-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.050 g, 0.111 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.023 g, 0.0564 mmol, 51%).