Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[C:30]1(=O)[CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:30]1([N:8]2[CH2:9][CH2:10][CH:11]([O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)[CH2:33][CH2:32][CH2:31]1
Reactant: O=C1CCC1
Reactant: N#Cc1ccc(OC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reaction time: 0.08 h

Procedure:
4-(4-Piperidinyloxy)benzonitrile trifluoroacetate (D22) (2.2 g) was dissolved in DCM (50 ml) and triethylamine (1.92 ml) was added followed by cyclobutanone (0.64 g). The mixture was stirred for 5 min, then sodium triacetoxyborohydride (1.94 g) was added and the reaction was stirred at rt under argon overnight. The reaction mixture was then washed with saturated potassium carbonate solution (3×30 ml) and brine (30 ml). The organic layer was dried (MgSO4) and evaporated to give the title compound (D23) as a white solid (1.91 g). 1H NMR δ (CDCl3): 7.56 (2H, d, J=6.84 Hz), 6.93 (2H, d, J=6.80 Hz), 4.41 (1H, m), 2.77 (1H, m), 2.75 (2H, m), 2.30 (2H, m), 2.06 (4H, m), 1.87 (4H, m), 1.66 (2H, m).
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].C[C:10]1[C:11](=[O:17])[CH2:12][CH2:13][CH2:14][C:15]=1[CH3:16].[CH2:18]1COC[CH2:19]1>>[CH3:18][C:19]1[CH2:16][CH2:15][CH:14]2[C:7]([C:5]=1[CH3:6])=[CH:10][C:11](=[O:17])[CH2:12][CH2:13]2
Reactant: C1CCOC1
Reactant: CC(C)[N-]C(C)C
Reactant: CC1=C(C)C(=O)CCC1
Agent: [Li+]
Product: CC1=C(C)C2=CC(=O)CCC2CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a stirred solution of lithium diisopropylamide (LDA) (22 mmol) in THF (200 ml) at -78° C. was added a solution of 2,3-dimethylcyclohexenone (2.48 g, 20 mmol) in THF (50 ml). The mixture was warmed to 25° C., and the solvent and the amine were removed under vacuum. The resulting solid was dissolved in THF (400 ml) and the solution cooled to -78° C. To this solution was added MVK (1.8 ml, 22 mmol) in THF (100 ml) over 10 min. The resulting mixture was stirred 12 hr at room temperature, then worked up. Removal of solvent yielded the dione as a yellow oil (2.8 g, 60%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15](Br)Br)[C:10]=1[CH2:18]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-:23])(=[O:22])[CH3:21].[Na+].C(O)(=[O:27])C>O>[C:20]([O:23][CH2:18][C:10]1[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[CH:15]=[O:27])(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: CC(=O)[O-]
Reactant: O=C(c1ccccc1)c1cccc(C(Br)Br)c1CBr
Agent: [Na+]
Solvent: O
Product: CC(=O)OCc1c(C=O)cccc1C(=O)c1ccccc1

Procedure:
To a stirred solution of crude 1-benzoyl-2-bromomethyl-3-(dibromomethyl)benzene (2.3 g, 5 mmol) in glacial acetic acid (30 ml) was added sodium acetate (4.5 g, 55 mmol) in water (8 ml). The stirred mixture was heated to reflux temperature for sixteen hours, cooled and partitioned between diethylether (100 ml), ethyl acetate (20 ml) and 10% sodium carbonate solution (100 ml). Further solid sodium carbonate was added until effervescence ceased. The organic layer was washed with 10% sodium carbonate solution (30 ml) and brine (30 ml) and dried over sodium sulphate. Removal of the solvent under reduced pressure gave an oil (1.1 g) that was chromatographed (SiO2 (40 g) using (4:1) pentane:ethyl acetate as eluent). This gave 2-acetoxymethyl-3-benzoylbenzaldehyde (0.35 g, 22% from 1-benzoyl-2,3-dimethylbenzene).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:9]2)=[C:4]([CH2:15][CH3:16])[CH:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:3][C:4]=2[CH2:15][CH3:16])[CH2:10][CH2:9]1)([CH3:14])[CH3:13]
Reactant: CCc1cc(Br)ccc1C1(OC(C)C)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCc1cc(C#C[Si](C)(C)C)ccc1C1(OC(C)C)CC1
Temperature: 70 °C
Yield: 99.5 %

Procedure:
Using General Procedure D; 4-bromo-1-(1-isopropoxycyclopropyl)-2-ethyl-benzene (Intermediate 93, 300.0 mg, 1.07 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (20.0 mg, 0.11 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (75.0 mg, 0.11 mmol). The resulting reaction mixture was heated to 70° C. for 5 d. The title compound (320.0 mg, 99%) was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: BrC1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:3]=1[C:20]([O:22]CC)=[O:21].BrC1C2C(=CC=CC=2)NC=1C(OCC)=[O:36].[CH3:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Cl)=[CH:44][CH:43]=1.[H-].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[CH2:40]1[O:41][C:42]2[CH:49]=[CH:48][C:45]([C:46]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[C:3]=3[C:20]([OH:22])=[O:21])=[CH:44][C:43]=2[O:36]1
Reactant: CCOC(=O)c1c(Br)c2ccccc2n1Cc1ccc(OC)cc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(Cn2c(C(=O)O)c(-c3ccc4c(c3)OCO4)c3ccccc32)cc1
Yield: 88 %

Procedure:
Ethyl 3-bromo-1-(4-methoxybenzyl)indole-2-carboxylate. To a solution of ethyl 3-bromoindole-2-carboxylate (2.0 g, 7.46 mmol) and 4-methoxybenzyl chloride (7.46 mmol) in HMPA (5 mL) was added a slurry of NaH (240 mg of 80% oil dispersion, oil removed by pentane washing, 8.0 mmol) in HMPA (1 mL). After 30 min at room temperature the reaction mixture was partitioned between 3N HCl (100 mL) and EtOAc (150 mL). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O, saturated aqueous NaCl and dried (Na2SO4). The solvent was removed in vacuo to afford the title compound (2.55 g, 88%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:43][C:44]#[N:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:43][C:44]#[N:45])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: N#CCBr
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N(CC#N)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: -78 °C
Reaction time: 16 h
Yield: 27.7 %

Procedure:
A solution of 6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide (0.01 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.026 ml), followed by bromoacetonitrile (0.013 g). The resultant solution was allowed to reach room temperature and stirred for a further 16 h. The mixture was then cooled to −78° C. and further lithium bis(trimethylsilyl)amide (0.026 ml) added. After reaching room temperature, the reaction mixture was stirred for a further 18 h and then quenched by the addition of methanol (1 ml). The resultant solution was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.003 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([C:11](O)=[O:12])[CH2:5]2.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([CH2:11][OH:12])[CH2:5]2
Reactant: O=C(O)[C@H]1Cc2ccc(Br)cc2C1
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1Cc2ccc(Br)cc2C1
Temperature: 1 °C
Yield: 99.2 %

Procedure:
(S)-5-Bromo-indan-2-carboxylic acid (12.65 mmol) was dissolved in dry THF (75 mL). The mixture was cooled with stirring to 0-2° C. under argon. 1M BH3 in THF (18.4 mL; 18.4 mmol) was added via syringe at a rapid dropwise rate. The mixture was stirred at 0° C. for 30 minutes then allowed to warm to rt and stir for 90 minutes. The reaction mixture was cooled again to 0° C. and treated carefully with 10 mL of water. Volatiles were removed under reduced pressure and the residue partitioned between diethyl ether (100 mL) and brine (50 mL). The aqueous phase was extracted with 100 mL ethyl ether and each extract washed with brine. The combined extracts were dried over Na2SO4, filtered and volatiles were removed under reduced pressure to give 2.85 g of ((S)-5-bromo-indan-2-yl)-methanol as a crystalline white solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CN(C)C=O>[C:12]1([C:11]2[O:9][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=c1oc(-c2ccccc2)nc2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Anthranilic acid (1.0 g, 7.29 mmol) was dissolved in pyridine (10 mL), benzoyl chloride (1.13 g, 8.02 mmol) was slowly added on an ice bath, and stirred at 50° C. overnight. The solvent was distilled off under reduced pressure, the residue was dissolved in dry methylene chloride (20 mL), oxalyl chloride (925 mg, 7.29 mmol) and a catalytic amount of dimethylformamide were added on an ice bath, and stirred at room temperature for 4 hours. Saturated sodium hydrogen carbonate aqueous solution was added, the mixture was extracted with methylene chloride, and the organic phase was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was washed by diethyl ether/heptane, and the target substance (1.13 g, 69%) was obtained as a light yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])[NH:21][N:20]=2)=[O:24])[CH2:52][CH2:53]1)=[O:69]
Reactant: O=C(O)c1cc(-c2ccccc2F)[nH]n1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2F)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 46.2 %

Procedure:
DIPEA (123 mg, 0.16 mL, 0.95 mmol) was added to a stirred solution of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (56 mg, 0.27 mmol) in DMF (2 mL). HOBT (39 mg, 0.28 mmol) and EDCI (55 mg, 0.28 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (100 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitate. The solid was purified by recrystallisation from a mixture of ethyl acetate and hexane to afford 65 mg (33.16% yield) of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 97.49%. 1H NMR (DMSO-d6): δ 13.6 (s, 1H), 7.7 (m, 4H), 7.6 (m, 1H), 7.38 (m, 3H), 7.1 (m, 2H), 6.98 (m, 4H), 4.5 (m, 1H), 4.0 (m, 1H), 3.2 (m, 2H), 2.9 (m, 2H), 1.91 (m, 1H), 1.65 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8](OCC=C)[NH:7]1)=[O:5].C(N(CC)CC)C.[C:22]([O:26][C:27]([NH:29][CH:30]([CH2:34][CH:35]=[CH2:36])[C:31]([OH:33])=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].[CH:37]1(N=C=NC2CCCCC2)[CH2:42]CCC[CH2:38]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([CH2:42][CH:37]=[CH2:38])[N:7]1[C:31](=[O:33])[CH:30]([NH:29][C:27]([O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:28])[CH2:34][CH:35]=[CH2:36])=[O:5]
Reactant: C=CCOC1CCC(C(=O)OC)N1
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(NC(=O)OC(C)(C)C)C(=O)N1C(CC=C)CCC1C(=O)OC
Yield: 87 %

Procedure:
To a solution of 5-allyloxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride, 5, (17.82 g, 86.6 mmol) and triethylamine (36 mL, 260 mmol) in CH2Cl2 (500 mL), 2-tert-butoxycarbonylamino-pent-4-enoic acid (41.1 g, 191 mmol), 1,3-dicyclohexylcarbodiimide (46.4 g, 225 mmol), and 4-dimethylaminopyridine (21.1 g, 173 mmol) are added. Once consumption of the starting material is complete, the precipitate that forms is filtered from the reaction mixture. The CH2Cl2 is reduced in vacuo and residue which remains is diluted with ether (500 mL). A white precipitate forms which is collected by filtration. The solvent is then removed and the resulting residue dissolved in ethyl acetate (250 mL) then further diluted with hexanes (250 mL). A white precipitate again forms and is removed. The solution which remains is concentrate in vacuo and the residue purified over silica (hexanes/ethyl acetate 80:20) to afford 27.69 g (87% yield) of the desired product as a slightly yellow oil. 1H-NMR (300 MHz, CDCl3): δ 5.91–5.74 (m, 2H), 5.22–5.01 (m, 5H), 4.55–4.40 (m, 3H), 3.81–3.74 (m, 3H), 2.60–1.90 (m, 4H), 1.45 (s, 9H); 13C-NMR (75.5 MHz, CDCl3): δ 183.85, 172.92, 172.52, 171.69, 155.58, 135.05, 134.27, 133.45, 118.63, 117.43, 80.00, 60.00, 59.58, 58.47, 52.41, 52.41, 52.10, 51.20, 39.69, 38.09, 29.82, 28.54, 27.11; MS (ESI): m/e=367.21 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=2[C:18]([CH3:35])([CH3:34])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Na].[O:37]=[O:38]>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[O:38][O:37][C:12]2([C:18]([CH3:35])([CH3:34])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:13]([CH3:17])([CH3:16])[CH2:14][O:15]3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=O
Reactant: CC(=O)Oc1cccc(C2=C(C(C)(C)COCCCCCCCCCCC(=O)O)C(C)(C)CO2)c1
Agent: [Na]
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C23OCC(C)(C)C2(C(C)(C)COCCCCCCCCCCC(=O)O)OO3)c1

Procedure:
5-(3-acetoxyphenyl)-4-(13-carboxy-1,1-dimethyl-3-oxatridecan-1-yl)-3,3-dimethyl-2,3-dihydrofuran (compound (22)) (125 mg, 0.256 mmol) and TPP (1 mg) were added to dichloromethane (12 mL), and the mixture was irradiated with visible light by a 940 W sodium lamp in an oxygen atmosphere at 0° C. for 30 minutes. The reaction mixture was concentrated, and the concentrate was put into a silica gel column and developed with a mixed solvent of hexane and ethyl acetate (10:1 to 5:1), whereby 1-(3-acetoxyphenyl)-5-(13-carboxy-1,1-dimethyl-3-oxatridecan-1-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (compound (23)) was obtained in an amount of 133 mg in a yield of 97.6%.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:26][CH2:27][CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:24])[C:8]=2[N:25]=1)[CH3:2].[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>ClCCl>[NH2:24][C:9]1[C:8]2[N:25]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:26][CH2:27][CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH:18]3[CH2:19][CH2:20][N:21]([C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])[CH2:22][CH2:23]3)=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)N=C=O
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCN(C(=O)NC(C)C)CC4)ccc3c21
Reaction time: 16 h

Procedure:
2-(Ethoxymethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.3 mmol) was slurried in dichloromethane (13 mL). Isopropyl isocyanate was added dropwise to the slurry and the reaction was stirred for 16 hours. The reaction was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-22% CMA in chloroform) followed by recrystallization from acetonitrile yielded 0.430 g of 4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}-N-isopropylpiperidine-1-carboxamide as a white solid, mp 163-164.5° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]1([NH:36][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with cyclopropylamine (20 mg, 0.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford the title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].I[CH2:24][CH:25]([OH:28])[CH2:26][OH:27].O>CN(C)P(N(C)C)(N(C)C)=O.CCOCC>[O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:17])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(O)CI
Reactant: O=C(O)c1ccc(NCCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(OCC(O)CO)c1ccc(NCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 5.5 g of 4-(3-phenoxypropylamino)benzoic acid, 4.80 g of 25% aqueous sodium hydroxide, and 12.6 g of 3-iodo-1,2-propanediol in 50 ml of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(3-phenoxypropylamino)benzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[Cl:20][C:21]1[C:22]([C:29]([OH:31])=[O:30])=[N:23][CH:24]=[C:25]([C:27]#[N:28])[CH:26]=1>>[CH:29]([OH:31])=[O:30].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:22]3[C:21]([Cl:20])=[CH:26][C:25]([C:27]#[N:28])=[CH:24][N:23]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncc(C#N)cc3Cl)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) and 3-chloro-5-cyano-pyridine-2-carboxylic acid (prepared according to Hori, A. et al., Int. Patent Application Publ. No. WO2009151098) yielded the title compound as a pale yellow solid. MS (ISP): m/z=438.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.C(N([CH2:28][CH3:29])CC)C.[CH2:30]([S:37](Cl)(=[O:39])=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>ClCCl>[CH2:8]([C:7]1[C:2]([N:1]([S:37]([CH2:30][C:29]2[CH:28]=[CH:33][CH:32]=[CH:31][CH:36]=2)(=[O:39])=[O:38])[S:37]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2cnc(N(S(=O)(=O)Cc3ccccc3)S(=O)(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C

Procedure:
2-Amino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-11) (prepared by the method described in Adamczyk M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (200 mg, 687 μmol) was dissolved in anhydrous dichloromethane (2 mL) and to this was added triethylamine (145 μL, 1.04 mmol), and cooled to 0° C. To this was added benzylsulfonyl chloride (196 mg, 1.03 mmol) and stirred for an hour after warming to room temperature. To this were sequentially added triethylamine (145 μL, 1.04 mmol), anhydrous dichloromethane (1.0 mL) and benzylsulfonyl chloride (131 mg, 687 μmol) and stirred for an hour. Furthermore, to this were sequentially added triethylamine (145 μL, 1.04 mmol), anhydrous dichloromethane (1.0 mL) and benzylsulfonyl chloride (131 mg, 687 μmol) and stirred for 2 h. To this was added 2 M hydrochloric acid to stop the reaction and, after separating the aqueous layer and organic layer, the organic layer was washed once with saturated brine and once with saturated aqueous solution of sodium sulfate, and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporater. The residue was purified by silica gel column chromatography (23 g, n-hexane/ethyl acetate=4/1) to give 3-benzyl-2-bis(benzylsulfonyl)amino-5-(4-methoxyphenyl)pyrazine (c-21) as a yellow amorphous (320 mg, 77.6%). Rf=0.63 (n-hexane/ethyl acetate=3/2). Mp. 78-80° C. UV (MeOH) λmax (log ε) 332.5 (4.31), 299.5 (4.20), 277.5 (4.06). UV (pH 7.4 PB) λmax (log ε) 342.5 (4.29), 303 (4.18), 280.5 (4.15). 1H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 3.97 (s, 2H), 4.78 (s, 1H), 4.82 (s, 1H), 4.94 (s, 1H), 4.97 (s, 1H), 6.96-7.02 (AA′BB′, 2H), 7.17 (d, J=7.2 Hz, 2H), 7.19-7.33 (m, 3H), 7.34-7.44 (m, 10H), 7.92-7.98 (AA′BB′, 2H), 8.80 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 37.4, 55.4, 61.0 (1C×2), 114.7 (2C), 126.4, 126.8 (1C×2), 128.1 (2C), 128.78 (2C), 128.84 (2C×2), 129.0, 129.3, 129.6 (2C), 131.6 (2C×2), 137.6, 138.5, 140.1, 151.9, 155.4, 161.5. IR (KBr, cm−1) 501, 611, 696, 773, 876, 922, 1028, 1144, 1163, 1250, 1354, 1373, 1422, 1431, 1454, 1495, 1514, 1607. HRMS (FAB+) m/z 600.1639 (M+H, C32H30N3O5S2 requires 600.1627).