Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([CH:34]=O)=[CH:4]1)[CH3:2].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([CH2:34][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(C=O)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCn1cc(CN2CCCC2)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
To a solution of 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (10 g, 21.12 mmol) in Dichloromethane (DCM) (150 mL) was added pyrrolidine (2.61 mL, 31.7 mmol), sodium triacetoxyborohydride (8.95 g, 42.2 mmol) and AcOH (0.060 mL, 1.056 mmol). The reaction mixture was stirred at 25° C. for 3 h. LCMS showed completion of the reaction. The mixture was extracted with DCM and washed with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The crude material was purified by normal phase automatic silica column chromatography (Combiflash RF), using a 120 g column and eluting with MeOH/DCM (0-20%). The product was further purified with reverse phase automatic silica column chromatography (Combiflash RF), using a 150 g golden column and eluting with acetonitrile/water (0-60%) to afford 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (4.6 g, 8.70 mmol, 41.2% yield) as a pale yellow solid. LCMS: (M+H)+: 529.4.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-])=O.[N+:12]([CH2:15][CH3:16])([O-])=O.C([O-])(=O)C.[NH4+].CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[NH2:12][CH:15]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:4][CH:5]=1)[CH3:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(N)Cc1ccccc1
Yield: 24.6 %

Procedure:
A mixture of 7.56 g (50 mmol) of 3-nitrobenzaldehyde, 11.25 g (150 mmol) of nitroethane and 4.24 g (55 mmol) of ammonium acetate was heated in 2 mL of acetic acid in a 110° C. oil bath for 2 1/2 hours. Subsequent examination of the mixture by preparative thin layer chromatography with hexane/ethyl acetate showed almost no starting material remaining. Volatile materials were removed with a rotary evaporator, and the residue was partitioned between dichloromethane and water, with washing of the organic layer twice with 10% sodium bicarbonate. Caution was necessary because gas evolution occurred during the first bicarbonate wash. Drying was performed with magnesium sulfate. Filtration and removal of solvent left 9.13 g of crude product. Half of this was chromatographed on a 3×35 cm flash silica column, packed with hexane and eluted with 7:1 hexane/ethyl acetate to give 1.66 g (32%) of pure title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C@H:9]([C:18]1[O:19]C=CC=1)[C@H:10]([CH3:17])[CH2:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH2:24].C(Cl)(Cl)(Cl)Cl.CC#N>CC#N.[Ru](Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[C:18]([OH:19])=[O:24])=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CCC(C)(C)O)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reactant: O
Agent: Cl[Ru](Cl)Cl
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@H](CCC(C)(C)O)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Ruthenium(III) chloride (0.031 g, 0.15 mmol) was added to a well-stirred mixture of NalO4 (0.567 g, 2.65 mmol) in water/CCl4/CH3CN (4.5/3/4.5 mL). After 15 minutes of stirring, at 0° C., 2.12e (0.144 g, 0.442 mmol) in MeCN (0.3 mL) was added. After stirring at room temperature for 30 minutes, another 1 equivalent of NalO4 was added and the resulting mixture was stirred for another 20 minutes. The reaction was quenched with water and extracted with ethyl acetate three times. The combined ethyl acetate layer was washed with 20% NaHSO3 aq. solution and brine, dried over MgSO4 and concentrated to give 2.12f (134 mg) which was used in the next step with out purification. MS m/z (M+23) 326.2.
Reaction SMILES: C(Cl)(Cl)=S.[CH:5]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])([CH3:7])[CH3:6].[C:16](=[O:19])([O-])[O-].[Ca+2].[C:21]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:42])[C:38]([NH:40][NH2:41])=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)(=[O:23])[CH3:22].CCN=C=NCCCN(C)C>C(Cl)Cl.O.CN(C=O)C.O>[C:21]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:37]([C:38]3[O:19][C:16]([NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH:5]([CH3:7])[CH3:6])[CH:10]=4)=[N:41][N:40]=3)=[O:42])=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]
Reactant: CC(C)Oc1cccc(N)c1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: CCN=C=NCCCN(C)C
Agent: S=C(Cl)Cl
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3nnc(Nc4cccc(OC(C)C)c4)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.8 %

Procedure:
Thiophosgene (46 μL, 0.60 mmol) was added dropwise to a stirred solution of 3-isopropoxy aniline (82 mg, 0.543 mmol) and calcium carbonate (272 mg, 2.72 mmol) in DCM/H2O (1:1) (4 mL). This was stirred at room temperature for 1 h. The phases were separated and the organic layer was dried and concentrated in vacuo. The residue was dissolved in DMF (3 mL) and added to a stirred solution of N-[4-(4-acetylpiperazin-1-yl)phenyl]-2-hydrazino-2-oxoacetamide (Intermediate 21, 100 mg, 0.33 mmol) in DMF at 85° C. This mixture was stirred at 85° C. for 1 h then EDAC (105 mg, 0.54 mmol) was added. The mixture was stirred at 100° C. for a further 1 h then allowed to cool and treated with H2O (10 mL). The resulting precipitate was filtered and washed sequentially with DMSO/MeCN/H2O (7:2:1) (5 mL) and ether (5 mL) to give the title compound as a white solid (12 mg, 8%); 1H NMR δ 10.90 (1H, s), 10.82 (s, 1H), 7.67 (2H, d), 7.25 (2H, d), 7.10 (1H, d), 6.97 (2H, d), 6.63 (1H, d), 4.59 (1H, m), 3.58 (4H, br. s), 3.15 (2H, m), 3.09 (2H, m), 2.04 (3H, s), 1.32 (3H, s), 1.30 (3H, s); MS m/e MH+ 465.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([CH2:24][C:25]([OH:27])=O)=[CH:18][C:19](=[O:23])[O:20]3)=[CH:15][CH:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[N:28]1C=CC=[CH:30][CH:29]=1.CN([CH:37]=[O:38])C>>[CH3:37][O:38][CH2:30][CH2:29][NH:28][C:25](=[O:27])[CH2:24][C:17]1[C:16]2[C:21](=[CH:22][C:13]([O:12][C@@H:1]3[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[CH:14][CH:15]=2)[O:20][C:19](=[O:23])[CH:18]=1
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1cc(=O)oc2cc(O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)ccc12
Reactant: c1ccncc1
Product: COCCNC(=O)Cc1cc(=O)oc2cc(O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)ccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 54 %

Procedure:
10 mg (0.026 mmoles) of 7-β-D-galactopyranosyloxycoumarin-4-acetic acid (i.e. compound 4 prepared as described in Scheme i) was dissolved in 1.6 ml of dry anhydrous DMF under nitrogen. Pyridine (0.075 ml, 0.92 mmoles) was added dropwise followed by the addition of pentafluorophenyltrifloroacetate (0.1 ml, 0.58 mmoles). The progress of the reaction was followed on a TLC plate by eluting with a mixture of i-PrOH/EtOH/NH4OH/water (60/35/5/20). The Rf of starting material (acid) was 0.4; and the Rf of the reactive intermediate was 0.533. The TLC plate was visualized by spraying a mixture of (anisaldehyde/H2SO4 /EtOH/CH3COOH in the ratio 1/1/18/2 drops) and heating on a hot plate. After the formation of the intermediate (3 hrs), 3-methoxy ethylamine (0.1 ml, 0.8 mmoles) was added dropwise and left to stir at room temperature under N2 for 12 hrs. The formation of the product was confirmed on TLC and the Rf of amide product was 0.41. The DMF was evaporated on a rotary evaporator under vacuum at 40-45° C. After evaporating to dryness the residue was dissolved in I ml of 50/50 CH3CN/water. The crude material was purified on a C-8 preparatory HPLC column using a gradient of 5/95 CH3CN/water (0.1% TFA) to 30/70 CH3CN/water (0.1% TFA) in 25.5 min. The peak eluting at 16 min was collected and the solvent lyophilized and the yield was 54%. The structure of the product was confirmed by 1H-NMR (CD3)2SO:δ 3.12 (t, 2H, CH2 --CH2 --OCH3), 3.32 (m, 5H, HN--CH2 --CH2 --CH3, CH2 --OCH3), 3.36-3.66 (m, 6H, H-2,3,4,5,6,6), 4.99 (d, 1H, J1,2 7.8 Hz), J1,2 of 7,8 Hz confirms β-configuration., 4.52, 4.54, 4.8, 5.45 (d,t,d,d, 1H, 1H, 1H, 1H, 2--OH, 3--OH, 4--OH, 6--OH), 6.38 (s, 1H, H-3), 7.0 (dd, 1H, H-6), 7.15 (d, 1H, H-8), 7.7 (d, 1H, H-5). MS: Mol. Formula. C20H25NO10. Calcd. 439.21, observed (M+Na)+ 462.0. Solubility in 0.1 mM Tris, 0.1 mM KCl pH 8.33: 1.5 mg/ml.
Reaction SMILES: [Br:1]Br.Cl.[CH:4]([C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:8]=1[NH2:9])([CH3:6])[CH3:5]>ClCCCl>[BrH:1].[Br:1][C:12]1[CH:13]=[C:7]([CH:4]([CH3:6])[CH3:5])[C:8]([NH2:9])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:11]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: BrBr
Agent: Cl
Solvent: ClCCCl
Product: Br
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 182.7 %

Procedure:
19.1 g of bromine are added dropwise at 0° C. over 1 hour to a suspension of 24.1 g of 2,6-diisopropylaniline hydrochloride in 250 ml of 1,2-dichloroethane. The reaction mixture is stirred for 1 hour at 0° C. and then filtered. The filter residue is washed with 1,2-dichloroethane and then dried at 40° C. under vacuum, affording 36.8 g (97% of theory) of 4-bromo-2,6-diisopropylaniline hydrobromide in the form of yellow crystals which melt at 235°-237° C. after recrystallisation from ethyl acetate.
Reaction SMILES: [C:1]([O:7]C)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].CO.[C:13](#[N:16])[CH2:14][CH3:15]>C1(C)C=CC=CC=1>[CH3:15][CH:14]([C:1](=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:13]#[N:16]
Reactant: COC(=O)C(C)(C)C
Reactant: CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C#N)C(=O)C(C)(C)C

Procedure:
234.6 grams (2 moles) of methyl pivalate and 120 grams (2 moles) of sodium hydride (80 weight % suspension in white oil) were heated to 90° C. in 1500 ml of dry toluene. There were dropped in at this temperature after addition of 1 ml of methanol 233.3 grams (2 moles) of propionitrile within 2.5 hours. After the end of the development of hydrogen the suspension was extracted with a total of 1200 ml of water and after phase separation the aqueous phase was acidified with concentrated HCl to a pH of 2. The deposited oil was separated off, the water phase extracted with chloroform, the organic extracts combined, dried and concentrated. The residue was fractionated in a water jet vacuum. 2,4,4-trimethyl-3-oxopentanenitrile came over at 87° C./11 Torr in an amount of 226.1 grams (81.2% of theory).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(O)=O>CC1C=CC(S(N[C@@H]([C@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.C(N(CC)CC)C.CO>[OH:12][C@H:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C(O)[C@H](O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
Into 1 ml of methanol were dissolved 7 mg (0.01 mmol) of [RuCl2(p-cymene)]2 and 8 mg (0.02 mmol) of (R,R)-TsDPEN to prepare a solution, and to the solution was dropwise added 2 mg (0.02 mmol) of triethylamine, followed by stirring for 0.5 hour at room temperature. To the reaction solution was dropwise added a solution prepared by dissolving 364 mg (2.2 mmol) of phenylpyruvic acid into 4 ml of methanol, and 1.2 ml (8.9 mmol) of triethylamine was furthermore dropwise added thereto. The bath was heated up to a temperature of 40° C., and then 0.25 ml (6.7 mmol) of formic acid was dropwise added over 1 hour, followed by stirring for 2 hours at a bath temperature of 40° C. Upon completion of the reaction, the solvent was distilled off under reduced pressure. Thereto was added 2 ml of water, and then concentrated hydrochloric acid was gradually dropwise added under ice cooling; thus, pH of the solution was adjusted to 2. Extraction was performed twice with 20 ml of ethyl acetate, and then the organic phase was washed with 2 ml of a saturated aqueous solution of sodium chloride, followed by concentration under reduced pressure. As a result, 370 mg (yield 99%, 94% ee) of (2R)-hydroxy-3-phenylpropanoic acid was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1.C(O)(=O)C>CN(C=O)C.O>[CH2:3]([O:10][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
Oil-free NaH (1.9 g,~5 eq.) was suspended in DMF (30 ml) and the suspension was cooled in an ice bath. Benzyl alcohol (8.6 ml, ~5.2 eq.) was added slowly to the suspension via syringe. The resulting reaction mixture was stirred at 0° C. for 20 min., after which it was transferred to a precooled (0° C.) solution of 6-chloronicotinic acid (2.5 g, 15.9 mmol) in DMF (30 ml). Additional DMF (20 ml) was added to the reaction mixture to facilitate stirring. The reaction mixture was refluxed for 2 hours. Aqueous acetic acid 5% (by volume) was added to the cooled reaction mixture, and the resultant acidic mixture was extracted (3x) with ethyl acetate. The organic layers were combined, washed with brine and the solvent was removed to give a yellow liquid, from which a white solid was obtained after addition of water. Recrystallization from acetone/water gave 6-benzyloxynicotinic acid (4, Scheme I, 88% yield) as colorless needles.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Li:15]>O1CCCC1>[C:1]1([Li:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]C
Solvent: C1CCOC1
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
In a 500-cm3 four-necked flask in which the atmosphere was replaced with nitrogen, 16.6 g of fluorene were dissolved in 150 cm3 of tetrahydrofuran, followed by treating the solution with methyllithium, thereby obtaining a tetrahydrofuran solution of fluorenyllithium. Next, 200 cm3 of a tetrahydrofuran solution containing 10.4 g of previously synthesized 1,4-biscyclopentadienylidenecyclohexane were added dropwise to the tetrahydrofuran solution at -10° C. over 30 minutes. After completion of the addition, the reaction temperature was elevated up to room temperature, followed by stirring for 15 hours. Then, 200 cm3 of a 3.6% hydrochloric acid solution were poured thereinto to bring the reaction to an end. The resultant solid was collected by filtration, washed with ether, and then dried to obtain 18.5 g of white powdery 1,4-dicyclopentadienyl-1,4-difluorenylcyclohexane.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:12][C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC[N:21]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N>C(Cl)Cl.O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:12][C:13]([C:16]([NH2:21])=[O:18])=[CH:14][N:15]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc(C2CCC3(CC2)OCCO3)s1
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1cnc(C2CCC3(CC2)OCCO3)s1

Procedure:
A solution of 2-(1,4-Dioxa-spiro[4.5]dec-8-yl)-thiazole-5-carboxylic acid (as prepared in Example 52, Step C, 700 mg, 2.60 mmol), EDCI (600 mg, 3.12 mmol), HOBT (420 mg, 3.12 mmol) and TEA (490 μL, 3.50 mmol) in DCM (10 mL) were treated with 2N NH3 in dioxane (2 mL) at room temperature overnight. The solvent was removed in vacuo and the residue was purified by a CombiFlash® system using hexanes and ethyl acetate to afford the title compound as a white solid.
Reaction SMILES: [F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[C:4]#[N:5].N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[F:1][CH2:2][C:3]([N:11]1[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]2[C:15]1=[O:16])([CH2:6][CH2:7][CH2:8][CH2:9][O:10][S:29]([CH3:28])(=[O:31])=[O:30])[C:4]#[N:5]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(CF)(CCCCO)N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of 2-fluoromethyl-2-phthalimido-6-hydroxyhexanenitrile (9.0 g, 31 mmol) and pyridine (60 ml) in dry dichloromethane (150 ml) is cooled in an ice bath, and methanesulfonyl chloride (3.6 g, 31 mmol), diluted with a small amount of dichloromethane, is added slowly with efficient stirring. Stirring is continued at room temperature overnight. The reaction mixture is washed with 2N HCl and dried. Evaporation of solvent gives 2-fluoromethyl-2-phthalimido-6-methanesulfonyloxyhexanenitrile as a yellow oil (10.84 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[NH2:23][CH:24]([CH3:26])[CH3:25]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][NH:23][CH:24]([CH3:26])[CH3:25])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: CC(C)N
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: CC(C)NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with 2-aminopropane similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 10-bromo-9-fluoro-3-((isopropylamino)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 34 mg (40%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(isopropylamino)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=411.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](C(CC)(CC)C([O-])([O-])[O-])[CH3:13]>>[CH3:12][C:13]1[O:11][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[N:1]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Product: Cc1nc2c([N+](=O)[O-])cccc2o1
Temperature: 100 °C
Yield: 95.1 %

Procedure:
To 2-amino-3-nitrophenol (6.17 g, 40.0 mmol) was added triethylorthoacetate (25.96 g, 160.0 mmol) and the mixture was heated at 100° C. for 12 h to give a dark red solution. Cooling to room temperature produced a crystalline mass which was filtered and washed with hexane to give compound 474A (6.78 g, 95%) as light maroon needles. HPLC: 98.1% at 1.86 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 179.08 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][NH:23][C:24](=[O:31])[C@@H:25]([NH2:30])[C@@H:26]([CH3:29])[CH2:27][CH3:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[CH2:39]([S:43](Cl)(=[O:45])=[O:44])[CH2:40][CH2:41][CH3:42].O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][NH:23][C:24](=[O:31])[C@@H:25]([NH:30][S:43]([CH2:39][CH2:40][CH2:41][CH3:42])(=[O:45])=[O:44])[C@@H:26]([CH3:29])[CH2:27][CH3:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCCc1ccc(OCc2cccc3ccccc23)c(OC)c1
Reactant: CCCCS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2cccc3ccccc23)c(OC)c1)[C@@H](C)CC
Reaction time: 16 h

Procedure:
3.4 g of (2S,3S)-2-amino-3-methyl-valeric acid N-{2-[3-methoxy-4-(naphthalen-1-ylmethoxy)-phenyl]-ethyl}-amide and 1.2 ml of triethylamine are placed in 50 ml of dioxane at room temperature. 1.0 ml of n-butylsulfonyl chloride is added thereto. Stirring is carried out for 16 hours. The reaction mixture is introduced into 200 ml of water. Extraction is carried out twice using 200 ml of ethyl acetate each time. The organic phases are washed once with 200 ml of saturated sodium chloride solution, combined, dried over magnesium sulfate and concentrated, yielding (2S,3S)-2-(butylsulfonyl-amino)-3-methyl-valeric acid N-{2-[3-methoxy-4-(naphthalen-1-ylmethoxy)-phenyl]ethyl}-amide, which can be purified by chromatography on silica gel with ethyl acetatein-hexane =1:1, in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]/[C:23](=[O:25])[CH3:24])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.C(Cl)Cl>[Pd].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][C:23](=[O:25])[CH3:24])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:27][CH:28]=1
Reactant: CC(=O)/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 0.75 h
Yield: 8 %

Procedure:
To a mixture of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(E)-3-oxo-1-butenyl]-3-quinolinecarboxamide from Example No. 153 (100 mg) and Et3N (0.35 mL) in 80 mL 3:1 CH2Cl2 :MeOH is added Pd/C (10%, 20 mg). The reaction mixture is placed under the Parr hydrogenator at 29 psi H2 and monitored by mass spectroscopy for complete reduction of the alkene. The old palladium catalyst is replaced with fresh palladium catalyst each time the reaction was taken off the Parr. In this case, the reaction is taken off the Parr once. The reaction is complete in 45 min. The reaction mixutre is filtered over celite to remove the palladium. The filtrate is concentrated. The crude mixture was separated by HPLC to afford 38.7 mg (8%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:14]([CH3:26])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>CC#N>[CH3:26][C@H:14]1[CH2:13][N:12]([CH2:11][C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([NH:1][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH3:27])(=[O:36])=[O:35])[CH:3]=2)[C@H:17]([CH3:18])[CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc(N)cc2ccoc12
Solvent: CC#N
Product: Cc1ccccc1S(=O)(=O)Nc1cc(CN2C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]2C)c2occc2c1

Procedure:
The title product was prepared according to the procedure of Example 121, Step 4, starting from tert-butyl trans-4-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-dimethylpiperazine-1-carboxylate (obtained in Example 121, Step 3) and 2-methylbenzenesulfonyl chloride (0.039 g, 0.2 mmol). Yield: 0.022 g (43%). HPLC 95% RT=1.99 min (System A; 10-97% MeCN over 3 min), 93% RT=1.85 min (System B; 10-97% MeCN over 3 min). MS (ESI+) m/z 514.2 (M+H)+.