Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[NH:4][C:3]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36]Cl)[CH3:33].O>C(OCC)(=O)C>[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36][N:4]1[C:3](=[O:25])[C@H:2]([OH:1])[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:33]
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)NC(=O)[C@@H]2O)cc1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Yield: 86.9 %

Procedure:
A mixture of 4.4 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one, 2.0 g of potassium carbonate and 1.8 g of 2-diethylaminoethyl chloride in 100 mL ethyl acetate was stirred and heated at reflux for 2 hours then an additional 0.5 g of 2-diethylaminoethyl chloride was added four times at 2 hour intervals. The mixture was heated at reflux for a total of 12 hours, then cooled to room temperature and to the mixture ethyl acetate and water were added. The organic phase was separated, washed with brine and dried (magnesium sulfate). Removal of the solvent gave the product which after crystallization from ether afforded 4.9 g (87%) (±)-cis-5-[2-(diethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one, mp 124°-125°.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH2:11][CH2:10]1.[Na].C1(=O)NC(=O)CC1.[H-].[Na+]>O.CN(C=O)C>[CH:2]1([N:13]2[C:9](=[O:15])[CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: BrC1C=CCCCC1
Reactant: O=C1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1C1C=CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromocycloheptene (1.75 g) was added dropwise at room temperature to a DMF suspension (10 ml) of sodium succinimide prepared from succinimide (0.99 g) and 60% sodium hydride (0.40 g). This mixture was stirred at room temperature for 24 hours, poured into water (10 ml) and extracted with ether. The oily product obtained by concentration was purified by chromatography on silica gel to obtain 0.09 g of N-(2-cycloheptenyl)succinimide [Compound (214)].
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([CH2:34][CH3:35])([C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH3:29])/[C:9]1=[O:36])=O)(C)(C)C.[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:53])=[C:42]([CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47])[CH:43]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:36])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([CH2:28][CH3:29])([C:30]([O:32][CH3:33])=[O:31])[CH2:34][CH3:35])[CH2:47][C:46](=[O:48])[NH:45][CH:44]3[C:42]3[CH:43]=[C:38]([Cl:37])[CH:39]=[CH:40][C:41]=3[CH3:53])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(Cl)ccc1C)O[Si](C)(C)C
Reactant: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)C(=O)OC
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OC
Yield: 19.4 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-3-[5-chloro-2-(1-methoxycarbonyl-1-ethyl-propoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (2.63 g, 4.9 mmol) prepared in Example 62f was reacted with 1-(5-chloro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (20 mmol) prepared in Example 13b in toluene (20 mL) to give the title compound as a white solid (600 mg).
Reaction SMILES: [C:1]([C@:3]([NH:14][C@H:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([NH2:18])=[O:17])([CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)#[N:2].C(Cl)Cl.[OH:28]S(O)(=O)=O.N>CCOC(C)=O>[C:16]([C@H:15]([NH:14][C@@:3]([CH3:13])([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:1]([NH2:2])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])[NH2:18]
Reactant: COc1ccc(C[C@@](C)(C#N)N[C@@H](C(N)=O)c2ccccc2)cc1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@](C)(N[C@@H](C(N)=O)c2ccccc2)C(N)=O)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a 500 mL flask were added nitrile 2 (10.0 g, 30.95 mmol) and CH2Cl2 (130 mL). The solution was cooled to −10° C. and H2SO4 (10 mL) was added dropwise over 15 min. The mixture was stirred for 2 h at 0° C. Ice (200 g) was added and the mixture was stirred for 1 h. The mixture was basified with 32% aq NH3 to pH 8-9, EtOAc (400 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2×250 mL). The combined organic phases were dried over MgSO4 and were concentrated to provide 3 (11.1 g (9.99 g theoretical, the sample contains 10% w/w of EtOAc by NMR) 94%, 92.9% chemical purity, 97% de by HPLC/MS) as a white solid. HPLC/MS tR=3.04 min; m/z=342.1 (M+1)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[C:21]3[S:17][C:18](=[O:23])[NH:19][C:20]3=[O:22])=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNc1cccc(-c2ccc(C=O)cc2)c1
Reactant: O=C1CSC(=O)N1
Product: CNc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 91.7 %

Procedure:
In a manner similar to Example 1(d), by reacting 2.9 g (13.7 mmol) of 3′-methylaminobiphenyl-4-carbaldehyde with 1.6 g (13.7 mmol) of 2,4-thiazolidinedione, 3.9 g (91%) of the expected product are obtained after trituration in dichloromethane and ether.
Reaction SMILES: CN(C)C(=N)N(C)C.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[CH2:26]([O:28][CH:29]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>C(Cl)(Cl)Cl>[CH2:33]([O:32][C:30](=[O:31])[C:29]([O:28][CH2:26][CH3:27])=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1)[CH3:34]
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Tetramethylguanidine (42.3 g; 0.37 mole) was slowly added to a solution of 4-benzyloxybenzaldehyde (75.6 g; 0.36 mole) and (1,2-diethoxy-2-oxoethyl) (triphenyl)phosphonium chloride (130.7 g; 0.304 mole) dissolved in chloroform (800 ml) at 0° C. After stirring at room temperature over night, the solvent was evaporated in vacuo. The residue was dissolved in diethyl ether, insoluble material was filtered off and the filtrate was washed with sodium bicarbonate and dried (magnesium sulfate). The procedure was repeated once and thereafter the crude product was stirred over night with a sodium bisulfite saturated water solution. The solid material was filtered off, the product was extracted with diethyl ether, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give 85 g (yield 73%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].I[CH3:37].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:37])[C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CI
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1N(C)c1cc(Br)cnc1N1CCOCC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (described herein) (18.0 mg, 0.035 mmol) in N,N-dimethylformamide (2 mL) was added 60% sodium hydride (2.11 mg, 0.053 mmol), followed by iodomethane (7.5 mg, 0.053 mmol). Stirring continued for 1.5 h. Water was added to quench the reaction and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-60% EtOAc/hexanes) to give N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-N,3-dimethyl-2-(pyridin-2-yl)quinolin-4-amine as a yellow foam. Mass Spectrum (ESI) m/e=526.2, (M+1).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])=[N:35][CH:36]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(C)C>[F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:13]=[CH:14][C:15]([C:31]3[CH:36]=[N:35][C:34]([CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])=[CH:33][CH:32]=3)=[CH:16][CH:17]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CS(=O)(=O)Cc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 120 °C
Yield: 123.2 %

Procedure:
2,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-3-yl)ethanone (100 mg, 0.24 mmol) in 1:1 toluene/isopropyl alcohol (4 mL) is treated with commercially available 5-bromo-2-(methylsulfonylmethyl)pyridine (60 mg, 0.24 mmol), sodium bicarbonate (1 mL of a 2M solution), and (1,1′-bis[diphenylphosphino]ferrocene)dichloropalladium (II) (10 mg, 0.012 mmol) then heated at 120° C. in a microwave for 30 minutes. The mixture is concentrated and purified by column chromatography on silica gel eluting with a gradient of ethyl acetate in heptane to give the title compound (135 mg). m/z (Cl) 457 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([Si:14]([CH3:24])([CH3:23])[O:15][CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH:19]=O)([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:19]/[CH2:18][C:17]([CH3:21])([CH3:22])[CH2:16][O:15][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:24])[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CC=O)CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C/C=N/CC(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 1, glycine tert-butyl ester (0.52 g, 3.64 mmol) was reacted with 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyraldehyde (0.84 g, 3.64 mmol) in CH2Cl2 at room temperature for 18 h to give [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.25 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:27]=1.C[O-].[Na+].C([NH2:33])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([NH2:33])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:27]=1
Reactant: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1ccc(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: Cn1nccc1Cc1c(C(N)=O)nc2n1C1CC(C1)c1ccc(Br)cc1-2

Procedure:
10-bromo-3-((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-3-((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 150 mg (110% crude yield) of the crude title compound which was carried forward without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH2:7][C@H:8]([NH2:12])[C:9](O)=[O:10])[C:4]([N+:13]([O-:15])=O)=[CH:3][CH:2]=1>CO.O.Cl.[Pt]>[NH2:12][C@H:8]1[CH2:7][C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:13]([OH:15])[C:9]1=[O:10]
Reactant: N[C@@H](Cc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: O
Product: N[C@H]1Cc2ccccc2N(O)C1=O
Reaction time: 1 h
Yield: 58.1 %

Procedure:
L-2-Nitrophenylalanine (20) (419.6 mg, 2.0 mmol) was dissolved in MeOH (23.8 mL) and water (240 μL). Concentrated HCl (2-4 drops) was added to aid solubility. Pt/C (42 mg) was added and the reaction was hydrogenated on a Parr shaker at 10 psi for 1 h, whereupon the reaction was filtered through Celite. The catalyst was washed with a 1N solution of NH4OH in MeOH and then with MeOH. The filtrate was concentrated to provide a crude product, which was subsequently dry packed with a minimum amount of silica, using a MeOH/DCM solution to dissolve the material. Purification using silica gel chromatography (Gradient: 0% to 20% MeOH (containing 1% NH4OH) in DCM) provided the product as a solid (207 mg, 58%). APCI m/z 179.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.88 (dd, J=14, 15 Hz, 1H), 3.09 (dd, J=15.3, 6.2 Hz, 1H), 3.67 (dd, J=13.6, 6.1 Hz, 1H,) 7.06 (ddd, J=7.2, 7.2, 1.7 Hz, 1H), 7.23 (br d, J=7.5 Hz, 1H), 7.27-7.34 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])=[CH:11][CH:10]=1.O>C1COCC1>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][NH:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]([CH3:25])[CH3:7])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(NC(=O)c2ccccc2N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc(NCc2ccccc2N)cc1
Yield: 58.2 %

Procedure:
To a suspension of lithium aluminium hydride (0.61 g) in THF (30 ml) was added dropwise under ice-cooling a solution of N-(4-dimethylaminophenyl)-2-aminobenzamide (2.0 g) in THF (20 ml) and the mixture was heated finder reflux. To this mixture was added dropwise small portions of water, the insolubles were filtered, and the solvent was distilled off. Purification of the residue by a silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallization from ethyl acetate/hexane afforded N-(2-aminobenzyl)-N',N'-dimethyl-1,4-phenylenediamine (1.1 g, 56%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1>>[CH3:15][C:16]1[C:17]([N:23]2[CH2:24][CH2:25][N:26]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=3)=[O:12])[CH2:27][CH2:28]2)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: CC(=O)NCc1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: CC(=O)NCc1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 70.9 %

Procedure:
Using 4-(acetylaminomethyl)benzoic acid (116 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (115 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (156 mg) was obtained.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([CH3:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[CH3:34][NH:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([CH3:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Reactant: CNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4C)c3c2Cl)C1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 68.2 %

Procedure:
To 90 mg of N,N-dimethylformamide were added 25 mg of 1-(6-amino-5-fluoro-3-methylpyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 25 mg of 3-(methylamino)azetidine dihydrochloride, and 70 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 45 minutes. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 20 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.[Na].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: Nc1nc(N)c([N+](=O)[O-])c(Cl)n1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Nc1nc(N)c([N+](=O)[O-])c(OCc2ccccc2)n1
Temperature: 160 °C

Procedure:
2,4-Diamino-6-chloro-5-nitropyrimidine (O'Brien et. al., J. Med. Chem., 9, 573-575 (1966)) (1.0 g, 5.28 mmol) was added to a solution of sodium (0.14 g, 6.08 mmol) in benzyl alcohol (9 mL). The solution was heated in a 160° C. oil bath for 3.5 h and the solvent was evaporated under reduced pressure to provide a yellow solid. This solid was washed with water, and air dried. Crystallization from benzene/ether gave a pale yellow filamentous solid: yield, 0.69 g (50%); mp 194°-195° C. (171° C.; Kosary et. al., Acta. Pharm. Hung., 49, 241-247 (1989)); UV (pH 1) λmax 236 nm (sh) (ε=1.452×104), 264 (0.522×104), 321 (1.294×104); (pH 6.9) 242 (sh) (0.965×104), 337 (1.493×104); (pH 13) 242 (sh) (0.952×104), 338 (1.479×104); 1H NMR δ5.43 (s, 2H, ArCH2), 7.26 (br s, 2H, NH2, exchange with D2O), 7.33-7.51 (m, 5H, ArH), 7.93 (br s, 2H, NH2, exchange with D2O); MS (EI) calcd. m/z for C11H11N5O3 261.0861, found 261.0866; Anal. (C11H11N5O3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][CH:14]=1)[C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:6]2.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:28][S:29]([NH:32][C:19]([C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1)=[O:20])(=[O:31])=[O:30]
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(=O)O)n1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(=O)NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 15.9 %

Procedure:
Under an argon atmosphere, to a solution of 6-(5-methoxy-2-phenylindol-1-ylmethyl)pyridine-2-carboxylic acid (84 mg) in dichloromethane (2.3 mL) were added methanesulfonamide (22 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (45 mg), and 4-dimethylaminopyridine (29 mg). This mixture was stirred for 66 hours at room temperature. To the reaction mixture, 1 mol/L hydrochloric acid was added and stirred vigorously. The organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: dichloromethane-methanol). The solvent was removed under reduced pressure. The residue was recrystallized from ethanol to obtain the title compound (16 mg). 1H-NMR (CDCl3) δ ppm: 3.38 (3H, s), 3.87 (3H, s), 5.49 (2H, s), 6.64 (1H, d, J=0.5 Hz), 6.84 (1H, dd, J=2.4, 8.9 Hz), 6.90-6.95 (1H, m), 7.05 (1H, d, J=8.9 Hz), 7.16 (1H, d, J=2.4 Hz), 7.30-7.50 (5H, m), 7.76 (1H, t, J=7.8 Hz), 8.00-8.10 (1H, m), 10.01 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:33][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-ethylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 5) 47.0 mg (0.108 mmol) in 3 ml of EtOH and 2 ml of THF was added 28.0 mg (0.70 mmol, 0.7 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.3 Hz), 7.59 (2H, d, J=8.3 Hz), 7.46 (2H, s), 7.29-7.21 (4H, m), 7.02 (1H, s), 6.01 (1H, t, J=4.5 Hz), 2.64 (2H, q, J=7.5 Hz), 2.33 (2H, d, J=4.5 Hz), 1.29 (6H, s), 1.22 (3H, t, J=7.5 Hz).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:21][N+:22]([O-:24])=[O:23])[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CO.C1COCC1>[C:17]([O:16][C:14]([NH:13][CH2:12][CH:9]1[CH2:8][CH2:7][C:6]([CH2:5][C:4]([OH:25])=[O:3])([CH2:21][N+:22]([O-:24])=[O:23])[CH2:11][CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CCC(CNC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCC(CC(=O)O)(C[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 109.9 %

Procedure:
To a solution of [4-(tert-Butoxycarbonylamino-methyl)-1-nitromethyl-cyclohexyl]-acetic acid ethyl ester (0.304 g, 0.848 mmol) in MeOH (5.0 mL) and THF (1.5 mL) was added sodium hydroxide (4.2 mL, 1N, 4.2 mmol) and the reaction stirred at RT for 5 hr. The reaction was acidified to pH ˜2 with 1N HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide 0.308 g of crude product that was carried to the next step without purification. ESI-MS m/z 331 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:10]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[S:8][C:6]=2[N:7]=1.[C:18]([O-])([O-])=[O:19].[K+].[K+]>O1CCOCC1.CO>[NH2:1][C:2]1[N:3]=[C:4]([O:19][CH3:18])[C:5]2[N:10]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(C3CC3)nc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1nc(N)nc2sc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 5-amino-2-cyclopropyl-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidine (54 mg, 0.2 mmol) and K2CO3 (69 mg, 0.5 mmol) in dioxane (10 ml) and methanol (5 ml) was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/60), yielding the pure title compound (40 mg, 90%).