Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20])=[O:15])(OCC1C=CC=CC=1)=O.Br>CC(O)=O>[NH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:20])=[O:21])=[O:15]
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCS(=O)(=O)O
Agent: Br
Solvent: CC(=O)O
Product: NCCC(=O)NCCS(=O)(=O)O
Temperature: 40 °C
Yield: 87.4 %

Procedure:
N-carbobenzoxy-β-alanyl-taurine (1.00 g, 3.4 mmol) was slurried in 23 ml glacial AcOH. To the mixture was added 3.4 mL HBr in AcOH (30 wt %) to result in a clear solution. The reaction was heated to 40° C. and allowed to mix overnight. The product precipitated out of solution and acetcnitrile was added to force the precipitation. The mixture was filtered, the filter cake washed and the product collected. The crude Br salt was loaded onto an ion exchange column (Dowex AG1-XB8). The column was eluted with H2O. The product cut was collected and lyophilized to give 583 mg of β-alanyl-taurine (87.3%). The zinc salt was prepared by treatment with Zn(OH)2 in H2O, followed by lyophilization. (See FIG. 1 for reaction Scheme.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6](=[O:20])[C:5]2=O>O.NN.C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6](=[O:20])[CH2:5]2
Reactant: COc1ccc(CN2C(=O)C(=O)c3cc(F)ccc32)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2C(=O)Cc3cc(F)ccc32)cc1
Yield: 90.3 %

Procedure:
A solution of 5-fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione (7.1 g, 24.9 mmol) in hydrazine hydrate (35 mL) and ethanol (15 mL) was refluxed overnight, diluted with water and extracted twice with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate in hexane to afford 6.1 g (90%) of 5-fluoro-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one; 1H NMR (CDCl3, 400 MHz) δ 3.59 (s, 2H), 3.77 (s, 3H), 4.83 (s, 2H), 6.63 (dd, 1H, J=4.2, J2=8.6), 6.82-6.91 (m, 3H), 6.96-7.01 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.31 (m, 1H); HPLC-MS calcd. for C16H14FNO2 (M+H+) 272.1, found 272.3.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[N:5][N:6]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=O)C(F)(F)F)=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2].[OH-].[K+].CI>CC(C)=O>[CH3:19][NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[N:6]2[N:5]=[C:4]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[C:3]([C:1]#[N:2])=[C:7]2[N:8]=[CH:9][CH:10]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3ccccc3NC(=O)C(F)(F)F)ccnc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CI
Product: CNc1ccccc1-c1ccnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn12
Reaction time: 15 h
Yield: 35.9 %

Procedure:
To a solution of N-(2-(3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide (50 mg, 0.1 mmol) in 5 mL of acetone was added KOH (11.2 mg, 0.2 mmol) and CH3I (0.5 mL). The reaction mixture was stirred at It for 15 hr, then concentrated to remove acetone. The residue was partitioned between 20 mL of water and 20 mL of EA. The organic layer was concentrated and purified by pre-TLC (PE/EA=2/1) to give the product as a white solid (15 mg, yield: 37%). 1H NMR (DMSO-d6) δ 8.82 (d, J=4.4 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.47-7.38 (m, 4H), 7.31 (dd, J=1.6, 7.2 Hz, 1H), 7.23-7.17 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.77-6.69 (m, 2H), 5.35-5.31 (m, 1H), 2.68 (d, J=4.8 Hz, 3H). MS (ESI) m/e [M+1]+ 417.9.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[CH:7]2)([O-])=O.[H][H]>CO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[CH:7]2
Reactant: [H][H]
Reactant: O=c1ccc2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1ccc2[nH]c(=O)ccc2c1

Procedure:
In a Parr catalytic hydrogenation apparatus 6-nitrocarbostyril, 5.3 g (0.028 mole), in 150 mL of methanol and 0.5 g PtO2 were shaken in a hydrogen atmosphere. The resulting yellow solid was extracted with refluxing methanol to yield 6-aminocarbostyril, 3.5 g, as yellow crystals; m.p. 315°-317° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH2:7][N:8]([CH3:25])[CH2:9][CH2:10][CH2:11][CH:12]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)[C:13]#[N:14].[NH2-].[Na+].[CH:31](Br)([CH3:33])[CH3:32].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH2:7][N:8]([CH3:25])[CH2:9][CH2:10][CH2:11][C:12]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)([CH:31]([CH3:33])[CH3:32])[C:13]#[N:14]
Reactant: CC(C)Br
Reactant: COc1cccc(CCN(C)CCCC(C#N)c2cc(OC)cc(OC)c2)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(CCN(C)CCCC(C#N)(c2cc(OC)cc(OC)c2)C(C)C)c1
Reaction time: 2 h
Yield: 110.5 %

Procedure:
38.3 g (0.1 mole) of 5-[(3-methoxyphenethyl)-methylamino]-2-(3,5-dimethoxyphenyl)-valeronitrile were dissolved in 200 ml of toluene, and the stirred solution was refluxed with 4.7 g (0.12 mole) of powdered sodium amide for 1 hour. Thereafter, a solution of 15.7 g (0.12 mole) of isopropylbromide in 30 ml of toluene was added dropwise in the course of 60 minutes, and refluxing was continued for a further 2 hours. The cooled reaction mixture was poured into water, the toluene phase was washed several times with water and the toluene was then distilled off. The residue was dissolved in 100 ml of isopropanol, and ethanolic hydrochloric acid was added. The hydrochloride was recrystallized from isopropanol. 46.9 g (92%) of a hydrochloride of melting point 141°-143° C. were isolated.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:18][C:17]=1[C:27]([F:30])([F:29])[F:28]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])/[CH:24]=[CH:25]/[C:2]2[CH:14]=[CH:13][C:5]([CH2:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[CH:18][C:17]=1[C:27]([F:28])([F:29])[F:30]
Reactant: C=CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Ic1ccc(Cc2ccncc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(Cc2ccncc2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 95 °C
Yield: 87.8 %

Procedure:
A mixture of 4-(4-iodobenzyl)pyridine (129 mg, 0.44 mmol), TEA (67 μL, 0.48 mmol), Pd(PPh3)4 (254 mg, 0.222 mmol) and N-[4-chloro-3-(trifluoromethyl)-phenyl]acrylamide (0.120 g, 0.44 mmol) in DMF (4.4 mL) was heated at 95° C. for 3 h. The reaction mixture was cooled to rt, diluted with water, extracted with EtOAc, washed with brine, dried over NaSO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound (161 mg, 40%). LCMS: (FA) ES+ 417.2 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>CN(C=O)C>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:9][CH2:8]1)[C:3]([O:5][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)[C@@H](O)CC1CC1
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H](O)CC2CC2)cc1

Procedure:
The title compound was prepared from 1.0 g (7.6 mmol) of 2-(S)-hydroxy-3-(cyclopropyl)propanoic acid (from EXAMPLE 21, Step A), 1.6 mL (11.4 mmol) of TEA and 1.6 mL (11.8 mmol) of 4-(methoxy)benzyl chloride in 10 mL of DMF using a procedure analogous to that described in EXAMPLE 20, Step G to provide 1.70 g (88%, ee=97.5%) of the title compound: RF: 0.20 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) 8-0.01-0.09 (m, 2H), 0.40-0.45 (m, 2H), 0.84 (m, 1H), 1.55-1.67 (m, 2H), 2.82 (br m, 1H), 3.81 (s, 3H), 4.25 (br m, 1H), 5.14 (ABq, J=11.8, 2H), 6.90 (d, J=8.7, 2H), 7.29 (d, J=8.7, 2H). HPLC Conditions:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:25])[N:16]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=2)=O)=[C:4]([CH3:36])[CH:3]=1.Cl.[NH2:38][OH:39].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:28][CH:27]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:25])[N:16]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=2)=[N:38]\[OH:39])=[C:4]([CH3:36])[CH:3]=1
Reactant: COCCOCCn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCCOCCn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-1-(2-(2-methoxyethoxy)ethyl)pyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing 12% of the corresponding Z isomer as a light yellow solid, MS (ESI+): m/z=547.3 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[N:10]=1)C1C=CC=CC=1.[CH2:30]([O:37][C:38]1[C:46]([F:47])=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][C:39]=1[F:48])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38]1[C:39]([F:48])=[CH:40][C:41]([C:42]([NH:15][C:14]2[C:9]([OH:8])=[N:10][C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[N:12][CH:13]=2)=[O:43])=[CH:45][C:46]=1[F:47])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)c1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1ncc(NC(=O)c2cc(F)c(OCc3ccccc3)c(F)c2)c(O)n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((4-(benzyloxy)-5-nitropyrimidin-2-yl)oxy)propan-2-yl)carbamate and 4-(benzyloxy)-3,5-difluorobenzoic acid, and in the same manner as in Step A of Example 4, Step D of Example 83 and Step B of Example 123, the title compound was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[N:21]1[C:30]2[C:25](=[CH:26][C:27]([C:31](O)=[O:32])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]=[CH:22][CH:23]=[N:24]3)=[O:32])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc2nccnc2c1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and quinoxaline-6-carboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](O)=O)[CH:2]=1.[NH2:11][C:12]1[C:13](=[O:34])[N:14]([CH2:31][CH2:32][CH3:33])[C:15](=[O:30])[N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:17]=1[NH2:18]>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:16]2[C:17]3[N:18]=[C:8]([CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[NH:11][C:12]=3[C:13](=[O:34])[N:14]([CH2:31][CH2:32][CH3:33])[C:15]2=[O:30])=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=C(O)Cc1cccnc1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3cccnc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 3-pyridylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine.
Reaction SMILES: [CH3:1][C:2]1[O:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:43]1([C:48]2[CH:49]=[C:50]([NH2:60])[CH:51]=[N:52][C:53]=2[O:54][CH2:55][C:56]([F:59])([F:58])[F:57])[CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C=O)C>[CH:43]1([C:48]2[CH:49]=[C:50]([NH:60][C:7]([C:3]3[N:4]=[CH:5][O:6][C:2]=3[CH3:1])=[O:9])[CH:51]=[N:52][C:53]=2[O:54][CH2:55][C:56]([F:57])([F:58])[F:59])[CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: Cc1ocnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ocnc1C(=O)Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a solution of 5-methyl-4-oxazolecarboxylic acid (CAN 103879-58-9) (73 mg, 0.57 mmol) in DMF (4 mL) were added DIPEA (0.1 mL, 1.15 mmol) and HATU (219 mg, 0.57 mmol) at 25° C. The reaction mixture was stirred for 30 min at 25° C. Then, 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.38 mmol) was added and the reaction mixture was stirred at 25° C. for 12 h. Volatiles were removed in vacuo and the resultant residue was purified by prep-HPLC to get the title compound (30 mg, 21.3%) as off-white solid. MS (ESI): 370 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[C:10]([O:12][CH3:13])=[O:11].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:13][O:12][C:10]([CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:8][CH2:9][C:2]2=[O:1])=[O:11]
Reactant: COC(=O)C1CCC2C(O)CCC12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C1CCC2C(=O)CCC21
Reaction time: 2 h

Procedure:
A solution of crude 6-hydroxy-2-methoxycarbonylbicyclo[3,3,0]octane (1.98 g; prepared as described in Reference Example 6 and predominantly in the 2β-configuration) in dichloromethane (10 ml) was added to a stirred suspension of pyridinium chlorochromate (3.5 g) in dichloromethane (35 ml), and the mixture was stirred for 2 hours. The mixture was then diluted with diethyl ether (200 ml), and the supernatant liquid was decanted onto a short column of silica gel. The residue was triturated with diethyl ether several times until it became granular in aspect and then all the ethereal washings were added to the column. The column was eluted with diethyl ether and the eluate was evaporated, to give crude 2-methoxycarbonylbicyclo[3,3,0]octan-6-one (1.71 g) [infra-red (I.R.) 1740 cm-1 ], predominantly in the 2β-configuration, and pure enough for use in the next stage.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[O:11])=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20].CO>O>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[OH:11])=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(C(=O)c2ccccc2F)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(C(O)c2ccccc2F)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 100 %

Procedure:
1.61 Parts of sodium tetrahydroborate were added dropwise to a stirred solution of 11 parts of (4-amino-3-nitrophenyl) (2-fluorophenyl)methanone in 120 parts of methanol. Upon complete addition, stirring was continued for 1 hour at room temperature. The reaction mixture was poured into water and the product was extracted three times with 75 parts of trichloromethane. The combined extracts were dried, filtered and evaporated, yielding 11.3 parts (100%) of 4-amino-α-(2-fluorophenyl)-3-nitrobenzenemethanol as a residue (interm. 26).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]#[N:21].C(#N)C>O>[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[O:1][CH2:19][C:20]#[N:21])=[O:5]
Reactant: N#CCBr
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C=O)c(OCC#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
The mixture of 2-hydroxy-4-methoxybenzaldehyde (9.50 g), potassium carbonate (17.3 g), bromoacetonitrile (11.2 g) and acetonitrile (100 ml) was stirred at room temperature for 12 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate), and then recrystallized from ethyl acetate-hexane to obtain the entitled compound (10.7 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C([Li])CCC.[B:22]([O:31]C(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>CCCCCC.C1COCC1>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([O:23][B:22]([OH:31])[OH:27])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COCC1CCC(c2ccc(I)cc2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC1CCC(c2ccc(OB(O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 20.2 %

Procedure:
To a mixture of 4-(4-methoxymethylcyclohexyl)-1-iodobenzene (297 mmol) and 250 ml of THF, was added dropwise 200 ml of a solution of n-butyl lithium (corresponding to 312 mmol) in hexane at −78° C. in 3.0 hours, and stirred at the same temperature for 1.2 hours. To the solution was added dropwise 100 ml of a solution of triisopropyl borate (594 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 270 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was washed with heptane to give a white solid of 4-(4-methoxymethylcyclohexyl) phenyl boric acid (60.1 mmol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[O:10][N:9]=1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:15]([S:22][C:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[O:10][N:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: CC1(C)CC(Cl)=NO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(SCc2ccccc2)=NO1
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
3.2 g (23.2 mmoles) of anhydrous potassium carbonate and 3.0 g (22.5 mmoles) of 3-chloro-5,5-dimethyl-2-isoxazoline were added, in a nitrogen atmosphere, to a solution of 2.8 g (22.5 mmoles) of benzylmercaptan dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 3.1 g (yield: 62.0%) of 3-benzylthio-5,5-dimethyl-2-isoxazoline as a yellow oily substance (nD20=1.5521).
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH2:3][C:4]([O:6]C)=O.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([NH:19][C:4](=[O:6])[CH2:3][CH:2]([OH:1])[CH2:8][CH2:9][CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH:16]([CH3:18])[CH3:17]
Reactant: CC=CC=CCCC(O)CC(=O)OC
Reactant: CC(C)CN
Product: CC=CC=CCCC(O)CC(=O)NCC(C)C
Temperature: 90 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Methyl 3-hydroxy-6,8-decadienoate (g) (86.1 g, 0.43 mol) and isobutylamine (95.3 g, 1.3 mol) were put into a 500-ml flask, followed by stirring at 90° C. for 24 hours. After isobutylamine was recovered under a reduced pressure, heptane (700 ml) was added thereto, followed by cooling to 0° C. A white solid thus precipitated was filtered and dried under a reduced pressure. Thus, N-isobutyl-3-hydroxy-6,8-decadienamide (h) was obtained (85.2 g, 0.35 mol, yield 82%).
Reaction SMILES: B(F)(F)F.C([N:12]1[C:21](=[O:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]2[S:16][CH2:17][CH2:18][CH2:19][N:14]2[C:13]1=[O:29])C1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[C:23]1([C:20]2[C:21](=[O:22])[NH:12][C:13](=[O:29])[N:14]3[CH2:19][CH2:18][CH2:17][S:16][C:15]=23)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1Cc1ccccc1)CCCS2
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CO
Product: O=c1[nH]c(=O)n2c(c1-c1ccccc1)SCCC2
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
Boron trifluoride (0.68 ml) was added to a solution of 7-benzyl-9-phenyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (1 g) in toluene (40 ml) and was refluxed for 14 hours. Methanol (7 ml) was added to the reaction solution and the mixture was stirred for 30 minutes. The resulting solution was concentrated to dryness, and the residue was dissolved in methylene chloride and ethyl ether. The insoluble material was obtained by filtration and the product was washed by aqueous methanol. After the washing, it was recrystallized from DMF-water to give colorless crystals (0.33 g, 44%).
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][C:11]([CH3:14])=[N:10][CH:9]=3.Cl.O1CCOCC1>CO>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:18]1[CH:2]=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[C:11]([CH3:14])[CH:12]=3)[C:7](=[O:15])[N:6]([CH3:16])[C:5]=2[CH:17]=1
Reactant: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-bromo-2,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (30 mg, 0.058 mmol) in MeOH (3 mL) at 0° C. was added 4M HCl in 1,4-dioxane (0.362 mL, 1.447 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford (S)-8-((2-amino-4-methylpentyl)oxy)-2,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (6 mg, 0.014 mmol, 24% yield) as an off-white solid. LC/MS (ESI) m/e 418.0 [(M+H)+, calcd for C20H25BrN3O2 418.1]; LC/MS retention time (method H): tR=1.70 min; HPLC retention time (method A): tR=6.33 min; HPLC retention time (method B): tR=7.19 min. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.31 (s, 1H), 9.28-9.33 (m, 1H), 8.58 (s, 1H), 8.08 (s, 1H), 7.09 (s, 1H), 4.42 (dd, J=9.79, 3.26 Hz, 1H), 4.25 (dd, J=9.91, 6.15 Hz, 1H), 3.78 (s, 3H), 3.63 (br. s., 1H), 2.73 (s, 3H), 2.00 (br. s., 4H), 1.85-1.92 (m, 1H), 1.71-1.80 (m, 1H), 1.57-1.66 (m, 1H), 1.06 (dd, J=6.40, 4.64 Hz, 6H).