Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:45][CH:46]1[CH2:48][CH2:47]1>CN(C=O)C.O>[CH:46]1([CH2:45][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][N:14]=3)[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:10]([NH:20][C:21]([NH:23][C:24]3[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=3[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]2=[O:19])[CH2:48][CH2:47]1
Reactant: BrCC1CC1
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CC3CC3)c3ncccc23)c1
Reaction time: 10 h
Yield: 78.8 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (400 mg, 0.85 mmol) in DMF (10 ml) were added potassium carbonate (141 mg, 1.02 mmol), potassium iodide (28 mg, 0.17 mmol), and (bromomethyl)cyclopropane (138 mg, 1.02 mmol), and the mixture was stirred at 40°-50° C. for 10 hours. After allowed to stand for cooling, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1% methanol in chloroform), and crystallized from ether to give the title compound (354 mg, 0.67 mmol) as a colorless crystal.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:4]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:3]1=[O:21].[OH:22][C@@H:23]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:24]([NH:26][C@H:27]([C:32](O)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25].CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:18]1([CH2:17][N:4]2[C@H:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH:6]=[CH:7][CH2:8][C@H:2]([NH:1][C:32](=[O:33])[C@H:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:26][C:24](=[O:25])[C@@H:23]([OH:22])[CH2:35][CH:36]([CH3:37])[CH3:38])[C:3]2=[O:21])[CH2:19][CH2:20]1
Reactant: COc1ccc([C@@H]2C=CC[C@H](N)C(=O)N2CC2CC2)cc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](O)CC(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc([C@@H]2C=CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C)C(=O)N2CC2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of (3S,7S)-3-amino-1-(cyclopylmethyl)-7-(4-methoxyphenyl)-1,3,4,7-tetrahydro-2H-azepin-2-one (11e) (35 mg) in DCM (3 mL) at 0° C. under N2 was added N-[(2S)-2-hydroxy-4-methylpentanoyl]-L-leucine (7b) (30 mg), HOBt-hydrate (41 mg), EDAC.HCl (35 mg) and N-methyl morpholine (25 mg). The reaction mixture was stirred 1 h at 0° C. and 3H at room temperature, then diluted with 30% Hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (2% MeOH/DCM) to afford the title compound as an off-white solid (60 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 0.40 (m, 2H), 0.58 (m, 2H), 0.74 (m, 1H), 0.87 (d, 6H), 1.26 (m, 1H), 1.53, (m, 2H), 1.59 (m, 1H), 1.67 (m, 2H), 2.00 (m, 2H), 3.20 (m, 2H), 3.66 (s, 1H), 3.89 (m, 1H), 4.28 (m, 1H), 4.96 (m, 1H), 5.32 (m, 1H), 6.13 (bd, 1H), 6.48 (m, 1H), 6.85-6.94 (m, 4H). MS APCI, m/z=514 (M+1). LC/MS 2.47 min., Method A.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([C:12]2([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:37][NH2:38]>C(O)C>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])([C:10]2[NH:38][N:37]=[C:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:9]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(C(=O)CC(=O)Cc2ccccc2)CC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(c2cc(Cc3ccccc3)n[nH]2)CC1
Temperature: 85 °C
Yield: 71.5 %

Procedure:
To a solution of tert-butyl 4-(4-phenyl-1,3-dioxobut-1-yl)-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (343 mg, 0.68 mmol) from Step G in ethanol (7 mL) was added hydrazine hydrate (0.040 mL, 0.82 mmol). The reaction was heated at 85° C. for 3 h and was then concentrated in vacuo. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to afford the title product (243 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[CH2:10]1.[BH3-]C#N.[Na+].CC(O)=O.[O:28]=[C:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][CH:39]=O)=[CH:37][C:32]=2[CH2:31][O:30]1.C([O-])([O-])=O.[Na+].[Na+]>CO>[O:1]=[C:2]1[CH2:7][N:6]([CH2:39][CH2:38][C:36]2[CH:35]=[CH:34][C:33]3[C:29](=[O:28])[O:30][CH2:31][C:32]=3[CH:37]=2)[CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[CH2:10]1
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1ccc2c(c1)CC(CN1CCNCC1=O)C2
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CC(CN1CCN(CCc3ccc4c(c3)COC4=O)CC1=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-[(2-Oxopiperazin-1-yl)methyl]-2,3-dihydro-1H-indene-5-carbonitrile (170 mg, 0.70 mmol), NaBH3CN (84 mg, 1.3 mmol) and HOAc (80 mg, 1.3 mmol) in 50 mL MeOH was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (235 mg, 1.3 mmol) and the mixture was stirred at RT overnight. Then saturated Na2CO3 (50 mL) was added and stirred for 30 min and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give the title product. 1H-NMR (400 MHz, MeOD) δ ppm 7.78 (d, J=7.8 Hz, 1H), 7.46˜7.51 (m, 4H), 7.34 (d, J=7.8 Hz, 1H), 5.34 (s, 2H), 3.48 (d, J=7.0 Hz, 2H), 3.43 (t, J=5.5 Hz, 2H), 3.21 (s, 2H), 2.69˜3.09 (m, 11H).
Reaction SMILES: C1(C)C=CC=CC=1.N1C=C[C:9]=1[C:12]([NH:14][CH:15]1[C:37](=[O:38])[N:17]2[CH:18]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[C:19]([CH3:23])([CH3:22])[S:20](=[O:21])[C@H:16]12)=[O:13].[Cl:39]N1C(=O)CCC1=O>O>[CH3:22][C:19](=[CH2:23])[CH:18]([N:17]1[C:37](=[O:38])[CH:15]([NH:14][C:12](=[O:13])[CH3:9])[CH:16]1[S:20]([Cl:39])=[O:21])[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:25]
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C3=NC=C3)[C@H]2S1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(C)=O)C1S(=O)Cl

Procedure:
Toluene (500 ml.) was heated in equipment containing a Dean-Stark water trap to azeotropically remove any moisture which may be present. To the resulting dried toluene was added 1.0 gms. (2.4 mmol.) of p-nitrobenzyl 6-azetamido-2,2-dimethylpenam-3-carboxylate-1-oxide. The resulting mixture was refluxed again using a Dean-Stark water trap to remove any additional amounts of water which may be present. The mixture then was cooled, and 400 mg. (2.9 mmol) of N-chlorosuccinimide were added. The mixture then was refluxed for 1 hour. A sample of the reaction mixture was withdrawn, and the solvent was removed. The product which was obtain was consistent by nmr analysis with the structure of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[Cl:21][CH2:5][C:4]1[CH:7]=[C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Oc2ccccc2Cl)cc1CO
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(Oc2ccccc2Cl)cc1CCl

Procedure:
A mixture of 2-methoxy-5-(2-chlorophenoxy)benzyl alcohol (8 g), thionyl chloride (4.4 ml) and pyridine (3 drops) in dried benzene (60 ml) was treated in a similar manner to that of Example 3-(6) to give oily 2-chlorophenyl 3-chloromethyl-4-methoxyphenyl ether (8.5 g).
Reaction SMILES: C(S([C:6]1[CH:38]=[CH:37][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[C@@H:20]([CH:34]([CH3:36])[CH3:35])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=O)=O)C.C([C@H]1C2=NC=C(C(NCC3C=CC([C:59]([O:61][CH3:62])=[O:60])=CC=3)=O)C=C2CN1)(C)C>>[CH:34]([C@H:20]1[C:17]2=[N:18][CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:9]3[CH:8]=[CH:7][C:6]([C:59]([O:61][CH3:62])=[O:60])=[CH:38][CH:37]=3)=[O:13])[CH:15]=[C:16]2[CH2:22][N:21]1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=1)([CH3:36])[CH3:35]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)[C@H]3C(C)C)cc1
Reactant: COC(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Product: COC(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)[C@H]3C(C)C)cc1
Reaction time: 0.03 h

Procedure:
Procedure same as that for (S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide, using methyl(S)-4-((7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamido)methyl)benzoate as a starting material. LC-MS tR=1.34 min in 2 min chromatography, MS (ESI) m/z 512 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([SH:15])[CH2:13][SH:14])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:29][O:28][C:24]1[CH:23]=[C:20]([CH:21]2[S:15][CH:12]([C:5]3[CH:6]=[C:7]([O:10][CH3:11])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][S:14]2)[CH:19]=[C:18]([O:17][CH3:16])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1cc(C(S)CS)cc(OC)c1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(C2CSC(c3cc(OC)c(OC)c(OC)c3)S2)cc(OC)c1O

Procedure:
1-(3,5-dimethoxy-4-hydroxyphenyl)-1,2-ethanedithiol (40) (2.10 g, 8.54 mmole), 3,4,5-trimethoxybenzaldehyde (24) (1.28 g, 6.57 mmole) and 0.857 g of pyridinium paratoluene sulfonate are added to 60 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope overnight. The benzene is removed in vacuo, and the remaining oil is extracted into 10% NaOH which was washed with diethylether. The basic layer is reacidified with 10% HCl and the desired product is extracted into ethyl acetate. The organic layer is dried over MgSO4, filtered, and evaporated in vacuo to an oil which is purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.2 cis/trans ratio after the first recrystallization (1.287 g, 59%). The trans isomer is isolated after six additional recrystallizations from methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[S:9](=[O:10])[CH:8]=[N:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>CC(C)=O>[C:22]([N:7]1[C:6]2[CH:11]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[S:9](=[O:10])[CH2:8]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)S(=O)C=N2
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CS(=O)c2c1cc(C)cc2[N+](=O)[O-]
Yield: 82.6 %

Procedure:
6.3 g (0.03 mol) of 5-methyl-7-nitro-benzothiazolone and 3.3 g (0.03 mol) of triethylamine are dissolved in 150 ml of acetone. 2.35 g (0.03 mol) of acetyl chloride are allowed to run in slowly dropwise, with stirring, at an internal temperature of 5°-10° C. The reaction mixture is stirred at room temperature for a further 3 hours and then poured onto ice. 6.3 g (83 % of theory) of 3-acetyl-5-methyl-7-nitro-benzothiazolone are obtained in the form of creamcolored flakes of melting point 141° C.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[S-:23][C:24]#[N:25].[K+].BrBr>O>[NH2:25][C:24]1[S:23][C:21]2[CH:22]=[C:16]([O:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=[CH:18][C:19]=2[N:20]=1
Reactant: N#C[S-]
Reactant: CCCCCCCCCCOc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCOc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
Next, acetic acid (100 ml) was added to the 4-decyloxyaniline 3 (23.4 g, 93.7 mmol) thus obtained, and potassium thiocyanate (23.5 g, 242 mmol) was then added thereto. The solution was thoroughly cooled in an ice bath, and an acetic acid solution of bromine (5.8 ml/50 ml) was then added dropwise thereto over a period of about 3 hr. After the completion of the dropwise addition of the solution, the mixture was stirred at room temperature for about 2 hr. Thereafter, water (200 ml) was added, and the mixture was refluxed for about 30 min and was then hot-filtered. The filtrate was made alkaline by the addition of aqueous ammonia, and saturated brine was further added thereto. The precipitated solid was collected by filtration to give 2-amino-6-decyloxybenzothiazole 4 (14.22 g, 49.5%) as a light purple solid. The product was purified by column chromatography on silica gel (hexane: AcOEt=1:2).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[CH:3]=1.[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>CCCCO>[Br:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:22][C:18]3[CH:17]=[C:16]([NH2:23])[CH:21]=[CH:20][CH:19]=3)[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc(Nc2cccc(Br)c2)ncn1
Reactant: Nc1cccc(N)c1
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Nc3cccc(Br)c3)ncn2)c1
Temperature: 150 °C
Yield: 65.1 %

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-(3-bromo-phenyl)-amine (300 mg, 1.1 mmol) and benzene-1,3-diamine (300 mg, 2.75 mmol) in 3 mL of n-BuOH was heated in a sealed tube to 150° C. for 16 hr. Solvent was removed by vacuum evaporation and the crude product was purified by flash chromatography on silica gel with EtOAc/DCM solvent system to afford 255 mg (65% yield) of the title compound as a yellow solid. MS (m/z): MH+=356, 358.
Reaction SMILES: [C:1]1([O:11][C:12](=[O:61])[C@H:13]([CH2:34][CH2:35][CH2:36][N:37](C(OCC2C=CC=CC=2)=O)[C:38](=[NH:50])[NH:39]C(OCC2C=CC=CC=2)=O)[NH:14][C:15](=[O:33])[C@H:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:62].O1CCOCC1.[H][H]>CN(C=O)C.[Pd]>[ClH:62].[C:1]1([O:11][C:12](=[O:61])[C@H:13]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:50])[NH:14][C:15](=[O:33])[C@H:16]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)Oc1cccc2ccccc12
Yield: 92 %

Procedure:
In 10 ml of DMF was dissolved 1.07 g of the above ester, after which 0.5 g of 10% Pd-C and 1.65 ml of 2 N hydrochloric acid-dioxane solution were added thereto. The mixture was stirred with ice-cooling for 3 hrs while passing hydrogen gas therethrough. After the reaction, the reaction mixture was filtered to remove the Pd-C, and 500 ml of anhydrous diethyl ether was added to the filtrate. The white powder thus precipitated was collected and vacuum-dried over P2O5 at 110° C. for 3 hrs to obtain 700 mg (yield 92%) of benzoyl-L-phenylalanyl-L-arginine 1-naphthyl ester hydrochloride, m.p. 112° C.-(decomp.).
Reaction SMILES: [CH2:1]([Si:5]([CH3:26])([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:16](B(O)O)=[C:15]([F:23])[C:14]([F:24])=[CH:13][C:12]=2[CH2:11]1)[CH2:2][CH2:3][CH3:4].Br[CH:28]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([Si:5]([CH3:26])([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([F:24])=[C:15]([F:23])[C:16]=2[C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:37][CH:36]=2)[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCC(Br)CCCc1ccccc1
Reactant: CCCC[Si](C)(C)CCCCC1CCc2c(cc(F)c(F)c2B(O)O)C1
Product: CCCCCCCCCCc1ccc(-c2c(F)c(F)cc3c2CCC(CCCC[Si](C)(C)CCCC)C3)cc1

Procedure:
From 6-[4-(butyldimethylsilanyl)butyl]-2,3-difluoro-5,6,7,8-tetrahydronaphthalene-1-boronic acid and 4-bromodecylbenzene by means of the Suzuki coupling.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[N:7][C:6]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:5]=2[CH:4]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[OH:35]>O.CN(C)C=O>[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[O:35][CH2:2][C:3]1[N:8]=[N:7][C:6]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:5]=2[CH:4]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: BrCc1cc2c(nn1)Oc1ccccc1O2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)Oc1cc(COc3ccc4ccccc4c3)nnc1O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
To 3-(bromomethyl)[1,4]benzodioxino[2,3-c]pyridazine (500 mg) were added dimethylformamide (10 ml), potassium iodide (30 mg), potassium carbonate (750 mg) and 2-naphthylalcohol (290 mg), and the mixture was stirred at room temperature for 24 hr. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was washed with diethyl ether and the resulting solid was filtered and dried under reduced pressure to give 3-[(2-naphthyloxy)methyl][1,4]benzodioxino[2,3-c]pyridazine (400 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:27])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reaction time: 0.75 h

Procedure:
A solution of tert-butyl{1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 141, 240 mg, 0.62 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (15 mL). After 45 minutes, the reaction was concentrated to dryness, the residue taken up in methanol/chloroform (15:85, 30 mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was re-extracted with methanol/chloroform (15:85, 3×30 mL. The combined organic phases were dried over magnesium sulfate and concentrated to dryness to give 170 mg (quantitative) of the crude product as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](O)=[O:7])#[N:2].Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)C(C)C)(C)C.P(C#N)(OCC)(OCC)=O>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:18]([O:19][CH3:20])[CH3:17])=[O:7])#[N:2]
Reactant: CNOC
Reactant: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of 3-cyano-5-(trifluoromethyl)benzoic acid (200 mg, 0.93 mmol) in tetrahydrofuran (2 mL) stirred on an ice bath was added N,O-dimethylhydroxyamine hydrochloride (145 mg, 1.49 mmol), N,N-diisopropylethylamine (470 mg, 3.64 mmol) and diethyl cyanophosphate (DEPC, 227 mg, 1.39 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with 1 M hydrochloric acid (0.5 mL), and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 3-cyano-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (196 mg, 82%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>CO.CCOC(C)=O.[Pd]>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cccnc2)cc1
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a mixture of 3-pyridylboronic acid (500 mg, 4.06 mmol), 1-iodo-4-nitrobenzene (1.01 g, 4.06 mmol) and Pd(Ph3P)2Cl2 (140 mg, 0.199 mmol) in dioxane (15 mL), a solution of Na2CO3 (1.00 g, 9.43 mmol) in H2O (10 mL) was added. The mixture was stirred at 100 C for 2 h. Water and EtOAc were added. Organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column on ISCO, eluted with 20-100% EtOAc in hexanes to give 3-(4-nitrophenyl)pyridine as a solid (487 mg). A mixture of 3-(4-nitrophenyl)pyridine (487 mg, 2.43 mmol) and Pd—C(10%, 80 mg) in MeOH (25 mL) and EtOAc (5 mL) was hydrogenated under balloon H2 for 5 h. The mixture was then filtered through celite. The filtrate was concentrated in vacuo to give 4-(pyridin-3-yl)aniline as a solid (403 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.[C:15](O)(=[O:17])[CH3:16]>C(OC(=O)C)(=O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:5][N:6]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Sc2cnc(N)s2)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Sc2cnc(N)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
A mixture of 2-amino-5-(4-aminophenylthio)thiazole, (4.0 g) in a mixture of acetic acid (40 ml) and acetic anhydride (2.2 g) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(4-acetylaminophenylthio)thiazole (2.1 g, yield: 44.2%). mp: 240°-245° C. (dec.)