Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([OH:16])[C@H:12]([NH2:15])[CH2:13][F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:17][CH:18]([Cl:23])[C:19](OC)=[O:20]>CO>[Cl:17][CH:18]([Cl:23])[C:19]([NH:15][C@H:12]([CH2:13][F:14])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[OH:16])=[O:20]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: COC(=O)C(Cl)Cl
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Yield: 69.8 %

Procedure:
To a solution of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (5 g, 0.02 moles) in methanol (50 ml) was added methyl dichloroacetate (14.5 g; 0.10 g) and heated to reflux at 60° C. to 65° C. for 18 hours. After completion of reaction, methanol was distilled off from reaction mass, toluene (25 ml) and water (5 ml) were added. The product thus precipitated was filtered, washed with methylene chloride (20 ml) and crystallized from 2-propanol/water (5:1) to give 5 g of Florfenicol with 99% HPLC purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=3[N+:23]([O-])=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.O1CCCC1>[Pd].C(OCC)(=O)C>[NH2:23][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:13]=1[C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(Cl)cc3)no2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2nc(-c3ccc(Cl)cc3)no2)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A mixture of methyl 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-nitrobenzoate (0.700 g), 5% palladium on carbon (0.700 g), tetrahydrofuran (15 ml) and ethyl acetate (30 ml) was stirred under a hydrogen atmosphere at room temperature and normal pressure for 30 min. Palladium on carbon was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1, volume ratio) to give methyl 3-amino-4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]benzoate (0.50 g, yield 79%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 227–228° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=1)[C:7]2=[O:12].[CH:24]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[CH:24]1([CH2:31][C:32]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]4[O:18][CH2:19][CH2:20][O:21][C:16]=4[CH:15]=2)[C:7]3=[O:12])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CC1CCCCCC1
Reactant: Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC1CCCCCC1)Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12

Procedure:
5-Amino-2-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-2H-isoquinolin-1-one (50 mg, 0.0002 mol), 2-cycloheptylacetic acid (63 mg, 0.00041 mol), fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (110 mg, 0.00041 mol) and N,N-diisopropylethylamine (100 mg, 0.0008 mol) were stirred in methylene chloride (3 mL, 0.05 mol) at room temperature for 72 hours. The mixture was purified via flash chromatography (12 g of silica gel, 50% EtOAc/Hexane) to give a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[N:21]([S:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)(=[O:34])=[O:33])[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=5)=[CH:23][C:16]=34)=[CH:13][N:12]([CH2:41][CH3:42])[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:43][NH:44][CH3:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[N:21]([S:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)(=[O:34])=[O:33])[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:44]([CH3:45])[CH3:43])[CH:25]=5)=[CH:23][C:16]=34)=[CH:13][N:12]([CH2:41][CH3:42])[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CNC
Reactant: CCn1cc(-c2ccnc3c2cc(-c2cccc(C=O)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(CN(C)C)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-(3-formylphenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (1.3 mmol) in tetrahydrofuran (20 mL) was added a solution of 2 M dimethylamine in tetrahydrofuran (2.0 mmol) followed by sodium triacetoxyborohydride (1.9 mmol). The reaction was stirred at room temperature for 4 h and concentrated to dryness under vacuum. The residue was taken up in ethyl acetate, washed with brine, dried (sodium sulfate), filtered, and evaporated under vacuum. Purification by flash chromatography on silica gel (0-5% (5% ammonium hydroxide, methanol)/methylene chloride) gave the title compound as a yellow solid (87%). ESMS [M+H]+: 607.4
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][O:6][C:5]2([CH2:21][CH2:20][CH2:19][C:11]3=[N:12][CH:13]=[C:14]([N+:16]([O-])=O)[CH:15]=[C:10]3[CH2:9][CH2:8]2)[O:4][CH2:3]1>C(O)C.C1COCC1.[Pd]>[CH3:1][C:2]1([CH3:22])[CH2:7][O:6][C:5]2([CH2:21][CH2:20][CH2:19][C:11]3=[N:12][CH:13]=[C:14]([NH2:16])[CH:15]=[C:10]3[CH2:9][CH2:8]2)[O:4][CH2:3]1
Reactant: CC1(C)COC2(CCCc3ncc([N+](=O)[O-])cc3CC2)OC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)COC2(CCCc3ncc(N)cc3CC2)OC1

Procedure:
The compound of formula (Cc), 5′,5′-dimethyl-3-nitro-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane], was hydrogenated in ethanol/THF solution over 10% Pd/C for 1 hour at 40 psi to give the compound of formula (Cd), 5′,5′-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxan]-3-amine, in quantitative yield; MS (ES) 277.67 (M+2H).
Reaction SMILES: O[CH:2]([CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:3](O)=[O:4].Cl.[NH2:17][NH2:18].N>O.C(O)(=O)C.C(N(CC)CC)C>[OH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[CH:6]=[CH:2][C:3](=[O:4])[NH:17][N:18]=1
Reactant: O=C(CC(O)C(=O)O)c1ccccc1O
Reactant: NN
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(-c2ccccc2O)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a stirred suspension of 2-hydroxy-4-oxo-4-(2-hydroxyphenyl)butyric acid (0.025M) in water (20 ml) was added triethylamine (3.3 ml), taking the pH to 9.5, followed by concentrated hydrochloric acid (2.5 ml) to take the pH to 4. Hydrazine (0.05M) was added slowly with the concurrent addition of sufficient glacial acetic acid to maintain a pH of 7.0. Steam heating was applied for 2 hours and during this time the pH of 7.0 was maintained by the addition of ammonia as necessary. The reaction mixture was allowed to cool to room temperature. The solid was filtered off, washed with water, 2-propanol and dried to afford 6-(2-hydroxyphenyl)-3(2H)-pyridazinone (78.3%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][C:19]1[NH:20][C:21]([CH3:26])=[CH:22][C:23](=[O:25])[N:24]=1)=[O:17].[N:27]1[C:34]([Cl:35])=[N:33][C:31](Cl)=[N:30][C:28]=1[Cl:29]>C(#N)C>[Cl:29][C:28]1[N:27]=[C:34]([Cl:35])[N:33]=[C:31]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][C:19]2[NH:20][C:21]([CH3:26])=[CH:22][C:23](=[O:25])[N:24]=2)=[O:17])[N:30]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cc(=O)nc(NC(=O)NCCCCN)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(=O)nc(NC(=O)NCCCCNc2nc(Cl)nc(Cl)n2)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
An aqueous solution (40 ml) containing 6 ml of diisopropylethylamine and 5 g (0.018 mol) of 1-(4-aminobutyl)-3-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)urea, prepared beforehand, was added, dropwise, to 5 g (0.018 mol) of cyanuryl chloride suspended in 80 ml of acetonitrile, at a temperature of −20° C. The reaction medium was stirred for 12 hours at ambient temperature and then poured into 200 ml of ice-cold water. The precipitate formed was filtered off and then dried under vacuum, so as to give 6.8 g (0.0175 mol) of a yellow powder with a yield of 97%.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10][C:9]2=[O:16])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].N([O-])=O.[Na+].[I-:25].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.C(Cl)Cl>[CH3:14][C:11]1([CH3:15])[NH:10][C:9](=[O:16])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:25])=[C:3]([C:17]([F:20])([F:19])[F:18])[CH:4]=2)[C:12]1=[O:13]
Reactant: [I-]
Reactant: CC1(C)NC(=O)N(c2ccc(N)c(C(F)(F)F)c2)C1=O
Agent: O=N[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)NC(=O)N(c2ccc(I)c(C(F)(F)F)c2)C1=O
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
140 g of the product of Example 1 and 210 ml of demineralized water are introduced at 20°±2° C., agitation is carried out and 210 ml of pure 22°Be hydrochloric acid is added over about 5 minutes. The reaction medium is maintained at 35°-40° C. for 30 minutes under agitation then cooled down to 0°±5° C. under agitation. Then 28 ml of methylene chloride is added, a solution of 43.7 g of sodium nitrite in 70 ml of demineralized water is then added over about 30 minutes, at 0°±5° C. The reaction medium is maintained for another hour under agitation at 0°±5° C., a solution of 87.7 g of sodium iodide in 140 ml of demineralized water is added over 45 minutes. The reaction medium is maintained under agitation for another hour and 700 ml of methylene chloride is added. Agitation is carried out for 15 minutes at 0°±5° C., 28 g of sodium metabisulphite is added in one go and agitation is carried out for another 30 minutes while leaving the temperature to return to 20° C. After pouring, the organic phase is decanted, the aqueous phase is reextracted with 280 ml of methylene chloride, then the organic phases are washed with 3×140 ml of a saturated aqueous solution of NaCl. The joint chloromethylenic phases are dried, followed by filtering and washing with 3×70 ml of methylene chloride and 184.5 g of expected product (white crystals) is obtained, M.p.=164-165° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[C:9](=[O:20])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=2.BrC1C=CC(S(O[C@@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]2)(=O)=O)=CC=1.CCOC(C)=O>CN1C(=O)CCC1.O>[Br:7][C:8]1[C:9]([O:20][C@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]2)=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=2
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc2cc(Br)c(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3cc2Br)CN1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 40 h

Procedure:
Cs2CO3 (2.11 g, 6.46 mmol) was added to a solution of 3-bromo-7-methoxyquinolin-2(1H)-one (1.31 g, 5.17 mmol) and 1-text-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (2.0 g, 4.31 mmol) in NMP (21.5 mL), and the reaction mixture was stirred for 40 h at 40° C. An additional portion of 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.0 g, 2.16 mmol) was added, and the reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was cooled and poured onto a mixture of EtOAc and water, and the layers were separated. The organic layer was washed with water twice, NaHCO3 twice and brine, dried over Mg2SO4, filtered and concentrated. The product was used with no further purification. LRMS (M+H-Boc)+=381.2.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O.O.CO>[CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC)ccc1-3
Reaction time: 8 h
Yield: 103.1 %

Procedure:
To a solution of 12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (2.40 g, 6.13 mmol) in N,N-dimethylformamide (20.0 mL) were successively added methyl 2-amino-2-methylpropionate hydrochloride (1.13 g, 7.36 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (1.41 g, 7.36 mmol), 1-hydroxybenzotriazole (0.99 g, 7.36 mmol) and triethylamine (1.00 ml, 7.36 mmol) at room temperature, and the mixture was stirred overnight. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution, methanol and water. The precipitate was collected by filtration, washed with water, and dried in vacuo to give methyl 2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionate (3.10 g). The obtained compound was used for Step 2 without purification.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[N-:45]=[N+:46]=[N-:47].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:45]([CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)=[O:33])=[N+:46]=[N-:47]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (7.1 g) in dimethylformamide (70 ml) was added sodium azide (1.09 g) and ammonium chloride (0.90 g) and the mixture was stirred at 80°-90° C. for 3 hours. The reaction mixture was poured into ice-water (200 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 g) eluting with n-hexane and ethyl acetate (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-azidomethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.20 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([N:25]2[CH2:26][CH2:27][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:29][CH2:30]2)=[N:21][CH:20]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(N)cn2)CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Yield: 65.9 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyrimidin-2-yl)piperidin-4-ylcarbamate (440 mg, 1.5 mmol) to afford the desired product (374 mg, 66%) as a yellow solid: ESI MS m/z 567 [C27H31BrN6O3+H]+.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:2]1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(#N)C>[CH2:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[CH2:4][C@H:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:2]1
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC#N
Product: CCOC(=O)[C@H]1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Temperature: 60 °C

Procedure:
8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (Japanese Unexamined Patent Publication (Kokai) No. 2004-002470, Example 21f; 25.0 g) and (S)-(+)-camphorsulfonic acid (18.6 g) were dissolved in acetonitrile (100 mL) and concentrated under reduced pressure. To the residue, methyl-tert-butyl ether (250 mL) was added and recrystallization was carried out by being left to stand at room temperature, and then a crystal was filtered (the crystal is used in Example 24). The filtrate was concentrated under reduced pressure and the resultant residue was diluted with a mixed solution of an aqueous saturated sodium hydrogen carbonate solution and saturated brine, and then extracted three times with ethyl acetate. The organic layer was washed with a mixed solution of an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue, (R)-(−)-camphorsulfonic acid (8.97 g) was added and the mixture was dissolved in acetonitrile (121 mL) and then concentrated under reduced pressure. To the residue, a mixed solution of acetonitrile (4 mL) and methyl-tert-butyl ether (121 mL) were added and crystallization was carried out by being left to stand at room temperature, and then a crystal (9.98 g) was filtered. The resultant crystal was dissolved by heating at 60° C. in a mixed solution of methyl-tert-butyl ether (425 mL) and acetonitrile (85 mL). The solution was recrystallized by being left to stand at room temperature, and a crystal (6.18 g) was filtered. The resultant crystal was diluted with a mixed solution of an aqueous saturated sodium hydrogen carbonate solution and saturated brine, and then extracted five times with ethyl acetate. The organic layer was washed with a mixed solution of an aqueous saturated sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (3.63 g, 99% ee) having the following physical properties. Optical purity was confirmed using a high-performance liquid chromatography (HPLC).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.C(=O)=O.[F:33][C:34]([F:40])([F:39])[S:35](Cl)(=[O:37])=[O:36]>CN(C)C1C=CN=CC=1.O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][S:35]([C:34]([F:40])([F:39])[F:33])(=[O:37])=[O:36])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1cc2c(OS(=O)(=O)C(F)(F)F)ccnc2cc1OCc1ccccc1
Reaction time: 0.42 h
Yield: 83.5 %

Procedure:
To a dry 2 L RBF containing 7-benzyloxy-6-methoxyquinolin-4-ol (75.3 g, 267 mmol) was added DCM (1 L), 4-dimethylaminopyridine (3.28 g, 26.8 mmol) and 2,6-lutidine (62 mL, 534 mmol). The mixture was cooled to −20° C. by controlled addition of dry ice to an acetone bath. Trifluoromethanesulfonyl chloride (37 mL, 350 mmol) was added dropwise to the cooled solution with magnetic stirring over 25 minutes. After addition was complete, the mixture was stirred in bath for 20 minutes, then at room temperature for 3 hours. LCMS indicated reaction completion. The reaction mixture was concentrated in vacuo and placed under high vacuum to remove residual 2,6-lutidine. To the resulting brown solids was added methanol (3.5 L). The resulting slurry was stirred with mechanical stirrer for 30 min before adding water (1.5 L). The solids were isolated by filtration, followed by a water wash. The resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolin-4-yl ester as a light brown solid (92.2 g, 83.8%). 1H NMR (400 MHz, DMSO, d6): δ 8.82 (d, 1H), 7.67 (s, 1H), 7.59 (d, 1H), 7.54-7.52 (m, 2H), 7.46-7.42 (m, 2H), 7.39-7.36 (m, 1H), 7.23 (s, 1H), 5.35 (s, 2H), 3.97 (s, 3H). LC/MS: M+H=414.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]([CH3:13])([CH3:12])[C:10]2[CH:9]=[C:8]([OH:14])[CH:7]=[CH:6][C:5]=2[CH2:4][C@H:3]1[S:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1.N[C@@H:24]1[C:33](C)(C)C2C=C(O)C=CC=2[CH2:26][C@H:25]1SC1C=CC(N)=CC=1.N[C@@H]1C(C)(C)C2C=C(O)C=CC=2C[C@H]1SC1C=CC=C(O)C=1.C(OC(=O)CCS[C@H]1[C@H](N)C(C)(C)C2C(=CC=C(O)C=2)C1)C.N[C@@H]1C(C)(C)C2C=C(O)C=CC=2C[C@H]1SCCC1C=CC=CC=1.N[C@@H]1C(C)(C)C2C(=CC=C(O)C=2)C[C@H]1SC(C)C(N)=O.N[C@@H]1C(C)(C)C2C(=CC=C(O)C=2)C[C@H]1SCCC(O)=O.N[C@@H]1C(C)(C)C2C(=CC=C(O)C=2)C[C@H]1SCCC(NC(CC1C=CC(O)=CC=1)C(N)=O)=O>>[NH2:1][C@@H:2]1[C:11]([CH3:12])([CH3:13])[C:10]2[CH:9]=[C:8]([OH:14])[CH:7]=[CH:6][C:5]=2[CH2:4][C@H:3]1[S:15][C:16]1[CH:21]=[CH:20][C:19]2[C:18](=[CH:33][CH:24]=[CH:25][CH:26]=2)[CH:17]=1
Reactant: CC1(C)c2cc(O)ccc2C[C@@H](Sc2ccc(N)cc2)[C@@H]1N
Reactant: CC1(C)c2cc(O)ccc2C[C@@H](Sc2ccc(O)cc2)[C@@H]1N
Agent: CC(S[C@@H]1Cc2ccc(O)cc2C(C)(C)[C@H]1N)C(N)=O
Agent: CC1(C)c2cc(O)ccc2C[C@@H](SCCC(=O)NC(Cc2ccc(O)cc2)C(N)=O)[C@@H]1N
Agent: CC1(C)c2cc(O)ccc2C[C@@H](SCCC(=O)O)[C@@H]1N
Product: CC1(C)c2cc(O)ccc2C[C@@H](Sc2ccc3ccccc3c2)[C@@H]1N

Procedure:
Trans7-Amino-6-(4-hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #36);Trans-7-amino-6-(4amino-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #37);Trans-7-amino-6-(3-hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #38);Trans-3-(3-Amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionic acid ethyl ester (Compound #39);Trans-7-amino-8,8-dimethyl-6-phenethylsulfanyl-5,6,7,8-tetrahydronaphthalen-2-ol (Compound #40);Trans-2-(3-amino-6-hydroxy-4,4-dimethyl 1,2,3,4-tetrahydronaphthalen-2-ylsulfanyl)-propionamide (Compound #41);Trans-3-(3-amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionic acid (Compound #42);Trans-2-[3-(3-Amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionylamino]-3-(4-hydroxy-phenyl)-propionamide (Compound #43); 3-trans-(2-ethoxycarbonyl-ethylsulfanyl)-1,1-diethyl-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl (Compound #44); 3-trans-(2-carboxy-ethylsulfanyl)-1,1-diethyl-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl (Compound #45);