Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1(C)[C:21](C)(C)OB(C(C)=C)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([O:11][C:12]([F:15])([F:14])[F:13])=[C:2]([C:17]([CH3:21])=[CH2:16])[CH:7]=1)([O-:10])=[O:9]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: ClCCl
Product: C=C(C)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0 h
Yield: 93.6 %

Procedure:
2-bromo-4-nitro-1-(trifluoromethoxy)benzene (0.56 g, 1.97 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.50 g, 2.96 mmol), PdCl2(dppf).CH2Cl2 adduct (0.16 g, 0.20 mmol), and Na2CO3 (0.63 g, 5.92 mmol) were combined in a 20 mL microwave vial and DME (15.78 mL) and Water (3.94 mL) were added. The mixture was stirred at RT for 6 s and then heated to 120° C. in the microwave for 30 min. The crude mixture was diluted with EtOAc and Water. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was diluted with DCM and silica gel was added. The mixture was concentrated under reduced pressure to dry-load material for purification. The crude was purified via silica gel FCC, 100% Heptane-100% EtOAc to give 4-nitro-2-(prop-1-en-2-yl)-1-(trifluoromethoxy)benzene (456 mg). 1H NMR (400 MHz, DMSO-d6) δ 2.08-2.13 (m, 3H), 5.21 (p, J=1.0 Hz, 1H), 5.43 (p, J=1.5 Hz, 1H), 7.68 (dq, J=9.0, 1.6 Hz, 1H), 8.21 (d, J=2.9 Hz, 1H), 8.28 (dd, J=9.0, 2.9 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[C:5](=[C:9]([CH3:11])[CH3:10])[CH2:4]1.CO>CCOC(C)=O.[Pt](=O)=O>[OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4]1
Reactant: CC(C)=C1C[C@H](CO)NC1=O
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C1C[C@H](CO)NC1=O
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of (R)-5-(hydroxymethyl)-3-(propan-2-ylidene)pyrrolidin-2-one (2.223 g, 14.32 mmol) and platinum (iv) oxide (0.325 g, 1.432 mmol) in EtOAc (40 mL)/MeOH (4 mL) at room temperature was stirred in the pressure bottle reactor under H2 (28 psi to 2 psi) overnight. The resulting mixture was filtered through a pad of Celite, washed with EtOAc, and concentrated to give (5R)-5-(hydroxymethyl)-3-isopropylpyrrolidin-2-one (2.251 g, 14.32 mmol, 90% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.56-6.71 (m, 1H), 3.64-3.80 (m, 2H), 3.37-3.53 (m, 1H), 2.48 (td, J=9.9, 4.5 Hz, 2H), 2.14-2.27 (m, 1H), 1.97-2.13 (m, 1H), 1.50 (ddd, J=12.7, 10.7, 8.3 Hz, 1H), 0.98 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H). m/z (ESI, +ve) 158 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7](O)(=O)[C:8]([CH3:11])([CH3:10])[CH3:9].S(=O)(=O)(O)O>>[C:8]([C:11]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]=1)([CH3:10])([CH3:9])[CH3:7]
Reactant: CC(C)(C)C(=O)O
Reactant: CNC(=S)NN
Agent: O=S(=O)(O)O
Product: CNc1nnc(C(C)(C)C)s1

Procedure:
feeding the contents of said first and second vessels concomitantly into a third vessel containing a heel, i.e., a reacted mixture having been formed previously by reacting 4-methyl-3-thiosemicarbazide with a solution of pivalic acid in the presence of a solution containing concentrated polyphosphoric acid and concentrated sulfuric acid to form 5-t-butyl-2-methylamino-1,3,4-thiadiazole in situ;
Reaction SMILES: [C:1]([CH2:3][C@@:4]12[C@@H:20]([C:21](=[O:23])[CH3:22])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C@:8]3([CH3:25])[C:13]([CH2:14][CH2:15]1)=[CH:12][C:11](=[O:24])[CH2:10][CH2:9]3)[CH2:6][CH2:5]2)#[CH:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([CH2:3][C@@:4]12[C@@H:20]([CH:21]([OH:23])[CH3:22])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C@:8]3([CH3:25])[C:13]([CH2:14][CH2:15]1)=[CH:12][C:11](=[O:24])[CH2:10][CH2:9]3)[CH2:6][CH2:5]2)#[CH:2]
Reactant: C#CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C#CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(C)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4.2 g of 18-ethynylpregn-4-ene-3,20-dione in 125 ml of methanol is cooled to 0° C. and 950 mg of sodium borohydride is added. The resulting mixture is stirred at 0° C. for 1 hour and then allowed to warm to room temperature over an additional hour. Acetic acid is then added and the solution is concentrated. The resulting residue is suspended in ethyl acetate, washed with water, aqueous sodium bicarbonate and brine and dried, and the solvent is evaporated. The residue is dissolved in 400 ml of chloroform, 42 g of activated manganese dioxide is added, and the resulting suspension is stirred for 24 hours. The inorganic solid is then removed by filtration through Celite and the filter cake is washed thoroughly with hot chloroform. The filtrate is then concentrated and the residue is purified by recrystallization from acetone/hexane to give 18-ethynyl-20-hydroxypregn-4-en-3-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:10]([N:17]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>C(Cl)Cl>[C:10]([N:17]1[CH2:21][CH2:20][C@H:19]([NH:22][CH:5]2[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3][CH2:4]2)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CC1(C)CCC(=O)CC1
Solvent: ClCCl
Product: CC1(C)CCC(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.5 %

Procedure:
To a solution of 4,4-dimethylcyclohexanone (3.8 g, 30 mmol) in DCM (200 ml) was added commercially obtained (3S)-1-Boc-3-aminopyrrolidine (5.6 g, 30 mmol), and NaBH(OAc) (12.7 g, 60 mmol) was added, and stirred at rt for 6 h. After the reaction finished, the solvent was concentrated in vacuo, a NaHCO3 aqueous solution was added, and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=2/1) to give the title compound (8.4 g, 94.5%).
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=O)[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[F:21]>C(O)(=O)C>[O:9]=[C:7]1[CH:2]2[CH:1]([CH2:6][CH2:5][CH2:4][CH2:3]2)[C:10](=[O:11])[N:12]1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[F:21]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: CC(=O)O
Product: N#Cc1ccc(N2C(=O)C3CCCCC3C2=O)c(F)c1

Procedure:
To a solution of 5 parts of cis-1,2-cyclohexane dicarboxylic anhydride in 75 parts of glacial acetic acid was added 4.8 parts of 4-amino-3-fluorobenzonitrile in one portion. The mixture was refluxed for 4 hours, poured over 200 parts of ice and filtered. The crude crystalline product was recrystallized from methanol to yield 4.4 parts of beige 4-(1,3-dioxo-2,3,3a,4,5,6,7,7a-octahydro-1H-isoindol-2-yl)-3-fluorobenzonitrile melting 120°-123°.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9](F)[CH:8]=2)=[CH:4][CH:3]=1.Br.[CH:17]1([CH2:20][S:21]C(=N)N)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([S:21][CH2:20][CH:17]3[CH2:19][CH2:18]3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(Cl)s2)cc1F
Reactant: N=C(N)SCC1CC1
Agent: Br
Product: N#Cc1ccc(-c2ccc(Cl)s2)cc1SCC1CC1
Yield: 89.9 %

Procedure:
0.9 g (4.0 mmol) of 4-(5-chlorothiophen-2-yl)-2-fluorobenzonitrile and 0.9 g (4.3 mmol) of S-cyclopropylmethylisothiourea hydrobromide were allowed to react in the same manner as described above in Example 8 (4), and purification of the crude product by silica gel column chromatography afforded 1.1 g of 4-(5-chlorothiophen-2-yl)-2-cyclopropylmethylthiobenzonitrile (yield 91%) as yellow feathery crystals (m.p. 123-124° C.).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:13])[NH:14][CH2:15][CH3:16])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(Br)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To an ice-cold solution of ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzothiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (25 g, 45.7 mmol) in DMSO (50 mL) was added potassium tert-butoxide (25.5 g, 228 mmol). The resulting mixture was stirred at rt for 1 h. After completion of reaction (by TLC), water (250 mL) was added followed by extraction with EtOAc (2×250 mL). The organic layer was discarded; the pH of the aqueous layer was adjusted up to 4-5 and then extracted with hot EtOAc (3×250 mL). The combined organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to obtain the desired product as off-white solid (21 g, 88%). 1H NMR (DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 1.18 (s, 3H), 1.41 (m, 2H), 2.02 (m, 2H), 3.20 (m, 2H), 3.33 (m, 2H), 4.29 (m, 2H), 6.80 (br s, 1H), 7.70 (s, 1H), 7.87 (s, 1H), 8.76 (s, 2H), 10.95 (br s, 1H) and 12.46 (br, s, 1H). MS: 519.19 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:30]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:31]1([C:34]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:30]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (300 mg, 0.727 mmol) in N,N-dimethylacetamide (3.0 mL) was added cyclopropanecarbonyl chloride (69 μL, 0.763 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (200 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), fractions containing the object product was concentrated under reduced pressure, and the residue was triturated with ethyl acetate, diisopropyl ether and hexane to give the title compound (145 mg, 42%) as a colorless solid.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C(=O)([O-])[O-].[Cs+].[Cs+].F[C:19]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:20]=1[CH:21]=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[I:27][C:24]1[CH:23]=[C:20]2[C:19](=[CH:26][CH:25]=1)[N:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)[N:2]=[CH:21]2
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=Cc1cc(I)ccc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
4-Hydrazinobenzoic acid (11.32 g, 60 mmol) and cesiumcarbonate (58.65 g, 180 mmol) are added to 2-fluoro-5-iodobenzaldehyde (15 g, 60 mmol) in 300 mL N-methylpyrrolidon. After 1 h stirring at r.t., the reaction is heated for 4 h at 150° C. The reaction mixture is allowed to cool off and poured on 1 L ice water. The reaction mixture is acidified with citric acid and vigorously stirred at r.t. for 30 min. The precipitate is filtered off and given in ethyl acetate. The slurry is vigorously stirred for 1 h and sucked off. The filter residue (few material) is discarded and the filtrate evaporated. This residue which is contaminated with N-methylpyrrolidine is treated with 300 mL of a mixture of ethyl acetate/hexane (1:3) and stirred overnight. The precipitated crystals are sucked off and dried. 17.11 g (78.32%) of 4-(5-iodoindazole-1-yl)-benzoic acid are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[O:10])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: CCCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCCCNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and n-butylamine (0.6 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was first purified by ISCO CombiFlash Rf silica chromatography eluted with 88:10:2 chloroform:MeOH:H2O to give the desired product as a yellow solid (228 mg, yield 54%). MS calcd for (C19H24BN3O5S): 417.2. MS found (ESI negative): (M−H)−=416.2. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.88 (s, 1H), 9.17 (s, 1H), 7.96 (t, J=5.2 Hz, 1H), 7.42 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.35 (dd, J=2.4, 8.8 Hz, 1H), 5.93 (bs, 2H), 4.87 (s, 2H), 3.77 (s, 2H), 3.08 (m, 2H), 1.39 (m, 2H), 1.30 (m, 2H), 0.87 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][C:27]=1[N+:36]([O-:38])=[O:37]>C(Cl)(Cl)Cl.O>[N+:36]([C:27]1[CH:28]=[N:29][C:30]2[C:35]([C:26]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:34][CH:33]=[CH:32][CH:31]=2)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)CCCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
Potassium carbonate (66.23 g, 0.479 mol), triethylamine (167 mL, 1.20 mol), and ethyl 5-aminovalerate hydrochloride (104 g, 0.575 mol) were added to a mixture of 4-chloro-3-nitroquinoline (100 g, 0.470 mol) in chloroform (1 L). The reaction mixture was stirred at room temperature for 4 hours, then water (200 mL) was added. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 151 g of ethyl 5-[(3-nitroquinolin-4-yl)amino]pentanoate.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC1.[O:11]=[C:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1C(OC(C)(C)C)=O>>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][C:12]1=[O:11]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCc2ccccc21
Agent: C1=Cc2ccccc2NC1
Product: O=C1CCc2ccccc2N1

Procedure:
A dihydroquinoline compound (ai1) having a tert-butoxycarbonyl group (Boc group) (i.e., tert-butyl 2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate) was produced from 3,4-dihydroquinolin-2(1H)-one (raw material (aa)) by the following method (see scheme (1-1)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[CH:4]([NH:16][C:17](=[O:46])[CH:18]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.Br[CH:49](Br)[CH3:50].C(=O)([O-])[O-].[K+].[K+].OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:47])[CH:4]([N:16]1[CH2:50][CH2:49][N:33]([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:17]1=[O:46])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CC(Br)Br
Reactant: COC(=O)C(Cc1ccc2ccccc2c1)NC(=O)C(CCCNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CCCNC(=O)OCc2ccccc2)C1=O
Temperature: 55 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[5-benzyloxycarbonylamino-2-(2-nitro-benzenesulfonylamino)-pentanoylamino]-3-naphthalen-2-yl-propionic acid methyl ester, 40, (2.4 g, 3.63 mmol), dibromoethane (3.8 mL, 4.36 mmol), potassium carbonate (5.0 g, 36.3 mmol) in DMF (50 mL) is stirred at 55° C. for 18 hours. The reaction mixture is cooled to room temperature, treated with 1M KHSO4 and the resulting solution is extracted with ethyl acetate. The crude product is purified over silica (sequential elution with EtOAc/hexanes mixtures 1:2, 1:1, 100% EtOAc, then EtOAc with 5% MeOH) to afford 2.76 g of the desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:23])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([O:27]CC)=[O:26])=[CH:4]1)[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:23])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2ccc(OCc3ccc(OC)cc3)c(O)c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)c2c(O)c(OCc3ccc(OC)cc3)ccc21
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a suspension of ethyl 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.5 g, 3.77 mmol) in a mixture of Methanol (60.0 mL) and Water (20 mL) was added KOH (0.424 g, 7.55 mmol) portionwise. The resulting mixture was stirred under reflux for 1 h. The mixture was cooled down to r.t. and concentrated. Water was added and the mixture was adjusted to pH˜2 using 6 N HCl (aq.). The precipitates were collected by filtration and dried in air to afford 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1.35 g, 3.65 mmol, 97% yield) as a light yellow solid. LCMS: (M+H)+: 370.2.
Reaction SMILES: [CH:1]1N=CN(C(N2C=NC=C2)=O)C=1.O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([OH:48])([C:42]4[N:46]([CH3:47])[CH:45]=[N:44][CH:43]=4)[C:33]4[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=4)[CH:30]=3)[NH:25][C:24](=[O:49])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1.N12CCN(CC1)CC2.CO>C1COCC1.O>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([OH:48])([C:42]4[N:46]([CH3:47])[CH:45]=[N:44][CH:43]=4)[C:33]4[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:1])=[O:38])=[CH:40][CH:41]=4)[CH:30]=3)[NH:25][C:24](=[O:49])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1cncc1C(O)(c1ccc(C(=O)O)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(O)(c2ccc3[nH]c(=O)cc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
CDI (0.00925 mol) was added to a mixture of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzoic acid monohydrochloride monohydrate (described in Example B3) (0.00185 mol) in THF (10 ml). The mixture was stirred at 40° C. for 1 hour.1,4 diazabicyclo[2,2,2]octane (0.00185 mol) and methanol (5 ml) were added. The mixture was stirred at 40° C. for 18 hours, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.44 g (48%) of (±-methyl 4-[[4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzoate, mp. 255° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][F:29]>C(#N)C>[F:29][CH2:28][CH2:27][CH2:26][N:15]1[CH2:16][CH2:17][C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[C:2]=2[F:1])([OH:18])[CH2:13][CH2:14]1
Reactant: FCCCBr
Reactant: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1(c2cccc(C(F)(F)F)c2F)CCN(CCCF)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.02 g, 0.076 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1-bromo-3-fluoropropane (0.010 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 323 (M+, 2), 276 (34), 191 (15), 116 (17), 42 (bp).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C([O-])(O)=O.[Na+].O.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([N:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:14])[CH:17]=[CH2:18]
Reactant: C1=CCNC1
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCOC(=O)N1CC=CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 3-pyrroline (3.5 gms) in ethanol (20 mL) was added ~25 mL saturated aq. NaHCO3 and enough water to allow rapid stirring. The mixture was cooled to 10° C. and allyl chloroformate (5.92 mL) was slowly added via pressure equalized addition funnel. The mixture was removed from ice bath and allowed to stir at room temperature for 2 hours. Product was extracted into Et2O (3×150 mL). The organic phase was washed with water (2×50 mL), dried (MgSO4) and solvent was evaporated at reduced pressure. Purification on silica (Et2O) afforded pure title compound.