Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:23])=O>CN(C=O)C>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([Cl:23])=[O:20])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(C(=O)O)cc2C1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCC1Cc2ccc(C(=O)Cl)cc2C1

Procedure:
In a 50 ml-round bottomed flask, 5.00 g (18.2 mM) of 2-octylindan-5-carboxylic acid was placed and 7.0 ml of thionyl chloride and one drop of N,N'-dimethylformamide (DMF) were added thereto, followed by heat-refluxing for 30 minute. An excessive thionyl chloride was distilled off under reduced pressure from the above mixture to obtain 2-octylindan-5-carbonyl chloride. A solution of the above-obtained 2-octylindan-5-carbonyl chloride in 50 ml of THF was gradually added dropwise to 45 ml of 30%-ammonia water which had been cooled to about 0° C. on an ice-common salt bath under stirring. After the addition, the resultant mixture was stirred for 4.5 hours at room temperature. After the reaction, 300 ml of water was added to the reaction mixture to precipitate a crystal. The crystal was recovered by filtration and successively washed with water and methanol to obtain 4.59 g of 2-octyl-5-carbamoylindan (Yield: 92.1%).
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C:8]1=[CH:7][CH2:6][C:5]12[O:26][CH2:25][CH2:24][O:23]1)[CH2:2][CH3:3].[H][H]>C1C=CC=CC=1.[Pd]>[CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C:5]12[O:23][CH2:24][CH2:25][O:26]1)[CH2:2][CH3:3]
Reactant: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)C1=CCC21OCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Product: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC21OCCO1
Yield: 71.6 %

Procedure:
Shake 13β-propyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaene (2.5 g.) in benzene (80 cc.) with hydrogen at atmospheric pressure in the presence of a 2% palladium on calcium carbonate catalyst (0.9 g.); hydrogen uptake ceases after the requisite amount (161 cc.) for monohydrogenation has been absorbed. Filter and evaporate to obtain a gum, which one crystallizes from ethanol to obtain the title product (1.8 g.), m.p. 119°-120°; ultraviolet absorption peak at 278 mμ (ε15,300).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][NH:5][CH2:6][C:7]1[N:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[S:10][CH:11]=1.[O:15]([C:22]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=O)C1C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:4][N:5]([C:22]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:15])[CH2:6][C:7]1[N:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[S:10][CH:11]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CNCc1csc(C(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To lithium hydroxide monohydrate (1.06 g, 25.2 mmol) slurried in 20 mL of THF and cooled to less than 5° C. in an ice bath was added N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.78 g, 22.2 mmol) followed by a 5 mL THF rinse. A solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) in 20 mL of THF was added followed by a 5 mL THF rinse. Water (1.04 mL) was added, the cooling bath was removed, and the reaction was stirred at ambient temperature for 4.5 hours. Water (55 mL) was added, and the THF was removed under reduced pressure. Methyl tert-butyl ether (50 mL) was added, and as the solution stirred, the pH was adjusted to 9 with 4 N HCl. The aqueous phase was separated and washed with another 50 mL portion of MTBE. The aqueous product layer was stirred with 50 mL of toluene and adjusted to pH 3 with 4 N HCl. The aqueous layer was separated and extracted once more with toluene (50 mL). The combined toluene extracts were concentrated under reduced pressure. The residue obtained was redissolved in toluene, filtered, and rinsed with toluene. The combined filtrates were concentrated under reduced pressure. The product was crystallized from toluene-heptane (50 mLs of a 1:1 v/v solution), washed with heptane, and dried under vacuum to afford the title compound as a white powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][Cl:7].Cl.[C:9](Cl)([Cl:11])=[O:10]>C1C=CC=CC=1>[Cl:11][C:9]([N:4]([CH2:5][CH2:6][Cl:7])[CH2:3][CH2:2][Cl:1])=[O:10]
Reactant: O=C(Cl)Cl
Reactant: ClCCNCCCl
Agent: Cl
Solvent: c1ccccc1
Product: O=C(Cl)N(CCCl)CCCl
Reaction time: 3 h

Procedure:
A solution in dry benzene of 82 g. of bis-(β-chloroethyl)-amine freshly liberated from its hydrochloride is added gradually to a solution of 36 g. of carbonyl chloride in benzene at a temperature below 10° C. The mixture is mechanically stirred for three hours, the precipitate of bis-(β-chloroethyl)-amine hydrochloride is removed by filtration, and the benzene is distilled off on a water bath. The residue is distilled in vacuo, and the N-chloroformyl-bis-(β-chloroethyl)-amine is obtained as a pale yellow oil with a B.P. of 114-116° C./1 mm. Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.C1(CN)CCCCC1.[O:20]=[C:21]1[C:29]2([CH2:33][O:32][C:31]3[CH:34]=[C:35]4[C:39](=[CH:40][C:30]2=3)[CH2:38][CH2:37][O:36]4)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH2:41][C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](O)=[O:45].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:44](=[O:45])[C:43]2[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=2[CH2:41][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3([CH2:33][O:32][C:31]4[CH:34]=[C:35]5[C:39](=[CH:40][C:30]3=4)[CH2:38][CH2:37][O:36]5)[C:21]2=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: COc1ccc(CCNC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-(4-methoxyphenyl)ethylamine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-[2-(4-methoxyphenyl)ethyl]-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (85%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.39-7.13 (m, 8H), 7.08-6.95 (m, 2H), 6.86-6.78 (m, 2H), 6.52-6.39 (m, 3H), 5.10-4.90 (m, 3H), 4.70 (d, J=9.0 Hz, 1H), 3.81-3.62 (m, 5H), 2.98 (t, J=8.7 Hz, 2H), 2.90 (t, J=8.7 Hz, 2H); MS (ES+) m/z 569.2 (M+23).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:17]3[N:21]=[C:20]([CH3:22])[O:19][N:18]=3)([CH3:16])[CH2:14][OH:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[CH:6][C:7]([C:10]([NH:12][C:13]([CH3:16])([C:17]3[N:21]=[C:20]([CH3:22])[O:19][N:18]=3)[CH:14]=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(CO)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1nc(C(C)(C=O)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 5-cyclopropyl-N-[1-hydroxy-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 113, 0.1 g, 250 μmol) in dry dichloromethane (2 ml) was added Dess-Martin periodinane (111 mg, 262 μmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane and quenched with a 1.0M aqueous solution of sodium bicarbonate with 5% sodium thiosulfate. The bi-phasic mixture was stirred for 20 minutes and then transferred into a separatory funnel. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/(solution of 3% Et3N in ethyl acetate) gradient to yield the title compound (71 mg, 71%). MS (ESI, m/z): 399.5 (M+H+).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[C:7]([CH3:15])[N:6]=1)(=O)=O.[NH3:16]>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:16][C:5]1[N:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[C:7]([CH3:15])[N:6]=1
Reactant: N
Reactant: Cc1cc(OC(F)F)nc(S(C)(=O)=O)n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(OC(F)F)nc(N)n1
Reaction time: 3 h
Yield: 85 %

Procedure:
4.0 g (0.017 mol) of 2-methylsulfonyl-4-difluoromethoxy-6-methylpyrimidine are suspended in 60 ml of chloroform. This suspension is saturated with gaseous ammonia, and then stirred for 3 hours at a temperature of between 20° and 25° C. The reaction mixture is subsequently diluted with 50 ml of methylene chloride; the organic phase is separated, washed with water and concentrated by evaporation. There are obtained, as crystalline residue, 2.5 g (85% of theory) of 2-amino-4-difluoromethoxy-6-methylpyrimidine, m.p. 137°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[C:6]([N+:12]([O-])=O)[C:5]=1[O:15][CH3:16].O.O.[Sn](Cl)Cl.O.[OH-].[Na+].[CH:26](O)=O>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]2[N:11]=[CH:26][NH:12][C:6]=2[C:5]=1[O:15][CH3:16])=[O:17]
Reactant: O=CO
Reactant: COC(=O)c1cc(Cl)c(N)c([N+](=O)[O-])c1OC
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(Cl)c2nc[nH]c2c1OC
Temperature: 130 °C
Yield: 31 %

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-3-nitro-benzoic acid methyl ester (1.00 g, 3.84 mmol, prepared as described in J. Med. Chem., 2006, 49, 4762-4766) in formic acid (10.5 mL), was added tin(II) chloride dihydrate (2.6 g, 11.5 mmol). The reaction mixture was heated at 130° C. in the microwave for 10 min. Upon cooling to RT, water was added (50 mL) and the pH of the resultant mixture was adjusted to ˜7 by careful addition of 5 M sodium hydroxide. The resultant mixture was filtered through a Celite® and sand filter cake, washing with EtOAc (5×30 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% EtOAc in pentane) to afford the title compound as an off-white solid (0.29 g, 31%). LCMS (Method A): RT=3.40 min, [M+H]+=241/243.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:26])=[C:7]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][NH:16][C:15](=[O:20])[C:14]=3[C:13]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=3[N:11]=2)[CH:8]=1.C(N(CC)CC)C.[F:34][C:35]([F:41])([F:40])[S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[F:34][C:35]([F:41])([F:40])[S:36]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:26])=[C:7]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][NH:16][C:15](=[O:20])[C:14]=3[C:13]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=3[N:11]=2)[CH:8]=1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: Cc1ccc(CN)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(CNS(=O)(=O)C(F)(F)F)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Reaction time: 1 h

Procedure:
To a solution of 5-{[5-(aminomethyl)-2-methylphenyl]amino}-9-fluorobenzo[c]-2,6-naphthyridin-1(2H)-one (35 mg, 0.10 mmol) in THF (1.0 mL) at 0° C. was added triethylamine (0.03 mL, 0.20 mmol) and trifluoromethanesufonyl chloride (0.01 mL, 0.11 mmol). The reaction was stirred for one hour and then quenched by the addition of citric acid. The mixture was extracted with EtOAc/water and the extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatographpy (0-10% MeOH/CH2Cl2) afforded the title compound. 1H NMR (600 MHz, CD6SO) δ 12.21 (d, 1H), 9.92 (s, 1H), 9.45 (dd, 1H), 8.85 (s, 1H), 7.68 (m, 1H), 7.45 (m, 1H), 7.34-7.38 (m, 2H), 7.26 (d, 1H), 7.22 (d, 1H), 7.09 (d, 1H), 4.32 (s, 2H), 2.12 (s, 3H). LRMS (ESI) calc'd for C21H16F4N4O3 [M+H]+, 481.1; found 481.0.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][S-:15].[Na+].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][S:15][CH3:14])[CH:3]=1
Reactant: C[S-]
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(Br)cc1CSC
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (12 g) and sodium thiomethoxide (2.5 g) in toluene was stirred at 100° C. for 2 hours. The mixture was then cooled, poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (anhydrous sodium sulphate) and evaporated to afford a brown oil which was purified by column chromatography on silica gel giving methyl 4-bromo-2-(methylsulphenylmethyl)benzoate (4.1 g) as white crystals, m.p. 79.3° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24](=O)[O:25]C3C=CC=CC=3)=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:43][C:24]([NH:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([N:4]3[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:20][CH:19]=2)=[O:25])(=[O:41])=[O:42])=[CH:38][CH:39]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[2-ethyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 527 [M+H]+, 525 [M−H]−, 1H-NMR (CDCl3) δ 1.24 (3H, t, J=7.5 Hz), 2.69 (2H, q, J=7.5 Hz), 2.83-2.90 (2H, m), 3.45-3.54 (2H, m), 6.50 (1H, br), 7.05 (2H, t, J=8.8 Hz), 7.18 (1H, s), 7.22-7.30 (2H, m), 7.42-7.52 (3H, m), 7.70-7.79 (4H, m).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH:17]([F:19])[F:18])[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH:17]([F:19])[F:18])[C:10]([Cl:22])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OC(F)F)c(OC2CCCC2)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(OC(F)F)c(OC2CCCC2)c1
Temperature: 80 °C

Procedure:
A mixture of 3-cyclopentyloxy-4-difluoromethoxybenzoic acid (0.47 g; that is prepared as described in Reference Example 42) and thionyl chloride (4 mL) in toluene (10 mL) is heated at 80° C. for 2 hours, and then evaporated under reduced pressure, to give 3-cyclopentyloxy4-difluoromethoxybenzoyl chloride (0.48 g), in the form of a pale yellow low melting solid, which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][NH:28][CH2:27]2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[C:3]([N:28]2[CH2:29][C@@H:30]([F:31])[C@@H:26]([CH2:25][NH:24][CH:21]3[CH2:22][CH2:23]3)[CH2:27]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 49.7 %

Procedure:
Using 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (300 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 23 to give 8-chloro-1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow solid (218 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH:25]([CH3:27])[CH3:26])[C:7]=1[C:8]1[N:9]=[C:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:15]=3[O:14][CH2:13][CH2:12][N:11]2[CH:24]=1)#[N:2].[NH3:28]>>[C:1]([C:3]1[CH:4]=[N:5][N:6]([CH:25]([CH3:27])[CH3:26])[C:7]=1[C:8]1[N:9]=[C:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([NH2:28])=[O:22])=[CH:20][C:15]=3[O:14][CH2:13][CH2:12][N:11]2[CH:24]=1)#[N:2]
Reactant: CC(C)n1ncc(C#N)c1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Reactant: N
Product: CC(C)n1ncc(C#N)c1-c1cn2c(n1)-c1ccc(C(N)=O)cc1OCC2

Procedure:
Following Example 109, 2-(4-Cyano-1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid from Example 16 was coupled with ammonia to give 138. Yield 27.8 mg (44%). MS (ESI): 363.1. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=8.4, 1H), 8.11 (s, 1H), 8.00 (d, J=4.7, 2H), 7.62 (dd, J=8.4, 1.5, 1H), 7.57 (d, J=1.4, 1H), 7.44 (s, 1H), 5.46 (dt, J=13.1, 6.5, 1H), 4.59 (dd, J=17.5, 4.8, 4H), 1.48 (d, J=6.6, 6H).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH:9]1([O:13][C:14]2[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:12][CH2:11][CH2:10]1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:16]([C:15]1[C:14]([O:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[C:21]([O:22][CH3:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=1[N+:7]([O-:8])=[O:6])#[N:17]
Reactant: O=[N+]=O
Reactant: COc1ccc(C#N)c(OC2CCC2)c1OC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])c(C#N)c(OC2CCC2)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
Nitronium tetrafluoroborate (4.64 g, 0.035 mol) was added portionwise to an ice cooled solution of 2-cyclobutyloxy-3,4-dimethoxybenzonitrile (6.28 g, 0.027 mol) in acetonitrile (150 ml) and the reaction stirred for 1 hour. Saturated aqueous sodium bicarbonate solution (150 ml) was added and the mixture extracted with ethyl acetate (400 ml). The combined organic extracts were washed with water (150 ml), dried (MgSO4), filtered and evaporated under reduced pressure to give a dark brown oil. The crude product was purified on silica gel eluting with dichloromethane to give the subtitle compound as a pale yellow solid (4.01 g, 53%). Rf 0.23 (hexane:isopropyl alcohol:0.880 aqueous ammonia 90:10:0.75, v/v). MS m/z 296 (MNH4)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[CH2:17]([C:24]1[CH2:28][C:27]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:31]2[CH2:32][CH2:33][C:27]3([O:26][N:25]=[C:24]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:28]3)[CH2:29][CH2:30]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(CC2=NOC3(CCNCC3)C2)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)c1ccc(NC(=O)N2CCC3(CC2)CC(Cc2ccccc2)=NO3)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
4-Tert-butylphenyl isocyanate (0.218 ml, 1.24 mmol), dissolved in abs. DCM (5 ml), was added dropwise to a solution of compound Y (286 mg, 1.24 mmol) in abs. DCM (10 ml) at RT within 20 min. After stirring for 3.5 h at RT, the solution was washed with 10% citric acid solution (1×10 ml) and water (1×10 ml), dried and concentrated. The colourless oil obtained (742 mg) contained few impurities. The oil was mixed with diethyl ether (10 ml) and stored at 5° C. The precipitated solid was removed by suction-filtration and washed with diethyl ether (5 ml). The desired product 3-benzyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylic acid-(4-tert-butylphenyl)amide was obtained in a yield of 73% (369 mg) having a melting point of 137-139° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([F:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(F)cc(C2(F)CCN(Cc3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a cooled (0° C.) solution of 1-benzyl-3-(3,5-difluorophenyl)pyrrolidin-3-ol (1.9 g, 6.6 mmol) in dichloromethane (20 mL) was added dropwise diethylaminosulphurtrifluoride (1.05 mL, 7.26 mmol) dissolved in dichloromethane (5 mL) and the mixture was stirred at ambient temperature for 1 h. Additional diethylaminosulphurtrifluoride (0.1 mL, 0.69 mmol) was added and stirring was continued 0.5 h. Aqueous sodium carbonate (10%, 50 mL) was added and the phases separated. The aqueous phase was extracted with dichloromethane (50 mL) and the pooled organic phase was dried (MgSO4) and evaporated. Purification by flash column chromatography gave the title compound (0.65 g). MS m/z (rel. intensity, 70 eV) 291 (M+, 44), 200 (17), 133 (51), 132 (45), 91 (bp).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:45][C:46]1[N:47]([C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]([CH:66]3[CH2:68][CH2:67]3)=[CH:58][CH:57]=2)[C:48]([S:51][CH2:52][C:53](O)=[O:54])=[N:49][N:50]=1>ClCCl>[Br:45][C:46]1[N:47]([C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]([CH:66]3[CH2:68][CH2:67]3)=[CH:58][CH:57]=2)[C:48]([S:51][CH2:52][C:53]([NH:6][CH:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[O:14])=[O:54])=[N:49][N:50]=1
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(Cc1ccccc1)NC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phenylalanine methyl ester hydrochloride (1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71 mmol) are added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture is stirred at room temperature for 18 hours and then purified by SGC (0-100% EtOAc/Hexanes).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH:14]=O>C(O)C.[Pd]>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COC(C=O)OC
Reactant: COc1cc(N)ccc1F
Agent: [Pd]
Solvent: CCO
Product: COc1cc(NCC(OC)OC)ccc1F
Yield: 101.1 %

Procedure:
To a solution of 4-fluoro-3-methoxyaniline (0.98 g 6.9 mmol) in ethanol (20 ml) was added glyoxal 1,1-dimethyl acetal (0.89 g 8.27 mmol). Pd/C 5% (50 mg) was added and the mixture hydrogenated. Removal of the catalyst by filtration and evaporation of solvent in vacuo gave N-(2,2-dimethoxyethyl)-4-fluoro-3-methoxyaniline 1.6 g