Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[OH-].[Na+].[OH:7][CH2:8][C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])[OH:10]>>[CH2:1]([O:18][CH2:17][C@@H:15]([C@H:13]([C@@H:11]([C@@H:9]([CH2:8][OH:7])[OH:10])[OH:12])[OH:14])[OH:16])[CH:2]=[CH2:3]
Reactant: C=CCCl
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 5.5 h

Procedure:
At 3.7 hours after the initiation of the reaction, the addition of 200 g of allyl chloride was completed. Then the addition was continued. The time required for adding 300 g of allyl chloride was 5.5 hours after the initiation of the reaction. At this point of time (at the time at which allyl halide was added in the amount of 20% by mol, based on total molar number of hydroxyl group contained in D-sorbitol), the reflux liquid is separated so that an oil layer alone is returned to the reactor by attaching a water metering reservoir between the reflux condenser and the reactor. The time required for adding total amount of 459 g of allyl chloride was 8 hours after the initiation of the reaction. At this point of time, the dropwise addition of 333 g of 48% aqueous sodium hydroxide solution from the other dropping funnel was initiated. The time required for adding total amount of 842 g of allyl chloride was 11 hours after the initiation of the reaction. The temperature was between 70° C. and 90° C. After the mixture was digested for one hour, the mixture was cooled.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].OO.C(O)(=O)C>CO.ClCCl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([OH:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CNc2ccc(F)cc2N1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Oc1cnc2ccc(F)cc2n1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A mixture of 7-fluoro-3,4-dihydro-1H-quinoxalin-2-one (4.00 g, 24.1 mmol, 1.0 eq), sodium hydroxide (1.93 g, 48.2 mmol, 2.0 eq) and of 3% hydrogen peroxide solution (50 mL) is refluxed for 2 hours, then it is acidified by slow addition of acetic acid. The resulting mixture is cooled to room temperature, the precipitated solid is collected by filtration, washed with ice-water, and dried under vacuum to give a crude that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 50:1, v/v) to afford 7-fluoro-quinoxalin-2-ol as a yellow solid (2.60 g, 69% yield).
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]1=[O:19]>C1COCC1.[NH4+].[Cl-].[Zn]>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[CH2:2][C:3]1=[O:19]
Reactant: C[Si](C)(C)CCOCN1C(=O)C(Br)(Br)c2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reaction time: 3 h

Procedure:
Zinc (100 g, 1.54 mol) was added to a solution of 3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (65 g, 0.154 mol) in THF (880 mL) and saturated aqueous NH4Cl (220 mL). After 3 h, the reaction mixture was filtered and concentrated in vacuo. The residue was partitioned between EtOAc and H2O which resulted in the formation of a white precipitate. Both layers were filtered through a Celite pad and the layers were separated. The aqueous layer was washed with EtOAc (2×500 mL) and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with CH2Cl2:EtOAc—90:10, to give the title compound. MS: m/z=265 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[OH:17]O>[OH-].[NH4+]>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:16])=[O:17]
Reactant: COc1ccccc1-n1ncc(C#N)c1N
Reactant: OO
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccccc1-n1ncc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile (1.53 g) in saturated ammonium hydroxide (30 mL) was added 30% hydrogen peroxide solution (6 mL). The reaction stirred for 18 h at ambient temperature and was slowly quenched with 60 mL of a saturated sodium sulfate solution. The aqueous layer was extracted with ethyl acetate, dried with magnesium sulfate, filtered and concentrated. MPLC Biotage chromatography eluting with 2-6% methanol/methylene chloride provided the title compound 1.38 g (84%). 400 MHz 1H NMR (DMSO) δ 7.79 (s, 1 H), 7.42 (m, 1H), 7.25 (d, J=7.5 Hz, 2H), 7.19 (d, J=8.3 Hz, 2 H), 7.03 (t, J=6.2 Hz, 1H), 5.83 (s,2H), 3.76 (s, 3 H); MS: (M+H m/z=233.2).
Reaction SMILES: [C:1]([N:5]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[NH:22][CH:21]=2)[N:14]=1)[CH2:6][C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([N:5]([CH2:6][C:7]([OH:9])=[O:8])[NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:30])[F:31])[CH:27]=3)[NH:22][CH:21]=2)[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CN(Nc1nc(-c2c[nH]c3ncc(C(F)(F)F)cc23)ncc1F)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)N(CC(=O)O)Nc1nc(-c2c[nH]c3ncc(C(F)(F)F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-[tert-butyl-[[5-fluoro-2-[5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]amino]acetate, 155a, (0.200 g, 0.440 mmol) in THF (40 mL) was added a solution of lithium hydroxide hydrate (0.074 g, 1.760 mmol) in H2O (4 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture concentrated in vacuo to remove the THF. The remaining aqueous phase was diluted to 8 mL and the solution was used directly in a preparatory HPLC. The product precipitated when the fraction was concentrated on rotavaporator. The solid was filtered and dried in desiccator with P2O5 to afford 120 mg of the desired product: 1H NMR (400 MHz, d6-DMSO) δ 12.65 (s, 1H), 12.41 (s, 1H), 9.28 (s, 1H), 8.86 (s, 1H), 8.65 (s, 1H), 8.30 (d, J=3.5 Hz, 2H), 3.97-3.70 (m, 1H), 3.51 (s, 1H), 1.18 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.92 min, (M+H) 427.40
Reaction SMILES: O1C[C@H]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:20]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].CC[O-].[Na+].[Br:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.Cl>C(O)C>[Br:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][C:21]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:30][C@@H:29]([C@@H:4]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:19])[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:28][C:20]2=[O:27])=[CH:38][CH:37]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccc(Br)cc2)C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 107.9 %

Procedure:
A solution of tert-Butyl(1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate (10.0 g, 38.0 mmol) and diethyl malonate (5.8 ml, 38.2 mmol) in ethanol (30 mL) at 0° C. was treated with a solution of NaOEt (13.5 mL, 21% in ethanol) over 10 minutes. The reaction was warmed to 25° C. and stirred for 18 hours. The reaction was re-cooled to 0° C. and treated with a solution of 4-bromobenzyl bromide (9.5 g, 38.0 mmol) in ethanol (40 mL), stirred at 50° C. for 3 hours, cooled to 0° C. and adjusted to neutral pH by addition of 4N HCl. The ethanol was removed under reduced pressure and the residue was partitioned between chloroform and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (22.4 g), which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH:21]3[CH2:26][CH2:25][CH:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[CH:16]=2)[N:11]=1)([CH3:9])[CH3:8].[OH-].[Li+].O1CCCC1.O>>[C:27]([C@H:24]1[CH2:23][CH2:22][C@H:21]([O:20][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])([CH3:9])[CH3:8])[CH:19]=[CH:18]3)[CH2:26][CH2:25]1)([CH3:28])([CH3:29])[CH3:30]
Reactant: COC(=O)CCNC(C)(C)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(NCCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
A solution of 3-{1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-1-methyl-ethylamino}-propionic acid methyl ester (36.0 mg, 0.0844 mmol) and Lithium hydroxide (20.2 mg, 0.844 mmol) in Tetrahydrofuran (1 mL, 20 mmol) and Water (0.3 mL, 20 mmol) was stirred at r.t. overnight. LCMS showed a single desired product peak RT 1.57 min M+1 at m/z 413.30, 100%. The solvent was concentrated and neutralized with citric acid and concentrated and Purified on HPLC to give product (20 mg, 57%). 1H NMR (400 MHz, CHLOROFORM-d) d=8.30 (d, J=8.7 Hz, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.39 (dd, J=2.7, 9.2 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 4.43-4.28 (m, 1H), 3.23 (t, J=6.6 Hz, 2H), 2.84 (t, J=6.6 Hz, 2H), 2.26 (d, J=10.4 Hz, 2H), 1.90 (d, J=13.6 Hz, 2H), 1.79 (s, 6H), 1.49-1.32 (m, 2H), 1.32-1.17 (m, 2H), 1.17-1.00 (m, 1H), 0.90 (s, 9H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[CH:6]([OH:32])[CH:7]([NH:15][C:16]([C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:17])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.O>ClCCl.Cl.C(OCC)C>[CH:1]1([NH:4][C:5](=[O:33])[C:6](=[O:32])[CH:7]([NH:15][C:16]([C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:17])[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: O=C(NC1CC1)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NC1CC1)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F
Reaction time: 8 h

Procedure:
(2R)—N-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxamide was oxidized in analogy to reaction step 1.4. The reaction mixture was stirred overnight. Water was added, the precipitate formed was filtered, washed with water and dried in vacuo. The residue obtained was redissolved in dichloromethane, a few drops of HCl (4M in dioxane) and a few drops of diethylether were added. The resulting precipitate was filtered, washed with diethylether and dried in vacuo providing the title compound. ESI-MS [M+H]+=452.2.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19][N:18]=2)[CH2:16][CH2:15][CH2:14]1.Br[CH2:30][CH:31]([CH3:33])[CH3:32]>O1CCCC1>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21]([CH2:20][CH2:19][N:18]=[C:17]2[C:13]2([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:14][CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: COc1ccc2c(c1)C(C1CCC1)=NCC2
Reactant: CC(C)CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C1(CC(C)C)CCC1)=NCC2
Temperature: -23 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.83 ml, 1.8M in hexanes) was added dropwise to a solution of diisopropylamine (0.71 ml) in dry tetrahydrofuran (5 ml) at ambient temperature. After 15 minutes the solution was cooled to -23° C. and treated slowly with a solution of 1-cyclobutyl-7-methoxy-3,4-dihydroisoquinoline (1 g) in tetrahydrofuran (11 ml). The dark green solution was stirred for 30 minutes, further cooled to -78° C. and treated with 1-bromo-2-methylpropane (5.1 ml). After 1 hour at -78° C. the mixture was allowed to warm to ambient temperature, then heated under reflux for 1 hour. The mixture was poured onto water, acidified, and washed with ether. The aqueous phase was then basified by addition of aqueous sodium hydroxide solution and extracted with ethyl acetate. The solvent was removed in vacuo to yield an orange gum which was purified by flash chromatography over silica gel using a 1:4 mixture of ethyl acetate and light petroleum ether as eluant to give 7-methoxy-1-[1-(2-methylpropyl)cyclobutyl]-3,4-dihydroisoquinoline as an oil (0.85 g).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][NH:40]2)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][N:40]2[CH2:18][C:13]1[N:14]([CH3:17])[C:15]2[C:11]([N:12]=1)=[C:10]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[N:9]=[C:8]([N:7]1[C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[N:4]=[C:3]1[CH2:1][CH3:2])[N:16]=2)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.51 mmol), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (122 mg, 0.62 mmol) and molecular sieves (4 Å, powdered, 520 mg) in DCE (10 mL) was stirred at ambient temperature for 3 h. Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 85:15) to give (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a white solid. TFA (3 mL) was added to a solution of (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 85:15) to afford 395 as a white solid (153 mg, 63%). LCMS (Method G): RT=5.78 min, M+H+=474. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.26 (m, 2 H); 4.34 (m, 4 H); 4.00 (d, J=13.6 Hz, 1 H); 3.92-3.83 (m, 8 H); 3.70 (s, 1 H); 3.45 (s, 1 H); 3.35 (q, J=7.5 Hz, 2 H); 3.25 (d, J=10.2 Hz, 1 H); 2.97-2.91 (m, 2 H); 2.70 (d, J=10.2 Hz, 1 H); 1.85 (d, J=10.1 Hz, 1 H); 1.70 (d, J=10.1 Hz, 1 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:20]2[NH:21][C:22](=O)[C:23]([OH:31])=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:25]=2)[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:20]2[NH:21][CH2:22][C:23]([O:31][S:34]([CH3:33])(=[O:36])=[O:35])=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:25]=2)[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(C2(NC(=O)OCc3ccccc3)CCC(CO)CC2)[nH]c(=O)c1O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C1=C(OS(C)(=O)=O)CNC(C2(NC(=O)OCc3ccccc3)CCC(COS(C)(=O)=O)CC2)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 815.4 %

Procedure:
To a stirred solution of ethyl 2-(1-(benzyloxycarbonylamino)-4-(hydroxymethyl)cyclohexyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.85 g, 4.15 mmol) in THF (40 mL) cooled to 0° C. was added methanesulfonyl chloride (0.96 mmol, 12.45 mmol) and triethylamine (1.79 mL, 12.87 mmol). The mixture was allowed to warm to room temperature and stirred for 18 h. The resulting precipitate was filtered off and washed with THF. The filtrate and washings were concentrated to afford an amber oil. A solution of this oil in methanol (10 mL) was treated with K2CO3 (574 mg, 4.15 mmol) at room temperature for 3 h. The mixture was then concentrated and the residue was dissolved in ethyl acetate (200 mL), washed with 1N HCl (100 mL) followed by brine (100 mL), then dried (Na2SO4), filtered and concentrated to give 2.3 g of title compound as a yellow oil. LCMS (M+H)=602.45.
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1.[C:24]([NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][N:41]=1)[C:36](O)=[O:37])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][N:41]=1)[C:36]([NH:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:37])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: COc1cccc(CCNC(=O)c2ccnc(NC(=O)c3ccccc3)c2)c1
Yield: 45 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 2-(3-methoxyphenyl)ethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-[2-(3-methoxyphenyl)ethyl]isonicotinamide was obtained as a colorless solid in 45% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.88 (t, J=5.5 Hz, 1H), 8.57 (s, 1H), 8.52-8.49 (m, 1H), 8.07-8.04 (m, 2H), 7.63-7.48 (m, 4H), 7.24-7.17 (m, 1H), 6.84-6.76 (m, 3H), 3.73 (s, 3H), 3.55-3.48 (m, 2H), 2.85 (t, J=7.3 Hz, 2H); MS (ES+) m/z 376.5 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4](=[O:13])[CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc(O)cc(=O)n1CC(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cc(O)c([N+](=O)[O-])c(=O)n1CC(=O)O
Temperature: 80 °C
Yield: 70 %

Procedure:
31.2 g (0.17 mol) of 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-1-acetic acid are suspended in 255 ml of acetic acid, 24 ml of a 68% aqueous nitric acid solution are added at room temperature and the mixture is heated to 80° C. on an oil bath. The reaction medium is cooled, the solvent is evaporated off and the residue is taken up in twice 100 ml of water. The mixture is evaporated to dryness and the residue is taken up with twice 100 ml of toluene. The product is recrystallized from isopropanol and dried in an oven. 27.2 g of product are obtained in the form of yellow crystals.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH:7]1([S:13][C:14]2[CH:23]=[CH:22][C:21]3[NH:20][C:19](=[O:24])[C:18]4[NH:25][CH:26]=[CH:27][C:17]=4[C:16]=3[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29].[OH2:33]>CO.C(#N)C>[CH:7]1([S:13]([C:14]2[CH:23]=[CH:22][C:21]3[NH:20][C:19](=[O:24])[C:18]4[NH:25][CH:26]=[CH:27][C:17]=4[C:16]=3[CH:15]=2)(=[O:1])=[O:33])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1.[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]
Reactant: O
Reactant: O=c1[nH]c2ccc(SC3CCCCC3)cc2c2cc[nH]c12
Reactant: O=S([O-])OO
Agent: CCC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: O=c1[nH]c2ccc(S(=O)(=O)C3CCCCC3)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A solution of 410 mg (0.66 mmol) of Oxone in 2 mL of water is added to a solution of 49 mg (0.13 mmol) of 8-cyclohexylsulfanyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in methanol (5 mL) and acetonitrile (1 mL). The solution is stirred at room temperature for 24 hours. The solvents are evaporated then the residue is taken up in water. The product is extracted with ethyl acetate and the organic phases are dried over magnesium sulfate, filtered and evaporated. The residue is triturated in diethyl ether to give 40 mg (74%) of 8-cyclohexanesulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: ClC(OCC)=O.[NH2:7][C:8]1[CH:9]=[C:10]([C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14].[CH2:22]([N:24](CC)CC)C.CN>O1CCCC1>[NH2:7][C:8]1[CH:9]=[C:10]([C:15]2([OH:21])[N:24]([CH3:22])[C:18](=[O:19])[CH2:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: CCN(CC)CC
Reactant: Nc1cc(C(=O)CCC(=O)O)ccc1Cl
Agent: CCOC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CN1C(=O)CCC1(O)c1ccc(Cl)c(N)c1
Reaction time: 0.17 h

Procedure:
42.8 g of ethyl chloroformate are metered into a solution of 60 g of 4-(3-amino-4-chlorophenyl)-4-oxobutyric acid and 27.8 g of triethylamine in 500 ml of tetrahydrofuran in such a way that the temperature does not exceed 10° C. The mixture is stirred in the icebath for a further 10 min and then, while maintaining the cooling, a solution of 35 g of gaseous methylamine in 250 ml of tetrahydrofuran is added, during which a temperature of 25° C. should not be exceeded. After stirring for a further 45 minutes in the icebath, the solvent is removed by distillation, water is added to the residue, and the crystalline precipitate is filtered off. Crystals of melting point 154° C. (from ethanol).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11](=[S:13])[NH2:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH:15]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:12]=[C:11]([CH:8]3[CH2:9][CH2:10][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[S:13][C:15]=2[C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:23][CH:22]=1
Reactant: NC(=S)C1CCC2(CC1)OCCO2
Reactant: COc1ccc(C(=O)C(Br)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2nc(C3CCC4(CC3)OCCO4)sc2-c2ccc(C)cc2)cc1
Yield: 81 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decane-8-carbothioamide (Reference Example 94) (389 mg, 1.93 mmol) and 2-bromo-1-(4-methoxyphenyl)-2-(p-tolyl)ethanone (588 mg, 1.84 mmol) in acetonitrile (9.2 mL) was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (630 mg, 1.49 mmol, 81%) as a colorless amorphous product.