Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]1[O:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: ClCc1ccco1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCc2ccco2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
20 mL of DMF was blended with 2.0 g (14.4 mmol) of 3-nitrophenol, 3.57 g (30.6 mmol) of 2-(chloromethyl)furan, and 2.0 g (14.4 mmol) of potassium carbonate, and the mixture was stirred at 80° C. for 3 hours. After cooling the reaction solution to room temperature, the reaction solution was extracted with ethyl acetate, and resultant solid material was washed with water 3 times and with a saturated sodium chloride solution, and dried over magnesium sulfate. Thereafter, filtration was conducted and the filtrate was condensed. The resulting crude product was separated and purified using silica gel column chromatography to give 2-[(3-nitrophenoxy)methyl]furan (yield: 91%).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:14]([CH3:27])=[C:13]([CH3:28])[N:12]=1>O1CCCC1>[O-:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:28][C:13]1[C:14]([CH3:27])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCO)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCO)c1C
Product: [O-]c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 138 %

Procedure:
Sodium hydride (6.63 g of 60%, 166 mmol) was added to chilled (0° C.) anhydrous tetrahydrofuran (200 mL) and the mixture was allowed to stir for 15 minutes. A solution of phenol (15.07 g, 160 mmol) in tetrahydrofuran (150 mL) was added dropwise over a period of 1 hour. A solution of 5-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]pentan-1-ol (31.723 g, 110 mmol) in tetrahydrofuran (150 mL) was added dropwise over a period of 30 minutes while maintaining the reaction temperature at 0° C. The reaction mixture was allowed to warm to ambient temperature and then it was heated at reflux overnight. Analysis by thin layer chromatography indicated that the reaction was 50–60% complete. An additional equivalent of phenoxide was prepared and added to the reaction mixture at ambient temperature; then the reaction mixture was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL); washed sequentially with water (2×50 mL), 5% sodium hydroxide (2×50 mL)) and 1N sodium hydroxide (2×50 mL); dried over magnesium sulfate and then concentrated under reduced pressure. The residue was divided into two portions and purified by column chromatography (450 g of silica gel eluting with 1:1 hexanes:ethyl acetate to 1:3 hexanes:ethyl acetate) to provide 38.13 g of 5-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]pentan-1-ol.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].Cl.[C:11]([C:14]1[C:15]([CH3:25])=[CH:16][C:17]([CH3:24])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])(=[NH:13])[NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:7][N:6]([CH3:8])[C:4]([C:3]1[NH:13][C:11]([C:14]2[C:15]([CH3:25])=[CH:16][C:17]([CH3:24])=[C:18]([CH:23]=2)[C:19]([O:21][CH3:22])=[O:20])=[N:12][CH:2]=1)=[O:5]
Reactant: COC(=O)c1cc(C(=N)N)c(C)cc1C
Reactant: CN(C)C(=O)C(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ncc(C(=O)N(C)C)[nH]2)c(C)cc1C
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A mixture of 3-bromo-N,N-dimethyl-2-oxopropanamide (246 mg), methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 237 mg), and potassium carbonate (311 mg) in acetonitrile (12 ml) was heated to reflux for 48 hours. After cooling to ambient temperature the mixture was concentrated. The residue was dissolved in EtOAc and washed with brine, dried over MgSO4, concentrated, and purified by flash chromatography (SiO2; EtOAc) to give 88 mg of the title compound. m/z (ES+) 302 (M+H)+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CSC.[Cl:12][C:13]1[CH:14]=[CH:15][C:16](=[O:27])[N:17]([C:19]2[CH:24]=[N:23][C:22]([CH2:25]O)=[CH:21][N:20]=2)[CH:18]=1.O>C(Cl)Cl>[Br:8][CH2:25][C:22]1[N:23]=[CH:24][C:19]([N:17]2[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]2=[O:27])=[N:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccc(Cl)cn1-c1cnc(CO)cn1
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: O=c1ccc(Cl)cn1-c1cnc(CBr)cn1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a slurry of NBS (0.598 g, 3.36 mmol) in CH2Cl2 (10 ml)at 0° C. was added methylsulfide (0.296 ml, 4.035 mmol). The slurry was cooled to -20° C. and the alcohol from step 3 (0.532 g, 2.24 mmol) was added followed by CH2Cl2 (10 ml). The reaction was stirred at 0° C. for 3 hrs and then at room temperature for 24 hrs. The reaction was poured into water and extracted into CH2Cl2 and the combined extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 30:70) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[O:11]>C(#N)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[NH:1][C:22]([NH:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]([O:9][CH3:8])=[O:11])(=[O:20])=[O:19])=[O:23]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Nc1ncccn1
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1ncccn1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
With stirring at ambient temperature, 1.0 g of 2-aminopyrimidine in 25 ml of anhydrous acetonitrile was added to 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. After stirring that mixture for 24 hours, the resultant precipitate was filtered off to yield 2.2 g of the desired compound which melted at 188°-192°. Its showing infrared absorption peaks at 1700, 1680 and 1580 cm-1 is consistent for N-[(pyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]([F:14])([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:28][O:29][C:30](=[O:33])[CH2:31][NH2:32]>O1CCCC1>[Cl:1][C:2]([F:14])([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([NH:32][CH2:31][C:30]([O:29][CH3:28])=[O:33])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)Cl)[nH]c1=O
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1ccc(C(F)(F)Cl)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg (1.34 mmol) of 6-[chloro(difluoro)methyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid were dissolved in 5 ml of tetrahydrofuran, 435 mg (2.68 mmol) of N,N-carbonyldiimidazole were added and the mixture was stirred initially at room temperature for 30 min and then under reflux for 30 min. A mixture of 168 mg (1.34 mmol) of glycine methyl ester hydrochloride in 3 ml of tetrahydrofuran was then added, and the mixture was heated under reflux for a further 2 h. The solution was evaporated to dryness, the residue was taken up in ethyl acetate and the solution was washed with 1N hydrochloric acid and water, dried and concentrated. This gave 92 mg (23% of theory) of a light-brown powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][C:14]=2[NH2:16])[C@H:9]([N:18]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:8][C@@H:7]1[CH3:38])=[O:5])[CH3:2].ClCCl.N1C=CC=CC=1.[C:48](Cl)(=[O:50])[CH3:49]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][C:14]=2[NH:16][C:48](=[O:50])[CH3:49])[C@H:9]([N:18]([CH2:23][C:24]2[CH:25]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:8][C@@H:7]1[CH3:38])=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)N1c2c(N)cc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)N1c2c(NC(C)=O)cc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 102.1 %

Procedure:
To a pre-dried flask under nitrogen atmosphere was added cis-8-amino-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 109) (30 mg, 0.053 mmol), followed by anhydrous dichloromethane (2 mL), pyridine (0.5 mL), and acetyl chloride (0.015 mL, 0.21 mmol). The reaction was stirred overnight at room temperature before ethyl acetate was added, and the mixture was extracted three times with 1N HCl, followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title product (33 mg, 100%) MS m/z 610 (M+ +H); 1H NMR (CDCl3) δ 7.8 (bs, 2H), 7.7 (bs, 1H), 7.65 (bs, 1H), 6. 8 (bs, 1H), 3.8 (s, 3H), 2.1 (s, 3H).
Reaction SMILES: [CH3:1][C@@:2]1([OH:8])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.CN(C=O)C.N1C=NCC=1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.CCOCC>[C:19]([Si:23]([CH3:26])([CH3:25])[O:8][C@:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]1(O)C=CCCC1
Agent: C1=NC=NC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@@]1(C)C=CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-methylcyclohex-2-enol, 50a, (1.00 g, 8.91 mmol) in 20 dry DMF at room temperature was added 4H-imidazole (1.82 g, 26.74 mmol), tert-butyldimethylchlorosilane (2.02 g, 13.33 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.11 g, 0.89 mmol). The resulting mixture was stirred at room temperature overnight. It was then diluted with ether, washed consecutively with water, citric acid and water. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The colorless crude oil 1.98 g was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].CCN(CC)CC.Cl.[NH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[C:26]2[B:27]([OH:34])[O:28][CH:29]([CH2:30][N+:31]([O-:33])=[O:32])[C:25]=2[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[OH:34][B:27]1[C:26]2[C:21]([O:20][CH2:19][CH2:18][CH2:17][NH:16][C:2](=[O:3])[CH3:1])=[CH:22][CH:23]=[CH:24][C:25]=2[CH:29]([CH2:30][N+:31]([O-:33])=[O:32])[O:28]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ac2O (1.16 mL, 12.3 mmol) was added slowly to a solution of Et3N (2.33 mL, 16.5 mmol) and 7-(3-amino-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (1.69 g, 76.5 mmol) in CH2Cl2 (50 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 1 h and then quenched with H2O (50 mL). The mixture was extracted with CH2Cl2 and the organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound as a viscous liquid: yield 1.29 g (75%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=O.[C:13](CC(OC)=O)#N.[OH-].[Na+].Cl>O.CN(C=O)C.C(N(CC)CC)C>[OH:12][C:5]1[CH:13]=[C:2]([OH:4])[C:1]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COC(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1cc(O)c2ccccc2n1
Reaction time: 1 h

Procedure:
Into a 150 ml three neck flask, equipped with an agitator, a reflux condenser sealed on its upper end with a gas bubbler, a thermometer and an electric heating mantle were charged 16.3 g pure isatoic anhydride (M.W. 163) 10.1 g triethylamine (M.W. 101), 9.9 g methyl cyanoacetate (M.W. 99) and 2 ml DMF. The reaction mixture, under agitation, was kept at a temperature within the range of 25° to 30° C. for approximately 1 hour. During this period a constant evolution of gas was observed. The temperature of the reaction mixture was then elevated to and maintained at 78° to 80° C. for approximately 2 hours. At the end of this heating period the evolution of gas practically stopped and the reaction mixture turned into a slightly yellow, good stirrable oil. A minimum of water (approximately 40 ml) and the still hot oil were transferred to a 300 ml stainless steel autoclave, equipped with an anchor agitator, a pressure gauge, a thermocouple and a vent-valve. A charge of 14.7 g sodium hydroxide (MW 40) pellets was added to the reaction mixture and the autoclave was closed. The contents of the autoclave, under agitation, were heated to and maintained at a temperature in the range of 150° to 155° C. for 3 hours. The pressure in the autoclave reached 275 to 280 psig during the heating; after cooling to 50° to 60° C. hot water was added to the autoclave and approximately 600 ml of a brownish colored solution was removed therefrom and treated with 1 g activated charcoal at 60° C. A slightly yellowish colored solution which resulted was then acidified with concentrated hydrochloric acid to a pH of approximately 2. White, slightly creamy colored precipitate which formed was recovered by filtration; the precipitate was then reslurried in 200 ml water, refiltered and dried at 110° C. The yield was 14.17 g (87.9 percent of theory based upon the isatoic anhydride charged) 2,4-dihydroxyquinoline, melting point 350°-355° C. Examination of the product by infrared spectroscopy and nuclear magnetic resonance indicated that it was of high purity.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[C:22](=[O:23])[NH:21][N:20]=[C:19]2[N:10]1[C:11]1[CH:12]=[C:13]3[N:26]([C:27]4([CH3:31])[CH2:30][NH:29][CH2:28]4)[CH2:25][CH2:24][C:14]3=[CH:15][C:16]=1[O:17][CH2:18]2.[O:32](C(OC(C)(C)C)=O)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:36]([O:35][C:33]([N:29]1[CH2:28][C:27]([CH3:31])([N:26]2[C:13]3[C:14](=[CH:15][C:16]4[O:17][CH2:18][C:19]5[N:10]([C:11]=4[CH:12]=3)[CH:9]([CH3:8])[C:22](=[O:23])[NH:21][N:20]=5)[CH2:24][CH2:25]2)[CH2:30]1)=[O:32])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC1C(=O)NN=C2COc3cc4c(cc3N21)N(C1(C)CNC1)CC4
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC1C(=O)NN=C2COc3cc4c(cc3N21)N(C1(C)CN(C(=O)OC(C)(C)C)C1)CC4
Yield: 50.7 %

Procedure:
To a solution of 1-methyl-10-(3-methyl-azetidin-3-yl)-3,5,9,10-tetrahydro-8H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one 2,2,2-trifluoroacetate (Example #158, 0.65 g, crude, 1.985 mmol) in DCM (15 mL) was added TEA (0.603 g, 5.96 mmol), DMAP (0.024 g, 0.199 mmol) and BOC2O (0.867 g, 3.97 mmol). The resultant mixture was stirred at ambient temperature for 3 h. Water (2×10 mL) was added and the reaction mixture was extracted with EtOAc (2×40 mL). The combined organic phase was washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was dried in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10%-50% EtOAc in petroleum ether) to give racemic 3-methyl-3-(1-methyl-2-oxo-1,2,3,5,8,9-hexahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-azetidine-1-carboxylic acid tert-butyl ester (0.43 g, 1.006 mmol). LC/MS (Table 1, Method 25) Rt=0.823 min; MS m/z: 428 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.[Br:12][CH2:13][C:14]([CH2:16]Br)=O.O>CN(C=O)C>[Br:12][CH2:13][C:14]1[N:11]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[S:10][CH:16]=1
Reactant: O=C(CBr)CBr
Reactant: NC(=S)Nc1ccc(Br)cn1
Solvent: O
Solvent: CN(C)C=O
Product: BrCc1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
(5-Bromo-pyridine-2-yl)-thiourea (2.5 mmol) is dissolved in DMF (5 ml) and 1,3-dibromacetone (1 eq.) is added and stirred 2 h at 70° C. After cooling to RT, the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. After column chromatography (ethyl acetate/methanol) (4-bromomethyl-thiazole-2-yl)-(5-bromo-pyridine-2-yl)-amine is obtained as a colourless powder with a yield of 16%. HPLC (method C): 1.92 min; LC-MS (method A): 1.977 min, 347.95 (M+H+); 1H-NMR (DMSO-d6, 300 MHz): δ [ppm] 11.583 (s, 1H), 8.391 (d, 1H, J=2.4 Hz), 7.902 (dd, 1H, J=2.4 Hz, J=8.9 Hz), 7.119 (s, 1H), 7.023 (d, 1H, J=8.9 Hz), 4.622 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>CCN(CC)CC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24]([N:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1)=[O:26]
Reactant: OC1CNC1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Solvent: CCN(CC)CC
Product: O=C(O)c1c(CC(=O)N2CC(O)C2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with azetidin-3-ol and NEt3 at 22° C. to give the title compound as a white solid. MS: 431.3 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9](N2CCOCC2)=S)=[CH:4][CH:3]=1.[OH-:17].[Na+].[OH2:19].CCO>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:19])=[O:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC(=S)N2CCOCC2)cn1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CC(=O)O)cn1

Procedure:
Crude 2-(6-Methyl-pyridin-3-yl)-1-morpholin-4-yl-ethanethione (39.5 mmol, 9.685 g) was suspended in 2:1 H2O/EtOH (75 cm3). NaOH (3.3 eq., 118.5 mmol, 4.8 g) added and the reaction heated to reflux for 16 hours. Volatiles were then removed from the cooled reaction medium, and the aqueous residue extracted with DCM (3×50 cm3). The pH was adjusted to precisely pH 7.0 with HCl, and a further DCM extraction performed (3×50 cm3). Water was removed from the residue, and the obtained solids slurried in methanol, filtered, and the filtrate evaporated to dryness. The orange solid obtained gave spectroscopic data consistent with the desired product. Mass recovery is typically >100% however this is due to NaCl within the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[C:9]2[C:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)=[N:19][N:18]2[CH2:28][CH2:29][CH2:30][C:17]=12.[OH-].[Li+]>CO.O>[NH3:12].[CH3:1][OH:2].[CH3:27][C:23]1[N:22]=[C:21]([C:20]2[C:16]([C:9]3[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([CH:5]=[CH:4][C:3]([OH:31])=[O:2])[CH:7]=4)[N:12]=[CH:11][CH:10]=3)=[C:17]3[CH2:30][CH2:29][CH2:28][N:18]3[N:19]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C=Cc1ccc2nccc(-c3c(-c4cccc(C)n4)nn4c3CCC4)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2nn3c(c2-c2ccnc4ccc(C=CC(=O)O)cc24)CCC3)n1
Product: N
Yield: 181.6 %

Procedure:
Dissolve 3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-6-yl}-acrylic acid methyl ester (0.040 g, 0.1 mmol) in methanol/water (3:1, 2 mL). Add lithium hydroxide (0.010 g, 0.25 mmol) and stir the mixture 18 h. Remove the solvent then load the residue on a SCX resin column with methanol. Elute the column with methanol (50 mL) then with 2 N ammonia/methanol to give the desired product as a pale yellow solid 0.036 g (92%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[C:26](O)([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C>[C:26]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 97 %

Procedure:
To a mixture of the compound (6.9 g) obtained in Example 63 and methylene chloride (70 ml) were added t-butanol (20 ml), N,N-dimethylaminopyridine (2.63 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.9 g) and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and washed successively with 2 N HCl and a saturated aqueous sodium chloride solution; the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 7.64 g of the titled compound (yield, 97%).
Reaction SMILES: [CH3:1][CH:2]([S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:18](Br)[C:19]#[CH:20]>>[CH3:1][CH:2]([S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][CH2:20][C:19]#[CH:18])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: C#CCBr
Reactant: CC(C)CCCC(C)Sc1ccc(CO)cc1
Product: C#CCOCc1ccc(SC(C)CCCC(C)C)cc1

Procedure:
By utilizing the procedure of Example 26, by reacting p-[(1.5-dimethylhexyl)thio]benzyl alcohol with propargyl bromide, there is obtained p-[(1,5-dimethylhexyl)thio]-α-propargyloxy-toluene; nD29 = 1.5243.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([C:25]1[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:29]=1)[C:10]([NH:12][C:13]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:22]([CH3:24])[CH3:23])=[O:11].[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1.C(OCC)(=O)C>[CH:22]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:13]=1[NH:12][C:10](=[O:11])[CH:9]([C:25]1[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:29]=1)[NH:8][C:42](=[O:44])[CH3:43])([CH3:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCn1nnc(C(N)C(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCn1nnc(C(NC(C)=O)C(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Temperature: 24 °C
Reaction time: 0.25 h
Yield: 46.1 %

Procedure:
Triethylamine (0.27 g, 2.75 mmol) was added in one portion to a stirred solution of 1.3 g (2.75 mmol) of (±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl-2H-tetrazol -5-yl)-2-amino-acetamide (prepared as in Example 10) in 50 mL of THF. To the solution was added in one portion 0.23 g (3.0 mmol) of acetyl chloride. The mixture was stirred at 24° C. for 15 minutes, diluted with 50 mL of ethyl acetate, washed with 50 mL of 1N hydrochloric acid, then with 50 mL of 1N sodium hydroxide, brine, and finally dried over MgSO4. The solution was filtered and concentrated by removing the solvents in vacuo to afford an oil. The oil was further purified by chromatography over silica gel (eluting with 1:1 ethyl acetate/hexane) to provide 0.65 g of (±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl-2H-tetrazol -5-yl)-2-acetylamino-acetamide;