Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].C(N(CC)CC)C.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:19]([Si:23]([CH3:26])([CH3:25])[O:11][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[NH2:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1Cc2ccccc2[C@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1R,2R)-1-amino-2-indanol (2.00 g) is suspended in 20 mL DCM and combined with triethylamine (3.61 mL) as well as DMAP (0.32 g). Then tert-butyldimethylchlorosilane (4.04 g in 2 mL CH2Cl2) is added. The reaction mixture is stirred for 16 h at RT and, once the reaction is complete, it is mixed with water, extracted with CH2Cl2 and the organic phase is freed from the solvent using the rotary evaporator. The residue is taken up in MeOH and isolate is added. After elimination of the solvent once again the mixture is purified by normal phase chromatography (CH2Cl2/EA). The product-containing fractions are combined and freed from the solvent using the rotary evaporator.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:37](=[O:38])[N:13]3[CH:14]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[O:26])[C:15]([CH:18]4[CH2:22][CH2:21][CH2:20][S:19]4(=[O:24])=[O:23])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:47])C=1>ClCCl>[O:47]=[S:17]1[C@@H:12]2[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:37](=[O:38])[N:13]2[C:14]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[O:26])=[C:15]([CH:18]2[CH2:22][CH2:21][CH2:20][S:19]2(=[O:24])=[O:23])[CH2:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COC(=O)C2C(C3CCCS3(=O)=O)=CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(C3CCCS3(=O)=O)CS(=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C

Procedure:
4-Methoxybenzyl (6R, 7R)-7-phenylacetamido-3-(1,1-dioxotetrahydrothien-2-yl)ceph-2-em-4-carboxylate (0.973 g) in dichloromethane (20 ml) was cooled in ice-water and treated with 3-chloroperbenzoic acid (0.343 g) and warmed to room temperature for 1 h. The solution was washed with saturated sodium metabisulphite, brine and then dried. Afar removal of solvent, the residue was flash chromatographed on silica gel eluting initially with 80, 90% ethyl acetate-hexane and then ethyl acetate. The first product eluted was the least polar isomer of the title compound, obtained as a pale yellow foam, (0.309 g, 31%); 5H (CDCl3) 2.02-2.39 (4H, m), 2.91-3.03 (1H, m), 3.11-3.20 (1H, m), 3.49 and 3.79 (2H, ABq, J 8.6 Hz), 3.58 and 3.66 (2H, ABq, J 15.9 Hz), 3.81 (3H, s), 4.52 (1H, d, J 4.7 Hz), 5.02 (1H, dd, J 7.3, 11.2 Hz), 5.20 and 5.26 (2H, ABq, J 11.4 Hz), 6.03 (1H, dd, J 4.7, 10.0 hz), 6.69 (1H, d, J 10.0 Hz), 6.90 (2H, d, J 8.7 Hz) and 7.26-7.39 (7H, m). Further elution with 10% ethanol-ethyl acetate provided the second more polar isomer as an off white, amorphous solid, (0.166g, 17%); 5H (CDCl3) 1.90-2.30 (4H, m), 2.88-3.20 (2H, m), 3.06 a 4.13 (2H, ABq, J 18.4 Hz), 3.57 (2H, s), 3.77 (3H, s), 4.43 (1H, d, J 4.1 Hz), 4.61 (1H, t, J 8.3 Hz), 5.18 (3H, m), 5.98 (1H, dd J 4.8, 9.6 Hz), 6.84 (2H, d, J 8.7 Hz) and 7.17-7.36 (7H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13]C1CCCCO1)([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)COCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of 36.21 g of 2-[4-(2-tetrahydropyranyloxy)butyloxy]acetic acid tert-butyl ester in 360 ml of methanol, 47.77 g of p-toluenesulfonic acid monohydrate was added. After stirring at room temperature for 30 minutes, the reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution and the solvent was evaporated under reduced pressure. The residue was diluted with water, extracted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 17.02 g of the desired compound as a colorless oily substance.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>C(O)C>[Cl:26][CH2:25][CH2:24][CH2:23][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: ClCCCN1CCC(n2ccc3ccccc32)CC1
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 1-(piperidin-4-yl)-indole (100 mg, 0.5 mmol) in absolute ethanol (2 mL) was added anhydrous potassium carbonate (70 mg, 0.5 mmol) and 1-bromo-3-chloropropane (150 mg, 1 mmol). After stirring overnight additional 1-bromo-3-chloropropane (150 mg) was added and stirring continued for 2 hours. The mixture was evaporated; and the residue dissolved in methylene chloride and shaken with water. The organic solution was dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed on silica gel with methylene chloride/ethanol (95:5) to give the title compound (90 mg, 65% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:20]=[C:19]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=4)[O:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:32][N:33]([CH3:43])[C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:20]=[C:19]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][CH:42]=[C:34]([N:33]([CH3:32])[CH3:43])[CH:35]=5)[CH:25]=4)[O:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3oc(-c4cccc(N)c4)nc3n2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=O)Nc2cccc(-c3nc4nc(CN5CCN(C(=O)OC(C)(C)C)CC5)ccc4o3)c2)c1
Temperature: 160 °C
Yield: 22.5 %

Procedure:
4-[2-(3-Amino-phenyl)-oxazolo[4,5-b]pyridin-5-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (83 mg, 0.2 mmol) was dissolved in 1 mL of pyridine along with 1 eq of 3-dimethylamino benzoyl chloride hydrochloride (44 mg, 0.2 mmol). The reaction mixture was heated in a Biotage microwave reactor (160° C.) for 10 min. It was then cooled to room temperature and concentrated. The resulting residue was purified by chromatography (Isco, gradient elution, CH2Cl2 to 95% CH2Cl2, 4% MeOH and 1% Et3N) to afford 25 mg of 4-{2-[3-(3-dimethylamino-benzoylamino)-phenyl]-oxazolo[4,5-b]pyridin-5-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (23% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:24])=[C:14]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:15]([CH3:17])[S:16][C@H:11]12)=[O:8]>C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([OH:25])=[O:24])=[C:14]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:15]([CH3:17])[S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S[C@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S[C@H]1C

Procedure:
A solution of 1.4 g of diphenylmethyl 7-(2-thienylacetamido)-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate in 3 ml of anisole and 20 ml of CF3COOH was stirred at room temperature for 15 minutes. After distilling off CF3COOH under reduced pressure, the residue was dissolved in AcOEt, and then transferred into 5% aqueous NaHCO3. The water layer was adjusted to pH 2.0 with 5% H3PO4 to extract again with AcOEt. The AcOEt layer was washed with saturated aqueous NaCl solution, and dried over Na2SO4, and the AcOEt was distilled off under reduced pressure, thus yielding crude crystals of 7-(2-thienylacetamido)-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylic acid. The crude crystals were dissolved in 5% aqueous NaHCO3, adjusted to pH 7.0 with addition of 5% H3PO4 and then added on a column of Amberlite XAD-II (produced by Rohm & Hass). The fractions eluted with H2O were collected, concentrated under reduced pressure and freeze-dried, thus yielding 829 mg (79%) of sodium 7-(2-thienylacetamido)-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)[CH:3]=1.C[O:19]C(OC)N(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:19])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)[CH:3]=1
Reactant: Cc1ccnc(-c2ccc(C)c([N+](=O)[O-])c2)c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-methylpyridin-2-yl)-2-nitrotoluene (3.42 g) in N,N-dimethylformamide (20 ml) was added N,N-dimethylformamide dimethyl acetal (2.59 ml), and the mixture was stirred at 150° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (80 ml) and water (80 ml). Sodium metaperiodate (10.59 g) was added to the solution, and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 75 g, 0-1% ethanol in dichloromethane) to give 4-(4-methylpyridin-2-yl)-2-nitrobenzaldehyde (3.58 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[C:7]([S:19][CH3:20])[CH:6]=[C:5]([CH3:21])[N:4]=1.C(N(CC)CC)C.[CH2:29]([NH:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][OH:48])[CH2:41][CH2:40]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1.O>[CH3:1][S:2][C:3]1[C:8]([NH:9][C:10](=[O:18])[N:36]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][OH:48])[CH2:41][CH2:40]2)=[C:7]([S:19][CH3:20])[CH:6]=[C:5]([CH3:21])[N:4]=1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)Oc1ccccc1
Reactant: CCCCCCCNCCN1CCN(CCCO)CC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCN(CCN1CCN(CCCO)CC1)C(=O)Nc1c(SC)cc(C)nc1SC
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a solution of this phenyl carbamate (188 mg, 0.59 mmol) in toluene (3 ml) were added triethylamine (72 mg, 0.71 mmol) and 3-[4-(2-heptylaminoethyl)piperazin-1-yl]propanol (168 mg, 0.59 mmol) and the mixture was stirred at 80° C. for 3 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 15 g, developing solvent; chloroform:methanol=40:1 10:1) to provide 249 mg (yield 83%) of N′-[2,4-bis(methylthio)-6-methyl-3-pyridyl]-N-heptyl-N-[2-[4-(3-hydroxypropyl)piperazin-1-yl]ethyl]urea as colorless oil.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C
Temperature: 55 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (0.67 g, 2.1 mmol) and o-toluidine (0.24 g, 2.3 mmol) in acetonitrile was heated to 55° C. and stirred for 3.5 h. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. The residue was triturated with diisopropylether. The precipitated product was filtered off and washed with diisopropyl ether giving 0.55 g (66%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1.CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Reactant: BrC1CCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(SC2CCCC2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, cyclopentyl bromide and sodium ethylate in ethanol. EI-MS m/e (%): 296 (M+, 36), 295 ([M—H]+, 100), 228 ([M—C5H8]+, 100).
Reaction SMILES: [CH2:1]([S:5][C:6]1[C:7]([C:12]2(O)[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:8][CH:9]=[CH:10][N:11]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:23][C:12]1([C:7]2[C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:11][CH:10]=[CH:9][N:8]=2)[CH:17]2[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]2)[CH2:13]1
Reactant: O=S(Cl)Cl
Reactant: CCCCSc1nccnc1C1(O)CN2CCC1CC2
Solvent: ClCCl
Product: CCCCSc1nccnc1C1(Cl)CN2CCC1CC2
Temperature: 25 °C

Procedure:
A 1 g sample of 60% NaH dispersion in oil was triturated twice with hexane then suspended in 300 ml of THF. The mixture was treated with 5 ml of butanethiol and after 30 min the mixture was heated to reflux for 45 min. After cooling to ambient temperature, 1.5 g of (7), (0.0063 mol) was added and the reaction was heated to reflux for 1 h. The mixture was diluted with 100 ml of butanethiol and the reaction was heated to reflux overnight. The solvent was removed by distillation, the residue suspended in 50 ml of H2O, and the mixture extracted 3× with 25 ml of CHCl3, the extracts washed with brine, and the solvent evaporated. The brown solid residue was recrystallized from ether to give 1.25 g of 3-(3-butylthiopyrazinyl)-1- azabicyclo[2.2.2]octan-3-ol (29a). NMR ppm (CDCl3) 0.97 (3H, t), 1.19 (1H, t), 1.19 (1H, m), 1.35-1.57 (4H, m), 1.7 (2H, m), 2.21 (1H, m), 2.5-3.02 (6H, m), 3.2 (2H, m), 4.1 (1H, d), 4.5 (1H, m), 8.17 (1H, d), 8.25 (1H, d). A solution of 1.2 g of (29a) (0.0041 mol) in 100 ml of CH2Cl2 was cooled to 0° C. as 0.95 ml of thionyl chloride in 10 ml of CH2Cl2 was added dropwise. The cooling was removed and after 1 h the reaction was heated to reflux for 45 min. After cooling to ambient temperature, the reaction was treated with ice and the solution was made basic with 1 N NaOH. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated to give a brown liquid. The liquid was purified by radial chromatography eluting with 5% ethanol-0.5% NH4OH-CHCl3 and then 10% ethanol-1% NH4OH-CHCl3 to give 1 g of 3-chloro-3-(3-butylthiopyrazinyl)-1-azabicyclo[2.2.2]octane (29b). NMR ppm (CDCl3) 0.99 (3H, t), 1.5 (3H, m), 1.7 (4H, m), 2.38 (1H, m), 2.7 (2H, m), 2.98 (1H, m), 3.05-3.4 (4H, m), 3.76 (1H, d), 4.19 (1H, d), 8.18 (1H, d), 8.3 (1H, d). A mixture of 1 g of (29b) (0.0032 mol) and 0.4 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated for 1 h at 60 psi of H2. The catalyst was removed, the solvent was evaporated, the residue suspended in 5 ml of H2O, and the mixture made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol-0.5% NH4OH-CHCl3 and then 10% ethanol-1% NH4OH-CHCl3. The hydrochloride salt (29) crystallized from ethyl acetate to give 0.44 g of a floculant white solid, mp 193°-194° C. NMR ppm (CDCl3) 0.99 (3H, t), 1.5 (2H. m), 1.7 (4H, m), 2.15 (2H, m), 2.5 (1H, m), 3.23 (3H, m), 3.4 (3H, m), 3.64 (2H, m), 4.38 (1H, q), 8.21 (1H, d), 8.31 (1H, d). Anal. C15H23N3S-HCl requires C: 57.40; H: 7.71; N: 13.37%. Found C: 57.14; H: 7.92; N: 13.12%.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:20][C:21]1[C:30]([O:31][CH3:32])=[CH:29][C:24]2[NH:25][C:26](=[O:28])[S:27][C:23]=2[CH:22]=1>>[CH3:32][O:31][C:30]1[C:21]([NH:20][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:22][C:23]2[S:27][C:26](=[O:28])[NH:25][C:24]=2[CH:29]=1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: CCOC(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CCOC(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1

Procedure:
130 mg (438 μmol) (RS)-ethyl 4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate (prepared according to intermediate example 1a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 98.1 mg (47%) of the title compound.
Reaction SMILES: ClCC([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([F:15])[C:7]=1[CH3:16])=O.[OH-].[Na+].O1CCCC1>O>[F:15][C:8]1[C:7]([CH3:16])=[C:6]([C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1)[NH2:5]
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1NC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)ccc([N+](=O)[O-])c1N

Procedure:
2-Chloro-N-(3-fluoro-2-methyl-6-nitrophenyl)acetamide (prepared from 47.2 g of 2-chloro-N-(3-fluoro-2-methylphenyl)acetamide, ca. 234 mmol) was suspended in water (220 ml) then treated with aqueous sodium hydroxide solution (12.5M, 110 ml, 1.37 mol). Tetrahydrofuran (110 ml) was added, then the mixture was heated to reflux for 5 hours, then evaporated (removing most of the tetrahydrofuran). The yellow solid was filtered off and washed with water until washing were non-alkaline. Drying in vacuo afforded a yellow solid (32.3 g, 81% over 2 steps) containing ˜13% isomer.
Reaction SMILES: [N+](C1C=C[C:7]([O:10][P:11]([CH3:23])(=[O:22])[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=CC=1)([O-])=O.[N:24]1([CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37]([C:42]2C4C(=CC=C(O)C=4)N[N:43]=2)=[CH:36]3)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1CCN2C(=NCCC2)CC1.CO>ClCCl>[N:24]1([CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37]([C:42]2[C:15]4[C:16](=[CH:17][CH:18]=[C:13]([O:12][P:11]([CH3:23])(=[O:22])[O:10][CH3:7])[CH:14]=4)[NH:19][N:43]=2)=[CH:36]3)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCOCC5)ccc4[nH]3)c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: ClCCl
Product: COP(C)(=O)Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCOCC5)ccc4[nH]3)c2c1
Temperature: 25 °C

Procedure:
A suspension of 170 mg of methylphosphonic acid bis-(4-nitrophenyl)ester (prepared according to procedure E) and 189.7 mg of 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-1H-indazol-5-ol in 17 ml of dichloromethane (stabilized with amylene) is stirred at ambient temperature. A solution of 75 μl of DBU in 500 μl of dichloromethane is added dropwise over 10 minutes. Stirring is maintained overnight. 204 μl of methanol are added with 75 μl of DBU. The solution is stirred for 24 hours. The reaction medium is concentrated under vacuum and the crude is then taken up with 25 ml of ethyl acetate and washed with 4 times 25 ml of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum. The reaction crude is purified by flash chromatography on 5 g of 40-63 μm silica. Eluents: 98/2 then 95/5 dichloromethane/methanol. 95 mg of methylphosphonic acid methyl ester 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-1H-indazol-5-yl ester are collected.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=c1cc(O)cc[nH]1
Product: O=C(Oc1cc[nH]c(=O)c1)c1ccccc1Cl
Yield: 68 %

Procedure:
The general procedure of Example 12 was followed using 1.00 g of 4-hydroxy-2-pyridone and 1.36 ml of 2-chlorobenzoyl chloride to produce 1.42 g of the title compound in a yield of 68%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:34])[C:31](Cl)=[O:32])=[CH:26][CH:25]=1)[CH:21]([CH3:23])[CH3:22]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[CH:30]([C:27]3[CH:28]=[CH:29][C:24]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=3)[CH3:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: CC(C)Cc1ccc(C(C)C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-isobutyl-α-methylphenylacetyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(4-isobutylphenyl)propanamide as a white powder, m.p. 172.0-173.0° C. 1H NMR (300 MHz, DMSO-d6) δ8.14 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.90 (t, J=5.6 Hz, 1H), 7.63 (dd, J=8.1, 1.0 Hz, 1H), 7.44 (dt, J=7.0, 1.0 Hz, 1H), 7.25 (dt, J=7.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.0 Hz, 2H), 6.58 (broad s, 2H), 4.55 (t, J=7.0 Hz, 2H), 3.47 (q, J=7.1 Hz, 1H), 3.06 (m, 2H), 2.34 (d, J=7.1 Hz, 2H), 1.80-1.69 (m, 3H), 1.44 (m, 2H), 1.24 (d, J=7.0 Hz, 3H), 0.82 (d, J=6.6 Hz,6H); MS (EI) m/e 443.2687 (443.2685 calcd for C27H33N5O).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[OH:30][C:6]1[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:10](=[O:23])[N:11]2[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1-phenethyl-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.075 mmol), β-alanine (668 mg, 7.5 mmol) and NaOMe solution (12 mL, 6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 27 mg of the title compound as a yellow solid. MS: (+) m/z 458.30 (M+1).