Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[N:29]=[CH:28]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:26][N:27]1[CH:31]=[C:30]([S:32]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:34])=[O:33])[N:29]=[CH:28]1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)c1
Yield: 60.8 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with 1-methylimidazole-4-sulfonyl chloride (0.031 g, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.048 g of white solid.
Reaction SMILES: [C:1]([S:20][CH2:21][CH2:22][NH2:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C([O:31][C:32](=O)[C:33]2[CH:38]=[CH:37][C:36]([CH2:39][OH:40])=[CH:35][CH:34]=2)=C(F)C(F)=C(F)C=1F.CN1CCOCC1>ClCCl>[OH:40][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:23][CH2:22][CH2:21][S:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:31])=[CH:34][CH:35]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(CO)cc1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 57.3 %

Procedure:
To a solution of S-trityl cysteamine (1.60 g, 5.00 mmol) and 4-hydroxymethylbenzoic acid pentafluorophenyl ester (MilliGen, 1.51 g, 5.00 mmol) in dichloromethane (40 ml) was added N-methylmorpholine (0.55 ml, 5.0 mmol). The mixture was stirred at room temperature for 36 hrs. Precipitated material was filtered off, washed with dichloromethane and dried to give 1.30 g (57%) of white solid. NMR analysis was in accordance with the structure.
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:37])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:25]([O:26][CH3:27])=[C:24]3[C:19]([C:20](=[O:35])[C:21]([C:32]([OH:34])=[O:33])=[CH:22][N:23]3[C@@H:28]3[CH2:30][C@@H:29]3[F:31])=[CH:18][C:17]=2[F:36])[CH2:10]1)=O)(C)(C)C>Cl>[NH2:8][C:9]1([CH3:37])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:16]2[C:25]([O:26][CH3:27])=[C:24]3[C:19]([C:20](=[O:35])[C:21]([C:32]([OH:34])=[O:33])=[CH:22][N:23]3[C@@H:28]3[CH2:30][C@@H:29]3[F:31])=[CH:18][C:17]=2[F:36])[CH2:10]1
Reactant: COc1c(N2CC3(CC3)C(C)(NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Product: COc1c(N2CC(C)(N)C3(CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
The 7-[7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid produced in Reference Example 29 (870 mg, 1.676 mmol) was dissolved in concentrated hydrochloric acid (10 mL) in an ice bath, and the mixture was stirred at room temperature for 20 minutes and washed chloroform (20 mL×5). Saturated aqueous solution of sodium hydroxide was added to the aqueous layer in an ice bath to adjust the pH to 12.0, and the pH was further adjusted to 7.4 by adding hydrochloric acid. The solution was extracted with a mixed solution (chloroform:methanol, 10:1) (200 mL×2), and then, with lower layer of a mixed solution (200 mL) (chloroform:methanol:water, 7:3:1). The organic layers were combined and dried with anhydrous sodium sulfate, and the solvent was removed by distillation. The residue was purified by recrystallization from ethanol, and the crystals were dried under reduced pressure to obtain 644 mg (1.535 mmol, 92%) of the title compound as a pale pink powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1.[OH-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:16][CH2:15][CH:12]1[CH2:14][CH2:13]1
Reactant: OCC1CC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)c(Cl)c1
Temperature: 0 °C

Procedure:
To a solution containing 38.4 g of 3,4-dichloronitrobenzene in 150 ml of DMSO was added 17.3 g of cyclopropylmethanol. This solution was stirred during the dropwise addition of 9.2 g of sodium hydroxide dissolved in 10 ml of water. This addition was exothermic to 45° C. The mixture was stirred and heated to 75°-80° for 18 hours, than poured over ice water and filtered. The filter cake was recrystallized from methanol to yield 27 g (59%) of light tan solid, melting point, 42°-44° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][O:11][C:10]=1[C:16]([OH:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([Cl:24])(=O)[C:20]([Cl:22])=O.C[N:26]([CH3:29])C=O>C(Cl)(Cl)Cl>[Cl:22][C:20]1[CH:1]=[C:2]([CH:3]=[CH:4][C:19]=1[Cl:24])[CH2:29][NH:26][C:16]([C:10]1[O:11][CH:12]=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1occc(=O)c1OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1occc(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (0.4 g) prepared according to the method described in references (JP-A-2-502281 (WO88/06588), J. Med. Chem., 1999, 42, 4814–4823) in chloroform (30 ml) were added oxalyl chloride (0.21 ml) and dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solvent was evaporated under reduced pressure, toluene was added, the mixture was concentrated and dissolved in chloroform (5 ml). 3,4-Dichlorobenzylamine (0.23 ml) and triethylamine (0.34 ml) were added successively under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. 5% Aqueous potassium hydrogen sulfate solution was added to the obtained reaction mixture and the mixture was extracted with. chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1–1:8) to give N-(3,4-dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxamide (0.43 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][N:13]2[C:17]3[N:18]=[CH:19][CH:20]=[C:21](O)[C:16]=3[C:15]([CH3:23])=[N:14]2)=[CH:10][CH:9]=1>ClC(Cl)C>[Cl:3][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[N:13]([CH2:12][C:11]3[CH:24]=[CH:25][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)[N:14]=[C:15]([CH3:23])[C:16]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Solvent: CC(Cl)Cl
Product: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Temperature: 115 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a 500 mL round bottom flask was added phosphorous oxychloride (6.63 mL, 72.4 mmol) followed by dichloroethane (120 mL). 1-(4-Methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (6.5 g, 24.1 mmol), prepared according to the procedure of Example 5, Step B, was added directly as a solid. The reaction mixture was stirred for 1 hour at refluxing temperature (115° C.) under N2. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduce pressure. Any remaining solvent was removed by toluene azeotrope (2×50 mL). The resulting crude material was dissolved in dichloromethane (50 mL), and saturated NaHCO3 was added slowly until vigorous bubbling ceased. The biphasic mixture was diluted with additional dichloromethane and aqueous sodium bicarbonate and the organic layer washed separated, washed with brine, dried over sodium sulfate and evaporated to afford 6.6 g of off-white solid. The crude was chromatographed on Silica (Biotage 40M) loading with dichloromethane and eluting with 80/20 hexanes/ethyl acetate to obtain the product (6.0 g, 87%) as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J=5.1 Hz, 1H), 7.24 (d, J=5.1 Hz, 1H), 7.15 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 5.46 (s, 2H), 3.64 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11]C=[C:13](C(O)=O)[CH:14]=2)[C:9]1=[O:21].CN(C)C=O>O1CCCC1>[CH3:7][N:8]1[C:9](=[O:21])[C:10]2[C:15](=[CH:14][CH:13]=[C:1]([C:2]([Cl:4])=[O:3])[CH:11]=2)[C:16]1=[O:17]
Reactant: CN1C(=O)c2ccc(C(=O)O)cc2C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccc(C(=O)Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (5.86 ml) was added by portions to a solution of 2-methyl-1,3-dioxo-5-isoindolinecarboxylic acid (9.2 g) obtained in Reference Example 229 and dimethylformamide (catalytic amount) in tetrahydrofuran (100 ml) at room temperature. After stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure. The resulting residue was filtered, washed with diethyl ether and dried under reduced pressure to give the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:19]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1nc(-c2ccccc2)no1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc(-c2noc(COc3ccc(CCCn4ccnc4)cc3)n2)cc1
Yield: 51 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with 5-chloromethyl-3-phenyl-1,2,4-oxadiazole to obtain 5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-3-phenyl-1,2,4-oxadiazole. The yield was 51%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 124-125° C.
Reaction SMILES: C([O:3][C:4](=[O:18])/[CH:5]=[CH:6]/[C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:9])[CH3:8])C.[OH-].[Li+].C(OCC)(=O)C>O1CCOCC1.O>[C:14]([O:13][C:11]([NH:10][C:7]([CH3:9])([CH3:8])/[CH:6]=[CH:5]/[C:4]([OH:18])=[O:3])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)/C=C/C(C)(C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(/C=C/C(=O)O)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
(2E)-4-tert-Butoxycarbonylamino-4-methylpent-2-enoic acid ethyl ester (5.0 g, 19.4 mmol) was dissolved in dioxane (50 ml). A solution of lithium hydroxide (0.61 g, 25.3 mmol) in water (25 ml) was added. The solution was stirred for 16 h at 20° C. Ethyl acetate (75 ml) and water (20 ml) were added. The phases were seperated, and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were extracted with 1N sodium hydroxide solution (30 ml). The combined aqueous phases were acidified with iN sodium hydrogensulfate solution until pH=2. The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (magnesium sulfate) and the solvent removed in vacuo. The crude (2E)-4-tert-butoxycarbonylamino-4-methylpent-2-enoic acid was used for further syntheses.
Reaction SMILES: [OH-].[Na+].CC1(C)[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[CH2:12](OCC=C)[CH:13]1O[CH2:14]1>CCOCC>[C:13](=[C:9]([CH:7]([CH2:6][OH:5])[OH:8])[OH:10])([CH3:14])[CH3:12]
Reactant: CC1(C)OCC(CO)O1
Reactant: C=CCOCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)=C(O)C(O)CO
Temperature: 80 °C

Procedure:
A catalytic quantity of NaOH (MW 40.00; 0.6 mol-24 g) is added to 1.2-isopropylidene-rac-glycerol (MW 132.16; 16 mol-2115 g), which is rendered a solution by stirring and heating to 80° C. At 80° C., allyl glycidyl ether (MW 114.14; 6 mol-685 g) is added dropwise over a period of 2 hours, and the reaction mixture stirred for another 2 hours at 80° C. By this point in time the epoxide (Rf in ether=0.8) has reacted completely to form the G3 constituent (Rf in ether=0.6) The excess isopropylidene-rac-glycerol has an Rf of 0.65 in ether and is removed from the reaction mixture at 75° C./10 mbar. The residue has 1 l diisopropyl ether added to it and is extracted twice with 1 l NaCl (1% solution in H2O) in each case. The organic phase is rotated in an evaporator and distilled (Kpi10-1 mbar 125° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:25])=[O:5])[CH3:2].[CH3:27][N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[NH:28][CH3:27])[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)NC)c1)N2
Yield: 101.7 %

Procedure:
The mixture solution of 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 3.3 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (1.52 g, 4.0 mmol), triethylamine (2.0 mL), methylamine (228.1 mg, 5.8 mmol) in dry dichloromethane (20.0 mL) was stirred at room temperature for 1 hour, LC/MS showed that reaction finished completely. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4,4-dimethyl-2-(3-methylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.23 g, quant.) as a light yellow solid which was used for next step without further purification: MS (ESI) M+1=367.1.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH2:21])=[CH:16][CH:15]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1.C(Cl)Cl>[C:22]1([C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([I:11])[CH:10]=[C:2]([I:1])[C:3]=3[OH:12])=[CH:19][CH:18]=2)=[CH2:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cc(I)cc(I)c1O
Reactant: C=C(c1ccccc1)c1ccc(N)cc1
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: C=C(c1ccccc1)c1ccc(NC(=O)c2cc(I)cc(I)c2O)cc1
Yield: 43.2 %

Procedure:
To a refluxing solution of 7.9 g (0.02 mole) of 3,5-diiodosalicylic acid and 4.6 g (0.02 mole) of 1-(4-aminophenyl)-1-phenylethylene in 125 ml of chlorobenzene was added 3 g (0.022 mole) of phosphorus trichloride over a 1 hour period. The resulting mixture was refluxed for 2 hours, cooled, diluted with 100 ml of methylene chloride. The organic phase was washed with 250 ml of water and dried. The extract was evaporated to dryness. After redissolving the residue in minimum amount of methylene chloride, the solution was flash-chromatographed on a silica gel column. The desired component was eluted with 2 liters of methylene chloride/n-hexane. Evaporation of its solvent gave 4.9 g of N-[4-(1-phenylethenyl)phenyl] -2-hydroxy-3,5-diiodobenzamide. Recrystallization from aqueous ethanol gave 4.2 g of purified product, m.p. 173°-174°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Yield: 47.1 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g. 3.36 mmol) was reacted with 4-morpholinecarbonyl chloride (830 mg, 5.55 mmol) to provide 650 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide as a white powder, m.p. 193.4-194.6° C. Analysis: Calculated for C22H30N6O2: %C, 64.37; %H, 7.37; %N, 20.47; Found: %C, 64.00; %H, 7.32; %N, 20.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(F)(F)F)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the 2-methoxy-5-(trifluoromethyl)benzoic acid (0.68 g, 3.1 mmol) in thionyl chloride (10 mL) was warmed to reflux and was allowed to stir for 2 h. The mixture was cooled to ambient temperature, concentrated under reduced pressure and diluted with 10 mL toluene. This material was again concentrated under reduced pressure and was again diluted with 10 mL toluene. This concentration and dilution was repeated for an additional time and the crude acid chloride was carried on.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][CH:15]([OH:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]2[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.N.[H][H].ClCCl.CO>C(O)C.[Ni]>[NH2:28][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([CH:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][CH:15]([OH:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: NCc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
930 mg of 4-[1-(4-fluorophenyl)-3-(3-hydroxy-3-phenylpropyl)-4-oxo-azetidin-2-yl]-benzonitrile, dissolved in 100 ml of ethanol, are admixed with 4 ml of conc. ammonia and hydrogenated for 20 hours over Raney Ni, at room temperature and a hydrogen pressure of 20 bar. The catalyst is filtered off and the filtrate is concentrated under reduced pressure, giving, after chromatography (SiO2, dichloromethane/methanol=0:1), the product of molecular weight 404.5 (C25H25FN2O2); MS (DCl+): 405 (M+H+), 387 (M+H+−H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2(O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19]CC.[NH3:23].C(O)C.O>C(Cl)Cl>[NH2:23][C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: N
Reactant: CCCOc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COc1ccccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Reaction time: 16 h

Procedure:
10 g (32.45 mmol) of the intermediate product 2a were suspended in 100 ml methylene chloride. After the addition of 100 ml 2-molar ethanol ammonia solution, the reaction mixture was stirred for 16 h. After this, everything was poured on to icy water and the organic phase was separated. The aqueous phase was cooled, wherein a white crystallizate formed, which was isolated. 5.7 g of the product were obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].Cl.[CH2:22]([O:24][C:25](=[O:37])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=1)[NH2:27])[CH3:23].[CH3:38]N1CCOCC1>ClCCl>[CH:25]([O:37][CH:13]([CH3:12])[CH3:14])([CH3:26])[CH3:38].[CH2:22]([O:24][C:25](=[O:37])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=1)[NH:27][S:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][N:5]([C:3](=[O:4])[C:2]([F:20])([F:19])[F:1])[CH2:6]2)=[CH:11][CH:10]=1)(=[O:17])=[O:16])[CH3:23]
Reactant: CN1CCOCC1
Reactant: CCOC(=O)[C@@H](N)Cc1cccc(C#N)c1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Yield: 194.6 %

Procedure:
2-Trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulphonyl chloride (Preparation 1; 7.72 g, 23.6 mmol) was added to a stirred, ice-cooled solution of 3-cyano-(S)-phenylalanine ethyl ester hydrochloride (Preparation 9; 6.0 g, 23.6 mmol) and N-methylmorpholine (5.0 g, 49.5 mmol) in dichloromethane (130 ml). After 18 hours at room temperature the reaction mixture was washed successively with water, 5% aqueous citric acid solution, water and saturated brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was dissolved in the minimum volume of dichloromethane. Treatment of this solution with diisopropyl ether provided the title compound (11.7 g) as a gum. Rf 0.56 (SS 8). m/e 510.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:22]([O:31][CH2:32][CH2:33][OH:34])[N:21]=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[Br:35][C:36]1[CH:37]=[N:38][C:39](Cl)=[N:40][CH:41]=1.Cl>CC(N(C)C)=O.O1CCCC1>[Br:35][C:36]1[CH:37]=[N:38][C:39]([O:3][CH2:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[C:23]([C:24]4[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[C:22]([O:31][CH2:32][CH2:33][O:34][C:39]4[N:40]=[CH:41][C:36]([Br:35])=[CH:37][N:38]=4)[N:21]=[CH:20][N:19]=3)(=[O:15])=[O:16])=[CH:10][CH:9]=2)([CH3:7])[CH3:6])=[N:40][CH:41]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)CO)cc3)ncnc2OCCO)cc1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)COc4ncc(Br)cn4)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 33.8 %

Procedure:
To a suspension of sodium hydride (65 mg) in dimethylacetamide (0.5 ml) and tetrahydrofuran (0.5 ml) is added dropwise a solution of 4-(2-hydroxy-1,1-dimethylethyl)-N-{6-[2-hydroxyethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (135 mg) in dimethylacetamide (2 ml) and THF (2 ml) solution over period of 5 minutes at room temperature, and thereto is added 5-bromo-2-chloropyrimidine (399 mg). The mixture is stirred at room temperature for 6 days. The reaction mixture is acidified with cold diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The oily residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=100:1), and evaporated to remove the solvent. The resulting crude crystals are recrystallized from methylene chloride/isopropyl ether to give 4-[2-(5-bromopyrimidin-2-yloxy)-l, 1 -dimethylethyl]-N-{6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (77 mg) as colorless crystals.