Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)[CH:8]=1.[C:26]([C:28]1[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)[CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(COc2cc(F)ccn2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3cc(F)ccn3)cc2)no1
Temperature: 50 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(4-fluoro-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (200 mg, 0.679 mmol) described in Manufacturing Example 59-1-5 and 3-ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (237 μL, 1.7 mmol) at room temperature, which was stirred for 4 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (57 mg, 22%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].[CH2:11]1[O:13][CH:12]1[CH2:14][OH:15].N1C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH:12]([OH:13])[CH2:14][OH:15])[CH3:2]
Reactant: CCOc1ccccc1O
Reactant: OCC1CO1
Solvent: c1ccncc1
Solvent: CCO
Product: CCOc1ccccc1OCC(O)CO
Yield: 65.6 %

Procedure:
A solution of 41.5 g (0.3 mole) of 2-ethoxyphenol, 29.6 g (0.4 mole) of glycidol, 2 ml of pyridine and 150 ml of absolute ethanol was heated at reflux temperature for 18 hr. The mixture was concentrated to a thick oil that crystallized slowly over several days. The crude product was chromatographed on a silica gel column (1.2 kg) using increasing portions of acetone in methylene chloride to elute the product. The desired fractions were combined and concentrated to give a yellow oil that crystallized on standing. The solid was triturated with petroleum ether and the mixture filtered to obtain 41.8 g of solid. Recrystallization from carbon tetrachloride yielded 37.2 g (58%) of white solid, mp 64°-65° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2O)([O-:3])=[O:2].C(N(C(C)C)C(C)C)C.P(Cl)(Cl)([Cl:26])=O>ClC(Cl)C>[Cl:26][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Temperature: 80 °C

Procedure:
To a solution of 6-nitroquinazolin-4-ol (4.40 g, 23.01 mmol) and N-ethyl-N-isopropylpropan-2-amine (11.89 g, 92.04 mmol) in dichloroethane (50 mL) was added phosphoryl trichloride (7.06 g, 46.02 mmol). After heating to 80° C. for 16 hours, the mixture was concentrated under reduced pressure. The residue was concentrated again with toluene (2×100 mL) to provide the product.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:26])[CH2:24][CH3:25])[CH2:18][CH2:17]2)[CH2:3]1.[BH4-].[Na+].[Cl-:30].[NH4+]>CO>[ClH:30].[CH3:27][C:2]1([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([OH:26])[CH2:24][CH3:25])[CH2:18][CH2:17]2)[CH2:3]1
Reactant: CCC(=O)CN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Reactant: [Cl-]
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(O)CN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Product: Cl
Reaction time: 1 h

Procedure:
To a mixture of 1-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}butan-2-one (298 mg, 0.802 mmol) produced as an intermediate in Example 25 and methanol (3 mL) was gradually added sodium borohydride (36.4 mg, 0.962 mmol) at an external temperature of room temperature, followed by stirring for 1 hour under the same conditions. Aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was stirred overnight and the mixture was made basic with aqueous solution of potassium carbonate, and extraction was performed with ethyl acetate. The separated organic layer was concentrated under reduced pressure to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 269 mg of the free form of the title compound as a colorless solid. The free form of the title compound (20 mg, 0.054 mmol) was dissolved in a mixed solvent of ethanol and ethyl acetate, and then a 4N solution of hydrogen chloride in ethyl acetate (0.015 mL, 0.059 mmol) was added. The mixed solution was concentrated under reduced pressure and the resulting solid residue was washed with a mixed solvent of diethyl ether and heptane and then dried under reduced pressure to give 20 mg of the title compound as a colorless solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1>ClCCl>[NH+:12]1([O-:9])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: ClCCl
Product: [O-][NH+]1C=Cc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-chloroperbenzoic acid (224.3 g) in dichloromethane (1500 mL) was cooled to 0° C. To this a solution of 1H-pyrrolo[2,3-b]pyridine (59.1 g) in dichloromethane (500 mL) was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated, diluted with methanol (1500 mL) and treated with 10% potassium carbonate in water (300 mL). The slurry was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on neutral alumina with 20% methanol in dichloromethane to give the title compound as a tan solid (47.0 g). MS: 135 (MH+). 1HNMR (CDCl3): δ 13.1 (s, 1H), 8.2 (d, 1H), 7.65 (d, 1H), 7.4 (d, 1H), 7.0 (m, 1H), 6.55 (d, 1H).
Reaction SMILES: [In].[NH2:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([CH:10]=[O:11])=[C:5]([Cl:12])[N:4]=1.[I-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C)C=O>[NH2:2][C:3]1[N:4]=[C:5]([Cl:12])[C:6]([CH:10]([OH:11])[CH2:17][CH:16]=[CH2:15])=[C:7]([Cl:9])[N:8]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: C=CCBr
Agent: [I-]
Agent: [In]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(O)c1c(Cl)nc(N)nc1Cl
Reaction time: 2 h
Yield: 74 %

Procedure:
Indium powder (45.81 g) was added to a mixture composed of 2-amino-4,6-dichloropyrimidine-5-carboaldehyde (63.83 g) and N,N-dimethylformamide (500 mL). Then, sodium iodide (99.66 g) was added at an internal temperature of 10° C. under cooling in an ice bath. Allyl bromide (67.5 mL) was added to the resulting mixture over 20 minutes. After confirming that the internal temperature once increased was decreased, the ice bath was removed and the mixture was stirred for two hours. The reaction mixture was concentrated to about 200 mL under reduced pressure. Then, ethyl acetate (1.5 L) and a saturated sodium bicarbonate solution (1 L) were added to the residue, followed by stirring. The mixture was filtered through Celite and the filtrate was separated. Then, the organic layer was sequentially washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated to about 150 mL under reduced pressure. Hexane was added to the resulting residue, followed by stirring. Then, the solid was collected by filtration to obtain the title compound (57.24 g, 74%) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1(C)[CH2:27][O:26][C:25]2=[CH:28][C:29]3OC[C:32]4([C:42]=3[CH:43]=[C:24]12)C1C(=CC=CC=1)NC4=O.ClCC1C=CC(OC)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:27][O:26][C:25]1[CH:28]=[CH:29][C:42]([CH2:32][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])=[CH:43][CH:24]=1
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: COc1ccc(CCl)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(chloromethyl)-4-methoxybenzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (56%) as a white solid: mp 120-121° C.; MS (ES+) m/z 400.2 (M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.C(OC(N[CH:35]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)[CH3:36])=O)(C)(C)C.[OH-:44].[Na+]>CN(C=O)C.CO>[C:7]([O:44][C:5]([NH:4][CH2:36][CH2:35][C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:42][CH:43]=1)=[O:26])([CH3:12])([CH3:8])[CH3:6]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: [OH-]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(1-tert.butoxycarbonylamino-ethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([C:12]#[N:13])=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.[Li]CCCC.CN([CH:43]=[O:44])C>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([C:12]#[N:13])=[C:10]([CH:43]=[O:44])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: N#Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
To a solution of THF (20 mL) was added N-[4-(4-amino-7-bromo-6-cyanopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea (230 mg, 0.430 mmol) which was cooled to −77° C. n-BuLi (2.5 M in hexanes, 0.86 mL, 2.15 mmol) was slowly added to the solution via syringe. The solution was stirred for 10 min and then DMF (0.20 mL, 2.58 mmol) was added. The cooling bath was removed and the reaction was allowed to warm to ambient temperature over the following 17 h. EtOAc (20 mL) and water (20 mL) were added to the reaction which was then transferred to a separatory funnel. The organic layer was washed with aq 1N NaOH (20 mL) followed by water (20 mL). The organic was isolated, dried (MgSO4), filtered, and concentrated to dryness yielding 207 mg (0.428 mmol, yield 99%) of product. 1H-NMR (DMSO-d6) δ 10.38 (s, 1H), 9.43 (s, 1H), 8.99 (d, J=2.7 Hz, 1H), 8.68 (br s, 1H), 8.61 (dd, J=6.8, 1.8 Hz, 1H), 8.27 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.52 (m, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.40 (m, 1H), 6.06 (br s, 1H); MS [M+H]+=484.1; LCMS RT=3.34.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].[CH2:25](N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:21]([CH:20]=[CH2:25])(=[O:23])=[O:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(N2CCNCC2)nc1-c1ccccn1
Solvent: ClCCl
Solvent: O
Product: C=CS(=O)(=O)N1CCN(c2ccc(Cl)c(-c3ccccn3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of 3-chloro-6-(piperazin-1-yl)-2,2′-bipyridine (197 mg, 0.717 mmol) in CH2Cl2 (7 mL) was added methanesulfonylchloride (0.0820 mL, 0.789 mmol) followed by triethylamine (0.110 mL, 0.789 mmol) and stirred at RT for 2 h. The reaction mixture was diluted with H2O (30 mL) and extracted with dichloromethane (2×30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude mixture was purified by column chromatography (10-50% ethyl acetate/heptane) and obtained the title compound as a white solid (68 mg, 26% yield). LCMS (M+H)+: 365.0.
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1C(=O)C2=CC=CC=C2C1=O)[CH2:3][PH:4]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([O-:8])[O:5][CH2:6][CH3:7].O.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C>[NH2:17][CH2:16][CH:2]([OH:1])[CH2:3][P:4]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=[O:8])[O:5][CH2:6][CH3:7]
Reactant: CCOC(OCC)[PH]([O-])(CC(O)CN1C(=O)c2ccccc2C1=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCOC(OCC)P(=O)(CC(O)CN)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g of ethyl 2-hydroxy-3-phthalimido-propyl(diethoxymethyl)phosphonite in 23 ml of isopropanol is added 4 ml of water. To this mixture is added 0.47 g of sodium borohydride and this is stirred for a period of 24 hours at room temperature. After this time 2.6 ml of glacial acetic acid are carefully added and the reaction heated to 80° for a period of 2 hours. After this time, the reaction is cooled to room temperature, the solvent evaporated under reduced pressure and the residue passed down a silica column using a mixture of one part ethyl acetate to one part ethanol as eluant. Ethyl 3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinate is obtained as colourless oil, 31P=+45.8 and +45.2 ppm (CDCl3).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[O:18][C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:29][CH:28]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (800 mg, 3.34 mM) and triethylamine (1.5 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-chiorophenyl isocyanate (641 mg/ml, 5.01 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally crystallized with methanol-ether (1:6) to give 8f as solid. Yield: 1.06 g, 80.70%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:26][O:27][NH:28][CH3:29].O>C1COCC1>[CH3:26][O:27][N:28]([CH3:29])[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred brown solution of 1H-indole-6-carboxylic acid (2.68 g, 16.6 mmol) in THF (25 mL) was added CDI (2.97 g, 18.3 mmol) and stirred at room temperature for 2 hours. The mixture was then cooled to 0° C. and O,N-dimethyl-hydroxylamine hydrochloride (1.95 g, 20.0 mmol) was added and stirred at room temperature over night. Water (50 mL) was added to the reaction and extracted with EtOAc (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give 1H-indole-6-carboxylic acid methoxy-methyl-amide as an oil (3.87 g, 114% crude yield): 1H NMR (CDCl3) δ 3.40 (s, 3H, NCH3), 3.59 (s, 3H, OCH3), 6.57-6.59 (m, 1H, Ar), 7.31-7.33 (m, 1H, Ar), 7.46-7.50 (m, 1H, Ar), 7.64 (d, J=8 Hz, 1H, Ar), 7.84 (s, 1H, Ar), 8.60 (brs, 1H, NH). The product was used in the next step without further purification.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.O.Cl>>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([CH:7]=[CH:8][C:1]=1[O:9][CH3:10])[C:20]([C:19]1[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=1)=[O:21]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccccc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(C(=O)c2ccc(F)cc2)cc1OC
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Veratrole (29.3 g) was added, while stirring, to a mixture of aluminum chloride (34 g) and 4-fluorobenzoyl chloride (35 g) which had been cooled to 0° C., and the resulting mixture allowed to stand for 12 hours at room temperature. It was then boiled for 1 hour. The reaction mixture was then decomposed with water/HCl and extracted with chloroform.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=[O:9])C=1Cl.[F:15][C:16]1[C:24]2[N:23]([CH3:25])[C:22]3[CH2:26][CH2:27][N:28]([CH2:30][C:31]4[N:32]=[CH:33][NH:34][C:35]=4[CH3:36])[CH2:29][C:21]=3[C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C1COCC1>[F:15][C:16]1[C:24]2[N:23]([CH3:25])[C:22]3[CH2:26][CH2:27][N:28]([CH2:30][C:31]4[N:32]=[CH:33][NH:34][C:35]=4[CH3:36])[C:29](=[O:9])[C:21]=3[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reaction time: 4 h
Yield: 20.5 %

Procedure:
A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (133 mg) in THF (4 ml) was added dropwise to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1Hpyrido[4,3-b]indole (70 mg) in THF (12 ml) at -10° under nitrogen, and stirring was continued for 4 h. Water (20 ml) was then added, and the resulting solution was left to stand overnight. Excess THF was removed in vacuo, and the resultant aqueous solution was extracted with ethyl acetate (3×50 ml). The combined, dried organic extracts were adsorbed onto silica and purified by FCC eluting with System A (100:10:1) to give the title compound (15 mg), m.p. 231.5°-233°.
Reaction SMILES: [OH-].[Na+:2].[NH2:3][C:4]1[CH:24]=[C:23]([Cl:25])[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=1>O.CO>[Na+:2].[NH2:3][C:4]1[CH:24]=[C:23]([Cl:25])[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([O-:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:13])(=[O:14])[CH2:12][C:6]=2[CH:5]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)[O-])cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium hydroxide (0.018 g, 0.47 mmol) in water (0.2 mL) was added to a solution of Example 2 (0.167 g, 0.47 mmol) in methanol (5 mL) and stirred at 25° C. for 15 min. The solvent was removed under vacuum, and dried to obtain the title compound. Yield: 0.16 g, (91%); 1H NMR (DMSO-d6, 300 MHz): δ 2.55 (s, 3H, CH3), 4.92 (s, 2H, CH2), 5.57 (s, 2H, NH2), 6.60 (m, 2H, Ar), 7.90 (s, 1H, Ar), 8.10 (s, 1H, Ar); MS: m/e (ES−) 352 (M−Na); analysis: C15H11ClNNaO5S.2H2O requires C, 43.75; H, 3.67; N, 3.40; Cl, 8.61; S, 7.79. found: C, 44.20; H, 3.34; N, 3.49; Cl, 9.25; S, 8.36%.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH3:11])[C:6]([N+:12]([O-:14])=[O:13])=[C:5](Cl)[N:4]=1.[CH3:16][SH:17]>C(N(CC)CC)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH3:11])[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([S:17][CH3:16])[N:4]=1
Reactant: CCNc1nc(SC)nc(Cl)c1[N+](=O)[O-]
Reactant: CS
Solvent: CCN(CC)CC
Product: CCNc1nc(SC)nc(SC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 g of 2-methylthio-6-chloro-5-nitro-4-ethylamino-pyrimidine are dissolved in 50 ml of absolute alcohol and 2.5 g of triethylamine are then added. Then 1 g of methylmercaptan is passed in at 25° to 30° C over a period of 10 minutes. The mixture is stirred at room temperature for 1/2 hour and subsequently evaporated by rotary evaporation. The residue is suspended in 50 ml of water and filtered off with suction and washed once with water. The product is dried in a water yet vacuum and at room temperature over phosphorous pentoxide for 16 hours to yield 2,6-di-methylthio-5-nitro-4-ethylamino-pyrimidine with a melting point of 149°-150° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]([CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[O:25])=[CH:19][CH:18]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1.O>CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:40]3[N:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[CH:9][CH:10]=2)[N:5]([CH:13]2[CH2:14][CH2:15][CH2:16]2)[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[O:25])=[CH:19][CH:18]=1)#[N:2]
Reactant: Clc1ncccn1
Reactant: CC(C)S(=O)(=O)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A mixture of 1-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-3-isopropylsulfonylurea (0.085 g, 0.2 mmol), Cs2CO3 (0.163 g, 0.5 mmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (2.0 mL) was stirred at 70° C. overnight. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate collected via filtration, washed with water and purified on silica gel (CH2Cl2/EtOAc, 8.5:1.5) to provide 1-{4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-3-isopropylsulfonylurea (0.061 g, 61%).
Reaction SMILES: CC(O)C[C:4]1[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1.[C:22]([O:25][C:26](=O)[CH3:27])(=[O:24])[CH3:23]>>[CH3:22][CH:17]([N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[CH:4]1)[CH:18]([CH3:19])[CH3:20].[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Cn1c(CC(C)O)nc2cnc3ccccc3c21
Product: CC(C)C(C)n1cnc2cnc3ccccc3c21
Product: CCOC(C)=O

Procedure:
Using the general method of Example 46, α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-ethanol (9.4 g, 33 mmol, Example 74) was reacted with acetic anhydride to provide the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.