Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]=[C:14]1[S:18][CH2:17][C:16]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[NH:15]1)([CH3:3])[CH3:2].[CH2:23](Br)[CH:24]([CH3:26])[CH3:25]>>[CH2:23]([N:15]1[C:16]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:17][S:18][C:14]1=[N:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: CC(C)CBr
Product: CC(C)CN1C(=Nc2ccc([N+](=O)[O-])cc2C(C)C)SCC12CCCC2

Procedure:
2-Isoropylaniline was converted to 2-isopropylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-isopropyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-isopropyl-4-nitroaniline. The aniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.[N:42]1([CH2:48][CH2:49][OH:50])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:45]3[CH2:46][CH2:47][N:42]([CH2:48][CH2:49][OH:50])[CH2:43][CH2:44]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: OCCN1CCNCC1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H43N5O5SCl2 [(M+H)+] 728.2435, observed 728.2431.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH:21]=3)=[CH:12]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1NS(C)(=O)=O
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1NS(C)(=O)=O
Yield: 17.2 %

Procedure:
According to Scheme 3 Method A: The title compound was prepared from 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 1.80 mmol, 0.55 g, Example 2 Step 1) and 4-methoxy-3-(methylsulfonamido)phenylboronic acid (1.1 eq, 2.00 mmol, 0.49 g) according to the procedure described for Example 1 Step 3. Reaction conditions: 4 hours at 80° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt (90/10) then recrystallized from pentane/Et2O to afford N-(5-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-2-methoxyphenyl)methanesulphonamide (0.31 mmol, 0.32 g, 41%) as a white solid.
Reaction SMILES: O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[CH:19]([O:24][CH3:25])([O:22][CH3:23])OC.O=[C:27]1C[CH2:30][CH:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:28]1>CCCCC>[CH3:25][O:24][C:19]1([O:22][CH3:23])[CH2:27][CH2:28][CH:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30]1
Reactant: COC(OC)OC
Reactant: COC(=O)CC1CCC(=O)C1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: CCCCC
Solvent: O
Product: COC(=O)CC1CCC(OC)(OC)C1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Tetrahedron, 57 (2001), 5183. A mixture of Montmorillonite K10 (188 g, 571 mmol) in trimethyl orthoformate (316 mL, 2856 mmol) was stirred for 2 hrs under nitrogen. To the mixture was slowly added methyl 2-(3-oxocyclopentyl)acetate (89.2 g, 571 mmol), as a suspension in pentane (500 mL). The mixture was stirred for 16 hrs, then filtered through a CELITE® pad rinsing with pentane. The filtrate was concentrated under reduced pressure to afford the title compound (104.9 g, 519 mmol, 91% yield) as an amber oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.67 (3 H, s) 3.20 (6 H, s) 2.35-2.46 (3 H, m) 2.11 (1 H, dd, J=13.18, 7.40 Hz) 1.86-1.96 (2 H, m) 1.74-1.83 (1 H, m) 1.44 (1 H, dd, J=13.05, 8.53 Hz) 1.34 (1 H, dd, J=12.55, 8.78 Hz). 13C NMR (101 MHz, CDCl3) δ ppm 172.73, 110.91, 50.93, 48.80, 48.61, 40.27, 39.66, 33.51, 33.25, 29.37.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.I[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1I
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 2-iodoanisole according to the general procedure C. Obtained as a yellow solid (735 mg).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].COC(=O)C1C=CC(C(OC)=O)=CC=1OC1C=CC=CC=1OC>>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[CH:13][C:4]2[C:3](=[O:22])[C:20]3[C:15]([O:14][C:5]=2[CH:6]=1)=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=3)=[O:9]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2C)c1
Agent: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2OC)c1
Product: COC(=O)c1ccc2c(=O)c3cccc(C)c3oc2c1

Procedure:
Using an adaptation of the method described in Procedure 15, substituting 2-o-tolyloxy-terephthalic acid dimethyl ester, 1h for 2-(2-methoxyphenoxy)-terephthalic acid dimethyl ester, 1c, the title compound 5-methyl-9-oxo-9H-xanthene-3-carboxylic acid methyl ester, 2h was obtained. MS m/z (MH+) 269.0.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][N:24]=[C:25]1[CH:29]([CH2:30][NH2:31])[CH2:28][NH:27][CH2:26]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH:29]([CH2:30][NH2:31])[C:25](=[N:24][O:23][CH3:22])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CON=C1CNCC1CN
Product: CON=C1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1CN
Yield: 39.9 %

Procedure:
143 mg (0.5 mmole) of 1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 205 mg (0.55 mmole) of 4-aminomethylpyrrolidin-3-one O-methyloxime ditrifluorcacetate were refluxed for 4 hours under heating according to the same manner as Example 177. Then, the reaction solution was concentrated and the residue was purified with preparative HPLC to obtain 84 mg (Yield: 40%) of the title compound.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2)([O-:5])=[O:4].Br[CH2:16][CH2:17][CH3:18]>CN(C=O)C.O.CCOC(C)=O>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)([O-:5])=[O:4]
Reactant: CCCBr
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN1CCc2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h

Procedure:
0.51 g (12.79 mmoles) of 60% NaH is added, at 20° C., by portions, to a solution of 2 g (12.18 mmoles) of 5-nitroindoline in 16 ml of anhydrous DMF. After stirring for a further 30 minutes, 2.32 ml (25.58 mmoles) of 1-bromopropane is added dropwise. Stirring is maintained overnight and the reaction mixture is finally diluted with 50 ml of water and 50 ml of AcOEt. After stirring and decanting, the organic phase is successively washed with 25 ml of water and 25 ml of salt water, dried over Na2SO4, filtered and concentrated to dryness under vacuum. The evaporation residue is then purified on a silica column (eluent: Heptane/AcOEt: 9/1). Orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[C:12]([C:19](=[O:21])[CH3:20])[CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:16][C:15]1[CH:14]=[CH:13][C:12]([C:19](=[O:21])[CH3:20])=[CH:11][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(N)c(Nc2ccc(F)cc2F)c1
Reaction time: 1 h
Yield: 22.3 %

Procedure:
A mixture of 3'-(2,4-difluorophenylamino)-4'-nitroacetophenone (8.5 g), iron powder (8 g), and ammonium chloride (0.8 g) in ethanol (100 ml) and water (50 ml) was refluxed with stirring for 1 hour. The insoluble was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated. The residual oil was purified by column chromatography on silica gel (150 g) eluting with a mixture of toluene and ethyl acetate (20:1) to give a powder of 4'-amino-3'-(2,4-difluorophenylamino)acetophenone (1.7 g).
Reaction SMILES: [C:1]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]>C(O)C.O1CCOCC1.[C].[Pd]>[C:1]([NH:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)NNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C(=O)NNc1ccc(N)cc1
Yield: 96.4 %

Procedure:
Then, 25.3 g of the resulting 1-ethoxalyl-2-(p-nitrophenyl)hydrazine was dissolved in a mixed solvent of 300 ml ethanol and 200 ml dioxane. To the solution was added 20 g of 10% palladium-carbon to carry out catalytic reduction in the conventional manner to obtain 21.5 g of 1-ethoxalyl-2-(p-aminophenyl)hydrazine. m.p. 97°-99° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:32][C:33]1[S:37][C:36]([C:38]2[CH:39]=[N:40][N:41]([CH3:46])[C:42]=2[C:43]([OH:45])=O)=[N:35][C:34]=1[CH:47]([F:49])[F:48].[C:50]1([C:56]2[N:57]=[C:58]3[CH:63]=[C:62]([NH2:64])[CH:61]=[CH:60][N:59]3[CH:65]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C)C=O>[Cl:32][C:33]1[S:37][C:36]([C:38]2[CH:39]=[N:40][N:41]([CH3:46])[C:42]=2[C:43]([NH:64][C:62]2[CH:61]=[CH:60][N:59]3[CH:65]=[C:56]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:57]=[C:58]3[CH:63]=2)=[O:45])=[N:35][C:34]=1[CH:47]([F:49])[F:48]
Reactant: Cn1ncc(-c2nc(C(F)F)c(Cl)s2)c1C(=O)O
Reactant: Nc1ccn2cc(-c3ccccc3)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc(-c2nc(C(F)F)c(Cl)s2)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.4 %

Procedure:
Diisopropylethylamine (0.30 ml) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (276 mg) were added to an N,N-dimethylformamide (0.72 ml) solution of the 4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (42 mg) obtained in (Example 1.7) <Step 2>. The obtained mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. Thereafter, 2-phenylimidazo[1,2-a]pyridin-7-amine (30 mg) was added to the reaction solution, and the obtained mixture was then stirred at 60° C. for 1 hour. Thereafter, the reaction solution was fractionated and purified by LC/MS to obtain the title compound (1 mg) in the form of a light brown solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15](Cl)=[O:16].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][C:15]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=2)=[O:16]
Reactant: Nc1nccs1
Reactant: CC(C)c1ccc2ncc(C(=O)Cl)c(O)c2c1
Product: CC(C)c1ccc2ncc(C(=O)Nc3nccs3)c(O)c2c1
Yield: 10.5 %

Procedure:
Using the procedure of Example 1, 10.74 g of the product of Step D and 3.9 g of 2-amino-thiazole were reacted to obtain 1.28 g of N-(2-thiazolyl)-4-hydroxy-6-isopropyl-quinoline-3-carboxamide melting above 340° C.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:24]CC)[CH:6]([PH:10]([CH2:12][S:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)=[O:11])C(C)C)C.[OH-].[Na+].CO.[CH2:33]1[CH2:37]OC[CH2:34]1>>[OH:24][C:5]([CH2:6][PH:10]([CH2:12][S:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)=[O:11])([CH2:27][CH:33]([CH3:37])[CH3:34])[C:4]([OH:3])=[O:28]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)(OCC)C(C(C)C)[PH](=O)CSc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(O)(C[PH](=O)CSc1ccc2ccccc2n1)C(=O)O

Procedure:
2-(Ethoxy)(quinolin-2-ylthiomethyl)phosphinoyl-methyl-4-methylpentanoic acid ethyl ester (4.5 g) was dissolved in 100 mL THF and 12.5 mL of 2N NaOH was added together with enough methanol to make the solution homogeneous. After 18 hours the THF was removed by evaporation, the residue diluted with 50 mL H2O and washed with 50 mL ethyl acetate. The aqueous phase was then acidified to pH 4, and the product extracted with 50 mL ethyl acetate (2×). The ethyl acetate was washed with 20 mL brine, dried with MgSO4 and evaporated to yield 3.8 g of 2-(hydroxy)(quinolin-2-ylthiomethyl)phosphinoylmethyl-4-methylpentanoic acid as a yellow oil, MS: 368 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S-:7])=[CH:3][CH:2]=1.[K+].Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[O:19][CH3:20]>CN(C)C=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([S:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:11]([O:19][CH3:20])[CH:12]=1)([O-:18])=[O:17]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: [S-]c1ccncc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1Sc1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A solution of potassium 4-pyridinethiolate (20.00 g, 134 mmol) and 2-chloro-5-nitroanisole (20.91 g, 112 mmol) in dimethylformamide (80 mL) was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and a brown solid was collected by filtration. The solid was stirred with 3N HCl (400 mL) for 30 minutes, and the solution filtered. The filtrate was basified with ammonium hydroxide with cooling in an ice bath. Filtration of the basic solution yielded the title anisole as an orange solid (26.23 g, 90%); mp 133°-135° C. 1H-NMR (300 MHz, d6-DMSO): 3.95 (s, 3H, OCH3) 7.24 (dd, 2H, J=4.6, 1.7 Hz, aromatic) 7.53 (d, 1H, J=8.3 Hz, aromatic) 7.88 (dd, 2H, J=8.3, 2.3 Hz, aromatic) 8.48 (dd, 2H, J=4.7, 1.3 Hz, aromatic). MS (CI, CH4): 263 (M+1). Analysis for C12H10N2O3S: Calculated: C, 54.95; H, 3.84; N, 10.68. Found: C, 54.81; H, 3.92; N, 10.70.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[CH:20]([CH:23]1[NH:28][CH2:27][CH2:26][NH:25][C:24]1=[O:29])([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:29])[CH:23]3[CH:20]([CH3:22])[CH3:21])[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)C1NCCNC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)C1C(=O)NCCN1Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (212 mg, 0.75 mmol), 3-isopropylpiperazin-2-one (128 mg, 0.90 mmol) and powdered 4 Å molecular sieves in DCE (18 mL) were stirred at RT. After 4 h, sodium triacetoxyborohydride (318 mg, 1.50 mmol) was added and the resulting mixture stirred for a further 17 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. Trituration of the resulting residue with EtOAc gave 4-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3-isopropylpiperazin-2-one as a yellow oil (198 mg, 65%). LCMS (Method H): RT=2.82 min, [M+H]+ 408.4
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16]([C:18]2[C:27]([NH:28]C(=O)OCC3C=CC=CC=3)=[CH:26][C:25]3[C:20](=[CH:21][C:22]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][C:40]4=[O:45])=[CH:23][CH:24]=3)[N:19]=2)=[O:17])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:28][C:27]1[C:18]([C:16]([NH:15][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:4]2[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([NH2:1])[CH2:3]2)=[O:17])=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][C:40]1=[O:45])[CH:21]=2
Reactant: [H][H]
Reactant: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4=O)ccc3cc2N)C1

Procedure:
A mixture of benzyl [2-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3-oxomorpholin-4-yl)quinolin-3-yl]carbamate (0.0067 g, 0.011 mmol) in 3.0 mL of MeOH was hydrogenated in the presence of 8 mg of 10% Pd on carbon under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C25H30N7O3 [M+H]+: m/z=476.2. found: 476.3.
Reaction SMILES: N1C=CN=C1N[C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][S:56]([C:59]1[CH:66]=[CH:65][C:62]([CH2:63][NH2:64])=[CH:61][CH:60]=1)(=[O:58])=[O:57]>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:55][S:56]([C:59]1[CH:66]=[CH:65][C:62]([CH2:63][NH:64][C:7]([C:9]2[C:17]3[N:16]=[C:15]([NH:18][C:19]([C:21]4[N:22]=[CH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:20])[NH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:61][CH:60]=1)(=[O:57])=[O:58]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cccc3[nH]c(NC(=O)c4cc5ccccc5cn4)nc23)cc1
Yield: 33.4 %

Procedure:
100 mg (0.3 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (from Example 58) was reacted with 130 mg (0.33 mmol) of HBTU and 55 mg (0.3 mmol) 4-methanesulfonyl-benzylamine in 3.0 mL of DMF and 1.0 mL of DIEA as described in general procedure A. After the usual work up as described in general procedure A, 50 mg (33%) of isoquinoline-3-carboxylic acid [4-(4-methanesulfonyl-benzylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was isolated. LCMS: 500 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].Cl[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:16]1([CH:13]([O:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[O:4][CH2:5][C:6]#[N:7])[C:14]#[N:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CCOc1ccccc1O
Reactant: N#CC(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccccc1OC(C#N)c1ccccc1

Procedure:
A mixture of 2-(2-hydroxyphenoxy)acetonitrile (14.9 g., 0.1 mole), 2-chloro-2-phenylacetonitrile (15.2 g., 0.1 mole), finely powdered potassium carbonate (13.8 g., 0.1 mole) and 80 ml. of acetone is refluxed 3 hours. The mixture is then treated with 2-chloro-2-phenylacetonitrile (7.6 g., 0.05 mole) and potassium carbonate (6.9 g., 0.5 mole) and refluxed six hours. The mixture is filtered, the solids washed with acetone and the combined filtrate evaporated in vacuo to give an oil. Crystallization of the oil affords 2-phenyl-2-(2-cyanomethoxyphenoxy)acetonitrile.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30]Cl)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[I-:32].[Na+]>CC(=O)CC>[CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][I:32])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCl)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 76.9 %

Procedure:
A solution of 2-(5-cholesten-3β-yloxy)ethyl chloride (17 g, 38 mmol) and sodium iodide (8.5 g, 57 mmol) in 2-butanone (200 ml) is heated for 5 hours under reflux. The mixture is concentrated to a residue which is partitioned between chloroform and water. The organic layer is washed with sodium thiosulfate, water, dried and evaporated to dryness. Crystallization from ether-methanol affords 2-(5-cholesten-3β-yloxy)ethyl iodide (15.8 g, 77%), m.p. 86°-88°.