Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25]Cl)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1([S-:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+]>CN(C)C=O>[CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][S:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [S-]c1ccccc1
Reactant: ClCCCCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3c3c2ncn3CCCCSc2ccccc2)cc1
Temperature: 60 °C
Yield: 92.3 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N,N-dibenzyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (7.0 g, 15.38 mmol), sodium benzenethiolate (3.46 g, 26.15 mmol), and anhydrous dimethyl formamide (77 mL) under a nitrogen atmosphere. The reaction mixture was heated to 60° C. to give a heterogeneous mixture that was maintained at 60° C. for 4 hours at which time the starting material was completely consumed. The cooled solution was partitioned between ethyl acetate and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a colorless oil. The material was purified by chromatography over silica gel (80/20 hexanes/ethyl acetate) to provide N,N-dibenzyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (7.5 g, 14.19 mmol) as a colorless oil. MS (CI) for C34H32N4S m/z 529 (MH+), 439, 349
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH:11]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:12]2)=[CH:8][C:7]=1[C:22]([O:24]C)=O)[CH2:2][CH2:3][CH3:4].[CH3:26][NH:27]C=O.C[O-].[Na+].CO.Cl>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH:11]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:12]2)=[CH:8][C:7]=1[C:22]([NH:27][CH3:26])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(cc1C(=O)OC)CC(N(CCC)CCC)C2
Reactant: CNC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCOc1cc2c(cc1C(=O)NC)CC(N(CCC)CCC)C2
Temperature: 25 °C

Procedure:
To a mixture of methyl 6-butoxy-2-(dipropylamino)-2,3-dihydro-1H-indene-5-carboxylate (75, 0.35 g, 1 mmol) and N-methylformamide (0.59 g, 10 mmol) in DMF (10 mL) at 100° C. and 25% was added sodium methoxide in methanol (0.22 mL, 1 mmol) dropwise over a period of 10 min. The resulting mixture is cooled to room temperature and quenched with water (100 mL). The resulting solid was purified by chromatography to give an oil that was converted into the HCl salt and crystallized from EtOAc/MeOH to yield the title compound 82 as a white solid (m.p.129-130° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:14][C:15](=[O:16])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3.[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[C:25]1[CH3:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([N:11]2[CH2:10][CH2:9][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[C:15](=[O:16])[O:14]3)[CH2:13][CH2:12]2)=[O:34])=[C:25]1[CH3:36])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccc(Br)cc21
Product: Cc1c(C(=O)N2CCC3(CC2)OC(=O)c2cc(Br)ccc23)c2ccccc2n1Cc1ccccc1

Procedure:
Following the general procedure I as described above, the acylation of 5-bromo-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with 1-benzyl-2-methyl-1H-indole-3-carboxylic acid (preparation described in example 1), gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(O)c1ccccc1Br
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCc1ccccc1Br

Procedure:
Following General Procedure J and using 1-(2-Bromo-phenyl)-heptan-1-ol (1.86 g, 6.9 mmol), anhydrous dichloromethane (5 mL), trifluoroacetic acid (2.5 mL, 32.5 mmol) and triethyl silane (5 mL, 31 mmol) followed by flash column chromatography, the title compound was obtained (0.4 g, 23%).
Reaction SMILES: [CH2:1]([P:7](=[O:10])([OH:9])[OH:8])[CH2:2][P:3](=[O:6])([OH:5])[OH:4].C(Cl)(=O)C(Cl)=O.[F:17]/[CH:18]=[C:19]1/[C@H:20]([N:27]2[CH:34]=[CH:33][C:31]([NH2:32])=[N:30][C:28]2=[O:29])[O:21][C@H:22]([CH2:25]O)[C@H:23]/1[OH:24]>CN(C=O)C>[CH2:1]([P:7]([O:9][CH2:25][C@H:22]1[O:21][C@@H:20]([N:27]2[CH:34]=[CH:33][C:31]([NH2:32])=[N:30][C:28]2=[O:29])/[C:19](=[CH:18]/[F:17])/[C@@H:23]1[OH:24])(=[O:8])[OH:10])[CH2:2][P:3](=[O:5])([OH:4])[OH:6]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)/C2=C\F)c(=O)n1
Reactant: O=P(O)(O)CCP(=O)(O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Nc1ccn([C@@H]2O[C@H](COP(=O)(O)CCP(=O)(O)O)[C@@H](O)/C2=C\F)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.7 %

Procedure:
Ethylenediphosphonic acid (100 mg, 0.53 mmol) was treated with oxalyl chloride (2 mL, as solvent) and anhydrous DMF (0.1 mL, cat.). After heating at reflux for 10 minutes under an argon atmosphere a solution was obtained and after a further 3 h the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was coevaporated with anhydrous acetonitrile (3×10 mL). The residue was dissolved in anhydrous trimethyl phosphate (2 mL), cooled to −15° C. under an argon and (E)-2′-deoxy-2′-(fluoromethylene)cytidine (64 mg, 0.25 mmol) was added. After stirring for 2 h the reaction mixture was quenched with ice-cold TEAB solution (1.0 M, 5 mL) and stirred for 30 minutes. Purification by HPLC gave 2.9 mg of the titled compound 80.
Reaction SMILES: O1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.Cl.[F:9][CH2:10][CH2:11][NH2:12]>N1C=CC=CC=1>[F:9][CH2:10][CH2:11][N:12]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1
Reactant: NCCF
Reactant: O=c1ccocc1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1ccn(CCF)cc1
Yield: 88.6 %

Procedure:
500 mg (5.2 mmol) of 4H-pyran-4-on was dissolved in 5 ml of pyridine, 1.54 g (15.5 mmol) of 2-fluoroethylamine hydrochloride was added, and reacted at 70° C. for 4 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chlroform-methanol (10:1)) to obtain 650 mg of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A mixture under N2 in DMF (18 mL) of 4-iodophenol (2.00 g, 9.09 mmol), 4-fluorophenylboronic acid (1.40 g, 10.0 mmol), cesium carbonate (4.44 g, 13.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.23 mmol) was stirred for 10 minutes at ambient temperature and then overnight at reflux. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and extracted twice with water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (10:1, then 5:1 hexanes-ethyl acetate) gave 4-(4-fluorophenyl)phenol (0.79 g, 46%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[C:10]([C:14]1[CH:29]=[CH:28][C:17]([C:18]([NH:20][C:21]2[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[NH2:1][C:2]1[S:3][C:4]([C:7]([NH:27][C:22]2[C:21]([NH:20][C:18](=[O:19])[C:17]3[CH:28]=[CH:29][C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])=[CH:15][CH:16]=3)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:9])=[CH:5][N:6]=1
Reactant: Nc1ncc(C(=O)O)s1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cnc(N)s2)cc1
Yield: 12.7 %

Procedure:
Using the procedure described in Example 102, Part A, 2-aminothiazole-5-carboxylic acid (1.0 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.5 mmol) yielded 50 mg (13%) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@H:11]1[CH2:15][O:14][C:13](C)(C)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=O)C>>[CH2:1]([NH:8][C:9](=[O:10])[C@H:11]([O:12][CH3:18])[CH2:15][O:14][CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC[C@H](C(=O)NCc2ccccc2)O1
Reactant: CC(=O)O
Product: COC[C@@H](OC)C(=O)NCc1ccccc1
Yield: 85 %

Procedure:
A 50% aqueous acetic acid solution (30 mL) containing (R)-N-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxamide (1.22 g, 5.19 mmol) was heated at reflux (30 min). The solvents were evaporated in vacuo and the resulting residue was purified by silica gel column chromatography (10% MeOH-CHCl3) to obtain the desired product as a white solid (0.86 g, 85%); mp 83°-84° C., Rf 0.35 (10% MeOH-CHCl3); [α]23D=+35.4° (c=0.19, MeOH); IR (KBr) 3336, 1649, 1623, 1542, 1400, 1319, 1110, 1049, 972, 739, 697 cm-1 ; 1H NMR (DMSO-d6) δ 3.42-3.55 (m, CHH'OH), 3.53-3.64 (m, CHH'OH), 3.89-3.95 (m, CHOH), 4.28 (d, J=6.0 Hz, CH2Ph), 4.74 (t, J=5.7 Hz, CH2OH), 5.57 (d, J=5.4Hz, CHOH) 7.19-7.35 (m, PhH), 8.24 (t, J=6.0 Hz, NH); 13C NMR (DMSO-d6) 41.7 (CH2Ph), 64.0 (CH2OH), 73.1 (CHOH), 126.6 (C4 '), 127.2 (2C2 ' or 2C3 '), 128.2 (2C2 ' or 2C3 '), 139.6 (C1 '), 172.2 (C(O)NH) ppm; MS(+Cl) (rel. intensity) 196 (M+ +1, 100); Mr (+Cl) 196.098 03 [M+ +1] (calcd. for C10H14NO3 196.097 37); Anal. (C10H13NO3) C, H, N.
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Cl.[OH:23][C:24]1[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([CH3:34])[C:24]=4[OH:23])[CH2:29]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc(-c2nc(C(=O)N3CCc4c(ccc(C)c4O)C3)c3ccccc3n2)cc1
Yield: 22 %

Procedure:
Reaction of 2-(4-methoxylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 26 (22% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.25 and 2.28 (2s, 3H), 2.81 and 3.04 (2t, 2H), 3.60 and 4.22 (2t, 2H), 3.93 (s, 3H), 4.49 and 5.09 (2s, 2H), 6.34-6.93 (m, 2H), 7.05-7.09 (m, 3H), 7.56-7.64 (m, 1H), 7.94-8.04 (m, 2H), 8.32-8.33 (m, 1H), 8.64-8.70 (m, 2H); MS (ESI) m/z 426 ([M+H]+).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14].C1COCC1.C([Li])CCC>O>[CH3:14][C:7]1([CH3:15])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:3]#[CH:2])[CH:5]=2)[S:10][CH2:9][CH2:8]1
Reactant: CC1(C)CCSc2ccc(C=C(Br)Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C

Procedure:
7.7 g (21.2 mmol) of 2,2-dibromo-1-(4,4-dimethylthiochroman-6-yl)ethylene and 80 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 17 ml (26.6 mmol) of an n-butyllithium solution (2.5M in hexane) were added dropwise at -78° C. and the mixture was permitted to heat to room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with heptane. 3.9 g (90%) of the expected acetylene derivative were recovered in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH2:23])=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)nn2-c2ccc(F)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazol-3-amine (0.8 g) and methanesulfonyl chloride (0.224 ml) in pyridine (8 ml) was stirred at ambient temperature for 2 hours. Pyridine was evaporated, and the residue was dissolved in ethyl acetate, washed with water and dilute hydrochloric acid, dried, and concentrated. The residual oil (1.1 g) was purified by column chromatography on silica gel (20 g) eluting with a mixture of toluene and ethyl acetate (2:1). The product (0.74 g) was recrystallized from ethanol to give pale brown crystals of N-{1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-pyrazolyl}methanesulfonamide (0.62 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)(=O)=O.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: COc1ccc(CCCOS(C)(=O)=O)cn1
Reactant: c1c[nH]cn1
Product: COc1ccc(CCCn2ccnc2)cn1
Yield: 94 %

Procedure:
In substantially the same manner as in Reference Example 88, 3-(2-methoxy-5-pyridyl)propyl methanesulfonate was reacted with imidazole to give 5-[3-(1-imidazolyl)propyl]-2-methoxypyridine. The yield was 94%. Oily substance.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[Cl:26][C:27]1[N:28]=[C:29]([C:34](O)=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:19]([O:18][C:16]([NH:15][C@H:3]1[C@H:2]([NH:1][C:34]([C:29]2[NH:30][C:31]([CH2:32][CH3:33])=[C:27]([Cl:26])[N:28]=2)=[O:35])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](NC(=O)OCc2ccccc2)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(=O)OCc2ccccc2)nc1Cl
Yield: 69 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl trans(±)-4-amino-3-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate obtained in Example (79c) (98 mg, 0.28 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (48 mg, 0.25 mmol), WSC hydrochloride (150 mg, 0.78 mmol) and HOBT (35 mg, 0.26 mmol), to obtain 88.2 mg of the title compound as a white solid (69%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH3:20])[CH2:11]1.N[C:22](N)=[O:23]>CC1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH3:20])[CH2:11]3)[C:22](=[O:23])[NH:1][C:2]=2[CH:7]=1
Reactant: NC(N)=O
Reactant: COC(=O)N1CCC(Nc2ccc(Cl)cc2N)CC1C
Solvent: Cc1ccccc1
Product: COC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1C
Temperature: 160 °C

Procedure:
A mixture of 36 parts of methyl 4-(2-amino-4-chlorophenylamino)-2-methyl-1-piperidinecarboxylate and 14 parts of urea is stirred and heated in an oil-bath at 160° C. for 4 hours. After cooling, the reaction mixture is disslved in methylbenzene. The solution is washed successively three times with water, twice with a diluted hydrochloric acid solution and again three times with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel, using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding methyl 4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-2-methyl-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[N:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[N:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: Cc1nccc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (89 mg 0.5 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (172 mg, 0.55 mmol) by refluxing in xylene according to the general procedure M. Obtained as a light yellow solid (131 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1.C1C(=O)N([Br:30])C(=O)C1.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:30][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:22])[CH3:1])[N:14]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)CCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.8 %

Procedure:
To a solution of 2-[(3-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (266 mg) in dry chloroform (3.15 mL) at 0° C. was added NBS (163 mg). The reaction was warmed to room temperature and was stirred for 5 h. The reaction was taken up into DCM (20 mL) and extracted with water (20 mL). The organics were separated, dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a green/brown solid (314 mg).
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[N:10]=[C:9]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27](Br)[CH:26]=3)[N:8]=2)[CH:2]=1.[CH:38](B(O)O)=[CH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[N:10]=[C:9]([C:25]3[CH:26]=[C:27]([C:43]4[CH:44]=[CH:45][C:40]([CH:39]=[CH2:38])=[CH:41][CH:42]=4)[CH:28]=[CH:29][CH:30]=3)[N:8]=2)[CH:2]=1
Reactant: Brc1cccc(-c2nc(-c3cccc(-c4ccccc4)c3)nc(-c3cccc(-c4ccccc4)c3)n2)c1
Reactant: OB(O)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(-c2cccc(-c3nc(-c4cccc(-c5ccccc5)c4)nc(-c4cccc(-c5ccccc5)c4)n3)c2)cc1
Temperature: 25 °C
Yield: 36 %

Procedure:
50 g (92.5 mmol) of 2,4-bisbiphenyl-3-yl-6-(3-bromophenyl)-1,3,5-triazine and 13.8 g (93.2 mmol) of styreneboronic acid [2156-04-9] are dissolved in 300 ml of toluene, and 100 ml of a 2 M sodium carbonate solution are added. The reaction mixture is carefully degassed, 200 mg of tetrakistriphenylphosphinepalladium are added, and the mixture is heated under reflux for 20 h. The solution is cooled to room temperature, and the phases are separated. The aqueous phase is extracted three times with toluene, the combined organic phases are subsequently washed twice with water, dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo. The residue is recrystallised from isopropanol, giving 18.8 g (33.3 mmol) (36%) of a white solid in a purity of 99.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:19])[C:14]([O:16]CC)=O.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24]>C(OCC)(=O)C.C(OCC)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:19])[C:14]([NH:24][CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])=[O:16]
Reactant: CCOC(=O)C(=O)Nc1cc(C(=O)OC)ccc1Cl
Reactant: COC(CN)OC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c(NC(=O)C(=O)NCC(OC)OC)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of methyl 4-chloro-3-{[ethoxy(oxo)acetyl]amino}benzoate (Example 330b, 11.2 g) dissolved in ethyl acetate (80 mL) was treated with aminoacetaldehyde dimethyl acetal (5.08 mL) under nitrogen. The resulting mixture was stirred at 20° C. for 3 h. The reaction mixture was diluted with diethyl ether (100 mL) and stirred at room temperature overnight. The solid formed was filtered off and dried under vacuum to afford the subtitle compound (12.64 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17])[CH3:2].[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24]>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:21]1[CH2:22][CH2:23][CH3:24])[CH3:2]
Reactant: CCOC(CNc1c(N)cnc2ccccc12)OCC
Reactant: CCCC(OC)(OC)OC
Product: CCCc1nc2cnc3ccccc3c2n1CC(OCC)OCC
Yield: 80.6 %

Procedure:
The general method described in Step 3 of Example 15 was used to cyclize N4-(2,2-diethoxyethyl)quinoline-3,4-diamine (26.5 g, 96.2 mmol) by reaction with trimethyl orthobutyrate (15.9 g, 107 mmol) to provide 1-(2,2-diethoxyethyl)-2-propyl-1H-imidazo[4,5-c]quinoline (25.4 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)([C:13]2[CH:18]=[C:17]([Cl:19])[N:16]=[C:15]([Cl:20])[CH:14]=2)[N:5]=1.[Cl:28][C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>O1CCCC1>[Cl:28][C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[C:30]=1[S:36]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:6]2([C:13]3[CH:14]=[C:15]([Cl:20])[N:16]=[C:17]([Cl:19])[CH:18]=3)[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([NH2:3])=[N:5]2)[CH:22]=1)(=[O:37])=[O:38]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: NC1=NC(c2cccc(O)c2)(c2cc(Cl)nc(Cl)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Oc1cccc(C2(c3cc(Cl)nc(Cl)c3)N=C(N)c3ccccc32)c1
Yield: 27.1 %

Procedure:
Aqueous sodium hydroxide (2.0 M, 0.559 ml, 1.12 mmol) was added to a solution of 3-(3-amino-1-(2,6-dichloropyridin-4-yl)-1H-isoindol-1-yl)phenol (Scheme #19, D, 0.069 g, 0.19 mmol) in tetrahydrofuran (1 mL) at 0° C. 5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.051 g, 0.22 mmol) was then added to the reaction mixture. After 30 minutes the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. Purification by flash chromatography using ethyl acetate followed by purification using preparative HPLC afforded 0.029 g (28% yield) of the title compound. 1H NMR (DMSO-d6) δ 7.87-7.77 (m, 2 H), 7.56-7.48 (m, 2 H), 7.41-7.34 (m, 2 H), 7.29 (s, 2 H), 7.12-7.01 (m, 3 H), 6.91 (d, J=1.77 Hz, 1 H), 3.74 (s, 3 H), 1.89 (s, 3 H); MS (AP) m/z 562 [M+1]+.