Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CN(C)/[CH:5]=[CH:6]/[C:7]([C:9]1[S:13][C:12]([N:14]=CN(C)C)=[N:11][C:10]=1[CH3:19])=O.Cl.[F:22][C:23]([F:31])([F:30])[C:24]([CH3:29])([CH3:28])[C:25]([NH2:27])=[NH:26].O>COCCO>[CH3:19][C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[C:7]1[CH:6]=[CH:5][N:27]=[C:25]([C:24]([CH3:29])([CH3:28])[C:23]([F:31])([F:30])[F:22])[N:26]=1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)/C=C/N(C)C
Reactant: CC(C)(C(=N)N)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: Cc1nc(N)sc1-c1ccnc(C(C)(C)C(F)(F)F)n1
Temperature: 125 °C

Procedure:
Powdered sodium hydroxide (0.42 g) is added to a solution of N′-[5-((E)-3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (0.93 g, prepared as described by S. Wang et al J. Med. Chem. 2004, 47, 1662-1675.) and 3,3,3-trifluoro-2,2-dimethyl-propionamidine hydrochloride (0.54 g) in 2-methoxyethanol (7 ml) and the mixture is heated at 125° C. for 1 hour with stirring. The reaction mixture is cooled, water is added, and the aqueous layer is extracted 4-times with 10% methanol in dichloromethane. The combined organic layers are purified by reversed phase chromatography and sodium bicarbonate is added to the fractions containing the title compound to give a white precipitate, which is collected by filtration. HPLC/MS: retention time 1.47 minutes, M+H 303.1.
Reaction SMILES: C([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]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:32])([CH3:31])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)c3ccccc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 53.6 %

Procedure:
A mixture of 2-(3-benzoylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (984 mg, 2.3 mmol) in methanol (15 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 50° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-benzoylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (494 mg, 44%) as a white solid: LC/MS m/e calcd for C25H24N2O3 (M+H)+: 401.48, observed: 401.2.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[N:10](COCC[Si](C)(C)C)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[SiH](CC)(CC)CC>>[CH3:1][O:2][C:3]1([C:9]2[NH:10][CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)CCOCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC1(c2nc(C(F)(F)F)c[nH]2)CCOCC1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 2-(4-methoxytetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 217.1, 1.3 g, 3.42 mmol), trifluoroacetic acid (4 mL), Et3SiH (2 mL). The resulting solution was stirred overnight at 20° C., then quenched by the addition of 20 mL of water. The pH of the solution was adjusted to 8 with sodium hydroxide (1 M). The aqueous phase was extracted with 2×100 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 1 g (crude) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[C:6]([S:19](Cl)(=[O:21])=[O:20])=[C:5]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3.N.C([N:33](CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[C:6]([S:19](=[O:21])(=[O:20])[NH2:33])=[C:5]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: CCOC(=O)COc1cc(OC)c2c(c1S(=O)(=O)Cl)OC1(CCCCC1)CC2=O
Reactant: CCN(CC)CC
Agent: N
Solvent: ClCCl
Product: CCOC(=O)COc1cc(OC)c2c(c1S(N)(=O)=O)OC1(CCCCC1)CC2=O
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
A solution of ethyl 2-{(5-methoxy-8-chlorosulfonyl -3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]-7-yl)oxy}acetate (prepared in Preparation 70) (0.32 g, 0.74 mmol) in dichloromethane (4 ml) is added dropwise to a solution of liquid ammonia (2 ml, 80 mmol) and triethylamine (0.1 ml, 0.7 mmol) in dichloromethane (4 ml) at -25° to -20 ° C. After stirring at the same temperature for 30 minutes, the solvent is removed by distillation. The residue is placed on a silica gel column and eluted with a mixture of acetone and dichloromethane (1:1) to yield the title compound as a crystalline solid (0.173 g, yield 56.5%). Recrystallization from a mixture of ethyl acetate and ether gives a product having a melting point of 188°-190° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][C:23]([O:25]CC=C)=[O:24])[C:10]([O:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10](=[O:11])[O:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14])[CH2:22][C:23]([OH:25])=[O:24])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)c1ccccc1
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.5 %

Procedure:
Pd(Ph3p)4 (210 mg, 0.181 mmol) was added to a solution of 4-allyl 1-(2-phenylpropan-2-yl) (S)-2-((tert-butoxycarbonyl)amino)succinate (Compound 108) (710 mg, 1.81 mmol) in dichloromethane (20 ml)-acetic acid (1.08 ml)-N-methylmorpholine (0.541 ml), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=100/0→30/70) to afford (S)-3-((tert-butoxycarbonyl)amino)-4-oxo-4-((2-phenylpropan-2-yl)oxy)butanoic acid (Compound 109) (525 mg, 82%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[NH2:31])[CH2:20][CH:19]2[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].CO[CH:35]1[CH2:39][CH2:38][CH:37](OC)O1>C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH:35]=[CH:39][CH:38]=[CH:37]3)[CH2:20][CH:19]2[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3-n3cccc3)CC2O)CCCCC1)c1ccco1

Procedure:
The mixture of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol (3.0 g) obtained in Step 2 of Example 87 and 2,5-dimethoxytetrahydrofuran (0.96 ml) was refluxed in 80 ml of acetic acid for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with 70 ml of dichloromethane and washed with a saturated sodium bicarbonate and brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 1.8 g of the titled compound as white color.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:16]1[C:24]2[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[CH2:10][C:11](OCC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:16]1[C:24]2[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[CH2:10][CH2:11][OH:12]
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1Cl)c1c[nH]c2c(CSC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.34 g (5.54 mmol) of the compound from Example 38A in 20 ml of tetrahydrofuran was added dropwise to 19.4 ml (19.4 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran at RT under argon. The mixture was stirred at RT for 15 min and then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 2.00 g (95% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.[CH:29]12[CH2:35][CH2:34][CH:33]1[CH2:32][NH:31][CH2:30]2.[OH-].[K+].O>CN1CCCC1=O>[CH:29]12[CH2:35][CH2:34][CH:33]1[CH2:32][N:31]([C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:4][CH:3]=1)[CH2:30]2
Reactant: O=C(Nc1ccc(Cl)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: C1CC2CNCC12
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1ccc(N2CC3CCC3C2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 15.3 %

Procedure:
A mixture of 0.2 g (0.5 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide, prepared in step 3.1, of 0.0806 g (0.6 mmol) of 3-azabicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621) and of 0.0564 g (1.01 mmol) of potassium hydroxide in 0.5 ml of N-methylpyrrolidinone is heated for 90 minutes in a microwave oven regulated at 150° C. under 150 watts. The reaction mixture is subsequently poured into 20 ml of water. The mixture is extracted with three times 30 ml of ethyl acetate. The combined organic phases are washed with 30 ml of water, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting solid is subsequently purified by silica column chromatography, elution being carried out with a mixture of n-heptane and ethyl acetate. 35 mg of the expected product are thus isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:24])=[C:19]([CH:21]=[CH:22][CH:23]=2)[NH2:20])[CH:5]=[CH:4][N:3]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[S:33](Cl)(=[O:35])=[O:34]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:24])=[C:19]([NH:20][S:33]([C:27]3[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])(=[O:35])=[O:34])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)o1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluoroaniline (150 mg, 0.433 mmol) and 2,6-difluorobenzenesulfonyl chloride (184 mg, 0.865 mmol), the title compound was obtained as a white solid (135 mg, 59%). MS (ES): 522 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:27])[CH:6]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][N:8]([C:12](=[O:15])[CH2:13]Br)[CH2:9][C:10]#[CH:11]>C1COCC1>[CH3:3][O:4][C:5]([CH:6]1[CH2:7][N:8]([CH2:9][C:10]#[CH:11])[C:12](=[O:15])[CH2:13][N:16]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:27]
Reactant: C#CCN(CC(NC(=O)OCc1ccccc1)C(=O)OC)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCN1CC(C(=O)OC)N(C(=O)OCc2ccccc2)CC1=O
Reaction time: 0.67 h
Yield: 85.4 %

Procedure:
Sodium hydride (0.20 mg, 4.9 mmol) is added to a solution of 2-benzyloxycarbonylamino-3-(bromoactyl-prop-2-ynyl-amino)-propionic acid methyl ester (2.0 g, 4.8 mmol) in THF (50 mL) at 0° C. The solution is stirred for 40 minutes then quenched with saturated NH4Cl solution. The reaction mixture is concentrated in vacuo then diluted with CH2Cl2 and washed with brine. The organic layer is dried over, filtered and concentrated in vacuo. The crude product is purified by chromatography eluting with 50% EtOAc/hexanes to give the title product (1.4 g, 4.1 mmol). 1H NMR (CDCl3, 300 MHz) δ7.30 (m, 5H), 5.20 (s, 2H), 5.10 (m, 1H), 4.30 (dd, 1H), 4.25 (d, 2H), 4.08 (m, 1H), 4.00 (dd, 1H), 3.78 (dd, 1H), 3.78 (s, 3H), 2.25 (t, 1H).
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C=CC(C)=CC=3C)CC2)=O)=CC=1.COC1C=CC(CN2CC(C)NC2=O)=CC=1.[CH3:40][C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:42]=1[N:48]1[CH2:53][CH2:52][N:51]([C:54]([C:56]2[CH:61]=[CH:60][C:59]([N:62]3[CH:66]([CH3:67])[CH2:65][N:64](CC4C=CC(OC)=CC=4)[C:63]3=[O:77])=[CH:58][CH:57]=2)=[O:55])[CH2:50][CH2:49]1>>[CH3:40][C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:42]=1[N:48]1[CH2:53][CH2:52][N:51]([C:54]([C:56]2[CH:61]=[CH:60][C:59]([N:62]3[CH:66]([CH3:67])[CH2:65][NH:64][C:63]3=[O:77])=[CH:58][CH:57]=2)=[O:55])[CH2:50][CH2:49]1
Reactant: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ccc(C)cc5C)CC4)cc3)C2=O)cc1
Agent: COc1ccc(CN2CC(C)NC2=O)cc1
Agent: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)cc3)CC2)c(C)c1

Procedure:
Using (4-bromophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (149 mg) described in Preparation Example 170 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 506, the title compound (120 mg) was obtained via 3-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13](O)[CH2:12][CH:11]2[CH3:21])=[O:9])=[CH:6][C:5]=1[O:24][CH3:25])[CH3:2].[NH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([N:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28][CH2:27]3)[CH2:12][CH:11]2[CH3:21])=[O:9])=[CH:6][C:5]=1[O:24][CH3:25])[CH3:2]
Reactant: CCOc1ccc(C(=O)N2c3ccccc3C(O)CC2C)cc1OC
Reactant: c1ccc2c(c1)CCCN2
Product: CCOc1ccc(C(=O)N2c3ccccc3C(N3CCCc4ccccc43)CC2C)cc1OC
Yield: 35.8 %

Procedure:
Starting with 1-(4-ethoxy-3-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (600 mg, 1.76 mmol) prepared in Reference Example 19 and 1,2,3,4-tetrahydroquinoline (703 mg, 5.28 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (288 mg, yield: 36%) as a white crystal. (cis:trans=2:3)
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:8]([OH:13])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 55.8 %

Procedure:
14 g (0.048 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one and 61.8 g (0.143 mol) of formic acid/triethylamine (5:2 addition compound) were heated at 145° C. for 4 hours. The reaction mixture was allowed to cool and was concentrated in vacuo. The residue was taken up in dilute sodium hydroxide solution and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was suspended in hot cyclohexane, the suspension was filtered hot and the solid was dried. 7.9 g (56% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol of melting point 145°-147° C. were obtained.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N-]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a suspension of 1-(diphenylmethyl)azetidin-3-ol (12 g) and rhodium(II) acetate dimer (1.1 g) in toluene (150 mL) was added dropwise ethyl diazoacetate (6.28 g) at 80° C. The mixture was stirred at 80° C. for 3 hr. Furthermore, ethyl diazoacetate (6.28 g) was added dropwise at 80° C., and the mixture was stirred at 80° C. for 3 hr. The mixture was allowed to cool, and filtered through a silica gel short column. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (9.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:30]4[N:26]([C:23]5[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:34])[F:35])=[CH:25][CH:24]=5)[N:27]=[CH:28][CH:29]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(Cl)cc4)c3c2)cc1

Procedure:
The title compound, light brown solid (56 mg, 39%), MS (ISP) m/z=439.4 [(M+H)+], mp 198° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-chloro-phenyl)-1H-benzo[d]imidazole (intermediate H) (100 mg, 325 μmol) and 1-(4-trifluoromethyl-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate C) (91.6 mg, 358 μmol).
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:4]2[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[C:10]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:23]=1.[CH2:32]([CH2:34][NH2:35])[OH:33].O>CN1C(=O)CCC1>[CH3:22][C:17]1[C:16]([C:10]2[C:11]([O:14][CH3:15])=[CH:12][C:13]3[C:4]4[N:3]([C@@H:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH3:25])[C:2]([NH:35][CH2:34][CH2:32][OH:33])=[N:23][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: NCCO
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n([C@H](C)c3ccccc3)c12
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCO)n([C@H](C)c3ccccc3)c12
Temperature: 150 °C
Yield: 53 %

Procedure:
2-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline (for a preparation see Intermediate 12) (30 mg, 0.035 mmol) was dissolved in NMP (0.5 ml), ethanolamine (30 mg) was added and the mixture was heated at 150° C. for 30 min, then cooled, added to water (10 ml) and extracted with EtOAc (10 ml). The organic phase was washed with water (2×10 ml), dried and evaporated. The residue was dissolved in DCM (2 ml), loaded onto a 10 g silica column and eluted with 2M methanolic ammonia/DCM (0-10%). The product-containing fractions were evaporated in vacuo to give 2-({7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-yl}amino)ethanol (8.4 mg, 0.018 mmol, 53.0% yield) as a light brown glass. LCMS (formate) Rt 0.77 min, MH+ 458
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:28]=1.C(N(CC)CC)C>CS(C)=O.O>[F:22][C:20]([F:23])([F:21])[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:9]=[C:8]([CH:26]=[CH:25][CH:24]=2)[CH:7]=[C:4]2[CH2:5][CH2:6][N:1]([C:34]([NH:33][C:29]3[N:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:2][CH2:3]2)=[N:13][CH:14]=1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: FC(F)(F)COc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.8 %

Procedure:
To a solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(2,2,2-trifluoroethoxy)pyridine (0.2 g, 0.54 mmol) in DMSO (3 mL) was added phenyl pyridazin-3-ylcarbamate (0.118 g, 0.54 mmol) followed by triethylamine (0.235 mL, 1.692 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% acetone, 70% hexane) to give the title compound (0.141 g, 55%). 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.6 (s, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.54 (s, 1H), 7.33 (m, 2H), 7.01 (d, J=7.5 Hz, 1H), 6.91 (m, 3H), 6.41 (s, 1H), 4.35 (q, J=8 Hz, 2H), 3.74 (m, 2H), 3.65 (m, 2H), 2.62 (m, 2H), 2.48 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 158.95, 156.57, 154.55, 150.42, 138.82, 137.61, 134.35, 129.50, 128.19, 127.97, 125.07, 124.87, 124.15, 121.03, 118.80, 112.57, 67.60, 67.31, 67.03, 66.74, 45.65, 44.63, 35.75, 29.14; m/z (486.1, M+ H+); HPLC: 93.7%.
Reaction SMILES: [CH2:1]([CH:11]1[NH:16][CH2:15][CH2:14][CH2:13][S:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[S:26])[CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[C:20]([NH:24][C:25]([N:16]2[CH2:15][CH2:14][CH2:13][S:12][CH:11]2[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[S:26])[CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCCCCCCC1NCCCS1
Reactant: S=C=Nc1cccc(Br)c1
Product: CCCCCCCCCCC1SCCCN1C(=S)Nc1cccc(Br)c1

Procedure:
The procedure of Example 25 was repeated, except that the reactants consisted of 0.9 g. of 2-decyltetrahydro-2H-1,3-thiazine and 0.7 g. of 3-bromophenyl isothiocyanate. The product was recrystallized from ethanol to give N-(3-bromophenyl)-2-decyltetrahydro-2H-1,3-thiazine3-carbothioamide, m.p. 73°-4°. The following elemental microanalysis was obtained: