Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:34]=[CH:33][C:32]([N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[CH:40][CH:39]=2)=[CH:24][C:6]=1[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Product: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (10 mg, 0.029 mmol) and 4-morpholinobenzoic acid (7 mg, 0.035 mmol) similar to Example 136 and isolated as a white solid (4 mg, 26%). 1H NMR (CDCl3): 8.76 (dd, J=1.8, 4.2 Hz, 2H), 8.29 (dd, J=1.8, 4.2 Hz, 2H), 7.99 (s, 1H), 7.95 (s, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.37 (dd, J=1.8, 8.1 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.07 (s, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.73 (s, 1H), 3.89-3.86 (m, 4H), 3.31-3.28 (m, 4H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:18]3[C@@H:17]4[CH2:19][C@@H:16]4[CH2:15][C:14]=3[C:13]([C:20](O)=[O:21])=[N:12]2)[CH:6]=1)(=[O:4])=[O:3].[NH2:23][C@@H:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:25][OH:26]>>[OH:26][CH2:25][C@@H:24]([NH:23][C:20]([C:13]1[C:14]2[CH2:15][C@H:16]3[CH2:19][C@H:17]3[C:18]=2[N:11]([C:7]2[CH:6]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:10]=[CH:9][N:8]=2)[N:12]=1)=[O:21])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CS(=O)(=O)c1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Reactant: CC(C)(C)[C@H](N)CO
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cc(S(C)(=O)=O)ccn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using (1aR,5aR)-2-(4-(methylsulfonyl)pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (S)-2-amino-3,3-dimethylbutan-1-ol. LCMS m/z=419.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.44-0.48 (m, 1H), 1.05 (s, 9H), 1.23-1.28 (m, 1H), 2.21 (t, J=5.8 Hz, 1H), 2.26-2.32 (m, 1H), 2.79-2.85 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.04 (dd, J=16.6 and 6.3 Hz, 1H), 3.16 (s, 3H), 3.67-3.74 (m, 1H), 3.94-4.04 (m, 2H), 6.96 (d, J=9.2 Hz, 1H), 7.69 (dd, J=5.0 and 1.5 Hz, 1H), 8.38 (s, 1H), 8.72 (d, J=5.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:18][O:19][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)(=[O:40])=[O:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(c2ccccc2)c2cc(Br)ccc2OCc2ccccc2)cc1
Reaction time: 18 h
Yield: 93.6 %

Procedure:
A cooled (5° C.) solution of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropan-1-ol (108.0 g) in dichloromethane (300 ml) was treated with pyridine (79.4 ml) and then p-toluenesulphonyl chloride (60.6 g) in dichloromethane (200 ml). After 18 hrs. at room temperature the solvent was removed in vacuum and the residue was extracted with diethyl ether. The extract was washed with hydrochloric acid, water, and dried over anhydrous sodium sulphate to give (±)-toluene-4-sulphonic acid 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester as a light yellow oil after concentration under reduced pressure (140.3 g, 93.6% yield), tlc: (1) 0.66. NMR (CDCl3): 21.67, 33.67, 39.69, 68.58, 70.28, 113.21, 113.76, 126.47, 127.84, 128.10, 128.25, 128.41, 128.51, 129.81, 130.26, 130.42, 132.91, 134.39, 136.41, 142.16, 155.07.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][O:6][CH2:5][C@H:4]1[OH:8].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:8][C@@H:4]1[CH2:5][O:6][CH2:7][C@H:3]1[NH:2][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: O=C1NC(=S)CS1
Reactant: N[C@@H]1COC[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1N=C(N[C@@H]2COC[C@H]2O)CS1
Yield: 40.8 %

Procedure:
To a solution of trans-4-aminotetrahydrofuran-3-ol hydrochloride (1.00 g) in ethanol (30 mL) were added 4-thioxo-1,3-thiazolidin-2-one (954 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (3.87 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (591 mg).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].[CH:14]1([CH2:20]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([CH2:20][N:5]2[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]2[C:10]([O:12][CH3:13])=[O:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrCC1CCCCC1
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: COC(=O)c1c(C=O)c(C)c(C)n1CC1CCCCC1

Procedure:
The title compound was prepared as an orange oil in 79.60% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and cyclohexylmethyl bromide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([O:53][CH2:54][CH:55]([CH3:57])[CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CC(O)C.Cl>[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=5[F:30])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([O:53][CH2:54][CH:55]([CH3:57])[CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)COc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 170 °C
Yield: 37.5 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.12 g, 0.25 mmol) and 4-(1,4′-bipiperidin-1′-yl)-2-[(2-methylpropyl)oxy]aniline (0.081 g, 0.24 mmol) in anhydrous iPrOH (3 mL) was added HCl (2 drops, 37% weight in H2O). The reaction was heated at 170° C. for 33 min in the microwave. The reaction mixture was poured into half saturated NaCO3, extracted with DCM and EtOAc, dried (MgSO4) and concentrated. Purification by flash chromatography followed by prep-HPLC provided the title compound (0.07 g, 0.09 mmol, 36%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78 (d, J=6.6 Hz, 6H), 1.33-1.42 (m, 2H), 1.47 (s, 3H), 1.54 (d, J=11.7 Hz, 3H), 1.72-1.82 (m, 2H), 1.82-1.93 (m, 2H), 2.31 (s, 2H), 2.45 (s, 3H), 2.58-2.69 (m, 2H), 3.75 (d, J=6.2 Hz, 3H), 6.41-6.50 (m, 2H), 6.66 (s, 1H), 6.87-6.98 (m, 1H), 7.20 (t, J=8.2 Hz, 2H), 7.29 (d, J=10.6 Hz, 1H), 7.35-7.47 (m, 2H), 7.59 (t, J=7.9 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 8.20 (d, J=5.1 Hz, 1H), 8.32 (s, 1H), 8.43 (s, 1H), 9.31 (d, J=9.9 Hz, 1H), 10.23 (s, 1H). MS (M+H, ES+) 757.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:15][CH3:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C>[CH2:15]([N:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:26][CH:25]=1)[CH3:16]
Reactant: [H][H]
Reactant: CCN(Cc1ccc(OCc2ccccc2)cc1)c1ccc(C#N)cc1
Solvent: CCOC(C)=O
Product: CCN(Cc1ccc(O)cc1)c1ccc(C#N)cc1
Yield: 35.5 %

Procedure:
The procedure of Preparation Example 9 was repeated, except that 111 mg of 4-[N-(4-benzyloxybenzyl)-N-ethylamino]benzonitrile was used in place of 4-[N-(4-benzyloxybenzyl)-N-methylsulfonylamino]phenyl methanesulfonate, and 3 ml of ethyl acetate was used in place of dioxane. The resulting mixture was stirred for 4 hours under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove any insoluble matter, and the solvent was distilled off from the filtrate. The resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 29 mg of 4-[N-ethyl-N-(4-hydroxybenzyl)amino]benzonitrile.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: BrC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(C3CCCCC3)c3c2CCNCC3)cc1
Yield: 11.4 %

Procedure:
The title compound (15 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.40 mmol) using bromo-cyclohexane (1.5 mmol) in place of chloro-cyclobutane according to Example 238. MS (ESI): exact mass calculated for C19H24ClN3, 329.17; found, m/z 330.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.45-7.41 (m, 4H), 4.30-4.27 (m, 1H), 3.44-3.42 (m, 2H), 3.31-3.26 (m, 4H), 2.98-2.96 (m, 2H), 1.93-1.84 (m, 5H), 1.70-1.65 (m, 1H), 1.46-1.40 (m, 2H), 1.24-1.89 (m, 2H).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[Cl:22])[C:15](=[O:23])[C:14]2([CH3:25])[CH3:24])[CH:11]=[N:10][CH:9]=1)(C)(C)C.Cl.O1CCOCC1>CO.C([O-])(O)=O.[Na+]>[Cl:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[CH:13]([N:12]1[C:8]([CH2:7][OH:6])=[CH:9][N:10]=[CH:11]1)[C:14]([CH3:25])([CH3:24])[C:15]2=[O:23]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncn1C1c2c(Cl)cccc2C(=O)C1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)C(=O)c2cccc(Cl)c2C1n1cncc1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-4-chloro-2,2-dimethyl-indan-1-one (2.4 g, 5.9 mmol) in methanol (40 mL) is added a 4N solution of HCl in 1,4-dioxane (9 mL, 36 mmol). The reaction is permitted to stir for 30 minutes, at which time the reaction is cooled to 0° C. and diluted with saturated aqueous NaHCO3. The reaction mixture is then concentrated in vacuo to ca. one fourth of the original volume and diluted with ethyl acetate. The layers are separated and the aqueous layer is extracted two times with ethyl acetate. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:19) to furnish 4-chloro-3-(5-hydroxymethyl-imidazol-1-yl)-2,2-dimethyl-indan-1-one; HRMS: (ESI) m/z 291.0909 [(M+H)+: Calcd for C15H16N2O2Cl: 291.0909]; 1H NMR (400 MHz, CD3OD) δ ppm 0.91 (s, 3 H), 1.40 (s, 3 H), 4.80 (d, J=4.29 Hz, 2 H), 5.88 (s, 1 H), 6.89 (s, 1 H), 6.97 (s, 1 H), 7.69 (t, J=7.71 Hz, 1 H), 7.79-7.87 (m, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][C:34]2[NH:38][CH:37]=[N:36][N:35]=2)[CH2:28]1>>[O:18]=[C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:35]2[N:36]=[CH:37][N:38]=[C:34]2[N:33]1[CH:29]1[CH2:30][CH2:31][CH2:32][O:27][CH2:28]1
Reactant: c1nnc(NC2CCCOC2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCCOC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.37 g) and N-(tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine (0.088 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.15 g, 63%).
Reaction SMILES: [O:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19](Cl)=[O:20]>>[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([N:13]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([C:19](=[O:20])[CH2:18][C:17]([CH3:23])([CH3:22])[CH3:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:15][CH2:14]1)=[O:20]
Reactant: C1COCCNCCOCCOCCN1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCOCCOCCN(C(=O)CC(C)(C)C)CCOCC1

Procedure:
Analogously to Example 2 from 1,4,10-trioxa-7,13-diazacyclopentadecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:20][CH2:19][CH2:18]3)[CH:14]=[C:13]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O1CCCC1>CO>[N:17]1([C:15]2[CH:14]=[C:13]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:12]=[C:11]([S:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][CH:6]=3)[N:16]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(N3CCC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)O)cc3)n2)[nH]n1
Temperature: 25 °C
Yield: 109.8 %

Procedure:
A 50 ml round bottom flask equipped with a condenser was charged with 4-[4-azetidin-1-yl-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-benzoic acid methyl ester (800 mg, 2.0 mmol), 2M sodium hydroxide aqueous solution (5 ml), tetrahydrofuran (30 ml) and methanol (5 ml). The reaction mixture was heated to reflux for one hour. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The solid residue was taken up in methanol (30 ml) and concentrated hydrochloric acid (1 ml). The solvent was then removed under reduced pressure to give the title compound (0.84 g, 100%) as a mono HCl salt. 1H NMR (DMSO) 2.05-2.10 (3H, s), 2.20-2.30 (2H, m), 3.80-3.85 (2H, t), 4.05-4.10 (2H, S), 7.40-7.45 (2H, d), 7.85-7.90 (2H, d). MS (ES+): 383
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH2:10][C:11](O)([CH2:13][S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[CH:10]=[C:11]([CH2:13][S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(CSc3ccccc3)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(CSc3ccccc3)nc2-c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(phenylthio)methyl]-4,5-dihydro-1H-imidazole (1 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (70 mL) is heated to reflux for 48 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using hexane/ethyl acetate to give 2-(4-chlorophenyl)-4-[(phenylthio)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCCCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.28 g (10.0 mmol) of 5-bromo-2,4-dichloro-pyrimidine and 1.7 ml (12.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed at 0° C. with 1.1 ml (12.0 mmol) of 4-amino-butanol. The reaction mixture is slowly heated to room temperature while being stirred by removal of the ice bath. After 16 hours, the precipitate that is formed is filtered off. The filtrate is completely concentrated by evaporation and digested with diisopropyl ether. 2.74 g (9.8 mmol, corresponding to 98% of theory) of the product is obtained.
Reaction SMILES: C([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:15]=1OC)([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:4]([O:6]CC)=[O:5])#N.I.C(O)(=O)C>O>[CH2:9]([CH:3]1[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[C:15]=2[O:5][C:4]1=[O:6])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: CCCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Yield: 54 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]-n-heptanoate (5.9 g), hydriodic acid (58%, 10 ml) and acetic acid (20 ml) was refluxed under heating for 48 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite and water in turn, dried and evaporated under reduced pressure. To the oily residue was added acetic anhydride (5 ml), and the mixture was refluxed under heating for 10 minutes and then evaporated under reduced pressure. The resultant oily residue was purified by column chromatography (silica gel 80 g, benzene) to give oily 3-(n-pentyl)-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (2.5 g).
Reaction SMILES: C([Li])CCC.CCOCC.Br[C:12]1[C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=2[S:15][CH:16]=1.Cl([F:26])(=O)(=O)=O>O>[F:26][C:12]1[C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=2[S:15][CH:16]=1
Reactant: Cc1cccc2c(Br)csc12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1cccc2c(F)csc12

Procedure:
50 ml of a 1.6M solution of butyllithium in abs. ether are added dropwise at -78° to a solution of 18.1 g of 3-bromo-7-methylbenzo[b]thiophene in abs. ether. After 20 Minutes 9 g of perchlorylfluoride are introduced under inert gas and with stirring whereby the reaction temperature is maintained below -60°. The resulting mixture is stirred for 30 minutes at -78° and then slowly warmed to 0°, mixed with water and the organic phase separated, washed, dried and concentrated under vacuum. The residue is chromatographed over silica gel (eluant: hexane) to obtain the title compound as an oil.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]=[C:13]([CH2:15][NH2:16])[O:12][N:11]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:16][CH2:15][C:13]2[O:12][N:11]=[C:10]([C:2]3[O:1][C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[N:14]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1nc(-c2cc3cnccc3o2)no1
Product: CC(C)(C)OC(=O)N1CCC(NCc2nc(-c3cc4cnccc4o3)no2)CC1

Procedure:
Reductive alkylation of C-(3-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-yl)-methylamine (Preparation 13) with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, utilising a procedure similar to that described in Example 30, afforded the title compound: RT=2.15 min; m/z (ES+)=400.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[CH3:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([CH3:34])=[C:12]([NH:11][C:7]([CH:6]5[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5]5)=[O:9])[CH:13]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: CC1=NN(C)C(C(=O)O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=NN(C)C(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)C1
Yield: 71.7 %

Procedure:
In the same manner as in Example 278 and using 1,3-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid (120 mg, 0.87 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), O-(7-azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate (330 mg, 0.87 mmol), N,N-diisopropylethylamine (240 mg, 1.8 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (199 mg, 72%) was obtained as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.FC(F)(F)S(O[C:33]1[C:42]([N+:43]([O-:45])=[O:44])=[C:41]([NH:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1)(=O)=O>C1(C)C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:26][CH:25]=2)[C:33]2[C:42]([N+:43]([O-:45])=[O:44])=[C:41]([NH:46][CH2:47][CH2:48][CH2:49][NH:50][C:51](=[O:52])[O:53][C:54]([CH3:56])([CH3:55])[CH3:57])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)nc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3c(NCCCNC(=O)OC(C)(C)C)c2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
Triethylamine (56.8 mL, 408 mmol) and N,N-bis(4-methoxybenzyl)amine (93.5 g, 0.340 mol) were sequentially added to a solution of 4-({3-[(tert-butoxycarbonyl)amino]propyl} amino)-3-nitroquinolin-2-yl trifluoromethanesulfonate (168 g, 0.340 mol) in toluene (200 mL) at ambient temperature. The solution was stirred at ambient temperature for a few minutes, heated at 65° C. overnight, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (>200 mL), and the resulting solution was washed three times with water, dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried under high vacuum to provide tert-butyl 3-({2-[bis(4-methoxybenzyl)amino]-3-nitroquinolin-4-yl} amino)propylcarbamate as a red oil, which was used without purification.