Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[CH:24]=[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)=[CH:29][CH:28]=3)[CH:22]=[C:21]([OH:45])[C:9]=2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([O:3]CC)=[O:2].C(=O)(O)[O-].[Na+].C(O)C>O>[C:1]([C:6]1[O:7][C:8]2[CH:24]=[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)=[CH:29][CH:28]=3)[CH:22]=[C:21]([OH:45])[C:9]=2[C:10](=[O:20])[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1oc2cc(OCc3ccc(OCc4ccc5ccccc5n4)cc3)cc(O)c2c(=O)c1-c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(C(=O)O)oc3cc(OCc4ccc(OCc5ccc6ccccc6n5)cc4)cc(O)c3c2=O)cc1

Procedure:
0.14 g 2-carboethoxy-5-hydroxy-3-(4-methoxyphenyl)-7-(4-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran and 0.78 g sodium bicarbonate are combined in 7 ml of water and 7 ml of ethanol and refluxed overnight. The mixture is extracted with ether and the aqueous neutralized to pH6. The resulting solid is collected, dried to give 2-carboxy-5-hydroxy-3-(4-methoxyphenyl)-7-(4-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1H-benzopyran; m.p. 195°-96° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7]2[CH:16]=[C:17]([C:20]3[C:21]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)=[N:22][N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:24]=3)[CH:18]=[CH:19][C:6]=2[N:5]=1)[CH3:2].[ClH:51]>>[ClH:51].[ClH:51].[CH2:1]([S:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7]2[CH:16]=[C:17]([C:20]3[C:21]([C:44]4[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=4)=[N:22][NH:23][CH:24]=3)[CH:18]=[CH:19][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCSc1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Agent: Cl
Product: CCSc1nc2ccc(-c3c[nH]nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1

Procedure:
A solution mixture of 7.2 g 2-(ethylsulfanyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazole obtained in Production Example 73, 3.5 g 4-fluorophenylboronic acid, 3.4 g copper (II) acetate, 2.0 mL pyridine, 4.6 g of 4 Å molecular sieves and 140 mL dichloromethane was stirred at room temperature for 96 hours. The reaction mixture was filtered through Celite, the solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 1.06 g 2-(ethylsulfanyl)-1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazole as colorless crystals. 30 mg of 2-(ethylsulfanyl)-1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazole was subjected to deprotection of the trityl group and converted into the corresponding hydrochloride by the same method as in Example 67, to give 13 mg of the title compound as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:23]O)[CH:19]=[CH:20][C:21]=1[CH3:22]>>[F:15][C:16]1[CH:17]=[C:18]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1ccc(CO)cc1F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1F

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-fluoro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.28 (3H, s), 5.19 (2H, s), 5.72 (1H, d, J=2.0 Hz), 7.18-7.20 (1H, m), 7.07-7.11 (2H, m), 7.41 (1H, dd, J=1.2, 4.8 Hz), 7.56 (1H, d, J=1.6 Hz), 8.03 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H13FN4O, 309; Found, 309.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl.C(N(CC)CC)C.[N-:18]=[N+:19]=[N-:20].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:18]=[N:19][NH:20][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2nn[nH]n2)c1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of 3-bromobenzonitrile (30.00 g, 164.8 mmol) in toluene (300 mL) was treated with triethylamine hydrochloride (68.05 g, 494.4 mmol) and sodium azide (32.14 g, 494.4 mmol) and the reaction mixture heated to reflux over night. Cooled to room temperature, diluted with water (300 mL), the layers were separated, and the aqueous portion acidified to pH 1 using concentrated HCl. The precipitated solid was collected by filtration, washed with water, and dried to give 34.96 g of product (94.3% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][N:10]=[C:11]=[S:12].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1.Cl>C(OCC)(=O)C>[CH3:7][O:8][CH2:9][NH:10][C:11]([N:28]1[C:29]([CH3:31])=[CH:30][C:26]([O:25][C:15]2[C:16]([Cl:24])=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:14]=2[Cl:13])=[N:27]1)=[S:12]
Reactant: COCN=C=S
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COCNC(=S)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
Potassium carbonate (0.23 g, 1.7 mmol) and methoxymethyl isothiocyanate (0.16 g, 1.5 mmol) were added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.47 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methoxymethyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carbothioamide (0.29 g, yield: 46.7%). mp: 95-96° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.82 (d, J=0.6 Hz, 3H), 3.41 (s, 3H), 5.10 (d, J=6.3 Hz, 2H), 5.91 (q, J=0.6 Hz, 1H), 7.68 (s, 2H), 8.80-9.20 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:29]1)=[O:27])C1C=CC=CC=1.Cl.CCOC(C)=O>CC(C)=O>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(O)cc1O

Procedure:
Hydrogenation of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihydro-isoindol-2-yl]-methanone (as described in method A5) followed by treatment with saturated HCl/EtOAc and trituration with hot acetone afforded 890 mg of the title compound (hydrochloride salt) as a cream solid. 1H NMR (DMSO-d6) 10.78 (1H, br s), 10.05 (1H, br s), 9.55 (1H, br s), 7.30 (1H, t), 7.08 (1H, s) 6.98-6.90 (2H, m), 6.45 (1H, s), 4.80 (2H, s), 4.75 (2H, s), 4.15 (2H, t), 3.95 (2H, br m), 2.80 (2H, br m), 3.50-3.35 (2H, br m), 3.25 (2H, br m,), 3.18-3.02 (3H, br m), 2.20 (2H, br m), 1.15 (6H, d). MS: [M+H]+ 441.
Reaction SMILES: [CH2:1]([CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1)[OH:4])[CH3:2].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[NH:29][CH:30]([CH:34]([CH3:36])[CH3:35])[C:31](O)=[O:32]>>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[NH:29][CH:30]([CH:34]([CH3:36])[CH3:35])[C:31]([O:4][CH:3]([CH2:1][CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1)=[O:32]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: CCC(O)c1cccc(Oc2ccccc2)n1
Product: CCC(OC(=O)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C)c1cccc(Oc2ccccc2)n1

Procedure:
Using the procedure of Example 11, α-ethyl(6-phenoxy-2-pyridyl)methanol is reacted with 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid to yield α-ethyl(6-phenoxy-2-pyridyl)methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, MS m/e 506 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:11]=O)[CH:7]=1.Cl.[NH2:16][OH:17].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:11]=[N:16][OH:17])[CH:7]=1
Reactant: COc1cc(Br)cn2ncc(C=O)c12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Br)cn2ncc(C=NO)c12
Reaction time: 1 h

Procedure:
6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde (100 mg, 0.365 mmol), hydroxylamine hydrochloride (27.9 mg, 0.401 mmol) and sodium bicarbonate (33.7 mg, 0.401 mmol) were suspended in absolute ethanol (4 ml) and stirred for 1 h (heavy colorless precipitate forms). The mixture was concentrated to dryness, then diluted in 8 mL of water and stirred for 5 minutes. The solid was filtered, washed with water, then placed under vacuum overnight to afford 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde oxime as a mixture of oxime isomers.
Reaction SMILES: [C:1]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[C@@H:2]([C@H:4]([C:6]([O:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[OH:5])[OH:3].[H-].[Na+].Br[C:31](Br)([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33].[Cl-].[Na+]>C(COC)OC.O>[O:5]1[C@@H:4]([C:6]([O:8][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:7])[C@H:2]([C:1]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:3][C:31]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1(C(=O)OCC)O[C@@H](C(=O)OC(c2ccccc2)c2ccccc2)[C@H](C(=O)OC(C)(C)C)O1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
3.92 g of tert-butyl diphenylmethyl L-tartarate was dissolved in 10 ml of dimethoxyethane, and 844 mg of 60% sodium hydride was added at 0° C. , followed by stirring at the same temperature for 45 minutes. Then, a solution of 3.37 g of diethyl dibromomalonate in 5 ml of dimethoxyethane, was added, followed by stirring under heating at 80° C. for 12 hours. The reaction solution was cooled to room temperature and then poured into water. The aqueous layer was saturated with sodium chloride and extracted with ethyl ether. The obtained organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1→5/1) to obtain 1.73 g (yield: 44%) of the above identified compound as white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 62.2 %

Procedure:
A mixture of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.400 mmol), 4-chloro-phenyl boronic acid (75 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 2:3) to afford the title compound as a yellow solid (95 mg, 62%).
Reaction SMILES: [C:1]1([C:9]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=O)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[OH:25][C:24]1[N:23]=[N:22][C:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=[C:9]([C:1]2[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=2)[N:26]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2nnc(O)nc2-c2ccc(OC)cc2)cc1

Procedure:
Two moles, 540 g., of anisil (4,4'-dimethoxybenzil), 222 g. (2 moles) of semicarbazide hydrochloride, 180 g. (2.2 moles) of sodium acetate and 2.5 liters of acetic acid were refluxed overnight. The cooled reaction mixture was poured into 5 liters of water. The crude solid product was collected by filtration, washed with water and recrystallized from acetic acid. The yield was 434 g. of 3-hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, mp about 272°-274°C.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][NH2:21])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][NH:21][S:26]([CH3:25])(=[O:28])=[O:27])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 45.6 %

Procedure:
Following procedures essentially as described in Example 90, reaction of the benzylamine (70 mg, 0.225 mmol) prepared in Example 144 and methanesulfonyl chloride (52□L, 0.68 mmol) affords 40 mg of the title compound in 46% yield as a colorless oil after purification using column chromatography (30% ethyl acetate/hexane). MS (ES) 388 (M−1). HPLC shows 97% purity.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:18]1>>[CH3:30][C:28]1[CH:27]=[CH:26][C:25]([C:31]([F:34])([F:32])[F:33])=[C:24]([C:22]([N:19]2[CH2:20][CH2:21][C@@H:17]([NH:16][C:2]3[CH:11]=[N:10][C:9]4[C:4](=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:8]=4)[N:3]=3)[CH2:18]2)=[O:23])[CH:29]=1
Reactant: FC(F)(F)c1ccc2ncc(Cl)nc2c1
Reactant: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](N)C2)c1
Product: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](Nc3cnc4ccc(C(F)(F)F)cc4n3)C2)c1

Procedure:
In analogy to the procedure described for example 200, the title compound was prepared from 2-chloro-7-trifluoromethyl-quinoxaline and ((R)-3-amino-pyrrolidin-1-yl)-(5-methyl-2-trifluoromethyl-phenyl)-methanone (intermediate 13). (M+H+) 469.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH3:22])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: c1ccncc1
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)N1CCOCC1
Reaction time: 1 h
Yield: 51.1 %

Procedure:
A solution of the compound of Example 46, 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.67 mmol) in 30 mL of pyridine was chilled in an ice water bath. With vigorous stirring, the solution was treated with 4-morpholinecarbonyl chloride (0.310 mL, 2.67 mmol). After 1 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) followed by trituration in ether gave 563 mg of N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}morpholine-4-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[C:17]([F:20])([F:19])[F:18])=[CH:4][C:5]([O:8]C)=[N:6][CH:7]=1.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[C:17]([F:18])([F:19])[F:20])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C(F)(F)F)c(Cl)cn1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: O=c1cc(-c2cc(Cl)ccc2C(F)(F)F)c(Cl)c[nH]1

Procedure:
193 mg (purity 93%, 0.56 mmol) of 5-chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-methoxypyridine and pyridinium hydrochloride were reacted according to General Method 3A. Yield: 123 mg (72% of theory)
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=[O:2].[Cl:15][S:16](O)(=[O:18])=[O:17].ClS(C1C=CC(OC)=C(C=1)C(O)=O)(=O)=O>>[C:1]([CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)COc1ccccc1C(=O)O
Agent: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Product: O=C(O)COc1ccc(S(=O)(=O)Cl)cc1C(=O)O

Procedure:
2-(Carboxymethoxy)-5-chlorosulfonyl-benzoic acid was synthesized by the reaction of 2-carboxymethoxy benzoic acid with chlorosulfonic acid using a method similar to the synthesis of Intermediate 6.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH:9](O)[CH3:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.P(Br)(Br)[Br:21]>C(OCC)C>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]([Br:21])[CH3:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)c1ccc(C(C)(C)C)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(Br)c1ccc(C(C)(C)C)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To 25 ml of ethyl were added 1.78 g of (+)-4-tert.-butyl-α-methylbenzyl alcohol of 100% e.e. and 1.8 g of dry pyridine. The resulting mixed solution was kept at -25° C. and added dropwise with a solution of 3.1 g of phosphorus tribromide dissolved in 18 ml of ethyl ether (at -15° to -25° C.). After completion of addition, the resulting mixture was stirred at -10° C. for one hour and then allowed to stand at 5° C. for 2 days. Ice water was added thereto. The resulting organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and with ice water, dried with anhydrous Glauber's salt, and freed of solvent by distillation under reduced pressure to give 1.6 g of 4-tert.-butyl-α-methylbenzyl bromide.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH:13]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>C1COCC1>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:13]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]1
Reactant: N#CC1CCC1
Reactant: Cc1ccccc1CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccccc1CC1(C#N)CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi (0.018 mol, 7.2 ml, 2.5M) was added to a solution of diisopropylamine (1.7 g, 0.017 mol) in THF (15 mL) at −78° C. After 5 minutes neat cyclobutancarbonitrile (1.2 g, 0.015 mol) was added and the mixture was stirred at −78° C. for 1 hour. Then a solution of 1-(bromomethyl)-2-methylbenzene (3.3 g, 0.018 mol) in THF (3 mL) was added and the mixture was stirred at −78° C. for 1 hour. The mixture was quenched with water and extracted with EtOAc. The organic phase was concentrated and the residue was directly used to the next step without further purification. MS: m/z 186 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5]O.F[C:15](F)(F)[C:16]([OH:18])=O>CC(=O)CC(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5][CH:9]([C:16](=[O:18])[CH3:15])[C:2](=[O:1])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: O=[N+]([O-])c1cc(CO)cc(O)c1O
Solvent: CC(=O)CC(C)=O
Product: CC(=O)C(Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(C)=O
Temperature: 100 °C

Procedure:
A mixture containing 6.0 g of 3,4-dihydroxy-5-nitrobenzyl-alcohol and 1.0 ml of trifluoroacetic acid in 70 ml of 2,4-pentanedione was heated for 20 h at 100° C. The solvents were evaporated in vacuo and the residue was crystallized from 2-propanol. Yield 3.0 g, mp 118°-128° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=1>O>[Cl:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:12]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: C1CNCCN1
Solvent: O
Product: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
Piperazine (40 g) was melted by heating at 140° C. and 2,3-dichloro-5-trifluoromethylpyridine (10 g) was added thereto. The mixture was stirred at 120° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-(3-chloro-5-trifluoromethyl-2-pyridyl)piperazine (12.8 g) as a brown solid.
Reaction SMILES: F[C:2]1[CH:16]=[C:15](I)[CH:14]=[CH:13][C:3]=1[C:4]([O:6][CH2:7][CH2:8][Si](C)(C)C)=[O:5].[CH:18](C1C=CC(C(O)=O)=CC=1)=[CH2:19]>>[CH:18]([C:15]1[CH:14]=[CH:13][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][CH:16]=1)=[CH2:19]
Reactant: C[Si](C)(C)CCOC(=O)c1ccc(I)cc1F
Reactant: C=Cc1ccc(C(=O)O)cc1
Product: C=Cc1ccc(C(=O)OCC)cc1

Procedure:
Employing the same general procedure as for the preparation of trimethylsilanylethyl 2-fluoro-4-iodobenzoate (Compound D), 323 mg (2.2 mmol) of 4-vinylbenzoic acid was converted into the title compound using 462 mg (2.4 mmol) of 1-(3-dimethylaminopropyl-3-ethyl carbodiimide hydrochloride), 264 mg (2.2 mmol) of 4-dimethylaminopyridine, 0.32 ml (250 mg, 5.45 mmol) of ethanol and 16 mL of dichloromethane. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a clear, colorless oil. PMR (CDCl3): δ 1.39 (3 H, t, J=7.2 Hz), 4.37 (2 H, q, J=7.2 Hz), 5.38 (1 H, d, J=10.8 Hz), 5.86 (1 H, d, J=17.6 Hz), 6.75 (1 H, dd, J=10.8, 17.6 Hz), 7.46 (2 H, d, J=8.4 Hz), 8.00 (2 H, d, J=8.4 Hz).