Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:25])[C:9]=3[C:8]2=[O:26])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C)C=O.C(OC(=O)C)C>[CH2:37]([O:25][C:10]1[C:9]2[C:8](=[O:26])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[C:19](=[O:20])[C:18]=2[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2)[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: COCOc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1c2c(c(OCOC)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxymethyl ether 6 (0.0172 g, 0.045 mmol) was dissolved in 1.5 mL dry dimethylformamide (DMF). Ground K2CO3 (0.0186 g, 0.135 mmol) was added, followed by allyl bromide (0.0077 mL, 0.09 mmol). The mixture was stirred at room temperature overnight, then diluted with 100 mL of ethylacetate, washed with saturated NH4Cl solution, dried (MgSO4), and concentrated to give crude 10. The crude product 10 was chromatographed on silica gel, eluting with ethylacetate and hexanes to give white solid allyl, methoxymethyl diether 10: (0.0063 g, 33%). 1H NMR (CDCl3) δ 9.1 (dd, 1H), 8.8 (dd, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 6.1 (m, 1H), 5.8 (s, 2H),5.5 (d, 1H), 5.3 (d, 1H), 5.1 (d, 2H), 4.8 (s, 2H). MS: 423 (M+1); 445 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[N:27]=1)([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[N:28]([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)[N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)C)nn4-c4cccnc4)c3)c2cc1OC
Yield: 28.9 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (92 mg, 0.3 mmol), prepared as described in Example 115B, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (106 mg, 0.33 mmol), described in Example 350A. The crude was purified by silica gel chromatography (DCM/MeOH 2-10%) to afford 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)urea (47 mg, 28%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.23 (d, J=7 Hz, 6H), 2.90 (m, 1H), 3.99 (s, 6H), 6.36 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.35 (d, J=4.8 Hz, 1H), 7.40-7.47 (m, 3H), 7.56 (dd, J=4.8, 1H), 7.77 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 8.58 (d, J=4.8 Hz, 2H), 8.69 (s, 1H), 8.78 (d, J=2.4 Hz, 1H), 9.19 (s, 1H); LC-MS (ESI) m/z 542 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.CO.[OH-].[K+].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>CN(C)C=O>[CH3:17][S:18]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2c(O)cccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)Oc1cccc2c1CCC(=O)N2
Yield: 38.6 %

Procedure:
10 g of 5-hydroxy-3,4-dihydrocarbostyril was added to 100 ml of methanol having dissolved therein 3.8 g of potassium hydroxide and the mixture was stirred at room temperature for 30 minutes followed by removing methanol under reduced pressure. Benzene was added to the residue to form crystals and then benzene was removed by evaporation. The residue thus-obtained was suspended in 50 ml of dimethylformamide and 10.6 g of methanesulfonyl chloride was added dropwise to the suspension while ice-cooling with stirring. After adding 3.5 g of methanesulfonyl chloride the resulting mixture was stirred at room temperature for 4 hours. After the completion of the reaction, the solvent was removed under reduced pressure and the residue was purified through silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform). Recrystallization of the elute from water-containing ethanol gave 5.7 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyril as colorless prismatic crystals having a melting point of 227° to 231° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)([C:8]([O:10]C)=[O:9])[CH2:4][O:3]1.C1COCC1.[OH-].[Na+:26]>CO>[CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)([C:8]([O-:10])=[O:9])[CH2:4][O:3]1.[Na+:26]
Reactant: COC(=O)C1(c2ccc(C)cn2)COC(C)(C)OC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C2(C(=O)[O-])COC(C)(C)OC2)nc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a mixture of 1.17 g of methyl 2,2-dimethyl-5-(5-methylpyridin-2-yl)-1,3-dioxane-5-carboxylate, 14 ml of THF, and 14 ml of methanol was added 4.7 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 50° C. for 20 hours. The reaction mixture was left to be cooled to room temperature and the solvent was then evaporated under reduced pressure to obtain 1.19 g of sodium 2,2-dimethyl-5-(5-methylpyridin-2-yl)-1,3-dioxane-5-carboxylate.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(Cl)Cl>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]2[C:14]3[N:13]([CH:17]=[CH:16][N:15]=3)[CH2:2][CH2:3][CH:1]=2)=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Product: Clc1ccc(C2=CCCn3ccnc32)cc1

Procedure:
Combine 25 g (0.14 mol) of 4-chlorophenyl cyclopropyl ketone with 50 g (0.73 mol) of imidazole, and heat to 175° C. for 18 hr. Isolation of the product by column chromatography using 200 g of silica gel and methylene chloride as solvent followed by crystallization from ether affords the title compound.
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=3[S:8][C:4]=2[C:3](=[N:13]O)[CH2:2]1.[OH2:15]>>[C:3]1(=[O:15])[C:4]2[S:8][C:7]3[CH2:9][CH2:10][CH2:11][CH2:12][C:6]=3[C:5]=2[CH2:1][CH2:2][NH:13]1
Reactant: ON=C1CCc2c1sc1c2CCCC1
Reactant: O
Product: O=C1NCCc2c1sc1c2CCCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 105d (285 mg, 1.38 mmol) and polyphosphoric acid (15 g). After stirring at 80° C. for 16 h, the reaction mixture was cooled to room temperature, and water (30 mL) was added. The resulting mixture was stirred for 30 min and filtered. The filter cake was washed with water (20 mL) and dried in a vacuum oven at 45° C. to afford a 75% yield (215 mg) of 105e as an off-white solid: mp 203° C. dec; 1H NMR (500 MHz, CDCl3) δ 5.62 (s, 1H), 3.59 (t, 2H, J=7.0 Hz), 2.81 (t, 2H, J=6.0 Hz), 2.72 (t, 2H, J=7.0 Hz), 2.48 (t, 2H, J=6.0 Hz), 1.84 (m, 4H). MS (APCI+) m/z 208.3 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:21]=1)(=O)C>>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:22]1[CH:21]=[C:20]([NH:19][C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)Nc1cccc(-c2ccccn2)c1
Reactant: O=[N+]([O-])c1cc(-n2cccc2)ccc1F
Product: O=[N+]([O-])c1cc(-n2cccc2)ccc1Nc1cccc(-c2ccccn2)c1
Yield: 30 %

Procedure:
N-(3-(2-Pyridyl)phenyl)-2-nitro-4-(1-pyrrolyl)aniline (3e) was prepared analogously from 1a and 2g. Yield: 30%. The product was isolated as an oil.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)C.Br[C:22]1[CH:27]=[C:26]([N+:28]([O-])=O)[C:25]([CH3:31])=[CH:24][C:23]=1[CH3:32]>>[CH3:31][C:25]1[C:24]([N:11]2[C:10]3[N:6]([N:7]=[C:8]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[CH:9]=3)[CH:5]=[CH:4]2)=[C:23]([CH3:32])[CH:22]=[CH:27][C:26]=1[NH2:28]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1Br
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Product: Cc1ccc(N)c(C)c1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
200 mg (0.72 mmol) of the compound of Example 4A together with 200 mg (0.87 mmol) of 1-bromo-2,4-dimethyl-5-nitrobenzene were reacted and worked up analogously to the procedure of Example 10A/Step 1. This gave 200 mg (86% pure, 56% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: NCc1ccc(F)cc1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(NCc2ccc(F)cc2)CC1

Procedure:
1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), 4-fluorobenzylamine (1.25 g, 1.0 eq.).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][S:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:30]1([N:33]([CH2:35][C:36]2[C:37]([CH3:44])=[C:38]([CH:42]=O)[NH:39][C:40]=2[CH3:41])[CH3:34])[CH2:32][CH2:31]1>N1CCCCC1.C(O)C>[CH:30]1([N:33]([CH2:35][C:36]2[C:37]([CH3:44])=[C:38](/[CH:42]=[C:23]3\[C:24](=[O:29])[NH:25][C:26]4[C:22]\3=[CH:21][C:20]([S:17]([CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:19])=[O:18])=[CH:28][CH:27]=4)[NH:39][C:40]=2[CH3:41])[CH3:34])[CH2:32][CH2:31]1
Reactant: Cc1[nH]c(C=O)c(C)c1CN(C)C1CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3OCCN3CCOCC3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4OCCN4CCOCC4)cc32)c(C)c1CN(C)C1CC1
Yield: 45.7 %

Procedure:
5-[2-(2-Morpholin-4-yl-ethoxy)-phenylmethanesulfonyl]-1,3-dihydro-indol-2-one (39 mg, 0.094 mmol) was condensed with 4-[(cyclopropyl-methyl-amino)-methyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (21 mg, 0.1 mmol) and piperidine (1 drop) in ethanol (1.5 mL) at rt for 48 hours. The solvent was removed and the residue was purified on a silica gel column to give 26 mg (46%) of the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH2:45]([O:44][CH:43]([O:47][CH2:48][CH3:49])[C@@H:42]([N:30]([CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)[C:28](=[O:29])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)[CH2:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH3:50])[CH3:46]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 78 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-4-oxobutanoate (Compound IV-16) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2CC)=[CH:6][C:5]=1[Br:19].[CH3:21][CH:22](C[AlH]CC(C)C)C.Cl.CCOCC>C1(C)C=CC=CC=1>[Br:19][C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:21][CH3:22])=[CH:15][CH:16]=2)[CH:8]=[CH:9][C:4]=1[CH2:3][OH:20]
Reactant: CCc1ccccc1Oc1ccc(C(=O)OC)c(Br)c1
Reactant: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCc1ccc(Oc2ccc(CO)c(Br)c2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
Under a nitrogen stream, to a solution of 2-bromo-4-(ethylphenoxy)-benzoic acid methyl ester (90 mg, 0.269 mmol) in anhydrous toluene (2 ml), a toluene solution of DIBAL (1M, 0.537 ml, 0.537 mmol) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours and at room temperature for 1.5 hours. The reaction mixture was cooled again to −78° C., followed by addition of 1N hydrochloric acid (0.2 ml) and ether (3.5 ml). The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:5)) to give the titled compound (78 mg, 94%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Li]CCCC.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[O:9][CH3:10])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-chloro-1-methoxybenzene (51 g, 0.23 mol) in THF (500 mL) was added dropwise n-BuLi (2.5 M in hexane, 138 mL, 0.345 mol) at −78° C. at nitrogen atmosphere. After being stirred at this temperature for 1 h, 1-benzyl-piperidin-4-one (42 g, 0.22 mol) was added dropwise. After addition, the mixture was stirred at −78° C. for 1 h, and then warmed to room temperature. The reaction was quenched with NH4Cl (Sat. aq., 300 mL), and the separated aqueous layer was extracted with ethyl acetate (150 mL×3). The combined organic layer was washed with water and brine, dried over Na2SO4, concentrated to dryness. The residue was purified by silica gel column to obtain 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-piperidin-4-ol 4b as white powder product. 1H NMR (CDCl3): δ 7.37-7.24 (m, 6H), 7.21 (q, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 3.88 (s, 3H), 3.80 (s, 1H), 3.59 (s, 2, H), 2.77-2.74 (m, 2, H), 2.59-2.54 (t, 2H), 2.13-2.06 (m, 2H), 2.00-1.96 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH:24]([O:27][CH2:28][CH2:29][NH2:30])([CH3:26])[CH3:25]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH2:29][CH2:28][O:27][CH:24]([CH3:26])[CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)OCCN
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Product: CC(C)OCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-isopropoxyethanamine 1H NMR (400 MHz, DMSO-d6) δ 1.10 (d, J=6.06 Hz, 6 H) 3.42 (q, J=5.81 Hz, 2 H) 3.48-3.55 (m, 2 H) 3.55-3.64 (m, 1 H) 7.79 (d, J=8.34 Hz, 2 H) 8.15 (br. s., 2 H) 8.42 (d, J=7.58 Hz, 1H) 8.68 (br. s., 1 H) 8.77 (t, J=5.05 Hz, 1 H) 8.92 (s, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 392.1.
Reaction SMILES: [CH3:1][N:2]([CH3:12])/[C:3](=[C:5]1\[N:6]=[C:7]([CH3:11])[O:8][C:9]\1=[O:10])/[CH3:4].[H-].[Na+].[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][C:9](=[O:10])/[C:5](/[NH:6][C:7](=[O:8])[CH3:11])=[C:3](/[N:2]([CH3:12])[CH3:1])\[CH3:4])[CH3:16]
Reactant: CCO
Reactant: CC1=N/C(=C(/C)N(C)C)C(=O)O1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C(NC(C)=O)=C(\C)N(C)C

Procedure:
4-[1-Dimethylamino-eth-(Z)-ylidene]-2-methyl-4H-oxazol-5-one (36.4 g, 216 mmol) was dissolved in ethanol (300 ml) and sodium hydride (0.52 g, 0.022 mmol) was added at room temperature. The dark solution was refluxed for 1 h. The solvent was evaporated and the crude product [MS: m/e=215.5 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[N:6][CH:5]=1.S(Cl)([Cl:15])=O>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Cl:15])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(CO)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CCl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
Add 6-hydroxymethyl-nicotinic acid methyl ester (9.6 g, 57.4 mmol) and dichloromethane (200 mL) to a flask and cool to 0° C. Add thionyl chloride (10.25 g, 86.14 mmol). Stir the mixture at room temperature for 1 hr. Concentrate the reaction mixture under reduce pressure to give the crude 6-chloromethyl-nicotinic acid methyl ester (13 g, 102% yield) as a yellow solid. MS (m/z): 223 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=12.[O:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>CN(C=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>[O:22]1[CH:26]=[CH:25][C:24]([C:2]2[C:11]3[O:10][CH2:9][C:8]4[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=4[C:6]=3[CH:5]=[C:4]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=23)=[CH:23]1
Reactant: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1Br
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1-c1ccoc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
A mixture of 7-bromo-5H-dibenzo[c,g]chromene-3,9-diol (342.mg, 1.0 mmol), furan-3-boronic acid (224 mg, 2 mmols) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmoles) in DMF (20 ml) is heated at 120° C. with stirring for 4 h. The mixture was filtered through celite, extracted with ethyl acetate (×3), washed with brine, dried over sodium sulfate, filtered, stripped of solvent and purified by silica column chromatography (18%-25% ethyl acetate-hexane) to yield 200 mg (61%) of the title compound as a yellowish solid: mp 216-218° C.; 1H NMR (DMSO-d6): δ 5.00 (2H, s), 6.66 (2H, m), 6.84 (1H, dd, J=8.45 Hz, J=2.35 Hz), 6.93 (1H, dd, J=8.77 Hz, J=2.35 Hz), 7.04 (1H, d, J=2.17 Hz), 7.76 (1H, d, J=8.83 Hz), 7.80-7.85 (3H, m), 8.16 (1H, s), 9.61 (1H, s), 9.71 (1H, s); MS (ESI) m/z 329 (M−H)−, 331 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:9]([CH3:22])=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:9]([CH3:22])=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([Cl:27])=[O:20])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(CCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: Cc1c(CCCCCC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
Using the procedure of Example 2, 3-(4-chlorobenzoyl)-2-methylbenzene hexanoic acid was reacted with thionyl chloride to form 3-(4-chlorobenzoyl)-2-methyl-benzenehexanoic acid chloride which was then reacted with 4-(3-trifluoromethylphenyl)-1-piperazinyl-ethanol followed by hydrochloric acid to obtain 2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-ethyl 3-(4-chlorobenzoyl)-2-methyl-benzenehexanoate hydrochloride melting at 108° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([C:23]2([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:40][CH2:41][CH2:42][N:43]1[CH2:49][CH:48]([OH:50])[C:45]2([CH2:47][CH2:46]2)[CH2:44]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:50][CH:48]1[C:45]2([CH2:47][CH2:46]2)[CH2:44][N:43]([CH2:42][CH2:41][CH2:40][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([N:20]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:21]([C:23]5([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]5)=[O:22])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:49]1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)CC1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide (240 mg, 0.525 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (261 mg, 1.05 mmol) and Cs2CO3 (512 mg, 1.575 mmol). The reaction was then stirred at rt for 24 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 (10 mL) aqueous solution and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as a white solid (170 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=O)[NH:7]2.[BH4-].[Na+].C(O)(=O)C>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2
Reactant: O=C1CCc2c(Cl)cccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Clc1cccc2c1CCCN2
Yield: 91.8 %

Procedure:
42.5 g of 5-chloro-3,4-dihydrocarbostyril was suspended in 250 ml of dioxane and 44.3 g of NaBH4 was added to the suspension. Then 67 ml of acetic acid (d=1.05) was added dropwise to the mixture at room temperature. After heat-refluxing the resulting mixture for 2 hours the solvent was removed under reduced pressure. Water was added to the residue and insoluble materials were removed by filtration followed by washing with diethyl ether. The residue was extracted with diethyl ether, dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 36.0 g of 5-chloro-1,2,3,4-tetrahydroquinoline having a boiling point of 116° to 120° C./0.2 mmHg.