Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][C:45]([OH:47])=[O:46])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][C:41]([CH2:44][C:45]([OH:47])=[O:46])=[CH:40][CH:39]=4)=[CH:34][CH:33]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1ccc(-c2ccc(CC(=O)O)cc2)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)Cc1ccc(-c2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and (4′-formyl-biphenyl-4-yl)-acetic acid according to the procedure of Example 66. MS (ES) m/z 617.2.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:6]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A solution of methanesulfonyl chloride (28 ml, 0.36 mole) in dichloromethane (50 ml) was added dropwise to a solution of piperidine-4-carboxylic acid ethyl ester (50 grams, 0.32 mole) and triethylamine (53 ml, 0.38 mole) in dichloromethane (350 ml) at 0° C. The reaction mixture was stirred at 0-5° C. for 3 hours. The solution was washed with 2×100 ml water, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The solid residue was triturated with 100 ml ethyl ether, collected by filtration and dried to give 1-methanesulfonylpiperidine-4-carboxylic acid ethyl ester (68 grams, 90%), m.p. 91-92° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[SH:18][CH:19]([OH:21])[CH3:20]>CC(C)=O>[CH2:7]([S:18][CH:19]([OH:21])[CH3:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCBr
Reactant: CC(O)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCSC(C)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
Under nitrogen, to a suspension of potassium carbonate (27 g, 200 mmol) in acetone (100 ml) was added decyl bromide (10 ml, 50 mmol) and mercaptoethanol (4.4 ml, 63 mmol). The suspension was stirred at room temperature for 2 days, then partitioned between water and 80% hexane/ethyl acetate. The organic phase was washed with 2N sodium hydroxide, dried over magnesium sulfate, and the volatiles removed under vacuum to give S-decyl mercaptoethanol (10.2 g, 47 mmol) as a colorless liquid that was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccc(C)cc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccccc2)CCCN3CCCCCCC(=O)O)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 7-(2-phenyl-3-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (1.07 g, 2.338 mmol) in THF (12 ml) and water (6 ml) was treated with LiOH (0.560 g, 23.38 mmol) and stirred at 70° C. for 18 hours. After cooling to RT, the reaction mixture was concentrated in vacuo. The residue was diluted with water (20 ml) and the pH was adjusted to pH˜4 using 2M HCl. The aqueous portion was extracted with EtOAc (2×20 ml). The organic extracts were washed with brine, dried (MgSO4) and evaporated under vacuum. The residue was dissolved in hot (˜80° C.) ethanol (20 ml) and water (˜15 ml) was added until the solution became turbid. Upon cooling a solid precipitated. The mixture was kept cold for 72 hours. The solid was collected by filtration, washed with water and dried at 40° C. for 5 hours to afford the title compound;
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][CH2:9][C:10]([N:12]([CH2:14][C@H:15]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)[CH3:16])[CH3:13])=[O:11]>>[OH:8][CH2:9][C:10]([N:12]([CH3:13])[CH2:14][C@H:15]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)[CH3:16])=[O:11]
Reactant: ClCc1cscn1
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1OCc1cscn1
Yield: 41 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide (obtained as described in Example 90, preparation of starting materials) to give the title compound as a white solid in 41% yield; NMR spectrum (DMSO-d6 373K) 1.43 (d, 3H), 2.24 (s, 3H), 2.97 (s, 3H), 3.57 (m, 1H), 4.07 (m, 3H), 5.13 (m, 1H), 5.25 (s, 2H), 7.09 (d, 1H), 7.11 (d, 1H), 7.34 (d, 1H), 7.57 (m, 2H), 7.69 (m, 2H), 8.42 (s, 1H), 9.07 (d, 1H), 9.82 (s, 1H); Mass spectrum MH+ 494.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])=[O:23].C([O-])(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[S:10][C:9]([N:28]3[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26][CH2:27]3)=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CS(=O)(=O)N1CCN(c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine (1.0 eq) was dissolved in 1,2-dichloroethane (0.1 M). 1-methylsulfonylpiperazine (1.1 eq) and sodium acetate (1.1 eq) were added. The solution was stirred for 2 h at 70° C. and the solvent was removed in vacuo. The residue was purified by silica gel chromatography to give 5-chloro-2-(4-methylsulfonylpiperazin-1-yl)-7-morpholinothiazolo[4,5-d]pyrimidine. This intermediate, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.0 eq), trans-dichlorobis(triphenylphosphine)palladium(II) (0.10 eq), 1M KOAc (3.0 eq) and a 6× volume of acetonitrile were microwaved at 150° C. for 15 minutes. Upon completion, reaction mixture was concentrated in vacuo and crude mixture was purified by silica gel chromatography to give 145. MS (Q1) 477 (M+)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:32][C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To 10 mL of a chloroform solution containing 252 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 136 mg of 2-naphtoaldehyde, 50 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 276 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=2:1], to give 279 mg of 7-fluoro-1-(2-(4-((naphthalen-2-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C.ClCCl>[Cl:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[CH2:8][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10.50 g (74.452 mmol) potassium carbonate was added to a solution of 7.400 g (29.543 mmol) of 1-bromomethyl-2-chloro-4-nitro-benzene and 5.00 mL (59.300 mmol) pyrrolidine in 150 mL acetonitrile and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with 200 mL dichloromethane, filtered and the filtrate evaporated down i. vac. The residue was taken up in EtOAc, the org. phase was washed with water, dried over magnesium sulphate and evaporated down i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:28]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:20](=[O:21])[O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:32][CH:31]=2)=[O:29])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)benzoic acid via Procedure G to yield tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCl in Dioxane to remove the Boc protecting group and form the HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 50 mg of the crude HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to picolinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 443.3 (M)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[CH:3]1.Cl.Cl[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]Cl>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])([CH3:8])[CH2:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:3]1
Reactant: ClCCNCCCl
Reactant: CC1(C)C=C(c2ccccc2N)CC1(C)C
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=C(c2ccccc2N2CCNCC2)CC1(C)C
Temperature: 200 °C
Reaction time: 9 h
Yield: 50.9 %

Procedure:
A mixture of 2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenylamine (331 mg, 1.54 mmol) produced in Example (54c), 1,2-dichlorobenzene (4.7 mL) and bis(2-chloroethyl)amine hydrochloride (330 mg, 1.85 mmol) was stirred for 9 hours at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was blown into the reactor several times to remove the hydrogen chloride gas in the reactor. The reaction mixture was air-cooled to room temperature, and then aqueous solution of potassium carbonate, ethyl acetate and methanol were added and extraction was performed three times with ethyl acetate. The obtained organic layers were dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 223 mg of the title compound as a brown oil.
Reaction SMILES: [CH2:1]([C:3]([CH2:19][OH:20])([CH2:17][CH3:18])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])[CH3:2].[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([O:20][CH2:19][C:3]([CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])([CH2:1][CH3:2])[CH2:17][CH3:18])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CCC(CC)(CO)COc1cccc([N+](=O)[O-])c1C#N
Product: CCC(CC)(COC(C)=O)COc1cccc([N+](=O)[O-])c1C#N
Yield: 82 %

Procedure:
Prepared as in Example 231c from 2-(2-ethyl-2-(hydroxymethyl)butoxy)-6-nitrobenzonitrile (Example 232d) and acetyl chloride in 82% yield. MS 321 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C1(S([N:21]2[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[C:23]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=3)=[CH:22]2)(=O)=O)C=CC=CC=1>>[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:10][CH:11]=3)[N:31]=2)=[CH:22]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccc(OCCO)cc1
Product: OCCOc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 70.5 %

Procedure:
Using the procedure of example 1, 2-(4-aminophenoxy)-ethanol (265 mg) was reacted with compound 1f (200 mg) to provide compound 4 (132 mg, 71%). 1H NMR (400 MHz, CD3OD) δ 8.85 (d, J=8.0 Hz, 1H), 8.25 (d, J=4.8 Hz, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.22 (s, 1H), 7.54 (d, J=9.0 Hz, 2H), 7.18 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.16 (d, J=5.2 Hz, 1H), 6.98 (d, J=9.0 Hz, 2H). MS (ESI) m/z: 348 (M+H)+.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)(OC)=O.[CH3:21][NH:22][C:23](=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:26].C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:21][N:22]1[C:23](=[O:31])[C:24]2[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:26]=[C:1]1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:19][CH:20]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1C
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carbomethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in Examples 23 or 24 (100 g, 0.34 M), N-methyl anthranilamide (58.7 g, 0.39 M), xylene (100 ml) and p-toluenesulfonic acid (200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 10-15 h while monitoring the reaction by TLC. After completion of the reaction, reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (30 g, Y=23%, P=98%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[C:15]2[S:20](Cl)(=[O:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>ClCCl>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:20]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[CH:17]=[CH:18][CH:19]=[C:10]3[NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:22])=[O:21])=[CH:35][CH:34]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Nc1cccc2c(S(=O)(=O)Cl)cccc12)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NS(=O)(=O)c2cccc3c(NC(=O)c4ccccc4)cccc23)cc1

Procedure:
To a solution of 5-benzoylamino-naphthalene-1-sulfonyl chloride 44 (0.1 g, 0.29 mmol) in dichloromethane (0.5 mL) was added triethylamine (0.06 ml, 0.43 mmol) and p-anisidine (0.05 g, 0.3 mmol). The resultant solution stirred at room temperature for 3 hours. The reaction mixture was quenched with water and the compound extracted into ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide the crude product as a yellow oil. 1H NMR (300 MHz, DMSO) δ 8.65 (d, 1H), 8.19 (d, 1H), 8.06 (m, 3H), 7.70 (m, 2H), 7.54 (m, 2H), 6.84 (d, 2H), 6.69 (d, 2H), 3.56 (s, 3H); LC/MS (M+H)+ m/z 433.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[CH3:1][C:2]1[N:6]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1
Reactant: CCOC(=O)c1nc(C)[nH]c1C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: CCOC(=O)c1nc(C)n(Cc2ccc([N+](=O)[O-])cc2)c1C(=O)OCC
Yield: 80.7 %

Procedure:
Following a procedure similar to that described in Preparation 42(i), but using 6.65 g of diethyl 2-methylimidazole-4,5-dicarboxylate and 6.35 g of p-nitrobenzyl bromide as starting materials, 8.57 g of the title compound were obtained as crystals, melting at 109° C.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([N+:19]([O-])=O)=[C:14]([CH3:22])[CH:13]=1.O.O.[Sn](Cl)Cl.Cl>CO>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([NH2:19])=[C:14]([CH3:22])[CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc2c(c1)CCCC2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cc1cc(Oc2ccc3c(c2)CCCC3)c(C)cc1N
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of 15.00 g (46.9 mmol) of 4-(5,6,7,8-tetrahydro-2-naphthoxy)-2,5-dimethylnitrobenzene in 60 ml of methanol is admixed first of all with 31.8 g (140.7 mmol) of tin(II) chloride dihydrate at room temperature and then slowly, with ice cooling, with 60 ml of concentrated hydrochloric acid. The reaction mixture is refluxed for 2 h, cooled to room temperature, concentrated and admixed with water and the residue is isolated by filtration and dried under reduced pressure (15.3 g, 86% purity, 99.5% yield, log P (pH 2.3)=3.08).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[Li]CCCC.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([B:16]([OH:19])[OH:17])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: COc1cc(Br)ccc1F
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1F
Reaction time: 18 h
Yield: 33.7 %

Procedure:
To a solution of 7B (2.7 g, 13.1 mmol) in THF (25 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 11.0 mL, 17.7 mmol). The mixture was stirred at −78° C. for 40 min before trimethyl borate (2.7 mL, 24.3 mmol) was added. The reaction was left stirring from −78° C. to rt over 18 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 7C (0.75 g, 35% yield) was collected as a white solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.86 (s, 3H) 7.03-7.45 (m, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][NH2:25]>CO.[Pt]=O>[CH2:1]([NH:25][CH2:24][CH2:23][O:22][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:20][C:21]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NCCOc1ccc2c(c1)[nH]c1ccccc12
Agent: O=[Pt]
Solvent: CO
Product: c1ccc(CNCCOc2ccc3c(c2)[nH]c2ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzaldehyde (9.38 g) was added to a solution of N-[2-(9H-carbazol-2-yloxy)]ethylamine (20 g; synthesized according to the process indicated in JP-A-9-249623) in methanol (500 mL). The mixture was then stirred at room temperature for 1 hour. Under an argon atmosphere, platinum oxide (1.00 g; mfd. by Wako Pure Chemical Industries) was added to the mixture, which was then stirred under a hydrogen atmosphere at atmospheric pressure for 3 hours. After replacing the atmosphere in the reaction system with argon, benzaldehyde (1.88 g) was added to the mixture, which was then further stirred under a hydrogen atmosphere at atmospheric pressure for 3 hours. After replacing the atmosphere with argon, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol and dried under reduced pressure to give the title compound (25.2 g) as a pale yellow crystal.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][NH:35][CH3:36].[I-].[Na+]>COCCOC>[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][N:35]([CH3:36])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: CNCC1OCCO1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN(C)CC1OCCO1
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 173.0 mg (0.44 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy- quinoline-3-carbonitrile, 515.5 mg (4.4 mmol) of 2-([1,3]-dioxolan-2-ylmethyl-methylamine and 66.0 mg (0.44 mmol) of sodium iodide in 4 mL of DME was heated at 135° C. for 16 hr. The work up gave 136.1 mg (65.2%) of the product as a yellow solid, m.p. 185-187° C., mass (electrospray, m/e): M+H 475.1
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([NH:2][C:27]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:28])[CH2:4][CH2:5]2)=[CH:12]1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C=NC1CCCCC1
Solvent: O
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 18 h
Yield: 102.7 %

Procedure:
4-Amino-1-[2-(3-indolyl)ethyl]piperidine, hydrate (1.307 g, 0.005 mole) in benzene (50 ml.) was treated with cyclohexyl isocyanate (0.688 g, 0.0055 mole) and the mixture stirred for 18 hrs. Filtration afforded the title compound as colourless prisms (1.893 g), m.p. 203.8°.