Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[C:10]([N:12]3[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]3=[O:20])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29]Br>>[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][N:14]1[C:15]([CH3:18])([CH3:19])[C:16](=[O:17])[N:12]([C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:11]=2)[C:13]1=[O:20]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C3CC3)c2)C1=O
Reactant: Fc1ccc(CBr)c(Br)c1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C3CC3)c2)C(=O)N1Cc1ccc(F)cc1Br

Procedure:
Under conditions as described for the preparation of 1.2, compound 158.1 was reacted with 2-bromo-1-bromomethyl-4-fluorobenzene and afforded 158.2. Molecular weight 455.06 (C22H19BrFN3O2); retention time Rt=2.15 min. [B]; MS (ESI): 456.02 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC([C:25]2([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)CCC[N:27]([CH2:31]C(O)=O)[C:26]2=O)=CC=1.FC1C=C2C(CCNC2)=CC=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:42][C:39]1[CH:38]=[C:37]2[C:36]([CH2:25][CH2:26][N:27]([C:14](=[O:16])[CH2:13][N:10]3[CH2:11][CH2:12][CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9]3=[O:17])[CH2:31]2)=[CH:41][CH:40]=1
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Agent: Fc1ccc2c(c1)CNCC2
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1CCc2ccc(F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 216A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 7-fluoro-1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.20 (m, 2H), 7.16-6.96 (m, 3H), 6.95-6.75 (m, 2H), 4.66 (d, J=26.3, 2H), 4.34 (d, J=16.0, 1H), 4.22-4.03 (m, 1H), 3.83 (dd, J=5.7, 11.4, 1H), 3.75-3.49 (m, 4H), 2.87 (dd, J=5.8, 11.7, 2H), 2.68-2.45 (m, 1H), 2.16 (dd, J=7.7, 13.2, 1H)); MS (DCI) m/z 371.1 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3cc(C(F)(F)F)ccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccnc3cc(C(F)(F)F)ccc23)c2ccccc12

Procedure:
0.33 g (7.77 mmol) of lithium hydroxide monohydrate and 8 cm3 of water are added to 0.96 g (2.59 mmol) of 3-methoxycarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole dissolved in 8 cm3 of tetrahydrofuran. After stirring at reflux for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water (pH=10). The resulting aqueous solution is washed with 30 cm3 of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with 50 cm3 of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.59 g of 3-carboxy-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 356 (M+•), m/e 311.
Reaction SMILES: C(=O)=O.C(O)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si]([N:25]1[C:29](=[O:30])[CH2:28][S:27][CH2:26]1)(C(C)(C)C)(C)C.[Si](OC1CSCN=1)(C(C)(C)C)(C)C.Br[CH2:45][CH2:46][CH2:47][CH2:48]Br>C1COCC1.CCOC(C)=O.CCCCCC>[S:27]1[C:28]2([CH2:48][CH2:47][CH2:46][CH2:45]2)[C:29](=[O:30])[NH:25][CH2:26]1
Reactant: CC(C)(C)[Si](C)(C)N1CSCC1=O
Reactant: BrCCCCBr
Agent: CC(C)(C)[Si](C)(C)OC1=NCSC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C1NCSC12CCCC2
Temperature: -75 °C
Reaction time: 1.17 h

Procedure:
To a -75° C. (CO2 /isopropanol bath) mixture of lithium bis(trimethylsilyl)amide (0.151 mol) and THF (151 mL) under nitrogen was added a 0° C. solution prepared from 14.95 g of a 70:30 mixture between 3-t-butyldimethylsilyl-4-oxothiazolidine and 4-t-butyldimethylsilyloxy-3-thiazoline (prepared as in Example 1) and 1,4-dibromobutane (14.85 g) in THF (50 mL) over a period of 0.5 h. The resultant homogeneous solution was stirred at -75° C. for 70 min. TLC analysis (silica gel, 10% EtOAc/hexane) showed a major product, (Rf =0.48) and a minor product (Rf =0.31). The reaction mixture was removed from the cold bath and acidified with 2N HCl (200 mL). The aqueous mixture was stirred rapidly for 3.5 h at room temperature, placed in vacuo to remove the tetrahydrofuran, and extracted with dichloromethane (5×75 mL). The organic extracts were dried over Na2SO4 and concentrated in vacuo to yield 14.2 g of an oily solid. The crude oily product was chromatographed (Waters Prep 500, 2 silica gel columns, 20% hexane/ethyl acetate) to give 2.75 g of a white solid (Rf =0.45). Recrystallization from diethylether/hexane yielded 1.37 g of a crystalline solid, mp 92°-94° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH:25]([C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][C:37]=1[OH:38])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26]>>[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][O:38][C:37]3[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][C:27]=3[CH:25]=[O:26])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: BrCCCc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: CCOC(=O)c1ccc(O)c(C=O)c1
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C=O)c1

Procedure:
Preparation takes place in analogy to Example XIII from 1,1′-biphenyl-4-ylmethyl 4-(3-bromopropyl)phenyl ether and ethyl 3-formyl-4-hydroxybenzoate.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:11]4[CH2:20][CH2:19][CH2:18][CH:12]4[C:13](=S)[NH:14][C:15]=3[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:21]>>[NH2:21][C:13]1[CH:12]2[CH2:18][CH2:19][CH2:20][CH:11]2[C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:16][C:15]=2[N:14]=1
Reactant: N
Reactant: S=C1Nc2cc(N3CCOCC3)ccc2C2CCCC12
Product: NC1=Nc2cc(N3CCOCC3)ccc2C2CCCC12
Yield: 53 %

Procedure:
Analogously to Example 4, 7-(4-morpholinyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (80 mg, 0.28 mmol) in 7N methanolic ammonia solution (15 ml) is reacted to form 40 mg (53%) of product.
Reaction SMILES: C([O-])=O.[NH4+:4].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+]>N.[Pd]>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH2:4])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd]
Agent: N
Agent: O=C[O-]
Product: CC(C)(C)OC(=O)N1CCC(N)CC1
Reaction time: 8 h
Yield: 83 %

Procedure:
Ammonium formate (300 mg, 4.8 mmol) was added to a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.2 mmol) in methanolic ammonia (2.5 mL) followed by 10% Pd/C (50 mg) and stirring was continued at room temperature overnight. The above mixture was filtered through celite, filtrate was collected, and concentrated under reduced pressure to furnish a crude residue. The residue was treated with 2N aqueous NaOH solution, extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure to afford 200 mg (83% yield) of (4-amino-piperidine-1-carboxylic acid tert-butyl ester. Titanium isopropoxide (756 mg, 2.66 mmol) was added to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (293 mg, 1.46 mmol) and adamantan-2-one (200 mg, 1.33 mmol) in EtOH (5 mL) and stirring was continued at room temperature overnight. NaBH4 (100 mg, 2.64 mmol) was added in portionwise and the resulting mixture was stirred at room temperature for 10 hrs. The reaction mixture was quenched with 2N aqueous NH3 solution and filtered. The filtrate was extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure The residue was purified by column chromatography (using neutral alumina and 20% EtOAc in hexane as eluent) to afford 420 mg (94.4% Yield) of 4-(adamantan-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3): δ 4.0 (s, 2H), 2.9-2.4 (m, 4H), 2.0-1.6 (m, 9H), 1.7 (s, 4H), 1.6-1.5 (d, 4H), 1.45 (s, 9H), 1.35-1.2 (m, 3H). A mixture of 4-(adamantan-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (420 mg, 1.25 mmol) in dioxane.HCl (20 mL) was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to get the residue, which was washed with ether to afford 363 mg (93.8% Yield) of 4-(adamantan-2-ylamino)-piperidine dihydrochloride. 1H NMR (300 MHz, DMSO-d6): δ 9.2 (s, 1H), 9.0 (s, 3H), 3.8 (s, 4H), 3.5-3.3 (m, 4H), 3.0-2.8 (m, 2H), 2.4 (d, 2H), 2.3 (d, 3H), 2.0 (t, 2H), 1.9-1.8 (m, 5H), 1.7 (s, 2H), 1.6-1.5 (d, 2H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:20]([CH2:26]Br)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:26][CH:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)CBr
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
To a solution of N1,N2-dibenzylethane-1,2-diamine (24 g, 100 mmol) in toluene (100 mL) was added TEA (24.2 g, 240 mmol). The mixture was heated to 80° C., and a solution of ethyl 2,3-dibromopropanoate (27.3 g, 105 mmol) in toluene (100 mL) was added dropwise over a period of 0.5 hour at 80° C. Then the mixture was stirred at the temperature for 12 hours and cooled to 25° C. The reaction mixture was washed with saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=5/1) to give the title compound as yellow oil (22.7 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23]([NH:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:29][CH2:28]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:30]2[CH2:31][CH2:32][CH:27]([CH2:26][NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:21])[CH3:19])[CH2:28][CH2:29]2)=[CH:35][CH:36]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccc(B(O)O)cc2)CC1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CN2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Yield: 15.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (110 mg, 0.31 mmol) was reacted with 4-({4-[(tert-butoxycarbonylamino)methyl]piperidin-1-yl}methyl)phenylboronic acid (80 mg, 0.26 mol) to afford the desired product (25 mg, 20%) as a yellow glass: 1H NMR (500 MHz, CD3OD) δ 7.69-7.66 (m, 2H), 7.57-7.54 (m, 2H), 7.41-7.38 (m, 3H), 5.96-5.95 (m, 1H), 4.48-4.44 (m, 2H), 3.75 (s, 3H), 3.70-3.64 (m, 2H), 3.27-2.91 (m, 4H), 2.25-1.95 (m, 2H), 1.57 (s, 1H), 1.52-1.42 (m, 10H); ESI MS m/z 534 [C30H35N3O4S+H]+; HPLC 97.6% (AUC), tR=14.10 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:12](=O)(O)[O-].[Na+]>CO.O>[OH:1][C:2]1[C:3]([C:8]([O:10][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ncccc1O

Procedure:
To a solution of 3-hydroxypyridine-2-carboxylic acid (100 g, 719 mmol) in anhydrous methanol (300 ml) was added dry HCl gas until the saturation point of the solution was achieved. The reaction was heated to reflux for 15 h and then cooled and degassed with argon. The solution was concentrated in vacuo to give a white solid which was dissolved in water (250 ml). The pH of the solution was adjusted to ˜7.5 with the slow addition of solid sodium bicarbonate. The resulting suspension was extracted with EtOAc (2×300 ml), and the organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo to yield methyl 3-hydroxypyridine-2-carboxylate as an oily residue which crystallized on standing (99.2 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH3:18])[C:14]=1[C:15]([OH:17])=O)[CH3:2].FC1C=CC(NC2C=NN(C)C=2C(O)=O)=CC=1>>[CH2:1]([C:3]1[C:4]2[NH:9][C:10]3[CH:11]=[N:12][N:13]([CH3:18])[C:14]=3[C:15](=[O:17])[C:5]=2[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccccc1Nc1cnn(C)c1C(=O)O
Agent: Cn1ncc(Nc2ccc(F)cc2)c1C(=O)O
Product: CCc1cccc2c(=O)c3c(cnn3C)[nH]c12

Procedure:
The title compound was prepared according to the procedure of step 2 in EXAMPLE 1 using 4-[(2-ethylphenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid (EXAMPLE 7, step 1), instead of 4-[(4-fluorophenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[CH3:14][N:15]1CCCC1=O.[Cu]C#N>CCOC(C)=O.[NH4+].[OH-]>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:14]#[N:15])[CH:7]=1)[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(C#N)c1
Temperature: 190 °C
Reaction time: 1 h

Procedure:
To a mixture of of (3-bromo-phenyl)-acetic acid ethyl ester (15.3 g, 62.9 mmol) and 1-methyl-2-pyrrolidinone (125 mL) was added copper (I) cyanide (8.46 g, 94.4 mmol). The reaction mixture was stirred in an oil bath at 190° C. for 1 h. The reaction was cooled to room temperature and was diluted with EtOAc and 2:1H2O/NH4OH. The mixture was stirred for 10 minutes and was filtered through Celite. The aqueous layer was washed with EtOAc (2×). The organic solution was washed with 2:1 H2O/NH4OH until the aqueous extracts were no longer blue. The organic solution was dried over MgSO4, filtered and concentrated to afford (3-cyano-phenyl)-acetic acid ethyl ester (11.95 g). 1H NMR (400 MHz, CDCl3) δ 7.51-7.58 (m, 3H), 7.43 (t, 1H), 4.16 (q, 2H), 3.63 (s, 2H), 1.25 (t, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].Br.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]3[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[C:15]4[CH3:20])=[O:8])[CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Agent: Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)c2nccc(C)c2c1
Yield: 71.1 %

Procedure:
A mixture of 4.3 g (0.012 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide, 4.0 g (0.0128 mole) of 1-(3,4-dichlorophenyl)piperazine, hydrobromide and 2 ml (0.014 mole) of triethylamine in 100 ml of benzene was heated under reflux for 28 hr, allowed to cool, and filtered to remove the precipitated triethylamine hydrobromide. The filtrate was again heated under reflux for 18 hr, allowed to cool, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to dryness in vacuo. Chromatography over 200 g of silica gel with first ethyl acetate and then with 10% methanol in ethyl acetate afforded 4.4 g of the desired product, Rf(silica--10% methanol/ethyl acetate)=0.3. Recrystallization from 2-propanol gave 3.8 g (62%), mp 99°-100°.
Reaction SMILES: [Br:1][CH:2]([C:10](Cl)=[O:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.Cl>C(OCC)C>[Br:1][CH:2]([C:10]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1ccccc1
Reactant: COC(=O)CCCC(Br)C(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCC(Br)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a solution of methyl 5-bromo-5-chloroformylpentanoate (2.57 g) in diethyl ether (15 ml) was added a mixture of phenol (0.94 g) and diisopropylethylamine (1.30 g) in diethyl ether (10 ml). The mixture was stirred at room temperature for 15 minutes and poured into ice water and diluted hydrochloric acid. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (5:1) to give methyl 5-bromo-5-phenoxycarbonylpentanoate as an oil (2.33 g).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:5]([C:18]([O:20]C)=[O:19])=[N:6][CH:7]=[C:8]([O:10][CH2:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:9]=1.Cl.O1CCOCC1>C1COCC1>[F:3][C:4]1[C:5]([C:18]([OH:20])=[O:19])=[N:6][CH:7]=[C:8]([O:10][CH2:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:9]=1
Reactant: COC(=O)c1ncc(OCC(F)(F)C(F)F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)c1ncc(OCC(F)(F)C(F)F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.4 %

Procedure:
Sodium hydroxide (2 M in water, 2 mL, 4.0 mmol) is added to a solution of methyl 3-fluoro-5-(2,2,3,3-tetrafluoropropoxy)pyridine-2-carboxylate (430 mg, 0.1.51 mmol) in THF (15 mL). The reaction is stirred at room temperature for 18 hours. The reaction is quenched by the addition of 4 M HCl in dioxane (1.25 mL, 5 mmol) and the solution concentrated to give the crude title compound (476 mg, 99%). ES/MS (m/e): 222.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C:14]([O:16]C2C=CC=CC=2)=O)[CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[C:26]([C:34]#[N:35])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:14]([NH:13][C:4]2[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=2[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:16])(=[O:32])=[O:31])=[C:26]([C:34]#[N:35])[CH:25]=1
Reactant: N#Cc1cc(Cl)ccc1S(N)(=O)=O
Reactant: CCOC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: CCOC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(Cl)cc1C#N

Procedure:
As the starting substances, ethyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-chloro-2-cyanobenzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-(4-chloro-2-cyanobenzenesulfonyl)-N'-(2-ethyloxycarbonyl-5-chlorophenyl)urea and further to obtain from 1.04 g (2.35 mmol) of N-(4-chloro-2-cyanobenzenesulfonyl)-N'-(2-carboxy-5-chlorophenyl)urea 31 mg of the above-identified compound (yield 3.3%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):7.32-7.36 (2H,m), 7.99 (1H,d), 8.05 (1H,d), 8.38 (1H,d), 8.54 (1H,s), 12.16 (1H,br).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[NH:5][C:4]=2[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([O:36][CH3:37])[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[S:10][C:9]3[C:8](=[O:11])[N:7]([CH:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)[C:6](=[O:25])[NH:5][C:4]=3[CH:3]=2)=[C:29]([O:36][CH3:37])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Br)sc3c2=O)CC1
Reactant: COc1cc(F)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1cc(F)ccc1-c1cc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c2s1

Procedure:
Tert-butyl 4-(6-bromo-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (3.00 g, compound B53), (4-fluoro-2-methoxyphenyl)boronic acid (1.30 g) and dichlorobis(tricyclohexylphosphine)palladium (257 mg) are reacted in the presence of aqueous cesium carbonate solution (5.23 ml, 2.0 M) in DME (12 ml) according to the procedure described in example B55. The reaction mixture is poured into ice-cold water and the mixture is extracted with DCM. The organic layer is washed with saturated aqueous sodium chloride solution and filtered using a phase separator. All volatile materials are removed in vacuo to yield the title compound as a solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH:17]=[N:18][N:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[NH:22][C:21]2=[O:30])[NH:13][C:12]=1[CH3:31])=[O:10].CO.[Li+].[OH-].Cl>O>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:30])[C:20]2=[N:19][N:18]=[CH:17][C:14]1[NH:13][C:12]([CH3:31])=[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[O:10])[C:15]=1[CH3:16]
Reactant: COC(=O)CCCCNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.1 %

Procedure:
5-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-pentanoic acid methyl ester (441 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (167 mg, 39% yield) as a red solid. LC-MS (m/z) 428 (M+1).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH:13]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][CH:15]=[CH2:16]>[Cu]Cl.N1C=CC=CC=1>[CH2:20]([O:19][C:18]([NH:17][C:13]1[C:2]2[C:1](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[C:3]=2[CH:16]=[CH:15][CH:14]=1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=CC=CNC(=O)OCc1ccccc1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: Cl[Cu]
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1C(=O)c1ccccc1C2=O)OCc1ccccc1
Yield: 89.6 %

Procedure:
0.79 g of 1,4-naphthoquinone, 1.07 g of benzyl N-butadienylcarbamate, 25 mg of copper(I) chloride and 25 ml of pyridine were stirred at 25° C. for 30 hours under a gentle stream of air and the solution was then concentrated in vacuo. The residue was taken up in chloroform, the solution was extracted with 2N hydrochloric acid and the organic phase was concentrated in vacuo. 1.60 g of 1-benzyloxycarbonylaminoanthraquinone (83% pure; 75% of theory) were obtained.