Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][N:18]4[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:35].[CH:36]1(B(O)O)[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH:36]1([C:2]2[C:7]3[N:8]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:9]([C@@H:11]([NH:13][C:14]4[N:22]=[CH:21][N:20]=[C:19]5[C:15]=4[N:16]=[CH:17][N:18]5[CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[CH3:12])=[N:10][C:6]=3[CH:5]=[CH:4][C:3]=2[F:35])[CH2:38][CH2:37]1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccn1
Yield: 24.2 %

Procedure:
To a solution of [(S)-1-(7-bromo-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]amine (267 mg, 0.49 mmol) in dioxane (10 mL) and water (0.5 mL) was added cyclopropylboronic acid (64 mg, 0.75 mmol), cesium carbonate (242 mg, 0.75 mmol) and tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.05 mmol) and the reaction mixture degassed by bubbling argon through the mixture whilst under sonication. The reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to preparative HPLC (C18 Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 25 min gradient) to yield the title compound as a white solid (59 mg, 24%). LCMS (Method C): RT=2.98 min, [M+H]+=499.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
A suspension of N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.0 g, 2.7 mmol, 1 equiv), ethyl 2-bromoisobutyrate (0.597 mL, 4.07 mmol, 1.50 equiv), and cesium carbonate (1.77 g, 5.42 mmol, 2.00 equiv) in N,N-dimethylformamide (15 mL) was heated at 50° C. After 5 h, the reaction mixture was concentrated in vacuo, and the resulting residue was partitioned between saturate aqueous sodium chloride solution (30 mL) and ethyl acetate (20 mL). The aqueous was extracted with ethyl acetate (2×20 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated to provide crude product (1.13 g, 84% yield). LCMS (ESI): M+H=483.2.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][C@@H:11]([OH:13])[CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][C@H:11]1[CH2:10][CH2:9][O:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCO[C@@H](c2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCO[C@@H](c2ccccc2)C1
Yield: 62.6 %

Procedure:
A solution of cis-2-phenyltetrahydro-2H-pyran-4-ol (1 g) in DCM (20 mL) was cooled in an ice-salt water bath and treated with DIEA (2.2 g) and methanesulfonyl chloride (0.7 g) for 2 hours. The mixture was diluted with DCM (50 mL) and washed with water and brine. The organic layer was dried and concentrated. Preparative TLC provided 0.9 g of cis-2-phenyl-tetrahydro-2H-pyran-4-yl methanesulfonate.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:14]([N:21]1[C:26]2[S:27][CH:28]=[CH:29][C:25]=2[C:24](=O)[O:23]C1=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:26]2[S:27][CH:28]=[CH:29][C:25]=2[C:24]=1[OH:23])=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2sccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2ccsc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Yield: 67 %

Procedure:
Diethyl malonate (2.14 mL, 0.014 mol) was added slowly to a suspension of sodium hydride (60% dispersion in mineral oil, 0.66 g, 0.017 mol) in 50 mL anhydrous DMF stirred at 0° C. under argon. The solution was stirred for 15 minutes. Solid 1-benzyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (58) (3.58 g, 0.014 mol) was added, and the solution was heated at 110° C. for 2 hours. The solvent was then removed under vacuum, and the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with dil. HCl to precipitate the product, which was collected by vacuum filtration to give 3.09 g (68%) of 7-benzyl-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester. MP 146° C. 1H-NMR (DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 4.32 (q, J=7.2 Hz, 2H), 5.25 (s, 2H), 7.24-7.36 (m, 7H), 13.21 (b, 1H) ppm; EIMS m/z 330 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O.S(Cl)([Cl:19])=O.O.C(=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Cl:19]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc(C)c1-c1cccc(CCl)c1

Procedure:
To 3-(2,6-dimethylphenyl)benzyl alcohol (51.9 g) synthesized according to a method described in [WO 2004/041266 pamphlet, (Reference Example 200)], thionyl chloride (130 mL) was gradually added and the resultant reaction mixture was heated under reflux for 3 hours. The reaction mixture was gradually dropped into ice-cooled methanol (inside temperature: 15° C. or less) and the resultant reaction mixture was adjusted to around pH 8 with saturated sodium bicarbonate water, followed by extracting the reaction mixture with ethyl acetate. The resultant organic phase was washed sequentially with a saturated aqueous sodium bicarbonate, water, and saturated saline, and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate: n-hexane:ethyl acetate=70:1) to obtain the subject compound (36.1 g) as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.[CH3:21][N:22]([CH3:36])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](N(OC)C)=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:30](=[O:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([N:22]([CH3:36])[CH3:21])=[CH:24][CH:25]=2)[C:17]([F:20])=[N:18][CH:19]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CON(C)C(=O)Cc1ccc(N(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN(C)c1ccc(CC(=O)c2cc(Br)cnc2F)cc1
Temperature: -20 °C
Yield: 42.5 %

Procedure:
Diisopropylamine (1.93 ml, 13.66 mmol) and tetrahydrofuran (80 ml) were combined and cooled to −20° C. with stirring. n-Butyl lithium (2.5 M in hexanes, 5.2 ml, 13.00 mmol) was slowly added and stirred at this temperature for 30 minutes. The temperature was decreased to −78° C. and neat 5-bromo-2-fluoropyridine (1.34 ml, 13.02 mmol) was added (internal temperature was not allowed to exceed −68° C.). The reaction mixture was stirred at −78° C. for 40 minutes. The reaction mixture was added to a solution of 2-(4-dimethylamino-phenyl)-N-methoxy-N-methyl-acetamide (2.76 g, 12.42 mmol) in tetrahydrofuran (10 ml). The combined reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was slowly warmed to room temperature, and quenched with saturate aqueous ammonium chloride. The reaction mixture was extracted with methylene chloride, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (0 to 40% ethyl acetate in hexanes) to give 1.78 g (43%) of 1-(5-bromo-2-fluoro-pyridin-3-yl)-2-(4-dimethylamino-phenyl)-ethanone. MS m/z 337.1+339.1 (M+H+).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[F:30][C:31]1[CH:32]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][NH:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:37][C:35]1[CH:34]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][N:39]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)C1

Procedure:
64 mg (0.17 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 70 mg (0.16 mmol) (S)-2-(3,5-difluorophenyl)-5,5-dimethylpiperidine, 40 μL (0.23 mmol) DIPEA and 65 mg (0.17 mmol) HATU in 0.80 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH2:23])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:1]([NH:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:18]([S:19](=[O:21])(=[O:22])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:23][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(=O)Nc1ccc(Oc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Oc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: To the mixture of 3.6 g of 4-(4-acetamidophenoxy)-3-amino-5-sulfamoylbenzoic acid, 10 ml of water and the sufficient amount of N aqueous sodium hydroxide to reach a pH = 7.4, 1.3 g of benzyl chloride are added while stirring at 30°. The mixture is stirred for 16 hours at room temperature, during which time 4N aqueous sodium hydroxide is added dropwise to keep said pH value. It is filtered, the filtrate acidified with glacial acetic acid and the precipitate formed filtered off, to yield the 4-(4-acetamidophenoxy)-3-benzylamino-5-sulfamoylbenzoic acid which, on recrystallization from aqueous ethanol, melts at 255° with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[C:10]#[C:11][CH3:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH:9]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:22][C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[CH:17][CH:18]=1)[C:10]#[C:11][CH3:12])[C:3]([O:2][CH3:1])=[O:20]
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: CC#CC(c1ccc(N)cc1)C(C(=O)OC)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CC(c1ccc(NCc2cccc(-c3ccccc3)c2)cc1)C(C(=O)OC)C(=O)OC
Temperature: 90 °C
Reaction time: 19 h

Procedure:
A mixture of compound 35.2 (1.0 mmol), 3-(bromomethyl)biphenyl (1.3 mmol) and K2CO3 (2.0 mmol) in DMF (10 ml) was stirred at 90° C. for 19 h. After diluting with ethyl acetate, the mixture was washed with aqueous Na2CO3 and then with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane/ethyl acetate=2/1) to give compound 35.3.
Reaction SMILES: [OH-].[K+].[CH:3]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])([CH3:5])[CH3:4].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>O>[CH:3]([CH:6]1[CH2:10][CH2:9][C:8](=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=2)[C:7]1=[O:11])([CH3:5])[CH3:4]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)C1CCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1CCC(=Cc2ccc(Cl)cc2)C1=O
Temperature: 120 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
A solution of 1.1 g of 85% strength aqueous potassium hydroxide solution and 100 ml of water was charged to a 0.31 stainless-steel autoclave, and then 25.2 g of 2-isopropylcyclopentanone and 28.1 g of 4-chlorobenzaldehyde were added, and the mixture was heated to 120° C. under the intrinsic pressure and subsequently stirred at this temperature (intrinsic pressure 1 bar) for 5 hours. After cooling to room temperature, the suspension was filtered with suction and the product was washed to neutrality with water and then dried in a vacuum oven at 55° C. In this way 46.8 g of 2-isopropyl-5-(4-chlorobenzylidene)-cyclopentanone (98.7% pure) were obtained. This corresponds to a yield of 93% of theory.
Reaction SMILES: [F:1][CH2:2][C:3](OCC)=[O:4].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl>C(Cl)Cl>[F:1][CH2:2][C:3]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:4]
Reactant: C1COCCN1
Reactant: CCOC(=O)CF
Agent: Cl
Solvent: ClCCl
Product: O=C(CF)N1CCOCC1
Temperature: 70 °C
Yield: 74.4 %

Procedure:
A mixture of ethyl fluoroacetate (50 g, 472 mmol) and morpholine (82 g, 944 mmol) was heated at 70° C. for 20 h. After cooling to ambient temperature, the mixture was added to a stirred mixture of 2 N HCl (240 mL) and methylene chloride (200 mL) over 20 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (200 mL×2). The combined organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to give 51.7 g (74.6%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 4.96 (d, J=47.2 Hz, 2H), 3.70 (bs, 4H), 3.64 (bs, 2H), 3.47 (bs, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)=[O:11].O.ON1C2C=CC=CC=2N=N1.[C:33]1([CH2:39][CH2:40][CH2:41][NH2:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:33]1([CH2:39][CH2:40][CH2:41][NH:42][C:17]([C:16]2[CH:20]=[CH:21][C:13]([NH:12][C:10]([N:2]3[CH2:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3]3)=[O:11])=[CH:14][CH:15]=2)=[O:19])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCCc1ccccc1)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Isoindoline-2-carboxamido)benzoic acid (150 mg, 0.531 mmol) and 1-hydroxybenzotriazole hydrate (122 mg, 0.797 mmol) were dissolved in dimethylformamide (3 ml) followed by addition of 3-phenylpropan-1-amine (110 mg, 0.797 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (153 mg, 0.797 mmol). The homogeneous solution was stirred at ambient temperature overnight. The solution was diluted with water to give a precipitate which was filtered, washed with cold ethyl acetate then ether and dried under vacuum to provide the title compound. 1H NMR (400 MHz, DMSO-d6, Temp=90° C.) δ ppm 8.27-8.34 (bs, 1H), 7.93-7.98 (m, 1H), 7.73-7.76 (m, 2H), 7.61-7.64 (m, 2H), 7.32-7.36 (m, 2H), 7.27-7.32 (m, 2H), 7.24-7.28 (m, 2H), 7.19-7.24 (m, 2H), 7.13-7.18 (m, 1H), 4.79 (s, 4H), 3.30 (q, J=6.5 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 1.86 (p, J=7.3 Hz, 2H); MS (ESI(+)) m/e 400 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[CH:5]=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].NCCC(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[CH:5]=[C:24]1[S:20][C:21](=[O:26])[NH:22][C:23]1=[O:25]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)c(Br)c1
Agent: NCCC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)c(Br)c2)S1

Procedure:
The title compound was prepared from 3-bromo-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde (which was obtained in Example 56), 2,4-thiazolidinedione and β-alanine according to the procedure of Example 33 as a yellow solid; mp 109–111° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.79 (t, J=5.1 Hz, 4H), 3.12 (m, 4H), 3.93 (s, 4H), 6.87 (d, J=8.7 Hz, 1H), 7.52–7.55 (m, 1H), 7.61 (s, 1H), 7.83–7.87 (m, 1H), 12.5 (s, 1H); MS (ES) m/z: 425.1 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:36])([F:35])[C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:28][C:24]([C:23]([F:36])([F:22])[F:35])=[CH:25][N:26]=3)[CH2:30][CH2:31]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1)C(F)(F)F
Yield: 52 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A15) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as an off-white crystalline solid (yield 52%). MS (m/e): 532.3 (M+H+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH3:23]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[CH2:21][CH2:22][CH3:23]
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc2c(c1)CCCC2=O

Procedure:
A solution of 2.50 g of 6-hydroxy-1-tetralone in 20 ml of acetone, 2.54 g of potassium carbonate and 2 ml of 1-bromobutane were heated under reflux for four days. After evaporation the residue was diluted carefully in 20 ml of 1N hydrochloric acid and extracted three times with ethyl acetate. Then the extracts were washed with aqueous saturated solutions of sodium hydrogen carbonate and sodium chloride and dried over sodium sulfate. After evaporation the resulting residue was purified by chromatography with diethyl ether/petroleum ether (1:2) to yield 3.08 g (91.5% of the theoretical yield) of 6-n-butoxy-1-tetralone in the form of a nearly colorless oil.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.CC(C)([O-])C.[K+].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>O>[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH:10]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Yield: 79.9 %

Procedure:
To a dimethylformamide (1.0 mL) solution of 3-hydroxy-benzoic acid methyl ester (183 mg, 1.2 mmol) was added potassium t-butoxide (147 mg, 1.2 mmol). Upon stirring the reaction at room temperature for 15 min, 2-bromo-5-trifluoromethyl-pyridine (300 mg, 1.32 mmol) was added. The reaction was stirred at room temperature for 15 h. Crude reaction mass was added to water, aqueous layer was acidified to pH 4.0 and product was extracted with ethyl acetate to give 3-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid methyl ester (285 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:5]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CCCC2)c1

Procedure:
Methyl-3-(bromomethyl)benzoate (0.115 g, 0.5 mmol), pyrrolidine (0.036 g, 0.5 mmol) and K2CO3 (0.069 g, 0.5 mmol) were dissolved in DMF (2.5 ml) and stirred at reflux for 18 h. The reaction mixture was the reduced in vacuo and subject to column chromatography eluting with hexane ethyl acetate (1:1) to give the crude 3-pyrrolidin-1-ylmethyl-benzoic acid methyl ester, which was added to a solution of LiOH (0.014 g, 0.33 mmol) in 1:1 THF:H2O (1 ml). The reaction mixture was stirred at ambient temperature for 18 h, reduced in vacuo and dried through azeotrope with toluene (×3). The resulting solid was dissolved in water (1 ml), acidified with 2M HCl (1 ml), reduced in vacuo and dried through azeotrope with toluene (×3) to give a clear, pale yellow gel. This was combined with 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (0.050 g, 0.25 mmol), EDC (0.058 g, 0.30 mmol) and HOBt (0.041 g, 0.30 mmol) and the reaction mixture was stirred at ambient temperature in DMSO (0.75 ml) for 64 h. The reaction mixture was purified by preparative LC/MS to give the formate salt of N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-3-pyrrolidin-1-ylmethyl-benzamide (0.018 g, 9% over 3 steps) as a buff coloured solid. (LC/MS: Rt 1.86, [M+H]+ 387.16).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]2[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=2I)[CH2:12][CH2:11]1)[C:5]#[N:6].[CH3:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]2[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=2[N:32]2[CH:31]=[C:30]([CH3:29])[CH:34]=[N:33]2)[CH2:12][CH2:11]1)[C:5]#[N:6]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C#N)cc3F)CC2)c1
Reactant: Cc1cn[nH]c1
Product: Cc1cnn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C#N)cc3F)CC2)c1
Yield: 20 %

Procedure:
The title compound was prepared according to the procedure described for example 294 from 3-Fluoro-4-[4-(2-iodo-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile (compound CL) and 4-Methyl-1H-pyrazole (20% yield, white foam, MS (m/e): 468.3 (M+H, 100%)