Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.O.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1N1CCNCC1)#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:7]1[CH2:6][CH2:5][N:4]([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)[CH2:3][CH2:2]1)#[N:23]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Solvent: O
Product: N#Cc1ccccc1C1CCN(c2cc(-c3ccccn3)cn(-c3ccccc3)c2=O)CC1
Temperature: 130 °C
Yield: 41.7 %

Procedure:
29 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 200 mg of 1-(2-cyanophenyl)piperazine, followed by heating at 130° C. for 72 hours. After the reaction solution was cooled to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 8 mg of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O>[Si:9]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCCc1cccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2-(2-Thienyl)ethanol (2.6 g) was dissolved in N,N-dimethylformamide (20 ml), followed by the addition of t-butyldimethylsilyl chloride (3.667 g) and imidazole (1.634 g) and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless oil (4.87 g, yield; 100%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.O>[C:5]([N:1]=[N+:2]=[N-:3])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium azide (19.0 g: 0.283 Mol.) in dimethyl-formamide (130 ml) is added trityl chloride (76.0 g: 0.273 Mol.), and the mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with water and extracted with ether. The extract is washed with brine, dried over sodium sulfate, and concentrated to give trityl azide. To a solution of this azide in acetone (300 ml) is added methyl propiolate (24 ml: 0.27 Mol.), and the mixture is heated under reflux for 6 days. The reaction mixture is cooled to the room temperature and diluted with ether. The separating crystals are collected by filtration to give 1-trityl-1,2,3-triazol-4-ylcarboxylic acid methyl ester (62.0 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([CH2:19][C:20]([O:22][CH2:23]C)=[O:21])=[CH:4][N:3]=1.[H-].[Na+].CI.[CH:29]([O:31][CH3:32])=O>CCOCC>[CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5]([C:19](=[CH:29][O:31][CH3:32])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1cnc(C)nc1Oc1cccc(C(F)(F)F)c1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: COC=C(C(=O)OC)c1cnc(C)nc1Oc1cccc(C(F)(F)F)c1

Procedure:
Ethyl α-[2-methyl-4-(3-trifluoromethylphenoxy)-5-pyrimidinyl]-acetate (3 g, 8 mmol) are dissolved in methyl formate (10 ml) and added to a suspension of NaH (0.6 g, 80% in oil, 20 mmol) in 1,2-dimethoxyaethane at room temperature. After 16 hours methyl iodide (2.5 ml, 40 mmol) is added with cooling. After further 2 hours the reaction mixture is diluted with ether and washed with brine. Drying and chromatography on silicagel (eluant: hexane/ethyl acetate 1:1) gives the methyl α-[2-methyl-4-(3-trifluoromethylphenoxy)-5-pyrimidinyl]-β-methoxyacrylate compound as a crystalline solid, m.p. 100°-102° C.
Reaction SMILES: [OH:1][CH:2]([C:34]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=1)[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])=[N:16][N:15](COC(=O)C(C)(C)C)[C:12]3=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C(N)CN.Cl.C(=O)(O)[O-].[Na+]>C(O)C.[OH-].[Na+].C(Cl)(Cl)Cl>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([C:5]3[CH:4]=[C:3]([CH:2]([C:34]4[C:39]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:37]=[CH:36][N:35]=4)[OH:1])[CH:8]=[CH:7][CH:6]=3)[CH:10]=2)[NH:15][N:16]=1
Reactant: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(-c3cccc(C(O)c4ncccc4C(F)(F)F)c3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: NCCN
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(O)c4ncccc4C(F)(F)F)c3)cc12
Reaction time: 16 h
Yield: 3.9 %

Procedure:
380 mg (0.64 mmol) of 2,2-dimethyl-propionic acid 5-{3-[hydroxy-(3-trifluoromethyl-pyridin-2-yl)-methyl]-phenyl}-3-(2-methoxy-phenyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester was dissolved in hot ethanol. 0.5 ml (450 mg, 7.5 mmol) of ethylene diamine was added and the mixture diluted with 2 M aqueous sodium hydroxide (30% v/v). The resulting mixture was gently heated until all material was dissolved and the solution left at room temperature for 16 h. The pH was adjusted to 8 by addition of concentrated aqueous hydrochloric acid and the resulting solution was distributed between chloroform and saturated aqueous sodium bicarbonate. The aqueous layer was extracted three times with chloroform. The combined organic phases were dried over sodium sulfate and evaporated. The residue was purified by mass-triggered reverse-phase HPLC to afford 12 mg (25 μmol, 4%) of {3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-(3-trifluoromethyl-pyridin-2-yl)-methanol as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13.83 (s, 1H), 8.86 (d, 1H), 8.79 (s, 1H), 8.28 (d, 1H), 7.79 (s, 1H), 7.66 (d, 1H), 7.62 (d, 1H), 7.54 (dd, 1H), 7.47 (t, 1H), 7.43 (t, 1H), 7.35 (d, 1H), 7.24 (d, 1H), 7.10 (t, 1H), 6.23 (d, 1H), 6.10 (d, 1H), 3.85 (s, 3H); MS: m/z 477.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH:15]=[CH:16][N+:17]([O-])=O)=[CH:9][NH:10]2)=[O:5])[CH3:2]>C(O)=O.[C].[Pd]>[NH2:17][CH2:16][CH2:15][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:10][CH:9]=1
Reactant: CCOC(=O)c1cccc2[nH]cc(C=C[N+](=O)[O-])c12
Agent: [Pd]
Solvent: O=CO
Product: CCOC(=O)c1cccc2[nH]cc(CCN)c12

Procedure:
0.5 g of 4-ethoxycarbonyl-3-(2-nitrovinyl)indole are heated under nitrogen for 45 minutes in the steam bath in 50 ml of formic acid with 1.5 g of 10% palladium-carbon. The palladium carbon is then filtered off, the filtrate evaporated, the evaporation residue [3-(2-aminoethyl)-4-ethoxycarbonyl indole] is then further reacted immediately.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:36]1C[O:39][CH2:38][CH2:37]1>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:38](=[O:39])[CH:37]=[CH2:36])=[CH:21][CH:20]=2)=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Reactant: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NCc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 23 %

Procedure:
N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide was prepared from (4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine, triethylamine instead of N,N-diethylethanamine, THF instead of methylpyrrolidin-2-one and dichloromethane using Method G (23% yield). HPLC: 93%, RT=4.014 min. MS: m/z=423 [M+H]+, RT=3.16 min. 1H-NMR (DMSO-d6) δ 8.99 (s, 1H), 8.36 (d, 1H), 8.18 (s, 1H), 8.08 (d, 2H), 7.89-7.83 (m, 4H), 7.65-7.48 (m, 7H), 7.25 (d, 1H), 6.80 (dd, 1H), 6.69 (d, 1H), 6.05 (d, 1H), 4.98 (d, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:15]3[CH:14]=[CH:13][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC1Cc2cccc(Cl)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: CC1Cc2cccc(-c3ccc4ccccc4c3)c2C1=O
Temperature: 125 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Using a method similar to Example 16d), 2.16 g (0.012 mol) of (1), 2.27 g (0.0132 mol) of 2-naphthylboronic acid, 2.8 g (0.0264 mol) of sodium carbonate were placed in 40 ml of ethylene glycol/8 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 13.5 mg (0.06 mmol) of palladium acetate and 0.102 g (0.18 mmol) of TMSPP, the reaction mixture was stirred for 2 hours at 125° C. After addition of 40 ml of water, the aqueous phase was extracted 4 times with 50 ml each time of ether, the combined ether phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 3.0 g of (19) as an oil which tends to crystallize.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)=[C:10]([CH2:20][CH2:21][CH3:22])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:27]=[CH:28][C:29]=1[OH:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:20]([C:10]1[CH:9]=[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:25][C:24]=1[Cl:23])[CH2:21][CH3:22]
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCCBr
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCCOc1ccc(CC(=O)OC)cc1Cl

Procedure:
A solution of 4-(4-bromobutoxy)-3-propylphenyl phenyl ether (5.7 g, 15.75 mmol), methyl 3-chloro-4-hyrdoxyphenylacetate (3.0 g, 15.00 mmol) and cesium carbonate (5.38 g, 16.50 mmol) in DMF (50 mL) was stirred at 40° C. overnight. The reaction mixturewas partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with 10% of ethyl acetate in hexane to afford the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][C:11](I)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:28][C:29]1[C:33](B(O)O)=[C:32]([CH3:37])[O:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][C:11]([C:33]2[C:29]([CH3:28])=[N:30][O:31][C:32]=2[CH3:37])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)nc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2c(C)noc2C)nc1F

Procedure:
By carrying out the operation analogously to example 213, starting from 2-fluoro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XII, and 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].N1C=CC=CC=1.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>O1CCCC1>[C:22]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:25])[CH:23]=[CH2:24]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)OCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
12-Hydroxydodecanoic acid (5.0 g, 0.023 mol) dissolved in tetrahydrofuran (100 ml) and pyridine (2.16 g, 0.027 mol) was cooled to 0° C. Acryloyl chloride (3.15 g, 0.023 mol) in tetrahydrofuran (75 ml) was then added dropwise to the solution. The mixture was stirred for 5 hours at 0° C. then stirred overnight at room temperature. The precipitated pyridinium salt was filtered off and the solvent removed under vacuum. The resulting liquid was purified by flash chromatography (silica gel/chloroform) to give 2.5 g (40%) of the title compound. 1H NMR (60 MHz, CDCl3): δ 1.20 (s, 18H, CH2), 2.15 (m, 2H, CH2COOH), 4.0 (m, 2H, COOCH2), 5.7-6.0 (m, 3H, CH2 = and =CH).
Reaction SMILES: [I:1]I.O[CH2:4][CH2:5][CH:6]1[CH2:10][C:9]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:8]=2[O:7]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[K+].[Br-]>C1(C)C=CC=CC=1>[I:1][CH2:4][CH2:5][CH:6]1[CH2:10][C:9]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:8]=2[O:7]1
Reactant: II
Reactant: Cc1c(C)c2c(c(C)c1O)CC(CCO)O2
Agent: [Br-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1O)CC(CCI)O2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4.4 g of iodine are added to a mixture of 3.1 g of 2-(RS)-2-hydroxyethyl-2,3-dihydro-5-hydroxy-4,6,7-trimethylbenzofurane, 5.5 g of triphenylphosphine and 1.4 g of imidazol in 60 ml of toluene. The mixture is stirred for 3 hours at 60° C. The imidazole*HBr is then filtered out and the filtrate is evaporated. After purification by a column chromatography (SiO2), 3.0 g of white solid are obtained. m.p. 96°-97° C.; IR (KBr): 3403 (νOH), 1195 cm-1 (w CH2I); 1H-NMR (CCl4): δ4.9-4.4 (1H,m), 4.0 (1H,s), 3.2 (2H,t), 3.0-2.5 (2H,m), 2.2 (2H,m), 2.1 (9H,s).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1.Br[CH2:24][CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:24][CH2:25][CH2:26][Cl:27])[CH:16]=1
Reactant: Nc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1c(C(=O)c2cccc(NCCCCl)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.5 %

Procedure:
5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole (0.5 g, 1.6 mmol), 1-bromo-3-chloropropane (0.26 g, 1.6 mmol) and cesium carbonate (0.52 g, 1.6 mmol) in dimethylformamide (25 ml) was heated at 80° C. After 2 days, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 20% acetone/hexanes) to give 5-amino-4-[3-(3-chloropropylamino)benzoyl]-1-(4-fluorophenyl)pyrazole (0.2 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][C@H:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([F:8])[C:5]=1[O:9][CH:12]([CH3:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: CCCCCC[C@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCC(C)Oc1c(F)cc(Br)cc1F

Procedure:
12.0 g of 4-bromo-2,6-difluorophenol, 10.0 ml of (S)-(+)-2-octanol and 16.5 g of triphenylphosphine were dissolved in 300 ml of tetrahydrofuran at about 20° C. with stirring under a nitrogen atmosphere. 12.5 ml of anhydrous (max. 0.0075% of H2O) diisopropyl azodicarboxylate were subsequently added dropwise. The reaction proceeds exothermically. The rate of addition was selected in such a way that the temperature of the mixture did not exceed 45° C. The reaction solution was subsequently stirred for 2 h, and the solvent was then removed in a rotary evaporator. The crude product was purified in a mixture of chlorobutane and heptane in the ratio 1:1 over 2 l of silica gel, giving 14.5 g of 3,5-difluoro-4-(1-methylheptyloxy)bromobenzene as a clear liquid.
Reaction SMILES: CCOCC.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([OH:19])=[O:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:31]([O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:42](Cl)=[O:43])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[CH2:31]([O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:42]([O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=1)=[O:43])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture consisting of 1.5 liter of anhydrous ether, 290 cc of pyridine, 100.2 g of 3,4-dibenzyloxybenzoic acid and 105.7 g of 3,4-dibenzyloxybenzoic acid chloride is stirred for 24 hours at ambient temperature in a round-bottom flask provided with a drying tube. The mixture is then poured in 8 liters of ice water. After 45 min stirring the precipitate is filtered, washed with one liter of 0.1N iced hydrochloric acid, one liter of iced 0.1N Na2CO3, then one liter of ice water. The solid is solubilized in CHCl3 ; it is decanted, dried and evaporated and the anhydride is recrystallized in ethyl acetate. Yield 88%.
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:26]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([N:31]2[CH2:32][CH2:33][N:34]([C:18]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])=[CH:17]4)=[O:20])[CH2:35][CH2:36]2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F)N1CCN(C2CCCC2)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 46, intermediate e), from 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid and 1-cyclopentylpiperazine (commercially available), to give the desired product as a white solid (49%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[Br:16][C:17]1[CH:18]=[C:19]([N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:20]=[CH:21][CH:22]=1
Reactant: Brc1cccc(Br)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 5 mmol), 1,3-dibromobenzene (1.7 g, 7.2 mmol), K3PO4 (3.18 g, 15 mmol), CuI (95 mg, 0.5 mmol) and L-proline (115 mg, 1 mmol) in dry DMF (5 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL). The organic layer was washed with water (6×30 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by column chromatography using neutral alumina and 5% EtOAc-hexane to yield 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[Br:14][C:15]1[S:19][C:18]2=[N:20][C:21]([C:23](O)=[O:24])=[CH:22][N:17]2[CH:16]=1>>[Br:14][C:15]1[S:19][C:18]2=[N:20][C:21]([C:23]([NH:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=3)=[O:24])=[CH:22][N:17]2[CH:16]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (4-(trifluoromethoxy)phenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.