Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[OH:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].N1C=CC=CC=1>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: OB(O)c1cccc(Br)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C1c2ccccc2C(=O)N1Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.6 %

Procedure:
To a mixture of 3-bromophenylboronic acid (246 mg, 1.23 mmol), 2-hydroxyisoindoline-1,3-dione (100 mg, 0.61 mmol), cupric acetate (223 mg, 1.23 mmol) and activated 4 Å molecular sieves (155 mg) in 1,2-dichloroethane (3 mL) under a nitrogen atmosphere was added pyridine (0.11 mL, 1.35 mmol). The reaction was stirred at ambient temperature for 24 h, concentrated in vacuo and purified by flash column chromatography (82:18 hexanes/ethyl acetate) to provide 2-(3-bromophenoxy)isoindoline-1,3-dione (102 mg, 52%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.93 (dd, J=5.4, 3.0 Hz, 2H), 7.83 (dd, J=5.6, 3.0 Hz, 2H), 7.33 (t, J=2.1 Hz, 1H), 7.29 (dt, J=7.8, 2.0 Hz, 1H), 7.22 (t, J=8.1, 1H), 7.16-7.10 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[C:17]([C:22]([O:24][CH3:25])=[O:23])=[N:18][CH:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1nccnc1Cl
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1nccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
To a 350 mL sealable tubed was added 4-(pyridin-2-ylamino)phenol (5.16 g, 27.7 mmol), methyl 3-chloropyrazine-2-carboxylate (4.78 g, 27.7 mmol), and cesium carbonate (9.93 g, 30.5 mmol) with DMSO. The tube was sealed and heated to 100° C. for three days. After cooling to temperature, the reaction was diluted with water and extracted with ethyl acetate. The combined, dark brown organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The brown residue was adsorbed onto silica under high vacuum and flash purified on (0.5 to 10% MeOH/DCM), affording the product as a pale tan solid (7.44 g, 23.1 mmol, 83%). MS (ESI, pos. ion) m/z: 323.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.Cl.[NH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:13][CH2:14]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CNCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Reaction time: 0.5 h

Procedure:
4-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]benzaldehyde (68 mg, 0.22 mmol) was dissolved in 1,2-dichloroethane (2.2 mL) and treated with ethyl aminoacetate hydrochloride (34 mg, 0.28 mmol) and acetic acid (25 uL, 0.44 mmol). The solution was stirred at ambient temperatures for 30 minutes and treated with sodium triacetoxyborohydride (51 mg, 0.24 mmol). The mixture was stirred at ambient temperature until complete, diluted with ethyl acetate (50 mL) and washed with sodium bicarbonate (2×30 mL, aqueous saturated). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 97:3; dichloromethane:methanol) to afford the titled compound as a clear oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CN(C=O)C>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10](=[O:11])[NH2:12])=[CH:8][CH:7]=2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: NC(=O)c1ccc(OCC2CO2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NCC(O)COc2ccc(C(N)=O)cc2)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 40.1 %

Procedure:
4-Oxiranylmethoxy-benzamide (76 mg, 0.393 mmol) was dissolved in 8 mL of dry DMF, followed by the addition of 4-amino-1-N-boc-piperidine (178 mg, 0.889 mmol). The reaction mixture was stirred at 80° C. for 48 h. The reaction mixture was concentrated and the residue was purified by flash chromatography eluting with 0-5% 2M NH3 in MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 62 mg of 4-[3-(4-carbamoyl-phenoxy)-2-hydroxy-propylamino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.C(N(CC)CC)C.[CH3:29][C:30](=[CH2:34])[C:31](Cl)=[O:32].O>O1CCCC1>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:31](=[O:32])[C:30]([CH3:34])=[CH2:29])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: C=C(C)C(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Yield: 53.1 %

Procedure:
To a solution of 0.5 g (1.48 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile and 0.194 g (1.92 mmol) of triethylamine in 6 ml tetrahydrofuran was added at 0° C., under nitrogen, with stirring, 0.21 g (1.92 mmol) of 2-methyl acryloyl chloride over a 10 minute period. The solution was stirred at room temperature overnight. The mixture was poured into water. The solid was collected and air dried. The solid was washed with bioling ethyl acetate and air dried giving 0.32 g of N-[4-[(3-bromophenyl)amino]-3-cyano -6-quinolinyl]-2-methyl-2-propenamide : mass spectrum (electrospray, m/e): M+H 407, 409.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42](O)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)Cl>[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]
Reactant: Nc1ccc(F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.1 %

Procedure:
4-Fluoroaniline (0.178 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.125 g, 0.268 mmol, 50%).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([Cl:17])[CH:6]=1)[CH3:4].[Mg].[CH:19](=[O:21])[CH3:20].[BH4-].[Na+]>>[Cl:17][C:7]1[CH:6]=[C:5]([CH:3]([CH3:4])[CH2:2][CH:19]([OH:21])[CH3:20])[CH:10]=[CH:9][C:8]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC=O
Reactant: CC(CBr)c1ccc(C2CCCCC2)c(Cl)c1
Agent: [BH4-]
Agent: [Mg]
Agent: [Na+]
Product: CC(O)CC(C)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
4-(3-Chloro-4-cyclohexyl-phenyl)-2-pentanol was prepared analogous to Example 64 from a Grignard reagent, prepared from 91.55 gm (0.29 mol) of 1-bromo-2-(3-chloro-4-cyclohexyl-phenyl)-propane and 7.08 gm (0.291 mol) of magnesium, and 14.2 gm (0.32 mol) of acetaldehyde, followed by reduction with sodium borohydride. The above compound was obtained as a mixture of the two possible pairs of diastereomeric isomers. The colorless oil (39.5 gm; 48% of theory) was not sufficiently heat-stable for distillation, and therefore had to be chromatographically purified (silicagel; benzene as the eluant).
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH:15]=[C:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCOCC1.[Pd]>[O:1]([CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCOc3ccccc3)cc2)S1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCOc3ccccc3)cc2)S1

Procedure:
5-[4-(2-Phenoxyethoxy)benzylidene]-2,4-thiazolidinedione (4 g) in dry 1,4-dioxan (200 ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (8 g) at ambient temperature and atmospheric pressure until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (mp 133° C.) was obtained after crystallisation from methanol.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Methyl 2-chloroisonicotinate (300 mg, 1.75 mmol) obtained in Step 1 of Reference Example 5 was dissolved in toluene (3.5 mL), and the solution was added with palladium acetate (11.8 mg, 0.0525 mmol), 2,2′-bis(diphenylphosphino)-2,2′-binaphthyl (49.1 mg, 0.0788 mmol), cesium carbonate (798 mg, 2.45 mmol) and 4-fluorophenylboronic acid (294 mg, 2.10 mmol), followed by stirring at 100° C. for 1 hour under argon atmosphere. After an insoluble matter of the reaction mixture was filtered off, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95 to 10/90) to obtain Methyl 2-(4-fluorophenyl)isonicotinate (284 mg, 70%).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:16]=[C:15]([CH2:17][CH2:18]O)[O:14][N:13]=2)[CH:7]=1.[OH-].[Na+]>>[CH:17]([C:15]1[O:14][N:13]=[C:12]([C:8]2[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=2)[CH:16]=1)=[CH2:18]
Reactant: OCCc1cc(-c2cccnc2)no1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1cc(-c2cccnc2)no1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Five ml. of concentrated sulfuric acid was cooled to 0°C. in an ice bath and added directly to 0.5 g. of 3-(3-pyridyl)-5-isoxazoleethanol. The reaction was allowed to stir 1/2 hour at 0°C. and then was poured over 50 g. of ice. The resulting solution was made basic with 5N NaOH, and was extracted with CHCl3. The organic layer was dried over sodium sulfate. Removal of the solvent resulted in a white oil which crystallized on standing, m.p. 60°-64°C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[CH2:25][C@@H:24]2[C:26]([NH:28][C@@H:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:33][N:32]=2)[CH3:30])=[O:27])=[CH:19][CH:18]=1.O>ClCCl>[F:42][C:39]([F:40])([F:41])[CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:29]([NH:28][C:26]([C@H:24]2[CH2:25][C@@H:23]2[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:22][CH:21]=2)=[O:27])[CH3:30])=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(O)cc1)c1ccc(OCC(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(OCC(=O)OC(C)(C)C)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
A mixture of tert-butyl 2-bromoacetate (0.063 ml, 0.434 mmol), potassium carbonate (109 mg, 0.789 mmol) and (1S*,2S*)-2-(4-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (150 mg, 0.394 mmol) in dichloromethane (4 ml) was refluxed with stirring for 3 hours. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from tetrahydrofuran/hexane. To give 137 mg (70% yield) of title compound as a white crystal:
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=4[F:43])=[O:31])=[CH:25][CH:24]=3)[C:14]([CH2:16][CH2:17][C:18](OCC)=[O:19])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.CC(C[AlH]CC(C)C)C>CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:34]=4[F:43])=[O:31])=[CH:25][CH:24]=3)[C:14]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)CCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncnn2cc(CCCO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of THF (6 mL) was added ethyl 3-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino }carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)propanoate (62 mg, 0.12 mmol) followed by DIBAL (0.6 mL, 0.6 mmol, 1.0M solution in toluene). The reaction was stirred at rt for 1 h. Additional DIBAL (1.2 mL, 1.2 mmol, 1.0M solution in toluene) was added and stirred at rt for an additional 1 h. The reaction was diluted with EtOAc and quenched with saturated aqueous Rochelle's salt. Reaction was extracted with EtOAc (4×). The combined organic layers were dried (Na2SO4), filtered, and evaporated to dryness to afford a crude yellow solid (56 mg, 98%) that was used directly in the next step without further purification. 1H-NMR (CD3OD) δ 8.62 (d, J=7.6 Hz, 1H), 7.74 (s, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.52 (s, 1H), 7.38 to 7.31 (m, 4H), 3.50 (t, J=7.1 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H), 1.77 to 1.65 (m, 2H); MS [M+H]+=489; LCMS RT=2.50 min.
Reaction SMILES: N[C:2](=[C:9]([C:14](=[O:24])[CH2:15][CH:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([NH:12][CH3:13])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.CCOCC>C(O)C>[C:3]1([C:2]2[O:23][CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][C:14](=[O:24])[C:9]=2[C:10]([NH:12][CH3:13])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNC(=O)C(C(=O)CC(O)c1ccccc1)=C(N)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CNC(=O)C1=C(c2ccccc2)OC(c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 21.4 grams (0.066 mole) of 2-(α-aminobenzylidene)-5-hydroxy-N-methyl-3-oxo-5-phenylvaleramide in 220 milliliters of ethanol is treated by dropwise addition with 10 milliliters of concentrated hydrochloric acid. The resulting suspension is stirred for 1.5 hours at room temperature. Ether is then added, and the mixture is filtered. The resulting solid is triturated thoroughly with hot methanol to give 5,6-dihydro-2,6-diphenyl-N-methyl-4-oxo-4H-pyran-3-carboxamide, m.p. 212° C. - 214° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl.Cl[CH2:37][C:38]1[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:37][C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: Cn1nccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ccnn6C)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 5-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride (50.1 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. Another portion of 5-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride (50.1 mg) and potassium carbonate (62 mg) was added and the mixture was shaken again for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 27.8 mg; LC (method 11): tR=1.13 min; Mass spectrum (ESI+): m/z=557 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:27])[CH2:12][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)(O)[C:14]([F:17])([F:16])[F:15])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.N1C=CC=CC=1>C(Cl)Cl.[NH4+].[Cl-]>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:27])[CH:12]=[C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:14]([F:15])([F:16])[F:17])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1cc2c(Cl)cccc2s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1cc2c(Cl)cccc2s1
Yield: 99.2 %

Procedure:
Stir a mixture of 1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one (1.1 g, crude, 2.43 mmol), SOCl2 (1.16 g, 0.7 mL, 9.43 mmol) and pyridine (384 mg, 0.4 mL, 4.86 mmol) in anhydrous DCM (10 mL) at ambient temperature for overnight. Dilute the mixture with saturated NH4Cl solution and extract the aqueous mixture with DCM (10 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to afford crude 1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-one as brown solid (1.05 g, 100%). 1H NMR (400 MHz, CDCl3) δ8.12-8.10 (s, 1H), 7.69-7.64 (m, 1H), 7.47-7.44 (m, 2H), 7.38-7.35 (m, 2H), 7.27-7.24 (m, 1H), 6.96-6.92 (s, 1H).
Reaction SMILES: NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1.[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[Cl:44])[CH:33]=[CH:32][C:31]=1[C:45]([C:47]1[CH:52]=[C:51]([N+:53]([O-])=O)[CH:50]=[CH:49][C:48]=1[CH3:56])=[O:46]>>[NH2:53][C:51]1[CH:50]=[CH:49][C:48]([CH3:56])=[C:47]([C:45]([C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[Cl:44])=[CH:35][C:30]=2[Cl:29])=[O:46])[CH:52]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 415, using compound 420 (0.21 mmol). The crude product was used without any further purification.
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([CH2:41]Br)[CH:38]=[CH:37][C:36]=1[N+:43]([O-:45])=[O:44])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[CH2:9]([CH:8]([CH2:41][C:39]1[CH:38]=[CH:37][C:36]([N+:43]([O-:45])=[O:44])=[C:35]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:40]=1)[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CCc1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)C(Cc1ccccc1)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,3 diphenylpropan-1-one (231 mg, 1.1 mmol) in THF (2.5 mL) at −78° C. is added dropwise LiHMDS (1M in THF, 1.3 mL), over a period of 15 min. The mixture is stirred at −78° C. for 30 min then a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (321 mg, 1 mmol) in THF (2.5 mL) is added over a period of 15 min. The mixture is stirred at −78° C. for 15 min, then allowed to slowly warm to RT and stirred there for 45 min. The mixture is diluted with EtOAc, cooled to −25° C. and a solution of saturated ammonium chloride is added dropwise. The organic phase is washed with saturated ammonium chloride and brine, dried over MgSO4, filtered and concentrated to afford crude product which is purified using flash chromatography to give the title compound as a gum.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:20]=[C:19]([CH:21]([NH2:23])[CH3:22])[C:18]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)=[C:17]2[C:13]=1[CH:14]=[N:15][N:16]2[CH3:32].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[CH:20]=[C:19]([CH:21]([NH:23][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:22])[C:18]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)=[C:17]2[C:13]=1[CH:14]=[N:15][N:16]2[CH3:32]
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2cnn(C)c2c1-c1cc(F)cc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cnn(C)c2c1-c1cc(F)cc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (0.30 g, 1.5 mmol), 1-[4-chloro-7-(3,5-difluorophenyl)-1-methyl-1H-indazol-6-yl]ethanamine (0.439 g, 1.36 mmol), and N,N-diisopropylethylamine (0.48 mL, 2.7 mmol) in isopropyl alcohol (5 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H17ClF2N7 (M+H)+: m/z=440.1; Found: 440.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (1H, br s), 8.10 (1H, s), 8.05 (1H, s), 8.04 (1H, s), 7.62 (1H, s), 7.52 (1H, d, J=8.8 Hz), 7.43 (1H, m), 7.31 (1H, d, J=8.8 Hz), 5.10(1H, br s), 3.41 (3H, s), 3.35 (1H, m), 1.41 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376 MHz) δ −110 ppm.