Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:29][C:30]([F:46])([F:45])[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[C:41]([CH2:43][NH2:44])[CH:40]=[CH:39][N:38]=2)=[CH:33][CH:32]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([NH:44][CH2:43][C:41]2[CH:40]=[CH:39][N:38]=[C:37]([C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:46])([F:29])[F:45])=[CH:32][CH:33]=3)[CH:42]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20.3 %

Procedure:
A solution of acid 4A (260 mg, 1 mmol) in THF (25 mL) was added with DEPC (0.18 mL, 1.3 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv., 277.5 mg) was added. The reaction mixture was then stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (30 mL) and washed with water (50 mL) and brine. The separated organic phase, after anhydrification over Na2SO4, was evaporated under reduced pressure and the residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a pale yellow solid (100 mg) after crystallization from a mixture of diethyl ether/petroleum ether. Yield=49%, 1HNMR (DMSO, 400 MHz) δ 2.93 (3H, s), 4.48 (d, 2H, J=6 Hz), 5.08 (s, 1H), 5.87 (s, 1H), 7.35 (d, 1H), 7.37 (t, 2H, J=8.8 Hz), 7.82 (m, 4H), 8.03 (s, 1H), 8.28 (d, 2H, J=8.4 Hz), 8.63 (d, 1H, J=5.2 Hz), 8.95 (bt, 1H); [M+1] 494.47 (C23H19F4N3O3S requires 493.47).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:17][CH2:18][CH:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][CH:19]1[CH2:20][O:21][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:10]1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1
Reactant: OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: ClCC1COC(Cc2ccc(Cl)cc2)(c2ccccc2)O1
Yield: 98 %

Procedure:
69 g (0.3 mol) of phenyl 4-chlorophenylmethyl ketone, 66.3 g (0.6 mol) of 3-chloropropane-1,2-diol and 5.2 g (0.03 mol) of p-toluenesulphonic acid in 600 ml of toluene are refluxed for three days in a water separator. The reaction mixture, when it is cold, is extracted with sodium bicarbonate solution, dried over sodium sulphate and evaporated down in vacuo. 95 g (98% of theory) of 4-chloromethyl-2-(4-chlorophenylmethyl)-2-phenyl-1,3-dioxolane of melting point 65° C. are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:4][CH:5]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: C1CCNC1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccc(Cl)cc1)c1ccc(CN2CCCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
Acetonitrile (55 ml) was added to [4-(bromomethyl)phenyl](4-chlorophenyl)methanone (6.71 g, 21.7 mmol), potassium carbonate (5.99 g, 43.3 mmol) and pyrrolidine (3.62 ml, 43.3 mmol), and the mixture was stirred at 80° C. for 16 hrs. The solvent was concentrated, and diethyl ether was added to the residue. The mixture was extracted with 1N hydrochloric acid. The extract was basified with potassium carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the solvent was evaporated under reduced pressure. The obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate) to give the title compound (4.79 g).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1/[CH:8]=[CH:9]/[CH:10]=[O:11])([O-:5])=[O:4].[Cl-].[Ce+3].[Cl-].[Cl-].[NH4+].[Cl-]>CO>[N+:3]([C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[CH:8]=[CH:9][CH2:10][OH:11])([O-:5])=[O:4]
Reactant: O=C/C=C/c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: O=[N+]([O-])c1ccccc1C=CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (1.15 g, 31.1 mmol) was added portionwise to an ice cooled suspension of trans-2-nitrocinnamaldehyde (5.00 g, 28.2 mmol), and cerium (III) chloride (12.61 g, 33.8 mmol) in methanol (140 ml). After stirring at room temperature for 30 minutes the mixture was poured into saturated aqueous NH4Cl (200 ml), extracted with DCM (3×150 ml) and the extacts dried (MgSO4). Filtration and evaporation of the solvent gave the product. (5.03 g, 100%)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:3][CH2:2]1.[ClH:41].COC(C)(C)C>CC(O)C.O1CCOCC1>[ClH:41].[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:3][CH2:2]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCNCC1
Temperature: 80 °C

Procedure:
tert-Butyl 4-[({7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}carbonyl)amino]piperidine-1-carboxylate from example D.e1 (2.72 g; 4.95 mmol) is dissolved in dry 2-propanol (50 mL). After addition of 4M HCl in dioxane (5.0 mL) the stirred reaction mixture is heated to 80° C. for two hours. At ambient temperature tert.-butyl methyl ether (100 mL) is added. The precipitated product is isolated by suction filtration, washed with several portions of tert.-butyl methyl ether and dried in high vacuo at 40° C. to yield of the title compound as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[C:4]([CH3:20])[N:3]=1.[N+:21]([O-])([OH:23])=[O:22]>OS(O)(=O)=O.O.C([O-])([O-])=O.[Na+].[Na+]>[NH2:1][C:2]1[C:7]([N+:21]([O-:23])=[O:22])=[CH:6][C:5]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])=[C:4]([CH3:20])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(N)ccc1CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1nc(N)c([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-amino-6-methyl-5-(phthalimidomethyl)pyridine (3.00 g, 11.2 mmol) in H2SO4 (17 mL) at 0° C. was added HNO3 (583 μL) dropwise. The solution was stirred for 1 h at 0° C. and was then warmed to room temperature at which it was stirred for an additional 3 h. The reaction was diluted with water and neutralized with solid Na2CO3. The resulting orange precipitate was filtered and washed with water. Silica gel chromatography (gradient 3% MeOH/CHCl3 to 4% MeOH/CHCl3) afforded the title compound as a bright yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:9]([NH:16][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(Cl)n1
Reactant: NCc1ccccc1
Solvent: CCO
Product: Oc1cccc(NCc2ccccc2)n1
Temperature: 25 °C

Procedure:
6-Chloro-2-pyridinol (6.1 g, 0.047 mole) and 10.1 g (0.094 mole) of benzylamine were mixed and heated in an oil bath at 120°-130° for 48 hours. The liquid mass gradually solidified. The cooled mixture was boiled with 100 ml of 50% aqueous ethanol and cooled to 25° C.; the supernatant was decanted from a gum (which was saved), cooled to 5° C., decanted from black tar, and diluted with 50 ml of water. A grey, granular solid, m.p. 158°-162° C., crystallized. An additional quantity of the same material was recovered as follows: The retained gum was digested with 50 ml of hot 95% ethanol until it was solid; the mixture was cooled to 5° C., the solid removed, and the filtrate diluted with water. The total yield of the title compound was 2.4 g (25%). Recrystallization from benzene-n-hexane raised the m.p. to 164°-165°. 1H nmr (CDCl3 +D2O, 100 MHz), δ4.28 (s, 2H, CH2), 5.28 (d, 1H, H5, J=8 Hz), 5.50 (d, 1H, H3, J=9 Hz), 7.17 (t, 1H, H4, J=8 Hz), 7.30 (s, 5H, C6H5).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([CH2:9][CH3:10])[NH:4][N:3]=1.CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=O>C(O)(=O)C>[CH2:9]([C:5]1[C:6]([C:7]#[N:8])=[C:2]2[N:1]=[CH:13][CH:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:3]2[N:4]=1)[CH3:10]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: CCc1[nH]nc(N)c1C#N
Solvent: CC(=O)O
Product: CCc1nn2c(-c3cccnc3)ccnc2c1C#N

Procedure:
As for Example 2, 2.72 g. of 3-amino-5-ethylpyrazole-4-carbonitrile is heated at reflux temperature for 16 hours with 3.52 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 25 ml. of glacial acetic acid to give 2.65 g. of the product of the example as colorless crystals, m.p. 170°-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:13])[CH2:11][Cl:12])=[C:7]([O:14][CH3:15])[N:6]=[CH:5][N:4]=1.[NH:16]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[N:17]1.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[NH:16]1[CH:20]=[CH:19][C:18]([CH2:21][N:9]([C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[N:6][C:7]=2[O:14][CH3:15])[C:10](=[O:13])[CH2:11][Cl:12])=[N:17]1
Reactant: ClCc1cc[nH]n1
Reactant: COc1ncnc(OC)c1NC(=O)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ncnc(OC)c1N(Cc1cc[nH]n1)C(=O)CCl
Temperature: 0 °C

Procedure:
347 g of N-(4,6-dimethoxypyrimidin-5-yl)-chloroacetamide, 60 g benzyltriethylammoniumchloride, 3 l CH2Cl2 and 252 g 1-pyrazolylmethylchloride are charged in a sulphonation flask and thereto added, quickly, 750 ml 30% aqueous NaOH (w/w) while cooling on a ice bath. The reaction temperature rises from 13° to 25°. The reaction mixture is further stirred under continued cooling on the ice bath until the temperature reaches 23°. Then the ice bath is removed and the reaction is stirred further for 2 hours. The reaction mixture is then diluted with 1.5 l of water and stirred. The organic phase is partitioned off, dried with Na2SO4 and filtered over a 6 cm SiO2 layer. The SiO2 -layer is washed with 10 l diethylether. The resulting reaction mixture is concentrated to 1.5 l and the precipitate, which has been falling out is filtered off and washed with pentane, then it is dried under vacuum at 50° to give the title compound m.p. 117°-119°.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[C:14]=2[NH:18][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[C:23]([C:32]([F:33])([F:35])[F:34])[CH:24]=2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Temperature: 50 °C
Reaction time: 120 h

Procedure:
A reaction vial was charged with (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (210 mg, 0.00071 mol), 2-(4-fluoro-3-(trifluoromethyl)phenyl)acetic acid (300 mg, 0.001 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (600 mg, 0.002 mol), N,N-diisopropylethylamine (600 μL, 0.003 mol) and the reaction was stirred at 50° C. for 5 days. At this point, the reaction was only 50% complete. The solvent was removed and the residue purified by flash chromatography to obtain the product as a light yellow oil. MS m/z=499.3 (M+H).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:32]=[CH:31][C:8]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:30])[NH:19][C:20]3[C:25]\2=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(O)=[O:2].[NH4+].O[N:35]1C(=O)CCC1=O>>[NH2:35][C:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:30])[NH:19][C:20]3[C:25]\2=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:31][CH:32]=1)=[O:2]
Reactant: O=C1CCC(=O)N1O
Reactant: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CC(=O)O)cc1)c1ccccc1)C(=O)N2
Agent: [NH4+]
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CC(N)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 3-(Z)-(1-[4-(carboxymethyl)-anilino]-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-hydroxy-succinimide-ammonium salt
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=O)[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.C(OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1
Reactant: CCC(CC)n1c(=O)[nH]c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(OCC)OCC
Product: CCC(CC)n1cnc2cnc(Cl)nc21
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 2-chloro-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one (0.5 g, 2.3 mmol) in DMF (5 mL) is added triethyl orthoformate (3.8 mL, 23 mmol) and TsOH (0.88 g, 2.6 mmol). The reaction is stirred overnight. The reaction mixture is quenched with ice water and extracted with EtOAc. The extracts are dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (SiO2, EtOAC/Hexane 1:3) gives 0.39 g of 2-chloro-9-(1-ethyl-propyl)-9H-purine.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc(N)c1C
Temperature: 80 °C
Yield: 75.1 %

Procedure:
To a stirred solution of methyl 2-methyl-3-nitrobenzoate (10.0 g, 56.4 mmol) in 60 ml of ethanol were added ammonium chloride (18.0 g, 338 mmol) dissolved in 60 mL of water and iron powder (18.8 g, 338.2 mmol). The resulting reaction mixture was heated at 80° C. for 3 h. Water was added to the reaction mixture and then it was filtered through celite. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4, concentrated under reduced pressure to give the title compound (7.0 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24].CN1CCOCC1>CO>[F:21][C:22]([F:26])([F:25])[CH2:23][NH:24][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCC(F)(F)F
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCC(F)(F)F)cc2s1
Yield: 9.4 %

Procedure:
the title compound (11 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 2,2,2-trifluoroethylamine (48 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 392.4 (M+1, 100%). Yield=9%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][N:27]=2)=[CH:34][CH:35]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: COc1ccnc(Oc2ccc(I)cc2)n1
Product: COC(=O)C(C/C=C/c1ccc(Oc2nccc(OC)n2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 32.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (60 mg) was reacted with 2-(4-iodophenoxy)-4-methoxypyrimidine (78 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxypyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (32 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1→cyclohexane/chloroform=1/1→1/10→0/1) was used for purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(OP([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(OCC)=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[CH:18]=[C:17]([CH:19]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:16]=[CH:15][N:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(-c2cc(C=O)ccn2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C=Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Reaction time: 3 h

Procedure:
2-(3,4,5-Trimethoxyphenyl)pyridine-4-carboaldehyde (507 mg) and ethyl diethylphosphonoacetate (570 μL) were dissolved in tert-butanol (16 mL), and to the solution potassium carbonate (438 mg) was added. The mixture was stirred for 3 hours under reflux and concentrated under reduced pressure. The residue was dissolved in chloroform, and the solution was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: N1C=CC=CC=1C[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.OC1(CC2C=CC=CN=2)C2C(=CC=CC=2)NC1=O.CO>O1CCCC1>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(Cc2c[nH]c3ccccc23)nc1
Agent: O=C1Nc2ccccc2C1(O)Cc1ccccn1
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pyridin-2-ylmethyl-1H-indole (Ind-49) A 2 M solution of borane-dimethyl sulfide complex (20 ml, 40 mmol) was added to a solution of 3-hydroxy-3-pyridin-2-ylmethyl-1,3-dihydroindol-2-one (4.80 g, 20 mmol) in anhydrous tetrahydrofuran (250 ml) and the mixture was stirred at room temperature overnight. Methanol (10 ml) was cautiously added to the reaction mixture and the mixture was concentrated i. vac. Methanol was repeatedly added to the residue, the mixture was in each case concentrated again i. vac., and the residue was taken up in 1N hydrochloric acid. The aqueous suspension was extracted with ethyl acetate (2×40 ml). The aqueous phase was adjusted to pH 10 with saturated potassium carbonate solution and extracted with ethyl acetate (3×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (4.0 g) was purified by flash chromatography (400 g, 20×7.6 cm) first with ethyl acetate/cyclohexane (2:1) and then chloroform.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1>C1COCC1>[Br:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])([CH3:1])[CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Oc2ccc(Br)cc2)cc1
Reaction time: 3 h

Procedure:
A 1.4 M solution of methylmagnesium bromide in THF (7.36 ml; 10.304 mmol) was added to a stirred solution of 4′-(4-bromophenoxy)acetophenone (1 g, 3.435 mmol; [CAS: 54916-27-7]) in THF (40 ml) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 3 hours. The reaction was quenched by the addition of an aqueous solution of saturated ammonium chloride and extracted with EtOAc. The combined organic extracts were dried (Na2SO4) and the solvent was evaporated to dryness. The crude residue was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D28 (0.8 g, 75%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:17]=[CH2:18])[CH:16]=1>CO.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][CH3:18])[CH:16]=1
Reactant: C=Cc1cncc(-c2cc3ccccc3n2C)c1
Agent: [Pd]
Solvent: CO
Product: CCc1cncc(-c2cc3ccccc3n2C)c1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
To a solution of 1-methyl-2-(5-vinyl-pyridin-3-yl)-1H-indole (Example 105, 0.473 g, 2.02 mmol) in methanol (10 mL) is added palladium on carbon (0.215 g, 0.202 mmol). The reaction mixture is stirred at 55° C. under H2 for 16 h. It is then cooled to room temperature and filtered through celite. The celite layer is washed with methanol thoroughly and the combined filtrate is concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:1) to afford 1-methyl-2-(5-ethyl-pyridin-3-yl)-1H-indole as a yellow oil. MS (ESI) m/z 237.24 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[C:16](O)=[O:17].O>C(OCC)C.O1CCCC1>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[CH2:16][OH:17]
Reactant: O=C(O)c1cc2ccccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Lithium aluminium hydride (467 mg, 12.3 mmol) was suspended in diethyl ether and the suspension was heated under reflux. The suspension was added dropwise with 1-benzofurane-2-carboxylic acid (2.00 g, 12.3 mmol), dissolved in tetrahydrofuran (10 ml) and further heated under reflux for 20 minutes. The reaction mixture was cooled to 0° C., and then added with water (0.8ml) and stirred at the same temperature for 30 minutes. Insoluble solids were removed by filtration using Celite, and then the solvent was evaporated under reduced pressure to obtain the title compound as yellow oil (1.72 g, yield: 94%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][CH2:6][C:7](Br)=[O:8].[CH3:10][O:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13]>C(Cl)Cl>[CH3:10][O:11][C:12]([C:14]1[CH:18]=[C:17]([C:7](=[O:8])[CH2:6][Br:5])[S:16][CH:15]=1)=[O:13]
Reactant: COC(=O)c1ccsc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1csc(C(=O)CBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
Aluminium trichloride (4.26 g, 32.0 mmol) was dissolved in DCM (15 mL) and cooled to 0° C. Bromoacetyl bromide (1.78 mL, 20.4 mmol) was added slowly as a solution in DCM (7 mL) and stirred at 0° C. for 1 hour. Thiophene-3-carboxylic acid methyl ester (2.89 g, 20.4 mmol) was then added slowly as a solution in DCM (15 mL) and the mixture stirred overnight warming to room temperature. The mixture was poured into ice/water and extracted with DCM (×2) then the organics were washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on a 50 g silica II cartridge, eluting with 2:1 pentane:DCM to neat DCM, to give the title compound as a white solid (2.1 g). 1H NMR (400 MHz, CHCl3-d): δ 8.4 (d, 1H), 8.2 (d, 1H), 4.4 (s, 2H), 3.9 (s, 3H).