Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.CC(C)[O-].[Na+].C([O:17][C:18](=O)[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])=[CH2:20])C.S(=O)(=O)(O)O>C(O)(C)C>[CH3:23][N:22]([CH2:21][CH:19]1[CH2:20][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:18]1=[O:17])[CH3:24]
Reactant: C=C(CN(C)C)C(=O)OCC
Reactant: NNc1ccc(Cl)cc1
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)CC1CN(c2ccc(Cl)cc2)NC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
p-Chlorphenylhydrazine (14.5g) was added to a solution of sodium isopropoxide (2.3g of sodium) in dry isopropanol (200 ml). The solution was boiled under reflux and ethyl-2-dimethylaminomethylacrylate (15.7g) was added in one portion. After boiling for 20 minutes, the solution was cooled to 0° C in a stoppered flask. Sulphuric acid (125 ml, 2N) was added and the mixture was extracted with ether (3 × 250 ml). The ether extract was discarded and the aqueous solution was adjusted to a pH of 8 with sodium hydroxide solution (approx 125 ml, 2N). Extraction of the aqueous mixture with chloroform gave a pale yellow extract, which, after evaporation of the chloroform, gave a buff solid. The solid was recrystallised from carbon tetrachloride as colourless needles of 4-dimethylaminomethyl-p-chlorphenylpyrazolidin-3-one (9g, 35%, melting point 107° C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=2[Cl:11])[CH:5]=[CH:6]1
Reactant: BrCCCCBr
Reactant: Clc1cc(Cl)c2[nH]ccc2c1
Product: Clc1cc(Cl)c2c(ccn2CCCCBr)c1

Procedure:
The procedure is as for Example 39 using as substrate 5,7-dichloro-1H-indole and 1,4-dibromobutane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]([OH:14])=O)=[CH:5]2.[NH2:15][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18]>>[CH2:26]([C@H:16]([NH:15][C:12]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][C:9]=2[F:11])=[O:14])[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1cc2cc(F)cc(F)c2[nH]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(F)cc(F)c2[nH]1

Procedure:
From 5,7-difluoro-1H-indole-2-carboxylic acid and (S)-2-amino-1-(4-hydroxy-piperidin-1-yl)-3-phenyl-propan-1-one. mp 95-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11].N1CCCCC1>CCO>[CH:7]1[CH:6]=[C:3]2[CH:4]=[C:12]([C:10]#[N:11])[C:13]([NH:1][C:2]2=[CH:9][CH:8]=1)=[O:14]
Reactant: CCOC(=O)CC#N
Reactant: Nc1ccccc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1cc2ccccc2[nH]c1=O
Temperature: 75 °C

Procedure:
To a solution of o-aminobenzaldehyde (Sigma) (5.80 g, 48 mmol) in 250 mL of EtOH was added ethyl cyanoacetate (Aldrich) (6.20 mL, 58 mmol) followed by piperidine (Aldrich) (1.4 mL, 14 mmol) at RT. The reaction was heated at 75° C. for 15 h then cooled to RT. The solid was filtered, washed with EtOH and dried in vacuo to give a pale yellow crystalline solid. MS m/z: 171 (M+1); 169 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:23]=1[CH:24]=O.CO>CS(C)=O>[CH3:20][C:15]1[CH:14]=[C:13]([NH:12][S:9]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]=[C:24]([C:23]4[C:22]([Cl:21])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:30])[NH:1][C:2]=3[CH:3]=2)(=[O:11])=[O:10])[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(N)c(N)c2)cc1C
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CO
Solvent: CS(C)=O
Product: Cc1ccc(NS(=O)(=O)c2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A freshly prepared solution of 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzenesulfonamide in DMSO (0.2 M, 0.40 mL) was placed in a vial. To it was added 2,6-dichloro-benzaldehyde (0.2 M in toluene, 0.48 mL), followed by FeCl3 (0.02 M in THF, 0.2 mL). The mixture was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-sulfonic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 446 (M+1).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]=O)=[CH:6][N:5]=1)([CH3:3])[CH3:2].N1C=CC=C[C:15]=1[CH:20]=[O:21]>>[CH:1]([C:4]1[N:5]=[CH:6][C:7]([CH:10]=[CH:11][CH:12]=[CH:15][CH:20]=[O:21])=[CH:8][N:9]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ncc(C=CC=O)cn1
Reactant: O=Cc1ccccn1
Product: CC(C)c1ncc(C=CC=CC=O)cn1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 5 by substituting 3-(2-isopropyl-pyrimidin-5-yl)-propenal (Reference Example 15) for the 2-pyridinecarboxaldehyde of Reference Example 5. MS 203 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccc(F)cc3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 4-fluoro-benzenesulfonyl chloride (73 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-fluoro-benzenesulfonamide (121 mg, 81.3%) as a white solid. MS (ESI+APCI) M+1=479.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](B(O)O)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][C:19]1[O:20][CH2:21][C:22]2([C:36]3[C:31](=[N:32][CH:33]=[C:34]([O:37][CH2:38][C:39](=[O:41])[CH3:40])[CH:35]=3)[O:30][C:29]3[C:24]2=[CH:25][C:26](Br)=[CH:27][CH:28]=3)[N:23]=1.O1CCOCC1>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.O>[NH2:18][C:19]1[O:20][CH2:21][C:22]2([C:36]3[C:31](=[N:32][CH:33]=[C:34]([O:37][CH2:38][C:39](=[O:41])[CH3:40])[CH:35]=3)[O:30][C:29]3[C:24]2=[CH:25][C:26]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:11])=[CH:27][CH:28]=3)[N:23]=1
Reactant: CC(=O)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cc(Cl)ccc1F
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(-c3cc(Cl)ccc3F)ccc1O2
Temperature: 80 °C

Procedure:
A vial charged with 5-chloro-2-fluorophenylboronic acid (0.431 g, 2.474 mmol), palladiumtetrakis (0.057 g, 0.049 mmol), potassium carbonate (0.684 g, 4.95 mmol), and 1-(2′-amino-7-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yloxy)propan-2-one (0.400 g, 0.990 mmol) was treated with 5 mL dioxane followed by 1 mL water. The vial was flushed with argon and was heated to 80° C. for 3 hours. The reaction mixture was diluted with EtOAc (25 mL) and dried over MgSO4. The organic layers were combined and concentrated, and the crude residue was purified by column chromatography yielding 1-(2′-amino-7-(5-chloro-2-fluorophenyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yloxy)propan-2-one. MS m/z=454.0 [M+H].
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:18]([CH2:21][C:22](Cl)=[O:23])=[N+:19]=[N-:20]>CC(C)=O>[N:18]([CH2:21][C:22]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23])=[N+:19]=[N-:20]
Reactant: NCCOCc1ccccc1
Reactant: [N-]=[N+]=NCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-benzyloxyethylamine (15 g) and potassium carbonate (40 g) in acetone (400 ml) was treated dropwise with azidoacetyl chloride at 20° C. After stirring for 3 h at room temperature, the mixture was filtered and concentrated in vacuo. Dichloromethane (800 ml) was added, and the solution was washed with aq. sodium bicarbonate. The organic phase was dried over magnesium sulfate. Removal of solvent in vacuo gave a yellow oil which was filtered through silica gel with ethyl acetate. Removal of the solvent in vacuo gave 6a as a colorless oil. Yield: 22 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:35]1([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)CCCCNC(=O)OC(C)(C)C)c1ccccc1
Yield: 48.1 %

Procedure:
The target compound was prepared as a pale yellow oil in an amount 7.8 g at a yield of 48.1% in the same manner as in Example 1 except that 10 g (45.8 mmol) of 5-(N-t-butoxycarbonylamino)pentanoic acid instead of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 70 ml of THF and 11.1 g (68.7 mmol) of CDI was added; 9.5 ml (72 mmol) of diisopropylamine and 40 ml of THF were added and 42 ml (69 mmol) of 1.63N BA solution was added dropwise; 10.6 g (68.7 mmol) of ethyl phenylacetate instead of methyl phenylacetate was dissolved in 20 ml of THF; and 30 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 70 g of 4N hydrochloric acid was added, and 100 ml of ethylacetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: [F:1][B-](F)(F)F.[C:6]([C:8]1[CH:13]=[C:12]([S:14][C:15]#[N:16])[CH:11]=[CH:10][C:9]=1[N+]#N)#[N:7]>O>[F:1][C:9]1[CH:10]=[CH:11][C:12]([S:14][C:15]#[N:16])=[CH:13][C:8]=1[C:6]#[N:7]
Reactant: N#CSc1ccc([N+]#N)c(C#N)c1
Reactant: F[B-](F)(F)F
Solvent: O
Product: N#CSc1ccc(F)c(C#N)c1
Temperature: 200 °C
Yield: 14.9 %

Procedure:
2-Cyano-4-(thiocyanato)benzenediazonium fluoroborate (2.98 g (10.9 mmol)) was decomposed by first heating with a heat-gun until until the whole mass became black and then by heating to 200° C. in an oil bath for 30 minutes. After cooling, water was added and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then distilled by means of a glass tube oven under reduced pressure, and a fraction which boiled at 180-240 ° C./0.2 mmHg was collected to give 0.29 g (15%) of 2-fluoro-5-(thiocyanato)benzonitrile as a pale yellow-white crystals.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])[O-]>>[N+:1]([C:4]1[C:9]([O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Product: O=C(O)Cc1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Yield: 24.3 %

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (15 g.), 2-chlorophenol (11.7 g.), anhydrous pottassium carbonate (12.8 g.) and cupric oxide (1.5 g.) was treated in a similar manner to the above Preparations to give 2-[2-nitro-3-(2-chlorophenoxy)phenyl]acetic acid (4.6 g.). mp 162° to 164° C. A mixture of thus obtained product, ethanol and a small amount of conc. sulfuric acid was treated in a similar manner to the above to give oily ethyl 2-[2-nitro-3-(2-chlorophenoxy)phenyl]acetate (5 g.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]=O)=O)[CH:2]=1.C(=O)(O)O.[NH2:15][NH:16][C:17]([NH2:19])=[NH:18]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:18]=[C:17]([NH2:19])[N:16]=[N:15][CH:9]=2)[CH:2]=1
Reactant: O=CC(=O)c1cccnc1
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: CCO
Product: Nc1nncc(-c2cccnc2)n1
Yield: 39.4 %

Procedure:
5-(Pyridin-3-yl)-1,2,4-triazin-3-amine (1.5 g, 16% over 2 steps) was prepared from a crude sample of 3-pyridylglyoxal (10.0 g) and aminoguanidine hydrogen carbonate (3.0 g, 22 mmol). The reagents were refluxed in EtOH (100 mL) for 4 hours. The reaction mixture was then cooled, concentrated under reduced pressure and purified by gradient flash chromatography (eluting with 0-30% ethyl acetate/hexane).
Reaction SMILES: C([O:8][CH:9]([CH:14]([CH:16]1[CH2:18][CH2:17]1)[CH3:15])[C:10]([O:12][CH3:13])=[O:11])C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[OH:8][CH:9]([CH:14]([CH:16]1[CH2:18][CH2:17]1)[CH3:15])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(OCc1ccccc1)C(C)C1CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(O)C(C)C1CC1
Reaction time: 6 h

Procedure:
To a stirred solution of methyl 2-benzyloxy-3-cyclopropylbutanoate (1.0 g, 4.0 mmol) and acetic acid (1 mL) in MeOH (25 mL) was added 10% palladium on charcoal (100 mg). Hydrogen gas was bubbled though the stirred solution for several minutes, and the reaction mixture was stirred under an atmosphere of hydrogen for 6 h. Nitrogen gas was bubbled through the solution to purge all of the hydrogen and the catalyst was removed by filtration. The filtrate solvents were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give methyl 2-hydroxy-3-cyclopropylbutanoate as a colorless oil. HPLC RT=2.47 min (Method A); LC-MS m/z=159; 1H NMR 400 MHz, CDCl3, 4.25 ppm (dd, J=3.3, 6.5 Hz, 1H), 3.77 ppm (s, 3H), 2.72 ppm (d, J=6.6 Hz, 1H), 1.05 ppm (m, 1h) 0.95 ppm (d, J=7 Hz, 3H), 0.84 ppm (m, 1H), 0.50 ppm (m, 2H), 0.19 ppm (m, 1H), 0.10 ppm (m, 1H)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([CH:30]2[CH2:32][CH2:31]2)[C:12](=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[CH:5][CH:4]=1)#[N:2].[S].[CH2:34](N)[CH2:35][NH2:36]>>[CH:30]1([N:11]([CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]3[NH:36][CH2:35][CH2:34][N:2]=3)=[CH:8][CH:7]=2)[C:12](=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])[CH2:31][CH2:32]1
Reactant: N#Cc1ccc(CCN(C(=O)CCCNCS(=O)(=O)c2cccc(Cl)c2Cl)C2CC2)cc1
Reactant: NCCN
Agent: [S]
Product: O=C(CCCNCS(=O)(=O)c1cccc(Cl)c1Cl)N(CCc1ccc(C2=NCCN2)cc1)C1CC1

Procedure:
Analogously to 13b), N-cyclopropyl-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}butyramide was prepared from 0.84 g (1.70 mmol) of N-[2-(4-cyanophenyl)ethyl]-N-cyclopropyl-4-[(2,3-dichlorobenzenesulphonyl)methylamino]butyramide, 0.143 g (4.46 mmol) of sulphur and 3 ml of ethylenediamine.
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7].Cl[C:14]1C=C(C=CC=1O)C(O)=O>CO>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([OH:12])=[C:3]([Cl:2])[CH:4]=1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(O)c(Cl)c1
Temperature: 55 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of 3-chloro-4-hydroxy-benzoic acid hemihydrate (9.08 g, 50 mmol) in methanol (150 mL) is added slowly (conc)sulfuric acid (22.5 mL). The resulting solution is heated to 55° C. and stirred 2 hours then cooled to 20° C. Poured solution into ice and extracted with ether. The organic is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 30% ethyl acetate in hexanes) to give 9.5 g of title compound as a white crystalline solid. 1H NMR (CDCl3) δ 3.90 (s, 3H), 7.06 (d, J=9 Hz, 1H), 7.88 (dd, J=9, 2 Hz, 1H), 8.05 (d, J=2 Hz, 1H). MS (EI) m/z 186/188 (M+, Cl).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:20])[N:4]=1.CN(C=O)C.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K]>>[Cl:20][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:3]([CH2:2][N:30]1[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]1=[O:31])=[N:4]2
Reactant: Fc1cccc(-c2nc3c(Cl)cccc3nc2CBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 100 °C

Procedure:
To a heterogeneous mixture of 2-(bromomethyl)-5-chloro-3-(3-fluorophenyl)-quinoxaline (0.2401 g, 0.6829 mmol) in DMF (5.003 mL, 0.6829 mmol) was added potassium phthalimide (0.3162 g, 1.707 mmol) and the heterogeneous mixture was stirred at 100° C. After stirring at 100° C. for 1 h, the mixture was concentrated under reduced pressure and triturated with water (30 mL). The precipitate was collected by filtration. The solid was washed with water (50 mL), then MeOH (100 mL), and dried to give 2-((5-chloro-3-(3-fluorophenyl)-quinoxalin-2-yl)methyl)isoindoline-1,3-dione as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (1H, dd, J=7.6, 1.4 Hz), 7.84-7.92 (5H, m), 7.60-7.81 (4H, m), 7.38-7.46 (1H, m), 5.22 (2H, s); LC-MS (ESI) m/z 418.1 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [CH3:1][CH:2]([NH2:26])[CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1C=[CH:18][CH:17]=[CH:16][N:15]=1)[N:9]=[CH:8]2.IC1C=C2C(=CC=1)N(C1N=CC=CN=1)[N:32]=C2>>[CH3:1][CH:2]([NH2:26])[CH:3]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:15]=[CH:16][CH:17]=[CH:18][N:32]=1)[N:9]=[CH:8]2
Reactant: Ic1ccc2c(cnn2-c2ncccn2)c1
Reactant: CC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Product: CC(N)C(Oc1ccc2c(cnn2-c2ncccn2)c1)c1ccccc1

Procedure:
Prepared as described for 118a using 5-Iodo-1-pyrimidin-2-yl-1H-indazole (120b). Yield 66 mg (20%).
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].Cl[CH:9]([C:15]([C:17]([F:20])([F:19])[F:18])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(Cl)Cl>[CH3:2][CH:1]([NH:4][C:5]1[O:6][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([C:17]([F:18])([F:20])[F:19])[N:7]=1)[CH3:3]
Reactant: CC(C)NC(N)=O
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1oc(NC(C)C)nc1C(F)(F)F
Yield: 47.3 %

Procedure:
By the procedure of Example 4, 6.1 g (60 mmol) of isopropyl urea was reacted with 10.9 g (50 mmol) ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 24 hours. The product mixture was treated with methylene chloride, washed with water, dried and concentrated. The residue was recrystallized from methylcyclohexane to yield 6.3 g of crystal product (m.p.=51°-52° C.) identified in Table I.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](#[N:13])[CH:11]=[CH2:12].C([O-])(=O)C.[Na+]>CN(C)P(=O)(N(C)C)N(C)C.[Pd]>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:12]=[CH:11][C:10]#[N:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CC#N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC=Cc1ccc(C=O)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A stock solution consisting of 0.1041 g (1.25×10-4 mol) of diacetato-bis-(tris-o-tolylphosphine)-palladium(II) in 50 ml of hexamethylphosphoric acid triamide is prepared under argon. 1 ml of stock solution, 9.25 g (50 mmols) of 4-bromobenzaldehyde, 3.66 ml (55 mmols) of acrylonitrile and 4.51 g (55 mmols) of anhydrous sodium acetate are added, under argon, to 19 ml of hexamethylphosphoric acid triamide, and the mixture is stirred at 130° C. for 8 hours. The hexamethylphosphoric acid triamide is removed under a high vacuum and the product is distilled. 6.58 g (41.9 mmols) of 4-formylcinnamonitrile are obtained, corresponding to a yield of 84% of theory (conversion figure 16800; Pd content 0.005 mol %).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=3)[CH2:11][CH2:10]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2cccc(Cl)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc(Cl)c3)CC2)cc1
Yield: 41 %

Procedure:
0.25 g (0.0011 mol) of 1-(3-chloro-benzyl)-piperidin-4-ol and 0.39 ml (0.0028 mol) of triethylamine were dissolved in 11 ml of toluene, treated with 0.184 ml (0.0014 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.155 g (41%) of 1-(3-chloro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a colorless oil.