Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:15])(=[O:14])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N1C=C[CH:19]=[CH:18][CH:17]=1.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:19]([O:14][C:1](=[O:15])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:18]=[CH2:17]
Reactant: CCCCCCC=CC=C/C=C/C(=O)O
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=CCOC(=O)/C=C/C=CC=CCCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.2 g of 3,7,11-trimethyl-2-cis/trans, 4-cis/trans, 10-cis/trans-tridecatrienoic acid are dissolved in 65 ml of absolute benzene and 3.5 ml of pyridine and then treated at a temperature between 5° C and 10° C with 3.4 ml of thionyl chloride (dropping time ca 15 minutes). The mixture is subsequently stirred for 1 hour at room temperature, then the liquid is decanted off and the residue is washed out with benzene. The solution is evaporated to dryness under anhydrous conditions. The residue is dissolved in 20 ml of absolute benzene and added dropwise at a temperature between 5° C and 10° C to a solution of 3.6 ml of allyl alcohol and 3.5 ml of pyridine in 50 ml of benzene (dropping time ca 30 minutes). After stirring overnight at room temperature, the solution is diluted with ether and washed with 1-N aqueous hydrochloric acid, then with saturated aqueous sodium bicarbonate solution and finally with sodium chloride solution. After drying, the ether phase is evaporated. The crude product is chromatographed on the 30-fold amount of Kieselgel (eluant: hexane/ether 19:1 parts by volume). 3,7,11-Trimethyl-2-cis/trans, 4-cis/trans, 10-cis/trans-tridecatrienoic acid allyl ester is obtained as a colorless oil of boiling point 120° C/0.05 mmHg (bulb-tube); nD25 = 1.5026.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.S([O-])(O)(=O)=O.[K+].O>C1COCC1.[Li]CCCC.CCCCCC>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]2)(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(C(=O)O)c3ccccc32)cc1
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
To a solution of 300 mg of 1H-indole-3-carboxylic acid in 9 mL of THF, 2.68 mL of 1.60 M n-BuLi hexane solution was added dropwise while the inner temperature was kept at −50° C. or lower by cooling in a dry ice-acetone bath, and the resulting mixture was stirred at the same temperature for 5 minutes, then at 0° C. for 1 hour. The solution was cooled in a dry ice-acetone bath and a solution of 461 mg of 4-methoxybenzenesulfonyl chloride in 1 mL of THF was added dropwise. The solution was stirred at 0° C. for 3 hours. To the solution, 20 mL of 5% aqueous potassium hydrogen sulfate solution and 40 mL of water were added in this order, and then the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. To the residue was added 5 mL of ethyl acetate, and the resulting mixture was stirred at room temperature for 15 minutes. The white crystals formed were collected by filtration to obtain 509 mg of 1-[(4-methoxyphenyl)sulfonyl]-1H-indole-3-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([CH3:12])=[CH:4][S:3]1(=[O:14])=[O:13].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClCCCl.C(Cl)Cl>[Br:15][C:4]1[S:3](=[O:13])(=[O:14])[N:2]([CH3:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]=1[CH3:12]
Reactant: CC1=CS(=O)(=O)N(C)c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CC1=C(Br)S(=O)(=O)N(C)c2ccccc21
Reaction time: 48 h

Procedure:
390 mg of 1,4-dimethyl-1H-benzo[c][1,2]thiazin-2,2-dioxide in 20 ml 1,2-dichloroethane are combined with 332 mg of N-bromosuccinimide and 50 mg of 2,2′-azodiisobutyronitrile. The yellow solution is refluxed for a total of 10 h and then left to stand for another two days at ambient temperature. The reaction mixture is distributed between water and methylene chloride, the organic phase is washed with water, dried over magnesium sulphate and evaporated down. A yellowish resin is left which is purified through a silica gel column with petroleum ether/ethyl acetate (5:1 to 4:1) as eluant. A mixture of 4-bromo-methyl-1-methyl-1H-benzo[c][1,2]thiazin-2,2-dioxide and 3-bromo-1,4-dimethyl-1H-benzo[c][1,2]thiazin-2,2-dioxide is obtained, which is further reacted as it is.
Reaction SMILES: [N:1]#[C:2]Br.O.[CH2:5]([O:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:11]([NH2:22])[CH:10]=1)[CH3:6].C(O)C>C(#N)C>[NH2:1][C:2]1[N:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[C:12]2[CH:13]=[CH:14][C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:23])=[CH:10][C:11]=2[N:22]=1
Reactant: N#CBr
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)nc(N)n2C1CCCCC1

Procedure:
5 M cyanogen bromide in acetonitrile (2.25 mL) was added to water (25 mL, 1.4 mol) in a 250 mL round bottom flask at room temperature with stirring. To this was added dropwise a solution of 3-amino-4-cyclohexylaminobenzoic acid ethyl ester (2.25 g, 0.00858 mol) in ethanol (25 mL, 0.43 mol) via an additon funnel over 45 minutes. After 3 hours the reaction was concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution then brine. The organic phase was dried over sodium sulfate and concentrated to a dark solid. The solid was triturated with ethanol, filtered and washed with ethanol to give 1.747 g of the title compound as a grayish solid.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[SH:6][CH2:7][C:8]([OH:10])=O.N1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([N:3]1[C:8](=[O:10])[CH2:7][S:6][C:4]1=[S:5])[CH3:2]
Reactant: CCN=C=S
Reactant: O=C(O)CS
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCN1C(=O)CSC1=S

Procedure:
Ethylisothiocyanate (10 g, 0.115 moles), 7.9 g(0.086 moles) mercaptoacetic acid and 5 mL pyridine in C6H6 was refluxed, cooled and filtered yielding 3-ethylrhodanine, which was used in the next step without any further purification. Reaction of 3-ethylrodanine with piperonal in the presence of sodium acetate was performed in CH3OH under refluxing for 1 h. The yellow precipitate obtained after cooling and filtration, was washed several times with CH3OH on the filter and crystallizated from CH3OH to give 3-ethyl-5-piperilidenerodanine. 1H-NMR(DMSO-d6, 300 MHz):7.72 (s, 1H), 7.1–7.3 (m, 3H), 6.14 (s, 2H), 3.95–4.15 (q, 2H), 1.15–1.20 (t, 3H). 13C-NMR (75.48 MHz): 12.76, 40.28, 103.07, 110.21, 110.47, 120.68, 127.89, 128.07, 134.01, 149.23, 150.74, 167.57, 193.68. (2) 3-Ethyl-5-piperilidene-rodanine (1 g, 3.4 mmoles) was added to a stirred solution of 0.16 g (6.8 mmoles) in 8 mL abs. ethanol and the mixture was refluxed for 30 min. To the solution cooled to room temperature 5 mL H2O were added and the mixture was hydrolized with 10% HCl and extracted with ether. The ether phase was separated, dried (MgSO4) and evaporated to an oil. Since the investigation by TLC of the crude reaction mixture indicated the presence of piperonal, the reaction mixture was dissolved in CH2Cl2 and the obtained solution was washed with 1M NaOH. The aqueous phase was extracted twice with CH2Cl2 and then neutralized with dilute HCl. Free thiol was extracted with ethyl ether. After concentration, the product was purified by column cromatography eluating with hexane/ethyl ether:8/2. Yield 0.4 g (62.4%). 1H-NMR(CDCl3, 300 MHz):7.69 (s, 1H), 7.7.25–7.29 (d, 1H, J 1.46), 7.1–7.18 (m, 1H), 6.85–6.9 (d, 1H, J 8.13), 6.01 (s, 2H), 4.75 (s, 1H), 4.28–4.38 (q, 2H, J 7.12), 1.35–1.42 (t, 3H, J 7.13). 13C-NMR (75.48 MHz): 14.20, 62.5, 101.41, 108.37, 109.43, 121.06, 125.45, 129.20, 134.68, 147.80, 148.05, 165.43.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH:16][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:29]C(C)(Br)C(N)=O.O.[CH3:37][N:38]([CH:40]=[O:41])[CH3:39]>>[CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[N:16]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH2:29][C:40](=[O:41])[N:38]([CH3:39])[CH3:37])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(Br)C(N)=O
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)C2CCCCC2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)N(C)C)c2ccc(Cl)cc2C(=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 g of 5-chloro-2-tosylaminophenyl cyclohexyl ketone are placed in 20 ml of DMF in the presence of 360 mg of 80% sodium hydride, after 15 minutes at RT 5.4 g of the compound prepared in step B are added and the mixture is stirred overnight at RT. The reaction medium is poured into water and the precipitate is filtered off and then taken up with DCM, dried and concentrated. The expected product crystallizes from isopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][CH2:31][F:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][CH2:31][F:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCF)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OCCF)nc1Cl
Yield: 93.2 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(2-fluoroethoxy)piperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (124a) (0.24 g, 0.49 mmol), 2 N lithium hydroxide (4 mL, 8 mmol), methanol (6 mL) and THF (6 mL), to obtain 0.21 g of the title compound as a light brown solid (93%).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19]Br.C(N(CC)CC)C.Cl.[CH3:29][N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][N:8]1[C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][C:4]=2[C:32]2[CH2:31][N:30]([CH3:29])[CH2:35][CH2:34][C:33]1=2
Reactant: Cc1ccc(NN)cc1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1ccccc1CCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2F)CCN(C)C1
Yield: 3 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. p-Tolylhydrazine hydrochloride (500 mg, 3.1 mmol), 2-fluorophenyl ethyl bromide (639 mg, 3.1 mmol), triethyl amine (313 mg, 3.1 mmol) and N-methyl-4-piperidone hydrochloride (692 mg, 4.6 mmol) were combined in ethanol (2 ml) to obtain 30 mg of 5-(2-fluorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole after purification on neutral alumina using ethyl acetate-hexane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:12]1[CH2:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1C=CC=C[CH:38]=1>C1CCCCC1.C(OCC)(=O)C>[C:18]([O:17][CH2:16][C:11]1([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH:12]1[CH2:14][O:15][S:33]([C:30]1[C:31]([CH3:38])=[CH:32][CH:27]=[CH:28][CH:29]=1)(=[O:34])=[O:35])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCC1(COC(=O)c2ccccc2)CC1CO)c1ccccc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1S(=O)(=O)OCC1CC1(COC(=O)c1ccccc1)COC(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 54 %

Procedure:
A solution of 4.5 g (13.2 mmole) of 1,1-bis(benzoyloxymethyl)-2-hydroxymethylcyclopropane in 50 ml of dry pyridine was treated with 7 g (37 mmoles) of p-tosyl chloride and stirred at 22° for 1.5 hours. TLC in cyclohexane-ethyl acetate (2:1) (Rf 0.6) indicated that the reaction was complete. The reaction was concentrated and the residue was dissolved in 150 ml of EtOAc and washed with 50 ml of water, 100 ml saturated NaHCO3, four 250 ml portions of water and 50 ml of saturated NaCl. The ethyl acetate layer was dried (MgSO4), filtered and concentrated to 9 g of residual solid. The crude product was chromatographed on 500 ml of silica gel in cyclohexane-ethyl acetate (5:1). Fractions containing only product were combined and concentrated to give 3.36 g (54%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[N:26]=2)=[CH:21][CH:20]=1)=[C:17]=S>>[F:40][C:37]([F:38])([F:39])[O:36][C:33]1[CH:32]=[CH:31][C:30]([N:27]2[CH:28]=[N:29][C:25]([C:22]3[CH:23]=[CH:24][C:19]([NH:16][C:17]4[O:5][CH2:4][CH2:3][CH:2]([C:6]5[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=5)[N:1]=4)=[CH:20][CH:21]=3)=[N:26]2)=[CH:35][CH:34]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CCO)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(NC4=NC(c5ccc(C(F)(F)F)cc5)CCO4)cc3)n2)cc1

Procedure:
The title compound was prepared with 3-amino-3-(4-(trifluoromethyl)phenyl)propan-1-ol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.10 g, 43%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22](=[O:52])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:51]=[CH:50][C:38]([C:39]([NH:41][NH:42]C(OC(C)(C)C)=O)=[O:40])=[CH:37][CH:36]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:42][NH:41][C:39]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:52])=[CH:26][CH:27]=2)(=[O:33])=[O:32])=[CH:51][CH:50]=1)=[O:40]
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 87 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-[4-({[4-(3-methoxy-3-oxopropyl)phenyl]sulfonyl}amino)benzoyl]hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. for 60 min gave 206 mg of the title compound (87%) as a yellow solid in 98.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[N:14]2[C:15](=[O:27])[C:16](=[O:26])[NH:17][C:18]3[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].F[B-](F)(F)F.[O:33]=[N+:34]=[O:35]>ClCCl>[CH2:6]([O:5][P:4]([CH:9]1[N:14]2[C:15](=[O:27])[C:16](=[O:26])[NH:17][C:18]3[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[C:21]([N+:34]([O-:35])=[O:33])=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)C1CCc2cc(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCc2c([N+](=O)[O-])c(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Reaction time: 15 h
Yield: 52.1 %

Procedure:
812 mg of 9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester is dissolved in 15 ml of dichloromethane and mixed with 531 mg of nitronium tetrafluoroborate at room temperature. It is stirred for 15 hours and concentrated by evaporation. The residue is taken up in ethyl acetate and washed with 5% sodium bicarbonate solution. After column chromatography, 470 mg of 8-nitro-9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester of melting point 254° C. is obtained.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[N:7]=[C:6]([N:19]2[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]2[CH3:25])[CH:5]=1)(=O)[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH3:25][C:20]1[N:19]([C:6]2[CH:5]=[C:4]3[C:1]([CH3:2])=[N:11][CH2:10][CH2:9][N:8]3[N:7]=2)[C:23]([CH3:24])=[CH:22][CH:21]=1
Reactant: CC(=O)c1cc(-n2c(C)ccc2C)nn1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=NCCn2nc(-n3c(C)ccc3C)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 287e(5.40 g, 1.0 eq., 15.6 mmol), CF3COOH (10 mL), and dichloromethane (50 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to afford crude 287f, which was used in the next step without further purification. MS-ESI: [M+H]+ 229.1
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11].[CH3:18][C:19]([CH2:23][OH:24])([CH2:21][NH2:22])[CH3:20].Cl>O>[C:10]([C:12]1[C:13](=[O:14])[N:22]([CH2:21][C:19]([CH3:20])([CH3:18])[CH2:23][OH:24])[C:1]([OH:7])=[CH:2][C:3]=1[CH3:5])#[N:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(CN)CO
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: O
Product: Cc1cc(O)n(CC(C)(C)CO)c(=O)c1C#N

Procedure:
Ethyl acetoacetate (13 g) and ethyl cyanoacetate (11.3 g) were added sequentially to a mixture of neo-pentanolamine (25.7 g) and water (5 cm3) keeping the temperature <10C. The mixture was then refluxed for 16 hrs before drowning into water (50 cm3). The aqueous solution was acidified with hydrochloric acid. The pinkish coloured solid which precipitated on stirring for several hours was isolated by filtration, washed with water and dried under reduced pressure. Yield -13.1 g
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]C.[CH3:11][C:12]([C:15]([NH2:17])=[NH:16])([CH3:14])[CH3:13].Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH3:11][C:12]([C:15]1[NH:17][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:16]=1)([CH3:14])[CH3:13]
Reactant: COC1=C(Br)C(=O)CCC1
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2c([nH]1)CCCC2=O
Temperature: 100 °C
Yield: 36.8 %

Procedure:
To a stirred solution of 2-bromo-3-(methyloxy)-2-cyclohexen-1-one (0.957 g) in anhydrous N,N-dimethylformamide (20 mL) at ambient temperature was added solid tert-butylcarbamidine hydrochloride (0.638 g) and potassium carbonate (1.613 g, 11.67 mmol). The reaction was then heated to 100° C. under an atmosphere of nitrogen for 2.5 h. The reaction was diluted with dichloromethane (50 mL) the resultant solid was removed by filtration. The filtrate was concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (330 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH:24]1[CH:28]=[C:27]([CH2:29][C:30](Cl)=[O:31])[S:26][CH:25]=1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:30](=[O:31])[CH2:29][C:27]3[S:26][CH:25]=[CH:24][CH:28]=3)=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Cc1cccs1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Cc3cccs3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and thiophene-2-acetyl chloride provided the title compound. ESMS [M+H]+: 428.4
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>C1(C)C=CC=CC=1>[O:20]=[C:16]([CH3:15])[CH2:17][C:18]([O:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[O:19]
Reactant: COC(=O)[C@@H](C)O
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)OC(=O)CC(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Methyl (2R)-2-hydroxypropanoate (5.0 g, 48 mmol) and triethylamine (49 mg, 0.48 mmol) are dissolved in toluene (40 ml). At 90° C., diketene (5.2 g, 62.4 mmol) is added dropwise. The reaction mixture is stirred at 100° C. for one hour. After cooling to room temperature, the mixture is poured into ice-water. The phases are separated and the aqueous phase is extracted with toluene two times. The combined organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C(#N)C>[CH2:4]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH2:18][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:25][C:33]2=[O:34])[CH2:15][CH2:16]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
In this reference example, 4.04 g of 1-benzyl-4-[N-(o-aminobenzyl)-amino]-piperidine trihydrochloride, 3.04 g of triethylamine, 2.03 g of 1,1'-carbonyldiimidazole and 50 ml of acetonitrile are mixed and stirred at room temperature for 4 hours. Then, 0.8 g of 1,1'-carbonyldiimidazole is further added to the mixture and the resultant mixture is refluxed with heating for 20 minutes. The solution is cooled to room temperature. The crystals deposited are separated by filtration, washed with water and dried to obtain 2.50 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 1.75 g of the desired product.