Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(S([Cl:18])(=O)=O)=CC=1Cl)(=O)C1C=CC=CC=1.[Cl:20][C:21]1[CH:39]=[CH:38][C:24]([C:25]([C:27]2[CH:28]=[C:29]([S:34]([Cl:37])(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=2[Cl:33])=[O:26])=[CH:23][CH:22]=1.C(C1C=C(S(Cl)(=O)=O)C=CC=1Cl)(=O)C1C=CC=CC=1.ClC1C=CC(S(Cl)(=O)=O)=CC=1C(C1SC=CC=1)=O>>[Cl:18][C:23]1[CH:22]=[C:21]([Cl:20])[CH:39]=[CH:38][C:24]=1[C:25]([C:27]1[CH:28]=[C:29]([S:34]([Cl:37])(=[O:35])=[O:36])[CH:30]=[CH:31][C:32]=1[Cl:33])=[O:26]
Reactant: O=C(c1ccc(Cl)cc1)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: O=C(c1ccccc1)c1ccc(S(=O)(=O)Cl)cc1Cl
Agent: O=C(c1ccccc1)c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: O=C(c1cccs1)c1cc(S(=O)(=O)Cl)ccc1Cl
Product: O=C(c1ccc(Cl)cc1Cl)c1cc(S(=O)(=O)Cl)ccc1Cl

Procedure:
3-benzoyl-4-chlorobenzenesulphonyl chloride 3-(4-chlorobenzoyl)-4-chlorobenzenesulphonyl chloride 4-benzoyl-3-chlorobenzenesulphonyl chloride and 4-chloro-3-(2-thienoyl)benzenesulphonyl chloride.
Reaction SMILES: [Br:1]Br.C(OC([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[O:19])[CH:14]=[CH:13][N:12]=1)=O)(C)(C)C>C(O)(=O)C>[BrH:1].[NH2:10][C:11]1[CH:16]=[C:15]([CH:17]([Br:1])[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[O:19])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1cccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Cc1cccc(C(=O)C(Br)c2ccnc(N)c2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
Bromine (3.2 mL, 62 mol) was added to a solution of 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone (20 g, 61 mmol) in acetic acid (60 mL) and the mixture was stirred at 80° C. for 2 hours. After the reaction mixture was cooled to room temperature, the precipitate was filtered to obtain 19 g (yield 81%) of the title compound.
Reaction SMILES: I.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17](SC)=[NH:18])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:27](O)=O.[NH2:40][NH2:41]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:41][N:40]=[C:17]([NH:16][C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH:14]=[N:13][C:12]([CH3:15])=[N:11]3)=[C:4]([O:3][CH3:2])[CH:5]=2)[N:18]=1)[C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:32][CH:31]=1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(C)n1
Reactant: CS(=O)(=O)c1ccc(C(CCCCCl)C(=O)O)cc1
Reactant: NN
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(S(C)(=O)=O)cc3)n2)ccc1-n1cnc(C)n1

Procedure:
Methyl 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.250 g, 0.617 mmol), from preparation F) and 6-chloro-2-(4-(methylsulfonyl)phenyl)hexanoic acid (0.282 g, 0.925 mmol, from preparation AAL) were coupled and then reacted with hydrazine (0.077 mL, 2.47 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-(methylsulfonyl)phenyl)pentyl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown residue. The crude product was used in the next step without purification. LC-MS (M+H)+ 530.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])([CH3:12])[CH3:11])=[CH:8][CH:9]=1
Reactant: CCOP(=O)(OCC)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(OCC)C(C)(C)c1ccc(N)cc1
Yield: 99.7 %

Procedure:
The diethyl [2-(4-nitrophenyl)propan-2-yl]phosphonate (103 mg) prepared as described above, was hydrogenated in the presence of 10% Pd/C (50 mg) in MeOH (5 mL) for 4 h. The mixture was filtered and the filtrate concentrated in vacuo to afford 92.5 mg of the desired diethyl [2-(4-aminophenyl)propan-2-yl]phosphonate (yield: 99%), which was used in further chemistries without purification. 1H-NMR (CDCl3, 400 MHz): δ=1.20 (t, J=7.2 Hz, 6 H), 1.54 (s, 3 H), 1.59 (s, 3 H), 3.65 (s, br, 2 H), 3.80-3.94 (m, 2 H), 6.66 (d, J=8.8 Hz, 2 H), 7.32 (dd, J=2.4, 8.8 Hz, 2 H). MS (ES+): m/z 272.02 (MH+). HPLC: tR=2.45 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[C:7]([OH:31])=[N:8][N:9]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=2[Cl:30])[C:10]=1[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])=[O:5].[H-].[Na+].S(OCC)(O[CH2:42][CH3:43])(=O)=O.O>CS(C)=O>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[C:7]([O:31][CH2:42][CH3:43])=[N:8][N:9]([C:22]2[C:23]([Cl:30])=[CH:24][C:25]([Cl:29])=[CH:26][C:27]=2[Cl:28])[C:10]=1[N:11]1[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]2[C:15]1=[O:16])=[O:5]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(c1ccccc1Cl)c1c(O)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 0.55 g (1.0 mmol) of the compound of Step C in 10 mL of dry dimethyl sulfoxide was treated portionwise with 36 mg (1.5 mmol) of sodium hydride and the resulting mixture was stirred for 30 minutes at room temperature. Then 0.21 mL (0.25 g, 1.61 mmol) of diethyl sulfate was added and the reaction mixture was stirred for one hour at room temperature. The reaction mixture was poured into water and the product was extracted into ethyl acetate. The extracts were washed with water and dried with brine and magnesium sulfate, and evaporated to a gum. The product was crystallized from boiling ethanol to give the product (230 mg, 40%) as fine crystals, m.p. 215-216° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)=[CH:2]1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH:21]([CH3:33])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH2:16][CH2:15]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH:21]([CH3:33])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[CH2:18][CH2:19]2)=[CH:2]1
Reactant: ClC(c1ccsc1)c1ccsc1
Reactant: CC(COc1ccccc1[N+](=O)[O-])CN1CCC(O)CC1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(COc1ccccc1[N+](=O)[O-])CN1CCC(OC(c2ccsc2)c2ccsc2)CC1

Procedure:
The procedure of Example 36 (a) was repeated except for using di(3-thienyl)methyl chloride and 4-hydroxy-1-[2-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-di(3-thienyl)methoxy-1-[2-methyl-3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [C:1]([N:11](C(OCC1C=CC=CC=1)=O)[C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CC(C)N=C=NC(C)C.CC[C@@]1(O)C(=O)OCC2C(N3C(=CC1=2)C1N=C2C(C=CC=C2)=CC=1C3)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:11]([C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: NCCCC[C@@H](C(=O)O)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Bis CBZ-Lysine (311 mg, 0.75 mmol) was dissolved in 56 mL of anhydrous methylene chloride at room temperature. To this solution were added DIPC (0.12 mL, 0.75 mmol), DMAP (0.61 mg, 0.5 mmol) and camptothecin (0.087 g, 0.25 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and left for 16 h. The solution was washed with 0.1 N HCl, dried and evaporated under reduced pressure to yield a light yellow solid, which was recrystallized from methanol to give camptothecin-20-ester of N,N-Bis CBZ-Lys 13. Purification of 13 was satisfactory based on TLC and HPLC analysis.
Reaction SMILES: [C:1]1(=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.ClCCl.[NH3:36]>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]1(=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH2:36])=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of (2E)-3-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoic acid (11) (0.23 g, 0.66 mmol) in toluene (6 mL) was slowly added oxalyl chloride (0.12 mL, 0.175 g, 1.38 mmol, 2.1 eq) followed by DMF (2-3 drops) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 0.25 h. Dichloromethane (6 mL) was added to the reaction mixture (to aid the dissolution of solids) and the reaction mixture was stirred at room temperature for 2 h. Oxalyl chloride (0.12 mL, 0.175 g, 1.38 mmol, 2.1 eq) and DMF (2 drops) were added to the reaction mixture and stirring was continued for 3 h. The reaction mixture was concentrated in vacuo. Toluene was added to the crude acid chloride and the solvent was removed in vacuo. To the crude acid chloride were added ammonia (0.5 M in 1,4-dioxane) (6 mL, 3 mmol, 4.5 eq) followed by CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was transferred to a separatory funnel with the aid of CH2Cl2 and the solution washed with water. The layers were separated and the organic phase was dried over MgSO4, filtered, and the filtrate was concentrated to give the crude amide as a gold-yellow oil. The crude product was purified by flash chromatography on silica gel with CH2Cl2:MeOH (100:0 to 95:5) to give a solid which was dried at 70° C. under vacuum to give 0.058 g (25%) of compound 13 as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (m, 8 H), 2.22 (m, 4 H), 6.53 (d, J=15.9 Hz, 1 H), 6.66 (d, J=8.5 Hz, 2 H), 6.91 (d, J=8.3 Hz, 2 H), 7.06 (br s, 1 H), 7.12 (d, J=8.1 Hz, 2 H), 7.35 (d, J=15.9 Hz, 1 H), 7.45 (d, J=8.1 Hz, 2 H), 7.50 (br s, 1 H), 9.29 (s, 1 H). HRMS (ESI) Calcd for C23H26NO2: 348.1964 (M+H)+. Found: 348.1951.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[C:20]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCCc1ccccc1
Yield: 88 %

Procedure:
The compound prepared in Example 3 was reacted with 3-phenyl-propylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 88%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH2:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O.[C:32]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>O1CCCC1.CCCCCC>[C:1]([C:5]1[CH:9]=[CH:8][C:7](=[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C1=CCC=C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Temperature: 25 °C

Procedure:
In a 300 ml three-necked flask equipped with a magnetic stirrer and three-way cock was thoroughly purged with nitrogen, 4.75 g of 3-tert-butyl-cyclopentadiene (38.9 mmol) was dissolved in 100 ml of dehydrated tetrahydrofuran in a nitrogen atmosphere. To the solution, 26 ml of n-butyl lithium/hexane solution (1.58M: 41.1 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 21 ml of hexamethyl phosphoramide (121 mmol) dried with molecular sieves 4A was added in the ice bath and further stirred at room temperature for 1 hr. To the solution, a solution prepared by dissolving 10.2 g of benzophenone (56.0 mmol) to 30 ml of dehydrated tetrahydrofuran was gradually added dropwise in an ice bath and stirred at room temperature 1 day. To the resulting reaction mixture, 100 ml of a hydrochloric acid aqueous solution (5%) was added. Thereafter, hexane was added to the mixed solution to separate an organic phase. The organic phase was washed with water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give dark-brown oil. The oil was purified with a column chromatography using 400 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure, and thereby the aimed compound was obtained in an amount of 4.42 g (15.4 mmol) as an orange solid (yield: 40%).
Reaction SMILES: C1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)C=CC=CC=1.[F:20][C:21]1[C:26](C[Br:28])=[C:25]([F:29])[C:24]([F:30])=[C:23]([F:31])[C:22]=1[F:32].[C:33]1([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Br-:28].[F:29][C:25]1[C:26]([P+:7]([CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:21]([F:20])[C:22]([F:32])=[C:23]([F:31])[C:24]=1[F:30]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Product: Fc1c(F)c(F)c([P+](Cc2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Product: [Br-]
Temperature: 25 °C
Yield: 90 %

Procedure:
A five-liter, three-necked flask equipped with a mechanical stirrer, reflux condenser, and thermometer was charged with toluene (3.3 liters), triphenylphosphine (686 g, 2.62 mole), and pentafluorobenzyl bromide (343 g, 1.31 mole). The contents were stirred and heated slowly to reflux. A white precipitate formed as the reaction progressed. At the completion of the reaction the flask was cooled to ambient temperature and the solid product was filtered and washed with hot toluene (2.6 liters). These solids were dried in a vacuum desiccator to give a 90% yield of pentafluorobenzyltriphenylphosphonium bromide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([C@@H:19]2[O:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O.O.C(Cl)Cl>[OH:21][C@@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][NH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: c1ccc([C@H]2CO2)cc1
Reactant: NCCCc1ccc(C(N)=O)s1
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)c1ccc(CCCNC[C@@H](O)c2ccccc2)s1

Procedure:
5-(3-Aminopropyl)-2-thiophenecarboxamide was heated with (S)-phenylethylene oxide at b 95° in dimethyl sulphoxide. The mixture was diluted with water and methylene chloride and the aqueous phase was extracted twice with methylene chloride. The methylene chloride phases were washed with water, dried over sodium sulphate and evaporated in vacuo. Chromatography of the residue with methanol on silica gel gave 5-[3-[[(S)-β-hydroxyphenethyl]amino]propyl]-2-thiophenecarboxamide of melting point 94°-96°; [α]589 =+19° (c=0.1% in dioxan); ε256 =8490; ε275 =10780.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>CN(C=O)C.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: C1CSCCN1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCSCC3)n2n1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 99 mg, 0.287 mmol) and thiomorpholine (91 mg, 0.861 mmol) in DMF (1.11 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with methanol and then purified by preparatory HPLC (35-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (26.9 mg, 39%). Melting point (229.1-229.2° C.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H), 2.38 (s, 3H), 2.75-2.90 (m, 4H), 4.02 (dt, J=4.67, 2.46 Hz, 4H), 6.16 (s, 1H), 7.35 (s, 1H), 7.60 (d, J=8.34 Hz, 2H), 7.99 (d, J=8.34 Hz, 2H), 10.86 (s, 1H); ESI-MS: m/z 412.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[C:15]3[O:14][C:13]([F:17])([F:16])[O:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.[B:18]([F:21])([F:20])[F:19].CCOCC.[N:27](OC(C)(C)C)=O>C1COCC1.CCCCC.[Fe].Cl>[F:19][B-:18]([F:16])([F:21])[F:20].[F:16][C:13]1([F:17])[O:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:3]3[C:2]([N+:1]#[N:27])=[CH:6][NH:5][N:4]=3)[C:15]=2[O:14]1
Reactant: Nc1c[nH]nc1-c1cccc2c1OC(F)(F)O2
Reactant: CC(C)(C)ON=O
Reactant: FB(F)F
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOCC
Product: F[B-](F)(F)F
Product: N#[N+]c1c[nH]nc1-c1cccc2c1OC(F)(F)O2
Temperature: 0 °C

Procedure:
3-(2,2-Difluoro-1,3-benzodioxol-4-yl)-4-nitropyrazole obtained above in Example 17 is reduced to 4-amino-3-(2,2-difluoro-1,3-benzodioxol-4yl)pyrazole according to the method described by Vogel (Practical Organic Chemistry, Fourth Edition p. 660: Fe/HCl). 0.8 g (0.003 mol) of 4-amino-3-(2,2-difluoro-1,3-benzodioxol-4-yl)pyrazole in solution in 10 ml of anhydrous THF is treated at 0° C. with a solution of 10 ml of THF-containing 1 ml (0.0081 mol) of boron trifluoride etherate. 0.6 ml (0.005 mol) of tert-butyl nitrite in solution in 5 ml of THF are then added to the reaction mixture. Stirring is maintained for 1 hour at 0° C., the reaction mixture is then diluted with pentane and filtered on a sintered glass. After drying, a beige powder is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31].C[O-].[Na+]>CO.C(Cl)Cl>[NH2:31][C:30]1[N:32]=[CH:18][C:7]2[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=3[C:6]=2[N:29]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 8 h

Procedure:
A stirred suspension of 16 g (0.047 mol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one and 12.5 g (0.07 mol) of guanidine carbonate in 460 ml of methanol was treated at room temperature, under argon, with 7.5 g (0.14 mol) of sodium methylate in one portion. Methylene chloride (290 ml) was added after 10 min. and stirring was continued. The same quantities of sodium methylate and guanidine carbonate were added two more times at 2 hr intervals and stirring was continued overnight. After diluting with 460 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Recrystallization of the residue from ethanol/methylene chloride solution gave off-white crystals: mp 245°-248° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:31])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:32]I>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:31])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([N:25]([CH3:32])[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CI
Reactant: Cc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1C
Product: Cc1ccc(C(=O)CCCN2CCC(c3cccc(N(C)C(=O)C(C)C)c3)CC2)cc1C

Procedure:
Prepared by Procedure T and Scheme AD using N-(3-{1-[4-(3,4-dimethylphenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-2-methylpropanamide and methyl iodide: 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.72 (dd, 1H, J=1.8, 7.7 Hz), 7.33 (t, 1H, J=8.8 Hz), 7.22 (d, 1H, J=7.8 Hz), 7.18 (d, 1H, J=8.8 Hz), 7.01 (m, 2H), 3.24 (s, 3H), 3.10 (d, 1H, J=10.6 Hz), 3.00 (t, 1H, J=7.6 Hz), 2.49 (m, 4H), 2.33 (s, 6H), 2.11 (m, 3H), 1.99 (m, 1H), 1.79 (m, 4H), 1.26 (t, 2H, J=7.6 Hz), 1.02 (d, 6H, J=7.6 Hz); ESMS m/e: 435.2 (M+H)+.
Reaction SMILES: CON(C)[C:4](=[O:30])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:29])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:8][CH2:7]1.O1CC[CH2:34][CH2:33]1.C([Mg]Br)=C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:29][N:20]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4](=[O:30])[CH:33]=[CH2:34])[CH2:7][N:8]=1)=[CH:19]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: C=C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: C=CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reaction time: 5 h
Yield: 38 %

Procedure:
N-Methoxy-N-methyl-2-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetamide (589 mg) was dissolved in absolute tetrahydrofuran (20 mL), and 1M vinylmagnesium bromide tetrahydrofuran solution (3.7 mL) was added under ice-cooling. The mixture was stirred for 5 hr under ice-cooling, 1M vinylmagnesium bromide tetrahydrofuran solution (2.0 mL) was added again, and the mixture was further stirred under ice-cooling for 2 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate), and the obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (210 mg, yield: 38%) as pale-yellow crystals. MS: 446 (MH+). melting point 157-158° C.