Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:17])([CH3:16])[O:4][C:5]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:6]=12.[Na].[S:19]1(=[O:25])(=[O:24])[CH2:23][CH2:22][CH2:21][NH:20]1.O>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([N:20]2[CH2:21][CH2:22][CH2:23][S:19]2(=[O:25])=[O:24])[C:6]2[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][C:3]1([CH3:17])[CH3:16]
Reactant: O=S1(=O)CCCN1
Reactant: CC1(C)Oc2ccc(S(C)(=O)=O)cc2C2OC21
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(S(C)(=O)=O)cc2[C@@H](N2CCCS2(=O)=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
To a solution of 3,4-dihydro-3,4-epoxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (1.5 g) in dimethyl sulfoxide (30 ml) was added sodium salt of isothiazolidine 1,1-dioxide (1.7 g). The mixture was stirred at room temperature overnight. Water was carefully added to the reaction mixture and the whole was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (50 g) with a mixture of chloroform and methanol (50:1) as eluents to give trans-3,4-dihydro-3-hydroxy-4-(1,1-dioxoisothiazolidin-2-yl)-6-mesyl-2,2-dimethyl-2H-1-benzopyran (0.47 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:4]([N+:17]([O-:19])=[O:18])=[CH:5][C:6]([C:12]([CH3:16])([CH3:15])[CH2:13][O:14][C:20](=[O:22])[CH3:21])=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)CO)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])cc(C(C)(C)COC(C)=O)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-(4-Methoxy-3,5-dinitro-phenyl)-2-methyl-propan-1-ol was dissolved in 5 mL of CH2Cl2. Acetic anhydride was added followed by DMAP. The mixture was stirred overnight, then diluted in 15 mL of CH2Cl2 and washed with 1 M NaSO4, saturated NaHCO3, and brine. The CH2Cl2 solution was then dried with Na2SO4, filtered, and concentrated to provide acetic acid 2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propyl ester (628 mg) as a brown oil.
Reaction SMILES: [C:1]1([NH:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C(C)=CC=CC=1>[C:12]1([CH:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10][NH:11][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCCC(Nc1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(NCCC(Nc1ccccc1)c1ccccc1)c1ccccc1
Yield: 27.5 %

Procedure:
A solution of N,1-diphenyl-1,3-propanediamine (5.0 g, 22 mmoles, described in Example 2) and benzoic acid (12.5 g, 105 mmoles) in dry xylene (300 ml) is refluxed for 20 hr using a Dean-Stark water separator. The mixture is cooled and washed with several portions of 2 N hydrochloric acid. The aqueous extracts are combined, basified with dilute sodium hydroxide and extracted with chloroform. The organic extract is washed with brine, dried over magnesium sulfate and evaporated. The residue is chromatographed an silica gel using chloroform and the eluates are evaporated. The residue is crystallized from benzene-hexane to obtain the title compound (2.0 g), mp 120°-121° C.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25](Br)[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:42][S-:43].[Na+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[S:43][CH3:42])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: C[S-]
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(Br)C2CCCCC2)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(bromo-cyclohexyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine (26 mg; 0.039 mmol) in THF (1 mL) was added sodium thiomethoxide (8 mg; 0.114 mmol). Reaction stirred at room temperature for 16 hours. Reaction was diluted with ethyl acetate and washed twice with water. The organic layer was dried sodium sulfate and concentrated to give 23 mg (93% yield) of the title compound as a gum. MS (ES+): Calc: 625.6, Found: 626.0 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (s, 1H), 7.67 (s, 2H), 7.57 (d, J=7.88 Hz, 1H), 7.75-7.56 (bs, 1H), 7.27 (s, 1H), 4.79 (t, J=15.35 Hz, 2H), 4.69 (t, J=15.77 Hz, 2H), 4.23 (s, 3H), 3.81 (bs, 1H), 2.21 (d, J=12.86 Hz, 1H), 1.76 (s, 3H), 1.76-1.57 (m, 4H), 1.36 (d, J=12.45 Hz, 1H), 1.25-1.03 (m, 3H), 1.0-0.76 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[C:27]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br)#[N:28]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:32][C:31]5[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=5)[C:27]#[N:28])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3cccc(C#N)c3)C2=O)CC1
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 3-cyanobenzyl bromide, to give the desired product as a white foam (66%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([N:12]3[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:13]3)=[N:10][C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[NH:7][C:6]=2[CH:30]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([N:12]3[CH2:17][CH2:16][N:15]([CH3:33])[C@@H:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:13]3)=[N:10][C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[NH:7][C:6]=2[CH:30]=1
Reactant: Cc1ccc2c(c1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc2c(c1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
Combine 3-methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (375.0 mg, 0.95 mmol), formaldehyde (84.4 μL, 1.04 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (300.6 mg, 1.42 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 329.5 mg (85%) of the title compound as a tan foam: mp 65°, dec; mass spectrum (ion spray): m/z=411.3 (M+1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CCO>[Br:16][C:14]1[N:15]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:12][CH:13]=1
Reactant: C1COCCN1
Reactant: Brc1csc(Br)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Brc1csc(N2CCOCC2)n1
Temperature: 140 °C
Yield: 68.5 %

Procedure:
To a microwave vial was added N,N-diisopropylethylamine (0.86 ml, 4.9 mmol), 2,4-dibromothiazole (1.00 g, 4.1 mmol), and morpholine (0.43 ml, 4.9 mmol) in EtOH (4 mL). The mixture was heated under microwave irradiation at 140° C. for 35 minutes. The reaction mixture was concentrated in vacuo. The crude material was dissolved in minimal DCM/MeOH and purified via MPLC (eluting with 0-30% EtOAc in hexnaes) to yield 4-(4-bromothiazol-2-yl)morpholine (0.700 g, 68% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1
Reactant: Fc1ccccn1
Reactant: Oc1ccc2nc(N3CCCc4ccccc4C3)cc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1cc(N2CCCc3ccccc3C2)nc2ccc(Oc3ccccn3)cc12
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 44.4 %

Procedure:
The mixture of 4-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-6-ol (200 mg, 0.617 mmol), 2-fluoro-pyridine (180 mg, 1.85 mmol), potassium carbonate (73 mg, 0.53 mmol) and dry dimethylsulfoxide was heated with stirring in a sealed tube for 40 minutes at 130° C. under microwave irradiation. The resulting mixture was cooled to room temperature, then diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layer was washed with brine (10 mL×3), and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:5) to give 110 mg of product as a yellow solid (yield was 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:23][C:24]([NH2:26])=[NH:25]>CO>[NH2:25][C:24]([NH2:26])=[N:23][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:11][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-c2ccc(C)cc2)cc1C
Reactant: N=C(N)N
Solvent: CO
Product: Cc1ccc(-c2cc(C)c(C(=O)N=C(N)N)cc2S(C)(=O)=O)cc1

Procedure:
A solution of 1.8 g of methyl 2-methyl-4-(4-methylphenyl) -5-methylsulphonylbenzoate [obtainable by reacting methyl 3-methylsulphonyl-4-bromo-6-methylbenzoate with tolylboronic acid] and 1.5 g of guanidine in 50 ml of methanol is boiled for five hours and the solvent is then removed. The residue is treated with water and the crop of crystals which remains is filtered off with suction and treated with dilute sodium hydroxide solution. The solid residue is filtered off and recrystallized from ethanol, and N-diaminomethylene-2-methyl-4-(4-methylphenyl)-5-methylsulphonylbenzamide is obtained, m.p. 222°-224°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:19]([O-:21])=[O:20].[H-].[Na+].[C:24]([C:28]1[CH:29]=[C:30]([C:34](Cl)=[O:35])[N:31]([CH3:33])[N:32]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:5]=[C:4]([NH:18][C:34]([C:30]2[N:31]([CH3:33])[N:32]=[C:28]([C:24]([CH3:26])([CH3:25])[CH3:27])[CH:29]=2)=[O:35])[C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Reactant: Cc1nc(-c2ccccc2C(F)(F)F)nc(N)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2cc(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (150 mg, 0.503 mmol, prepared as described in Example 2, STEP A) in THF (10 mL) was treated with NaH (60.4 mg, 1.51 mmol, 60% dispersion in oil), and the resulting mixture was allowed to stir for 30 min at room temperature. 5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (131 mg, 0.654 mmol) was added as a solution in THF (3 mL). After 15 min, the mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted twice with EtOAc (25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 10 min, then 1:99 to 1:4 v/v over 40 min) to yield 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide as a colorless glassy solid. 1H-NMR (400 MHz, CDCl3) δ: 9.10 (s, 1H), 7.79-7.86 (m, 2H), 7.60-7.72 (m, 2H), 6.64 (s, 1H), 4.14 (s, 3H), 2.83 (s, 3H), 1.33 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H21F3N6O3: 463.2 (M+H). Measured: 463.2.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[C:10]3[CH:11]=[CH:12][C:13]4[C:18]([N:9]3[N:8]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:21]N>[Pd].C(O)C>[NH2:21][C:19]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=12
Reactant: NN
Reactant: c1ccc(-c2cc3ccc4ccccc4n3n2)cc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccccc2)nn2c1ccc1ccccc12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
1.0 g. 2-Phenylpyrazolo[1,5-a]quinoline (see J. Het. Chem., 12, 481/1975) are nitrosated analogously to Example 3. There is obtained 1 g. (89% of theory) of the corresponding 3-nitroso compound which is suspended in 90 ml. ethanol and mixed with 200 mg. palladium on carbon. The mixture is heated to 80° C. and 0.25 ml. hydrazine hydrate added portionwise thereto. After 10 minutes, the palladium-carbon is filtered off and the filtrate is evaporated. The residue is dissolved in ethanol and mixed with ethanolic hydrogen chloride. The precipitated hydrochloride is filtered off with suction to give 0.7 g. (72% of theory) of the title compound; m.p. 255°-258° C. TLC (Silica gel/methylene chloride): Rf =0.2
Reaction SMILES: Cl.C(O[CH:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[NH2:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1.C[O-].[Na+].Cl>CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]5)=[N:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: NNC(=O)CN1CCC(O)CC1
Reactant: CCOC(N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: OC1CCN(Cc2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 7.3 %

Procedure:
A solution of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methaneamine hydrochloride (521 mg, 1.63 mmol), N-amino-2-(4-hydroxypiperidyl)acetamide (850 mg, 4.9 mmol), and sodium methoxide (1.2 mL, 4.9 mmol) in methanol (˜8 mL) was taken up in a sealed tube and allowed to stir at room temperature for 25 minutes and then heated at 95° C. overnight. The reaction was acidified with hydrochloric acid to neutral pH. The product was extracted using ethyl acetate. The material was concentrated and purified by semipreprative HPLC. The purified material was taken up in ethyl acetate and washed with an aqueous solution of sodium bicarbonate to yield the title compound (47 mg, 7% yield). 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 8.6 (s, 1H), 8.0 (m, 3H), 7.6 (m, 1H), 7.4 (t, 2H), 3.6–3.8 (m, 2H), 3.4 (m, 2H), 3.2 (d, 1H), 2.4 (m, 2H), 2.0 (s, 4H)H, ES-MS (m/z) 393 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 73.2 %

Procedure:
2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.00 g, 2.57 mmol) and ethyl formate (0.619 mL, 7.72 mmol) were dissolved in anhydrous ethanol (5.20 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (4.80 mL, 12.80 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.786 g, 1.88 mmol, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=[O:20])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=[O:20])=[O:8]
Reactant: CC(C)NNC(=O)c1cccs1
Reactant: O=C(O)COc1ccc(F)cc1Br
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1cccs1)C(=O)COc1ccc(F)cc1Br
Yield: 69.6 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (220 mg, 0.91 mmol) and thiophene-2-carboxylic acid N′-isopropyl-hydrazide (200 mg, 1.09 mmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.40 mL, 2.28 mmol) and PyBroP (636 mg, 1.37 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 10-50% ethyl acetate/hexanes gradient to afford the product as a solid (263 mg, 70%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 77 °C
Reaction time: 2 h

Procedure:
To the solution of thionyl chloride (1.63 ml, 22.4 mmol) in CCl4 (30 ml) was added the solution of (1,4-dibenzylpiperazin-2-yl)-methanol (2.74 g, 9.25 mmol) in CCl4 dropwise in 10 minutes. The produced suspension was stirred for 2 hours at 77° C. After cooled to room temperature, 20 ml of ice water was added and the aqueous layer was separated from the organic solvent. The PH of aqueous layer was adjusted to 12 with 4N NaOH aq., and extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, and concentrated to give brownish oil which was purified by column chromatography on silica gel (CH2Cl2/MeOH=30/1) to give 1,4-dibenzyl-2-chloromethyl-piperazine in crude form (3.08 g, 95%, ca. 90% purity from HPLC analysis). The compound was used for next reaction without further purification: HPLC-MS (ESI): Calcd for C19H23ClN2[M+H]+ 315, found: 315.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH2:5][C:6]1[C:14]2[O:13][C:12]([F:16])([F:15])[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:1]([NH:5][C:6]1[C:14]2[O:13][C:12]([F:16])([F:15])[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[C:2]#[CH:3]
Reactant: Nc1cccc2c1OC(F)(F)O2
Reactant: C#CCBr
Solvent: Cc1ccccc1
Product: C#CCNc1cccc2c1OC(F)(F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
At 20-25° C., 53.3 g of an 80% strength solution of propargyl bromide in toluene (=0.36 mol of propargyl bromide) are added dropwise to a solution of 120 g (0.67 mol) of 4-amino-2,2-difluorobenzo-1,3-dioxole in 150 ml of toluene. After 2 hours at 80° C., the reaction mixture is cooled to room temperature and the precipitate is filtered off with suction and washed with n-hexane. The filtrate is concentrated under reduced pressure and the residue is purified over silica gel using cyclohexane/ethyl acetate mixtures and then-crystallized from pentane. 33.2 g (44% of theory) of N-propargyl-4-amino-2,2-difluorobenzo-1,3-dioxole of mp.: 66-68° C. are obtained in this manner. NMR: (CDCl3): 2.25 (t, 1H); 3.9 (2*s, 3H); 6.30 (dd, 1H); 6.50 (d, 1H); 6.85 (d, 1H)
Reaction SMILES: C(P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](/[C:33](/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:34]/[CH2:35]O)=[CH:29][CH:28]=1>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:35]/[CH:34]=[C:33](/[C:30]2[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][CH:31]=2)\[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.94 ml, 786 mg, 3.0 mmol), methyl 4-hydroxyphenylacetate (332 mg, 2.0 mmol) and (E)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol (578 mg, 2.0 mmol) in dry THF (25 ml), the mixture was stirred for 1 h. The mixture was filtered and concentrated I vacuo. The residue was purified by flash chromatography on silica gel (toluene as eluent) to give 710 mg (81%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:21][NH2:22])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:23](OCC)(OCC)OCC>>[Br:1][C:2]1[N:3]2[CH:23]=[N:22][N:21]=[C:4]2[C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2NN)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3cnnc23)CC1
Temperature: 130 °C
Yield: 69 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(5-bromo-3-hydrazinylpyrazin-2-yl)piperazine-1-carboxylate (5.8 g, 20 mmol) and triethyl orthoformate (60 mL). The resulting solution was heated at 130° C. for 3 h. TLC indicated a complete conversion. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 5.3 g (69%) of the product as a yellow solid. MS m/z: 383 (M+H+).