Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5([C:31]#[N:32])[CH2:30][CH2:29]5)[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.O>CN(C)C=O>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
A solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (91 mg, 0.20 mmol) produced in Example A18(iv) and 2-chloro-2-oxoethyl acetate (137 mg, 1.00 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 mL)/tetrahydrofuran (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with acetone to give the title compound (22 mg, 21%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH2:2][C:3]#[CH:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][C:3]#[CH:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CCCOCCCCCCBr
Reactant: NCc1ccccc1
Product: C#CCCOCCCCCCNCc1ccccc1
Yield: 105.8 %

Procedure:
A mixture of 6-bromohexyl but-3-ynyl ether (21.5 g) and benzylamine (49.3 g) was heated at 120° for 2 h. The mixture was cooled and partitioned between 2M hydrochloric acid (40 ml) and ethyl acetate (2×200 ml). The combined extracts were washed with an aqueous sodium bicarbonate solution (100 ml), water (200 ml) and dried (Na2SO4). The solvent was removed in vacuo and the residue was purified by chromatography (Merck 9385) eluting with 2% methanol/chloroform. The appropriate fractions were evaporated to give the title compound (25.3 g). LCMS RT=2.2 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:41])[C:5]([CH3:40])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:36]C(=O)C)=[C:17]([CH:35]=2)[C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:41])[C:5]([CH3:40])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:36])=[C:17]([CH:35]=2)[C:18]([NH:20][C:21]2[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)=C(C)C1=O
Yield: 41.5 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,5-bistrifluoromethylaniline (0.130 g, 0.222 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.0921 mmol, 41%).
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1>[Pd].CO>[F:1][CH:2]([F:10])[CH2:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1
Reactant: O=C1CC(C=C(F)F)CN1
Agent: [Pd]
Solvent: CO
Product: O=C1CC(CC(F)F)CN1
Yield: 100 %

Procedure:
A solution of 4-(2,2-difluoroethenyl)pyrrolidin-2-one a1 (2.8 g, 18.77 mmol, 1 eq) and palladium on charcoal (10% Wt, 300 mg) in methanol (500 ml) is stirred overnight under an hydrogen atmosphere (40 psi) at room temperature. The reaction mixtured is filtered over celite and the solvent is removed under reduced pressure to afford 4-(2,2-difluoroethyl)pyrrolidin-2-one a11 which can be used in the next step without any further purification.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cl-].[Hf+4:5].[O:6]=[C:7]1[O:13][C@H:12]([C@H:14]([CH2:16][OH:17])[OH:15])[C:10]([OH:11])=[C:8]1[OH:9].[OH-].[NH4+]>O>[O:6]=[C:7]1[O:13][C@H:12]([C@H:14]([CH2:16][OH:17])[OH:15])[C:10]([OH:11])=[C:8]1[OH:9].[Hf:5]
Reactant: [Hf+4]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: [Hf]

Procedure:
Hydrated hafnium-ammonium-ascorbate was prepared as follows: 1.6 grams of hafnium-tetrachloride and 1.86 grams of crystalline ascorbic acid were dissolved in 5 ml of water, and the pH was adjusted to 6.5 with ammonium hydroxide. Two ml portions of the resulting solution were administered orally to rats and radiographs were obtained comparable to those seen with preparations described in the previous examples. Soluble complexes of ascorbic acid and hafnium possessing similar properties were obtained using molar ratios of ascorbic acid to hafnium of from 1:1 to 4:1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.Br[C:14]1C(OC)=CC=C2[C:15]=1C=CN2>>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:7]=1[NH:8][CH:15]=[CH:14]2
Reactant: COc1ccc2[nH]ccc2c1Br
Reactant: COc1ccc([N+](=O)[O-])c(Br)c1
Product: COc1cc(Br)c2[nH]ccc2c1

Procedure:
7-Bromo-5-methoxy-1H-indole CLXXVIII was prepared from 3-bromo-4-nitro-anisole using the procedure described for preparation of 4-bromo-5-methoxyindole XLVI (Example 12).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24](O)=[O:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:48][CH2:49][C:50]([NH:52]O)=[NH:51]>CN(C=O)C.CCOC(C)=O>[Cl:48][CH2:49][C:50]1[N:52]=[C:24]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=2)[CH2:7]3)[O:25][N:51]=1
Reactant: N=C(CCl)NO
Reactant: Cc1cc(C(=O)O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(CCl)no2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 135 °C
Yield: 29.4 %

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (80.0 mg, 0.49 mmol), EDCI (104.0 mg, 0.54 mmol), HOBT (73.0 mg, 0.54 mmol) and 2-chloro-N-hydroxyacetamidine (59.0 mg, 0.54 mmol) were mixed in DMF (4.0 mL) over the weekend. The reaction mixture was diluted with EtOAc and washed with water, brine, dried over sodium sulfate, filtered and concentrated. The product was subjected to column chromatography (100% EtOAc). The product was heated to 135° C. in DMF for 1.5 hours. The reaction mixture was cooled and diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The product was purified by column chromatography to yield the title compound as a brown oil (63.0 mg, 33%). 1H NMR (300 MHz, CDCl3): δ 8.01 (d, 2H), 7.37 (d, 2H), 7.21 (d, 2H), 4.81 (s, 2H), 4.69 (s, 2H), 4.34 (s, 2H), 2.85 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
To a solution of 3-methoxy-5-(trifluoromethyl)benzonitrile (1.30 g, 6.46 mmol) in dry dichloromethane (30 mL) was added BBr3 (0.0920 mL, 0.969 mmol) at 0° C. The reaction mixture was stirred at rt for two days, quenched with 10% sodium bicarbonate (50 mL) and extracted with DCM (2×200 mL). Combined organic portions were dried over anhydrous sodium sulphate and concentrated to afford the title product (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([OH:13])=[CH:6][C:5]2=[O:14].C(=O)(O)[O-:16].[Na+].OO>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([OH:13])=[C:6]([OH:16])[C:5]2=[O:14]
Reactant: O=C1C=C(O)C(=O)c2ccc(Cl)cc21
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C1C(O)=C(O)C(=O)c2cc(Cl)ccc21

Procedure:
A solution of 1.2 gm 6- chloro-2-hydroxy-1,4-naphthoquinone (or 7-chloro or mixture thereof) and 0.48 g sodium bicarbonate in 58 ml of water is cooled to 5° C. and 2.3 ml of 30% hydrogen peroxide is added in one portion. The mixture is then stirred at 22° C. for 16 hours where the red crystalline product (0.24 g) is removed by filtration and crystallized from water:methanol (2:1) giving the 6-chloro-2,3-dihydroxy-1,4-naphthoquinone, m.p. 228°-229° C.
Reaction SMILES: [CH:1]1C2C(=O)NC3C=CC=CC=3NC=2C=CC=1.CC1C=NC=CC=1C(Cl)=O.C1C2C(=O)N=C3C=CC=CC3=NC=2C=CC=1.C(OC(C)C)(C)C.CO.[CH3:52][C:53]1[CH:54]=[N:55][CH:56]=[CH:57][C:58]=1[C:59]([N:61]1[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=2[C:65](=[O:72])[NH:64][C:63]2[CH:73]=[CH:74][CH:75]=[CH:76][C:62]1=2)=[O:60]>>[CH3:1][N:55]1[CH2:54][CH:53]([CH3:52])[C:58]([C:59]([N:61]2[C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=3[C:65](=[O:72])[NH:64][C:63]3[CH:73]=[CH:74][CH:75]=[CH:76][C:62]2=3)=[O:60])=[CH:57][CH2:56]1
Reactant: Cc1cnccc1C(=O)N1c2ccccc2NC(=O)c2ccccc21
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: Cc1cnccc1C(=O)Cl
Agent: O=c1nc2ccccc2nc2ccccc12
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CC1CN(C)CC=C1C(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
By reacting 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one with 3-methylisonicotinic acid chloride (m.p. 155°-156° C.) via 5,10-dihydro-5-[3-methyl-4-pyridinyl)carbonyl]-11H-dibenzo[b,e][1,4]diazepin-11-one, m.p. 223°-224° C. (diisopropylether/methanol) and 5,10-dihydro-5[(3-methyl-4-pyridinyl)carbonyl]-11H-dibenzo[b,e][1,4]-diazepin-11-one methoiodide;
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH3:27])[CH:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][N:24]([CH3:26])[CH2:23]4)[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:47]1([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:58])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH3:27])[CH:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:23][N:24]([CH3:26])[CH2:25]3)[CH2:20][CH2:21]2)[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN1CC(N2CCC(N(C)C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)C1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: CN1CC(N2CCC(N(C)C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ncn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.4 %

Procedure:
To a solution of 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1-methyl-1-[1-(1-methylazetidin-3-yl)piperidin-4-yl]urea (68.0 mg) in ethanol (2.0 ml) was added (1S)-(+)-10-camphorsulfonic acid (70.2 mg), followed by stirring at room temperature for 10 min. A solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 1.91 ml) was added to the reaction mixture, followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=25:1). Fractions containing the target compound were concentrated to give a residue, which was added diethyl ether (2 ml) to give a precipitate. The precipitate was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (12.9 mg, 13.4%) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Cl.[CH3:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:22]1[N:21]=[C:20]([CH3:19])[NH:24][CH:23]=1
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)C(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)(c1ccccc1)c1c[nH]c(C)n1

Procedure:
13 g diphenyl-α-chloroacetic acid methyl ester (0.05 mole) are heated to the boil for 20 hours with 12.1 g 2-methyl-imidazole in 100 ml acetonitrile. The acetonitrile is distilled off in a vacuum. 200 ml of water are added to the residue, which is then taken up in 200 ml methylene chloride. The methylene chloride is extracted twice with, in each case, 150 ml of water, dried and distilled off in a vacuum. The residue is recrystallized from a little ethyl acetate. There is so obtained the diphenyl-2-methyl-imidazolyl-acetic acid methyl ester of the melting point 136°C.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH3:15]I>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[C:10]([CH3:15])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:14]
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Reactant: CI
Product: CCN(CC)C(=O)c1c(C)cccc1Cl
Yield: 92 %

Procedure:
The compound from example e (1.0 eq) and MeI (3.0 eq) were combined according to Method A. The crude product was purified by HPLC with 1:4 EtOAc/hexanes to give 5.2 g of N,N-diethyl 2-chloro-6-methylbenzamide as a yellow solid, a 92% yield. m.p. 48°-49° C.
Reaction SMILES: [OH:1][C:2]1([CH2:16][C:17](O)=O)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:20][C:21]1[C:34]([Cl:35])=[CH:33][C:24]2[NH:25][C:26]([CH2:28][CH2:29][CH2:30][NH:31][CH3:32])=[N:27][C:23]=2[CH:22]=1>>[Cl:35][C:34]1[C:21]([Cl:20])=[CH:22][C:23]2[NH:27][C:26]([CH2:28][CH2:29][CH2:30][N:31]([CH3:32])[CH2:17][CH2:16][C:2]3([OH:1])[CH2:7][CH:6]4[CH2:8][CH2:9][CH:3]3[CH:4]=[C:5]4[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:25][C:24]=2[CH:33]=1
Reactant: CNCCCc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=C(O)CC1(O)CC2CCC1C=C2c1ccccc1
Product: CN(CCCc1nc2cc(Cl)c(Cl)cc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1

Procedure:
Prepared according to procedures P2.2 to P2.3 in Example 21 using rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid and [3-(5,6-dichloro-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:20]([CH3:22])[CH3:21]>C(#N)C>[CH3:21][CH:20]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12])[CH3:22]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1cccc2c1CCCC2=O
Temperature: 80 °C

Procedure:
A mixture of 2.5 g of 5-hydroxy-1-tetralone, 30 ml of acetonitrile, 5 g of caesium carbonate and 3.87 ml of 2-iodopropane is heated for one hour at 80° C. and then evaporated to dryness. The residue is taken up in ethyl acetate and water. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure, so as to give 4.87 g of 5-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one in the form of an orangey-coloured oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:6])[C:2]#[CH:3].[H-].[Na+]>C1COCC1>[CH3:3][CH:2]1[N:7]([CH:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[C:5](=[O:6])[NH:4][CH2:1]1
Reactant: C#CCNC(=O)NC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CNC(=O)N1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A 5° C. solution of 1-(prop-2-yn-1-yl)-3-(tetrahydro-2H-pyran-4-yl)urea (0.40 g, 2.195 mmol) in THF (20 mL) under Ar, was treated with NaH (60% in mineral oil, 0.097 g, 2.415 mmol), warmed to RT and stirred overnight. The mixture was treated with satd. NH4Cl, extracted with EtOAc (2×) and the combined organics were washed with 5% LiCl, then brine and dried over Na2SO4. The solution was treated with Pd on C (260 mg) and hydrogenated (30 psi) for 5 h. The mixture was filtered, treated with fresh Pd on C (260 mg) and hydrogenated (44 psi) overnight. The solids were removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate concentrated to dryness to afford crude 5-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazolidin-2-one (190 mg, 47%) which was used without further purification. MS (ESI) m/z: 185.1 (M+H+).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[OH-].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CC(C)=O.O>[I:1][C:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cccc2c(I)n[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Cn2nc(I)c3cccc([N+](=O)[O-])c32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
3-Iodo-7-nitro-1H-indazole (2.50 g, 8.65 mmol) prepared in Step A was dissolved in acetone (50 mL). Potassium hydroxide (0.73 g, 12.97 mmol) and 4-methoxybenzylchloride (1.63 g, 10.38 mmol) were added in drops thereto at 0° C., and the mixture was stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (3.2 g, Yield 91%).
Reaction SMILES: [C:1]([CH:4]([C:9]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:5]([O:7]C)=O)(=O)[CH3:2].[CH2:18]([N:20]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[S:21]([C:24]1[CH:25]=[N:26][C:27]([NH:30][NH2:31])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH3:19]>CCO.CC(O)=O.CCCCC>[CH2:18]([N:20]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[S:21]([C:24]1[CH:25]=[N:26][C:27]([N:30]2[C:5](=[O:7])[C:4]([C:9]([CH3:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])=[C:1]([CH3:2])[NH:31]2)=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH3:19]
Reactant: CCN(c1ccccc1)S(=O)(=O)c1ccc(NN)nc1
Reactant: COC(=O)C(C(C)=O)C(C)(C)c1ccccc1
Solvent: CCO
Solvent: CCCCC
Solvent: CC(=O)O
Product: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]c(C)c(C(C)(C)c3ccccc3)c2=O)nc1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
To a solution of 200 mg (0.85 mmol) of methyl 2-acetyl-3-methyl-3-phenylbutanoate in 2 mL of EtOH/AcOH mixture (1:1) are added 249 mg (0.85 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and the reaction mixture is then heated for 2 hours at 90° C. After concentrating under reduced pressure, the residue is taken up in 100 mL of DCM, washed with 2×30 mL of saturated NaHCO3 solution, dried over Na2SO4, filtered, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 20% EtOAc. After concentrating under reduced pressure, 312 mg of a yellow oil are obtained, and are solidified in 20 mL of pentane. The solid obtained is filtered off, and then dried under vacuum. 178 mg of N-ethyl-6-[3-methyl-4-(1-methyl-1-phenylethyl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-phenylpyridine-3-sulfonamide are obtained in the form of a white powder.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[C:18]([F:26])[C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:27])[C:15]([C:28]([OH:30])=[O:29])=[CH:14]2)[C:10]([F:31])=[CH:9][C:8]=1[F:32].Cl.Cl.[NH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([F:23])=[C:22]3[C:17]([C:16](=[O:27])[C:15]([C:28]([OH:30])=[O:29])=[CH:14][N:13]3[C:11]3[C:10]([F:31])=[CH:9][C:8]([F:32])=[C:7]([NH2:6])[N:12]=3)=[C:18]([F:26])[C:19]=2[F:25])[CH2:37]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(F)c(F)c(F)c(F)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(F)c(F)c(N4CC(N)C4)c(F)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 50 mg of the title compound as a pale yellow powder.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[O:26][CH3:27])(=O)=O>>[CH3:27][O:26][C:19]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: COc1ccc(OC)c(COS(C)(=O)=O)c1
Product: COc1ccc(OC)c(Cn2ccc3c(C=O)cccc32)c1

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 2,5-dimethoxybenzyl methanesulfonate instead of the benzyl bromide used in Example 1 to give 940 mg of 1-(2,5-dimethoxybenzyl)indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 64%.