Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=O)[O:4][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:6]=1[Br:7].[NH2:16][NH2:17]>C(O)C>[Br:7][C:6]1[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:17][NH:16][C:3](=[O:4])[CH:2]=1
Reactant: NN
Reactant: Cc1ccc(C2OC(=O)C(Br)=C2Br)cc1
Solvent: CCO
Product: Cc1ccc(-c2n[nH]c(=O)cc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a mixture of 3,4-dibromo-5-p-tolylfuran-2(5H)-one (0.5 g, 1.506 mmol) in ethanol (5 mL) was added NH2NH2 (0.047 mL, 1.506 mmol) at 0° C. The mixture was stirred at room temperature overnight. The precipitate was filtered and dried under reduced pressure to give the title compound as a beige solid (0.22 g). LCMS m/z=264.9 [M+H]+.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH2:22]([O:24][C:25]([C:27]1[C:28]2[N:29]=[CH:30][CH:31]=[N:32][C:33]=2[C:34]([C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=2)=[CH:35][CH:36]=1)=[O:26])[CH3:23].C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[CH2:22]([O:24][C:25]([C:27]1[C:28]2[N:29]=[CH:30][CH:31]=[N:32][C:33]=2[C:34]([C:37]2[CH:38]=[C:39]([O:45][CH3:46])[CH:40]=[C:41]([O:43][CH3:44])[C:42]=2[F:21])=[CH:35][CH:36]=1)=[O:26])[CH3:23]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2nccnc12
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2nccnc12
Reaction time: 12 h
Yield: 46.8 %

Procedure:
SelectFluor (105 mg, 0.30 mmol) was added to a cold (−5° C.) solution of 8-(3,5-dimethoxyphenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 115.1) (100 mg, 0.30 mmol) in CH3CN (2 mL), under an argon atmosphere. The reaction mixture was allowed to warm to it over 6 h and stirred at that temperature for additional 12 h and diluted in EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) to provide 50 mg of the title compound as an off-white solid. Title compound: ESI-MS: 357.2 [M+H]+; tR=4.58 min (System 1); TLC: Rf=0.24 (Hex/EtOAc, 3:2).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:26][O:25][CH2:24]1)=[N+]=[N-].N.Cl>C1COCC1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C@H:27]2[CH2:26][O:25][CH2:24][C@H:23]2[NH2:20])=[CH:29][CH:30]=1
Reactant: [N-]=[N+]=N[C@@H]1COC[C@@H]1c1ccc(F)cc1
Agent: Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N[C@@H]1COC[C@@H]1c1ccc(F)cc1
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Triphenylphosphine (45 g, 0.17 mol, 1.20 eq) was added in portions to a solution of compound (3S*,4R*)-3-azido-4-(4-fluorophenyl)tetrahydrofuran (Preparation 61, 29.6 g, 0.14 mol, 1 eq) in THF (200 mL) on a water bath under stirring for 1 h. The mixture was stirred at room temperature for 2 h, and ammonia 880 (50 mL) was added. The mixture was refluxed for 2 h and cooled. Then concentrated hydrogen chloride (13 mL) was added, and the mixture was evaporated. The residue was diluted with water (150 mL) and extracted with carbon tetrachloride (3×200 mL). Then the aqueous layer was alkalized with the saturated potassium carbonate solution and extracted with chloroform (3×200 mL). The combined organic layer was dried and evaporated to give title compound as a yellow oil (17.82 g, 0.1 mol, 69%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=1>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:12]=2[CH:11]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1ccc(O)c(I)c1
Product: Cc1ccc2oc(-c3ccccc3)cc2c1

Procedure:
The general procedure was used to convert phenylacetylene and 4-methyl-2-iodophenol to the title product. Purification by flash chromatography (hexanes as the eluent) gave the analytically pure product as a white solid (353 mg, 85% yield). 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=7.16, 2H), 7.41-7.30 (m, 5H), 7.06 (d, J=7.35, 1H), 6.88 (s, 1H), 2.41 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 155.92, 153.29, 132.2, 130.57, 129.27, 128.70, 128.35, 125.49, 124.79, 120.70, 110.61, 101.06, 21.30. Anal. Calcd. for C15H12O: C, 86.51; H, 5.81. Found C, 86.28; H, 5.90. m.p.: 131° C. (lit., 6131-133° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]2)[CH2:6]1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][O:27][C:33](=[O:35])[CH3:34])[CH2:18][CH2:17]2)[CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: OCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1

Procedure:
A solution of 0.02 g (0.04 mmol) of 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-hydroxypropyloxymethyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine (Example 17), 0.25 mL (0.12 mmol) of acetic anhydride, 0.25 mL (0.3 mmol) of pyridine and a catalytic amount of DMAP in 0.5 mL of CH2Cl2 was stirred at rt for 2 h. TO the reaction mixture was added 10 mL of sat'd Na2CO3 solution and it was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 1:1) to give the title compound. Mass Spectrum (ESI) m/e=539 (M+1 35Cl, 35Cl), 541 (M+1 35Cl, 37Cl), and 543 (M+1 37Cl, 37Cl).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:24]=[CH:23][C:15]3[O:16][C:17]([CH3:22])([CH3:21])[C:18](=[O:20])[NH:19][C:14]=3[CH:13]=2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[N:31][NH:32]2)=[CH:28][CH:27]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:32]1[C:33]2[C:29](=[CH:28][CH:27]=[C:26]([NH:25][C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:24]=[CH:23][C:15]5[O:16][C:17]([CH3:22])([CH3:21])[C:18](=[O:20])[NH:19][C:14]=5[CH:13]=4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:34]=2)[CH:30]=[N:31]1
Reactant: CC1(C)Oc2ccc(Nc3nc(Cl)nc4[nH]ccc34)cc2NC1=O
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC1(C)Oc2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)nc4[nH]ccc34)cc2NC1=O
Temperature: 115 °C
Yield: 6.2 %

Procedure:
To a mixture of 6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.050 g) inn-butyl alcohol (0.6 mL) was added 6-aminoindazole (0.028 g) and trimethylsilyl chloride (TMSCl) (0.013 mL). After heating at 115° C. for 15 h, the mixture was purified by preparative HPLC to give 6-(2-(1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.004 g, MS [MH] 441.1) (Compound 16-1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11].[CH3:12][CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:17]([CH3:18])=[C:13]([CH3:12])[C:14]([CH3:15])=[N:11]1
Reactant: CC(=O)C(C)C(C)=O
Reactant: COc1ccccc1NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1-n1nc(C)c(C)c1C

Procedure:
200 mg of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 4 ml of ethanol, and 134 μl of 3-methyl-2,4-pentanedione was added and heated at reflux for 3 hours. To the reaction mixture was added 50 ml of water, neutralized with a saturated aqueous solution of sodium carbonate, and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 209.8 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].BrCC1C=CC=CC=1[F:25]>>[F:25][C:14]1[CH:15]=[CH:16][CH:2]=[CH:3][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: Fc1ccccc1CBr
Reactant: CCOP(=O)(Cc1cccc(F)c1)OCC
Product: CCOP(=O)(Cc1ccccc1F)OCC

Procedure:
Prepared according to the method used to prepare diethyl 3-fluorobenzylphosphonate starting with 1-(bromomethyl)-2-fluorobenzene. 1H NMR (CDCl3) δ: 7.36 (t, J=7.5 Hz, 1H), 7.19-7.25 (m, 1H), 7.07-7.13 (m, 1H), 7.04 (t, J=9.2 Hz, 1H), 3.99-4.08 (m, 4H), 3.15-3.24 (m, 2H), 1.25 (td, J=7.0, 0.9 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:5]2.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[C:26]([CH3:28])=[CH2:27]>C1COCC1>[CH3:28][C:26](=[CH2:27])[C:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:5]2)=[O:29]
Reactant: COC(=O)/C=C/c1ccc2cc(O)ccc2c1
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc2cc(/C=C/C(=O)OC)ccc2c1
Temperature: 0 °C

Procedure:
0.89 g (3.9 mmol) of methyl (E)-3-(6-hydroxy-naphthalen-2-yl)-acrylate, a spatula tip of BHT and 0.66 ml of triethylamine were dissolved in 10 ml of THF. After cooling to 0° C. a solution of 0.39 ml (4.07 mmol) of methacryloyl chloride in 4 ml of THF was added dropwise within 30 minutes. The white suspension was stirred at 0° C. for a further hour and then partitioned in ether and water. The organic phase was back-washed twice with water and the aqueous phases were back-washed twice with diethyl ether. The combined organic phases were dried over magnesium sulphate, filtered over Celite and evaporated completely in a vacuum. The crude product was recrystallized from a mixture of 5 ml of hexane and 20 ml of toluene. This gave 0.92 g of white (E)-2-(2-methoxycarbonyl-vinyl)-naphthalen-6-yl 2-methyl-acrylate.
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[C:7]=2[CH:6]=[N:5]1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:28]1[CH2:32]CC[CH2:29]1>C(#N)C>[CH:1]1([N:4]2[C:12]3[CH:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[C:7]=3[CH:6]=[N:5]2)[CH2:32][CH2:28][CH2:29][CH2:2]1
Reactant: COC(=O)c1cc(C(F)(F)F)cc2c1cnn2C(C)=O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc(C(F)(F)F)cc2c1cnn2C1CCCC1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 30 %

Procedure:
To a stirred solution of methyl 1-acetyl-6-(trifluoromethyl)-1H-indazole-4-carboxylate (1 equiv.) in acetonitrile (3 mL per 1 mmol), cesium carbonate (1.5 equiv.) was added followed by bromocyclopentane (2 equiv.). The reaction mixture was stirred at 90° C. for 3-4 h. On completion of reaction, acetonitrile was removed under reduced pressure and water was added. Extraction was carried out using ethyl acetate and the combined organic layers washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain methyl 1-cyclopentyl-6-(trifluoromethyl)-1H-indazole-4-carboxylate (yield 30-35%). The structure was confirmed as the desired regioisomer by NOE.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:25])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.O>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:25])[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 5-bromo-2-(2-(3-(trifluoromethyl)phenyl)acetamido)benzoate (3.86 g, 9.28 mmol, Intermediate 5: step b) in THF (100 mL) at −78° C. was added KHMDS (0.5 M in toluene, 55.6 mL, 27.8 mmol) over 8 minutes. The resulting light yellow solution was stirred at −78° C. for 5 minutes, then was transferred to an ice bath and stirred for 1 hour 15 minutes. The mixture was diluted with water and extracted once with EtOAc. The aqueous phase was acidified to pH 2 by addition of 1 N aqueous HCl solution. A white precipitate formed upon acidification and was collected by vacuum filtration and air dried to afford the title compound as a white powder.
Reaction SMILES: C([Li])CCC.[OH:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][OH:14])[O:11][C:10]([CH3:16])([CH3:15])[O:9]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[Cl-].[Na+]>O1CCCC1>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:14][CH2:13][C@@H:12]2[C@@H:8]([CH2:7][OH:6])[O:9][C:10]([CH3:16])([CH3:15])[O:11]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)O[C@H](CO)[C@@H](CO)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2OC(C)(C)O[C@@H]2CO)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
21.7 mmol of n-butyllithium (1.59 molar in n-hexane, 13.6 ml) were added at -78 C to a solution of (4R,5R)-4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (3.32 g, 20.5 mmol) in 60 ml of tetrahydrofuran ((4R,5R)-4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane was prepared according to J. Org. Chem. 33 (1968), page 2171). After stirring for 10 minutes, a solution of p-toluenesulfonyl chloride (4 g, 21 mmol) in 20 ml of tetrahydrofuran which was cooled to −78° C. was added. After stirring at −78° C. for 15 minutes, the mixture was warmed to 20° C. and poured into 200 ml of concentrated sodium chloride solution. The organic phase was separated off and the aqueous phase was extracted twice with 50 ml of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on 400 g of silica gel using ethyl acetate and n-hexane in the weight ratio 60:40 as eluent. 74.6% of (4R,5R)-[5-hydroxymethyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl p-toluenesulfonate were obtained ([α]D19=+11.80 (c=1.88 in trichloromethane); cf. J. Org. Chem. 55 (1990), page 4417: [α]D21=+11.30 (c=2.70 in trichloromethane)).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][NH:15][C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[C:10]2[CH2:9]1)C1C=CC=CC=1>C(O)C.[Ni]>[F:32][C:29]1[CH:28]=[CH:27][C:26]([N:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][C:16]3[NH:15][N:14]=[C:11]4[CH2:12][CH2:13][NH:8][CH2:9][C:10]=34)[CH2:25][CH2:24]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(N2CCN(CCCc3[nH]nc4c3CN(Cc3ccccc3)CC4)CC2)cc1
Agent: [Ni]
Solvent: CCO
Product: Fc1ccc(N2CCN(CCCc3[nH]nc4c3CNCC4)CC2)cc1

Procedure:
5-Benzyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (0.5 g) obtained in Example 139 was dissolved in ethanol (10 ml), and Raney nickel (0.2 g) was added to perform catalytic reduction. After the completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine,
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:34][C@@H:33]2[C@:20]([CH3:37])([CH2:21][CH:22]=[C:23]3[C@H:32]2[CH2:31][CH2:30][C:29]2[C@:24]3([CH3:36])[CH:25]=[CH:26][C:27](=[O:35])[CH:28]=2)[C@H:3]1[C:4](=[O:19])[CH2:5]OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O.[CH2:38]1[CH2:69][O:68][C:40]2([CH2:45][CH2:44][N:43]([C:46]3[N:51]=[C:50]([N:52]4[CH2:57][CH2:56][C:55]5([O:61][CH2:60][CH2:59][O:58]5)[CH2:54][CH2:53]4)[CH:49]=[C:48]([N:62]4[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]4)[N:47]=3)[CH2:42][CH2:41]2)[O:39]1>>[CH2:38]1[CH2:69][O:68][C:40]2([CH2:41][CH2:42][N:43]([C:46]3[N:51]=[C:50]([N:52]4[CH2:57][CH2:56][C:55]5([O:61][CH2:60][CH2:59][O:58]5)[CH2:54][CH2:53]4)[CH:49]=[C:48]([N:62]4[CH2:67][CH2:66][N:65]([CH2:5][C:4](=[O:19])[C@@H:3]5[C@:20]6([CH3:37])[C@H:33]([C@H:32]7[C:23](=[CH:22][CH2:21]6)[C@:24]6([CH3:36])[C:29](=[CH:28][C:27](=[O:35])[CH:26]=[CH:25]6)[CH2:30][CH2:31]7)[CH2:34][C@H:2]5[CH3:1])[CH2:64][CH2:63]4)[N:47]=3)[CH2:44][CH2:45]2)[O:39]1
Reactant: c1c(N2CCNCC2)nc(N2CCC3(CC2)OCCO3)nc1N1CCC2(CC1)OCCO2
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCC4(CC3)OCCO4)nc(N3CCC4(CC3)OCCO4)n2)CC1
Yield: 77.5 %

Procedure:
The reaction of 16α-methyl-21-(4-nitrobenzenesulfonyloxy)pregna-1,4,9(11)-triene-3,20-dione with 2,4-bis(4,4-ethylenedioxy-1-piperidinyl)-6-(1-piperazinyl)pyrimidine as described in Example 5 leads to the title compound in a yield of 77.5%, m.p.:156°-174° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][C:11](=O)N(C)C)=[C:6]([CH:9]=1)[CH:7]=O.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].[OH-].[Na+].Cl.Cl[CH2:36][C:37](=[O:39])C.C(=O)([O-])[O-].[K+].[K+]>C([O-])([O-])OC.CO.CC(C)=O>[C:37]([C:11]1[S:10][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:39])[CH3:36]
Reactant: CC(=O)CCl
Reactant: CN(C)C(=O)Sc1ccc(Br)cc1C=O
Agent: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: CC(=O)c1cc2cc(Br)ccc2s1
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
21.0 g of 5-bromo-2-[(N,N-dimethylcarbamoyl)thio]benzaldehyde was dissolved in 50 ml of methyl orthoformate. The resulting solution was mixed with 1.0 g of p-toluenesulfonate, and refluxed under heating for 50 minutes. After cooling, the resulting reaction solution was poured into saturated sodium bicarbonate solution and extracted with benzene. The resulting organic layer was dried to remove the solvent. The residue thus obtained was dissolved in 100 ml of methanol, followed by adding 37 ml of 2N sodium hydroxide and by refluxing under heating for 1 hour in a stream of nitrogen. After cooling, the resulting reaction solution was adjusted to pH 1 with concentrated hydrochloric acid, extracted with benzene, and then dried to remove the solvent. The residue thus obtained was dissolved in 20 ml of acetone and added dropwise, at room temperature, to a stirred mixture consisting of 6.74 g of chloroacetone, 22.1 g of anhydrous potassium carbonate and 150 ml of acetone. After 30 minutes of stirring, the resulting reaction mixture was refluxed under heating for 30 minutes. After cooling, insoluble materials were removed by filtration, and the resulting filtrate was concentrated to dryness. The thus obtained residue was purified by silica gel column chromatography using toluene as an elution solvent and the resulting product was recrystallized from ethanol to obtain 7.5 g of 2-acetyl-5-bromobenzo[b]thiophene.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([NH2:42])[CH3:41])=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([NH:42][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH3:41])=[CH:36][CH:35]=1
Reactant: CC(N)c1ccc(F)cc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 1-(4-fluorophenyl)-ethylamine (32 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 120 mg of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[OH-].[K+].[CH3:11]I>CS(C)=O>[CH3:11][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Hydroxy-2-methylpyridine (16.4 g, 150.3 mmol) was added to a suspension of KOH (34.6 g, 616 mmol) in DMSO (250 ml) and stirred for 1 h at r.t. followed by the dropwise addition of methyl iodide (10.3 ml, 165 mmol). The reaction mixture was stirred for a further 16 h, poored onto ice-cold water (500 ml) and extracted with diethyl ether (4×350 ml). The combined ether extracts were washed with water (50 ml), brine (50 ml) and dried (MgSO4). Filtration and concentration of the filtrate under reduced pressure gave a crude oil which was purified over silica gel (ethyl acetate/n-heptane 1:2 to 1:1): light brown oil 10.5 g (54%);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:26][C:25]([C:24]3[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=3)=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
Ethyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate and 4-nitrobenzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-chlorophenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate, which is dissolved in ethyl alcohol. 1 M Sodium hydroxide solution is added and the mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-chlorophenyl)-2-(4-nitrophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:18][CH2:19][OH:20])[C:7]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:20][CH2:19][CH2:18][N:6]1[C:5]2[CH:21]=[CH:22][C:2]([Br:1])=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][NH:10][C:11]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:17])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCc1nc2cc(Br)ccc2n1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1nc2cc(Br)ccc2n1CCOS(C)(=O)=O
Reaction time: 2 h
Yield: 106.2 %

Procedure:
tert-Butyl ((5-bromo-1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (648 mg, 1.75 mmol) was stirred in methylene chloride (25 mL), and triethylamine (530 mg, 0.74 mL, 5.3 mmol) and methanesulfonyl chloride (400 mg, 0.27 mL, 3.5 mmol) were added. The mixture was stirred for 2 h and then washed with water, dried over sodium sulfate and concentrated to provide the title compound (833 mg, quant) as a yellow solid: ESI MS m/z 448 [M+H]+.