Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[O:15]1[C:19]2([CH2:24]CC(=O)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:21][CH2:20][C:19]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:24][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CC1(CC2)OCCO1
Temperature: 60 °C
Reaction time: 17 h
Yield: 81.8 %

Procedure:
The title compound was prepared according to the procedure of Takada (J. Med. Chem. 1996, 39, 2844-2851). A 350 mL pressure vessel, equipped with a magnetic stir bar, was charged with 1-methyl-3,5-dinitropyridin-2(1H)-one (5.0 g, 25.1 mmol) and 1,4-dioxaspiro[4.5]decan-8-one (4.7 g, 30.1 mmol). Ammonia in MeOH (1M, 200 mL) was added, the vessel was sealed with a screw cap, and the mixture was heated to 60° C. and stirred for 17 hours. The reaction mixture was concentrated and the residue was partitioned with ethyl acetate (200 mL) and water (200 mL). The layers were separated and the aqueous portion was extracted with ethyl acetate (2×100 mL). The organic portions were combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (7/3, hexanes/ethyl acetate) to afford the title compound (4.85 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2([CH2:25][C:26]([O:28][CH3:29])=[O:27])[NH:18]S(C(C)(C)C)=O.[ClH:30]>CO.O1CCOCC1>[ClH:30].[NH2:18][C:5]1([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: COC(=O)CC1(NS(=O)C(C)(C)C)CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CC1(N)CC(c2ccccc2)Oc2ccc(Br)cc21

Procedure:
A solution of methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)-2-phenylchroman-4-yl)acetate (427 mg, 0.89 mmol) in MeOH (7 mL) and 4 M HCl solution in 1,4-dioxane (14 mL) is stirred at rt for 30 min. The solvent is removed under reduced pressure to give 418 mg methyl 2-(4-amino-6-bromo-2-phenylchroman-4-yl)acetate HCl salt as a white foam, which is used for next step without further purification. MS ESI+ve m/z 376 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O>C(Cl)Cl>[N+:11]([C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH3:10])[CH:6]=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 99 %

Procedure:
68.6 g (0.5 mol) of 2-nitrotoluene were dissolved in 80 ml of methylene chloride and 38.6 g (0.6 mol) of 98% by weight nitric acid, followed by the addition under reflux with stirring over a period of 1 hour at boiling temperature of 40 g of 100% by weight sulphuric acid. After stirring for 2 hours under reflux, the methylene chloride phase was separated off without cooling and washed three times while still hot with 3 × 200 ml of water. After the washing water had been carefully separated off, the methylene chloride was distilled off, leaving 89.9 g (98% of the theoretical yield) of dinitrotoluene containing 99% of 2,4- and 2,6-dinitrotoluene.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>C1COCC1>[NH2:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1cccnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ncccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of methyl 2-aminonicotinate (4 g) and 2M aqueous sodium hydroxide solution (35 mL) in THF (50 ml) was stirred at room temperature overnight. The reaction mixture was neutralized with 1M hydrochloric acid, and extracted with ethyl acetate. The aqueous layer was acidified with 1M hydrochloric acid, and extracted with THF. The organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (1.78 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1.O.[SH-:15].[Na+]>C(O)C>[SH:15][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1
Reactant: [SH-]
Reactant: CCCn1c(Cl)cc(=O)n(C)c1=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCn1c(S)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 6-chloro-3-methyl-1-propyl-pyrimidine-2,4(1H,3H)-dione (3.76 g), sodium hydrosulphide hydrate (6 g) and ethanol (100 ml) was stirred at room temperature for 48 hours then concentrated in vacuo. The residue was dissolved in water (500 ml) and washed with ethyl acetate (2×100 ml). The aqueous phase was acidified with dilute hydrochloric acid, then extracted with ethyl acetate (3×100 ml). The combined organic phase was dried (MgSO4) and evaporated to leave a pale yellow solid which was used directly in the next step.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[Cl:18][C:19]1[N:24]=[C:23]2[CH:25]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[S:27][C:22]2=[CH:21][CH:20]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:28]([C:26]2[S:27][C:22]3[C:23](=[N:24][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH:25]=2)(=[O:29])=[O:30])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)ccc2s1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride as described in EXAMPLE 1, Part E using 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride in place of benzo[b]thiophene-2sulfonyl chloride. The product is obtained as a white solid.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:23]([C:21]3[CH:20]=[CH:19][C:18]4[O:13][CH2:14][CH2:15][O:16][C:17]=4[CH:22]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2c(c1)OCCO2

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 1,4-benzodioxan-6-carboxylic acid (Maybridge) according to methods A and C; yield 49 mg, 0.13 mmol (42%): 1H NMR (300 MHz, methanol-d4) δ 2.08-2.29 (m, 5H), 2.49 (s, 2H), 3.50 (d, J=13 Hz, 2H), 3.56 (s, 2H), 3.85 (d, J=13 Hz, 2H), 4.28 (s, 1H), 7.38-7.50 (m, 2H), 7.87-7.96 (m, 2H), 8.14 (d, J=1 Hz, 1H); MS (DCI/NH3) m/z 315 (M+H)+; Anal. C18H22N2O3.HCl.0.25NH4OH: C, H, N.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][N:5]=1>>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:2][CH3:1])=[O:9])=[CH:6][N:5]=1
Reactant: CN
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CNC(=O)c1ccc(Cl)nc1

Procedure:
The title compound (D42) was prepared from methylamine and 6-chloronicotinic acid according to the procedure described for Description 35.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:18])[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]([F:30])([F:29])[CH2:27]I.O>CN(C=O)C>[F:25][C:26]([F:30])([F:29])[CH2:27][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH2:9][C:10]1=[O:18]
Reactant: O=c1cnc(-c2ccccc2)c2ccccc2n1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Reaction time: 8 h

Procedure:
A solution of 5-phenyl-1,4-benzodiazepine-2-one (50 g, 0.211 mole) in DMF (100 mL) was treated with cesium carbonate (103.5 g, 0.317 mole) and trifluoroethyl iodide (109.7 g, 0.525 mole). The mixture was stirred at 50° C.-60° C. overnight. The reaction mixture was then poured into water (2 L) and extracted with ethyl acetate (3×1 L). The combined ethyl acetate fractions were dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The material was chromatographed on silica gel (1.5 Kg) eluting with 1:1 ethyl acetate/heaxane. The combined pure fractions were concentrated at reduced pressure. The residue was swished with warm ethyl ether, cooled and filtered to give the product. MP=130°-131° C.; 1H NMR CDCl3, δ7.65-7.60 (m, 2H), 7.60-7.45 (m, 5H), 7.40-7.20(m, 2H), 5.25 (dq, J=14, 8.6 Hz, 1H), 4.82(d, J=10.5 Hz, 1H), 4.15 (app sextet, J=8.6 Hz, 1H), 3.81 (d, J=10.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].CN(C)C=O.[H-].[Na+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][C:9]=1[OH:10])=[O:3]
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Fifty grams of 2,4-dihydroxyacetophenone were dissolved in 250 ml. of dimethylformamide and the solution was cooled to 0° C. by means of an external ice-bath. After the addition of 15 grams of a 50% oil dispersion of sodium hydride, 40 ml. of benzyl chloride were added in a dropwise fashion and the reaction was allowed to warm to room temperature. After stirring overnight, the reaction mixture was added to 700 ml. of ethyl acetate. The organic phase was washed with 1000 ml. of 1N hydrochloric acid and twice each with 1000 ml. of a saturated sodium chloride solution. The organic layer was dried, and the solvent removed in vacuo. The oily residue was treated with 100 ml. of methanol and 50 ml. of hexane. The desired 2-hydroxy-4-benzyloxyacetophenone (36.7 grams) was recovered by filtration.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[N:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>O>[Cl:2][CH2:3][CH2:4][CH2:5][N:6]=[CH:13][C:10]1[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=1
Reactant: NCCCCl
Reactant: O=Cc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCCCN=Cc1ccncc1

Procedure:
To 3-chloropropylamine HCl (15.1 g, 0.120 moles (hereinafter mol)) and H2O (100 mL) was added pyridine-4-carboxaldehyde (9.55 mL, 0.100 mol), then K2CO3 (8.28 g, 0.060 mol) then CH2CL2 (100 mL) and the mixture was stirred for 40 min. The phases were separated and the aq phase was extracted with additional CH2Cl2 (2×50 mL), dried (Na2SO4) and concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (d, J=4.5 Hz, 2H, 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.71 (m, 2H), 3.63 (t, J=6Hz, 2H), 2.24 (t, J=6Hz, 2H). The presence of 9% of the aldehyde was evident by 1H NMR.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].N1C=CN=C1.[C:16]([Si:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[Si:20]([O:1][CH2:2][C@H:3]1[O:4][CH:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1OC(O)[C@@H](O)[C@@H]1O)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
D-Arabinose (200 g) and imidazole (199 g) were placed in a three-neck round bottom flask and connected to high vacuum for 30 minutes. The vacuum was released under nitrogen atmosphere and dimethylformamide (1.8 L) was added to the above mixture at room temperature followed by drop-wise addition of t-butyldiphenylchlorosilane (443 mL) for 10 minutes under a nitrogen atmosphere. The resulting mixture was stirred for 16 hours at the same temperature. Dimethylformamide was evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a crude residue which was purified by column chromatography over silica gel using 80% ethyl acetate in hexane as eluant to afford the title compound (273 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[CH:4]([CH2:5][C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.O1CCCC1.N.[Li]>CO>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[CH:4]([CH2:5][C@H:6]([OH:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)CC4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](O)CC4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -32 °C
Reaction time: 0.88 h
Yield: 103.5 %

Procedure:
A mixture of 100 g of 3α-hydroxy-7-keto-cholanic acid, 1000 ml of tetrahydrofuran and 30 ml of methanol was stirred until dissolution occured and the solution was cooled to -32° C. Then, 1000 ml of liquid ammonia were added thereto all at once and then 10 g of lithium in small particles were added thereto at -32° C. over 45 to 60 minutes. 100 ml of methanol were added to the mixture over 15 minutes and the ammonia was evaporated by placing the mixture in a water bath at 30° C. for one hour. 400 ml of demineralized water were added all at once to the reaction mixture which was then adjusted to a pH of ≃2 by addition of 200 ml of 22° Be hydrochloric acid. The mixture was extracted four times with 200 ml of ethyl acetate and the organic phase was washed with demineralized water and evaporated to dryness of 60° C. under reduced pressure. The residue was taken up 3 times with 100 ml of ethyl acetate and the organic phase was evaporated to dryness at 70° C. under reduced pressure to obtain 104 g of crystalline crude 3α,7β-dihydroxy-cholanic acid with a specific rotation of [α]D20 =+50°±1° (c=1% in ethanol). Thin layer chromatograpy showed the raw product contained about 8% of chenodesoxycholic acid (3α,7α-dihydroxy-5β-cholanic acid).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:13]([O:15][CH3:16])=[O:14])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[O:21]=[S:22]1(=[O:38])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:24](=[O:32])[N:23]1[CH2:33][CH2:34][CH2:35][CH2:36]Br>C(Cl)Cl>[O:38]=[S:22]1(=[O:21])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:24](=[O:32])[N:23]1[CH2:33][CH2:34][CH2:35][CH2:36][N:10]1[CH2:11][CH2:12][C@@H:7]([N:6]2[C:5]3[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=3[NH:3][C:2]2=[O:1])[C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Reactant: COC(=O)[C@@H]1CNCC[C@H]1n1c(=O)[nH]c2ccccc21
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(CCCCN2C(=O)c3cc(Cl)ccc3S2(=O)=O)CC[C@H]1n1c(=O)[nH]c2ccccc21

Procedure:
From (±) cis/trans-4-(2-oxo-1-benzimidazolinyl)-3-methoxycarbonyl-piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 22) using the procedures described in Example 1, Step 3, there was obtained a white solid from methylene chloride, melting point 170-176° C. Analysis calculated for C25H27ClN4O6S: C, 54.89; H, 4.98; N, 10.24; found: C, 54.65; H, 4.98; N, 10.22. The NMR was consistent with the structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1([CH3:27])[C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:26])[O:14]1>>[CH3:12][C:13]1([CH3:27])[O:14][C:15](=[O:26])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=3)=[CH:19][C:18]1=2
Reactant: N#CCc1ccc(Br)cc1F
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(CC#N)c(F)c3)cc21

Procedure:
Prepared according to procedure B from 4-bromo-2-fluorophenylacetonitrile (T. Alessi A. H. P. U.S. Pat. No: 4,895,862) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. A grey solid; mp 253-256° C. 1HNMR(DMSO-d6) □10.35 (s,1H) 7.67-7.49(m,5H), 6.97(d,1H; J=8.6 Hz) 4.09 (s,2H) (s,2H) 1.67(s,6H); MS [M−H]− m/z 309. Anal. Calc. For C18H15N2FO2.0.15H20: C,69.07, H, 4.93, N, 8.95. Found C,69.27, H 5.05, N, 8.50
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH:15]=[N:16]3)=[CH:11][C:10]=2[F:25])=[O:7])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[C:14]([CH2:19][N:20]5[CH2:21][CH2:22][CH2:23][CH2:24]5)[CH:15]=[N:16]4)=[CH:11][C:10]=3[F:25])=[O:7])=[CH:26][CH:27]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(Nc1cc2ncc(CN3CCCC3)cc2cc1F)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ncc(CN3CCCC3)cc2cc1F)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a solution of 4-bromo-N-[6-fluoro-3-(1-pyrrolidinylmethyl)-7-quinolinyl]benzamide (100 mg, 0.233 mmol) obtained in Example 49, 4-fluorophenylboronic acid (65.3 mg, 0.467 mmol) and 2N sodium carbonate (0.233 ml) in 1,2-dimethoxyethane (3 ml) was added tetrakistriphenylphosphine palladium (8.1 mg, 0.007 mmol) at 90° C., and the mixture was stirred under a nitrogen atmosphere for 16 hrs. The reaction solution was diluted with ethyl acetate and dried over anhydrous sodium sulfate. The obtained crude product was purified by NH-silica gel chromatography (eluting solvent; ethyl acetate) and treated with ethyl acetate-isopropyl ether (1:5) to give the title compound (55.2 mg) as a powder.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[O:8][C@H:7]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>>[CH2:5]([CH:6]1[O:8][CH:7]1[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:7]1[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:8]1)=[O:21])[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC[C@H]1O[C@H]1C/C=C\CCCCCCCC(=O)OC
Reactant: NCCCCN
Product: CCCCCC1OC1CC=CCCCCCCCC(=O)NCCCCNC(=O)CCCCCCCC=CCC1OC1CCCCC

Procedure:
Precursor 8 was prepared from methyl vernolate and 1,4-diaminobutane according to the procedure described in Example 1(f) and shown in Scheme 11.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([OH:12])(=O)[CH:8]=[CH:9][CH3:10].[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:13]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][C:16]([C:9]([CH3:10])=[CH:8][CH2:7][OH:12])=[CH:15][CH:14]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CC=CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=CCO)c1ccc(-c2ccccc2)cc1
Yield: 40.6 %

Procedure:
LiAlH4 reduction of ethyl 3-([1,1′-biphenyl]-but-2-enoate (3e) using THF as solvent under similar conditions furnished 40.6% yield of 3-([1,1′-biphenyl]-4yl)-2-butenol (4e).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:24])[CH2:19]2)=[N:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([CH:20]3[CH2:21][CH2:22][N:18]([C:15]4[CH:16]=[CH:17][N:12]=[CH:13][N:14]=4)[CH2:19]3)=[O:24])[CH2:26][CH2:27]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: O=C(C1CCN(c2ccncn2)C1)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2ccncn2)C1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reaction time: 2 h
Yield: 56.1 %

Procedure:
4-Bromophenylsulphonyl chloride (129 mg) was added at ambient temperature to a stirred solution of 1-[1-(4-pyrimidinyl)pyrrolidin-3-ylcarbonyl]piperazine (130 mg) in THF (8 ml) containing triethylamine (0.14 ml). The mixture was stirred for 2 hours then evaporated. The residue was treated with water (16 ml) and dichloromethane (30 ml) added. Aqueous was separated and re-extracted with dichloromethane (20 ml). The combined organic phases were washed with saturated brine (2×10 ml), dried and evaporated. The residue was purified by chromatography on neutral alumina eluting with dichloromethane/methanol (99/1 v/v) to give, as a colourless solid, 1-(4-bromophenylsulphonyl)-4-[1-(4-pyrimidinyl)pyrollidin-3-ylcarbonyl]piperazine (134 mg), mp 94-6°;
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.Br[CH:18]([CH3:22])[CH:19](Br)[CH3:20]>C1COCC1>[F:3][C:4]([F:15])([F:16])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:13]#[N:14])[CH2:20][CH2:19][CH2:18][CH2:22]2)=[CH:10][CH:11]=1
Reactant: CC(Br)C(C)Br
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(OC(F)(F)F)cc2)CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.9 %

Procedure:
To sodium hydride (600 mg, 15 mmol) in anhydrous THF (5 mL) at 0° C., was added dropwise 2-(4-(trifluoromethoxy)phenyl)acetonitrile (1006 mg, 5 mmol) and then the reaction mixture was stirred for 5 mins, followed by dibromobutane (1075 mg, 5 mmol) dropwise. The reaction mixture was heated to reflux for 16 h, then cooled to 0° C., quenched with MeOH (1 mL), diluted with EtOAC (50 mL) and washed with brine (3×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give 1-(4-(trifluoromethoxy)phenyl)cyclopentanecarbonitrile as a yellow oil (905 mg, 71%) (1H NMR (400 MHz, CDCl3) 7.50 (dd, J=2.1, 6.7 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 2.53-2.49 (m, 2H), 2.10-1.97 (m, 6H)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36](C)=[C:35]([CH:38]=O)[NH:34][C:33]=2[CH3:40])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:38])[NH:34][C:33]=2[CH:40]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (52.2 mg, 40%).