Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6].N([O-])=O.[Na+].[ClH:22]>>[Cl:22][C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: N#Cc1cc(Cl)ncc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 2-amino-5-(2,4-dichloro-phenyl)-isonicotinonitrile (880 mg, 3.3 mmol) in HCl conc. (15 mL) was vigorously stirred and cooled to −15° C. (ice/MeOH bath). NaNO2 (4.6 g, 66.7 mmol) was carefully added, then the reaction mixture was slowly warmed to RT and stirred for 24 h. The formed precipitate was filtered, washed with water, and purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→5:95) to yield the title compound (453 mg, 1.6 mmol, 48%). MS: 284 [M+1]+; HPLC: AtRet=2.70.
Reaction SMILES: [Br-:1].[Li+].C1(C)C=CC(S([CH:12]([C@:14]2([O:28][CH2:27][C@@H:21]([O:22][C:23](=[O:26])[NH:24][CH3:25])[C@@H:18]([O:19][CH3:20])[C@@:16]2([C:29]([CH3:31])=[CH2:30])[OH:17])[OH:15])O)(=O)=O)=CC=1>CC(C)=O>[Br:1][CH2:12][C@:14]1([O:28][CH2:27][C@@H:21]([O:22][C:23](=[O:26])[NH:24][CH3:25])[C@@H:18]([O:19][CH3:20])[C@@:16]1([C:29]([CH3:31])=[CH2:30])[OH:17])[OH:15]
Reactant: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC(=O)NC)CO[C@]1(O)C(O)S(=O)(=O)c1ccc(C)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC(=O)NC)CO[C@]1(O)CBr
Temperature: 75 °C
Yield: 94.2 %

Procedure:
0.29 g (3.34 mmol) of lithium bromide is added at room temperature, in a single portion, to a solution of 0.31 g (0.69 mmol) of the compound obtained in Example 10 in 15 ml of acetone. The reaction mixture is placed under stirring and then heated at 75° C. for 1.5 hours. A further 0.26 g (2.99 mmol) of lithium bromide is then added and the whole is again heated at 75° C. for one hour. The acetone is evaporated off under reduced pressure and the residue is taken up in 20 ml of ethyl acetate. Customary treatment of the organic phase yields 0.23 g (0.65 mmol) of the desired product in the form of a white-coloured foam.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11].C(OS([O-])(=O)=O)CCCCCCCCCCC.[Na+]>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Agent: [Pt]
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 20 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst in the presence of sodium dodecylsulfate. 427 mg Styrene and 498 mg methyldichlorosilane were introduced into a glass tube, and 55 mg of sodium dodecylsulfate was added. 1 mg Of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.4 wt % platinum content) was added. The tube was sealed and placed in a 100° C. oil bath where it was heated for 20 hours. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 45% and a phenethylmethyldichlorosilane yield of 20%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 34:1.
Reaction SMILES: [OH:1][C@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4].O[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O>>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H]1O
Agent: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O
Product: O=C[C@H](O)[C@H](O)[C@H](O)CO

Procedure:
α-D-ribofuranose; β-D-ribofuranose
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=[O:26])/[CH:23]=[CH:24]/[CH3:25]>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:22](=[O:26])[CH:23]([CH2:24][CH3:25])[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: C/C=C/C=O
Product: CCC1C(=O)Oc2[nH]c(-c3cc(F)ccc3F)nc2C1c1ccccc1
Yield: 80 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and trans-crotonaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 18 as an off-white solid (85 mg, 80%). Analytical data for 18: 1H NMR (500 MHz, CDCl3) δ 9.43 (br s, 1H), 7.91 (ddd, J=9.3, 6.1, 3.2 Hz, 1H), 7.37-7.28 (m, 3H), 7.15-7.03 (m, 3H), 7.02-6.93 (m, 1H), 4.31 (d, J=6.9 Hz, 1H), 3.06 (q, J=6.8 Hz, 1H), 1.89-1.78 (m, 1H), 1.31-1.20 (m, 1H), 1.04 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 126 MHz) δ 169.0, 159.1 (d, JCF=243.5 Hz), 155.4 (d, JCF=240.5 Hz), 149.3, 137.1, 136.4, 129.2, 128.2, 127.7, 118.5 (dd, JCF=13.1, 9.2 Hz), 117.1 (dd, JCF=25.7, 8.8 Hz), 116.5 (dd, JCF=24.9, 9.5 Hz), 114.5 (dd, JCF=27.0, 4.0 Hz), 110.5 (d, JCF=3.9 Hz), 47.8, 39.1, 20.4, 11.9; IR (film) cm−1 2968, 2933, 2877, 1773, 1763, 1618, 1528, 1482, 1464, 1388, 1174, 1138, 1115, 1089, 1067, 766, 736, 699; LRMS (ESI): Mass calcd for [M+H]+ C20H17F2N2O2: 355.1. found 355.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 15% IPA/hexanes 1.0 mL/min, 280 nm), Rt1=20.2 min (major), Rt2=36.1 min (minor)); er=>99:1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][OH:22])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.O>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][O:22]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(CN2CCC3(CC2)OCc2ccccc23)cc1
Temperature: 53 °C
Yield: 94.7 %

Procedure:
Crude 1-benzyl-4-(2-hydroxymethyl-phenyl)-piperidin-4-ol (180 g, 0.605 mol) was dissolved in THF (1000 mL). Triethylamine (176.18 mL, 1.27 mol) was added. A solution of methanesulfonyl chloride (33.03 mL, 0.424 mol) in THF (100 mL) was added slowly which caused an increase of the temperature from ambient to 53° C. The reaction was then refluxed for 4 h. Water (500 mL) and AcOEt (500 mL) were added to the reaction mixture. The organic phase was separated, dried and evaporated to give a brown oil (160 g).The crude product was purified by chromatography on silica gel with heptane/AcOEt 100:0 to 60:40 to give a light yellow solid (120 g, 71%). MS: m/z=280 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4](=[O:16])[C:3]=1[S:17][C:18]#[N:19].O>CN(C)C=O>[NH2:19][C:18]1[S:17][C:3]2[C:4](=[O:16])[N:5]=[C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:7][C:2]=2[N:1]=1
Reactant: N#CSc1c(N)[nH]c(SCc2ccccc2)nc1=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2[nH]c(SCc3ccccc3)nc(=O)c2s1

Procedure:
The product of example 1 step a) (7.35 g) was heated at 120° C. in N,N-dimethylformamide (40 ml)/water (10 ml) for 10 hours. After cooling, the resulting solid was filtered off, washed with water, then ethyl acetate to give the subtitle compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7](=O)[CH2:8][CH3:9])[C:3]([OH:5])=[O:4].Cl.[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([N:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)N)=[O:18])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([N:19]2[C:21]3[C:22](=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:8]([CH3:9])=[C:7]2[CH2:6][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[O:18])=[CH:15][CH:14]=1
Reactant: CCC(=O)CC(C)C(=O)O
Reactant: COc1ccc(N(N)C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(C)c(CC(C)C(=O)O)n2C(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
2-methyl-4-oxohexanoic acid (27.6 mg, 0.19 mmol) was added to a stirred solution of 4-chloro-N-(4-methoxyphenyl)benzohydrazide hydrochloride (50 mg, 0.16 mmol) in acetic acid (0.5 mL), the mixture was heated at 80° C. under nitrogen for 3 h, then it was allowed to cool to ambient temperature and stirred overnight. Ice-water (2 mL) was poured into the cold reaction mixture and the formed precipitate was collected by filtration, carefully washed with water and dried in vacuo to yield the title compound (27 mg, 44%) as an off-white solid. C21H20ClNO4, Mr=385.84; 1H NMR (400 MHz, DMSO-d6) d: 1.01 (d, J=6.8 Hz, 3H), 2.19 (s, 3H), 2.54 (sex, J=7.2 Hz, 1H), 2.91-3.19 (m, 2H), 3.76 (s, 3H), 6.46 (d, J=9.2 Hz, 1H), 6.64 (dd, J=2.4/9.0 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H); LCMS (ESI) tR: 2.78 min (>99%, ELSD), m/z: 386.1 [M+1]+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:9]=[C:8]([CH:10]([CH3:24])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([F:23])[CH:12]=2)[O:7][N:6]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:30]O>>[CH3:30][O:2][C:1]([CH2:4][C:5]1[N:9]=[C:8]([CH:10]([CH3:24])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([F:23])[CH:12]=2)[O:7][N:6]=1)=[O:3]
Reactant: CO
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CC(=O)O)no1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Reaction time: 8 h

Procedure:
To a solution of 1.27 g of 3-carboxymethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole obtained in Example 39 in 20 ml of dry methanol was added a drop of conc. sulfuric acid. The mixture was allowed to stand at room temperature overnight and then concentrated to dryness under reduced pressure. The solution of the residue in benzene was washed successively with a sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene to give 0.95 g of 3-methoxycarbonylmethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, nD25 1.5618.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:41])=[C:9]([CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[CH:22][N:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:39][CH3:40])[N:10]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:41])=[C:9]([CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:22][N:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:39][CH3:40])[N:10]=1
Reactant: CCOC(=O)CCc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2CCC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A mixture of ethyl 3-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]propionate (340 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]propionic acid (300 mg, yield 94%), which was then recrystallized from ethyl acetate-hexane. melting point: 161–162° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:13])[CH2:8][CH2:7][CH2:6][N:5](C(OC)=O)[CH2:4]1>O>[NH2:1][CH2:2][C:3]1([OH:13])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: COC(=O)N1CCCC(O)(CN)C1
Solvent: O
Product: NCC1(O)CCCNC1

Procedure:
5.1 g (27.1 mmol) of methyl 3-aminomethyl-3-hydroxypiperidine-1-carboxylate are heated overnight under reflux with 15.8 g of Ba(OH)2 . 8H2O in 150 ml water. The product is filtered off from BaCO3 with suction and concentrated. The residue is boiled five times using 70 ml of dioxane each time, and the dioxane solutions are concentrated and distilled.
Reaction SMILES: [CH2:1]([Li])CCC.[NH2:6][C:7]1[N:8]=[C:9]([CH:30]=[CH2:31])[C:10]([C:20]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=2[CH:22]=O)=[N:11][C:12]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[NH2:6][C:7]1[C:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]([C:20]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=2[CH:22]=[CH2:1])=[C:9]([CH:30]=[CH2:31])[N:8]=1
Reactant: [Li]CCCC
Reactant: C=Cc1nc(N)c(Cc2ccccc2)nc1-c1ccc(OC)cc1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(N)nc1C=C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
Under an argon atmosphere, to a suspension of methyltriphenylphosphonium bromide (1.29 g, 3.61 mmol) in anhydrous THF (5 mL) was gradually dropwise added n-butyl lithium (1.65 M in n-hexane) (1.70 mL, 2.81 mmol) at 0° C. The mixture was stirred at 0° C. for 15 minutes as it was. To the mixture was added 2-(5-amino-6-benzyl-3-vinylpyrazin-2-yl)-5-methoxybenzaldehyde (8) (871 mg, 2.52 mmol) at 0° C. After elevating to room temperature, stirring was continued for 1.5 hours. After to this was added water, the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give 2-amino-3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazine (9) (570 mg, 1.66 mmol, 65.8%) as a white solid. TLC Rf=0.37 (n-hexane/ethyl acetate=3/1); 1H NMR (500 MHz, CDCl3) δ 3.88 (s, 3H), 4.16 (s, 2H), 4.39 (s, 2H), 5.18 (dd, 1H, J=1.0, 10.5 Hz), 5.30 (dd, 1H, J=2.0, 10.5 Hz), 5.67 (dd, 1H, J=1.0, 17.5 Hz), 6.25 (dd, 1H, J=2.0, 17.5 Hz), 6.47 (dd, 1H, J=10.5, 17.5 Hz), 6.50 (dd, 1H, J=10.5, 17.5 Hz), 6.90 (dd, 1H, J=2.5, 8.0 Hz), 7.20-7.26 (m, 5H), 7.29-7.35 (m, 2H); 13C MR. (126 MHz, CDCl3) δ 41.2, 55.6, 110.5, 113.8, 115.4, 119.3, 127.2, 128.7 (2C), 129.2 (2C), 129.8, 132.1, 133.0, 135.1, 137.0, 138.3, 140.3, 141.9, 144.8, 151.4, 159.8.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[CH:4]=[CH:3]1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:30]=[C:31]([CH2:35]O)[CH:32]=[CH:33][CH:34]=3)=[N:27][CH:28]=2)[CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=3)[CH2:35][N:7]3[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:8]4[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=4)[C:11]#[N:12])=[N:6]3)=[N:25][CH:24]=2)[CH2:21][CH2:22]1
Reactant: N#Cc1cccc(-c2ccc(=O)[nH]n2)c1
Reactant: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
149 mg (0.76 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile and 256 mg (0.76 mmol) of {3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}-methanol are suspended in 5 ml of DMF with 378 mg (1.13 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and shaken at room temperature for 30 min. 266 mg (1.134 mmol) of ditert-butyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 2 h. A further 378 mg (1.13 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and 266 mg (1.134 mmol) of di-tert-butyl azodicarboxylate are added, and the reaction mixture is shaken at room temperature for 2 h. The reaction mixture is filtered, the filtrate is evaporated, and the residue is purified by means of column chromatography on silica gel; yield: 59 mg of “A287”; HPLC: Rt=2.38 min (method C); LC-MS: 464 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)([O-])=O>CO>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2N)CC1
Yield: 99 %

Procedure:
Following the method of Example 49 (Method 2), tert-butyl 4-(2-nitro-4-(trifluoro-methyl)phenyl)piperazine-1-carboxylate in MeOH was reduced yielding tert-butyl 4-(2-amino-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (99%). LCMS (m/z): 346.1 (MH+); LC Rt=3.38 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:36]4[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:35]=4[F:34])(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3ccc(F)cc3F)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (49.75 mg, 0.49 mmol) in dichloromethane (6 ml) was added 2,4-difluorobenzene-1-sulfonyl chloride (52 mg, 0.25 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 30 mg (42%); 1H NMR (DMSO-d6, 300 MHz): δ9.31(s, 1H), 8.21-8.24(m, 1H), 7.968-7.998 (d, 1H, J=9.0 Hz.), 7.63-7.81 (m, 6H), 7.374-7.440 (m, 1H), 6.741-6.748 (d, 1H, J=2.1 Hz), 1.77(s, 6H); Mass m/z: 583 (M+).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1.[H-].[Na+].I[CH2:37][CH3:38]>CN(C=O)C.CO>[ClH:1].[CH2:37]([N:30]1[CH2:31][CH2:32][N:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][N:17]3[CH2:18][CH2:19][N:14]([C:10]4[CH:9]=[CH:8][CH:7]=[C:6]5[C:11]=4[CH:12]=[CH:13][C:4]([CH3:3])=[N:5]5)[CH2:15][CH2:16]3)[CH:23]=2)[C:29]1=[O:33])[CH3:38]
Reactant: CCI
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCN1CCN(c2cccc(CCN3CCN(c4cccc5nc(C)ccc45)CC3)c2)C1=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (Example 85, 50 mg) in DMF (1 mL) was added sodium hydride (60%, 10 mg). The mixture was stirred for 15 minutes, then iodoethane (11 □L) was added. The mixture was stirred for 90 minutes then diluted with methanol (5 mL) and purified by ion exchange chromatography [SCX-2; MeOH-(1M NH3/MeOH): (100:0)→(0:100)]. The basic washings were concentrated in vacuo and purified by column chromatography [SiO2; cyclohexane-EtOAc-MeOH: (1:1:0)→(0:10:1)] and converted to the hydrochloride salt according to the description given in the general procedure (D6) to give the title compound (49 mg).
Reaction SMILES: [C:1]1([S:7][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)P(=O)(N(C)C)N(C)C.[CH2:23](Br)[CH3:24].C(OCC)(=O)C>O>[C:1]1([S:7][CH2:23][CH3:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)Sc1ccccc1
Reactant: CCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCSc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of 11.52 g (63 mmoles) of phenylthio(trimethyl)silane, 22 ml of hexamethylphosphoric triamide and 18.8 ml (250 mmoles) of ethyl bromide was heated in a bath at 40° C. for 2 hours after which the conversion was complete. A solid formed in the reaction mixture and heating was continued for 1 hour after which the mixture was poured into a mixture of 150 ml of ethyl acetate and 50 ml of water. The ethyl acetate layer was separated and washed sequentially twice with 50 ml of water, 50 ml of a saturated sodium bicarbonate solution and twice with 25 ml of water. The combined water layers were extracted three times with 25 ml of ethyl acetate and the combined organic phases were washed twice with 25 ml of water, dried and evaporated to dryness. The residue was vacuum distilled to obtain 7.25 g (83% yield) of ethyl phenyl sulfide with a boiling point of 81.5°-84° C./14 mm Hg and a refractive index of nD25 =1.5632.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(C)[CH:25]=CC(S(O)(=O)=O)=C[CH:21]=1.O>C1C=CC=CC=1.C(O)C#C>[C:1]([NH:9][CH:10]([CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)[C:11]([O:13][CH2:25][C:20]#[CH:21])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1c[nH]cn1)C(=O)O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C#CCO
Solvent: c1ccccc1
Solvent: O
Product: C#CCOC(=O)C(Cc1c[nH]cn1)NC(=O)c1ccccc1

Procedure:
5 gm of 2-(benzoylamino)-3-(imidazol-4-yl)propanoic acid in 100 ml of benzene, 5 ml of propargyl alcohol, and 5.22 gm of p-toluenesulfonic acid.H2O was heated at reflux with the azeotropic removal of water by means of a Dean-Stark apparatus. After approximately 2 days of refluxing and the stoichiometric amount of water was produced, the reaction mixture was cooled, and a precipitate, the p-toluenesulfonic acid salt of the title compound was filtered out. The salt was taken up in water, the pH adjusted to 7.5 with 1.0N NaOH in a two phase system of water-dichloromethane. The layers were separated and the aqueous portion extracted 3×30 ml of CH2Cl2. The organic fractions were pooled, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][C:12]([O:18]CC4C=CC=CC=4)=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].Cl>[Pd].C(O)C>[C:1]([NH:4][CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCc2[nH]c3cc(OCc4ccccc4)ccc3c2C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)NC1CCc2[nH]c3cc(O)ccc3c2C1

Procedure:
3-Acetamido-7-(benzyloxy)-1,2,3,4-tetrahydrocarbazole (16 g.) was hydrogenated in 200 ml. of ethyl alcohol containing 6 ml. of concentrated hydrochloric acid and 3 g. of 10% palladium on charcoal at 40 psig following a procedure similar to that described in Example 2B to yield 3-acetamido-7-hydroxy-1,2,3,4-tetrahydrocarbazole as a foam.