Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:30])=[CH:5][CH:4]=1)#[N:2].C(C1SC=C(CN2CC[C@H](NS([C:48]3[CH:57]=[CH:56][C:55]4[C:50](=[CH:51]C(OC)=CC=4)[CH:49]=3)(=O)=O)C2=O)C=1)#N.C(Br)C1C=CC=CC=1.CI>>[C:1]([C:3]1[S:7][C:6]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:51][C:50]3[CH:55]=[CH:56][CH:57]=[CH:48][CH:49]=3)[S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:30])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(C#N)s4)C3=O)cc2c1
Agent: BrCc1ccccc1
Solvent: CI
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@H]3CCN(Cc4ccc(C#N)s4)C3=O)cc2c1

Procedure:
The title compound is prepared as in EXAMPLE 126, Part A using 7-methoxynaphthalene-2-sulfonic acid[1-(5-cyanothiophen-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as in EXAMPLE 148, Part A, in place of 7-methoxynaphthalene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide and benzyl bromide for methyl iodide.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(Oc2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(Oc2ccc(F)cc2)c1
Yield: 91.8 %

Procedure:
EX-634B) 3-(4-Fluorophenoxy)nitrobenzene (1.15 g, 4.93 mmol) from EX-634A was dissolved in ethanol (45 mL), and the solution was hydrogenated for 4 h in the presence of 5% palladium on charcoal. After the mixture was filtered through celite, the ethanol was removed in vacuo. The product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:10) to give 0.92 g (90%) of 3-(4-fluorophenoxy)aniline as a yellow oil, 99% pure by HPLC analysis. HRMS calcd. for C12H11FNO: 204.0824 [M+H]+, found: 204.0837.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38].CN(C)C=O>O>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:17]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])=[N:5][CH:4]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: O=S(=O)(c1cccs1)N(CC1CC1)c1cccc2cc(-c3ncc(CCl)s3)[nH]c12
Reactant: CC(=O)N1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2cnc(-c3cc4cccc(N(CC5CC5)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-(cyclopropylmethyl)thiophene-2-sulfonamide (100 mg), triethylamine (60 μL), 1-acetylpiperazine (55 mg) and N,N-dimethylformamide (3 ml) was stirred at room temperature for 16 hr. Water 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 residue was subjected to silica gel column chromatography to give the title compound (91 mg, yield 76%) as colorless crystals from a fraction eluted with ethyl acetate. MS 556 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[C:23]([CH3:29])[N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][N:8]=2)[C:5](=[O:30])[NH:4][C:3]1=[O:31].[CH3:32]C(C)([O-])C.[K+].CI.O>O1CCCC1>[CH3:32][N:4]1[C:3](=[O:31])[CH:2]([CH3:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[C:23]([CH3:29])[N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][N:8]=2)[C:5]1=[O:30]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)nc3)CC2)nc1C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)nc3)CC2)nc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.7 %

Procedure:
5-Methyl-1-{5-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}imidazolidine-2,4-dione (60 mg) described in Example 549 was dissolved in tetrahydrofuran, potassium tert-butoxide (17 mg) and methyl iodide (9.3 μL) were added under ice-cooling, and the mixture was stirred at the same temperature for 15 min and at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (50 mg).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]2[C:16]([CH3:20])=[C:17]([CH3:19])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C(Cl)(Cl)Cl>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[C:6]3[C:16]([CH3:20])=[C:17]([CH3:19])[S:18][C:5]=3[N:4]3[C:21]([CH3:24])=[N:22][N:23]=[C:3]3[CH:2]([NH:1][C:34]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH3:25])=[O:35])[N:8]=2)=[CH:14][CH:13]=1
Reactant: COc1ccccc1N=C=O
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(N)c1nnc(C)n1-2
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)NC1N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Reaction time: 0.5 h

Procedure:
6-Amino-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepine (4 g) was dissolved in chloroform (30 ml). 2-Methoxyphenyl isocyanate (1.7 ml) was added, and the mixture was stirred for 30 minutes. The reaction mixture was subjected to silica gel column chromatography, and the resultant crystals were recrystallized from ethanol to give 5.14 g of N-(4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin- 6-yl)-N'-(2-methoxyphenyl)urea, melting point 261°-262° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C@H:5]1[CH2:8][C@@H:7]([OH:9])[CH2:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31].C1(C)C=CC=CC=1>C1COCC1.N(C(OCC)=O)=NC(OCC)=O>[CH3:1][O:2][C:3]([CH2:4][C@H:5]1[CH2:8][C@H:7]([O:9][C:37](=[O:38])[C:36]2[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:41][CH:40]=2)[CH2:6]1)=[O:10]
Reactant: COC(=O)C[C@H]1C[C@@H](O)C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of cis-(3-hydroxy-cyclobutyl)-acetic acid methyl ester (570 mg, 3.96 mmol), triphenylphosphine (2.08 g, 7.92 mmol), and 4-nitrobenzoic acid (1.32 g, 7.92 mmol) in dry THF (50 mL), 40% diethyl azodicarboxylate in toluene (1.42 mL, 7.92 mmol) is added at room temperature. The mixture is stirred at room temperature for 15 hours. The solvent is removed under reduced pressure, and the obtained residue is purified by silica gel column chromatography to give trans-4-nitro-benzoic acid 3-methoxycarbonylmethyl-cyclobutyl ester (558 mg, 48%); TLC (hexane/AcOEt, 3:1) Rf 0.31, 1H NMR (400 MHz, chloroform-d) δ ppm 2.28-2.35 (m, 2H), 2.44-2.51 (m, 2H), 2.56 (d, 2H), 2.82-2.87 (m, 1H), 3.69 (s, 3H), 5.33-5.40 (m, 1H). 8.18-8.30 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(CN(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and α-bromo-p-xylene
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(I)C>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[N:16]([CH2:1][CH3:2])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1CC
Reaction time: 1 h
Yield: 1139.8 %

Procedure:
Potassium t-butoxide (2.3 g, 2.05 mmol) was added to a solution of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5 g, 1.56 mmol) in 100 ml of THF at 0° C. and the mixture was stirred at this temperature for 1 hour. To the mixture was added ethyl iodide (11.64 g, 7.46 mmol) at 0° C. and the resulting mixture was allowed to stir at room temperature for 40 hours. The resulting mixture was quenched with brine, extracted with ethyl acetate (150 ml) and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 5.27 g of 2-phenylmethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =propyl; R3 =ethyl) as an oil.
Reaction SMILES: [C:1]1([CH:7]([C:20]([O-:22])=O)[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[CH2:16][CH2:15][CH2:14]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[C:37](=[O:38])[N:26]2[CH:27]([C:32]3[NH:36][N:35]=[N:34][N:33]=3)[C:28]([CH3:31])([CH3:30])[S:29][C@H:25]12>>[CH2:15]1[C:14]2[C:13](=[CH:12][C:11]([O:10][C:8]([CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:20]([NH:23][CH:24]3[C:37](=[O:38])[N:26]4[CH:27]([C:32]5[NH:33][N:34]=[N:35][N:36]=5)[C:28]([CH3:30])([CH3:31])[S:29][C@H:25]34)=[O:22])=[O:9])=[CH:19][CH:18]=2)[CH2:17][CH2:16]1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: O=C([O-])C(C(=O)Oc1ccc2c(c1)CCC2)c1ccccc1
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccc4c(c3)CCC4)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Yield: 63 %

Procedure:
(2.0 mmole) of 5-indanyl 2-phenylmalonate with 480 mg. (2.0 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, according to the procedure of Example CXLVII affords 680 mg. (63% yield) of 6-(2-[5-indanyloxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its sodium salt. The infrared spectrum (KBr disc) of the product shows absorption bands at 1780 cm-1 (β-lactam), 1705 cm-1 (ester), 1680 cm-1 (amide I) and 1565 cm-1 (amide II). The NMR spectrum (D2O) shows absorption bands at 7.80-6.80 ppm (multiplet, aromatic hydrogens), 5.70 ppm (multiplet, C-5 and C-6 hydrogens), 5.25 ppm (doublet, C-3 hydrogen), 2.60-2.00 ppm (multiplet, C-1 and C-3 indanyl hydrogens), 2.00-1.80 ppm (multiplet, C-2 indanyl hydrogens), 1.35 ppm (doublet, C-2 methyl hydrogens) and 0.90 ppm (doublet, C-2 methyl hydrogens).
Reaction SMILES: [C:1](=[O:17])([O-])[O:2][C:3]1[CH:8]=CC([N+]([O-])=O)=C[C:4]=1C(C)(C)C.[NH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][NH2:24].[CH:25](Cl)(Cl)[Cl:26]>>[ClH:26].[ClH:26].[C:1]([N:21]([CH2:22][CH2:23][NH2:24])[CH2:20][CH2:19][NH2:18])([O:2][C:3]([CH3:4])([CH3:8])[CH3:25])=[O:17]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])ccc1OC(=O)[O-]
Reactant: ClC(Cl)Cl
Reactant: NCCNCCN
Product: CC(C)(C)OC(=O)N(CCN)CCN
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of t-butyl-p-nitrophenyl carbonate (10 g; 0.0418 mole) in CHCl3 (400 ml) was added to a solution of diethylenetriamine (45 ml; 0.0417 mole) in CHCl3 (250 ml) at 0° C. over a period of 3 h. The reaction mixture was stirred overnight at room temperature. The precipitate that appeared was filtered and washed in CHCl3. The solvent was evaporated, first under reduced pressure with a water-aspirator, then with an oil-pump (0.05 mmHg; 50° C.). The residue was dissolved in a mixture ethylacetate (50 ml)/H2O (50 ml) and the solution was acidified to pH 4 with HCl 4N, extracted with ethylacetate (3×50 ml). The aqueous solution was adjusted to pH 9 with NaOH 2N and extracted with ethylacetate (3×50 ml). The aqueous phase was adjusted to pH 11.5 and extracted with ethylacetate (10×50 ml). The combined organic phases of the last extraction were evaporated under reduced pressure and the resulting oil was dissolved in water (50 ml) and acidified to pH 5. Evaporation of water yielded a slightly yellow solid, which was thoroughly washed with ether (yield: 6.41 g; 55%). 1H-NMR (D2O): 6 (ppm): 1.4 (s, 9H); 3.0 (t, 2H); 3.3 (s broad, 4H); 3.4 (t, 2H)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH3:13][Si:14]([CH3:21])([CH3:20])[C:15]#[C:16][CH2:17][CH2:18][NH2:19]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]2[C:4]([CH:3]=1)=[N:10][N:19]([CH2:18][CH2:17][C:16]#[C:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:6]=2
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C#CCCN
Product: C[Si](C)(C)C#CCCn1cc2ccc(F)cc2n1
Yield: 100 %

Procedure:
The title compound was prepared in accordance with the general method of Example 149(A), from 4-fluoro-2-nitro-benzaldehyde (180 mg, 1.06 mmol) and 4-trimethylsilanyl-but-3-ynylamine (200 mg, 1.40 mmol). The crude product was purified by by flash chromatography (cyclohexane/AcOEt 4:1) to yield 6-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (310 mg, 1.06 mmol).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]3[CH2:13][CH2:14][CH:15]([CH2:17][O:18][CH2:19][C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH2:16][C:11]=3[N:10]=[CH:9]2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C3CC(COCC4C=C(C=CC=4)C#N)CCC=3N=C2)C=CC=CC=1>C(O)(=O)C.O>[NH:8]1[C:12]2[CH2:13][CH2:14][CH:15]([CH2:17][O:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[CH2:16][C:11]=2[N:10]=[CH:9]1
Reactant: N#Cc1cccc(COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c1
Agent: N#Cc1cccc(COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)c1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(COCC2CCc3[nH]cnc3C2)c1
Temperature: 90 °C

Procedure:
A solution of a mixture of 3-(((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methoxy)methyl)benzonitrile and 3-(((3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methoxy)methyl)benzonitrile (0.18 g, 0.34 mmol) in acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/−25% aqueous ammonia (100:10:1) as eluent, to give 71 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:28])([CH3:27])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:35](Br)[CH:36]=[CH2:37].CC(N(C)C)=O>CCOCC>[C:1]([C:5]1[C:14]2[CH:13]=[C:12]([N:15]([CH2:37][CH:36]=[CH2:35])[C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:27])([CH3:28])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: C=CCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C
Temperature: 75 °C

Procedure:
A mixture of ethyl 4-(8-t-butyl-5,5-dimethyl-5,6-dihydronaphthalen-2-ylamino)-benzoate (Compound 84, 170 mg, 0.45 mmol), K2CO3 (900 mg), allyl bromide (1 mL) and dimethylacetamide (5 mL) was heated to 75° C. in a sealed tube for 7 days. The mixture was diluted with ether (70 mL), washed with brine, dried and the solvent was removed. Silica gel flash chromatography gave the title compound.
Reaction SMILES: CCN(CC)CC.[Al+3].[Cl-].[Cl-].[Cl-].[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:24]1(=[O:30])[O:29][CH2:28][CH2:27][CH2:26][CH2:25]1>ClC(Cl)C.ClCCCl>[OH:30][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([N:21]1[CH2:22][CH2:23][N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][CH2:20]1)=[O:29]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1CCCCO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCO)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5.4 mL (37.5 mmol) Et3N in 10 ml, 2-dichloroethane was added drop by drop under ice cooling to a suspension of 3.70 g (27.5 mmol) AlCl3 in 20mL dichloroethane. At room temperature a solution of 4.21 ml (27.5 mmol) 1-phenylpiperazine and 2.32 mL (25 mmol) delta-valerolactone in 15 mL 1,2-dichloroethane was added to the mixture. After one hour of stirring at room temperature the mixture was quenched with ice water and stirred for another 30 minutes. The suspension was filtered by Celite. After adding of dichloromethane, separating of the organic layer, washing it with water, drying it with Na2SO4 and evaporating of the solvent, followed.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[Se:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[Li]CCCC.[CH:28](N1CCOCC1)=[O:29].Cl>C(OCC)C.O>[CH:20]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[Se:13][C:14]([CH:28]=[O:29])=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)([CH3:22])[CH3:21]
Reactant: CC(C)[Si](Oc1ccc(-c2ccc[se]2)cc1)(C(C)C)C(C)C
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc(-c2ccc(C=O)[se]2)cc1)(C(C)C)C(C)C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
11.0 g (27.9 mmol) of triisopropyl-(4-selenophen-2-ylphenoxy)silane are initially introduced in 200 ml of diethyl ether, and 20 ml (31.8 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 30 min and subsequently cooled to −70° C. 15.0 ml (0.15 mol) of N-formylmorpholine in 50 ml of diethyl ether are added, and the mixture is warmed to RT and stirred for 1 h. The mixture is added to water, and 2 N hydrochloric acid is added. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). 5-(4-Triisopropylsilanyloxyphenyl)selenophene-2-carbaldehyde is obtained as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH2:16][CH2:17][CH2:18][OH:19].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:19][CH2:18][CH2:17][CH2:16][C:4]1[C:5]([CH3:15])=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])(=[O:30])=[O:29]
Reactant: COc1c(C)c(CCCO)c(OC)c(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(CCCOS(C)(=O)=O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A solution of 9 (3.88 g, 15 mmol) and triethylamine (3.0 g, 30 mmol, 4.2 mL) in CH2Cl2 (50 mL) was stirred at room temperature for 10 mins. Methane sulfonyl chloride (1.8 g, 1.20 mL, 15.75 mmol) in CH2Cl2 (50 mL) was added dropwise over 20 mins and the reaction mixture stirred at room temperature for 1 hr. The mixture was then diluted with CH2Cl2 (50 mL) and the organic layer washed with H2O (5×100 mL), 10% aqueous NaHCO3 (100 mL), dried (MgSO4), filtered and the solvent removed in vacuo by rotary evaporation to afford pure 3 as a liquid (4.8 g, 95%).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4](=[O:17])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[N:8][C:9]=2[N:10]=1.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>O>[F:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[O:41][C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4](=[O:17])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[N:8][C:9]=2[N:10]=1
Reactant: Oc1cccc(F)c1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(C)c3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCn1c(Oc2cccc(F)c2)nc2nc(-c3cnn(C)c3)[nH]c2c1=O
Temperature: 87.5 °C
Yield: 74.3 %

Procedure:
The first two steps were carried out as described earlier. A mixture of 2-Chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one (0.1 g, 0.34 mmol), N-methyl pyrrolidone (2 ml), potassium carbonate (0.093 g, 0.68 mmol) and 3-Fluoro phenol (0.036 ml, 0.4 mmol), were heated at 85-90° C. for 20 hours. The reaction mixture was cooled to 0° C. and then added water (10 ml). The solid obtained was filtered, washed with cold water, then washed with diethyl ether, dried to obtain -(3-Fluoro-phenoxy)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7dihydro-purin-6-one (0.093 g, 75%) as an off white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH3:20][CH:21]1[O:26][CH:25]([CH3:27])[CH2:24][N:23]([C:28](N2C=C[N+](C)=C2)=[O:29])[CH2:22]1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:28]([N:23]3[CH2:24][CH:25]([CH3:27])[O:26][CH:21]([CH3:20])[CH2:22]3)=[O:29])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CC1CN(C(=O)n2cc[n+](C)c2)CC(C)O1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Product: CC1CN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC(C)O1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(2,6-dimethyl-morpholine-4-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was purified by preparative HPLC (39%, colorless oil). HPLC-MS m/z=397.1 (M+1), Rt: 4.64 min.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[CH2:14])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>O>[O:31]=[C:30]1[C:29]2[C:28](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27](=[O:36])[N:1]1[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[CH2:14])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: C=Cc1ccccc1CC(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=Cc1ccccc1CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 2.5 h
Yield: 60.1 %

Procedure:
Dissolve 2-amino-3-(2-vinyl-phenyl)-propionic acid (3.40 g) in water (75 mL) and add sodium carbonate (1.97 g, 18.6 mmol) and N-carbethoxyphthalimide (2.81 g, 12.8 mmol). Stir for 2.5 hours, wash with methylene chloride (200 mL), acidify to pH 1 with cold concentrated hydrochloric acid and extract with ethyl acetate (3×200 mL), dry (Na2SO4), evaporate the solvent in vacuo and purify by silica gel chromatography (1:1:2% hexane/ethyl acetate/acetic acid) followed by recrystallization (isopropranol) to give the title compound as a pale yellow solid (2.47 g).