Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26](F)[C:27](F)=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.[Cl:40]C1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=CC=CC=3N=2)=CC=1.NC1C=CC(C(O)=O)=CC=1Cl>N1C=CC=CC=1>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([Cl:40])[CH:10]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Agent: Nc1ccc(C(=O)O)cc1Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)c(Cl)c1

Procedure:
The title compound was synthesized in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-benzoimidazol-1-yl]-cyclohexyl-acetic acid, 4-amino-3-chloro-benzoic acid and using pyridine as a base.
Reaction SMILES: [CH2:1]([S:3][CH:4]([S:12][CH2:13][CH3:14])[C:5](F)([F:10])[C:6]([F:9])([F:8])[F:7])[CH3:2]>C(Cl)Cl.[OH-].[K+]>[CH2:13]([S:12][C:4]([S:3][CH2:1][CH3:2])=[C:5]([F:10])[C:6]([F:7])([F:8])[F:9])[CH3:14]
Reactant: CCSC(SCC)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCSC(SCC)=C(F)C(F)(F)F
Yield: 125 %

Procedure:
A solution of 3,3-bis-ethylsulfanyl-1,1,1,2,2-pentafluoro-propane (example C.26 step 1) (125.8 g, 495 mmol) in DCM (495 mL) and 3M KOH (97.97 g KOH (85%) in 495 mL H2O), with a catalytic amount of n-BuN4Br (4.785 g, 3 mol %), was stirred at 23° C. for 3 h. The organic layer was separated and dried over MgSO4. The solvent was removed by cautious rotary evaporation (470 mbar, 40° C., 100 rpm) to give an orange liquid (ca. 145 g, 125%). Vacuum distillation gave the title compound as a colorless liquid (109.82 g, 95%; bp 86-87° C. at 32 mbar). [according to J. Org. Chem. 1993, 58(1), 29-31.] MS (GC-MS; EI) 234.1 [(M)+].
Reaction SMILES: FC(F)(F)C(O)=O.COC[O:11][CH2:12][C@:13]1([CH3:24])[O:17][C:16]2=[N:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][N:15]2[CH2:14]1>C(Cl)Cl>[OH:11][CH2:12][C@:13]1([CH3:24])[O:17][C:16]2=[N:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][N:15]2[CH2:14]1
Reactant: COCOC[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(CO)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 25 h
Yield: 46.3 %

Procedure:
Trifluoroacetic acid (15 ml) was added to a solution of (R)-2-methoxymethoxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 28 (3.1 g, 13 mmol) in methylene chloride (30 ml) followed by stirring at room temperature for 25 hours. The reaction mixture was concentrated under reduced pressure. Methanol was added to the solution, and the resulting mixture was concentrated under reduced pressure. To the residue, 2-propanol was added, and the precipitates were filtered off and washed with 2-propanol to afford (R)-2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (1.2 g, yield 46%) as a light yellow powder.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:20]1
Reactant: ICCC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CCC4CCCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and (2-iodoethyl)cyclohexane.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.[C:12]1([C:18]2([NH2:21])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(C#N)(C)=O>[Cl:11][C:4]1[CH:3]=[C:2]([NH:21][C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:20][CH2:19]2)[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=1
Reactant: NC1(c2ccccc2)CC1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Agent: CC(=O)C#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Cl)cc1NC1(c2ccccc2)CC1
Temperature: 60 °C
Yield: 36.5 %

Procedure:
To a suspension of 4,6-dichloronicotinamide (191 mg, 1 mmol) in AcCN (2 mL) was added 1-phenylcyclopropanamine (160 mg, 1.2 mmol) and DIPEA (0.213 mL, 1.2 mmol). The mixture was heated at 60° C. for 2 days. The mixture was concentrated and purified by column chromatography to give 6-chloro-4-(1-phenylcyclopropylamino)nicotinamide (105 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27]([OH:29])=O)[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:53]=[CH:54][CH:55]=[N:56][C:51]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH2:66]>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27]([N:56]4[CH2:55][CH2:54][C@@H:53]([OH:66])[CH2:51]4)=[O:29])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: O
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N1CC[C@@H](O)C1
Reaction time: 4 h

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.2 mmol), R-3-hydroxypyrrolidine (35 mg, 0.4 mmol), HATU (152 mg, 0.4 mmol) and DMAP (73 mg, 0.6 mmol) in DMF (2 mL) was stirred for 4 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phase was washed with saturated NaCl aqueous solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (50 mg).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>CN(C=O)C>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([CH:12]([O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:10][CH:11]=2)=[CH:32][CH:31]=1
Reactant: c1ccc(CCCC(OC2CCCCO2)c2ccc(OCC3CO3)cc2)cc1
Reactant: Oc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: OC(COc1ccc(Br)cc1)COc1ccc(C(CCCc2ccccc2)OC2CCCCO2)cc1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A mixture of the crude product (5.5 g) of Step 2, 4-bromophenol (5.2 g) and 2 drops of Triton B in 30 mL of DMF was heated for 8 hrs. in a 160° C. oil bath. The mixture was then cooled to r.t., quenched with 100 mL of 2N NaOH, and extracted with 200 mL of Et2O. The extract was dried over NaSO4 and concentrated. The crude product was purified by flash chromatography eluted with 2.5:1 Hexane/EtOAc to give 5.2 g of the title compound.
Reaction SMILES: [O:1]1[CH:10]2[CH:5]([CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH2:9]2)[O:4][CH2:3][CH2:2]1.Cl>CO>[O:1]1[CH:10]2[CH:5]([CH2:6][NH:7][CH2:8][CH2:9]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2OCCOC2C1
Agent: Cl
Solvent: CO
Product: C1CC2OCCOC2CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl hexahydro-[1,4]dioxino[2,3-c]pyridine-6(7H)-carboxylate (800 mg, 4.47 mmol, 1 eq) in a solution of HCl in MeOH (15 mL) was stirred for 1 h at room temperature and concentrated in vacuo to give octahydro-[1,4]dioxino[2,3-c]pyridine. A mixture of the above residue, 1-bromo-3-chloropropane (2.84 g, 8.17 mmol, 4 eq) and K2CO3 (2.46 mg, 17.80 mmol, 4 eq) in acetone (60 mL) was heated to reflux overnight, cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/MeOH) to give the title compound as pale yellow oil (500 mg, 45.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 220.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH2:22]([NH2:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:22]([NH:30][S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CCCCCCCCN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCNS(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of 3,4-dimethoxybenzenesulfonyl chloride (0.750 g, 3.17 mmol), triethylamine (1.12 mL, 7.93 mmol) in 10 mL of ethyl acetate, octylamine (0.525 mL, 3.17 mmol) was added dropwise and the resulting solution was stirred overnight. The reaction mixture was filtered and the filtrate was washed 1N HCl (2×), dried with MgSO4, filtered and concentrated in vacuo to afford 0.611 g (78%) of the title compound as a white solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:31])([C@@H:27]([CH3:30])[CH:28]=[CH2:29])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>C(Cl)Cl.C(OCC)(=O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:31])([C@@H:27]([CH3:30])[C@@H:28]1[O:6][CH2:29]1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: C=C[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]([C@H]1CO1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 8 h

Procedure:
1.360 g (6.19 mmole) of 3-chloroperoxybenzoic acid of 80% purity) were added at 0° C. to a solution of 960 mg (3.44 mmole) of (2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-penten-2-ol (which was synthesized following the procedure disclosed in Japanese Patent Provisional Publication No. Sho 60-36468) in 30 ml of methylene chloride. Five minutes after the addition, the reaction mixture was stirred, and this stirring was continued overnight at room temperature. The reaction mixture was then diluted with ethyl acetate, after which it was washed, in turn, with an aqueous solution of sodium sulfite, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride. After it had been dried, the mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, using a 1:2 by volume mixture of ethyl actate and hexane as the eluent, to afford 320 mg of stereoisomer A of the title compound (having the lower polarity), melting at 160°-180° C. and 206 mg of the desired stereoisomer B of the title compound (having the higher polarity) as an oil.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)S(O[C:13](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=O)=O.[C:28]12([C:38]3[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=3[O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.[Cl-:55].[Li+]>C(COC)OC>[C:28]12([C:38]3[CH:39]=[C:40]([C:23]4[CH:24]=[CH:25][C:20](/[CH:19]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:21][C:22]=4[Cl:55])[CH:41]=[CH:42][C:43]=3[O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2
Reactant: [Cl-]
Reactant: OB(O)c1ccc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: CCOC(=O)C(=Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)/C=C/c1ccc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)c(Cl)c1
Temperature: 82.5 °C
Yield: 79.7 %

Procedure:
Aqueous Na2CO3 (1.4 mL, 2.0 M) was added to the ethyl (trifluoro-methane-sulfonyloxy)cinnamate (0.55 g, 1.53 mmol), 3-(1-adamantyl)-4-benzyloxyphenylboronic acid (0.50 g, 1.38 mmol) [1H NMR spectrum (300 MHz, CDCl3) δ 1.77, 2.26 (2 s, 12, AdCH2), 2.07 (s, 3, AdCH), 5.21 (s, 2, CH2), 7.06 (d, J=8.2 Hz, 1, ArH), 7.3-7.5 (mn, 5, ArH), 8.03 (d, J=7.8 Hz, 1, ArH), 8.19 ppm (s, 1, ArH)], tetrakis (triphenylphosphine)palladium (0.16 g, 0.14 mmol), and lithium chloride (0.13 g, 3.1 mmol) in dimethoxyethane (12 mL) under argon. The mixture was heated at reflux (80-85° C.) overnight to achieve the biaryl coupling, then worked-up, and chromatographed (10% ethyl acetate/hexane) to give ethyl (E)-4-[3-(1-adamantyl)-4-benzyloxyphenyl]-3-chloro-cinnamate as a white solid (0.58 g, 79%): m.p. 148-150° C.; Rf0.61 (20% ethyl acetate/hexane); 1H NMR spectrum (300 MHz, CDCl3) δ 1.73, 2.17 (2 s, 12, AdCH2), 2.04 (s, 3, AdCH), 1.33 (t, J=7.1 Hz, 3 CH3), 4.26 (q, J=7.1 Hz, 2, CH2), 5.17 (s, 2, CH2), 6.46 (d, J=15.9 Hz, 1, HC═CCO), 7.00 (d, J=8.2 Hz, 1, ArH), 7.3-7.5 (m, 8, ArH), 7.52 (d, J=7.1 Hz, 1, ArH), 7.62 (s, 1, ArH), 7.65 ppm (d, J=15.4 Hz, 1, C═CHCO).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:13]N1C(=O)CCC1=O>ClCCl.CN(C=O)C>[Cl:13][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of indole-6-carboxylic acid (2.45 g, 15.2 mmol) in dichloromethane (100 mL) and DMF (10 mL) was added N-chlorosuccinimide (2 g, 15.2 mmol). After 3 h, the solvent was removed in vacuo and the residue was suspended in dichloromethane, sonicated and filtered to give 2.38 g (80%) of the title compound.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[SH:12][CH2:13][C:14]([OH:16])=[O:15].C(OCC)(=O)C>O1CCCC1.N1CCCC1>[N+:1]([CH2:4][CH:5]([S:12][CH2:13][C:14]([OH:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: O=C(O)CS
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: O=C(O)CSC(C[N+](=O)[O-])c1ccccc1
Reaction time: 2 h
Yield: 81.3 %

Procedure:
A solution of nitrostyrene (10 g, 0.067 mol) in tetrahydrofuran (250 ml) is treated with mercaptoacetic acid (7.4 g, 5.6 ml, 0.08 mol) followed by pyrollidine (3 drops). After stirring for 2 hours the reaction mixture is concentrated onto silica gel and chromatographed, eluting with 4:1, hexanes:ethyl acetate, to give the title product as a solid (13.14 g, 81% yield). Analysis: C8H7NO2. Calculated: C, 49.78; H, 4.60; N, 5.81%. Found: C, 49.50; H, 4.66; N, 5.81%.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:6]=2)[CH:31]=[CH:30][CH:29]=1)#[N:27]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: N#Cc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Temperature: 120 °C
Yield: 33.4 %

Procedure:
A mixture of 4-bromo-1-trityl-1H-imidazole (0.2 g, 0.51 mmol), 3-cyanophenylboronic acid (0.11 g, 0.77 mmol), and Pd(PPh3)4 (0.06 g, 0.05 mmol) in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a sealed vial overnight at 120° C. After cooling, the reaction mixture was diluted with dichloromethane (30 mL) and washed with water (50 mL) and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography of the crude residue using 2% ethyl acetate in hexanes afforded 0.07 g (34%) 4-(3-cyanophenyl)-1-trityl-1H-imidazole as white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:15][N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2([OH:24])[CH2:20][CH:21]3[N:16]([CH3:15])[CH:17]([CH2:23][CH2:22]3)[CH2:18]2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CN1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CC3CCC(C2)N3C)cc1

Procedure:
The title compound was prepared from 4-bromoanisole (15.1 g, 80.5 mmol), n-butyllithium in hexanes (31.2 mL, 2.5 M; 77.9 mmol) and 8-methyl-8-azabicyclo-[3.2.1]octan-3-one (5 g, 36 mmol) in anhydrous tetrahydrofuran (40 mL). Yield 2.1 g (24%), m.p. 161.8-162.3° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.[C:11]([Si:15]([O:18][CH2:19][CH2:20]I)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:11]([Si:15]([CH3:17])([CH3:16])[O:18][CH2:19][CH2:20][NH:10][C:5]1[CH:4]=[C:3]([S:2][CH3:1])[CH:8]=[C:7]([NH2:9])[N:6]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: CSc1cc(N)nc(N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CSc1cc(N)nc(NCCO[Si](C)(C)C(C)(C)C)c1
Yield: 22 %

Procedure:
In a glass vessel were mixed together the above prepared 4-methylsulfanyl-pyridine-2,6-diamine (0.350 g, 2.25 mmol), tert-butyl-(2-iodo-ethoxy)-dimethyl-silane (CAS 101166-65-8, 0.700 g, 1.08 eq.), and 1.2 eq. of Cs2CO3 (0.882 g) in 3.5 mL of abs. acetonitrile, and the mixture allowed to react for 2 h at 125° C. in a microwave oven. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=4/6) afforded 0.155 g of the title compound as light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][C:7]([N+:14]([O-:16])=[O:15])=[CH:6]2.P(Cl)(Cl)([Cl:19])=O>ClCCl>[Cl:19][C:8]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(c1)cc([N+](=O)[O-])c[n+]2[O-]
Solvent: ClCCl
Product: COc1ccc2nc(Cl)c([N+](=O)[O-])cc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8.0 g of 6-methoxy-3-nitroquinoline-1-oxide (compound D3) in 80 ml of phosphorus oxychloride is stirred at 100° C. for 30 min. After cooling to room temperature, the reaction mixture is added to 500 ml of ice water, diluted with 250 ml of dichloromethane and extracted three times each with 250 ml of a halfsaturated aqueous potassium carbonate solution. The organic layer is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystallized from diethylether to give 5.6 g of the title compound as violet solid.
Reaction SMILES: [Ni:1].C[OH:3].[CH2:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[C:5]1([OH:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Ni:1].[CH3:4][OH:11]
Reactant: OCc1ccccc1
Agent: [Ni]
Solvent: c1ccccc1
Solvent: CO
Product: Oc1ccccc1

Procedure:
[2,2'-thiobis-(4-t-octyl-phenolato)]-benzyl alcohol Nickel II, NiTBP.C6H5OH was prepared as follows: p [2,2'-thiobis-(4-t-octylphenolato)]-2-propanol nickel II prepared as described in Example 4 (83.9 g) was dissolved in benzene (250 ml) and benzyl alcohol (16.2 g) was then added. The resulting solution was heated and refluxed for 1 hr. The displaced 2-propanol and most of the benzene solvent was then removed by distillation and the remainder by rotary evaporation. The complex[2,2'-thiobis-(4-t-octylphenolato)]benzyl alcohol nickel II was thus obtained as a green solid which softened at 150° C., melted partially at 210° C. and was completely fused at 260° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=O)[C:7](=[O:13])[NH:8]2)([O-:3])=[O:2].[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1)[C:7](=[O:13])[NH:8]2)([O-:3])=[O:2]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2cccc([N+](=O)[O-])c2C1=O
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc([N+](=O)[O-])c32)cc1
Yield: 33 %

Procedure:
The title compound was prepared from 4-nitro-1H-indole-2,3dione (Gassman, et al., Journal of Organic Chemistry 1977, 42, 1344-8) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 33% yield: 1H NMR (DMSO-d6): δ 7.23 (d, J=7.7 Hz, 1H), 7.31 (s, 2H), 7.47 (t, J=7.9 Hz, 1H), 7.56 (d, J=7.9 Hz, 2H), 7.59 (d, J=7.2 Hz, 1H), 7.83 (d, J=7.7 Hz, 2H), 11.59 (s, 1H), 13.20 (s, 1H); APCI−MS m/z 361 (M)−. Anal. Calcd for C14H11N5O5S: C, 46.54, H, 3.07; N, 19.38; S, 8.87. Found C, 46.62, H, 3.09; N, 19.46; S. 8.81.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)[NH:8][C:4]=2[C:3]=1[CH2:23][C:24]([OH:26])=O.Cl.CN(C)CCCN=C=NCC.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CC(N(C)C)=O>[F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=3)[NH:8][C:4]=2[C:3]=1[CH2:23][C:24]([NH:46][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:26]
Reactant: COc1cc(-c2nc3ccc(F)c(CC(=O)O)c3[nH]2)cc(OC)c1OC
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2nc3ccc(F)c(CC(=O)NCc4ccccc4)c3[nH]2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-[5-fluoro-2-(3,4,5-trimethoxyphenyl)benzimidazolyl]acetic acid (1.8 mmole, 650 mg) in DMA (5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (2.7 mmole, 0.52 g) and benzylamine (2.52 mmole, 0.28 ml) is stirred at room temperature for 22 hours. The reaction mixture is added dropwise onto ice (50 g), and the precipitate is filtered off and dried in vacuo (R1=(CH2)x—C(O)—NH—(CH2)y—R5, x=1, R5=phenyl, R2=3,4,5-trimethoxy-phenyl, R3=F, n=1, y=1).