Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH:6][C:7]1[N:12]2[N:13]=[C:14]([CH3:25])[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[CH3:24])=[C:11]2[N:10]=[C:9]2[CH2:26][CH2:27][O:28][C:8]=12)[CH2:4][CH3:5]>C1(OC2C=CC=CC=2)C=CC=CC=1.CO.[C].[Pd]>[CH3:1][CH2:2][CH:3]([NH:6][C:7]1[N:12]2[N:13]=[C:14]([CH3:25])[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[CH3:24])=[C:11]2[N:10]=[C:9]2[CH:26]=[CH:27][O:28][C:8]=12)[CH2:4][CH3:5]
Reactant: CCC(CC)Nc1c2c(nc3c(-c4ccc(OC)cc4C)c(C)nn13)CCO2
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Product: CCC(CC)Nc1c2occc2nc2c(-c3ccc(OC)cc3C)c(C)nn12
Temperature: 250 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To a solution of the compound prepared in Example 2(6) (215 mg) in diphenyl ether (3 ml), 10% palladium carbon (150 mg) was added, and the mixture was stirred for 4 hours at 250° C. After the reaction mixture was cooled to room temperature, it was diluted with methanol (10 ml). The diluted solution was filtered though celite (registered trademark). The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (n-hexane:acetone=9:1) to give the title compound (150 mg) having the following physical data.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.P(Br)(Br)([Br:14])=O>ClC(Cl)C>[Br:14][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Reactant: O=P(Br)(Br)Br
Solvent: CC(Cl)Cl
Product: Cc1cc(Br)ncc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a suspension of 2-hydroxy-4-methyl-5-nitropyridine (1 g, 6.5 mmol) in dichloroethane (10 mL) was added a solution of phosphorus oxybromide (2.8 g, 9.7 mmol) in dichloroethane (10 mL). The reaction mixture was heated under reflux for 4 h, then cooled to rt and quenched with water (40 mL). The layers were separated and the aqueous layer extracted into dichloromethane (2×3 mL). The combined organics were dried (MgSO4), concentrated in vacuo and chromatographed on silica gel eluting with dichloromethane to give the title compound as a pale yellow solid. δH (CDCl3): 2.63 (3H, s), 7.52 (1H, s), 8.96 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:33])([CH3:32])[CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([C:29]([OH:31])=O)=[CH:17]2)=[O:12].C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:33][C:9]([CH3:8])([CH3:32])[CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([C:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:31])=[CH:17]2)=[O:12]
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2-c1ccccc1
Reactant: Nc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.9 mg (0.09 mmol) of aniline are added to a solution of 27 mg (0.08 mmol) of 5-[(3,3-dimethylbutanoyl)amino]-1-phenyl-1H-indole-2-carboxylic acid (Example LIX), 4.7 mg (0.09 mmol) of DMAP and 22.2 mg (0.12 mmol) of EDC in 2 ml of dichloromethane, and the mixture is stirred at RT for 3 h. For work-up, 1-molar hydrochloric acid is added and the mixture is extracted repeatedly with dichloromethane. The combined organic phases are washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and filtered. Removal of the solvent under reduced pressure gives 35 mg (99% of theory) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:12])[C@@H:11]2[C@@H:9]([O:10]2)[CH2:8][CH2:7][CH2:6]1)=[O:4].CO.[NH4+].[Cl-].[N-:17]=[N+:18]=[N-:19].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1([CH3:12])[CH2:6][CH2:7][CH2:8][CH:9]([N:17]=[N+:18]=[N-:19])[CH:11]1[OH:10])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1(C)CCC[C@@H]2O[C@@H]21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1(C)CCCC(N=[N+]=[N-])C1O

Procedure:
Racemic cis-methyl-5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate, 66b, (2.2 g, 12.93 mmol) was added to a flask containing MeOH (90 mL) and H2O (10 mL) under nitrogen atmosphere. NH4Cl (1.38 g, 0.90 mL, 25.86 mmol) and NaN3 (2.52 g, 38.79 mmol) were then added to the reaction mixture. The mixture was heated to reflux for 16 hours. The solvent was evaporated under reduced pressure and the oil was taken up in H2O and extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. The crude product was purified by silica gel chromatography to afford 900 mg of racemic methyl-3-azido-2-hydroxy-1-methyl-cyclohexanecarboxylate.
Reaction SMILES: S([O-])(=O)(=O)C.C([BH-]([CH2:11][CH3:12])CC)C.[Li+].[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(O[CH2:23][CH3:24])C>O1CCCC1>[CH3:14][CH:15]([C:16]1[CH:18]=[CH:17][C:19]2[C@:11]3([CH3:12])[C@@H:19]([CH2:11][CH2:12][C:18]=2[CH:17]=1)[C:23]([CH3:24])([CH3:24])[CH2:16][CH2:15][CH2:14]3)[CH3:23]
Reactant: CCCCCC
Reactant: CCOCC
Reactant: CC[BH-](CC)CC
Agent: CS(=O)(=O)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(c1)CC[C@H]1C(C)(C)CCC[C@]21C
Yield: 41.3 %

Procedure:
Under an inert atmosphere, the mesylate (21.5 mg, 0.06 mmol) was dissolved in tetrahydrofuran in a Schlenk flask equipped with a cold finger. Excess lithium triethylborohydride (263 μL, 1 M in tetrahydrofuran, 0.26 mmol) was added dropwise to the solution, the reaction was stirred at reflux for 6 hours and monitored by TLC (6:1 hexane:diethyl ether). The reaction was quenched with ice-cold H2O, extracted with hexane (3×), dried with MgSO4, filtered over a silica plug, and concentrated. (Walter, 1988) GC analysis indicated that an 85:15 mixture of levopimaradiene:abietatriene had been obtained in 41.3% yield (6.6 mg). The isomeric mixture was separated by argentic TLC (Li et al., 1995) (SiO2—AgNO3, 3 developments with 85:15 hexane:diethyl ether) giving pure abietatriene (Rf 0.96) (Kutney and Han, 1996) and pure levopimaradiene (Rf 0.92) as identified by de novo characterization based on 1H, COSY-DEC, 13C, DEPT-135, HSQC, and HMBC NMR, and GC/MS analyses.
Reaction SMILES: C[Al](C)C.[C:5]([C:9]1[CH:13]=[C:12]([NH2:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)([CH3:8])([CH3:7])[CH3:6].[O:21]=[C:22]1[NH:27][C:26]2[N:28]=[CH:29][CH:30]=[C:31]([O:32][C:33]3[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=3)[C:36](OC)=[O:37])[C:25]=2[N:24]=[CH:23]1>C1COCC1>[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:36](=[O:37])[C:35]2[CH:40]=[CH:41][CH:42]=[C:33]([O:32][C:31]3[C:25]4[N:24]=[CH:23][C:22](=[O:21])[NH:27][C:26]=4[N:28]=[CH:29][CH:30]=3)[CH:34]=2)[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: COC(=O)c1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)c2cccc(Oc3ccnc4[nH]c(=O)cnc34)c2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Method H1: A solution of AlMe3 (solution in toluene 2M, 0.85 mL, 1.68 mmol,) was added dropwise to a cooled (0 C) solution of 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (362 mg, 1.68 mmol) in THF (5.0 mL). When the addition was complete, the mixture was allowed to warm to room temperature and stirring was continued for 30 minutes. Then methyl 3-(3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yloxy)benzoate (100 mg, 0.336 mmol) was added and the mixture was heated under reflux for 19 h. The mixture was cooled to room temperature and carefully quenched with 5% aq HCl (3.0 mL). After evaporation of solvent, the residue was retaken in CH2Cl2, washed with saturated solution of NaHCO3 and dried over MgSO4 and evaporated under vacuum. The obtained residue was chromatographied (eluent: CH2Cl2/EtOAc: 2/1 towards 1/3) and the title compound was obtained as a slightly yellow solid (29 mg, 18%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[C:15]([Br:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[Br:18])[N:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C([N:31](CC)C(C)C)(C)C.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:31][C:6]1[N:5]=[C:4]([NH:9][C:10]2[C:15]([Br:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[Br:18])[N:3]=[C:2]([NH:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(Br)c(Nc2nc(Cl)nc(Cl)n2)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(Br)c(Nc2nc(N)nc(Nc3ccc(C#N)cc3)n2)c(Br)c1
Temperature: 25 °C
Yield: 9.7 %

Procedure:
4,6-dichloro-N-(2,6-dibromo-4-methylphenyl)-1,3,5-triazin-2-amine (0.00651 mol), was dissolved in 1,4-dioxane (30 ml). Sequentially, 4-aminobenzonitrile (0.0066 mol) and N,N-diisopropylethylamine (0.0066 mol) were added, and the clear solution was heated to reflux for 4 days. The reaction was allowed to cool to room temperature overnight, and the mixture was diluted with ethyl acetate and treated with cold 1 M NaOH. The layers were separated, and the organic phase was re-extracted with fresh 1 M NaOH. The combined aqueous phases were treated with solid NaOH to maintain pH>10 and backwashed with ethyl acetate (2×). The combined organic phases were dried, filtered and concentrated. The residue was separated and purified by flash column chromatography over silica gel (eluent: CH2Cl2). The desired fractions were combined, treated with CH3CN, triturated with CH3CN, filtered off and dried, yielding 0.30 g (8.0%) of 4-[[4-amino-[(2,6-dibromo-4-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:39][NH:40][CH2:41][C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:40]([CH3:39])[CH2:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CNCc1ccc2ccccc2c1
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCCC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1ccc2ccccc2c1)C(=O)/C=C/c1cnc(N)c(CN2CCCC2)c1
Yield: 57 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-(6-amino-5-pyrrolidin-1-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-naphthalen-2-ylmethyl-amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (51 mg, 57%) was prepared as a light, yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.36-8.25 (m, 2H), 7.52-6.98 (m, 4H), 6.40-6.15 (m, 1H), 5.05-4.84 (m, 2H), 4.20 (s, 2H), 3.74-3.67 (m, 3H), 3.58-5.30 (m, 8H), 3.10-2.73 (m, 6H); MS (ESI) m/e 401 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:12])[CH:8]([OH:11])CO.I(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]([CH3:13])([CH3:14])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:12])[CH:8]=[O:11]
Reactant: COC(C)(C)CCCC(C)C(O)CO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Product: COC(C)(C)CCCC(C)C=O
Yield: 29.7 %

Procedure:
7-Methoxy-3,7-dimethyl octan-1,2-diol (40 g) was treated with periodic acid in tetrahydrofuren; work up with water followed by diluted sodium bicarbonate wash gave the aldehyde (10 g) with specific rotating α(22/D+13.69.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:17]([NH:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(2-tert-butoxy-2-oxoethylamino)-4-oxobutanoate (Intermediate 6-1: 40 mg, 0.088 mmol) and TFA (0.5 mL, 6.49 mmol) in DCM (1.5 mL) is allowed to stir for 2 hours at room temperature. The reaction is concentrated under reduced pressure, and the obtained residue is suspended in DCM (0.5 mL) and heptane (2 mL), and collected on a funnel, giving (R)-3-biphenyl-4-ylmethyl-N-carboxymethyl-succinamic acid (9.6 mg). HPLC retention time=1.26 minutes (condition A); MS (m+1)=342.0; 1H NMR (400 MHz, CD3OD) δ ppm 2.39 (dd, J=16.67, 5.31 Hz, 1 H) 2.63-2.82 (m, 2 H) 2.98-3.14 (m, 2 H) 3.84 and 3.95 (AB, 2 H, J=17.8 Hz) 7.26-7.33 (m, 3 H) 7.40 (t, J=7.71 Hz, 2 H) 7.56 (dd, J=19.96, 8.08 Hz, 4 H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:26](=[O:27])[CH2:25][Cl:24])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)CCl)cc1
Yield: 99.1 %

Procedure:
A solution of 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (886 mg, 3.86 mmol), pyridine (465 μL, 5.80 mmol) and chloroacetyl chloride (462 μL, 5.80 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was diluted with aq. sat. sodium bicarbonate and DCM and the resulting aqueous layer was extracted twice with DCM. The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford the title compound (1.17 g, 100%) as a yellow solid. LCMS (Method 5): Rt 4.41 min, m/z 306 [MH+].
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (400 mg, 0.98 mmol) was added to a solution of ethyl piperidine-3-carboxylate (771 mg, 4.90 mmol) and DMAP (600 mg, 4.90 mmol) in MeCN (50 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was purified by MPLC using 50-90% EtOAc/Heptane on silica gel to provide the title compound as colorless oil. Yield: 182 mg (38%); 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.13 Hz, 3 H), 1.29-1.38 (m, 1 H), 1.49-1.57 (m, 4 H), 1.59 (s, 9 H), 1.63-1.83 (m, 2 H), 1.91-2.02 (m, 1 H), 2.30 (td, J=11.43, 2.93 Hz, 2 H), 2.44 (t, J=11.13 Hz, 1 H), 2.57-2.69 (m, 1 H), 3.28-3.40 (m, 2 H), 3.65-3.75 (m, 1 H), 3.91 (dd, J=11.82, 3.81 Hz, 1 H), 3.96-4.05 (m, 2 H), 4.13 (q, J=7.03 Hz, 2 H), 4.25 (d, J=7.23 Hz, 2 H), 7.43 (d, J=8.20 Hz, 1 H), 7.64 (dd, J=8.59, 1.76 Hz, 1 H), 8.19 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+ 491.9.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17]>O>[C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3ccccc3s2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3)sc2c1
Temperature: 5 °C
Reaction time: 1.17 h

Procedure:
2-Phenylbenzothiazole (Aldrich, 63.89 g, 0.302 mol) is nitrated with 100% nitric acid (190 ml, 4.53 mol) at 5° C. The mixture is stirred at 5° C. for 70 minutes, quenched in ice-water and basified with 32% NaOH (pH=10). The product is filtered off and the solid obtained is suspended in water and filtered off. The product is recrystallized from isopropyl ether. Yield: 73.6 g (95%); Rf (8/2 petroleum ether/ethyl acetate): 0.76; m.p.: 178.9-181.3°; 1H-NMR (d6-DMSO): 9.16 (d, 1H); 8.35 (dd, 1H); 8.23 (d, 1H); 8.15 (dd, 1H) 7.58; (m, 4H).
Reaction SMILES: [CH:1]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:5][CH2:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][NH:13]C(=O)OCC1C=CC=CC=1)=[O:9])([CH3:3])[CH3:2]>C(O)C.[OH-].[Pd+2].[OH-]>[NH3:4].[NH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][CH2:6][CH2:5][N:4]([CH:24]([CH3:26])[CH3:25])[CH:1]([CH3:2])[CH3:3])=[O:9]
Reactant: CC(C)N(CCNC(=O)NCCNC(=O)OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(CCNC(=O)NCCN)C(C)C
Product: N
Yield: 216.3 %

Procedure:
A solution of benzyl 2-[({[2-(diisopropylamino)ethyl]amino}carbonyl)amino]ethylcarbamate (Preparation 50) (6.25 g, 14.45 mmol) in ethanol (100 ml) was hydrogenated at room temperature over palladium (II) hydroxide (250 mg) for 4 hours at 414 KPa. The catalyst was removed by filtration through Arbocel (trade mark) and solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (90:10:1, by volume) changing to dichloromethane:methanol:concentrated aqueous ammonia (90:10:2, by volume) to afford the title compound as a yellow oil (3.6 g).
Reaction SMILES: [Br-].[CH2:2]([N+]1C=CC=CC=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1.C([O-])(=O)C.[NH4+:41]>C(O)(=O)C>[CH3:34][N:33]([CH3:35])[C:30]1[CH:31]=[CH:32][C:27]([C:26]2[CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:41]=[C:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:25]=2)=[CH:28][CH:29]=1
Reactant: O=C(C[n+]1ccccc1)c1ccccc1
Reactant: [NH4+]
Reactant: CN(C)c1ccc(C=CC(=O)c2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: CC(=O)O
Product: CN(C)c1ccc(-c2cc(-c3ccccc3)nc(-c3ccc(Cl)cc3)c2)cc1

Procedure:
13.9 parts of 1-phenacylpyridinium bromide and 14.27 parts of 1-(4-chlorophenyl)-3-(4-dimethylaminophenyl)-1-oxoprop-2-ene are heated at 120° C. for 3.5 hours together with 34 parts of ammonium acetate in 50 parts of glacial acetic acid. Working up as described in Example 1 gives 4-(4'-dimethylaminophenyl)-2-(4'-chlorophenyl)-6-phenylpyridine in the form of a colorless powder, which dissolves in glacial acetic acid to give a yellow color (λmax: 425 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](I)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([NH:16]OC)=[O:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:31]1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC(O)=O.CC(O)=O.[Pd]>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([NH:16][CH3:31])=[O:15])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1cnc(Cl)cc1I
Reactant: CONC(=O)c1ccccc1N
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C#N
Temperature: 110 °C
Reaction time: 8 h
Yield: 740.3 %

Procedure:
A mixture of 6-chloro-4-iodo-nicotinonitrile (14 g, 53.03 mmole, 1 eq), 2-amino-N-methoxy-benzamide (7.96 g, 53.03 mmole, 1 eq) and K3PO4 (28.14 g, 132.57 mmole, 2.5 eq) in 1,4-dioxane (250 mL) was degassed with N2 for 1 h. To this mixture were added Pd(OAC)2 (0.238 g, 1.06 mmole, 0.02 eq) and DPEPhos (2.28 g, 4.24 mmole, 0.08 eq). The resulting reaction mixture was degassed with N2 for another 15 min after which the resulting reaction mixture was stirred at 110° C. overnight. After completion of reaction solid material was collected by filtration, dissolved in water (500 mL), and extracted with ethyl acetate (5×200 mL). Combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude material. It was purified by column chromatography over silica gel (60-120 mesh) using 0.2% methanolic ammonia (10% ammonia in MeOH) in dichloromethane as the eluant to give the title compound as a pale yellow solid (9 g, 59%). 1H-NMR (400 MHz, DMSO-d6): δ 2.75 (d, 3H, J=4.56 Hz), 7.09 (s, 1H), 7.25-7.35 (m, 1H), 7.53-7.60 (m, 2H), 7.72 (d, 1H, J=7.48 Hz), 8.56 (s, 1H), 8.69-8.79 (brs, 1H), 10.65 (s, 1H). LC-MS calculated for C14H11ClN4O (M+H) 287.06, found 286.9.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([O:24]C)(=[O:23])=[O:22]>COCCOC>[CH3:20][C:15]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([CH3:12])[C:14]=1[S:21]([O-:24])(=[O:23])=[O:22].[CH3:12][N+:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1]
Reactant: COS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: Cc1ccc2ccccc2n1
Solvent: COCCOC
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Cc1ccc2ccccc2[n+]1C
Temperature: 70 °C
Reaction time: 96 h
Yield: 50 %

Procedure:
2-methylquinoline (18.5 ml, 0.130 mol) and methyl 2,4,6-trimethylbenzenesulfonate (27.82 g, 0.130 mol, 1 equiv.) were dissolved in 1,2-dimethoxyethane and stirred at 70° C. for four days. The solution became violet-colored and the white solid was precipitated. The solution was filtered, and the filtered solution was dried in a vacuum oven at 50° C., affording light pink powder at a yield of 50%.