Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[CH2:32]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:33]#[CH:34].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:34]#[C:33][CH2:32][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:19]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCC3CCCCC3)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCCC3CCCCC3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (300 mg; 0.59 mmol) and 4-prop-2-ynyl-morpholine (222.0 mg; 1.77 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 200 mg (30%). HPLC-MS: m/z: 551.8 (M)+; Rt: 2.35 min
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.ClCCl.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][O:15][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 2 h

Procedure:
Combine (S)-1-(t-butoxycarbonyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (17 g, 47.0 mmol), N,N-diisopropylethylamine (20 mL), and dichloromethane (300 mL). Cool the reaction mixture in an ice bath. Add dropwise methanesulfonyl chloride (4.8 mL). After 30 minutes add additional methanesulfonyl chloride (0.9 mL). After 2 hours, extract the reaction mixture with saturated aqueous sodium bicarbonate solution and then three times with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 20% ethyl acetate/hexane, 35% ethyl acetate/hexane, 50% ethyl acetate/hexane and then ethyl acetate to the title compound: Rf =0.24 (silica gel, 35% ethyl acetate/hexane).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[N:7][CH:8]=1)#[CH:2]>CO.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[N:7][CH:8]=1)[CH3:2]
Reactant: C#Cc1cncc(N)c1
Agent: [Pd]
Solvent: CO
Product: CCc1cncc(N)c1
Yield: 55.6 %

Procedure:
5-Ethynylpyridin-3-amine (0.122 g, 1.03 mmol) and 10% Pd/C (0.11 g, 0.102 mmol) were suspended in MeOH (15 mL). This was hydrogenated (42 psi) in a Parr hydrogenation apparatus overnight. The reaction was filtered through Celite® and washed forward with MeOH. The filtrate was concentrated to afford 5-ethylpyridin-3-amine (0.070 g, 56% yield) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, J=2.4 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 6.71 (t, J=2.0 Hz, 1H), 5.16 (s, 2H), 2.43 (q, J=7.2 Hz, 2H), 1.11 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:63][CH:64]1[CH2:69][CH2:68][N:67](C(OC(C)(C)C)=O)[CH2:66][CH2:65]1>O1CCCC1.ClCCl>[NH:67]1[CH2:68][CH2:69][CH:64]([NH:63][C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:16]3[N:17]=[C:10]4[C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:28])[CH:4]=5)=[CH:14][CH:13]=[CH:12][N:11]4[N:15]=3)=[CH:27][CH:26]=2)[CH2:65][CH2:66]1
Reactant: O=C(O)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCNCC1)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Reaction time: 16 h
Yield: 42.3 %

Procedure:
To a solution of 4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid (1.0 g, 2.5 mmol, 1 equiv), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3.00 mmol, 1.2 equiv), N,N-diisopropylethylamine (484 mg, 3.74 mmol, 1.5 equiv) in 2:1 tetrahydrofuran/dichloromethane (50 mL) was added tert-butyl 4-amino-1-piperidinecarboxylate (0.60 g, 3.0 mmol, 1.2 equiv) at room temperature. After 16 h, the reaction mixture was filtered, and the filtrate was concentrate. The resulting residue was dissolved in 1:1 trifluoroacetic acid/tetrahydrofuran (50 mL) at room temperature. After 2 h, the reaction mixture was concentrated in vacuo. Purification by preparative HPLC provided product (508 mg, 42%). LCMS (ESI) m/z: 481.0; 1H NMR (400 MHz, DMSO-d6) δ: 10.06 (s, 1H), 8.85 (d, J=7.6 Hz, 1H), 8.60 (s, 1H), 8.38 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.84 (br s, 2H), 7.72-7.79 (m, 3H), 7.32 (d, J=7.6 Hz, 2H), 7.15 (m, 1H), 4.02 (m, 1H), 3.27-3.32 (m, 2H), 2.95-3.05 (m, 2H), 1.87-1.94 (m, 2H), 1.41-1.48 (m, 2H).
Reaction SMILES: C(=O)([S:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]1=[O:14])C.O.[OH-].[Na+]>CO>[SH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:12])([CH3:13])[NH:8][C:7]1=[O:14]
Reactant: CC(=O)SCCN1C(=O)NC(C)(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)NC(=O)N(CCS)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
To a cold (0° C.) solution of S-(2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl) ethanethioate (17 g, 74 mmol) prepared as described in International Patent Publication Number WO 2010/054009 A1 (Jain et al., Apr. 11, 2009), in 150 mL of methanol and 100 mL of water was added 22.5 mL of 5 N NaOH. The external ice bath was removed and the mixture was allowed to warm to room temperature, and stirred for 18 hours. Concentrated hydrochloric acid (8 mL) and 10 mL of water were added and the resultant solution was concentrated to about half of its original volume. White solid product precipitated out of solution and was collected on a glass fritted filter. The remaining aqueous solution was extracted with ethyl acetate, and the organic layer was then successively washed with water and sat. NaCl solutions. The organic fraction was dried over sodium sulfate and concentrated to a white solid, which was combined with the precipitated material to give the desired product (13.2 g, 70.2 mmol, 95%). 1H NMR (CDCl3, 400 MHz) δ 1.37-1.41 (t, J=8.5 Hz, 1H), 1.48 (s, 6H), 2.81-2.86 (m, 2H), 3.69-3.73 (t, J=7.0 Hz, 1H), 5.53 (br s, 1H); LRMS (ESI/APCI) m/z 189 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.[BH4-].[Na+].[Cl-].[Na+].CCOCC>CO>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCC(C)(C)c1ccc(C2=CC(O)CCC2)c(O)c1
Reaction time: 0.5 h

Procedure:
To a -18° C. solution of 70.0 g (0.20 mol) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cyclohex-2-enone in 200 ml of methanol is added 7.6 g (0.20 mol) of sodium borohydride. The reaction mixture is stirred for 30 minutes and then added to one liter of saturated sodium chloride-one liter of ether. The ether extract is washed once with 500 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 500 g of silica gel eluted with 50% ether-pentane to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][C:6]1([C:19]([O:21]CC)=[O:20])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>CCCCO.[OH-].[K+]>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1([C:19]([OH:21])=[O:20])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1([OH:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(CCCN(C)C)CCCCC1(O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CN(C)CCCC1(C(=O)O)CCCCC1(O)c1ccccc1
Reaction time: 1.25 h

Procedure:
The ester from Example 2 (9.6 gm) in a mixture of 135 ml n-BuOH and 45 ml 45% KOH (aq) was refluxed with good stirring for 75 min., allowed to cool, and acidified with 68 ml conc. HCl. The reaction mixture was transferred to a 1 liter round bottom flask, rinsing and diluting with 40 ml n-BuOH. The mixture was concentrated to about 350 ml, cooled, and the KCl filtered off. The filtrate was concentrated to dryness then warmed and shaken with 40 ml acetonitrile, filtered and rinsed with acetonitrile (5 ml). The filtrate was cooled, seeded and the product allowed to crystallize. Wgt.=4.1 gm, m.p.=144°-145°. A second crop was obtained from the filtrate, Wgt.=1.1 gm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[ClH:19].[N:20]([O-])=O.[Na+]>O.O.Cl[Sn]Cl>[ClH:19].[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][NH2:20])=[CH:11][CH:12]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
4-[3-(Trifluoromethyl)phenoxy]benzenamine (15 g) was added to a stirred solution of 6 M HCl (190 mL). The resulted suspension was cooled to −5° C., and then an aqueous solution of NaNO2 (4.5 g in 15 mL water) was added dropwise over a period of 15 min. The reaction mixture was stirred for another 30 min, followed by the gradual addition of a solution of SnCl2.2H2O (69 g in 100 mL conc HCl). After stirring at −5° C. for 2 h, the stirred mixture was warmed to room temperature overnight, filtered, and the collected solid was washed with 6 M HCl, water, and dried (18 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([N:6]([CH3:22])[C:7]2[N:12]=[C:11]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:9][N:8]=2)[CH2:2]1.[C:23]1([N:33]=[C:34]=[O:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:23]1([NH:33][C:34]([N:1]2[CH2:5][CH2:4][CH:3]([N:6]([CH3:22])[C:7]3[N:12]=[C:11]([N:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[N:15]=[CH:14]4)[CH:10]=[CH:9][N:8]=3)[CH2:2]2)=[O:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCNC1
Solvent: ClCCl
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCN(C(=O)Nc2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a solution of 9.5 mg of 2-[(pyrrolidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (from EXAMPLE 12, step A) in 1 mL of CH2Cl2 was added 7.1 mg of naphthyl isocyanate. The mixture was stirred at room temperature overnight, then concentrated. The residue was purified by flash chromatography, eluting with a gradient system of 1:1 hexanes-acetone to 1:2 hexanes-acetone, to yield 7.3 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.63 (s, 1H), 8.38 (br s, 1H) 8.19 (d, J=7.8 Hz, 1H), 7.80-7.90 (m, 3H), 7.63 (d, J=8.0 Hz, 1H), 7.35-7.52 (m, 5H), 6.85 (d, J=5.0 Hz, 1H), 6.52 (s, 1H), 3.83 (br t, J=8.2 Hz, 1H), 3.56-3.80 (m, 4H), 3.45 (br t, J=8.0 Hz, 1H), 2.75-2.84 (m, 1H), 2.27 (br s, 1H), 1.62-2.00 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[C:4](=[O:18])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:36])[N:28]2[CH2:31][CH2:32][CH2:33][CH:34]=O)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:36])[N:28]2[CH2:31][CH2:32][CH2:33][CH2:34][NH:1][CH:2]2[CH2:6][N:5]([C:7]3[CH:8]=[CH:9][C:10]4[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=4[CH:17]=3)[C:4](=[O:18])[CH2:3]2)=[CH:23][CH:22]=1
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CCCC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCCCNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2c1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 84.3 %

Procedure:
6-(4-Amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (56.9 mg, 0.230 mmol) and 4-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)butanal (Reference Example 3; 56.6 mg, 0.230 mmol) were dissolved in chloroform/methanol (10:1, v/v, 3 ml), molecular sieve 3 A (powder 700 mg) was further added, and the mixture was stirred at 60° C. for 4.5 hours. After cooling, sodium triacetoxyborohydride (154 mg, 0.69 mmol) was added to the reaction solution and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the molecular sieve was removed by filtration and a saturated sodium hydrogen carbonate aqueous solution was added to the filtrate and stirred. After separating the organic layer, the aqueous layer was extracted twice with chloroform/methanol (10:1, v/v) and combined with the organic layer. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 92.6 mg (84%) of the title compound in the form of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[NH2:15][C:14]1[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(Cl)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Nc1cccnc1Nc1cccc(Cl)c1
Yield: 81.1 %

Procedure:
A mixture of 2-(3-chlorophenylamino)-3-nitropyridine (394 mg), hydrochloric acid (35% 1.3 ml) and iron powder (0.44 g) in ethanol (5 ml) was refluxed for 15 minutes. The mixture was poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-amino-2-(3-chlorophenylamino)pyridine (281 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:5]1.C1(P([C:30]2[CH:35]=[CH:34]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.C([Sn](CCCC)(CCCC)C1CC1)CCC.[OH-].[Na+]>CN(C=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH:34]1([C:13]2[CH:14]=[CH:15][C:10]([N:6]3[CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:11][CH:12]=2)[CH2:35][CH2:30]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COCC1CN(c2ccc(Br)cc2)C(=O)O1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)C1CC1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Solvent: CN(C)C=O
Product: COCC1CN(c2ccc(C3CC3)cc2)C(=O)O1
Yield: 19.3 %

Procedure:
3.0 g (10.48 mmol) of (RS)-5-methoxymethyl-3-(4-bromo-phenyl)-oxazolidin-2-one, 6.29 g (6.29 mmol) of triphenylphosphine, 0.88 g (1.25 mmol) of bis(triphenylphosphine)palladium-II dichloride, 3.73 g of lithium chloride, 1 spatula tip of 2,6-di-tert-butyl-p-cresol and 6.94 g of tributyl-cyclopropylstannane in 50 ml of DMF were stirred at 120° for 6 hours. The reaction mixture was treated with water and 1N sodium hydroxide solution and extracted with ether. The crude product obtained was chromatographed on a 30-fold amount of silica gel. The extracts which were uniform according to tlc (silica gel, ethyl acetate-hexane 1:1) were pooled and the solvent was distilled off. 0.3 g of colorless crystals was obtained from tert-butyl methyl ether/hexane. M.p. 58°-60°.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3C=C(C=CC=3)C#N)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].IC1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1>>[CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[S:24][CH:25]=[C:26]([CH3:28])[N:27]=3)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21]
Reactant: Cc1csc(I)n1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Product: Cc1csc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1

Procedure:
The title compound was prepared analogously to 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9.0 Step 4) by replacing 3-bromobenzonitrile by 2-iodo-4-methylthiazole (Intermediate O) in step 3;
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2=[CH:12][S:13][C:14]([NH2:15])=[C:10]2[C:9](=[O:16])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1)=O)C.O.[NH2:24][NH2:25]>C(O)C>[NH2:15][C:14]1[S:13][CH:12]=[C:11]2[C:10]=1[C:9](=[O:16])[N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:7]=[C:6]2[C:4]([NH:24][NH2:25])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2c(N)scc12
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nn(-c2ccccc2)c(=O)c2c(N)scc12
Yield: 94.3 %

Procedure:
To a solution of 5-Amino-4-oxo-3-phenyl-3,4-dihydro-thieno[3,4-d]pyridazine-1-carboxylic acid ethyl ester (20 g, 0.063 mol, prepared as described in example 25) in ethanol (400 ml) was added hydrazine hydrate (3.3 g, 0.066 mol). The reaction mixture was stirred at reflux temperature for 6 h at which time an additional portion of hydrazine hydrate (3.3 g, 0.066 mol) was added and the resulting mixture was stirred for an additional 66 h at reflux temperature. An additional portion of hydrazine hydrate (1.5 g, 0.03 mol) was added and the reaction mixture was stirred for an additional 16 h at reflux temperature. The reaction mixture was cooled and the precipitated was filtered off, washed with small portions of ethanol and dried in vacuo at 50° C. for 18 h which afforded 17.9 g (94%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15](N)=[O:16].[OH-].[Na+]>CC(O)=O>[N+:11]([C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:15](=[O:16])[NH:14][C:4]2=[O:6])([O-:13])=[O:12]
Reactant: NC(N)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 200 °C
Yield: 73.2 %

Procedure:
A mixture of 2-amino-5-nitrobenzoic acid (0.588 g, 3.23 mmol) and urea (1.164 g, 19.38 mmol) was heated at 200° C. under N2 for 1 h. The mixture was cooled to room temperature and 4 M NaOH was added until pH=14. It was acidified to pH=5.0 via addition of AcOH. The mixture was filtered and the yellow solid was dried to give the title compound (0.49 g, 72.8%) as a yellow solid. MS: m/z 208.1 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[N:3]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([NH:28][CH3:29])=[CH:26][CH:25]=1>C(OCC)(=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([N:28]([CH3:29])[C:2]2[N:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]4)=[C:11]([O:21][CH3:22])[CH:10]=3)[N:5]=[CH:6][N:7]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(Nc2ncnc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: CNc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncnc(N(C)c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Yield: 23 %

Procedure:
This compound was prepared from (4-chloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-chloro-N-methylaniline in analogy to example 1c. Chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 23% yield.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)=[O:4].[CH3:14][C:15]([CH3:18])([NH2:17])[CH3:16]>CC(O)C>[Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:10]=[N:17][C:15]([CH3:18])([CH3:16])[CH3:14])[CH:12]=1)=[O:4]
Reactant: O=Cc1cc(C(=O)CBr)ccc1O
Reactant: CC(C)(C)N
Solvent: CC(C)O
Product: CC(C)(C)N=Cc1cc(C(=O)CBr)ccc1O
Temperature: -3 °C

Procedure:
5-(Bromoacetyl)-2-hydroxybenzaldehyde (109g) is suspended in 2-propanol (920ml) and cooled to -3° C. with stirring. The reaction mixture is treated with 1,1dimethylethanamine (29.24g) and stirred at -3° C. to 0° C. for 30 minutes whereupon precipitation occurs. The reaction mixture is allowed to warm to room temperature, stirred for 90 minutes then cooled to 10° C. and filtered. The solid obtained is washed with ice cold 2-propanol (2×100ml) and dried in vacuo at 55° C for 18 hours providing 89g of 2-bromo-1-[3-[[(1,1-dimethylethyl)imino]methyl]-4-hydroxyphenyl]ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[CH:7]=[CH:6]2.C([O-])(=O)C.[NH4+:29]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:29][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:14]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(=O)CCC(=O)c3ccccc3)ccc2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Temperature: 100 °C
Yield: 91.5 %

Procedure:
A mixture of 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (1.00 g, 3.14 mmol), prepared in the previous step, ammonium acetate (12.1 g, 157 mmol) and acetic acid (100 mL) was heated to 100° C. under a nitrogen atmosphere for three hours. The mixture was cooled to ambient temperature, and the precipitate was isolated by filtration to give 2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole as a white solid (0.86 g, 91%), mp 208.5–209.5° C. Elemental Analysis for C21H17NO Calc'd: C, 84.25; H, 5.72; N, 4.68. Found: C, 84.25; H, 5.77; N, 4.56.