Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=[C:2]([NH:25][C:24]3[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][O:18][CH3:17])=[CH:27][CH:26]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COCCc1ccc(N)cc1
Reactant: CCc1nc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(Nc2ccc(CCOC)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 75 °C
Yield: 62.2 %

Procedure:
A mixture of 2-chloro-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazine (0.105 g, 0.41 mmol) and 4-(2-methoxyethyl)aniline (0.075 g, 0.49 mmol) were suspended in acetic acid (1 mL) and the mixture was heated at 75° C. for 3 h. After this time, the reaction was cooled, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.094 g, 62%) as a white solid. MW=368.86. 1H NMR (DMSO-d6, 500 MHz) δ 10.21 (s, 1H), 8.41-8.30 (m, 2H), 7.72-7.68 (m, 3H), 7.61 (t, J=7.5 Hz, 1H), 7.27-7.19 (m, 2H), 3.54 (t, J=7.0 Hz, 2H), 3.25 (s, 3H), 2.80-2.75 (m, 4H), 1.32 (t, J=7.5 Hz, 3H); APCI MS m/z 369 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([N:21]([CH3:25])[CH:22]([CH3:24])[CH3:23])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:26]([O:28]C)=[O:27])[CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]([N:21]([CH3:25])[CH:22]([CH3:23])[CH3:24])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:26]([OH:28])=[O:27])[CH:17]=3)[N:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(NC(C)=O)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(-c2nc3ccc(C(=O)O)cc3nc2N(C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of methyl 2-(4-acetamidophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (110 mg, 0.28 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (45 mg, 1.12 mmol), and the reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo, dissolved in water (50 ml), adjusted to pH 6 with HCl (1N), and collected by filtration to give 2-(4-acetamidophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a yellow solid (70 mg, 66%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:24])=O.[NH2:25][C:26]([NH2:28])=[S:27]>CCO>[CH3:23][O:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:25]=[C:26]([NH2:28])[S:27][CH:2]=3)=[C:6]([CH3:24])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: NC(N)=S
Reactant: COCCOc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: COCCOc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 41.4 %

Procedure:
A mixture of 2-bromo-1-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}ethanone (12-5, 835.6 mg, 2.1 mmol) and thiourea (161.7 mg, 2.1 mmol) in 95% EtOH (5.0 mL) was heated at reflux for 2.0 h. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (10.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were collected and dried under vacuum to give 4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-amine (12-6, 322.2 mg), which was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[N:29]([CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[C:30]=S>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:30]([NH:29][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: S=C=NCCN1CCOCC1
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCN3CCOCC3)n(CC3CCOCC3)c12
Yield: 60 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (70 mg) and 4-(2-isothiocyanatoethyl)morpholine (50 mg) to give the title compound as beige solid (57 mg, 60%). LCMS (formate) Rt 0.51 min, MH+ 521
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.CI.[CH3:11]COC(C)=O.CC(O)=O>[OH-].[Na+]>[CH3:11][S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CC(=O)O
Product: CSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
2-thioxo-2,3-dihydropyrimidin-4(1H)-one (66.7 g, 0.497 mol) was dissolved in aq. NaOH (41.6 g of solid in 365 mL of H2O). The mixture was then treated with CH3I (100.1 g, 0.704 mol) and was stirred at room temperature for 18 h. TLC (petroleum ether: EtOAc=4:1) indicated that the reaction was complete. The resulting mixture was adjusted to pH=5˜6 with HOAc (30 mL). The solid formed was collected and dried on vacuum to give title compound (40 g, 54%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH:6]1[CH2:19][C:18]2[C:9]([CH3:28])([CH:10]3[CH:15]([CH2:16][CH:17]=2)[CH:14]2[CH2:20][CH2:21][CH:22]4[CH:23]([CH3:27])[N:24]([CH3:26])[CH2:25][C:13]24[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](Cl)=[O:4].[CH2:29]([OH:33])[CH2:30][CH2:31][OH:32]>N1C=CC=CC=1>[OH:32][CH2:31][CH2:30][CH2:29][O:33][C:3](=[O:4])[N:2]([CH3:1])[CH:6]1[CH2:19][C:18]2[C:9]([CH3:28])([CH:10]3[CH:15]([CH2:16][CH:17]=2)[CH:14]2[CH2:20][CH2:21][CH:22]4[CH:23]([CH3:27])[N:24]([CH3:26])[CH2:25][C:13]24[CH2:12][CH2:11]3)[CH2:8][CH2:7]1
Reactant: OCCCO
Reactant: CC1C2CCC3C4CC=C5CC(N(C)C(=O)Cl)CCC5(C)C4CCC32CN1C
Solvent: c1ccncc1
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)OCCCO)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 26.9 %

Procedure:
Compound 189A (30 mg, 0.074 mmol) and 1,3-propanediol (54μL, 0.061 mmol), were dissolved in pyridine (1 mL). The mixture was stirred at room temperature for 5 days. Stripped of pyridine, the crude reaction mixture was purified on silica gel column using 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (7.3 mg, 22.8% yield).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH2:16](O)[CH3:17]>>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCO
Reactant: O=C(O)Cc1ccc2ccccc2c1
Agent: Cl
Product: CCOC(=O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A steady stream of anhydrous hydrochloric acid was bubbled subsurface into a solution of 2-naphthylacetic acid (251.38 grams, 1.35 mol) dissolved in ethanol (1760 mL) over a period of 10 minutes. The resulting solution was stirred at ambient temperature until complete as determined by hplc (2 hours). The reaction mixture was concentrated to dryness. The resulting oil was dissolved in ethyl acetate (200 mL) and filtered through silica gel (300 grams) eluting the product with ethyl acetate (1400 mL). The filtrate was concentrated to give 286.33 grams (99%) of ethyl 2-(2-naphthyl)acetate as a colorless oil. MS (FIA) m/z 215.3 [(M+H)+] . 1H nmr (DMSO-d6) δ1.15-1.24 (t, 3H), 3.81-3.86 (d, 2H), 4.07-4.15 (q, 2H), 7.41-7.55 (m, 3H), 7.80-7.92 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(O)(C)C>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=2[Cl:12])[C:4]([CH3:8])=[N:3]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1cc(=O)n(C)[nH]1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 66.7 %

Procedure:
In 65 ml. of isopropanol are suspended 4.48 g. of 1,3-dimethyl-5-pyrazolone and 3 g. of calcium hydroxide and the resulting suspension is heated under reflux for 30 minutes with stirring. After cooling, 8.4 g. of 2,4-dichlorobenzoyl chloride is added dropwise thereto. After completion of the dropwise addition, the mixture is heated under reflux for 2 hours. The solvent is distilled off from the reaction mixture and 15 ml. of water is added to the residue. The mixture is made acidic with 23 ml. of a 2N hydrochloric acid solution and extracted with 60 ml. of chloroform. The chloroform layer is washed with water and the organic phase is separated and dried. The chloroform is distilled off. The residue is recrystallized from ethanol to give 7.6 g. of the desired product as colorless prisms of mp. 165°-166° C. Yield 66.7%
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[Si:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:18])[CH:3]=1.C([Li])CCC.[F:24][C:25]([F:36])([F:35])[C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:27]>O1CCCC1>[F:36][C:25]([F:24])([F:35])[C:26]([C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[Si:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:18])[CH:3]=1)[OH:27]
Reactant: Cc1cc(Br)cc(C)c1N([Si](C)(C)C)[Si](C)(C)C
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1N([Si](C)(C)C)[Si](C)(C)C

Procedure:
To a solution of 2-(4-bromo-2,6-dimethyl-phenyl)-1,1,1,3,3,3-hexamethyl-disilazane (Example II) (1.72 g, 5.0 mmol) in tetrahydrofuran (12 ml) under a nitrogen atmosphere was slowly added a solution of n-butyl lithium in hexanes (1.6 M) (3.3 ml, 5.28 mmol) at −70° C. The reaction mixture was stirred at −70° C. for 30 minutes before addition of 2,2,2,4′-tetrafluoroacetophenone (commercially available) (1.01 g, 5.25 mmol) at −70° C. The cooling bath was removed after 15 minutes. Once the reaction mixture had reached ambient temperature, it was poured onto water. The mixture was extracted with diethyl ether. The organic phase was washed with water and brine, dried over sodium sulfate, and then concentrated. The title compound was isolated as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>O.C(N(CC)CC)C.[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Agent: [Pt]
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1cnc2cccnc2c1O
Reaction time: 8 h
Yield: 76.3 %

Procedure:
3-Nitro[1,5]naphthyridin-4-ol (40 g, 0.2 mol) was dissolved in water (80 mL) and triethylamine (60 mL), and the solution was added to a Parr vessel. Platinum on carbon (1.0 g of 5%) was added, and the mixture was shaken under hydrogen pressure (40 psi, 2.8×105 Pa) overnight. The vessel was pressurized again, and the mixture was shaken under hydrogen pressure for four hours. The vessel was purged with nitrogen, and the reaction mixture was filtered through a layer of CELITE filter agent. The filter cake was washed with water and methanol, and the filtrate was concentrated under reduced pressure to a volume of 150 mL. A precipitate formed and was isolated by filtration to provide 24.6 g of 3-amino[1,5]naphthyridin-4-ol as a yellow solid. The filter cake was washed again with water (500 mL at 80° C.), and the filtrate was concentrated to a volume of 100 mL. A precipitate formed and was isolated by filtration to provide an additional 10.7 g of 3-amino[1,5]naphthyridin-4-ol as a yellow solid.
Reaction SMILES: N.[Na].[CH3:3][C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:21][CH2:22][CH2:23][NH2:24]>O.C1(C)C=CC=CC=1>[CH3:3][C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9]([CH2:21][CH2:22][CH2:23][N:24]=[CH:3][C:4]3[CH:14]=[CH:8][CH:7]=[CH:6][CH:5]=3)([OH:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc2c1CCc1ccccc1C2=O
Reactant: NCCCCl
Agent: N
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc2c1CCc1ccccc1C2(O)CCCN=Cc1ccccc1
Temperature: 80 °C

Procedure:
To a 250 ml. 3-neck vessel, equipped with a stirrer, a dropping funnel and an ammonia coolant, are added 75 ml. of liquid ammonia, and it is treated by adding a sodium chip to obtain a stable blue color. A solution containing 22.2 g. of 1-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in 50 ml. of dry toluene is added dropwise with stirring. Thereafter, 4.6 g. of sodium are added piece by piece over a 30-minute period. The mixture is stirred for an additional 30 minutes and a solution containing 11.4 g. of freshly distilled 1-chloro-3-aminopropane in 40 ml. of dry toluene is added. The ammonia coolant is replaced by a water-cooler and the mixture is stirred overnight. The following morning, the mixture is cautiously decomposed with 50 ml. of water, whereby the 1-methyl-10,11-dihydro-5-(3-aminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene partially crystallizes. Its melting point, after recrystallization from benzene/petroleum ether, is 155°-156° C. The crystals are removed by filtration and together with the separated toluene layer are treated with 13 g. of freshly distilled benzaldehyde. The mixture is heated at 80° C. under reduced pressure, so that the toluene and the residual water distil over. After recrystallization of the residue from ethanol, there is obtained 1-methyl-10,11-dihydro-5-(3-benzylideneaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene as colorless crystals having a melting point of 130°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([CH:8]([N:11]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:21][CH:22]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([CH:8]([N:11]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:32]5[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=5)[CH2:27][CH2:28]4)=[CH:21][CH:22]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CCC(C(=O)c1ccc(Cl)cc1)n1ncn(-c2ccc(N3CCNCC3)nc2)c1=O
Reactant: Cc1cc(C)nc(Br)c1
Solvent: ClCCl
Product: CCC(C(=O)c1ccc(Cl)cc1)n1ncn(-c2ccc(N3CCN(c4cc(C)cc(C)n4)CC3)nc2)c1=O
Temperature: 140 °C
Yield: 48 %

Procedure:
(±)-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-(1-piperazinyl)-3-pyridinyl]-3H-1,2,4-triazol-3-one (6.02 g) and 2-bromo-4,6-dimethylpyridine (5.25 g) were stirred and heated under N2 at 140° C. for 2 days. The mixture was dissolved in CH2Cl2 and purified on a glass filter over silica gel (eluent: CH2Cl2 /CH3OH 100/0 to 97/3). The pure fractions were collected and evaporated, yielding 3.6 g (48%) of (±)-2-[1-(4-chlorobenzoyl)propyl]-4-[6-[4-(4,6-dimethyl-2-pyridinyl)-1-piperazinyl]-3-pyridinyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; mp. 113.2° C. (comp. 32).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12](=[NH:19])[CH:13]=[CH:14][C:15]=2[CH2:16]OC)[N:9]=1)[NH2:3].[N:20]#[C:21][NH2:22].C(OCC)C>CO>[NH2:19][C:12]1[N:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[C:15]([CH:16]=[N:22][C:21]#[N:20])=[CH:14][CH:13]=1
Reactant: COCc1ccc(=N)[nH]c1-c1csc(N=C(N)N)n1
Reactant: N#CN
Solvent: CCOCC
Solvent: CO
Product: N#CN=Cc1ccc(N)nc1-c1csc(N=C(N)N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-(imino)(methoxy)methylpyridin-2-yl]thiazole (4.0 g) and cyanamide (1.2 g) in methanol (80 ml) was stirred for 16 hours at ambient temperature. To the mixture was added a diethyl ether (80 ml) and isolated precipitate was collected by filtration. The precipitate was added to a mixture of ethyl acetate and water and adjusted to pH 9.5 with 20% aqueous potassium carbonate. The precipitate was collected by filtration and recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give 4-[6-(amino)(cyanoimino)methylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (3.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Cl:9])[C:3]=1I.CCCCCC.C([Li])CCC.FC(F)(F)S(O[Si:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[Si:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Clc1cc(Br)cc(Cl)c1I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1c(Cl)cc(Br)cc1Cl
Reaction time: 1 h
Yield: 89.5 %

Procedure:
The 2,6-Dichloro-4-bromoiodobenzene (4.48 g, 12.7 mmol) was dissolved in diethyl ether (50 ml). To the solution was then added dropwise a hexane solution of n-butyl lithium (1.56 M, 8.2 ml) at −78° C. At the same temperature, the mixture was then stirred for 1 hour. To the mixture was then added dropwise trimethylsilyl trifluoromethanesulfonate (3.2 ml, 16.5 mmol). The mixture was then stirred at −78° C. for 1 hour and at room temperature for 30 minutes. After the quenching of the reaction with water, the mixture was then extracted with ether. The resulting organic phase was then dried over magnesium sulfate. The solvent was then distilled off. The crude product thus obtained was then distilled under reduced pressure in a glass tube oven so that it was purified to obtain 3,5-dichloro-4-trimethylsilyl-bromobenzene (3.39 g; yield: 90%).
Reaction SMILES: Br[C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1>O1CCOCC1.O.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>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:18]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:3]3[C:2]([C:49]4[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=4)=[CH:7][N:6]=[C:5]4[NH:8][CH:9]=[CH:10][C:4]=34)[CH2:16][CH2:15]2)=[O:38])[CH2:19][N:20]([CH:28]([CH3:29])[CH3:30])[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[CH:32][CH:33]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)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: O
Solvent: C1COCCO1
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3cnn(C)c3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 150 °C
Yield: 9.9 %

Procedure:
(S)-tert-Butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.05 g, 0.083 mmol, see Example 4) was placed in dioxane (1 mL) and Na2CO3 (aq., 0.087 g, 0.82 mmol) in H2O (0.3 mL). 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.034 g, 0.16 mmol) and PS-Pd(PPh3)4 (0.075 g, 0.1 g/mmol) were then added. The reaction was heated to 150° C. in a microwave for 1 hour. The reaction was then diluted with water and extracted with DCM. The organic fractions were dried, filtered, and concentrated. Purification of the crude residue (500:10 to 500:20 DCM:MeOH) gave (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.005 g, 9.9% yield).
Reaction SMILES: C(O[C:9](=O)[N:10]([CH2:12][C:13](=[O:35])[NH:14][CH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)C)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[C:29]1([S:26]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[C:16]([CH2:15][NH:14][C:13](=[O:35])[CH2:12][NH:10][CH3:9])=[CH:17][CH:18]=[CH:19]3)(=[O:28])=[O:27])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(CC(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CNCC(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
To a stirring solution of {[(6-Benzenesulfonyl-naphthalen-1-ylmethyl)-carbamoyl]-methyl}-methyl-carbamic acid benzyl ester in methanol and formic acid at room temperature is added palladium on carbon. The mixture is stirred at room temperature, filtered thru Celite, and the filtrate is concentrated to give N-(6-benzenesulfonyl-naphthalen-1-ylmethyl)-2-methylamino-acetamide.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][NH:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1.[CH2:28]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:28]([C:33]1[CH:34]=[CH:35][C:36]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[O:26])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[CH:37][CH:38]=1)[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCc1ccc(B(O)O)cc1
Reactant: CCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCc1ccc(-c2ccc(OC(CCC)c3ccc(C(=O)NCCC(=O)O)cc3)cc2)cc1

Procedure:
This compound is made in a substantially similar manner as Example 117 using isomer 1 of 3-{4-[1-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid methyl ester and 4-pentylphenylboronic acid as starting materials in step D. MS (ES): 488.3 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(c3ccccc3)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1 074 549 A2) was treated with the 1-phenylpiperazine in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield the 2-methyl-5-nitro-6-(4-phenyl-piperazin-1-yl)-3H-pyrimidin-4-one as yellow solid; m.p.>250° C. (decomposition); MS: [M−H]−=314.