Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([Mg]Br)#[CH:12]>>[N+:1]([C:4]1[O:8][C:7]([CH:9]([OH:10])[C:11]#[CH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: C#C[Mg]Br
Product: C#CC(O)c1ccc([N+](=O)[O-])o1

Procedure:
Using the procedure of Stage B of Preparation 2, 2.82 g of 5-nitro-2-furaldehyde and 45 ml of ethynylmagnesium bromide were reacted to obtain 1.84 g of the expected product after chromatography on silica (eluent: 8/2 hexane/ethyl acetate).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23]Cl)[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4].[N:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>CN(C)C=O>[CH2:32]([N:27]([CH2:28][CH3:29])[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4])[CH3:31]
Reactant: CCNCC
Reactant: c1ccncc1
Reactant: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Solvent: CN(C)C=O
Product: CCN(CC)CC(=O)Nc1cccc2c1C(=O)c1c(NC(=O)CN(CC)CC)cccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Add 0.4 g, 1.0 mmol 1,8-bis(chloroacetamido)anthraquinone (compound 3) with pyridine (0.5 ml), and 0.6 ml, 6 mmole Diethylamine, dissolved in 20 ml dehydrated dimethylformamide (DMF). The mixture is reacted in a mini-reactor. The reaction temperature is 120° C. in the oil bath and the reaction time is 30 minutes. The reacted mixture is poured into 50 ml ice water and is filtered to collect precipitate. The precipitate is recrystallized from ethanol to get yellow compound 3l.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[N:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]([C:30]1[CH:31]=[N:32][N:33]2[CH:38]=[C:37]([C:39]3[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=3[F:46])[C:36]([C:47]3[CH:52]=[CH:51][C:50]([CH:53]=O)=[CH:49][CH:48]=3)=[N:35][C:34]=12)=[O:29].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[N:32][N:33]2[CH:38]=[C:37]([C:39]3[C:40]([F:46])=[CH:41][CH:42]=[CH:43][C:44]=3[F:45])[C:36]([C:47]3[CH:48]=[CH:49][C:50]([CH2:53][N:16]4[CH2:17][CH2:18][CH:13]([C:11]5[N:12]=[C:8]([C:4]6[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=6)[NH:9][N:10]=5)[CH2:14][CH2:15]4)=[CH:51][CH:52]=3)=[N:35][C:34]=12)=[O:29]
Reactant: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(C=O)cc3)nc12
Reactant: Cc1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(CN4CCC(c5n[nH]c(-c6cccc(C)n6)n5)CC4)cc3)nc12
Reaction time: 1 h

Procedure:
402 mg (1.27 mmol) 2-Methyl-6-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 10 mL NMP. After addition of 0.43 mL triethylamine the reaction mixture is stirred for one hour. 500 mg (1.27 mmol) 6-(2,6-Difluorophenyl)-5-(4-formylphenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester and 0.13 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 296.3 mg (1.40 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 5 hours. After treatment of the reaction mixture with saturated NaHCO3 the precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 368.6 mg (44.4%) of the desired product are obtained.
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH3:5][Si:6](C)([O:10][CH2:11]C)[O:7][CH2:8]C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[Cl:4][CH2:1][CH2:2][CH2:3][Si:6]([CH3:5])([O:10][CH3:11])[O:7][CH3:8]
Reactant: CCO[Si](C)(C)OCC
Reactant: C=CCCl
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CO[Si](C)(CCCCl)OC
Temperature: 50 °C
Yield: 19.7 %

Procedure:
306 mg of allyl chloride, 530 mol of dimethyldiethoxysilane, and 77 mg of toluene were placed in a glass reaction tube. Then, 0.005 mol of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed and heated for 2 hours in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of allyl chloride was 100% and γ-chloropropylmethyldimethoxysilane was produced at a yield of 19.7%.
Reaction SMILES: [S:1]1[CH:5]=[C:4](B(O)O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N:13]1([CH2:18][C:19]2[CH:20]=[CH:21][C:22](Br)=[N:23][CH:24]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>>[S:1]1[CH:5]=[C:4]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[CH:24][N:23]=2)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1csc2ccccc12
Product: c1ccc2c(-c3ccc(Cn4ccnc4)cn3)csc2c1

Procedure:
Synthesized using benzo[b]thiophen-3-ylboronic acid (224 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 100 mg, 0.34 mmol, 54%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.27 (s, 2H), 6.99 (t, J=1.3 Hz, 1H), 7.18 (brs, 1H), 7.39-7.42 (m, 1H), 7.43-7.47 (m, 1H), 7.59 (dd, J=8.2, 2.5 Hz, 1H), 7.70 (dd, J=8.2, 0.9 Hz, 1H), 7.82 (s, 1H), 7.90-7.92 (m, 1H), 8.01 (s, 1H), 8.46-8.48 (m, 1H), 8.66-8.67 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=45.5, 119.3, 122.6, 122.8, 124.1, 124.7, 124.8, 127.1, 128.7, 129.4, 135.7, 135.9, 137.0, 137.1, 140.9, 148.6, 155.0; MS (ESI): m/z=292.05 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16][N:17]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:12][C:10]=3[CH:11]=2)=[CH:4][CH:3]=1.O1CCCC1.O.NN.C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][C:10]=3[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2oc(Cc3ccc(F)cc3)cc2c1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: NCc1ccc2oc(Cc3ccc(F)cc3)cc2c1
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a mixed solution of 2-(2-(4-fluoro-benzyl)-benzofuran-5-ylmethyl)-isoindole-1,3-dione (81 mg, 0.21 mmol) described in Production Example 76-1-3 in ethanol (5 mL) and tetrahydrofuran (3 mL) was added hydrazine monohydrate (52.6 mg, 1.05 mmol). This mixture was stirred for 3 hours while heating under reflux. After allowing the reaction mixture to cool on standing, saturated aqueous sodium bicarbonate solution was poured thereinto followed by extraction with ethyl acetate. The organic layer was separated followed by washing with sat. NaCl, drying over anhydrous magnesium sulfate and concentrating under a reduced pressure to obtain the title compound (42 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]([C:20](=O)[CH:21]([CH3:23])[CH3:22])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][C@H:35]1[O:40][C:39]([CH3:42])([CH3:41])[O:38][C@@H:37]([CH2:43][C:44]([N:46]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:45])[CH2:36]1.CCCCCCC.C(O)(=O)C(C)(C)C>C1(C)C=CC=CC=1.O1CCCC1>[C:53]1([N:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:44](=[O:45])[CH2:43][C@@H:37]2[O:38][C:39]([CH3:42])([CH3:41])[O:40][C@H:35]([CH2:34][CH2:33][N:32]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:9]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[O:12])=[C:20]3[CH:21]([CH3:23])[CH3:22])[CH2:36]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)O1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: CC(C)(C)C(=O)O
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)OC(C)(C)O1
Temperature: 25 °C

Procedure:
A nitrogen purged 500 mL three-neck flask is charged with 4-fluoro-α-(2-methyl-1-oxopropyl)-γ-oxo-N,β-diphenylbenzenebutanamide (Baumann, supra) (13.6 g, 0.032 mol), (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamide (10.0 g, 0.027 mol), heptane (100 mL), pivalic acid (3 g), tetrahydrofuran (50 mL), and toluene (60 mL). The mixture is heated to reflux for 48 hours, cooled to room temperature, and diluted with toluene (300 mL). The solution is washed with 0.5N aqueous sodium hydroxide (150 mL), followed by 0.5N aqueous hydrochloric acid (250 mL), and concentrated by vacuum distillation to a foam. The product, (4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2--dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide, is used in the next step without further purification. Fourier Transform Infrared Spectroscopy (FTIR)(KBr) 3450, 2860, 1650, 1620 cm-1 ;
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=2)[CH:7]=1
Reactant: Clc1ccc2ncc(Br)n2c1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc2ncc(-c3ccnc(Cl)c3)n2c1
Temperature: 100 °C

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-a]pyridine (1 eq, 18.1 mmol, 4.2 g), 2-chloropyridin-4-yl boronic acid (1.05 eq, 19 mmol, 3 g), Na2CO3 (2 eq, 36.2 mmol, 3.84 g) in dioxane (30 ml) and water (10 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (1.23 g). The reaction mixture is heated at 100° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title compound; [M+H]+=264 (266).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21](O)([CH3:23])[CH3:22])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3=[C:13]([C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]2([CH3:23])[CH3:22])[CH:14]=1
Reactant: CC(C)(O)c1ccccc1-n1c2ccccc2c2cc(Br)ccc21
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)c2ccccc2-n2c3ccccc3c3cc(Br)cc1c32
Temperature: 60 °C

Procedure:
16.3 g (43.6 mmol) of 2-[2-(3-bromocarbazol-9-yl)phenyl]propan-2-ol are dissolved in 1.2 l of degassed toluene, a suspension of 40 g of polyphosphoric acid and 28 ml of methanesulfonic acid is added, and the mixture is heated at 60° C. for 1 h. The batch is cooled, and water is added. A solid precipitates out and is dissolved in methylene chloride/THF (1:1). The solution is carefully rendered alkaline using 20% NaOH, the phases are separated and dried over MgSO4. The solid obtained is washed by stirring with heptane. Yield: 13.5 g (37 mmol), 87% of theory, purity according to 1H-NMR about 95%.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([NH:17][CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(C)(C)C.Cl>O>[CH:11]1([N:17]([CH3:18])[C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CNC1CCCCC1
Agent: Cl
Solvent: O
Solvent: CC(C)(C)O
Product: CN(c1ncnc2[nH]ccc12)C1CCCCC1
Yield: 87.8 %

Procedure:
A mixture of 200 mg (1.30 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (prepared by the method of Davoll, J. Am. Chem. Soc., (1960). 82, 131), the product from Method A (589 mg/5.21 mmol) and 3 mL of tert-butanol was stirred in a sealed tube at 100° C. for 24 h. The reaction mixture was added to water, acidified to pH 1 with 1 N HCl (aq), washed twice with diethylether (ether) and basified to pH 14 with 1 N sodium hydroxide (NaOH). The resulting precipitate was filtered and dried in vacuo to obtain 263 mg (88%) of the title compound, mp 177-180° C. 1H NMR (400 MHz, CDCl3): δ1.11-1.22 (m, 1H), 1.43-1.63 (m, 4H), 1.73 (br d, 1H, J=13.3 Hz), 1.83-1.90 (m, 4 H), 3.23 (s, 3H), 4.69 (br, 1H), 6.53 (d, 1H, J=3.5 Hz), 7.03 (d, 1H, J=3.5 Hz), 8.30 (s, 1H), 10.6 (br, 1H). LRMS: 231 (M+1).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1.C(#N)C>O>[CH3:13][C@H:14]1[NH:15][C@@H:16]([CH3:20])[CH2:17][N:18]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:19]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
2-Chloro-5-nitrobenzonitrile (13.3 g) and cis-2,6-dimethylpiperazine (25 g) were added to acetonitrile (25 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added to water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether to give cis-2-(3,5-dimethylpiperazin-1-yl)-5-nitrobenzonitrile (14.3 g), melting point: 109–110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[C:30]([CH3:37])=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=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:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:29]1[CH:34]=[N:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=1[CH3:37]
Reactant: CN(C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1)c1ccccc1O
Reactant: Cc1cc(C#N)ncc1Br
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2ccccc2O)ccc1Cl
Temperature: 95 °C
Yield: 69.2 %

Procedure:
A mixture of 4-chloro-N-(2-hydroxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (100 mg, 0.26 mmol), 5-bromo-4-methyl-pyridine-2-carbonitrile (61 mg, 0.31 mmol), Pd(PPh3)4 (15 mg, 0.013 mmol), K2CO3 (90 mg, 0.65 mmol) in dioxane (1.2 mL), was heated at 95° C. for 12 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and concentrated in vacuo. Silica gel column chromatography (eluent: ethyl acetate/hexane (1/4 up to 4/1)) yielded 4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide 8-1 (68 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=3)=[CH:17][CH:16]=1)=[N:8]2.[H][H]>CCO.CC(O)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:25][CH2:26]3)=[CH:17][CH:16]=1)=[N:8]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2c1
Yield: 101.1 %

Procedure:
A solution of tert-butyl 4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.160 g, 0.34 mmol) in EtOH (10 mL) and HOAc (5 mL) was purged with nitrogen, and 10% Pd/C (0.016 g) was added. The mixture was stirred under 1 atmosphere of hydrogen overnight. Then, the solution was filtered through Celite, with MeOH washings, and the filtrate was concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 30% to 70% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.160 g, 100%). 1H NMR (300 MHz, DMSO-d6): δ 11.91 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 4.00-4.22 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 2.65-2.97 (m, 3H), 1.68-1.88 (m, 2H), 1.48-1.68 (m, 2H), 1.42 (s, 9H). ESI MS m/z 466 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[N:5]2[CH:4]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C=O)C.C(Cl)Cl>[N:18]1([CH2:2][C:3]2[S:17][C:6]3=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[N:5]3[CH:4]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnc2sc(CBr)cn2c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2sc(CN3CCOCC3)cn2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture of ethyl 2-(bromomethyl)-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate (Preparation 9, 159 mg) and morpholine (0.5 mL) in DMF (10 mL) is stirred for 4 h at rt. The mixture is diluted with CH2Cl2 (100 mL) and is washed with water. The organic layer is dried (MgSO4) and concentrated to afford 130 mg (80%) of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 324 (M+H)+. 1H NMR (DMSO) δ8.62, 8.22, 4.25, 3.75, 3.59, 2.49, 1.28.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:15]([NH2:18])[CH:16]=[CH2:17]>CN(C=O)C>[CH2:15]([NH:18][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:16]=[CH2:17]
Reactant: CC(C)c1csc2c(Cl)nc(Cl)nc12
Reactant: C=CCN
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(C(C)C)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
In 5 ml of DMF, 71 mg (0.29 mmol) of 2,4-dichloro-7-isopropylthieno[3,2-d]pyrimidine was dissolved, and then 36 mg (0.63 mmol) of allylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 73 mg (yield: 94.8%) of the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].C1C(=O)N([Br:19])C(=O)C1.CC(N=N[C:27]([C:30]#N)(C)C)(C#N)C>>[Br:19][CH2:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:27][CH3:30])=[O:9]
Reactant: Cc1ccccc1CC(=O)O
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCOC(=O)Cc1ccccc1CBr

Procedure:
o-Tolylacetic acid was brominated with NBS and AIBN as described in Example 21 to give ethyl o-bromomethylphenylacetate, and this was reacted with triethyl phosphite as described in Example 2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:19]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([C:10]2[S:11][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:19][C:8]=3[N:9]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3s2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3cc(N)ccc3s2)cc1
Temperature: 80 °C
Reaction time: 1.25 h
Yield: 61.9 %

Procedure:
5-Nitro-2-p-tolylbenzo[d]thiazole (400 mg, 1.48 mmol) was suspended in ethanol/water (8 mL/4 mL) and heated at 80° C. Ammonium chloride (160 mg, 2.96 mmol) and iron powder (414 mg, 7.40 mmol) were added to the suspension, and the mixture was left stirring at 80° C. for 75 min. After cooling, the solution was filtrated through a pad of Celite® and the pad washed with ethanol. Water was added to the filtrate, ethanol was evaporated and the remaining aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 220 mg (62%) of the title compound (LCMS RT=6.51 min, MH+ 241.0)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[Cl:11].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:15]([CH3:16])[CH3:14])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1cc(F)ccc1Cl
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)C)ccc1Cl
Yield: 99 %

Procedure:
To a stirred solution of 4.00 g (20.6 mmol) 2-Chloro-5-fluoro-benzoic acid methyl ester (Rarechem) and 60 ml dimethylsulphoxid were added 2.03 g (24.7 mmol) dimethylamine hydrochloride and 5.97 g (43.2 mmol) potassium carbonate. The reaction mixture was stirred over night and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 18a was obtained in 99% yield (4.46 g, 20.9 mmol) and was used for the next step without purification.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=1.Br[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2.C1C=CC(P([C:38]2[C:47]([C:48]3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=[C:46]3[C:41]([CH:42]=CC=C3)=[CH:40][CH:39]=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1>[CH3:42][C:41]1[CH:40]=[CH:39][CH:38]=[C:47]([CH3:48])[C:46]=1[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH:10][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: Brc1cccc2cccnc12
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Reactant: Cc1cc(Br)cc2nnc(N)nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1-c1cc(C)c2nc(Nc3cccc4cccnc34)nnc2c1
Reaction time: 24 h
Yield: 473.1 %

Procedure:
About 100 mg (0.4 mmol) of 7-bromo-5-methyl-benzo[1,2,4]triazin-3-ylamine and about 158 mg (0.8 mmol) of 8-bromo-quinoline were dissolved in about 10 ml toluene. About 17 mg (0.018 mmol) of Pd(dba)3, about 17 mg (0.027 mmol) of BINAP, and about 50 mg (0.226 mmol) of KOt-Bu were added to the solution. The mixture was kept at about 100° C. for about 24 hours under argon. The crude product was purified by preparative HPLC. About 50 mg [7-(2,6-dimethyl-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-quinolin-8-yl-amine (product having formula (XII)) was isolated. Yield: about 33.8%; ESI-MS: [M+H]+, 392; 1H NMR (DMSO-d6): δ 2.07 (s, 6 H), 2.79 (s, 3H), 7.19 (d, J=7.4 Hz, 2 H), 7.25 (m, 1 H), 7.71-7.79 (m, 4 H), 8.04 (s, 1 H), 8.50 (d, J=8.3 Hz, 1 H), 9.05 (m, 2 H).