Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH3:6][O:7][C:8]([C:10]1(C(OC)=O)[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11]1)=[O:9]>CO>[C:1]1(=[O:3])[CH2:13][CH2:14][CH2:10][CH2:8][CH2:2]1.[CH3:6][O:7][C:8]([CH:10]1[C:14]2([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:13][N:12]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:11]1)=[O:9]
Reactant: COC(=O)C1(C(=O)OC)CN(Cc2ccccc2)CC12CCCCC2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: COC(=O)C1CN(Cc2ccccc2)CC12CCCCC2
Product: O=C1CCCCC1
Reaction time: 0.17 h

Procedure:
A solution of (1) (4 g; 20.70 mmol), N-benzylglycine hydrochloride (10.4 g; 51.57 mmol),triethylamine (7.2 mL; 51.65 mmol), and paraformaldehyde (5.2 g; 173.30 mmol) in benzene (120 mL) was refluxed for 2 hours using a Dean-Stark apparatus. After cooling, the reaction mixture was diluted with toluene (200 mL) and washed with brine. The aqueous phase was extracted with toluene (3×30 mL). The organic extracts were combined, dried over MgSO4, and concentrated in vacuo. The crude oil was purified over silica-gel chromatography in EtOAc/heptane (1:3) to give a yellow oil which was diluted in ether (30 mL) and extracted with 3N HCl (3×25 mL). The aqueous phase was washed with ether (2×30 mL) and was concentrated under vacuum to give (2) as a white powder (6.20 g; 17.08 mmol) which was used without any further purification. A solution of (2) (6.2 g; 17.08 mmol) in 6N HCl (120 mL) was refluxed overnight. Evaporating the solvent in vacuo gave 5 g (16.13 mmol; 77% from (1)) of (3) as a pale yellow solid which was immediately esterified. Acetyl chloride (5 mL; 70.32 mmol) was slowly added to methanol (100 mL), at 0° C., under an argon atmosphere. After stirring for 10 minutes, this solution was transferred to a flask containing (3) (5 g; 16.13 mmol), under an argon atmosphere. The reaction mixture was then stirred at 95° C. for 3 hours. After cooling, the methanol was removed in vacuo. The residue was basified with saturated aqueous Na2CO3, and was extracted with ether (3×30 mL). The organic phases were combined, dried over MgSO4, and concentrated to give 3 g (10.44 mmol; 50% from (1)) of (4) as a pale yellow liquid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:25]>>[Cl:25][C:1]1[NH:2][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccccc1F
Reactant: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccccc2F)[nH]c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
A mixture of ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate (19.3 g) and 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1→3:1) to give the title compound as a brown solid (yield 8.76 g, 53%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[C:27]([Br:37])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[Br:37][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]([F:35])([F:34])[F:36]
Reactant: O=C(CBr)Nc1nc(-c2ccc(OCC(F)(F)F)c(Br)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3ccc(OCC(F)(F)F)c(Br)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[3-bromo-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}acetamide (158 mg, 0.333 mmol) in the presence of NaH (10 mg, 0.416 mmol) in dry DMF (5.0 mL) to give 30 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.17 (s, 3H), 3.39 (s, 3H), 4.91 (d, J=8.7 Hz, 2H), 5.32 (s, 2H), 6.22 (s, 1H), 7.30-7.38 (m, 2H), 7.69 (s, 1H), 7.89-7.95 (m, 1H), 8.17 (m, 1H), 12.65 (br s, 1H); APCI-MS (m/z) 572.27 (M+H)+.
Reaction SMILES: Cl.[C:2]12([NH3+:12])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2>O>[C:2]12([NH2:12])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: [NH3+]C12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: O
Product: NC12CC3CC(CC(C3)C1)C2

Procedure:
The reaction of the 1-adamantylammonium hydrochloride with aqueous base takes place preferably in the presence of an organic solvent which is water-immiscible and in which the 1-adamantylamine formed dissolves. A water-immiscible organic solvent in the context of the present invention is a solvent which under standard conditions (20° C., 1013 mbar) dissolves to an extent of not more than 10 g in 100 g of water, and in which under standard conditions not more than 10 g of water dissolve in 100 g of solvent. Suitable organic solvents are aromatic hydrocarbons, such as benzene, toluene, ethylbenzene or xylene; halogenated solvents, such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or chlorobenzene; aliphatic solvents, such as pentane, hexane, heptane, octane, ligroin, petroleum ether, cyclohexane or decalin; and mixtures thereof. Toluene or xylene is preferred. The reaction then takes place as an extractive reaction, the amine liberated undergoing essentially complete transfer to the organic phase. The 1-adamantylamine can be isolated by removing the organic solvent by customary methods, such as evaporation. The evaporation of the solvent may take place in apparatus customary for the purpose. Solvent evaporation takes place preferably under reduced pressure and/or at elevated temperature. For the further reaction it is preferred to use the 1-adamantylamine as a solution in the organic solvent.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:10][O:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=2)[CH:14]=1
Reactant: COC(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1cnc(Br)c(Cl)c1
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: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Temperature: 90 °C
Yield: 94.8 %

Procedure:
A mixture of 2-bromo-3,5-dichloropyridine (2.72 g, 12 mmol), 4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.78 g, 6 mmol)), 2N Na2CO3 (9.0 mL, 18 mmol), Pd(PPh3)4 (0.35 g, 0.3 mmol) in toluene/ethanol (30 mL/6 mL) was sealed and heated at 90° C. for 12 hrs. The mixture was concentrated and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine and was dried over MgSO4. After filtration and concentration, purification by silica gel chromatography eluting with ethyl acetate/hexane (5/95) gave 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid methyl ester (1.8 g). MS (M+H)+: 315.6, tR=8.505 min (method 2)
Reaction SMILES: [S:1]([O:6]C)([O:4][CH3:5])(=[O:3])=[O:2].[CH3:8][N:9]([CH3:26])[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)[C:11]#[N:12]>CC(CC)=O>[CH3:5][O:4][S:1]([O-:6])(=[O:3])=[O:2].[C:11]([CH:10]([N+:9]([CH3:5])([CH3:26])[CH3:8])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)#[N:12]
Reactant: CN(C)C(C#N)c1cccc(Oc2ccccc2)c1
Reactant: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: COS(=O)(=O)[O-]
Product: C[N+](C)(C)C(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 203.7 %

Procedure:
Dimethyl sulfate (2.52 g) was added to a solution of α-(dimethylamino)-3-phenoxybenzeneacetonitrile (5.2 g) in ethyl methyl ketone (40 ml) and the mixture was stirred overnight at ambient temperature. The solvent was removed by distillation under reduced pressure to give the title compound (7.7 g) as a golden oil. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 3.4 (9H, s, N(CH3)3); 3.65 (3H, s, CH3SO4); 6.7 (1H, s, CH); 7.0-7.7 (9H, m, aromatic protons).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=O)[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[S:22])[NH2:10])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(Cl)nc(C(N)=O)c1
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(C(N)=S)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of compound 18 (9 mmol) in THF (30 mL) was added Lawesson reagent (5.4 mmol). The reaction mixture was stirred at 90° C. for 2 hrs. After cooling at room temperature, the solution was concentrated under reduced pressure and the residue was triturated in DCM to give compound 19 as a yellow solid in 71% yield. MS (ESI, EI+): m/z=203 (MH+).
Reaction SMILES: [N+:1]([CH:4]([CH2:9][CH2:10][CH:11]=O)[CH2:5][CH2:6][CH:7]=[O:8])([O-:3])=[O:2].N1CCCC1.C(O)(=O)C1C=CC=CC=1>C(Cl)Cl>[N+:1]([CH:4]1[CH2:5][C:6]([CH:7]=[O:8])=[CH:11][CH2:10][CH2:9]1)([O-:3])=[O:2]
Reactant: O=CCCC(CCC=O)[N+](=O)[O-]
Agent: O=C(O)c1ccccc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=CC1=CCCC([N+](=O)[O-])C1
Temperature: 25 °C

Procedure:
To a solution of 4-Nitro-heptanedial (35.2 g, 0.2 mol) in methylene chloride (0.7 L) were added pyrrolidine (2 ml, 0.024 mol) and benzoic acid (1.46 g, 0.012 mol), and the resulting mixture was refluxed for 10 to 15 hours. The reaction mixture was cooled to room temperature, washed with 1N HCl (170 ml), saturated with NaHCO3 (170 ml) and water (170 ml) and concentrated to give brownish oil with a purity of about 80%. The product was carried to the next step without further purification. Yield: 32.2 g, 75%. 1H NMR (400 MHz, CDCl3) d 2.29-2.34 (m, 2H), 2.46-2.64 (m, 2H), 2.85-2.88 (m, 2H), 4.74 (m, 1H), 6.86 (m, 1H), 9.50 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH:3]([S:6][C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)([CH3:5])[CH3:4].[CH:14](Cl)([F:16])[F:15]>O1CCOCC1>[CH:3]([S:6][C:7]1[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][N:8]=1)([CH3:5])[CH3:4]
Reactant: CC(C)Sc1ncccc1O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Sc1ncccc1OC(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
In the course of 15 minutes, 464 ml of 30% aqueous sodium hydroxide solution are added dropwise to a solution of 118.4 g of 2-isopropylthio-3-hydroxypyridine in 560 ml of dioxane. Then in the course of 2 hours, at a temperature of 80° C., 121 g of Freon-22 are introduced and the reaction mixture is stirred for a further 90 minutes. The reaction mixture is cooled to room temperature and then extracted with a mixture of 2500 ml of ice water and 1000 ml of methylene chloride and the phases are washed four times with 50 ml of methylene chloride each time and once with 100 ml of ice water. The combined organic phases are then dried over sodium sulfate and concentrated by evaporation in vacuo. Purification by silica gel chromatography with ethyl acetate/n-hexane 1:9 as eluant yields 105.7 g of 2-isopropylthio-3-difluoromethoxypyridine in the form of an oil having an nD21 of 1.5088.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:11])=[N:6][C:7]([CH3:10])=[CH:8][CH:9]=1)[CH3:2].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:10][C:7]1[N:6]=[C:5]([F:11])[C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=1
Reactant: CCOc1ccc(C)nc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOc1ccc(CBr)nc1F
Reaction time: 8 h
Yield: 65.1 %

Procedure:
3-Ethoxy-2-fluoro-6-methylpyridine (400 mg) was initially introduced in carbon tetrachloride (30 ml) and, after addition of N-bromosuccinimide (505 mg) and 2,2′-azobis(2-methylpropionitrile) (85 mg), the reaction mixture was heated at reflux for 7 h. After standing overnight at RT, it was treated with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (n-heptane-ethyl acetate gradient). After the combination of the product-containing fractions, it was brought to dryness. 393 mg of the desired compound were obtained.
Reaction SMILES: C(S([C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([N:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)[N:13]=[C:12]([N:27]2[CH2:32][CH2:31][N:30]3[CH:33]=[CH:34][N:35]=[C:29]3[CH2:28]2)[N:11]=1)=O)C1C=CC=CC=1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH2:41].C(N(CC)CC)C>CN(C)C(=O)C>[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH:41][C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([N:20]2[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH2:25]2)[N:13]=[C:12]([N:27]2[CH2:32][CH2:31][N:30]3[CH:33]=[CH:34][N:35]=[C:29]3[CH2:28]2)[N:11]=1
Reactant: COC(=O)c1c(N2CCC(O)CC2)nc(N2CCn3ccnc3C2)nc1S(=O)Cc1ccccc1
Reactant: COc1ccc(CN)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 4-benzylsulfinyl-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine (prepared in the above (6)) 83 mg, 3-chloro-4-methoxybenzylamine 86 mg, triethylamine 51 mg and N,N-dimethylacetoamide 3 ml is stirred at 110° C. for 1 hour. The reaction mixture is diluted with ice water and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; ethyl acetate ethyl acetate:methanol=15:1→10:1) and crystallized from a mixture of methanol, ethyl acetate and isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless crystalline powder 43 mg.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:10]3=2)[N:5]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[CH:3]=1.S(Cl)([Cl:28])=O>ClC(Cl)C.CN(C)C=O>[Cl:28][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:10]3=2)[N:5]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc(=O)c2c(ccc3nc(C(=O)OC)cc(O)c32)o1
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(=O)c2c(ccc3nc(C(=O)OC)cc(Cl)c32)o1

Procedure:
The product of step (a) (1.35 g; 3.9 mmole) suspended in dichloroethane was treated with thionyl chloride (0.9 g; 7.5 mmole) and dimethylformamide (4 drops). The mixture was heated under reflux for 6 hrs adding more thionyl chloride (0.2 ml) after 3 hrs. The mixture was evaporated to dryness and triturated with ether to give a buff solid (1.35 g; 96%), mp 193° shown to be the title compound by its NMR and mass spectrum.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1>O1CCOCC1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([NH:29][CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: NCc1cccnc1
Reactant: COc1ccccc1CNc1ccc2c(Br)cccc2n1
Solvent: C1COCCO1
Product: COc1ccccc1CNc1ccc2c(NCc3cccnc3)cccc2n1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
(5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.583 mmol) was dissolved in 3 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. 3-Picolylamine (127 mg, 1.18 mmol), sodium tert.-butylate (144 mg, 1.50 mmol), 1,1′-bis(diphenylphosphin)ferrocen (50 mg, 0.09 mmol) and 1,1′-bis(diphenylphosphin)ferrocen-palladium(II)chloride (24 mg, 0.03 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 2.5 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The title compound was obtained as a light brown solid (183 mg, 85%), MS: m/e=371.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.[CH3:21][O-:22].[Na+]>CO>[I:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:4]1[N:3]=[C:2]([O:22][CH3:21])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:11]
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 85 °C
Yield: 86 %

Procedure:
A mixture of compound 6 (21 mg, 0.052 mmol) and sodium methoxide in methanol (1.5 mg of Na) was heated for 14 h at 85° C. After evaporation of the solvent, the residue was triturated with methanol-water to give compound 15 (19 mg, 86.0%). 1H NMR (DMSO-d6) δ 3.64 (s, 3 H, 9-CH3), 3.81 (s, 3 H, OCH3), 4.59 (br s, 2 H, CH2), 7.11 (t, J=7.6 Hz, 1 H, H-16), 7.37 (d, J=7.6 Hz, 1 H, H-17), 7.59 (d, J=7.6 Hz, 1 H, H-15), 7.74 (s, 1 H, H-13), 7.92 (s, 1 H, H-8), 8.37 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[N:10]=2)[CH:7]=1.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.ClCCl.C(#N)C>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:27]3[CH:28]=[C:23]([CH2:22][OH:21])[CH:24]=[CH:25][CH:26]=3)=[CH:7][N:6]2[CH:8]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Brc1ccc2nc(-c3ccc4ccccc4c3)cn2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: OCc1cccc(-c2ccc3nc(-c4ccc5ccccc5c4)cn3c2)c1
Yield: 406 %

Procedure:
Under a stream of nitrogen, 500 mg of 6-bromo-2-(naphthalen-2-yl)imidazo[1,2-a]pyridine, 235 mg of 3-(hydroxymethyl)phenylboronic acid and 90 mg of tetrakis(triphenylphosphine)palladium are placed in a microwave tube containing 5 ml of toluene degassed beforehand under a stream of nitrogen, 5 ml of acetonitrile and 6 ml of a 0.5M solution of sodium carbonate. The tube is placed in a microwave apparatus and irradiated at 150° C. for 15 min. The organic phase is separated and dried and the filtrate is concentrated under reduced pressure. The residue obtained is taken up with 5 ml of dichloromethane. A precipitate forms and is recovered by filtration, washed with dichloromethane and then with diisopropyl ether and dried under reduced pressure. The experiment is repeated several times (6) and the solids are combined. 2.2 g of compound are obtained and are recrystallized from a 1/1 n-propanol/water mixture. The precipitate is filter-dried, washed with diisopropyl ether and dried under reduced pressure. 1.96 g of compound are obtained. Mp=161-163° C. 1H NMR (DMSO-d6, δ in ppm): 4.58 (d, J=5.5 Hz, 2H); 5.24 (t, J=5.7 Hz, 1H); from 7.29 to 7.73 (m, 8H); from 7.86 to 8.13 (m, 4H); 8.52 (m, 2H); 8.84 (m, 1H). M+H=351.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][CH:11]=1.[OH-].[NH4+]>>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[N:4]3[CH:5]=[CH:6][N:7]=[CH:8][C:3]3=[N:1][N:2]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NNc1cnccn1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccc(-c2nnc3cnccn23)cc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To 2-hydrazinopyrazine (1.60 g, 14.55 mmol) was added 4-chloro-benzoic acid (3 eq) followed by 20 mL of polyphosphoric acid, and the reaction mixture was stirred at 110° C. for 18 h. The hot PPA solution was added to ice and neutralized by the addition of ammonium hydroxide (highly exothermic!). The aqueous solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Concentration followed by flash chromatography (silica gel, 1:1 hexanes: ethyl acetate) afforded 3-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine, as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10]S(C(C)(C)C)=O)[CH3:9])=[N:6][CH:7]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1ccc(F)cn1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1ccc(F)cn1
Reaction time: 0.5 h

Procedure:
To a solution of N-[(1R)-1-(5-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide (34.3 g, 140 mmol) in methyl alcohol (700 mL) at 0° C. was added hydrogen chloride (4.0 M in dioxane; 105 mL, 421 mmol). After 30 min, the mixture was concentrated to dryness. The residue was recrystallized using ethyl alcohol (15 mL) and ether (40 mL). The white solid was filtered and dried under reduced pressure to give the hydrochloride salt of the title compound. MS 141.1 (M+1).