Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[NH:13][CH:12]=3)=[CH:10][C:3]=12.[OH-].[Na+].[Cl:36][CH2:37][CH2:38]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:36][CH2:37][CH2:38][N:13]1[C:14]2[C:15](=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)[C:11]([C:9]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]3[CH:10]=2)=[CH:12]1
Reactant: ClCCCl
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2nc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCl
Temperature: 50 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
Heat a mixture of bisazaindole 28 (180 mg, 0.373 mmol), 1,2-dichloroethane (2.0 mL), 9N NaOH (2.0 mL) and tetrabutylammonium bromide (16 mg), with stirring, at 50° C. for 16 h. Then leave the reaction medium to cool to room temperature, extract it with CH2Cl2 (3×), dry (Na2SO4) and concentrate under vacuum. Purification on SiO2 by flash chromatography gives 31 (110 mg, 54%) as a yellow solid: 1H NMR (CDCl3) δ 8.40 (d, 1H, J=5.4 Hz), 7.76 (d, 1H, J=5.2 Hz), 7.70 (d, 2H, J=8.4 Hz), 7.59 (s, 1H), 7.15 (m, 2H), 7.06 (d, 2H, J=8.4 Hz), 7.02 (s, 1H), 4.51 (t, 2H, J=6.4 Hz), 4.06 (s, 3H), 4.00 (s, 3H), 3.90 (t, 2H, J=6.4 Hz), 2.30 (s, 3H), TLC (EtOAc at 40%/heptane) Rf=0.20.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13](C)[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N1CC=C(C2C3C(=CC(C(N4CCN(C(C)C)CC4)=O)=CC=3)NC=2)CC1)C(C)C.[CH3:63][S:64](Cl)(=[O:66])=[O:65]>>[CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13]([S:64]([CH3:63])(=[O:66])=[O:65])[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1CC=C(c2cn(C)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)CN1CC=C(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: Cl
Product: CC(C)CN1CC=C(c2cn(S(C)(=O)=O)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1

Procedure:
According to the procedure described for the synthesis of [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone; hydrochloride (example 42) the title compound was prepared from [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone and methanesulfonylchloride (commercially available). MS (m/e): 487.3 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[CH:7][NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[CH:7][N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1ncn(Cc2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A mixture of 4′-[(4-butyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), sodium hydride (0.07 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-fluorobenzene (0.22 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.54 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Cl[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[N:10]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: Cc1nc2c(Cl)nccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2c(C)nc3c(Cl)nccc32)nc1
Yield: 51 %

Procedure:
4-Chloro-2-methylimidazo[4,5-c]pyridine described in C.A. 79, 105515f but made by the method of Chem. Pharm. Bull, 12 (8) 866-872 (1964) (3.34 g, 20 mmol), and ethyl 6-chloronicotinate (3.71 g, 26.2 mmol) were dissolved in N,N-dimethylformamide (42 ml). Potassium carbonate (2.76 g, 20 mmol) was added and the reaction was refluxed overnight. The reaction mixture was cooled, the solvent removed under reduced pressure and the crude product purified by flash chromatography eluting with ethyl acetate. Fractions containing product were evaporated and the resulting foam triturated with ether. The solid was filtered and dried under reduced pressure yielding the title compound as a yellow solid (3.2 g, 51%).
Reaction SMILES: [NH2-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH2:10](Cl)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)(Cl)Cl>[CH2:3]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCCCCCCCCl
Reactant: Cc1ccncc1
Agent: [NH2-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCc1ccncc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Into a 300-mL flask equipped with a mechanical stirrer, N2 inlet, pressure-equalizing addition funnel which is thermostated in oil bath, were added 14.8 g of sodium amide (0.38 mol) and 64.0 mL of 4-methylpyridine (61.1 g, 0.656 mol). The mixture was stirred under N2 for 1 h while a color change to deep red was observed. A 110-mL sample of n-octadecyl chloride (95.0 g; 0.33 mol) was added to the rapidly stirred reaction mixture over a period of 1.5 h. Shortly after addition was begun, the reaction mixture was warmed to 60° C. to prevent solidification and was subsequently stirred overnight at 100° C. The reaction mixture was cooled to room temperature, diluted with 200 mL of chloroform, washed three times with 200 mL of H2O, and reduced to dryness with the rotary evaporator. The resultant dark brown product was vacuum distilled three times at 0.07 mmHg to finally afford 48.8 g of constant-boiling (180° C. (0.07 mmHg)), white, waxy solid (0.141 mol, 43% yield based on n-octadecyl chloride). Anal. Calcd for C24H43N: C, 83.41; H, 12.54; N, 4.05. Found: C, 83.6; H, 12.7; N, 4.0. MS (ESIMS): m/z: 345.3.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][NH:8][C:7]=1[CH2:17][CH2:18][NH2:19])=[O:5])C.O.[OH-].[Li+].O.[CH2:24]([OH:26])C>>[O:5]=[C:4]1[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:9]([CH:24]=[O:26])[NH:8][C:7]=2[CH2:17][CH2:18][NH:19]1
Reactant: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCN
Reactant: CCO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
A stirred solution of 2-(2-amino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester, lithium hydroxide monohydrate (840 mg, 20 mmol) in ethanol (20 ml) was heated to reflux under an argon atmosphere for 3 hours. The mixture was added with cold water (150 ml), stirred for 10 minutes, extracted with dichloromethane:methanol=5:1 (50 ml×7), washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from dichloromethane and methanol to give 4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (280 mg, 38.9%) as a red solid.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@@H:11]([N:13]5[CH2:14][CH2:18][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][N:24]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@@H](N5CCCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 32A for the product of Example 1E, and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.04 (d, J=8.42 Hz, 1H) 7.98 (s, 1H) 7.58 (dd, J=8.42, 1.87 Hz, 1H) 4.08 (s, 3H) 3.55-3.68 (m, 1H) 2.79-2.91 (m, 1H) 2.66-2.77 (m, 2H) 2.23-2.49 (m, 6H) 1.52-1.73 (m, 6H). MS: (M+H)+=381.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]([NH:9][C:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:21][CH2:22][S:23][CH3:24])[C:13]1=[O:25])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].ClC1C=CC=C(C(OO)=[O:34])C=1.C([O-])(O)=O.[Na+]>ClCCl>[NH2:1][C:2]([C@@H:4]([NH:9][C:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:21][CH2:22][S:23]([CH3:24])=[O:34])[C:13]1=[O:25])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCn1c(=O)n(C(=O)N[C@H](C(N)=O)C(C)(C)C)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)CCn1c(=O)n(C(=O)N[C@H](C(N)=O)C(C)(C)C)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture of N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (Example 32, 150 mg), m-chloroperbenzoic acid (70%, 170 mg) and NaHCO3 (150 mg) in dichloromethane (5 mL) was stirred overnight and quenched with sat. Na2S2O3 aq. (25 mL) The whole was extracted with ethyl acetate (25 mL×2). The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated in vacuo. The residue was purified by preparative TLC to yield the titled compound. (180 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH-:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][CH3:27])[N:17]=[CH:16][N:15]=1>CN(C=O)C>[CH2:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:17]=[CH:16][N:15]=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:19]=1)[CH3:27]
Reactant: CCc1ccccc1-c1cc(Cl)ncn1
Reactant: [NH-]S(=O)(=O)Cc1cccc(N)c1
Solvent: CN(C)C=O
Product: CCc1ccccc1-c1cc(Nc2cccc(CS(N)(=O)=O)c2)ncn1
Temperature: 80 °C

Procedure:
A mixture of (3-aminophenyl)methanesulfonyl amide (0.112 g, 0.60 mmol) and 4-chloro-6-(2-ethylphenyl)-pyrimidine (0.131 g, 0.60 mmol) in DMFA (3 mL) was stirred at 80° C. till the reaction completion (TLC control), then concentrated in vacuo, and the residue was recrystallized from isopropanol to give {3-[6-(2-ethyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (Compound 26)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:5]1[C:4]([OH:9])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Cl)cnc1O
Product: Oc1cc(Cl)cnc1Cl
Temperature: 180 °C

Procedure:
A mixture of 5-chloro-2,3-dihydroxypyridine (1.0g.) and phosphoryl chloride (10ml.) was heated overnight at 180° C. in a sealed tube. The phosphoryl chloride was distilled off, and the residue was chromatographed, to give 2,5-dichloro-3-hydroxypyridine, m.p. 160°-161° C. (ethyl acetate - petrol).
Reaction SMILES: C(O[C@H:5]1[CH:14]=[C:13]([CH3:15])[C@H:12]([C:16](=[O:18])[CH3:17])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)(=O)C.Cl.[CH2:20]1CCN2C(=NCCC2)CC1>>[CH3:20][CH2:17][C:16]([C:12]1[C:7]2([CH2:6][CH:5]=[CH:14][C:13]=1[CH3:15])[CH2:8][CH2:9][CH2:10][CH2:11]2)=[O:18]
Reactant: CC(=O)O[C@H]1C=C(C)[C@H](C(C)=O)C2(CCCC2)C1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Product: CCC(=O)C1=C(C)C=CCC12CCCC2
Yield: 72 %

Procedure:
A solution of 8:92 cis/trans-10-acetyl-9-methylspiro[4.5]dec-8-en-7-yl acetate (4.1 g, 16.4 mmol) in DBU (30 ml) was stirred for 19 h at 40° C. The reaction mixture was poured into cold 2N aqueous HCl (100 ml), and extracted twice with cyclohexane (50 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (40 ml), dried (MgSO4), concentrated. FC (500 g SiO2, hexane/MTBE 50:1) of the crude product (2.92 g) gave methyl 1-(7-methylspiro[4.5]deca-6,8-dien-6-yl)ethanone (2.25 g, 72%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH:8][C:15]([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[S:16])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ncccc1Br
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ncccc1Br
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-pyridin-2-ylamine (9.72 g, 56.2 mmol) in 1,4-dioxane (100 mL) was added dropwise ethoxycarbonyl isothiocyanate (6.70 mL, 56.7 mmol). The mixture was stirred under an atmosphere of nitrogen for 18 hours. The volatiles were evaporated to yield a waxy solid. The recovered material was triturated with hexane (250 mL). N-(3-Bromo-2-pyridinyl)-N′-carboethoxy-thiourea was isolated and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 11.46 (s, 1H), 11.43 (s, 1H), 8.49 (dd, J=4.6, 1.5 Hz, 1H), 8.18 (dd, J=8.0, 1.5 Hz, 1H), 7.33 (dd, J=8.0, 4.7 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). MS=215 (MH)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:46][C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1>O1CCCC1>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][CH:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][S:46][C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[CH:8][CH:7]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11]1
Reactant: Sc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CSc3ncccn3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
To a solution of 100 mg (0.22 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 10 ml of tetrahydrofuran were added 68 mg (0.66 mmol) of triethylamine and thereafter dropwise at 0° C. 25 mg (0.26 mmol) of methanesulphonyl chloride. The reaction solution was stirred at room temperature for 90 minutes, thereafter 38 mg (0.33 mmol) of 2-mercaptopyrimidine were added and the mixture was stirred at room temperature for a further 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure, the residue was taken up in 20 ml of methylene chloride and then extracted with 10 ml of water. The organic phase was dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 5:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 100 mg (82% of theory) of tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(pyrimidin-2-ylsulphanylmethyl)-phenyl]-piperidine-1-carboxylate as a yellowish oil; MS: 542 (M+H)+.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:17]([OH:19])=O)[CH2:13][CH2:14][S:15][CH3:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1C=C2N=NN(O)C2=CC=1.O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:62][C:63]1[CH:69]=[CH:68][C:66]([NH2:67])=[CH:65][CH:64]=1>CN(C)C1C=CN=CC=1.C1COCC1>[Cl:62][C:63]1[CH:69]=[CH:68][C:66]([NH:67][C:17](=[O:19])[C@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:13][CH2:14][S:15][CH3:16])=[CH:65][CH:64]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CSCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CSCC[C@@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
CBZ-d-Methionine (5.4 g, 20 mmol), N-hydroxybenzotriazole H2O (HOBt, 3.0 g, 20 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 7.7 g, 20 mmol), 4-(dimethylamino)-pyridine (DMAP, ˜0.020 g, ˜0.16 mmol) and triethylamine (2.8 ml, 20 mmol) were added to a solution of 4-chloroaniline (1.3 g, 10 mmol) in THF. The non-homogeneous solution was stirred at room temperature for 24 hours. The solvent was then removed and the residue taken into ethyl acetate (˜200 ml) and washed sequentially with NaHCO3 (3×100 ml), 10% citric acid (3×100 ml), water (3×100 ml) and saturated NaCl (1×75 ml). The organic layer was then dried with sodium sulfate, filtered, and concentrated to yield (2R)—N-(4-chlorophenyl)-4-methylthio-2-[(phenylmethoxy)carbonylamino]butanamide (M+1=393.26)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][N:21]([C:25](=[S:27])[NH2:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[CH2:29](O)C.CI>CO>[CH3:29][S:27][C:25]([N:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][C:15]([O:14][CH2:13][CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[CH:16][CH:17]=2)[CH2:22]1)=[NH:26]
Reactant: CCO
Reactant: NC(=S)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Agent: Cl
Solvent: CI
Solvent: CO
Product: CSC(=N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
7-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (200 mg) was treated with hydrogen chloride—ethanol solution. To a suspension of the obtained residue in methanol (6 ml) was added methyl iodide (0.1 ml), and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was dissolved in water and ethanol and neutralized with ion-exchange resin (IRA-410). This was filtrated and the filtrate was concentrated and dried under reduced pressure to give the title compound (200 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](OCC)=[O:10])[CH:6]=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[OH:10][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCOC(=O)c1ccnc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(CO)ccn1
Temperature: 5 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of ethyl 2-methoxy-pyridine-4-carboxylate (0.93 g, 5 mmol) in ether (5 ml) was added to lithium aluminium hydride (0.3 g, 8 mmol) in ether (10 ml) cooled to 5° C. and the mixture stirred for 2 hours. Water was added, the mixture was filtered through diatomaceous earth and the pad was washed through with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation to give 4-hydroxymethyl-2-methoxypyridine (0.64 g, 89%) as a yellow oil. 1H NMR Spectrum: (CDCl3) 3.86(s, 3H); 4.62(s, 2H); 6.65(s, 1H); 6.76(d, 1H); 8.05(d, 1H) MS-ESI: 140 [MH]+
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:17]=2)[N:12]=1.C(#N)C>O>[N:21]1([C:15]2[N:14]=[C:13]3[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc2ccc(N3CCCC3)nc2n1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(N3CCCC3)nc2n1)c1ccccc1
Temperature: 4 °C
Yield: 90 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with benzoic acid (6.5 g), N,N'-carbonyldiimidazole (8.6 g) and 2-amino-7-(1-pyrrolidinyl)-1,8-naphthyridine (8.6 g). The product obtained by precipitation in water (13 g; m.p. 110° C.) is dissolved in boiling acetonitrile (85 cc). After cooling for 2 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (15 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(1-Pyrrolidinyl)-1,8-naphthyridin-2-yl]benzamide (11.5 g), m.p. 130° C., is obtained.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:7].[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH4+].[Cl-]>O1CCCC1.CCOCC>[OH:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:7]
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CCC(O)(c1ccccc1)c1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of 4,4-bis(4-hydroxyphenyl)pentanoic acid methyl ester (4.58 g, 15.3 mmol) in 100 mL of anhydrous tetrahydrofuran was cooled to 0° C. and treated dropwise with phenylmagnesium bromide (10 mL of a 3M solution in ether). Additional tetrahydrofuran (50 mL) was added to the reaction mixture followed by phenylmagnesium bromide (10.4 mL of a 3M solution in ether). The reaction was warmed to room temperature and stirred for 3 hours. The reaction was cooled to 0° C. and treated with phenylmagnesium bromide (10.2 mL of a 3M solution in ether). The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was cooled to 0° C. and treated with saturated aqueous NH4Cl solution (100 mL). The organic phase was collected and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 40% ethyl acetate/hexanes) to give the title compound (6.22 g, 96%) as a white solid.