Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>C1C=CC=CC=1.O.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH:9]([CH3:10])[O:11][CH:19]2[C:18]2[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(O)Cc1ccc(Cl)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: c1ccccc1
Product: CC1Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)O1

Procedure:
11.94 g (70 mM) of 1-(4-chlorophenyl)-2-propanol [J. Med. Chem. 21, 454 (1978)] and 10.57 g (70 mM) of 4-nitrobenzaldehyde were dissolved in 70 ml of anhydrous benzene, then 9.56 g (70 mM) of freshly prepared anhydrous zinc chloride were added and dry hydrochloric acid gas was led into the mixture for 3 hours. Then the mixture was refluxed for 1.5 hours, cooled, diluted with water and the layers were separated. The organic layer was first washed with water then with a solution of sodium hydrogen carbonate, dried and evaporated. The resulting crude product was recrystallized from ethanol.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][N:12]([CH2:14][C:15](OC)=[O:16])[CH2:11][CH2:10][N:9]1[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[NH3:37]>>[CH2:1]([C@@H:8]1[CH2:13][N:12]([CH2:14][C:15](=[O:16])[NH2:37])[CH2:11][CH2:10][N:9]1[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reactant: N
Solvent: CO
Product: NC(=O)CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
(2R)-2-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(methoxycarbonylmethyl)piperazine (0.2 g) was treated with 20% ammonia methanol solution (5 ml), and the resulting mixture was left overnight in a refrigerator. The reaction mixture was concentrated under reduced pressure and the residue was purified on a silica gel column (7 g) eluting with a mixture of dichloromethane and methanol (10:1) to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(carbamoylmethyl)-piperazine. This compound was treated with 4N hydrogen chloride in ethyl acetate solution to give the corresponding hydrochloride (0.18 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21].O>ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=2[F:1])=[O:19])=[CH:13][C:12]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(O)cc1F
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
At room temperature, 3-fluoro-4-amino-phenol (500 mg, 3.93 mmol, 1 eq) was dissolved in N,N-dimethylformide (3 mL). A solution of 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (917 mg, 4.13 mmol, 1.05 eq) in dichloromethane (3 mL) was added dropwise. The resulted mixture was stirred at room temperature for 16 h. The mixture was added with water (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL×3), and dried over anhydrous sodium sulfate. The solvent in the organic phase was removed under reduced pressure, and the resulted solid was refluxed in petroleum ether (15 mL) and ethyl acetate (5 mL) for 2 h. The mixture was cooled to room temperature and filtered to give title compound (1.2 g, purity 98%, yield 89%) as a brown solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][CH2:8][C:9]1([CH3:16])[NH:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].[N-]=[N+]=[N-]>O.CN(C)C=O>[N:1]([CH2:6][CH2:7][CH2:8][C:9]1([CH3:16])[NH:13][C:12](=[O:14])[NH:11][C:10]1=[O:15])=[N+:2]=[N-:3]
Reactant: CC1(CCCCl)NC(=O)NC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CCCN=[N+]=[N-])NC(=O)NC1=O
Reaction time: 21 h

Procedure:
A solution of sodium azide (13 g, 0.2 mol) in water (100 ml) was added to a solution of 5-(3-chloropropyl)-5-methyl-2,4-imidazolidinedione (19.06 g, 0.1 mol) in dimethylformamide (900 ml.) and the mixture was kept at 75° C. for 21 hours. Iodometric determinations of azide ions indicated the consumption of the expected quantities of azide at that time. The mixture was concentrated to a syrup which was redissolved in chloroform (200 ml.), filtered, diluted with chloroform (500 ml.) and water (100 ml.), the chloroform phase was collected after equilibration and combined with four additional chloroform extracts which were dried (MgSO4) and concentrated. Crystalline 5-(3-azidopropyl)-5-methyl-2,4-imidazolidinedione was obtained from chloroform/petroleum ether (17.3 g, 88%), m.p. 104° C. after one recrystallization from the same solvent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C@@H:24]([NH:29][C:30]([N:32]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39](=O)[CH2:40][CH:41]([CH3:43])[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:42][CH:41]([CH3:43])[CH2:40][CH3:39])[CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C@@H:24]([NH:29][C:30]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[O:31])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCC(Nc2ccc(OCc3ccccc3)cc2)CC1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(C)CN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 169.3 %

Procedure:
(S)-Azepane-1-carboxylic acid {1-[4-(4-benzyloxy-phenylamino)-piperidine-1-carbonyl]-3-methyl-butyl}-amide (Example 28) (0.30 g, 0.28 mmol) was dissolved in CH2Cl2 (5 mL) and treated with isovaleraldehyde (62 μL, 0.58 mmol). The reaction was stirred for 30 minutes at RT, then cooled to 0° C., treated with NaBH(OAc)3, allowed to warm to room temperature as the ice melted and stir overnight. The reaction was then diluted with EtOAc (100 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 3:2 hexane/EtOAc to give 0.28 g (82%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH2:17][CH2:18][O:8][C:6]=2[CH:7]=1
Reactant: Oc1cc(Br)ccc1NC1CCOCC1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)OCCN2C1CCOCC1
Temperature: 180 °C
Yield: 56 %

Procedure:
A mixture of intermediate D9 (0.433 g, 1.591 mmol), 1,2-dibromoethane (0.411 ml, 4.773 mmol and potassium carbonate (1.099 g, 7.955 mmol) in DMF (10 ml) was heated at 180° C. for 15 min. under microwave irradiation. After cooling to r.t. the r.m. was filtered through diatomaceous earth. The filtrate was evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield a colorless oil that crystallized to yield D11 (0.267 g, 56%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]1([C:29]#[N:30])[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:29]([C:26]1([NH:25][C:21]([C:18]2[C:16]3=[N:17][C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)=[CH:13][N:14]=[C:15]3[NH:20][CH:19]=2)=[O:23])[CH2:28][CH2:27]1)#[N:30]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: N#CC1(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C#N)CC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (90 mg, 0.29 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (41 mg, 0.348 mmol), EDCI (110 mg, 0.58 mmol) and DMAP (75 mg, 0.58 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered to give the crude product which was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 40% acetonitrile/60% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(1-cyanocyclopropyl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (25 mg, 23%) as a white solid. MS: (M+H)+=376; 1H NMR (300 MHz, DMSO): δ 12.95 (s, 1H), 9.10 (s, 1H), 8.87 (s, 1H), 8.56-8.53 (m, 2H), 6.69 (d, 1H, J=8.7 Hz), 7.26 (t, 1H, J=8.7 Hz), 4.15 (s, 3H), 1.70 (brs, 2H), 1.64 (brs, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CC(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13])[CH3:2]
Reactant: CN1CCNCC1
Reactant: C=Cc1ccc([N+](=O)[O-])c(OCC)c1
Solvent: CC(C)O
Product: CCOc1cc(CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 87.6 %

Procedure:
To 5-ethenyl-2-nitrophenyl ethyl ether (0.53 g, 2.74 mmol) in 10 mL of iPrOH was added, 1-methylpiperazine (0.41 g, 4.11 mmol). The mixture was heated to 120° C. for 2 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step C (0.708 g, 2.4 mmol, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (d, J=8.42 Hz, 1H), 6.90 (d, J=1.47 Hz, 1H), 6.82 (dd, J=8.42, 1.47 Hz, 1H), 4.15 (q, J=6.96 Hz, 2H), 2.78-2.83 (m, 2H), 2.33-2.88 (m, 10H), 2.30 (s, 3H), 1.46 (t, J=6.96 Hz, 3H).
Reaction SMILES: Cl.C([N:9]1[C:13]([C:14]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=[CH:10]1)C1C=CC=CC=1>C(O)C.[H][H].[Pd]>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:14]([C:13]2[N:9]=[CH:10][NH:11][CH:12]=2)[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:29][CH:28]=1)#[N:31]
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=CCCc2ccccc2)c2cncn2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(C(CCCc2ccccc2)c2c[nH]cn2)cc1

Procedure:
1-benzyl-5-[1-(4-cyanophenyl)-4-phenyl-1-butenyl]-1H-imidazole hydrochloride (1,77 g) is dissolved in ethanol and a catalytic amount of 10% Pd/C is added. The reaction mixture is agitated vigorously at room temperature in hydrogen atmosphere until the reduction of the double bond and the debenzylation are complete. The reaction mixture is filtered and evaporated to dryness. The product is purified by flash chromatography.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)OCC)C.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O>>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Product: O=[N+]([O-])c1ccc(C=Cc2cccc(F)c2)cc1
Yield: 82 %

Procedure:
Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 3-fluoro-benzaldehyde. Yellow solid. Yield=82%. MS: m/e=243.0 (M+).
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([Cl:11])=[N:8][CH:7]=1)=[O:5])C.[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[O:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:4]([C:6]2[S:10][C:9]([Cl:11])=[N:8][CH:7]=2)=[O:5])[CH2:14][CH2:15]1
Reactant: CCOC(=O)c1cnc(Cl)s1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1cnc(Cl)s1
Yield: 73 %

Procedure:
As described for example 135a, 2-chloro-thiazole-5-carboxylic acid ethyl ester (500 mg, 2.6 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (471 mg, 73%) which was obtained as a white solid after purification by chromatography (silica, 0 to 3% methanol in dichloromethane). MS: m/e=247.3 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][C:12](=O)[CH2:11][NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)C(Cc2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: c1ccc(CC2CNCCN2)cc1
Temperature: 0 °C

Procedure:
To a suspension of 3-benzyl-piperazine-2,5-dione (14.98 g, 73 mmol, prepared following generally the procedure of Halpern and Westley, J. Org. Chem. 1968, 33, 864) in dry diethyl ether (500 mL) is added dropwise to a solution of lithium aluminum hydride (400 mL of a 1 M solution in diethyl ether, 400 mmol, 5.4 eq). The suspension is heated at reflux for 23 hours and then cooled to 0° C. Water (70 mL) is then cautiously added and the resulting suspension is warmed to room temperature. After 3 hours the suspension is filtered and the solid washed with diethyl ether (1 L). The filtrate is concentrated under vacuum to provide crude title compound (11.40 g, 88%) as a yellow, crystalline solid. A sample (2 g) is recrystallized from cyclohexane and then from toluene to provide the purified title compound (0.83 g) as a fine, white crystals: mp 80-81° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:46])[N:16]2[CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH2:35][C:36]3[N:41]=[CH:40][C:39]4[O:42][CH2:43][CH2:44][O:45][C:38]=4[CH:37]=3)C(=O)OC(C)(C)C)[CH2:23][CH2:22]2)=[N:11][CH:10]=1)=O)(C)(C)C.Cl.C(OCC)(=O)C>CO>[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:46])[N:16]2[CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([NH:27][CH2:35][C:36]3[N:41]=[CH:40][C:39]4[O:42][CH2:43][CH2:44][O:45][C:38]=4[CH:37]=3)[CH2:25][CH2:26]2)=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Reaction time: 18 h
Yield: 68.5 %

Procedure:
To a solution of 0.66 g of tert-butyl (1-(2-(7-((tert-butoxycarbonyl)amino)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate in 8 mL of methanol, 8 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, the mixture was stirred for 18 hours, and then the solid was filtered off. Subsequently, the solid was suspended in 3 mL of chloroform, thereto was added 6 mL of trifluoroacetic acid at room temperature, the mixture was stirred for 2 hours, and the solvent was then distilled off under reduced pressure. The residue was charged with chloroform and water and adjusted to pH 9 with a 2 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The aqueous layer was extracted with chloroform three times and combined with the organic layer, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.31 g of 7-amino-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one as a white foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([CH2:10][NH:11][C@@H:12]([CH3:31])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23]CC4C=CC=CC=4)[CH:21]=3)[NH:16][CH:15]=2)[OH:9])=[CH:4][CH:3]=1.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([CH2:10][NH:11][C@@H:12]([CH3:31])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[NH:16][CH:15]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](Cc1c[nH]c2ccc(OCc3ccccc3)cc12)NC[C@H](O)c1ccc(N)nc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: C[C@@H](Cc1c[nH]c2ccc(O)cc12)NC[C@H](O)c1ccc(N)nc1
Yield: 46.2 %

Procedure:
A solution of (R)-6-Amino-α-[[(1(S)-methyl-2-(5-benzyloxy-1H-indol-3-yl)ethyl)amino]methyl]-3-pyridinemethanol (619 mg) in 47 ml of absolute ethanol containing 7.9 g of cyclohexene and 198 mg of 10% Pd/C was heated at reflux under nitrogen for 3 hours. The reaction mixture was filtered and concentrated to dryness (510 mg). This residue was purified twice by preparative TLC (85:15:0.5 CH2Cl2 :MeOH:NH4OH) to give 224 mg of (R)-6-Amino-α-[[(1(S)-methyl-2-(5-hydroxy-1H-indol-3-yl)ethyl)amino]methyl]-3-pyridinemethanol.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[N:30]=[CH:31][C:32]([SH:35])=[N:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu](I)I>[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[N:30]=[CH:31][C:32]([S:35][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:4]([CH3:23])[CH:3]=2)=[N:33][CH:34]=1
Reactant: COCCOc1cnc(S)cn1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cnc(Sc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 100 °C
Reaction time: 7 h
Yield: 58.8 %

Procedure:
A mixture of 25-1 (3.00 g, 6.89 mmol), 5-(2-methoxyethoxy)pyrazine-2-thiol (27-2, 2.57 g, 13.8 mmol), copper iodide (66.0 mg, 0.35 mmol), and potassium carbonate (2.86 g, 20.7 mmol) in 13.8 mL of DMF was stirred at 100° C. for 7.0 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (EtOAc:hexnaes=2:1 as eluant) to give N-(4-{4-(5-(2-methoxyethoxy)pyrazin-2-ylthio)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (27, 2.00 g) as light yellow solids in 59% yield: 1H NMR (500 MHz, CDCl3) δ 8.75 (d, J=4.0 Hz, 2 H), 8.19 (d, J=1.0 Hz, 1 H), 8.00 (d, J=1.0 Hz, 1H), 7.63 (d, J=5.0 Hz, 2 H), 6.96 (s, 1 H), 6.79 (s, 2 H), 4.44 (t, J=4.5 Hz, 2 H), 3.72 (t, J=4.5 Hz, 2 H), 3.41 (s, 3 H), 1.95 (s, 6 H). ESI-MS: m/z 494.2 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:26]1[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=1>>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([NH:22][C:26]4[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=4)[CH:17]=3)[CH2:12][CH2:11]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cc(N2CCN(CCCN3CCOCC3)CC2)ncn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(CCCN4CCOCC4)CC3)ncn2)s1

Procedure:
6-[4-(3-Morpholin-4-ylpropyl)piperazin-1-yl]pyrimidin-4-amine 10-2 (0.317 g, 1.04 mmol), sodium hydride (0.083 g, 2.08 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.15 g, 1.04 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column and isolated via lyophilization. Hi-Res MS: calc: 415.2023 found: 415.2030. 1NMR (CD3OD): 8.48 ppm (s, 1H); 8.02 ppm (s, 1H); 6.27 ppm (s, 1H); 3.94 ppm (m, 6H); 3.43–3.27 ppm (m, 14H); 2.29 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:40])[CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][C@H:9]([O:25][C:26](=[O:38])[CH2:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33](Cl)=[N:32][CH:31]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[C:12]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH:11]=1.[CH3:41][NH:42][CH3:43]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:40])[CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][C@@H:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:18])[F:19])=[C:12]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH:11]=1)[O:25][C:26](=[O:38])[CH2:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([N:42]([CH3:43])[CH3:41])=[N:32][CH:31]=1
Reactant: O=C(COC(=O)c1ccc(Cl)nc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cn1
Yield: 88 %

Procedure:
A solution of (S)-3,5-dichloro-4-(2-(2-(6-chloronicotinoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide (202 mg, 0.327 mmol) and dimethylamine (327 μl, 0.654 mmol) in dry THF (5 ml) was stirred at room temperature for 2 days. The solvent was evaporated and the residue was portioned between sat. sol. NaHCO3 and ethyl acetate; the organic phase was washed with brine, dried over Na2SO4, filtered and evaporated and the residue was triturated with iPr2O, filtered and dried under vacuum to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(dimethylamino)nicotinoyloxy)acetoxy)-ethyl)pyridine 1-oxide as a white solid (180 mg, 0.287 mmol, 88% yield, LC-MS purity (BPI): 98%, MS/ESI+ 626.24 [MH]+, [αD]=−37.04, c=0.50, DCM).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[C:19]#[CH:20])[CH3:16].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]([C:20]#[C:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])=[CH:7][N:6]=1
Reactant: C#CC(OCC)OCC
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(C#Cc1cnc(Cl)nc1NC(CC)CC)OCC
Temperature: 55 °C
Yield: 37.2 %

Procedure:
To a mixture of (5-Bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (420 mg, 1.5 mmol) and propiolaldehyde diethyl acetal (0.32 mL, 2.25 mmol) in DMF (6 mL) is added PdCl2(PPh3)2 (105 mg, 0.15 mmol) and CuI (28 mg, 0.15 mmol), followed by Et3N (0.42 mL, 3 mmol). The mixture is degassed and heated at 55° C. for 16 h. Then the mixture is cooled down to room temperature, diluted with EtOAc, washed with water and brine. The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, EtOAc:Heptane=5:95 to 40:60) to give 182 mg of the title compound as a light brown oil.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[SH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:11][S:10][C:2]1[NH:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2cnccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2cnccc2[nH]1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of 1H-imidazo[4,5-c]pyridine-2-thiol (4 g) in acetone (50 mL) were added potassium carbonate (11 g) and MeI (1.8 mL). After stirring for 3 h, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-70% EtOAc in hexane) to give 2-(methylsulfanyl)-1H-imidazo[4,5-c]pyridine (4.07 g) as a yellow solid.