Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Br[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][O:23][CH2:25][C:26]([OH:28])=[O:27])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCO)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCOCC(=O)O)cc2)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)ethanol (80 mg, 0.259 mmol) and tert-butyl 2-bromoacetate (605 mg, 3.10 mmol) in CHCl3 (3 mL) was added 2M Na2CO3 (1.939 mL, 3.88 mmol). The mixture was stirred overnight at 55° C. The aqueous layer was separated, washed with DCM, and neutralized with 2M HCl. The aqueous mixture was then purified by HPLC. LCMS m/z=368.4 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[N:6]=1)=[O:4].[OH-].[K+:19]>CCO.CCOCC>[K+:19].[CH3:15][Si:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][O:11][CH2:10][N:7]1[CH:8]=[N:9][C:5]([C:3]([O-:4])=[O:2])=[N:6]1
Reactant: COC(=O)c1ncn(COCC[Si](C)(C)C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1cnc(C(=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylic acid methyl ester (as prepared in the previous step, 257 mg, 1.00 mmol) in EtOH (2 mL), 2 N KOH (0.5 mL, 1 mmol) was added. The resulting solution was stirred at RT for 20 min and concentrated in vacuo. The residue obtained was suspended in ether (10 mL) and sonicated for 5 min. The ether was then removed in vacuo and the resulting residue was dried for 4 hr to obtain 1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylic acid potassium salt (273 mg, 97%) which was directly used in the next step without any further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1>C(OC(=O)C)(=O)C>[Br:5][C:6]1[S:7][C:8]([N+:1]([O-:4])=[O:2])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])O
Reactant: Brc1cccs1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Nitric acid (24.00 g, 1.42 sp gr, 0.381 mol) in acetic anhydride (50 ml) at 0° C. was added dropwise to a cooled (0° C.) rapidly stirred solution of the compound of step 5.1 (24.77 g, 0.152 mol) in acetic anhydride (50 ml). At the end of the addition the stirring was continued for 0.5 hr and the mixture was refrigerated overnight. The mixture was poured into ice water (400 ml) and the precipitate was filtered off, dissolved in ether (2×200 ml), and washed with water until free of acid. The solvent was removed in vacuo and the residue was purified by column chromatography [silica gel/petroleum fraction (bp40-60° C.), dichloromethane, 5:1] and was recrystallised from ethanol/dimethoxyethane. 100:1 to give a pale yellow solid which was dried in vacuo (P2O5) to give 66% yield of 20.89 g.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][C:23]([O:25]C(C)C)=[O:24])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CO>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][C:23]([OH:25])=[O:24])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CC(=O)OC(C)C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.9 %

Procedure:
To a solution of isopropyl [4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (Reference Example 11; 861 mg, 1.75 mmol) in methanol (5 mL) was added 8N aqueous sodium hydroxide (1.5 mL), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, followed by neutralization with 6N hydrochloric acid. The mixture was concentrated in vacuo, and the residue was dissolved in methanol. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound (781 mg, 1.73 mmol, 99.1%) as an amorphous.
Reaction SMILES: C(OC([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)=O)C.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:12]([N:7]1[CH2:6][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-ethoxycarbonylpiperazine (4.6 g, 29.1 mmol) in dry methylene chloride (200 mL), was added benzoyl chloride (3.55 ml, 29.1 mmol) and triethylamine (2 ml) sequentially. After stirring for 8 hours at room temperature, a saturated NaHCO3 solution was added and the aqueous phase was extracted with ethyl acetate (3×200 ml). The organic layers were combined, dried over MgSO4 and concentrated to give a crude mixture, which included the desired product XXXIX. The crude was then used for the further reaction without purification.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:21]=2)[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:33]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][CH2:42]Br)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][CH2:42][N:16]1[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:31]=[CH:32][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:19]=2)[CH2:14][CH2:15]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCNCC3)c2)cc1
Product: CC(C)(C)OC(=O)NCCCN1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 73.4 %

Procedure:
Following the procedure of Example 11(e) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine 0.35 g (0.82 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (0.195 g, 0.82 mmol) were used to afford 0.35 g of the required product. NMR (DMSO-d6): δ 1.39 (9H, s), 1.52 (2H, m), 2.35 (8H, m), 2.95 (2H, m), 3.56 (2H, brs), 6.79 (1H, m), 6.90 (2H, d), 7.04 (1H, t), 7.25 (4H, d), 7.88 (4H, d).
Reaction SMILES: [CH2:1]([CH:5]([C:8](=O)[CH3:9])[CH:6]=O)[CH2:2][CH2:3][CH3:4].[Na].[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13].C([O-])(=O)C.C(O)(=O)C>O>[C:12]([C:14]1[C:15](=[O:16])[NH:17][C:8]([CH3:9])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)#[N:13]
Reactant: CCCCC(C=O)C(C)=O
Reactant: N#CCC(N)=O
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
According to the method described in J. Heterocyclic Chem., 24, 351 (1987), a mixture of crude sodium 2-butyl-3-oxobutanal (7.39 g), cyanoacetamide (4.15 g, 39 mmol), aqueous piperidinum acetate (3.5 mL) [prepared from glacial acetic acid (0.85 ml), water (2.0 mL) and piperidine (1.45 ml)] in water (32 mL) was refluxed for 3 hours. Acetic acid (2.5 mL) was cautiously added. After cooling to room temperature and stirring overnight, the precipitated solids were collected by filtration. These residues (2.87 g) was chromatographed on silica gel by gradient elution with 1-3% methanol/ethyl acetate. The appropriate fractions were combined and evaporated. Crystallization from methanol gave 1.01 g of pure product.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[C:8](Cl)(=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:8](=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of N,N-dimethyl-1,3-propanediamine (1.00 mL, 7.95 mmole) in methylene chloride (20 mL) was added palmitoyl chloride (2.19 g, 7.97 mmole). The reaction mixture was stirred at room temperature over night. The solvent was removed under reduced pressure and the residue titurated with diethyl ether. The precipitate (2.34 g) was filtered and stirred in saturated aqueous sodium bicarbonate over night. The precipitate was filtered to give the title compound (2.00 g, 74%) as a white solid. Analysis calculated for C21H43H2O 1.25H2O: C: 69.46; H: 12.91; N: 7.72. Found: C: 69.30 C: 9.46; H: 12.91; N: 7.72 Found: C: 69.30, H: 12.13; H: 12.13; N: 7.58.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[N+:10]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[F:23])=[O:15])([O-:12])=[O:11].I[CH2:25][C:26]([CH2:28]I)=[CH2:27]>CN(C)C=O>[CH2:25]=[C:26]1[CH2:28][C:13]([N+:10]([O-:12])=[O:11])=[C:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[O:15][CH2:27]1
Reactant: O=C(C[N+](=O)[O-])c1cc(F)ccc1F
Reactant: C=C(CI)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C1COC(c2cc(F)ccc2F)=C([N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
N,N-diisopropylethylamine (184 mL) was added to a solution of 2-nitro-1-(2,5-difluorophenyl)ethanone (92.7 g, 461 mmol) in N,N-dimethylformamide (1000 mL) and 3-iodo-2-(iodomethyl)prop-1-ene (156 g, 507 mmol). The mixture was heated at 60° C. for 2 h, evaporated and purified by chromatography (silica gel, gradient 0-30% dichloromethane in hexane) to yield 3-methylene-5-nitro-6-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:16]=[C:15]2[N:10]([C:11](=[O:21])[NH:12][C:13]3[CH2:20][CH2:19][NH:18][CH2:17][C:14]=32)[N:9]=1.[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC>[C:22]1([CH2:28][C:29]([N:18]2[CH2:19][CH2:20][C:13]3[NH:12][C:11](=[O:21])[N:10]4[N:9]=[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:16]=[C:15]4[C:14]=3[CH2:17]2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)nn13)CNCC2
Solvent: CCOCC
Product: O=C(Cc1ccccc1)N1CCc2[nH]c(=O)n3nc(-c4ccccc4F)nc3c2C1
Yield: 85 %

Procedure:
A mixture of 2-(2-fluorophenyl)-7,8,9,10-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)one (0.57 g, Example 15) and phenylacetylchloride (3 mL) is heated under nitrogen at 120° for 4 hours. The mixture is diluted with ether (30 mL) and the solid collected, washed with ether and air dried to afford pure 9-phenylacetyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)one, m.p. 310°-313°, in 85% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.Cl.[NH2:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[OH:28][C@@H:26]([CH3:27])[CH2:25][O:24][NH:23][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: C[C@H](O)CON
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](O)CONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (130 mg, 0.33 mmol) in THF (1.7 mL) was added (S)-1-aminooxy-propan-2-ol hydrochloride (84 mg, 0.66 mmol), DIPEA (0.23 mL, 1.32 mmol), HOBt (88 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol). After 18 hours stirring at ambient temperature, further (S)-1-aminooxy-propan-2-ol hydrochloride (84 mg, 0.66 mmol), DIPEA (0.23 mL, 1.32 mmol), HOBt (88 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) and THF (1.7 mL) were added. The reaction mixture was stirred at ambient temperature for a further 5 hours. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was then washed with methanol and the desired compound was eluted using a 2M solution of ammonia in methanol. Appropriate fractions were combined and concentrated under reduced pressure and the residue azeotroped with dichloromethane. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 10%, methanol in dichloromethane) to afford the title compound as a yellow solid (17 mg, 11%). LCMS (method A): RT=6.01 min, [M+H]+=471. 1H NMR (DMSO-d6): 8.07 (1 H, s), 7.58 (1 H, dd, J=10.71, 1.92 Hz), 7.43 (1 H, s), 7.38 (1 H, d, J=9.31 Hz), 7.31-7.28 (1 H, m), 6.89 (1 H, d, J=9.31 Hz), 6.35 (1 H, t, J=8.68 Hz), 3.69-3.60 (1 H, m), 3.45-3.38 (2 H, m), 0.96 (3 H, d, J=6.35 Hz).
Reaction SMILES: Cl.[N:2]1([C:7]2[N:12]=[C:11]([C:13]3[S:17][C:16]([NH:18]C(=O)C)=[N:15][C:14]=3[CH3:22])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1>C(O)C>[N:2]1([C:7]2[N:12]=[C:11]([C:13]3[S:17][C:16]([NH2:18])=[N:15][C:14]=3[CH3:22])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: CC(=O)Nc1nc(C)c(-c2cccc(-n3ccnc3)n2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1cccc(-n2ccnc2)n1
Reaction time: 18 h

Procedure:
Concentrated hydrochloric acid (0.3 ml) is added to N-[5-(6-imidazol-1-yl-pyridin-2-yl)-4-methyl-thiazol-2-yl]-acetamide (30 mg) in ethanol (2 ml) and heated at reflux for 3 hours and then stood for 18 hours at room temperature. The reaction mixture is evaporated and partitioned between aqueous sodium bicarbonate solution and 10% methanol in dichloromethane, extracting a further 4× with 10% methanol in dichloromethane. Evaporation of the combined organic layers gives the title compound which is used in Step. 60.1 without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][S:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([C:39]3([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)O1>>[OH:24][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:36]([C:39]3([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])[CH2:41][CH2:40]3)=[CH:37][CH:38]=2)=[CH:3][CH:4]=1)[CH2:15][S:16][C:17]1[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cccc(SCC(O)c2c(C)noc2-c2ccc(Br)cc2)c1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Product: Cc1cccc(SCC(O)c2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-m-tolylsulfanyl-ethanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: C([C:3]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#N.[N-:24]=[N+:25]=[N-:26].[Na+]>CS(C)=O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[NH:26][N:25]=[N:24][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2ccccn2)CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nn[nH]c2-c2ccccn2)CC1
Temperature: 110 °C

Procedure:
To a stirred solution of tert-butyl 4-(1-cyano-2-(pyridin-2-yl)vinyl)piperazine-1-carboxylate (2.5 g), sodium azide (0.4 g) were taken in dry DMSO (4 ml) and heated to 110° C. overnight. The reaction mixture was carefully quenched with water (10 ml) and the reaction mixture was extracted with dichloromethane (3×10 ml). The combined organic layer was washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using methanol:chloroform (1:9) as an eluent to afford tert-butyl 4-(5-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate as white solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[Si:24]([C:28]#[CH:29])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CN(C=O)C.[Cu]I.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>[F:1][C:2]1[CH:22]=[C:21]([C:29]#[C:28][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1
Reactant: O=C(NCCCO)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Yield: 94 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with TMS-acetylene in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-{2-fluoro-4-[(trimethylsilyl)ethynyl]anilino}-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as an off-white solid (94%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 11.48 (br s, 1H), 10.50 (s, 1H), 8.49 (t, J=5.4 Hz, 1H), 7.93 (s, 1H), 7.49 (t, J=8.5 Hz, 1H), 7.43 (dd, J=11.5, 1.8 Hz, 1H), 7.30 (dd, J=8.3, 1.5 Hz, 1H), 5.66 (s, 1H), 4.46 (t, J=5.1 Hz, 1H), 3.45 (q, J=5.9 Hz, 2H), 3.25 (q, J=6.5 Hz, 2H), 1.65 (pentet, J=6.7 Hz, 2H), 0.23 (s, 9H). HRMS (FAB+) calcd C20H25FN3O3Si (MH+) 402.1649, found 402.1649.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[C:24]3[C:23](=[N:25]O)[CH2:22][CH2:21][CH2:20][C:19]=3[NH:18][C:17]=2[CH3:27])=[CH:11][CH:10]=1.[I-].[Na+]>C(O)(=O)C.C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:25][C:5](=[O:7])[CH3:6])[NH:18][C:17]=2[CH3:27])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1[nH]c2c(c1Sc1ccc(Cl)cc1)C(=NO)CCC2
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c12
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
Acetic anhydride (1.1 mL, 11.6 mmol) was added to a stirred slurry of N-[-3-(4-chlorophenylsulfanyl)-2-methyl-4,5,6,7-tetrahydro-1H-indol-4-ylidene]hydroxylamine (3.0 g, 9.8 mmol) in a mixture of acetic acid (15 mL) and xylene (15 mL) at r.t. in reaction flask 1 (mildly exothermic addition) then the mixture was held with stirring for 45 mins. Meanwhile, reaction flask 2 was charged with acetic acid (7.5 mL), xylene (7.5 mL), acetic anhydride (1.1 mL, 11.6 mmol), and sodium iodide (70 mg, 0.47 mmol) and the mixture was heated to 110° C. with stirring. The contents of reaction flask 1 were transferred to reaction is flask 2 in aliquots over a period of 2 h, whilst maintaining the reaction temperature at 110° C. Reaction flask 1 was rinsed with a mixture of xylene (2 mL) and acetic acid (2 mL) which was transferred to reaction flask 2. Subsequently, the reaction mixture was maintained at 110° C. for a further 3 h then allowed to cool to r.t. and held overnight. The reaction mixture was evaporated to dryness in vacuo to leave a dark brown solid residue. This was purified by chromatography on silica gel, eluting with dichloromethane/ethyl acetate to provide the title compound as an off-white solid; 2.74 g (85%); purity 95.6 area % by HPLC; m/z: 331/333 (MH+); 1H-NMR: 11.84 (1H, s), 9.45 (1H, s), 7.45 (1H, d, J=7.7 Hz), 7.29 (2H, d, J=8.3 Hz), 7.17 (1H, d, J=8.0 Hz), 7.04 (1H, t, J=7.9 Hz), 6.98 (2H, d, J=8.2 Hz), 2.40 (3H, s), 1.84 (3H, s).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19]>CC1C=CC=CC=1>[CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:16]([O:17][CH2:18][CH3:19])=[O:20])[CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=O)C(C)C1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of 152 parts of 3-methyl-1-(phenylmethyl)-4-piperidinone in 900 parts of methylbenzene were added dropwise 218 parts of ethyl carbonochloridate at room temperature. Upon completion, stirring was continued overnight at reflux. After cooling, the reaction mixture was washed with water and hydrochloric acid, dried, filtered and evaporated. The residue was distilled, yielding 120.5 parts (83%) of ethyl 3-methyl-4-oxo-1-piperidinecarboxylate; bp. 98°-105° C. at 1 mm pressure (intermediate 26).
Reaction SMILES: C(O)C(N)(CO)C[OH:4].Cl.[CH2:10]1[C@H:14]([N:15]2[C:19]3[N:20]=[C:21]([NH2:25])[N:22]=[C:23](N)[C:18]=3[N:17]=[CH:16]2)[O:13][C@H:12]([CH2:26][OH:27])[C@H:11]1[OH:28]>>[C@@H:14]1([N:15]2[C:19]3[N:20]=[C:21]([NH2:25])[NH:22][C:23](=[O:4])[C:18]=3[N:17]=[CH:16]2)[O:13][C@H:12]([CH2:26][OH:27])[C@@H:11]([OH:28])[CH2:10]1
Reactant: NC(CO)(CO)CO
Reactant: Nc1nc(N)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Agent: Cl
Product: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Yield: 99 %

Procedure:
The washed cells described above were added to 50 mM Tris-HCl buffer (pH 7.2) containing 20.0 g/l 2,6-diaminopurine-2′-deoxyriboside to a concentration of 5 g/l and reacted at 30° C. for 3 hours while keeping pH at 7.2. The concentration of 2′-deoxyguanosine produced in the reaction solution was measured by high performance liquid chromatography. The result showed that the concentration was 19.8 g/l (conversion molar yield: 99%), respectively.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.[NH2:10][C@H:11]([CH3:14])[CH2:12][OH:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)Nc1nc(Cl)ncc1I
Yield: 88 %

Procedure:
In the reaction of 2,4-dichloro-5-iodopyrimidine (3.0 g, 10.9 mmol) with (R)-2-amino-1-propanol (884 mg, 11.8 mmol) according to procedure 2, the desired product is obtained in 88% yield (1.6 g) after chromatographic purification (silica gel, dichloromethane/methanol (0% to 20% methanol)).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]([CH3:14])[N:7]=1)[CH3:5]>CO>[CH2:4]([C:6]1[CH:11]=[C:10]([CH:9]=[C:8]([CH3:14])[N:7]=1)[C:12]([NH:2][OH:3])=[NH:13])[CH3:5]
Reactant: CCc1cc(C#N)cc(C)n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CCc1cc(C(=N)NO)cc(C)n1
Temperature: 0 °C
Yield: 105.7 %

Procedure:
To an ice-cooled solution of potassium tert.-butylate (7.11 g, 63.4 mmol) in methanol (50 mL), hydroxylamine hydrochloride (3.78 g, 54.4 mmol) is added. The suspension is stirred for 30 min before 2-ethyl-4-cyano-6-methyl-pyridine (2.65 g, 18.1 mmol) is added. The mixture is refluxed for 3 h before it is filtered. The filtrate is evaporated to dryness and the resulting solid is dissolved in water (30 mL) and extracted with EA (3×150 mL). The combined org. extracts are concentrated and dried under HV to give 2-ethyl-N-hydroxy-6-methyl-isonicotinamidine (3.43 g) as a white powder; LC-MS: tR=0.31 min, [M+1]+=180.07; 1H NMR (D6-DMSO) δ 1.22 (t, J=7.5 Hz, 3H), 2.44 (s, 3H), 2.71 (q, J=7.5 Hz, 2H), 5.89 (s, 2H), 7.31 (s, 2H), 9.87 (m, 1H).