Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][N:3]=[N:2]1.[CH2:10]([N:12]=[C:13]=[S:14])[CH3:11]>C(O)C>[CH2:10]([NH:12][C:13]([N:2]1[N:3]=[CH:4][C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1]1)=[S:14])[CH3:11]
Reactant: CCN=C=S
Reactant: C1CCC2(C1)CN=NC2
Solvent: CCO
Product: CCNC(=S)N1CC2(C=N1)CCCC2
Yield: 0.3 %

Procedure:
1.05 g (1 mol equiv.) 2,3-diaza-spiro[4.4]non-2-ene (synthesized as described in WO 2008/034863) and 0.95 mL (1.3 mol equiv.) ethyl isothiocyanate were added to 10 mL ethanol. The reaction mixture was refluxed for 2.5 hours under magnetic stirring. Silica gel was added and volatiles were removed in vacuo. The product was purified by flash chromatography on silica gel (Et2O:PA=1:2) and, after evaporation of the volatiles, stirred with diisopropylether and collected by filtration to yield 0.57 g (32%) of 2,3-diazaspiro[4.4]non-3-ene-2-carbothioic acid ethylamide. 1H NMR (400 MHz, CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 1.64-1.86 (m, 8H), 3.68 (dq, J=7.2, 5.5 Hz, 2H), 4.00 (s, 2H), 6.80 (s, 1H), 7.08-7.18 (br.s., 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:26])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:26][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:30]([CH:27]2[CH2:29][CH2:28]2)=[O:31])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the procedure as described in step-2 Intermediate-30 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one (0.500 g, 1.33 mmol), cyclopropylcarbonyl chloride (0.207 g, 1.99 mmol), DIPEA (2.0 mL) and THF (30 mL) to afford 0.300 g of crude product which was triturated with methanol:DEE to afford 0.300 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (s, 4H), 1.60 (m, 1H), 3.97 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.42-7.55 (m 3H), 7.70 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.69-8.71 (m, 1H), 12.83 (s, 1H); MS (m/z): 442.14 (M−H)−.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([O:26]CC)=O)=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[NH2:42][OH:43]>C(O)C.[OH-].[Na+]>[O:1]([C:8]1[N:13]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:43][N:42]=[C:24]([OH:26])[CH:23]=3)=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)C=Cc1ccc(OCc2cccc(Oc3ccccc3)n2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(-c2ccc(OCc3cccc(Oc4ccccc4)n3)cc2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(4-((6-phenoxypyridin-2-yl)methoxy)phenyl)prop-2-enoate (20.2 mg) in ethanol (1 ml), 0.05 ml of 50% aqueous hydroxylamine solution and 0.03 ml of 2N aqueous sodium hydroxide were added, and the reaction solution was stirred overnight at room temperature. The reaction solution was acidified with 10% aqueous citric acid, then extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., chloroform/methanol (8:1)) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:9][CH2:10][CH2:11][CH2:12][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(S)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(SCCCBr)cc1

Procedure:
4-Fluorothiophenol (5.3 ml), 1,3-dibromo-propane (15.3 ml), K2CO3 (14 g) were dissolved in CH3CN (100 ml) and refluxed for 3 h. The insoluble salts were removed, the solvent was evaporated and the residue dissolved in ethyl acetate (70 ml). The solution was extracted with diluted NaOH and water, dried and the solvent evaporated in vacuo. The residue was purified by distillation to yield 8 g of the title compound as a colourless oil. Bp. 150-155° C. @ 20 mmHg.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([S:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][N:13]=[CH:14]3)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[N:28]1([C:2]2[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([S:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][N:13]=[CH:14]4)[CH:7]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1Sc1cccc2cnccc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
According to the method in Example 10, a mixture of 5-(5-chloro-2-nitrophenylsulfanyl)isoquinoline 630 mg (2.0 mmol), DMF 5 ml, potassium carbonate 300 mg (2.2 mmol) and imidazole 140 mg (2.1 mmol) was stirred at 140° C. for 3 hours, and 5-[5-(1H-1-imidazolyl)-2-nitrophenylsulfanyl)isoquinoline 340 mg (49.0%) was obtained.
Reaction SMILES: [NH2:1]C(OCC)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][CH2:15][CH:16]1[CH2:20][O:19][C:18](=O)[O:17]1>CN(C)C=O>[CH3:13][O:14][CH2:15][CH:16]1[O:17][C:18](=[O:19])[NH:1][CH2:20]1
Reactant: CCOC(N)=O
Reactant: COCC1COC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC1CNC(=O)O1
Temperature: 140 °C
Reaction time: 100 h
Yield: 23.2 %

Procedure:
Urethane (10.0 g, 113 mmol) was dissolved in N,N-dimethylformamide (40 ml), and thereto were added potassium carbonate (20.8 g, 151 mmol) and 4-methoxymethyl-1,3-dioxolan-2-one (10.0 g, 75.7 mmol), in order. The mixture was stirred for 100 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by silica gel chromatography give the subject 5-methoxymethyloxazolidin-2-one (2.3g, yield 23.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1)=[O:10].[N:19]1([CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][CH2:25][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:30][CH:31]=2)[N:15]=[CH:14][N:13]=1)=[O:10]
Reactant: Nc1ccc(OCCCN2CCOCC2)cc1
Reactant: O=C(Nc1cc(Cl)ncn1)Nc1ccccc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(Nc1cc(Nc2ccc(OCCCN3CCOCC3)cc2)ncn1)Nc1ccccc1Cl
Temperature: 25 °C

Procedure:
A solution of 1-(2-chloro-phenyl)-3-(6-chloro-pyrimidin-4-yl)-urea (99 mg, 0.35 mmol), 4-(3-morpholin-4-yl-propoxy)-phenylamine [Chabrier et al. Bull. Soc. Chim. Fr. 1955; 1353] (83 mg, 0.35 mmol), and concentrated HCl (0.1 ml, 1.4 mmol) in ethanol (5 ml) was refluxed for 32 h. The reaction mixture is cooled to RT, and diluted with water. The acidic solution is washed with ethyl acetate, basified with aqueous ammoniac, and extracted with DCM. The combined organic phases are dried over sodium sulfate, evaporated in vacuo, the residue is crystallized from water/methanol/1 N HCl to afford the title compound.
Reaction SMILES: C([O:5][C:6]([N:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]1[N:20]([CH3:23])[CH2:21][CH2:22][C:13]21[CH3:24])[CH3:9])=O)(C)(C)C.[CH3:25][N:26]=C=O>ClCCl>[CH3:25][NH:26][C:6]([N:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]1[N:20]([CH3:23])[CH2:21][CH2:22][C:13]21[CH3:24])[CH3:9])=[O:5]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N(C)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
5-(t-Butoxycarbonyl-N-methylamino)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (100 mg) was heated under nitrogen without solvent to 200°-210° C. in an oil bath. After 1 hour, TLC (thin layer chromatography) indicated a conversion to a new compound. The flask was allowed to cool to ambient temperature and dichloromethane (5 ml) was added followed by the slow addition of a solution of methyl isocyanate (18 mg) in dichloromethane (3 ml) over a period of 45 minutes. The mixture was washed with water (2 ml), dried (Na2SO4), concentrated and purified by flash chromatography (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 5-(methylaminocarbonyl-N-methylamino)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (0.05 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:19](=O)[CH3:20])[C:15]([O:17][CH3:18])=[O:16].[NH2:22][C:23](=[CH:25][C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24]>C(O)C>[CH3:20][C:19]1[NH:22][C:23]([CH3:24])=[C:25]([C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(N)=CC(=O)CC(C)C
Reactant: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)CC(C)C)C1c1cccc2c(=O)cc(C)oc12

Procedure:
50 mg (0.175 mmol) of methyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 34.7 mg (0.227 mmol) of 2-amino-6-methylhept-2-en-4-one in 3 ml of ethanol and heated under reflux under argon for 24 h. The reaction mixture is purified by preparative HPLC. Concentration of the fractions results in 36 mg (43% of theory) of the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24]5[N:29]=[C:28]([NH2:30])[C:27]([N+:31]([O-])=O)=[CH:26][N:25]=5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.CO.[Pd]>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24]5[N:29]=[C:28]([NH2:30])[C:27]([NH2:31])=[CH:26][N:25]=5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1nc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cnc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)nc1N
Temperature: 25 °C
Reaction time: 28 h
Yield: 69.6 %

Procedure:
2-[1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidyl amino]-4-amino-5-nitropyrimidine (1.000 g, 2.3 mmol, prepared as described in Example 97), 0.2 weight equivalents of 10% Pd/C, and ammonium formate (1.000 g, 15.9 mmol) were combined in 20 mL 50% ethyl acetate/methanol and stirred under a nitrogen atmosphere at room temperature for 28 hours. The reaction mixture was filtered through celite and concentrated on a rotary evaporator to give the title compound as a tan glassy solid (0.643 g, 1.6 mmol, 69%), mp 138°-140°C.; MS(CI): 413 (M+H); NMR (250MHz, DMSO-d6): 7.29-7.18(m, 5H), 6.98-6.87(m, 4H), 6.33(s, 2H), 5.75-5.72(br m, 1H), 4.32(s, 1H), 3.56(br m, 1H), 3.36(br, m, 2H), 2.99-2.94(d, J=11.3Hz, 2H), 2.47(s, 2H), 2.32-2.23(m, 2H), 1.80-1.75(m, 2H), 1.41-1.37(m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][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:3][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:1]=1
Reactant: Sc1nc2c([nH]1)CCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2c([nH]1)CCCC2
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-benzimidazole-2-thiol (500 mg) in acetone (5 mL) were added K2CO3 (1344 mg) and MeI (0.223 mL) at room temperature. After stirring for 1 h, the mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine and dried over magnesium sulfate. The residue was purified by column chromatography (silica gel, eluted with 40%-90% EtOAc in hexane) to give 2-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-benzimidazole (545 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13](/[CH:14]=[CH:15]/B(O)O)=[CH:12][CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(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>[Cl:8][C:6]1[CH:7]=[C:2](/[CH:15]=[CH:14]/[C:13]2[CH:19]=[CH:20][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:3]=[CH:4][N:5]=1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(/C=C/c2cc(Cl)ncn2)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 24.4 %

Procedure:
A mixture of commercially available 4,6-dichloropyrimidine (300 mg, 2.01 mmol), (E)-4-chlorostyrylboronic acid (441 mg, 2.41 mmol), potassium phosphate (1282 mg, 6.04 mmol), and PalladiumTetrakis (116 mg, 0.10 mmol) in DMF (1 mL) was stirred under nitrogen at 40° C. for 2 days. The reaction was filtered, diluted with CH2Cl2, washed with water, brine, dried (MgSO4), and concentrated. The crude product was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 50:50 gradient) to afford the desired product (E)-4-chloro-6-(4-chlorostyryl)pyrimidine 20A (120 mg, 0.49 mmol, 23.73% yield) as a light yellow solid. LC/MS 252 (M+H)+, tR 1.07 min (method 5).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[CH:16][NH:15][C:14](=O)[CH:13]=1.N.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:14]1[CH:13]=[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][O:2][CH3:1])[N:17]=[CH:16][N:15]=1
Reactant: COCCOc1ccccc1-c1cc(=O)[nH]cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: COCCOc1ccccc1-c1cc(Cl)ncn1
Temperature: 5 °C

Procedure:
A stirred suspension of 6-[2-(2-methoxy-ethoxy)-phenyl]-3H-pyrimidin-4-one (0.2 g, 0.81 mmol) in POCl3 (2 mL) was heated at reflux for 1 h. The reaction mixture was cooled to about 5° C. and poured cautiously into 10 ml ice-water, ammonia (10 mL) was added and extracted with ethyl acetate (2×10 mL), organic layers were combined, washed with water (5 mL) then dried over anhydrous sodium sulfate and concentrated. The residue was triturated with hexane yielding 0.18 g (84%) 4-chloro-6-[2-(2-methoxy-ethoxy)-phenyl]-pyrimidine as white powder.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([NH2:35])[CH3:34]>>[CH3:34][C:33]1[N:35]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:30][N:32]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (about 0.153 mmol) of the compound from Example 108A and 22 mg (0.306 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 12 mg (17% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15]O)[O:13][CH:14]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][Cl:22])[O:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(COc2coc(CCl)cc2=O)cc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
5-p-Methoxybenzyloxy-2-hydroxymethyl-4-pyrone, 24 g, was dissolved in 120 ml of dry tetrahydrofuran. The solution was cooled to 5° C. and 15 ml of thionyl chloride was dropwise added to the solution over 30 minutes. The reaction solution was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction liquid was concentrated to approximately 20 ml and the concentrate was added to 50 ml of water and 100 ml of dichloromethane. Under ice cooling, the pH was adjusted to 7.0 with saturated sodium hydrogencarbonate aqueous solution and the organic phase was washed with 20 ml of water. After drying over anhydrous magnesium sulfate, the organic phase was concentrated under reduced pressure and crystallized with ethyl acetate-ether. The formed crystals were taken out by filtration and dried under reduced pressure to give 20 g of the title compound.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:28])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:33]([CH3:40])=[C:34]2[C:39]=1[O:38][CH2:37][CH2:36][CH2:35]2.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:28])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[CH:20]=2)[C:16]=1[C:32]1[C:33]([CH3:40])=[C:34]2[C:39](=[C:30]([F:29])[CH:31]=1)[O:38][CH2:37][CH2:36][CH2:35]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 115 °C
Yield: 48.9 %

Procedure:
To a 2-5 ml microwave tube was added methyl 2-(tert-butoxy)-2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (200 mg, 0.474 mmol), tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.047 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (180 mg, 0.616 mmol), DMF (3 mL), followed by 2M K2CO3 solution (300 μl). The reaction mixture was heated in a microwave reactor at 115° C. for 45 min. The reaction mixture was filtered and the filtrate was purified by silica gel chromatography to afford (128 mg, 48.9%) of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.82 (s, 1H), 7.76-7.65 (m, 1H), 7.41-7.29 (m, 2H), 7.01-6.73 (m, 2H), 5.02 (s, 1H), 4.37 (dt, J=6.5, 3.5 Hz, 2H), 3.66 (s, 3H), 2.93-2.69 (m, 5H), 2.21 (dd, J=5.6, 2.4 Hz, 2H), 1.86 (s, 3H), 1.18 (s, 9H).
Reaction SMILES: [O-:1][P:2]([O-:5])([O-:4])=[O:3].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[P:22](=O)(O)(O)[OH:23]>>[O:3]=[P:2]12[O:5][P:7]3([O:10][P:12]([O:15][P:22]([O:9]3)([O:4]1)=[O:23])(=[O:13])[O:1]2)=[O:8]
Reactant: O=P(O)(O)O
Reactant: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Agent: [F-]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3

Procedure:
continuously introducing into a pre-reactor (i) phosphate rock containing 66-75% tricalcium phosphate comminuted to a size such that 90% passes a 100-mesh screen and 70-80% passes a 200-mesh screen, (ii) phosphoric acid containing 38-54% P2O5 in an amount sufficient to provide a ratio of P2O5 to CaO in the reaction mixture of 0.7 to 1.0, and (iii) water in an amount sufficient to dilute the phosphoric acid to 38-44% P2O5,
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14]CC)=[O:13]>>[O:5]1[CH2:6][CH2:7][CH:2]([O:1][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[C:12]([OH:14])=[O:13])[CH2:3][CH2:4]1
Reactant: OC1CCOCC1
Reactant: CCOC(=O)c1cccc(O)c1
Product: O=C(O)c1cccc(OC2CCOCC2)c1

Procedure:
Prepared from 4-hydroxy-tetrahydropyrane and ethyl 3-hydroxybenzoate. LC-MS (m/z): 245 (M−23 (Na)).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing 2-nitrobenzoyl chloride (Fluka, Buchs, Switzerland) (1.97 mL, 15 mmol) and 4-dimethylaminopyridine (Fluka, Buchs, Switzerland) (10 mg) in dichloromethane (10 mL) is added to a stirred mixture of 4-aminobenzotrifluoride (Ruka, Buchs, Switzerland) (2.66 g, 16.5 mmol) and triethylamine (1.90 g, 18.8 mmol) in dichloromethane (100 mL) under an argon atmosphere and the mixture is stirred for 16 hours at 25° C. The stirred mixture is then treated with a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and then extracted with dichoromethane (2×50 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 10-50% ethyl acetate in hexane, to give the title compound as a colourless crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:13]([NH:21][C:22](=[S:23])[NH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(N)nc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(NC(=S)NC(=O)c2ccccc2)nc1
Yield: 82 %

Procedure:
A solution of ethyl 6-amino-nicotinate (830 mg, 5 mmol) and benzoyl isothiocyanate (830 mg, 5.1 mmol) in acetone was refluxed for 2 h. The mixture was concentrated to thin slurry and methanol was added. The solid was filtered, washed with methanol and dried to afford ethyl 6-(3-benzoyl-thioureido)-nicotinate (1.35 g, 82%). 1H NMR (CDCl3) δ 13.34 (s, 1 H), 9.04 (m, 3 H), 8.38 (s, 1 H), 7.93 (m, 2 H), 7.66 (m, 3 H), 4.42 (q, 2 H, J=7.6 Hz), 1.41(t, 3 H, J=7.6 Hz).