Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[I-:10].CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.[Na+].O>CN(C=O)C>[I:10][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH3:8])[CH:2]=1
Reactant: [I-]
Reactant: Cc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.8 %

Procedure:
To a solution of 10 g of o-cresol and 16.5 g (1.2 equiv) NaI in 250 ml of DMF was added 31 g (1.2 equiv) of chloramine-T hydrate. The dark green solution was stirred at rt for 1.5 h. The mixture, now a heterogeneous light brown, was poured into water, acidified, extracted with ethyl acetate, and the organic phase washed with water and bisulfite solution. The organic phase was dried over MgSO4. Concentration, trituration with hexane, and flash chromatography (silica gel, hexane, hexane/ethyl acetate (5:1)) provided 13.6 g (63%) of the title compound as a white solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:11]=[C:12]([Br:16])[CH:13]=[CH:14][CH:15]=1.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1COCC1>[Br:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[C:11]=1[CH2:17][CH:18]([OH:20])[CH3:19]
Reactant: CC1CO1
Reactant: Clc1cccc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)Cc1c(Cl)cccc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LDA (6 mL, 12 mmol) in THF (10 mL) was added 3-chlorobromobenzene (1.91 g, 10.0 mmol) in THF (5 mL) at −78° C. under nitrogen, the resulting mixture was stirred at −78° C. for 1 h, then a solution of propylene oxide (1.7 g, 30 mmol) in THF (5 mL) was added. The mixture was slowly warmed to rt. The mixture was quenched with sat. aq NH4Cl (10 mL), then extracted with EtOAc (50 mL). The organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography Hexane/EtOAc (80:20) to give the title compound as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ=1.34 (d, J=6.1 Hz, 3H), 1.49 (d, J=5.8 Hz, 1H), 3.11-3.26 (m, 2H), 4.20-4.31 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 7.36 (dd, J=8.0, 1.1 Hz, 1H), 7.50 (dd, J=8.0, 1.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([NH:16][NH2:17])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]=1>C1(C)C=CC=CC=1>[C:5]1([C:8]2([C:14]3[N:27]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[N:17][N:16]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: NNC(=O)C1(c2ccc(Cl)cc2)CCCCC1
Reactant: COC1=NCCCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(C2(c3nnc4n3CCCCCC4)CCCCC2)cc1
Temperature: 120 °C

Procedure:
Anhydrous toluene was added to a mixture of 1-(4-chlorophenyl)cyclohexanecarbohydrazide (62 mg) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (40.1 mg). The reaction vessel was heated to 120° C. overnight, whereupon it was cooled to room temperature and the solvent was evaporated. The crude product was purified by column chromatography to give 3-(1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2-51) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:30])[N:9]3[CH2:13][C:12]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)(O)[C:11]=1[C:10]=23.C(N(S(F)(F)[F:37])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:30])[N:9]3[CH2:13][C:12]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)([F:37])[C:11]=1[C:10]=23
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CC2(F)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Yield: 33.4 %

Procedure:
A solution of 1,1-dimethylethyl {1-[(3-fluoro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (15.93 g, 38.1 mmol) in dichloromethane (320 ml) was cooled in an ice bath and treated with (diethylamino)sulphur trifluoride (10.1 ml, 75.9 mmol). After 2.5 hours at room temperature saturated aqueous sodium bicarbonate solution was added, then the phases separated. The aqueous phase was extracted twice more with dichloromethane and the combined organic extracts combined and evaporated. Chromatography eluting with a methanol in dichloromethane gradient afforded the product (5.35 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl.[OH-].[Na+]>[NH3:3].[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:17]2[CH2:18][CH2:19][N:14]([CH:11]([CH3:13])[CH3:12])[CH2:15][CH2:16]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)N1CCNCC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc(Cl)nc2)CC1
Product: N
Yield: 111.6 %
Yield: 2 %

Procedure:
To a solution of 6-chloronicotinic acid (0.985 g, 6.25 mmol) and 1-isopropyl-piperazine (1.50 g, 7.50 mmol) in DCM (100 mL) was added HOBt (1.20 g, 9.40 mmol), EDC (1.80 g, 9.40 mmol), and N-methyl morpholine (3.4 mL, 31.3 mmol). After 18 h the reaction was diluted with 1 N NaOH (50 mL) and extracted with DCM (3×50 mL). The organic extracts were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2: 2-4% 2 M NH3 in MeOH/DCM) gave the title compound as a solid (0.934 g, 56%).
Reaction SMILES: C(OC(=O)[N:10]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:27]2[C:28]([CH3:35])=[C:29]([CH2:31][O:32][CH2:33][CH3:34])[O:30][C:26]=2[CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH3:10].[CH2:33]([O:32][CH2:31][C:29]1[O:30][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:27]=2[C:28]=1[CH3:35])[CH3:34]
Reactant: [H][H]
Reactant: CCOCc1oc2cccc(OCCCN(Cc3cccnc3)C(=O)OCc3ccccc3)c2c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOCc1oc2cccc(OCCCNCc3cccnc3)c2c1C
Product: N
Temperature: 25 °C
Reaction time: 8 h
Yield: 130.6 %
Yield: 25 %

Procedure:
To a solution of [3-(2-ethoxymethyl-3-methyl-benzofuran-4-yloxy)-propyl]-pyridin-3-ylmethyl-carbamic acid benzyl ester (19 mg) in ethyl acetate (1 ml) was added 5% Pd on charcoal catalyst (10 mg) under N2. The nitrogen atmosphere was replaced by hydrogen (1 atom) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through a pad of celite and washed with methanol and dichloromethane. The filtrate combined was concentrated in vacuo. The residue was purified by preparative thin layer chromatography (using dichloromethane : MeOH : ammonia solution (25-28%)=10:1:0.2 as a developing solvent) to give [3-(2-ethoxymethyl-3-methyl-benzofuran-4-yloxy)-propyl]-pyridin-3-ylmethyl-amine (9 mg) as a colorless oil. ESI-MS: m/z 355 (MH+); 1H-NMR (CDCl3): δ 1.24 (3H, t, J=7 Hz), 2.06 (2H, quintet, J=6.5 Hz), 2.31 (3H, s), 2.89 (2H, t, J=7 Hz), 3.56 (2H, q, J=7 Hz), 3.85 (2H, s), 4.14 (2H, t, J=6 Hz), 4.54 (2H, s), 6.58 (1H, d, J=8 Hz), 7.04 (1H, d, J=8 Hz), 7.14 (1H, t, J=8 Hz), 7.21 (1H, dd, J1=8 Hz, J2=5 Hz), 7.68 (1H, dd, J1=8 Hz, J2=2 Hz), 8.49 (1H, dd, J1=5 Hz, J2=2 Hz), 8.57 (1H, d, J=2 Hz).
Reaction SMILES: [CH2:1]([C:9]1[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]#[CH:27])[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C:9]1[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]#[C:27][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Ic1ccccc1
Reactant: C#CCOCCn1c(CCCCCCCC)nc2cnc3ccccc3c21
Product: CCCCCCCCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.75 h
Yield: 71.7 %

Procedure:
Using the general method of Example 12 Part A, 2-octyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (4.84 g, 13.32 mmol) was reacted with iodobenzene (1.7 mL, 14.65 mmol) at 40° C. After 45 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil purified by chromatography over silica gel (98/2 (dichloromethane/methanol) to provide 4.2 g of 2-octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)[CH:4]=4)[CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (100 mg) and homopiperazine (17 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: C(O)(C)C.N12CCCNC1CCCC=C2.[CH3:16][C:17]1([CH3:29])[C:21]([CH3:23])([CH3:22])[O:20][B:19]([C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[O:18]1.[C:30]([CH:32]=[C:33]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)#[N:31]>CCCCCCC>[C:30]([CH2:32][C:33]1([N:27]2[CH:28]=[C:24]([B:19]3[O:20][C:21]([CH3:22])([CH3:23])[C:17]([CH3:29])([CH3:16])[O:18]3)[CH:25]=[N:26]2)[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)#[N:31]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: C1=CN2CCCNC2CCC1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a 1-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were sequentially added isopropanol (IPA, 200 mL), 1,8-diazabicyclo[5,4,0]undec-ene (DBU, 9.8 g, 64.4 mmol, 0.125 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 101 g, 520.51 mmol, 1.01 equiv) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 100 g, 514.85 mmol) at ambient temperature to generate a reaction mixture as a suspension. The resulting reaction mixture was heated to reflux in 30 minutes to provide a homogenous solution and the mixture was maintained at reflux for an additional 2-3 hours. After the reaction was complete as monitored by HPLC, n-heptane (400 mL) was gradually added to the reaction mixture in 45 minutes while maintaining the mixture at reflux. Solids were precipitated out during the n-heptane addition. Once n-heptane addition was complete, the mixture was gradually cooled to ambient temperature and stirred at ambient temperature for an additional 1 hour. The solids were collected by filtration, washed with n-heptane (200 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3, 181 g, 199.9 g theoretical, 90.5%) as a white to pale yellow solid. For 3: 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.74 (s, 1H), 4.45-4.23 (m, 2H), 4.23-4.03 (m, 2H), 3.56 (s, 2H), 1.38 (s, 9H), 1.25 (s, 12H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 155.34, 145.50, 135.88, 116.88, 107.08 (br), 83.15, 79.36, 58.74 (br), 56.28, 27.96, 26.59, 24.63 ppm; C19H29BN4O4 (MW 388.27), LCMS (EI) m/e 389 (M++H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.S(C)C.CO.Cl>C1COCC1>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:5][NH2:7])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1c(Br)cccc1C(N)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: Cc1c(Br)cccc1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
3-Bromo-2-methylbenzamide (1.4 g) was dissolved in dry THF (15 mL) under nitrogen, then Me2S.BH3 (94%, 1.34 mL) was added slowly. After stirred at room temperature for 1 h, the mixture was heated to 50° C. overnight. When 3-bromo-2-methylbenzamide disappeared, methanol was added dropwise until there was no more air bubble formed. Then 10 min later, 10% HCl was added dropwise, the mixture stirred for 1 h, and then solvent was removed. The white residual was recrystallized with iPrOH to obtain 1.1 g of the product. Yield: 35%. 1H NMR (400 MHz, DMSO-d6) δ 2.42 (s, 3H), 4.09 (s, 2H), 7.20 (t, J=7.8 Hz, 1H), 7.44 (d, J1=8.0 Hz, 1H), 7.63 (d, J1=7.6 Hz, 1H), 8.49 (br, 3H); 13C NMR (100 MHz, DMSO-d6) δ 18.8, 19.0, 46.1, 125.2, 127.4, 127.5, 129.0, 129.1, 132.1, 132.5, 134.7, 135.9, 136.1, 136.5; HPLC: retention time: 4.696 min; purity: 96.0%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[C:18]([F:29])[CH:17]=1.BrC1C=C2C(=CC=1)[C:37](=[O:41])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:41][CH3:37].[F:29][C:18]1[CH:17]=[C:16]([NH2:15])[CH:21]=[CH:20][C:19]=1[N:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]1
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2F)CC1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N)cc2F)CC1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 3.0 g (92.0% yield) of light brown solid is obtained from 2.0 g (7.09 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 1.63 g (7.8 mmol) of [3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amine and 25 mL of N,N-dimethylformamide: mp 206-207° C.; MS (ESI) m/z 459.0-461.0 (M+H)+1
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.Cl.[CH3:34][NH:35][OH:36]>ClCCl>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]([N:35]([OH:36])[CH3:34])=[O:18])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc(SCC(=O)O)cc1
Reactant: CNO
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1ccc(SCC(=O)N(C)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g of 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenylthio]-acetic acid in 75 ml of dichloromethane and 0.8 ml. triethylamine, is cooled in an ice bath. To this solution is added 0.5 ml of trimethylacetyl chloride and the solution is stirred at room temperature overnight. Triethylamine (2 ml) is added followed by 1 g of N-methylhydroxylamine hydrochloride and the mixture is kept at room temperature for 20 hours. The mixture is washed with 0.3 N aqueous hydrochloric acid, ice cold dilute sodium bicarbonate and brine. The organic phase is dried over MgSO4 and filtered. The solvent is evaporated at 50° at reduced pressure, the residue is dissolved in diethyl ether and the solutions filtered through 10 g of silica gel to yield 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)phenylthio]-N-hydroxy-N-methylacetamide; NMR (DMSO-d6 : δ7.1, 5.85, 3.25, 1.95.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:25])[C:21](OC)=[O:22])=[CH:16][CH:15]=1.[CH2:26]=[O:27].[O:28]1CCC[CH2:29]1>CCCCCC>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH3:25])([CH2:21][OH:22])[C:26]([O:28][CH3:29])=[O:27])=[CH:18][CH:19]=1
Reactant: C=O
Reactant: COC(=O)C(C)c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)(CO)c1ccc(Cl)cc1

Procedure:
35 ml of a 1.6 molaric solution of n-butyl lithium (61 mmol) in hexane were dropped to a solution of 8.1 ml (85 mmol) of diisopropylamine in 20 ml of tetrahydrofurane at −78° C. Subsequently, a solution of 10.0 g (50 mmol) of methyl 2-(4-chloro-phenyl)-propionate in 30 ml of tetrahydrofurane were dropped into the reaction mixture at −78° C. and subsequenty formaldehyde was introduced as gas at −20° C. within 30 minutes. The reaction mixture was extracted with ethyl acetate after addition of 5 percent citric acid and glacial acetic acid. The organic phase was washed with IN sulfuric acid, water, saturated sodium bicarbonate solution and sodium chloride solution and died over magnesium sulfate. The raw product was purified over silica gel whereby the eluation was carried out with cyclohexane/ethyl acetate (19:1; 9:1; 4:1; 1:1; and 0:1). The uniform fractions were combined and evaporated down.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C[OH:29]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24][CH2:25][CH2:26][OH:29])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: OCCO
Product: O=C(OCCO)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1

Procedure:
200 mg (0.6 mmol) of 1-benzyl-3-(5-ethoxycarbonyl-2-furyl)indazole were dissolved in ethylene glycol and heated under reflux for 1.5 h. For work-up, the mixture was concentrated using a rotary evaporator and the crude product was chromatographed over silica gel using hexane/ethyl acetate (1:1). This gave 68 mg (31%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]=[C:12]=[S:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16].O>CCOCC>[NH2:16][CH2:15][CH2:14][NH:17][C:12]([NH:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[S:13]
Reactant: NCCN
Reactant: COc1cc(N=C=S)cc(OC)c1
Solvent: O
Solvent: CCOCC
Product: COc1cc(NC(=S)NCCN)cc(OC)c1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A slurry of 9.75 g (0.05 mole) of 3,5-dimethoxyphenyl isothiocyanate in 27 ml of ether was added dropwise to a stirred solution of 3.0 g (0.05 mole) of ethylenediamine at room temperature. A five-degree rise in temperature was noted at the start of the one hour addition period. A solid appeared during the addition, and stirring was continued for 2.5 hours. The batch was allowed to stand overnight, and 100 ml of H2O was added. The solid was removed by filtration and the filtrate acidified with 4.5 ml of concentrated HCl and evaporated to dryness on the steam bath. The residue was sonicated with 100 ml of water and warmed to 50° C. for 10 minutes. This was filtered and basified to pH 10 with 10% NaOH. This gave 2.6 g of 14, m.p. 125°-126° C. Analysis satisfactory for C11H17N3O2S.
Reaction SMILES: P([O-])([O-])([O-])=O.[CH2:6]([C:8]1[S:20][C:11]2[N:12]([CH3:19])[C:13](=[O:18])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=2[C:9]=1[CH2:21][C:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([F:40])[CH:31]=2)[N:29]=1)=[O:23])[CH3:7].[P:41]([O:53][CH2:54]I)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].[H-].[Na+]>CN(C=O)C>[P:41]([O:53][CH2:54][N:29]1[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([F:40])[CH:31]=2)=[CH:27][S:26][C:25]1=[N:24][C:22](=[O:23])[CH2:21][C:9]1[C:10]2[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[S:20][C:8]=1[CH2:6][CH3:7])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:42]
Reactant: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Reactant: CCc1sc2c(c1CC(=O)Nc1nc(-c3ccc(C(F)(F)F)c(F)c3)cs1)c(=O)n(C)c(=O)n2C
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1sc2c(c1CC(=O)N=c1scc(-c3ccc(C(F)(F)F)c(F)c3)n1COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared according to the general procedure as described in method A for the preparation of phosphate derivatives by coupling reaction of 2-(6-Ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide (1.00 g, 1.901 mmol) with freshly prepared intermediate 2 (1.33 g, 3.802 mmol) in presence of sodium hydride (60% dispersion in mineral oil, 115 mg, 2.0851 mmol) in dry DMF (10 ml) to yield 1.15 g of pure product a pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 1.20-1.38 (m, 3H), 1.50 (s, 18H), 2.81 (q, J=7.8 Hz, 2H), 3.32 (s, 3H), 3.53 (s, 3H), 4.40 (s, 2H), 6.47 (d, J=7.2 Hz, 2H), 7.21-7.33 (m, 1H), 7.59-7.81 (m, 3H); ESI (m/z): 748.71 (M)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:24][NH:25][O:26][CH3:27].CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[C:3]([C:8]([N:25]([O:26][CH3:27])[CH3:24])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ncccc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ncccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a suspension of 3-fluoropicolinic acid (17.7 g) in THF (300 mL) was added CDI (22.4 g) at room temperature, and the mixture was stirred at room temperature for 30 min and heated to 50° C. After stirring at 50° C. for 1 h, the mixture was cooled to room temperature. To the mixture were added N,O-dimethylhydroxylamine hydrochloride (18.4 g) and DIPEA (32.9 mL) at room temperature, and the mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt) to give the title compound (21.8 g).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+]>CN(C=O)C.C(O)C.C(Cl)Cl>[OH:5][C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=1)=[CH:10][C:11](=[O:12])[CH:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccccc1)C=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of hydroxyl benzaldehyde in DMF was added K2CO3 (2 eq. each hydroxyl group) at 4° C. in an ice-bath and methyl chloromethyl ether (MOM chloride) (1.3 eq. each hydroxyl group). After the solution was stirred at room temperature and monitored by TLC for 3-5 hours, hexanes/dichloromethane (1:1) was added and allowed to stir for 30 min. The solid was filtered out and the filtrate was concentrated. The resulting residue was diluted with EtOAc and washed with H2O twice. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by a CombiFlash chromatography system using a Grace silica gel column and hexanes/ethyl acetate (as the eluent) to give MOM protected hydroxylbenzaldehyde. The resulting compound further reacted with excess acetone in ethanol catalyzed by 10% NaOH (1.2 eq. of NaOH). After stirred at room temperature and monitored by TLC for 1-5 hours, the reaction mixture was diluted with CH2Cl2, washed with H2O twice, and extracted with CH2Cl2 twice. The MOM protected hydroxy-phenyl-but-3-en-2-one was obtained after purification by a ConmbiFlash system using hexanes/ethyl acetate as the eluent. The resulting compound reacted with an appropriate MOM protected hydroxybenaldehyde to afford MOM protected hydroxyl 1,5-diphenyl-penta-1,4-dien-3-one, which was deprotected by heating in 50% acetic acid aqueous solution to afford the desired product.