Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2][C:3]1([CH3:10])[C:7]([CH3:9])([CH3:8])[O:6][BH:5][O:4]1.Br[CH2:12][C:13]([CH3:15])=[CH2:14].Cl>C1COCC1>[CH3:2][C:3]1([CH3:10])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([CH2:14][C:13]([CH3:15])=[CH2:12])[O:4]1
Reactant: C=C(C)CBr
Reactant: CC1(C)OBOC1(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C(C)CB1OC(C)(C)C(C)(C)O1

Procedure:
To a suspension of magnesium turning (1.139 g, 46.9 mmol) in THF (65.1 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.67 mL, 39.1 mmol) at room temperature under nitrogen. 3-bromo-2-methylprop-1-ene (3.97 mL, 39.1 mmol) was added slowly, after 30 min, more 3-bromo-2-methylprop-1-ene (3.97 mL, 39.1 mmol) was added, The reaction mixture was stirred at room temperature for 1 h. heptanes was added, followed by 1N HCl. The reaction mixture was then extracted by heptanes. The organic was washed by water and brine, dried and concentrated to yield 4,4,5,5-tetramethyl-2-(2-methylallyl)-1,3,2-dioxaborolane. The product was used in the next step without purification, 1H NMR (400 MHz, CDCl3) δ ppm 4.67 (d, J=6.7 Hz, 2H), 1.77 (s, 3H), 1.34-1.20 (m, 12H).
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][N:6]=[C:5](O)[C:4]1=[O:10])[CH3:2].P(Br)(Br)([Br:13])=O.C(=O)([O-])[O-].[Na+].[Na+].O>ClC(Cl)C>[Br:13][C:5]1[C:4](=[O:10])[N:3]([CH2:1][CH3:2])[CH:8]=[CH:7][N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCn1ccnc(O)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCn1ccnc(Br)c1=O
Temperature: 10 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
10.5 g (75 mM) of 1-ethyl-3-hydroxypyrazine-2(1H)-one and 23.1 g (80.5 mM) of phosphorous oxybromide in 75 ml of dichloroethane were refluxed under stirring for 2 h. The reaction mixture was then neutralized to pH 7-8 with a saturated aqueous solution of sodium carbonate, while maintaining the temperature at 10° C. The reaction mixture was then stirred at room temperature for 1 h. Water was added and the organic phase was extracted with dichloromethane. The combined organic layer was washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum. The compound was further purified by silica gel column chromatography, using dichloromethane as eluant, to give 6.1 g of 3-bromo-1-ethylpyrazin-2(1H)-one as a solid. Yield: 40.2%.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([C:15]1[N:20]2[N:21]=[C:22]([CH3:33])[C:23]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[CH3:32])=[C:19]2[N:18]=[C:17]([CH3:34])[C:16]=1[CH2:35][CH2:36][CH2:37][C:38](OCC)=[O:39])[CH2:12][CH2:13][CH3:14].C(OCC)(=O)C.O>CCCCCC.O1CCCC1>[CH2:11]([C:15]1[N:20]2[N:21]=[C:22]([CH3:33])[C:23]([C:24]3[C:25]([CH3:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=3[CH3:30])=[C:19]2[N:18]=[C:17]([CH3:34])[C:16]=1[CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1c(CCCC(=O)OCC)c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1c(CCCCO)c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn12
Reaction time: 0.5 h
Yield: 114.5 %

Procedure:
A 1.0M solution of diisobutylaluminium hydride in hexane was added dropwise into a solution of ethyl 4-(7-(butyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)butanoate (320 mg, 0.71 mmol) in tetrahydrofuran (10 mL) under nitrogen stream, followed by stirring for 30 minutes. After Celite was added, the mixture was treated by adding ethyl acetate and water dropwise, and the insoluble matters were filtered off. The solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated, to give the title compound (320 mg) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.Cl.[CH3:37]O>>[CH3:37][O:34][C:33](=[O:35])[CH2:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)CCc1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)CCc1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1

Procedure:
Into a 100 mL roundbottom flask is placed 3-{4-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl]phenyl}propionic Acid (Example 30 before reverse phase purification) (160 mg, 0.35 mmol), 20 mL of MeOH, and 1.5 mL of conc HCl solution. The mixture is refluxed 3 h, and solvent removed under reduced pressure. The product is partitioned between CH2Cl2 (20 mL) and saturated K2CO3 solution. The organic layer is collected and dried (MgSO4) and concentrated under vacuum. The title compound, 88.4 mg (54%), is crystallized from a concentrated CH2Cl2-Hexanes mixture.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]([O:29]C(C)(C)C)=[O:28])=[O:21])=[O:14].FC(F)(F)C(O)=O>ClCCl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]([OH:29])=[O:28])=[O:21])=[O:14]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCCCCN1C(=O)C=CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCCCCN1C(=O)C=CC1=O
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To a mixture of the tert-butyl ester 77 in dichloromethane (4 mL) was added trifluoroacetic acid (4 mL). After 40 min the reaction was determined to be complete by HPLC analysis. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in dichloromethane and concentrated a second time to give 37 mg (100%) of 78 as a white solid: 1H-NMR (400 MHz, CDCl3) δ 6.68 (s, 2H), 4.62 (m, 2H), 3.81 (m, 1H), 3.70 (m, 1H), 3.57 (m, 2H), 3.45 (m, 2H), 2.40-1.91 (m, 10H), 1.70-1.45 (m, 4H), 1.33 (m, 2H); MS (ES+) m/z 406.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:10][C:11]1([CH3:24])[NH:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C(OC(C)(C)C)=O>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]2([CH3:24])[CH3:10])=[N:3][CH:4]=1)#[N:7]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: N#Cc1ccc(Br)nc1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cn2)C(C)(C)C1
Yield: 43 %

Procedure:
This compound was synthesized from 6-bromonicotinonitrile and tert-butyl 3,3-dimethylpiperazine-1-carboxylate as described for example 43 step 1 (0.12 g, yield 43%). 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J=1.5 Hz, 1H), 7.59 (dd, J=9.0 Hz, J=2.2 Hz, 1H), 6.64 (d, J=9.0 Hz, 1H), 3.89-3.82 (m, 2H), 3.58-3.51 (m, 4H), 1.52 (s, 6H), 1.49 (s, 9H). MS (ESI) m/z: Calculated for C17H24N4O2: 316.19. found: 217.2 (M+H-Boc)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[Br:18][C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[C:9](\[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[O:17])/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)/C(=C/c1ccc(Br)cc1)C(=O)c1ccccc1O
Yield: 57.4 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (289 mg, 1.2 mmol), 4-bromobenzaldehyde (226 mg, 1.2 mmol), 20.0 mL benzene, piperidine (10 μL, 0.1 mmol) and glacial acetic acid (5.6 μL, 0.1 mmol), refluxed for 3 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 278 mg (57%) of clear crystals. mp=98-100° C.; IR (film) 2978.4; 1712.8; 1629.0; 1155.7 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.84 (bs, 1H); 7.78 (s, 1H); 7.52-7.48 (m, 2H); 7.43-7.21 (AA′BB′, 4H); 7.04 (d, J=7.0 Hz, 1H); 6.83 (t, J=7.3 Hz, 1H); 1.41 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 201.3, 163.5, 162.9, 140.8, 137.4, 132.5, 132.3, 131.9, 131.8, 131.6, 125.3, 120.0, 119.7, 118.7, 83.1, 28.1; LRMS (electrospray): Mass calculated for C20H19BrO4, [M]+, 402.1, 404.0. Found [M+23]+, 424.7, 426.8. An NOE difference experiment was conducted for this compound and a positive NOE was seen for the alkene proton when the tert-butyl signal was irradiated and a positive NOE was seen for the tert-butyl signal upon irradiation of the alkene proton. This compound was further characterized by X-ray crystal structure, see S56.
Reaction SMILES: O[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1
Reactant: Oc1cnc2cc(Cl)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nc(Cl)cnc2c1

Procedure:
45 g of 2-hydroxy-6-chloroquinoxaline are treated in a sulphonation flask with 100 ml of phosphorus oxychloride. The mixture is stirred at reflux temperature for 20 minutes. The excess phosphorus oxychloride is thereupon distilled off and the residue is treated with 500 ml of ice-water. The product obtained is filtered off and washed with water until it is neutral. By crystallization from ethanol/water there is obtained 2,6-dichloroquinoxaline of melting point 152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][OH:15].[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1.C(OCC)(=O)C>ClCCl.O>[C:16]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][OH:15])(=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc(N)c(OCCO)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(C)=O)c(OCCO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To methyl 4-amino-3-(2-hydroxyethoxy)benzoate (2.98 g, 0.0141 mol) dissolved in dichloromethane (200 mL) was added acetic anhydride (1.49 mL, 0.0156 mol) and pyridine (1.34 mL, 0.0156 mol). After stirring for 3 h at room temperature, thin-layer chromatographic analysis (SiO2, ethyl acetate) showed disappearance of the starting material along with the appearance of a new lower-running spot (Rf =03) indicating the reaction was complete. The reaction was poured into water (70 mL) and the organic layer washed three times with water (50 mL). The organic layer was concentrated and then dried in vacuo. Thin-layer chromatographic analysis (SiO2, ethyl acetate) showed formation of some material as a higher-running spot (Rf =0.8) in addition to the product. Methanol (50 mL) and a catalytic amount of sodium methoxide was added to the residue. After 1 h, thin-layer chromatographic analysis (SiO2, ethyl acetate) showed only the desired product. The solution was neutralized with H+ resin, filtered, and then concentrated. The residue was recrystallized from ethyl acetate to give 1.88 g (53%) of methyl 4-acetylamino-3-(2-hydroxyethoxy)benzoate as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[O:15][C:10]3=[C:9](O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=[C:11]2[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[O:15][C:10]=12
Reactant: Oc1cc(-c2ccccc2)nc2c1oc1ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccccc2)nc2c1oc1ccccc12
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
1D (53.6 mmol) was added to POCl3 (90 mL), heated to dissolve and stirred at 110° C. for 2.5 hours. TLC showed the reaction completed. POCl3 was evaporated under reduced pressure. The residue was cooled and poured into ice-water under stirring. The solids were collected by filtration and dried to give the desired product M1 (11.5 g).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:39][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(C(F)(F)F)cc1)N1CCN(C2CCC2)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (49%).
Reaction SMILES: [C:1]([C:3]1([NH:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[ClH:15].C([OH:20])CCC>>[ClH:15].[CH2:10]([C:9]1[NH:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[C:1](=[O:20])[N:2]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCO
Reactant: CCCCC(=O)NC1(C#N)CCCC1
Agent: Cl
Product: CCCCC1=NC(=O)C2(CCCC2)N1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
6.88 g (30 mmol) of N-(1-cyanocyclopentyl)pentanamide (content 84.7 percent), 16.66 g of dried butanol and 10.06 g (39 mmol) of a freshly-prepared 14.13 percent solution of hydrogen chloride in butanol were heated to the reflux point (preheated oil bath) under nitrogen, with stirring, and product precipitated out as soon as the internal temperature reached ca. 100° C. After 2.9 hours of reflux (115° C.), the mixture was cooled to 1° C. and left to stand for 1 hour at this temperature. The product which had precipitated out was filtered off, washed with 10 ml of ice-cold butanol and dried at 40° C./24 mbar. The yield of the product was 4.93 g (66 percent), content 92.7 percent (HPLC).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C(=O)C)[C:14]4=[CH:15][CH:16]=3)[O:11][CH2:10][C:9]=2[CH:26]=1)(=O)C.C1C(=O)N([Br:34])C(=O)C1>CN(C=O)C>[Br:34][C:15]1[C:14]2=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=[C:13]2[C:12]2[O:11][CH2:10][C:9]3[CH:26]=[C:5]([OH:4])[CH:6]=[CH:7][C:8]=3[C:17]=2[CH:16]=1
Reactant: CC(=O)Oc1ccc2c(c1)COc1c-2ccc2c(OC(C)=O)cccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)COc1c-2cc(Br)c2c(O)cccc12

Procedure:
The title compound was prepared by reacting 1-(Acetyloxy)-6H-dibenzo[c,h]chromen-8-yl acetate (510 mg, 1.46 mmol), NBS (315 mg, 1.77 mmol), and anhydrous DMF (30 ml) at room temperature for 1.5 hours according to method B. The reaction was concentrated under reduced pressure, dissolved in MeOH (30 ml), and NH3 was bubbled in for 1.5 h while acetate removal was monitored by LC-MS. The reaction was concentrated to a dark sludge and purified by silica chromatography (1:1 EtOAc:hexanes) to afford 340 mg (68%) of product as a tan solid. Mp: decomposes above 130° C.; 1H NMR (500 MHz, DMSO-d6) δ 5.23 (2H, s), 6.72 (1H, d, J=1.9 Hz), 6.81 (1H, dd, J=8.2 Hz, 2.5 Hz), 6.92 (1H, dd, J=7.7 Hz, 1.1 Hz), 7.33 (1H, t, J=8.0 Hz), 7.64 (1H, dd, J=8.5 Hz, 1.1 Hz), 7.68 (1H, d, J=8.5 Hz), 8.01 (1H, s), 9.78 (1H, s), 10.15 (1H, s); MS m/z341/343 (Br pattern) (M−H+).
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3].CC([NH:33][C@@H]1C2C(=CC=C(OC)C(C=2)=O)C2C(OC)=C(OC)C(OC)=CC=2CC1)=O.CSC.[Na].CC(CC(C1C(O)=CC(O)=C(CC=C(C)C)C=1[O-])=O)C.[O-]CC.[Na+]>CO>[CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:12]([O:24][CH3:25])=[C:11]([O:26][CH3:27])[C:10]([O:28][CH3:29])=[CH:9][C:8]=2[CH2:7][CH2:6]1)=[O:3].[NH3:33]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC)c(=O)cc1C(NC(C)=O)CC2
Agent: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Agent: CC[O-]
Agent: COc1cc2c(c(OC)c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Solvent: CSC
Solvent: CO
Product: N

Procedure:
FIG. 6 illustrates how alternative colchine derivatives were prepared. For example, thiocholcine (compound IX) was prepared by reacting colchicine with sodium methyl sulfide (Velluz). Another colchicine derivative, 10-demethoxy-10-ethoxycolchicine (compound X) can be prepared by reacting colchicine with sodium ethoxide to generate 10-demethoxy-10-ethoxycolchicine. Colchicinamide (compound XI) can be formed by reaction of colchicine with ammonia in methanol (Lettre). Colchicinamide can be further reacted with ethyliodide to generate 10-demethoxy-10-ethylaminocolchicine (compound XII) (Bishop). Alternatively, 10-demethoxy-10-ethylaminocolchicine (compound XII) can be prepared directly from colchicine by reaction with ethylamine (Lettre).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[N:10]1([C:16]2[C:17]3[C:24]([C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=4)[C:28]#[N:29])=[CH:23][N:22]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C.O>[OH:3][N:2]=[C:28]([C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([C:24]2[C:17]3[C:16]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[N:21][CH:20]=[N:19][C:18]=3[N:22]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:23]=2)[CH:26]=1)[NH2:29]
Reactant: NO
Reactant: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C(N)=NO)c2)c2c(N3CCOCC3)ncnc21

Procedure:
Hydroxylamine hydrochloride (278 mg, 4.00 mmol) and sodium carbonate (318 mg, 3.00 mmol) were added to a stirred solution of 3-[4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (C34) (436 mg, 1.00 mmol) in ethanol (10 mL) and water (5 mL). The reaction mixture was heated at reflux for 2 hours, then concentrated in vacuo, poured into water (25 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated, affording the product as a white solid. Yield: 280 mg, 0.60 mmol, 60%. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.43 (s, 1H), 7.89 (br s, 1H), 7.72 (s, 1H), 7.64 (br d, J=7.8 Hz, 1H), 7.53 (br d, J=7.8 Hz, 1H), 7.46 (dd, J=7.6, 7.6 Hz, 1H), 5.89 (br s, ˜1.6H), 5.61 (s, 2H), 3.53-3.61 (m, 2H), 3.39-3.47 (m, 4H), 3.13-3.21 (m, 4H), 0.81-0.88 (m, 2H), −0.09 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]1([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH2:24][C:25]1[C:26]2[CH:39]=[C:38]([C:40]([NH:42][N:43]([CH3:50])[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[S:37][C:27]=2[N:28](C(OC(C)(C)C)=O)[N:29]=1>O1CCCC1>[CH3:50][N:43]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:42][C:40]([C:38]1[S:37][C:27]2[NH:28][N:29]=[C:25]([NH:24][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([CH2:14][N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[CH:16][CH:17]=3)[C:26]=2[CH:39]=1)=[O:41]
Reactant: CN(NC(=O)c1cc2c(N)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: O=C(Cl)c1ccc(CN2CCOCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCOCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
193 mg (1.39 mmol) of potassium carbonate, followed by 240 mg (0.87 mmol) of 4-morpholin-4-ylmethylbenzoyl chloride hydrochloride, are added to a solution of 0.27 g (0.70 mmol) of tert-butyl 3-amino-5-(N′-methyl-N′-phenylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 20 mL of tetrahydrofuran under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 2 hours, and then refluxed for 4 hours. The reaction mixture is then cooled to a temperature in the region of 25° C., and then treated with 40 mL of ice-cold water. The mixture is extracted successively with 60 mL, and then with twice 40 mL of ethyl acetate. The organic phases are combined, washed twice with 40 mL of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography on a cartridge of 25 g of silica gel (0.015-0.040 mm), eluting successively with pure dichloromethane, and then with dichloromethane/methanol mixtures (99/1 by volume, and then 98.5/1.5, 98/2 and finally 97/3) at a flow rate of 10 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 30° C. 0.1 g of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-morpholin-4-ylmethylbenzamide is thus obtained in the form of an off-white solid melting at 190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[C:19]([O:23][C:24](=[O:27])[CH2:25][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cl)c(OCC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Methyl 4-chloro-3-hydroxybenzoate [Chem. Pharm. Bull. 1994, 42(11),2365-9] (0.73 g), caesium carbonate (1.27 g) and tert butylbromoacetate (0.58 mL) in DMF (6 mL) were heated and stirred at 60° C. for 3 h. Water was added and the product was extracted into ethyl acetate. The extracts were dried over sodium sulphate, filtered and the solvent was evaporated. The resulting oil was purified by flash chromatography, using 1:10 ethyl acetate/isohexane as eluent, to yield the subtitle compound as a colourless oil (1.25 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:15][CH2:14][CH2:13][CH2:12][N:7]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:16])[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CN(CCCO)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
tert-Butyl(3-hydroxypropyl)(isobutyl)carbamate (0.73 g, 3.15), triethylamine (0.64 g, 6.30 mmol) and CH2Cl2 (30 mL) were added to a round-bottom flask. To the solution was added methanesulfonyl chloride (0.54 g, 4.72 mmol) and the reaction mixture was stirred for 5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (hexanes/EtOAC) to afford the desired product (0.63 g, 64%) as a yellow oil.