Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(=O)C.C1(C)C=CC(S([O:16][C:17]2[CH:22]=[C:21]([C:23]([CH3:30])([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:19][C:18]=2[NH2:48])(=O)=O)=CC=1.[O:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][C:57]=2[S:65](Cl)(=[O:67])=[O:66])[CH2:52][CH2:51]1.Cl>N1C=CC=CC=1>[O:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][C:57]=2[S:65]([NH:48][C:18]2[CH:19]=[C:20]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:21]([C:23]([CH3:29])([CH3:30])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][C:17]=2[OH:16])(=[O:66])=[O:67])[CH2:52][CH2:51]1
Reactant: CCCCCCCCCCCCCCCCOc1cc(N)c(OS(=O)(=O)c2ccc(C)cc2)cc1C(C)(C)CC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N2CCOCC2)c(O)cc1C(C)(C)CC(C)(C)C

Procedure:
To a solution of N,N-dimethylacetamide (200 ml) containing 20 g (0.0314 mol) of 2-amino-4-hexadecyloxy-5-(1,1,3,3-tetramethylbutyl)phenol paratoluene sulfonate and 12.7 ml of pyridine was added 10.6 g (0.0346 mol) of the compound obtained in Step (b) above with stirring while introducing a nitrogen gas and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to 500 ml of aqueous solution containing 15 ml of hydrochloric acid and the precipitate was extracted with ethyl acetate. The ethyl acetate was washed with water and concentrated. To the residue was added 100 ml of methanol and the crystals thus precipitated were collected by filtration. Yield: 22 g (94%).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.[C:22]([OH:26])(=[O:25])[CH:23]=[CH2:24]>ClCCl>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:24][CH2:23][C:22]([OH:26])=[O:25])[CH2:11][CH:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCNCC1OC
Reactant: C=CC(=O)O
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CCC(=O)O)CC1OC

Procedure:
A solution of 4-amino-5-chloro-2-methoxy-N-(3-methoxy-piperidin-4-yl)-benzamide (1 g, 3.2 mmol), and 241 μL of acrylic acid in 50 ml dichloromethane was stirred under nitrogen for 6 hr then concentrated in vacuo. The residue was slurried with hot ethyl acetate and filtered at room temperature to yield 1.15 g of product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])N=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)=[C:4]([O:37][CH3:38])[CH:3]=1.F[C:40](F)(F)C1C=C(C=C(C(F)(F)F)C=1)C(O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:31][CH2:32][S:33]([CH3:36])(=[O:34])=[O:35])[C:15](=[O:30])[C:16]2[CH:17]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:40]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=2)=[C:4]([O:37][CH3:38])[CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine (example 162, intermediate) and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) after a reaction time of 40 hours. The compound was purified by silica gel chromatography using a MPLC system (ISCO) and a 10 g and 5 g column, respectively, eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). A third chromatography, using preparative HPLC (Gemini NX column) eluting with a gradient of methanol:water (containing 0.05% formic acid) (20:80 to 98:2), yielded the product as a colorless solid (4%). MS (ESI): m/z=565.10 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.[NH3:31]>CO>[NH2:31][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Solvent: CO
Product: Nc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,5,6-Trichloro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)benzimidazole (42, 0.48 g; 1 mmole) was dissolved in dry MeOH (10 ml). Liq. NH3 (10 ml) was added and the mixture heated in a steel bomb at 100° C. for 2 hr. This mixture was stirred at room temperature for 24 hr. Excess NH3 was allowed to evaporate and the solution evaporated to dryness, absorbed onto silica gel (2 g), and chromatographed on a silica gel column using silica gel (20 g; 60-200 mesh). Elution of the column with CH2 Cl2 : CH3OH (96:4) gave the desired compound 44 as the major nucleoside. Evaporation of the solvent and crystallization of the residue from EtOH gave 44 (0.02 g; yield 6.06%). mp. 145° C.; UV Imax. (MeOH): 259 (7941) and 301 (8348) nm; Imax (pH1): 215 (26000) and 292 (7520) nm; Imax (pH11): 257 (7967) and 298 (7107) nm. 1H NMR(DMSO-d6): d 8.70 (s, 1H, C7 -H, 8.28(s,1H, C4 -H), 7.90 (bs,2H, D2O exchangeable, NH2), 6.75(d,C1'H, J1,2 =4.5 Hz) and the rest of the sugar protons.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][C:19]([Cl:22])=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:23]#[N:24])=[C:4](I)[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)O1>>[Cl:22][C:19]1[S:18][C:17]([NH:16][S:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=3[C:36]3[CH:37]=[N:38][NH:39][CH:40]=3)=[C:8]([C:23]#[N:24])[CH:9]=2)(=[O:15])=[O:14])=[N:21][CH:20]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(Cl)cc1I
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(Cl)cc1-c1cn[nH]c1

Procedure:
The title compound was prepared according to the same method as that used for Example 785 above using 4-(4-chloro-2-iodophenoxy)-N-(5-chloro-1,3-thiazol-2-yl)-3-cyanobenzenesulfonamide (Preparation 219) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials. Purification by preparative HPLC afforded the title compound. Yield 7.8 mg 17%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[Br-:11].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(=O)([O-])[O-].[Ca+2]>C(Cl)Cl.CO>[NH2:10][C:9]1[CH:8]=[C:7]([Br:11])[S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1sc(Br)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Methyl-3-amino-2-thiophene carboxylate (1 eq. 25 g) was dissolved in 250 ml methylene chloride and 250 ml of methanol. Phenyl trimethylammonium tribromide (3 eq. 180 g) was added followed by calcium carbonate (4 eq. 63.75 g) and the reaction was left stirring at room temperature overnight. The calcium carbonate was filtered off and the filtrate concentrated down and water (750 ml) was added followed by ethyl acetate (1 L). The ethyl acetate layer was washed with more water, sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography to yield 21.46 g (57%) of methyl 3-amino-5-bromothiophene-2-carboxylate as a light brown oil, MH+=238.1.
Reaction SMILES: S(=O)(=O)(O)O.[N+]([C:9]1[CH:10]=C(S(O)(=O)=O)C=C[CH:14]=1)([O-])=O.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[O:27][CH3:28].[OH-].[NH4+].Cl>O.[Cl-].[Zn+2].[Cl-].OCC(CO)O>[Cl:19][C:20]1[CH:26]=[C:25]2[C:23](=[CH:22][C:21]=1[O:27][CH3:28])[N:24]=[CH:10][CH:9]=[CH:14]2
Reactant: COc1cc(N)ccc1Cl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Solvent: OCC(O)CO
Product: COc1cc2ncccc2cc1Cl
Temperature: 75 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
A solution of sulfuric acid (35 mL) in water (35 mL) was treated with 3-nitrobenzenesulfonic acid (35.1 g, 159 mmol) and glycerol (80 ml, 1.1 mol) to give a thick grey suspension. The suspension was heated to 75° C. and 4-chloro-3-methoxyaniline (25.0 g, 159 mmol) was added. The mixture was stirred at 140° C. for 1 h. Additional quantities of water (35 mL), sulfuric acid (35 mL) and glycerol (40 mL) were added and the reaction was stirred an additional 2 h at 140° C. The solution was cooled to room temperature, poured onto ice, and the pH was adjusted to 13 by addition of concentrated ammonium hydroxide. The mixture was extracted with EtOAc (3×) and the extracts were washed with brine, dried over Na2SO4 and concentrated. Following the general procedure for quinoline purification described by Leir, C. M. J. Org. Chem., 1977, 42, 911, the residue was dissolved into 2 M HCl (500 mL) and zinc chloride (43.2 g, 317 mmol) was added, resulting in immediate formation of a precipitate. The mixture was stirred for 30 min. The solids were isolated by filtration, washing with cold 2 M HCl, 2-propanol, then water. The solids were added to concentrated ammonium hydroxide (400 mL) and the mixture was stirred for 10 min. EtOAc was added and the mixture was stirred for 5 min. The mixture was extracted with EtOAc (3×) and the extracts were washed with brine, dried over Na2SO4 and concentrated to a dark brown residue consisting of a mixture of the two possible cyclization regioisomers. Silica gel chromatography (15-100% gradient of EtOAc in DCM) provided 6-chloro-7-methoxyquinoline (7.03 g) as a beige solid. MS (M+1)=194.1, 1H NMR (400 MHz, Methanol-d 4) δ 8.78 (dd, J=4.5, 1.6 Hz, 1H), 8.24 (dd, J=8.4, 1.4 Hz, 1H), 8.01 (s, 1H), 7.47 (s, 1H), 7.43 (dd, J=8.3, 4.5 Hz, 1H), 4.06 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[CH:8]2.[Cl:20][C:21]1[C:29]2[NH:28][N:27]=[CH:26][C:25]=2[C:24]2[CH2:30][N:31]([CH2:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:32](=[O:55])[C@H:33]([CH2:35][C:36](=[O:54])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:34][C:23]=2[CH:22]=1>>[Cl:20][C:21]1[C:29]2[NH:28][N:27]=[CH:26][C:25]=2[C:24]2[CH2:30][N:31]([CH2:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:32](=[O:55])[C@H:33]([CH2:35][C:36]([N:17]3[CH2:18][CH2:19][CH:14]([C:9]4[C:10](=[O:13])[NH:11][C:12]5[C:7]([CH:8]=4)=[CH:6][CH:5]=[CH:4][C:3]=5[F:2])[CH2:15][CH2:16]3)=[O:54])[CH2:34][C:23]=2[CH:22]=1
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C1=O
Yield: 36 %

Procedure:
Title compound was prepared from 8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 36% yield. MS m/e (M+H)+=592.2. 1H NMR (500 MHz, DMSO-D6): δ=13.54 (s, 1H), 11.78 (s, 1H), 8.36 (s, 1H), 7.76 (d, J=5.19, 1H), 7.46 (d, J=7.93, 1H), 7.34 (dd, J1=10.53, J2=8.70, 1H), 7.24 (s, 1H), 7.14 (m, 1H), 5.36 (d, J=16.48, 1H), 4.63 (d, J=17.40, 1H), 4.55 (d, J=11.29, 1H), 4.12 (m, 1H), 3.87 (m, 1H), 3.58 (d, J=13.12, 1H), 3.17 (m, 1H), 3.05 (m, 4H), 2.88 (m, 1H), 2.65 (m, 1H), 2.34 (d, J=15.87 1H), 1.92 (d, J=12.51, 1H), 1.84 (d, J=11.29, 1H), 1.57 (m, 1H), 1.40 (m, 1H), 0.72 (s, 9H).
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=S)[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:9]=2[CH:22]=1>O1CCCC1>[NH2:1][C:13]1[CH2:12][N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:9]2[CH:22]=[C:5]([Cl:4])[CH:6]=[CH:7][C:8]=2[N:14]=1
Reactant: N
Reactant: S=C1CN=C(c2ccccn2)c2cc(Cl)ccc2N1
Solvent: CO
Solvent: C1CCOC1
Product: NC1=Nc2ccc(Cl)cc2C(c2ccccn2)=NC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
300 ml of 25% aqueous ammonia solution and 100 ml of methanol were added to a solution of 18.5 g of 7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione in 800 ml of tetrahydrofuran. The mixture was stirred at room temperature for 17 h., with the solution which formed being concentrated to about 200 ml in a vacuum. The crystals were filtered off, washed with water and dried, stirred in 25 ml of dioxan at 100° C., cooled and filtered off. There were obtained 16.3 g of 2-amino-7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine which was used without further purification for the next step. A sample recrystallized from dioxan melted at 213-215° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([NH2:15])=O)=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]#[N:15])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(N)=O)c(I)cc1OCc1ccccc1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C#N)c(I)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 74.4 %

Procedure:
To a mixture of 4-benzyloxy-2-iodo-5-methoxybenzamide (reference example 6-3) (5.25 g) and dichloromethane (70 mL) were added triethylamine (8.2 mL) and trifluoromethanesulfonic anhydride (4.6 mL) at 0° C. The mixture was stirred at 0° C. for 20 minutes, at room temperature for 3.5 hours and at reflux temperature for an hour. After cooling to 0° C., to the mixture were added triethylamine (4 mL) and trifluoromethanesulfonic anhydride (2.3 mL). After stirring at room temperature overnight, to the mixture were added ice-water and 1 mol/L hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A mixture of the residue, ethyl acetate, dichloromethane, silicagel and aminopropylsilicagel was stirred for 30 minutes. The mixture was passed through a layer of Celite (registered mark). The filtrate was concentrated under reduced pressure. The residue was triturated with methanol to give the title compound (3.72 g).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([OH:11])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]=[N:6][C:5]=2[N:4]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[N:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.CC(C)([O-])C.[Na+]>O1CCOCC1.CS(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][N:4]2[C:5]3[N:6]=[N:7][C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:9]([OH:11])[C:10]=3[C:2]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:3]2)[CH2:21][CH2:22]1
Reactant: CN1CCN(CCn2nc(I)c3c(O)c(-c4ccccc4)nnc32)CC1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CN1CCN(CCn2nc(N3CCCC3)c3c(O)c(-c4ccccc4)nnc32)CC1
Temperature: 100 °C
Yield: 88.7 %

Procedure:
To a solution of 3-iodo-1-[2-(4-methylpiperazin-1-yl)ethyl]-5-phenyl-pyrazolo[3,4-c]pyridazin-4-ol (120 mg, 0.26 mmol) in dioxane (1.7 mL) and DMSO (0.9 mL) was added pyrrolidine (233 μL, 2.8 mmol) and sodium t-butoxide (37 mg, 0.39 mmol) and nitrogen was bubbled in the resulting mixture for 30 min. Pd2dba3 (24 mg, 0.026 mmol) and Xantphos (9 mg, 0.016 mmol) were then added, the tube flushed with nitrogen, sealed and heated to 100° C. for 5 h. Pyrrolidine (40 μL, 0.49 mmol), Pd2dba3 (24 mg, 0.026 mmol) and Xantphos (9 mg, 0.016 mmol) were added and the mixture was heated to 100° C. for another 1 h. The mixture was left to cool to rt, then neutralised to pH 2-3 before loading on an SCX (10 g) cartridge. The cartridge was eluted with MeOH then CH2Cl2/MeOH (1:1) and finally the product was released with 10% methanolic ammonia (7 N) in CH2Cl2/MeOH (1:1). Evaporation of the solvent gave the title compound as a yellow glass (94 mg) which was reacted as such in the next step.
Reaction SMILES: [CH3:1][C@@H:2]([CH:12]1[O:31][C:29](=[O:30])[C@H:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[O:27][C:25](=[O:26])[C:24](C)([CH3:36])[CH2:23][NH:22][C:20](=[O:21])[C@@H:19]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([Cl:47])[CH:40]=2)[NH:18][C:16](=[O:17])[CH:15]=[CH:14][CH2:13]1)[C@@H:3]1[O:5][C@H:4]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(P(=S)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:36][CH:24]1[C:25](=[O:26])[O:27][CH:28]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:29](=[O:30])[O:31][CH:12]([CH:2]([CH:3]2[O:5][CH:4]2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:1])[CH2:13][CH:14]=[CH:15][C:16](=[O:17])[NH:18][CH:19]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([Cl:47])[CH:40]=2)[C:20](=[O:21])[NH:22][CH2:23]1
Reactant: COc1ccc(C[C@H]2NC(=O)C=CCC([C@H](C)[C@@H]3O[C@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)C(C)(C)CNC2=O)cc1Cl
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/CC([C@H](C)[C@@H]3O[C@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)C(C)(C)CNC2=O)cc1Cl
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Cryptophycin 53 (5 mg, 0.007 mmol) in 0.5 mL of dry benzene was added triphenylphosphine sulfide (4 mg, 0.014 mmol) followed by 0.65 μL of trifluoroacetic acid as a solution in dry benzene (100 μl). The solution was allowed to stir at room temperature for 6 h, neutralized with sodium bicarbonate, filtered and evaporated. The residue was partitioned between water and CH2Cl2. The CH2Cl2 -soluble material was purified by reversed-phase HPLC on C18 using 4:1 MeCN/H2O to obtain pure Cryptophycin 61 (1.9 mg, 37%). 1H NMR (300 MHz, CDCl3) unit A 7.24-7.35 (10/11/12/13/14-H; m), 6.73 (3-H; ddd, 15.0/10.2/4.8), 5.67 (2-H; d, 15.0), 5.23 (5-H; bm, W1/2 ≈15 Hz), 3.68 (8-H; d, 5.1), 3.01 (7-H; dd, 8.3/5.1), 2.52 (4-Hb ; bm, W1/2 ≈15 Hz), 2.41 (4-Ha ; ddd, -14.6/11.1/10.8), 1.6-1.8 (6-H; m), 1.15 (6-Me; d, 6.9); unit B 7.18 (5-H; d, 2.1), 7.04 (9-H; dd, 8.4/2.1), 6.84 (8-H; d, 8.4), 5.45 (NH; d, 7.8), 4.75 (2-H; ddd, 7.8/7.2/6.9), 3.88 (OMe; s), 3.08 (3-Hb /3-Ha ; bm, W1/2 ≈15 Hz); unit C 7.17 (NH; m), 3.40 (3-Hb ; dd, -13.6/8.4), 3.13 (3-Ha ; dd, -13.6/3.6), 1.23* (2-Me; s), 1.16* (2-Me'; s); unit D 4.86 (2-H; dd, 9.9/3.6), 1.6-1.8 (3-Hb /4-H, m), 1.43 (3-Ha ; bm, W1/2 ≈15 Hz), 0.92.dagger. (4-Me; d, 6.6), 0.88.dagger. (5-H3 ; d, 6.6).
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15]C)=[O:14])(=[O:9])=[O:8].[OH-].[Na+]>O1CCOCC1>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])(=[O:9])=[O:8]
Reactant: COC(=O)c1cccc(S(=O)(=O)Nc2nncs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cccc(S(=O)(=O)Nc2nncs2)c1
Yield: 52.2 %

Procedure:
A solution of methyl 3-[(1,3,4-thiadiazol-2-ylamino)sulfonyl]benzoate (Preparation 103, 1.0 g, 3.35 mmol, 1 eq) in 2.5M sodium hydroxide (5 ml, 13.4 mmol, 4 eq) and dioxane (1 ml) was heated at 50° C. for 4 hours. The organic solvent was evaporated in vacuo and the residue acidified with 2M hydrochloric acid. The resultant precipitate was collected by filtration and washed with water to yield the title compound (0.5 g, 1.75 mmol, 52%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)=[CH:15][N:16]3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[C].[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)=[CH:15][N:16]3[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3c(-c4ccc(O)cc4)cn(-c4ccncc4)c3c2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2ccc3c(-c4ccc(O)cc4)cn(-c4ccncc4)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methanol (2 mL) was added to 4-(6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indol-3-yl)phenol (4.6 mg, 0.0113 mmol) and 10% (w/w) palladium-carbon (Pd—C, 5.0 mg). The mixture was stirred at room temperature for 12 hours under hydrogen gas (1 atm). The reaction solution was filtered using a diatomite pad and concentrated under reduced pressure. The target compound was obtained as brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH:4]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:20]([O:26][CH2:27][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:4]([C:5]2([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:3][N:2]([CH3:1])[CH3:19])=[CH:17][CH:16]=1)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CC(c1ccc(OCOC(=O)C(C)(C)C)cc1)C1(O)CCCCC1

Procedure:
4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol (1 g, 3.79 mmol), chloromethyl pivalate (0.75 g, 5 mmol), anhydrous K2CO3(0.7 g, 5 mmol) and KI (75 mg, 0.5 mmol) were stirred in acetonitrile (50 mL) and refluxed overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate was dried (MgSO4) and evaporated to give the title compound as a minor component.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]1[CH2:23][CH2:24][OH:25])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26]I>O1CCCC1.[Cl-].[NH4+]>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[CH2:23][CH2:24][O:25][CH3:26])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCO)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCC1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
Add sodium hydride (0.675 g, 16.9 mmol) in portions to a 0° C. solution of (S)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylic acid di-tert-butyl ester (3.72 g, 11.3 mmol) in tetrahydrofuran (50 mL) and stir. After 20 minutes, add methyl iodide (1.4 mL, 22.5 mmol) dropwise. Allow the mixture to reach room temperature overnight, dilute with saturated ammonium chloride and extract three times with ethyl acetate. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purify by flash chromatography, eluting with a step gradient starting with dichloromethane up to 7% 2N ammonia-methanol in dichloromethane to obtain 2-(2-methoxyethyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester.