Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][CH:46]1[CH2:49][CH:48]([CH2:50][OH:51])[CH2:47]1>>[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][CH:46]1[CH2:47][CH:48]([CH2:50][O:51][C:21]([C@@:19]23[CH2:18][N:17]([S:24]([C:27]4[CH:28]=[N:29][C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[CH:31][CH:32]=4)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)=[O:22])[CH2:49]1
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reactant: OCC1CC(OC2CCCCO2)C1
Product: O=C(OCC1CC(OC2CCCCO2)C1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 48c using (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride and [3-(tetrahydro-pyran-2-yloxy)-cyclobutyl]-methanol. LCMS (Method G): 624.1 (M+H)+, Retention time 4.06 minutes.
Reaction SMILES: [H-].[Na+].CS(OCCCN1CCN(C2C=CC=CC=2OC)CC1)(=O)=O.OC[C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH2:32][C:33](=[O:37])[NH:34]2)=[CH:29][CH:28]=1>C1COCC1>[NH:34]1[C:35]2[C:30](=[CH:29][CH:28]=[CH:27][CH:36]=2)[CH:31]=[CH:32][C:33]1=[O:37]
Reactant: O=C1CCc2ccc(CO)cc2N1
Agent: COc1ccccc1N1CCN(CCCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1ccc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred suspension of sodium hydride (0.019 g, 0.0004 mol) in 5 mL of anhydrous THF was added a solution of 3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl methanesulfonate (40) (0.13 g, 0.0004 mol) in 5 mL THF at ice-bath temperature followed by 7-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one (37) (0.07 g, 0.0004 mol) in 5 mL THF dropwise. After the completion of the addition, the resulting reaction mixture was allowed to warm up to room temperature and stirred at 50° C. for 6 h. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was evaporated, diluted with 50 mL ethyl acetate, washed with saturated aqueous NaHCO3 solution (25 mL) followed by brine (25 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography using 0-100% gradient of hexane and ethyl acetate to give the pure compound 41. Colorless oil (0.1 g, 62%). 1H NMR (400 MHz, CDCl3): δ 1.88 (quintet, J=6.8 Hz, 2H); 2.50 (t, J=7.6 Hz, 2H); 2.59 (t, J=7.6 Hz, 2H); 2.66 (broad s, 4H); 2.84 (t, J=7.6 Hz, 2H); 3.06 (broad s, 4H); 3.83 (s, 3H); 3.98 (t, J=7.6 Hz, 2H); 4.63 (s, 2H); 6.82-6.84 (m, 2H); 6.88-6.99 (m, 4H); 7.08-7.10 (m, 2H). MS (ESI): m/z=410.5 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][Si](C)(C)C)=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.O1CCCC1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[C:17]([C:18]#[CH:19])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2c(C#C[Si](C)(C)C)c[nH]c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: C#Cc1c[nH]c2nc(NC(=O)C(C)(C)C)nc(O)c12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.7 %

Procedure:
To a mixture of 5.0 g (15.1 mmol) of N-[4-hydroxy-5-(trimethylsilyl) ethynyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethylpropionamide, in 40 mL of DMF and 10 mL of tetrahydrofuran was added 6.6 g (15.1 mmol) of tetrabutylammonium fluoride hydrate and the resulting solution was stirred at ambient temperature for 3.5 hours. After addition of 1.18 g of acetic acid and stirring for 15 minutes the mixture was poured into 50 mL of water. After stirring for about 1 hour the resulting suspension was filtered and the precipitate washed with water and dried, affording 3.38 g (86%) of N-(4-hydroxy-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropionamide, mp>300° C. NMR δ1.21 (s, 9H) , 3.89 (s, 1H), 7.28 (s, 1H), 10.82 (br s, 1H), 11.82 (br s, 1H), 11.85 (br s, 1 H); IR (KBr) 3354, 3250, 2973, 2120, 1699, 1676, 1608, 1536, 1433, 1243 cm-1 ; UV (EtOH) 292 nm (ε13,900), 280 nm (ε14,500), 236 nm (ε14,900). Anal. Calcd for C13H14N4O2 : C, 60.46; H, 5.46; N, 21.69. Found: C, 60.25; H, 5.32; N, 21.49.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@@H:7]([CH3:12])[NH:8][CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[C@@H:7]([CH3:12])[N:8]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN[C@H](C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(C(=O)OCc1ccccc1)[C@H](C)C(=O)OC(C)(C)C

Procedure:
N-Allyl-D-alanine t-butyl ester (69) is treated with 1.1 equivalents of benzyl chloroformate and 1.1 equivalents of triethylamine in methylene chloride at room temperature overnight. After evaporation of solvent, the product is purified by silica gel chromatography to give (70).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.[CH2:9]([Sn:13]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])Cl)[CH2:10][CH2:11][CH3:12]>>[CH3:7][N:6]1[C:2]([Sn:13]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][N:4]=[C:5]1[CH3:8]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ncc(Br)n1C
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C)n1C

Procedure:
The title compound was prepared following a similar procedure to previous example using 5-bromo-1,2-dimethyl-1H-imidazole and tributylchlorostannane.
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[CH:9]=1)#[N:4]>O>[F:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:18])[C:11]=1[CH2:10][N:8]1[CH:9]=[C:5]([C:3]([NH2:4])=[O:1])[N:6]=[N:7]1
Reactant: [OH-]
Reactant: N#Cc1cn(Cc2c(F)cccc2F)nn1
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
1 N sodium hydroxide solution (0.11 ml) is added to a mixture of 4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole (2.20 g) and water (44 ml) at an external temperature of 95-100° C. while stirring. After 90 minutes, the suspension is cooled to 10° C. and the product is isolated by filtration, washed with water and dried at about 60° C. in vacuo. 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide is obtained in this manner, yield: 99.2% by weight, Modification A.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:26]=[C:25]([CH3:27])[C:21]2[N:22]=[CH:23][NH:24][C:20]=2[C:19]=1[CH3:28]>CN(C)C1C=CN=CC=1.ClCl.CO>[CH3:28][C:19]1[C:20]2[NH:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:27])=[CH:26][C:18]=1[N:17]=[C:8]=[S:9]
Reactant: Cc1cc(N)c(C)c2[nH]cnc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Agent: ClCl
Solvent: CO
Product: Cc1cc(N=C=S)c(C)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (2.29 g) and 4-dimethylaminopyridine (0.03 g) in CH2 Cl2 (150 mL) is added dropwise over 30 minutes a solution of 5-amino-4,7-dimethylbenzimidazole (0.816 g) in methanol (50 mL). The mixture is stirred for 3 hours at room temperature, then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with a gradient of 50% to 80% ethyl acetate/hexane to afford 4,7-dimethyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[H-].[Na+].[O:25]1[CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]12>CN(C)C=O>[OH:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4]1
Reactant: C1CCC2OC2C1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1[C@@H]1CCCC[C@@H]1O
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 3.1 %

Procedure:
To a solution of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (1.58 g) in 80 ml of N,N-dimethylformamide was added sodium hydride (60% dispersion in mineral oil, 242 mg) at 5° C. After being stirred for 15 minutes at 5° C., the mixture was treated with epoxycyclohexane (1.62 g) and heated to 127° C. for 4.5 hours. The reaction mixture was poured into ice-water (200 ml), and the mixture was extracted with ethyl acetate (100 ml, 50 ml). The combined extracts were washed with water (50 ml) and brine (50 ml), dried over sodium sulfate, and concentrated in vacuo. The crude materials were purified by column chromatography on silica gel (40 g). The fractions containing minor cis isomer eluted with a mixture of dichloromethane and ethyl acetate (10:1-10:2) were collected, and the solvent was removed in vacuo to give cis-3-[2-(2-hydroxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (65.1 mg). The physical data for this compound were idendical with those of the authentic sample prepared by the method described in Example 4.
Reaction SMILES: C(N1CCC(C#N)CC1)(=O)C.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1.FC(F)(F)C1C=C(C=CC=1)[C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30]>>[F:12][C:13]([F:23])([F:22])[C:14]1[CH:19]=[CH:18][C:17]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:16][CH:15]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C1CCNCC1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Agent: CC(=O)N1CCC(C#N)CC1
Product: O=C(c1ccc(C(F)(F)F)cc1)C1CCNCC1

Procedure:
The title compound is prepared from 1-acetyl-4-cyanopiperidine and 4-trifluoromethylphenylmagnesium bromide according to the procedure given for 4-(3-trifluoromethylbenzoyl)piperidine in J. Med. Chem. 13, 1-6 (1970).
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH2:9][OH:10])[CH:5]=1)([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH:1]([C:4]1[O:8][N:7]=[C:6]([CH:9]=[O:10])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(CO)no1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)c1cc(C=O)no1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
7.59 g of (5-i-propyl-isoxazol-3-yl)methanol was dissolved in 100 ml of 1,4-dioxane, and 21.74 g of manganese dioxide was then added. The mixture was stirred and heated under reflux for 10 hours. The reaction mixture was cooled to room temperature and then filtered through Celite®. The filtrate was concentrated under reduced pressure to obtain 6.72 g of 5-i-propyl-isoxazole-3-carbaldehyde.
Reaction SMILES: [CH2:1]([C:3]1([CH3:18])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].FC(F)(F)C(O[I:24](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([C:3]1([CH3:18])[C:7](=[O:8])[C:6]([I:24])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2]
Reactant: CCC1(C)OC(c2ccc(S(C)=O)cc2)=CC1=O
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(C)OC(c2ccc(S(C)=O)cc2)=C(I)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 162.1 %

Procedure:
8.2 g of 2-ethyl-2-methyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone in 200 ml carbon tetrachloride and 200 ml chloroform was mixed with 6.8 g of [bis(trifluoroacetoxy)iodo]benzene (BTI) and 4.1 g of iodine. The mixture was stirred at room temperature for 6 hours, followed by quenching the reaction by adding saturated aqueous sodium thiosulfate until the characteristic color of iodine disappeared. The quenched solution was extracted with 300 ml water and dichloromethane (200 ml×3). The organic layer was concentrated in vacuo and the resulting residue was purified by column chromatography (hexane/ethylacetate=1:1) to give 10.0 g of 2-ethyl-4-iodo-2-methyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone. NMR: δ0.89 (t, J=7.5 Hz, 3H), 1.51 (s, 3H), 1.93 (m, 2H), 2.73 (s, 3H), 7.81 (d, J=8.7 Hz, 2H), 8.38 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26]([C@@H:28]([OH:37])[C@@H:29](Cl)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([Cl:47])[CH:40]=2)[C:5](=[O:6])[NH:4][CH2:3]1.[Li+].[Br-]>CC(C)=O>[CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:37][CH:29]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([Cl:47])[CH:40]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@@H](O)[C@@H](Cl)c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](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/C[C@@H]([C@H](C)[C@@H](O)[C@@H](Cl)c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: [Br-]
Solvent: CC(C)=O
Product: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of Cryptophycin 8 (20 mg) in 1.0 mL of dry acetone(distilled from K2CO3) was added 20 mg of LiBr. The mixture was stirred for 24 h at 90° C. After cooling to room temperature, the solvent was evaporated and the residue was subjected to normal-phase HPLC using 50/50 EtOAc/hexane to give Cryptophycin 25 (5.2 mg) and Cryptophycin 37 (4.2 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>CCO.CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C=C(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of tert-butyl 4-(4-nitrophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (I134 and I135) (0.442 g, 1.52 mmol) in EtOH (10 mL) and DMF (10 mL) was added to a solution of 10% Pd/C (255 mg) in DMF (10 mL). The reaction was stirred at room temperature for 17 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and washed through with EtOAc (130 mL). The solvent was removed in vacuo to yield a brown oil which was purified by column chromatography on silica gel (0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I136) (0.307 g, 77%) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J=8.4 Hz, 2H), 6.64 (d, J=8.4 Hz, 2H), 3.85-3.49 (m, 4H), 3.43-3.29 (m, 1H), 3.29-3.15 (m, 2H), 2.18 (d, J=6.5 Hz, 1H), 1.97-1.85 (m, 1H), 1.47 (d, J=4.7 Hz, 9H). LCMS Method C: rt 4.88 min; m/z 163.2 [M-Boc+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[NH:11][N:10]=1
Reactant: COc1ccccc1-c1nn(S(=O)(=O)c2ccc(C)cc2)c2nccc(-c3ccsc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: COc1ccccc1-c1n[nH]c2nccc(-c3ccsc3)c12
Temperature: 60 °C

Procedure:
To a stirred solution of (23) (50 mg, 0.108 mmol) in methanol (5 mL) and water (5 mL) was added potassium carbonate (29 mg, 0.216 mmol). The RM was heated to 60° C. overnight. After completion of the SM, the solvents were completely distilled off and diluted with water and extracted with chloroform twice. The organic layer was dried over sodium sulphate and completely distilled off to get the crude product, which was passed through 100-200 mesh silica gel eluting the pre compound at 28-30% ethyl acetate in hexane as eluent to get the pale yellow colored solid (24). 1H NMR (CDCl3) δ: 11.05 (1H), 8.57 (d, J=4.75 1H), 7.50 (m, J=5.85 1H), 7.48 (m, J=5.73 1H), 7.16 (m, J=4.87 1H), 7.12 (m, J=3.17 1H), 6.98 (m, J=4.87 3H), 6.61 (d, J=8.17 1H), 3.21 (3H) and MS m/z=308.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].BrBr.C([O-])(=O)C.[Na+].[C:14]1([CH2:20][CH2:21][NH:22][C:23]([NH2:25])=[S:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>CO>[CH:2]([C:3]1[N:25]=[C:23]([NH:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:24][CH:4]=1)([CH3:6])[CH3:1]
Reactant: NC(=S)NCCc1ccccc1
Reactant: CC(=O)C(C)C
Agent: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CO
Product: CC(C)c1csc(NCCc2ccccc2)n1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
To a solution of 3-methyl-2-butanone (0.86 g) in methanol (10 mL) was added bromine (1.60 g) at −30° C. The mixture was allowed to warm to room temperature and stirred until the red color of bromine disappeared. To the obtained colorless solution were added sodium acetate (1.60 g) and N-(2-phenylethyl)thiourea (1.80 g) and the mixture was stirred with heating under reflux for 4 hr. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added to the reaction mixture and the mixture was concentrated. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:9-2:1 in volume ratio) to give the title compound (1.26 g, yield 51%) as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:23]([O:22][C:20]([NH:19][CH2:18][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=2)[CH2:14]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC1Cc2ccc(OCc3ccccc3)cc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1Cc2ccc(O)cc2C1
Yield: 105.9 %

Procedure:
3.53 g (10.0 mmol) of 5-benzyloxy-2-(t-butoxycarbonylaminomethyl)indan was dissolved in 100 ml of methanol and added with 0.3 g of 10% palladium on carbon, followed by stirring for 4 hours in the stream of hydrogen gas. The catalyst was removed by filtration, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane=1:2) to obtain 2.79 g of a colorless oil. Yield: 94%
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([N:12]([CH2:20][C:21]2([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:24][CH2:23][CH2:22]2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1)=[CH2:5])C.Cl>CCO>[C:4]([C:6]1[N:11]=[N:10][C:9]([N:12]([CH2:20][C:21]2([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:22][CH2:23][CH2:24]2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1ccc(N(CC2(c3ncccc3F)CCC2)C(=O)OC(C)(C)C)nn1
Agent: Cl
Solvent: CCO
Product: CC(=O)c1ccc(N(CC2(c3ncccc3F)CCC2)C(=O)OC(C)(C)C)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
t-Butyl 6-(1-ethoxyvinyl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (1.0 g, 2.3 mmol), EtOH (75 mL), and 1N HCl (15 mL) were combined at 0° C., warmed to 25° C., and stirred for 1 h. The reaction mixture was concentrated and silica gel chromatography provided a colorless oil (0.6 g, 64%), (m/z [M+H]=401.1).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[C:4]([C:7](=[O:17])[CH2:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=O)[S:5][CH:6]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[Br:1][C:2]1[C:3]2[O:18][C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:8][C:7](=[O:17])[C:4]=2[S:5][CH:6]=1
Reactant: O=C(CC(=O)N1CCOCC1)c1scc(Br)c1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Temperature: 25 °C
Yield: 82.5 %

Procedure:
An oven-dried 100 mL round-bottom flask was charged with a magnetic stirring bar, 1-(4-bromo-3-hydroxythiophen-2-yl)-3-morpholinopropane-1,3-dione (1.95 g, 5.83 mmol) and dissolved in dichloromethane (30 mL) under magnetic stirring. Trifluoromethanesulfonic anhydride (2.45 mL, 14.6 mmol) was added portionwise over 2 minutes, and the reaction was stirred at room temperature. After stirring overnight, the reaction was concentrated in vacuo and redissolved in methanol (10 mL). After stirring for 4 hours, the reaction was concentrated in vacuo and diluted with aqueous 5% sodium bicarbonate solution (100 mL). The reaction was transferred to a separatory funnel and extracted three times with dichloromethane (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (1.52 g, 4.81 mmol, 82%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5](Cl)[CH:6]([OH:9])[CH2:7][CH3:8].[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH:6]([OH:9])[CH2:7][CH2:8][N:24]1[CH2:25][CH2:26][N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23]1
Reactant: CCC(O)C(Cl)Oc1ccccc1Cl
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: OC(CCN1CCN(c2ccccc2)CC1)COc1ccccc1Cl

Procedure:
A mixture of 35.1 g. (0.15 mole) of 1-(o-chlorophenoxy)-2-hydroxybutyl chloride, 32.6 g. (0.2 mole) of N-phenylpiperazine and 400 ml. of isopropanol was refluxed for 48 hr. The reaction mixture was allowed to stand in a refrigerator overnight and filtered. The filtrate was treated with ethereal hydrogen chloride and the salt precipitated by the addition of ether. The white crystalline solid which formed was dissolved in 0.1 mole of hydrochloric acid and then neutralized with sodium hydroxide producing a crystalline precipitate. This was recrystallized with isopropanol yielding 36 g. of the free base of the product which melted at 100°-101.5° C.