Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH3:15][NH:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>O>[CH3:15][NH:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[CH:18][N+:19]([O-:21])=[O:20]
Reactant: NCCCCCCCCCCCCN
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
A mixture of 1,12-diaminododecane (3 g) and N-methyl-1-(methylthio)-2-nitroethenamine (1.48 g) in water (50 ml) was stirred at room temperature for 20 hours. The solution was evaporated in vacuo and the residue chromatographed (silica/methanol). The appropriate eluate was evaporated to yield the title compound (1.8 g), mp. 123°-125°.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9](=[NH:11])[NH2:10])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:12][C:13]1[S:16][N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[N:11]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Fc1cccc(-c2nsc(Cl)n2)c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of 3-fluorobenzenecarboximidamide hydrochloride (1.75 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (20 ml) was added dropwise a solution of sodium hydroxide (2.00 g, 50.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.52 g (71.0%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.[Cl:20][CH2:21][C:22]([CH2:24]Cl)=O.C(=O)([O-])O.[Na+].ClC(Cl)C(=O)C>O1CCOCC1>[Cl:20][CH2:21][C:22]1[N:1]=[C:2]2[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:5]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:4]=3[N:3]2[CH:24]=1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccn2)=NC1
Reactant: O=C(CCl)CCl
Agent: CC(=O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: ClCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Cl)ccc1-2
Reaction time: 16 h
Yield: 43.6 %

Procedure:
A solution of 16.3 g of 2-amino-7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine and 8.4 g of 1,3-dichloroacetone in 600 ml of dioxan was treated with 5.6 g of anhydrous sodium hydrogen carbonate and stirred at 100°0 C. for 16 h. A further 0.84 g of dichloroacetone and 0.56 g of anhydrous sodium hydrogen carbonate were added and the mixture was stirred at 100° C. for a further 8 h. The mixture was evaporated in a vacuum and the residue was partitioned between chloroform and water. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were evaporated in a vacuum. The residue was dissolved in dichloromethane and chromatographed over 800 g of silica gel. With dichloromethane/ethanol 197:3 there were eluted small amounts of impurities, with dichloromethane/ethanol 196:4 there were eluted 10.2 g of the desired product. After recrystallization from ethyl acetate there were obtained 9.0 g of 2-chloromethyl-8-chloro-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine of m.p. 161° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([OH:11])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH:45]1[C:57]2[CH:56]([CH2:58][O:59][C:60](=[O:77])[NH:61][C:62]3[CH:67]=[CH:66][C:65]([NH2:68])=[C:64]([O:69][CH2:70][C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[CH:63]=3)[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]=2[CH:48]=[CH:47][CH:46]=1>CN(C=O)C.CCOC(C)=O>[CH:45]1[C:57]2[CH:56]([CH2:58][O:59][C:60](=[O:77])[NH:61][C:62]3[CH:67]=[CH:66][C:65]([NH:68][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=4[OH:11])=[C:64]([O:69][CH2:70][C:71]4[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=4)[CH:63]=3)[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]=2[CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(NC(=O)c2ccc(F)cc2O)c(OCc2ccccc2)c1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
4-Fluoro-2-hydroxy-benzoic acid (74) (0.15 g, 0.961 mmol) was dissolved in DMF (6 mL), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU) (0.382 g, 1.01 mmol) was added followed by iPr2EtN (0.167 mL, 0.961 mmol) and the mixture was shaken in a Teflon septum capped 40 mL I-Chem vial at room temperature for 25 minutes. (4-Amino-3-benzyloxy-phenyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (0.419 g, 0.961 mmol) was added and the mixture was shaken at room temperature for 16 h. LC-MS indicated complete coupling at this point. The mixture was diluted with EtOAc (50 mL), washed with water (25 mL), aqueous saturated NaHCO3 (25 mL) and brine (25 mL) via extraction, dried over MgSO4. The organic layer was concentrated to give a yellow oil. Purification by flash chromatography using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc in hexane in 30 minutes) gave the desired product (75) upon concentration (0.192 g, 0.334 mmol, 35% yield). LC-MS (ESI): (exact mass: 574.19) m/e=575.2 [M+1]+ (100%), 1149.5 [2M+1]+ (25%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.BrC(C(F)(F)F)=C.BrC1C=CC([C:25](N(OC)C)=[O:26])=CC=1C.C[CH:35]([N:37](C(C)C)[C:38]([C:50]([F:53])([F:52])[F:51])=[CH:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([Br:48])=[C:44]([CH3:49])[CH:43]=1)=[O:41])C>O1CCCC1.O>[Br:48][C:45]1[CH:46]=[CH:47][C:42]([C:40](=[O:41])[CH:39]=[C:38]([NH:37][CH2:35][O:26][CH3:25])[C:50]([F:53])([F:52])[F:51])=[CH:43][C:44]=1[CH3:49]
Reactant: Cc1cc(C(=O)C=C(N(C(C)C)C(C)C)C(F)(F)F)ccc1Br
Reactant: CON(C)C(=O)c1ccc(Br)c(C)c1
Agent: C=C(Br)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: COCNC(=CC(=O)c1ccc(Br)c(C)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a stirred solution of diisopropylamine (11.1 mL, 83.3 mmol) in tetrahydrofuran (100 mL) at −78° C. was added 2.5 M n-BuLi in hexanes (33.31 mL, 83.3 mmol). The reaction mixture was allowed to warm to 0° C., stirred for 20 minutes, and then cooled to −78° C. 2-Bromo-3,3,3-trifluoropropene (6.78 g, 38.7 mmol) was added to the reaction mixture, which was stirred for 30 minutes. Then a solution of 4-bromo—N-methoxy-N,3-dimethylbenzamide (i.e. the title product of Step A) (5.0 g, 19.4 mmol) in tetrahydrofuran (20 mL) was added to the reaction mixture at −78° C., which was then warmed to 0° C. Water (25 mL) was added to the mixture, which was then stirred for 1 hour at 0° C. The reaction mixture was extracted with ether and concentrated under reduced pressure, and the oily residue was purified by chromatography on silica gel to afford a mixture of 3-[bis(1-methylethyl)amino]-1-(4-bromo-3-methylphenyl)-4,4,4-trifluoro-2-buten-1-one and 1-(4-bromo-3-methylphenyl)-4,4,4-trifluoro-3-(methoxymethylamino)-2-buten-1-one (2.5:1 ratio by LCMS) (6.55 g, approx. 92% yield) as a bright orange oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][C:11](=[O:15])[CH2:12][CH:13]=[CH2:14])[CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([CH2:10][CH:11]([OH:15])[CH2:12][CH:13]=[CH2:14])[CH2:9][CH2:8]1
Reactant: C=CCC(=O)CC1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(O)CC1CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminium hydride (17.1, 0.45 mol) in tetrahydrofuran (700 mL) at −78° C. was added drop-wise a solution of 1-cyclopropylpent-4-en-2-one (C64) (38 g, 0.3 mol) in tetrahydrofuran (100 mL). After the addition, the mixture was stirred at −78° C. for 1 hour. The reaction mixture was quenched with water (20 mL) at −78° C., then dichloromethane (200 mL) was added and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the filter cake was washed with dichloromethane (2×200 mL), and the combined filtrates were dried and concentrated in vacuo to give crude product; purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 16 g, 127 mmol, 43% over 2 steps. 1H NMR (400 MHz, CDCl3) δ 5.81-5.87 (m, 1H), 5.01-5.14 (m, 2H), 3.75 (m, 1H), 2.30-2.34 (m, 1H), 2.18-2.23 (m, 1H), 1.34-1.43 (m, 2H), 0.68-0.80 (m, 1H), 0.39-0.49 (m, 2H), 0.02-0.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([NH:15][NH2:16])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:20])=O>>[C:18](=[N:16][NH:15][C:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:14])([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: NNC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Product: CC(C)=NNC(=O)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
A mixture of 50 g (0.21 mole) of 5-(p-chlorophenyl)-2-furoic acid hydrazide in 500 ml of acetone was heated at reflux overnight. The reaction mixture was filtered while still warm. Crystalline solid separated readily from the filtrate upon cooling. The solid was collected, washed well with acetone and air dried. The yield was 40 g (69%). Recrystallization of 2 g from acetone gave 1.3 g of analytically pure product, m.p. 167°-169°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: ClCCN1CCCCC1
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)piperidine
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:37])[CH3:36])[C@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2CCc3ccccc32)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-((R)-indan-1-ylaminomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=2)[CH:10]=[N:9][CH:8]=1)(=O)=O.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=3)[CH:10]=[N:9][CH:8]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: O=Cc1ccc(OB(O)O)cc1
Product: C[Si](C)(C)CCOC(=O)c1ccc2cncc(-c3ccc(C=O)cc3)c2c1
Yield: 79.7 %

Procedure:
Using 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate (600 mg, 1.42 mmol) and 4-formylphenylboric acid (320 mg, 2.14 mmol), the desired title compound (427 mg, yield 79%) was obtained by the same method as in Example 8 (8a).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Br[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: COC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC[C@@H]1CCCN1CCNC(=O)OC(C)(C)C
Temperature: 85 °C

Procedure:
A suspension comprising (S)-2-(methoxymethyl)pyrrolidine (1 g, 8.68 mmol), tert-butyl 2-bromoethylcarbamate (1.946 g, 8.68 mmol), triethylamine (1.210 ml, 8.68 mmol) and potassium carbonate (1.200 g, 8.68 mmol) in MeCN (10 ml) was heated at 85° C. overnight. The resulting mixture was filtered and washed with MeCN. Purification of the crude product by chromatography on silica eluting with 0-5% MeOH in DCM afforded the title compound as a colourless oil;
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].CCN(CC)CC>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([O:15][C:13]([NH:12][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:6][C:2]=1[C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c(Br)s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)s1
Temperature: 50 °C
Yield: 70 %

Procedure:
A solution (0.1 M) of ethyl 5-bromo-4-[(tert-butoxycarbonyl)amino]thiophene-2-carboxylate in THF was treated with trimethylsilylacetylene (1.3 eq.), Et3N (1.5 eq.), CuI (0.04 eq.) and PdCl2(PPh3)2 (0.01 eq.). The solution was heated at 50° C. for 3 h. After cooling down, it was filtered through a pad of celite and washed with AcOEt. The organic layer was washed with brine and dried then concentrated and the residue was purified by flash chromatography on silica gel (1:19 AcOEt/petroleum ether) to afford the title compound (70%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:14][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CCOC(=O)C(OC(C)=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (6 mL) of the compound (1.46 g) prepared in Example 22 in pyridine, acetic anhydride (2 mL) was added, and the mixture was stirred for 1 hour at room temperature. The title compound (135 mg) having the following physical data was obtained by concentrating the reaction mixture and azeotroping in toluene.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH:5]1[C:10]([OH:11])=[CH:9][C:8]2[O:12][C:13]([S:15][C:7]=2[CH:6]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:11][C:10]1[CH:5]=[CH:6][C:7]2[S:15][C:13](=[O:14])[O:12][C:8]=2[CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: O=c1oc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2sc(=O)oc2c1
Yield: 77.4 %

Procedure:
Allyl bromide (28.3 ml, 0.327 mol) was added to a mixture of tioxolone (50 g, 0.297 mol) and potassium carbonate (82 g, 0.595 mol) in acetone (300 ml), and the resultant suspension stirred at RT overnight. After removal of the solvent in vacuo, the residue was partioned between EtOAc (700 ml) and water (500 ml). The aqueous phase was removed, extracted with further EtOAc (2×300 ml), and the combined organics dried over MgSO4 and concentrated to an off-white solid (66.6 g). Purification by flash column chromatography on silica eluting with EtOAc:pentane (1:39 to 1:9) gave the title compound as a white solid (48.3 g, 0.23 mol).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=[N:16][CH:15]=3)[OH:13])[C:6]3[CH2:38][CH2:39][N:40]4[CH:44]([C:5]=3[C:4]=2[CH:3]=1)[CH2:43][CH2:42][CH2:41]4.C(=O)(O)[O-].[Na+]>CO.Cl>[NH:18]1[C:14]([CH:12]([OH:13])[CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]3[CH:44]4[N:40]([CH2:39][CH2:38][C:6]2=3)[CH2:41][CH2:42][CH2:43]4)=[CH:15][N:16]=[CH:17]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN2CCCC12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cnc[nH]2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.2 %

Procedure:
To a stirred solution of compound 2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(1-trityl-1H-imidazol-5-yl)ethanol (400 mg, 0.69 mmol) in MeOH (10 mL), 1N HCl (1 mL) at 0° C. was added. The reaction mixture was stirred at RT for 2 h. The reaction mixture concentrated under vacuum to obtain the crude product that was basified with sat sodium bicarbonate solution and extracted with EtOAc (50 mL). The organic layer dried on anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product that was purified by reverse phase HPLC to obtain 1-(1H-imidazol-5-yl)-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethanol (12 mg) as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.79 (s, 1H), 7.4 (s, 1H), 7.27 (s, 1H), 7.2 (dd, 1H), 7.01 (d, 1H), 5.18 (t, 1H), 5.04 (m, 1H), 4.39 (m, 2H), 3.67 (m, 3H), 3.42 (m, 2H), 3.2 (m, 1H), 2.7 (m, 1H), 2.4 (s, 3H), 2.2 (m, 3H). Separation by chiral HPLC provides diastereomers II-140a-d.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([CH3:19])=[CH:4][CH:3]=1.[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][NH:25][NH2:26])[CH3:21]>>[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][N:25]1[C:2]2[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]3[O:7][C:8]4[CH:9]=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][C:13]=4[C:14]([C:15]=23)=[N:26]1)[CH3:21]
Reactant: CCN(CC)CCNN
Reactant: COc1ccc2c(=O)c3c(Cl)ccc(C)c3oc2c1
Product: CCN(CC)CCn1nc2c3c(c(C)ccc31)Oc1cc(OC)ccc1-2

Procedure:
By the condensation of 1-chloro-6-methoxy-4-methyl-9-xanthenone with 2-(diethylamino)ethyl hydrazine was obtained 2-(2-(diethylamino)ethyl)-8-methoxy-5-methyl-2H(1)benzopyrano[4,3,2-cd]indazole. To 0.27 g. of this base in acetone (4 ml.) was added 30% aqueous hydrogen peroxide (0.35 ml.). After standing for 90 hours at room temperature the solution was evaporated under reduced pressure. Addition of ether to an ethanolic solution of the residue gave an oil which slowly crystallized. Further crystallization from acetonitrile gave yellow crystals m.p. 132°-133° (decomp.) of 2-(2-(diethylamino)ethyl)-8-methoxy-5-methyl-2H(1)benzopyrano[4,3,2-cd]indazole N-oxide 1.75 hydrate.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10](=[S:12])[NH2:11])[CH:2]=1.Br[CH:14]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[S:12][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:11]=2)[CH:2]=1
Reactant: CCOC(=O)C(Br)C(=O)c1ccccc1
Reactant: NC(=S)c1cnn2ccccc12
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cnn3ccccc23)nc1-c1ccccc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a suspension of commercially available pyrazolo[1,5-a]pyridine-3-carbothioamide (580 mg, 3.3 mmol) in ethanol (20 mL) was added ethyl 2-bromo-3-oxo-3-phenylpropanoate (1.0 g, 3.7 mmol), and the mixture was heated under reflux for 11 hr. The reaction solution was allowed to cool to room temperature, and the resulting solid was collected by filtration and washed with methanol. The collected filtrate and washing solution was concentrated under reduced pressure, and the obtained residue was suspended in ethyl acetate (100 mL). The obtained suspension was washed with saturated aqueous sodium bicarbonate solution (50 mL×2), and the collected aqueous layer was extracted with ethyl acetate (50 mL). The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→100/0) to give the title compound (360 mg, 31%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19]C)=[O:18])[C@@H:14]([NH:21][C:22](=[O:40])[CH:23]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[NH:24]C(OC(C)(C)C)=O)[C@H:12]1[OH:13].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(OCC)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:21][C:22](=[O:40])[CH:23]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[NH2:24])[C@H:12]1[OH:13]
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)C(N)Cc2ccc(Cl)cc2)[C@H]1O
Yield: 68.2 %

Procedure:
A mixture of methyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-β-(4-chlorophenyl)-D,L-alanylamino]-β-D-ribofuranuronate (150 mg) prepared in Example 64 and anisol (0.3 ml) was stirred in an ice-bath, and trifluoroacetic acid (3 ml) was added. After stirring for 1 hour in an ice-bath, diethyl ether was added to the mixture. The resulting precipitates were collected by filtration, added to 1N sodium hydroxide (3 ml), and stirred for 30 minutes in an ice-bath. The reaction mixture was neutralized with 1N hydrochloric acid, subjected to column chromatography on a non-ionic adsorption resin "HP-20" (trade mark, Mitsubishi Chemical Industries Ltd.) (30 ml). After the column was washed with water, the elution was carried out with 50% aqueous methanol. The eluate was evaporated to remove methanol under reduced pressure and lyophilized to give 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[β-(4-chlorophenyl)-D,L-alanylamino]-β-D-ribofuranuronic acid (82 mg), mp. 170°-178° C. (dec.).