Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)(=O)[CH3:8].[S].C1(C)C=CC([S:26](O)(=O)=O)=CC=1>CO>[O:17]1[C:13]2[CH:12]=[CH:11][C:10]([CH2:7][C:8]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[S:26])=[CH:18][C:14]=2[CH2:15][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)c1ccc2c(c1)CCO2
Reactant: C1COCCN1
Agent: [S]
Solvent: CO
Product: S=C(Cc1ccc2c(c1)CCO2)N1CCOCC1
Reaction time: 3 h

Procedure:
Morpholine (1.5 ml), 2,3-dihydro-5-acetylbenzofuran (2.0 g), sulfur (0.395 g) and p-toluene sulfonic acid (0.060 g) were heated at reflux. After 3 hours, the reaction mixture was cooled and 6 ml of methanol added. This solution was further cooled which precipitated the morpholide. The precipitate was filtered and washed with cold methanol to give 2,3-dihydrobenzofuran-5-ylthioacetic acid morpholide, m.p.--144°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH2:13]Cl)[CH2:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=1.[O-]CC.[K+].C1OCCOCCOCCOCCOCCOC1.[OH2:49]>C1(C)C=CC=CC=1>[C:20]([OH:25])(=[O:10])[C:21]([OH:24])=[O:49].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH2:13][O:24][C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=3[O:25][CH3:26])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: ClCC1CN(Cc2ccc(Cl)cc2)CCO1
Reactant: O
Reactant: COc1cc(Cl)ccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1OCC1CN(Cc2ccc(Cl)cc2)CCO1
Product: O=C(O)C(=O)O

Procedure:
A mixture of (±)-4-(4-chlorobenzyl)-2-chloromethylmorpholine (10.0 g, 38.5 mmol), 4-chloro-2-methoxyphenol (9.0 g, 58 mmol), potassium ethoxide (6.5 g, 77 mmol), and 18-crown-6 (10.2 g, 38.5) was refluxed in toluene (100 ml) for 34 h. Water (200 ml) was added and the phases were separated. Drying and evaporation of the toluene phase was followed by column chromatography on silica gel with 3% ethanol in dichloromethane as eluent. The free base was dissolved in ether and precipitated with oxalic acid to give the title compound. Yield 10.3 g, 57%, mp 133-139° C.
Reaction SMILES: [CH2:1]([O:13][C:14](=[O:20])[NH:15][S:16](Cl)(=[O:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[OH:33])([CH3:23])[CH3:22].C(N(CC)CC)C>C1COCC1>[CH3:31][CH:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]([CH3:23])[CH3:22])[C:25]=1[O:33][S:16]([NH:15][C:14](=[O:20])[O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:17])=[O:18])[CH3:32]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: CCCCCCCCCCCCOC(=O)NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)NS(=O)(=O)Oc1c(C(C)C)cccc1C(C)C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
A solution of n-dodecyl(chlorosulfonyl)carbamate (5.0 g, 15.2 mmoles) in 80 mL THF was added dropwise to a solution of 2,6-diisopropyl phenol (2.72 g, 15.2 mmoles) and excess triethylamine in 100 mL THF at room temperature under an atmosphere of N2. The mixture was stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between 1N HCl and EtOAc. The organic layer was dried with MgSO4, filtered, and evaporated to give a clear oil. Chromatography (SiO2, 5% EtOAc/hexanes) gave 4.26 g of the title compound as a waxy solid, mp 32°-35° C.
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:26])[C:24]#[CH:25])=[CH:20][C:19]([NH:27][NH2:28])=[C:18]([F:29])[CH:17]=1>O.C(OCC)C>[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:26])[C:24]#[CH:25])=[CH:20][C:19]([N:27]([C:2]2[CH:1]=[CH:18][CH:17]=[CH:16][CH:21]=2)[N:28]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:18]([F:29])[CH:17]=1
Reactant: C#CC(C)Oc1cc(NN)c(F)cc1Cl
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C#CC(C)Oc1cc(N(N=CC(=O)C(F)(F)F)c2ccccc2)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 117.4 %

Procedure:
To a solution of 2.870 g of sodium acetate dissolved in 20 ml of water was added 3.139 g of 1,1-dibromo-3,3,3-trifluoroacetone, and the mixture was stirred at 80° C. for 30 minutes. The reaction solution was left cooling to room temperature, to which a solution of 2.000 g of 4-chloro-2-fluoro-5-(1-methyl-2-propynyl)oxyphenylhydrazine dissolved in 10 ml of diethyl ether, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was extracted with 100 ml of ethyl acetate. The organic layer was washed with 100 ml of saturated aqueous sodium bicarbonate solution and then with 100 ml of saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to give a crude product. The crude product was recrystallized from toluene to give 2.120 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-(1-methyl-2-propynyl)oxyphenylphenylhydrazone), compound 3-5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C(Cl)Cl>[C:15]([NH:14][CH2:13][CH:11]1[O:10][C:9](=[O:18])[N:8]([C:6]2[CH:5]=[CH:4][C:3]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:21][CH:20]=3)=[C:2]([F:1])[CH:7]=2)[CH2:12]1)(=[O:17])[CH3:16]
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(CO)cc3)c(F)c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(COS(C)(=O)=O)cc3)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A suspension of 51 (12.49 g, 34.90 mmol) in methylene chloride (CH2Cl2, 150 mL) was treated with triethylamine (Et3N, 7.07 g, 9.7 mL, 70 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0-5° C. before being treated dropwise with methanesulfonyl chloride (4.80 g, 3.24 mL, 41.9 mmol, 1.2 equiv) at 0-5° C. The resulting reaction mixture was subsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was treated with H2O (100 mL) at 0-5° C. The mixture was then concentrated in vacuo to remove most of the CH2Cl2, and the resulting slurry was treated with H2O (150 mL). The mixture was stirred at room temperature for 10 min before being cooled to 0-5° C. for 30 min. The solid precipitates were collected by filtration, washed with H2O (2×100 mL) and 20% EtOAc/hexane (2×50 mL), and dried in vacuo. The crude desired methanesulfonic acid 4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl ester 52 (11.84 g, 78% yield) was obtained as off-white solids, which by TLC and HPLC was found to be essentially pure and was directly used in the subsequent reaction without further purification. LCMS (ESI) m/e 437 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[O:13][CH2:12][C:11](=O)[NH:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.B.B.O1CCCC1>O1CCCC1.CO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COC(c2cccc(Cl)n2)CN1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Clc1cccc(C2CNCCO2)n1
Reaction time: 1 h

Procedure:
1 g (0.0047 mol) of 2-(6-chloro-pyridin-2-yl)-morpholin-5-one are dissolved in 20 ml of absolute tetrahydrofuran, added with stirring at ambient temperature to 5 ml of a 1 molar solution of borane in tetrahydrofuran and the reaction solution is stirred for 60 minutes. Then sufficient borane/tetrahydrofuran solution is added in batches until all the starting material has reacted, according to thin layer chromatography. The solvent is then drawn off, the residue is stirred in 20 ml of methanol for 18 hours and then evaporated down. This residue is taken up in 20 ml of 2N hydrochloric acid and stirred at 50° C. for 2 hours. The acid solution is cooled in an ice bath, made alkaline with ammonia solution and extracted with methylene chloride. The organic phase is dried over sodium sulphate, concentrated by evaporation and the residue is purified over a silica gel column with methanol as eluant.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][NH2:19])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: N#Cc1cccc(NC(=O)NCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 2-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 210-a) as a starting material, and using 3-cyanophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.O1C2C(=CC=CC=2)CCC1.[Li]CCCC.[C:27](=[O:29])=[O:28]>C(O)(=O)C.[Zn]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:27]([OH:29])=[O:28])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C=O
Reactant: O=C1CCOc2ccccc21
Agent: [Li]CCCC
Agent: [Zn]
Agent: c1ccc2c(c1)CCCO2
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1OCCC2

Procedure:
The synthesis of chroman-5-carboxylic acid derivatives started with the alkylation of 3-hydroxy-benzoic acid methyl ester (49; commercially available) with propargyl bromide in the presence of K2CO3 to give phenylether (50) which was cyclised to the chromen derivative (51) by heating to reflux in N,N-diethylaniline. The carboxylic ester was saponified by treatment of (51) with NaOH in MeOH and water and the obtained chromen derivative (52) was hydrogenated to give the desired acid (53). The corresponding chroman-8-carboxylic acid derivatives were synthesized by reduction of 4-chromanone (54; commercially available) with zinc in acetic acid and subsequent ortho-metalation of the intermediate chroman derivative (55) with n-BuLi and trapping with carbon dioxide to give the desired acid (56).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH3:20])[CH:16]=3)[NH:11][C:10]=2[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[S:7]1)=[O:5])[CH3:2].S(C1C=CC(C)=CC=1)(O[CH2:31][CH2:32][F:33])(=O)=O.[H-].[Na+]>CN(C=O)C>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH3:20])[CH:16]=3)[N:11]([CH2:31][CH2:32][F:33])[C:10]=2[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[S:7]1)=[O:5])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CCN(CC)C(=O)C1Sc2ccccc2-c2[nH]c3ccc(OC)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C1Sc2ccccc2-c2c1c1cc(OC)ccc1n2CCF
Temperature: 80 °C
Yield: 45.5 %

Procedure:
To a solution of (+−)-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-6-carboxylic acid diethyl amide (51) (150 mg, 0.41 mmol; prepared according to Example 17(b)) in anhydrous DMF (4 ml) was added 2-fluoroethyl tosylate (166 mg, 0.82 mmol), prepared as described in L. Cronin et al (J. Org. Chem. 2004; 69: 5934-5946) followed by sodium hydride 60% dispersion in mineral oil (34 mg, 0.82 mmol) under nitrogen. The reaction mixture was heated at 80° C. for 1 h. After cooling, the solvents were removed in vacuo, the residue quenched with water (30 ml), extracted with DCM (2×30 ml), dried (MgSO4) and solvents removed in vacuo. The residue was purified by column chromatography on silica, eluting with 5-10% EtOAc/CH2Cl2. The crude solid was quenched with ether/pet.spirit, filtered, dried in vacuo (45° C.) to give the title compound (non-radioactive tetracyclic indole imaging agent) (77 mg, 46%) as a pale brown solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δ 1.12 (t, J=7.0 Hz, 3H), 1.36 (t, J=7.0 Hz, 3H), 3.25-3.70 (m, 4H), 3.83 (s, 3H), 4.45-4.70 (m, 2H), 4.80 (t, J=5.2 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 5.09 (s, 1H), 6.84-6.93 (m, 2H), 7.13-7.32 (m, 3H), 7.46 (m, 1H), 7.58 (d, J=8.0 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.OC1[C:19]2([CH2:21][CH2:20]2)[CH2:18][N:17]([C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])C1>C(OCC)(=O)C>[C:5]([O:4][CH:1]1[C:19]2([CH2:20][CH2:21]2)[CH2:18][N:17]([C@@H:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:23])[CH2:2]1)(=[O:7])[CH3:6]
Reactant: C[C@H](c1ccccc1)N1CC(O)C2(CC2)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CN([C@H](C)c2ccccc2)CC12CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1.5 g of compound 12 and 500 mg of lithium aluminum hydride in 30 ml of tetrahydrofuran was refluxed for 16 hours. 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water were added to the mixture in the mentioned order, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated to dryness to yield 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane as a pale yellow oil. 5 ml of acetic anhydride and 5 ml of pyridine were added to 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane which was cooled on an ice-bath. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added thereto and the solution was washed with saturated aqueous sodium bicarbonate and water, then, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane as a yellow oil. A mixture of 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane and 1.2 g of palladium-on-carbon (50% water wet) in 20 ml of ethanol was shaken under 3.8 atm of pressured hydrogen atmosphere for 5 hours. During the reduction reaction, the reaction vessel was warmed by a tungsten lamp. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give 880 mg of title compound 69 as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\C1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3C=COC=3CO2)=CC=1)(=O)=O)[CH3:2].Br[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[S:45]([NH:48][C:49]1[C:58]([C:59]([O:61][CH3:62])=[O:60])=[C:57]2[C:52]([CH:53]3[C:63]([F:65])([F:64])[CH:54]3[CH2:55][O:56]2)=[CH:51][CH:50]=1)(=[O:47])=[O:46].C(N(CC)C/C=C\[Sn](CCCC)(CCCC)CCCC)C>>[CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[S:45]([NH:48][C:49]1[C:58]([C:59]([O:61][CH3:62])=[O:60])=[C:57]2[C:52]([CH:53]3[C:63]([F:65])([F:64])[CH:54]3[CH2:55][O:56]2)=[CH:51][CH:50]=1)(=[O:47])=[O:46])[CH3:2]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1C2C1(F)F
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1C2C1(F)F

Procedure:
Prepared by proceeding in a similar manner to Intermediate 9, starting from methyl (1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 60) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)amine (Intermediate 11) as a pale yellow gum.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([OH:16])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:23][C:24]([C:34]([F:37])([F:36])[F:35])=[CH:25][C@@H:26]1[C@H:28]([C:29](Cl)=[O:30])[C:27]1([CH3:33])[CH3:32]>C1(C)C=CC=CC=1>[Cl:23][C:24]([C:34]([F:35])([F:36])[F:37])=[CH:25][C@@H:26]1[C@H:28]([C:29]([O:16][CH:10]2[CH2:9][C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11]2)=[O:30])[C:27]1([CH3:33])[CH3:32]
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A stirred solution of 0.25 g (0.0012 mole) of 4-phenyl-2-indanol and 0.11 g (0.0014 mole) of pyridine in 10 ml of toluene was cooled to 5° C., and a solution of 0.28 g (0.0011 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride, prepared in accordance with Example 8, in 5 ml of toluene was added portionwise. Upon complete addition the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to a residual oil. The oil was placed on a silica gel pad, and the product was eluted with 50 ml of 1:1 hexane:toluene. The eluate was concentrated under reduced pressure at 100°-115° C./0.02 mm using a Kugelrohr distilling system to give 0.12 g of 4-phenyl-2-indanyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:44]([CH3:46])[CH3:45])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36]CC5C=CC=CC=5)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.O[Li].O>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:44]([CH3:45])[CH3:46])[CH:28]4[CH2:29][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH2:31]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 123 %

Procedure:
To a solution of benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoate (2.7 g, 3.78 mmol) in THF/MeOH (15 mL/15 mL) was added a solution of LiOH.H2O (1.6 g, 37.82 mmol) in water (5 mL). The mixture was stirred at 30° C. for 2 h. The volatiles were removed under reduced pressure. To the residue was diluted with water (10 mL) and extracted with EA (15 mL×2). The suspension water layers were adjusted to pH=3-4 with 1 N HCl solution and extracted with EA (30 mL×3). The combined organic layers were washed with brine (50 in L). The organic phase was dried over Na2SO4, filtered and concentrated to afford the desired compound as a yellow solid (2.9 g). 1H NMR (500 MHz, MeOD): δH 8.20 (s, 1H), 7.92 (s, 0.5H), 7.38-7.32 (m, 3H), 7.28-7.23 (m, 1.5H), 7.14 (d, J=8.5 Hz, 1H), 6.68 (brs, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.44 (d, J=8.5 Hz, 1H), 6.25 (s, 1H), 5.51-5.47 (m, 1H), 5.18-5.13 (m, 1H), 4.66 (s, 2H), 4.61 (s, 1H), 4.43-4.40 (m, 1H), 3.96-3.90 (m, 0.5H), 3.85 (s, 3H), 3.77 (s, 3H), 3.65-3.58 (m, 0.5H), 3.50-3.40 (m, 2H), 2.46-2.36 (m, 1H), 2.20-2.00 (m, 4H), 1.98-1.70 (m, 2.5H), 1.70-1.58 (m, 4.5H), 1.40 (s, 3H), 1.18 (d, J=5.0 Hz, 3H), 0.90 (t, J=6.0 Hz, 3H) ppm; ESI-MS (m/z): 624.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(Cl)(Cl)Cl.Cl.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
3 g of cis-(+)-2-(4'-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one and 6.4 g of barium hydroxide octahydrate were added with vigorous stirring to 60 ml of chloroform and 10 ml of water. A solution of 3.2 g of 2-(dimethylamino)-ethyl chloride-hydrochloride in 5 ml of water was added dropwise to the above mixture in the course of 5 minutes. Stirring was continued for 24 hours at room temperature and then for 8 hours at 40°. After cooling to room temperature the aqueous phase was separated and discarded and the chloroform was removed under vacuum. Petroleum-ether (40°-60°) was added to the viscous residue which induced crystallisation. The precipitated crystals were filtered off and dried under vacuum to yield 3.63 g of cis-(+)-2-(4'-methoxyphenyl)-3-hydroxy-5-(2'-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one; m.p. 88°; [α]D22 +169 (C=0.25 CH 3 OH).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[NH2:20])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([NH:20][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COc1ccc(N)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncccc2[N+](=O)[O-])cc1OC1CCCC1
Yield: 32.9 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (2.17 g), 3-cyclopentyloxy-4-methoxyaniline (2.58 g) and potassium carbonate (2.6 g) in 1,4-dioxane (30 ml) was stirred under reflux for 20 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]-3-nitropyridine (1.35 g) as an orange solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[C:16](/[CH:18]=C/OCC)[N:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[N:13]=3)[CH2:7][CH2:6]2)O[CH2:3][CH2:2]1.[OH2:27].I([O-])(=O)(=O)=[O:29].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[O:27]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:13]=[C:14]([C:23]([F:26])([F:25])[F:24])[N:15]=[C:16]([CH:18]=[O:29])[CH:17]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCO/C=C/c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-6-[(E)-2-ethoxyvinyl]-2-(trifluoromethyl)pyrimidine (2.50 g, 6.68 mmol) was dissolved in 1,4-dioxane (190 mL,) and water (48 mL) and then sodium periodate (4.3 g, 20. mmol, Aldrich) was added, followed by a 4% solution of osmium tetraoxide in water (1.47 mL, 0.232 mmol). The solution began to form a whitish solid after a few minutes. The reaction was stirred at 25° C. for 48 hours until LCMS analysis of the reaction mixture showed no starting material present. The reaction was transferred to a separatory funnel and partitioned between water and EtOAc, the phases were separated, and then the aqueous phase was washed with EtOAc. The combined organic phase was washed with water, then saturated NaCl, dried over MgSO4 and filtered and stripped to dryness to leave the crude product. The crude material was used in the next reaction without purification. 1H NMR (400 MHz, CDCl3) δ: 10.01 (s, 1H), 7.33 (s, 1H), 5.38 (m, 1H), 3.97 (s, 4H), 1.20-2.05 (m, 8H).