Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.C[Al](C)C.C1N2CCN(CC2)C1.Cl.[F:18][C:19]([F:30])([F:29])[CH2:20][S:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[NH2:31][C:32]1[N:37]=[C:36]([N:38]([CH3:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:35]=[C:34]([C:46]2[N:50]=[C:49]([C:51](OCC)=[O:52])[O:48][N:47]=2)[N:33]=1>C1COCC1>[CH3:45][N:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36]1[N:37]=[C:32]([NH2:31])[N:33]=[C:34]([C:46]2[N:50]=[C:49]([C:51]([N:26]3[CH2:27][CH2:28][CH:23]([CH2:22][S:21][CH2:20][C:19]([F:29])([F:18])[F:30])[CH2:24][CH2:25]3)=[O:52])[O:48][N:47]=2)[N:35]=1
Reactant: CCOC(=O)c1nc(-c2nc(N)nc(N(C)c3ccccc3)n2)no1
Reactant: FC(F)(F)CSCC1CCNCC1
Agent: C1CN2CCN1CC2
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(=O)N3CCC(CSCC(F)(F)F)CC3)n2)n1
Reaction time: 2 h
Yield: 11 %

Procedure:
Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (225 mg, 0.88 mmol) was added to 4-{[(2,2,2-trifluoroethyl)sulfanyl]methyl}piperidine hydrochloride (Intermediate 267, 219 mg, 0.88 mmol) in dry THF (6 mL) in a sealed tube at room temperature. The reaction mixture was stirred at 40 C for 2 h. Ethyl 3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazole-5-carboxylate (prepared in an analogous manner to Example 73, 200 mg, 0.58 mmol) was added at 40 C. The reaction was heated at 80 C for 2 h before being concentrated under vacuum. The residue was taken up in DMSO (6 mL) and the inorganic residue was filtered off. The filtrate was purified by preparative HPLC, Method C, to provide two batches of the title compound (batch 1: 33 mg, 11%). Some impure product was recovered from the preparative HPLC purification, this material was concentrated, diluted with water (50 mL), acidified with a 1N aq. solution of HCl (to pH 4) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate. This crude material was then purified by preparative HPLC, Method C, to provide the title compound (Batch 2: 83 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:3]=1[NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1.[C:40]([C:43]1[CH:44]=[C:45]([N:49]2[C:53]([SH:54])=[N:52][N:51]=[N:50]2)[CH:46]=[CH:47][CH:48]=1)([OH:42])=[O:41].BrN1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:3]=1[NH:4][C:5]1[CH:9]([S:54][C:53]2[N:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([C:40]([OH:42])=[O:41])[CH:44]=3)[N:50]=[N:51][N:52]=2)[C:8](=[O:10])[N:7]([C:11]2[C:12]([Cl:19])=[CH:13][C:14]([Cl:18])=[CH:15][C:16]=2[Cl:17])[N:6]=1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Reactant: O=C(O)c1cccc(-n2nnnc2S)c1
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Sc2nnnn2-c2cccc(C(=O)O)c2)c1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
15 g of 3-(2-chloro-5-tetradecanamidoanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one and 5.4 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole were dissolved in 100 ml of DMF and to the solution was added dropwise at room temperature 20 ml of a DMF solution containing 4.9 g of N-bromosuccinimide. After stirring for 30 minutes, 500 ml of water was added to the mixture which was extracted with ethyl acetate. The ethyl acetate was distilled off under reduced pressure and the residue was crystallized from a solvent mixture of ethyl acetate and acetonitrile to obtain 14 g of 3-(2-chloro-5-tetradecanamidoanilino)-1-(2,4,6-trichlorophenyl)-4-[1-(3-carboxyphenyl)-5-tetrazolylthio]-2-pyrazolin-5-one. Yield: 68%. Melting Point: 155° to 165° C.
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:6]([C:17]([O:19][CH3:20])=[O:18])[CH2:5]1.CS(C)=O.[C-:25]#[N:26].[Na+].O>[Cl-].[Na+].O>[C:25]([CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:6]([C:17]([O:19][CH3:20])=[O:18])[CH2:5]1)#[N:26]
Reactant: [C-]#N
Reactant: COC(=O)[C@H]1C[C@@H](CCBr)CCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)[C@H]1C[C@@H](CCC#N)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 12.95 g (0.031 mol, containing triphenylphosphine oxide) of methyl cis-4-(2-bromoethyl)-N-t-butoxycarbonyl-2-piperidinecarboxylate and 40 ml of DMSO was added 2.30 g (0.047 mol) of sodium cyanide. The mixture was stirred for approximately 30 minutes at 50° C. To the mixture was added 50 ml each of water and brine and the mixture was extracted four times with methylene chloride and once with diethyl ether. The organic extracts were combined, washed twice with water and once with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The resultant residue was dissolved in 100 ml of ethyl acetate:hexane (1:3, v:v) and filtered through a one inch pad of silica gel (230-400 mesh) in a 150 ml medium porosity sintered glass funnel. The silica gel pad was washed with an additional 400 ml of ethyl acetate:hexane (1:3, v:v). The filtrate was concentrated under vacuum to afford 7.85 g of methyl cis-4-(2-cyanoethyl)-N-t-butoxycarbonyl-2-piperidinecarboxylate.
Reaction SMILES: [N:1]([C@@H:4]([C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH3:20])[C:5](N1[C@H](C2C=CC=CC=2)COC1=O)=[O:6])=[N+:2]=[N-:3].[OH2:28].OO.[OH-].[Li+]>C1COCC1>[N:1]([C@@H:4]([C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH3:20])[C:5]([OH:6])=[O:28])=[N+:2]=[N-:3]
Reactant: C[C@@H](c1ccc(Br)cc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1c1ccccc1
Reactant: O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)[C@H](N=[N+]=[N-])C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of the product from Step D (2.77 g, 6.23 mmol) in THF (60 mL) was added water (20 mL). The solution was stirred at 0° C. for 15 min, and then 30% hydrogen peroxide (6.0 mL, 52.9 mmol) was added followed by slow addition of lithium hydroxide (0.50 g, 21.2 mmol). The resultant mixture was stirred at 0° C. for 4 h. The reaction was quenched by addition of saturated aqueous sodium sulfite solution and stirred at room temperature for 30 min. The aqueous phase was separated and washed with three portions of dichloromethane. The aqueous phase was then acidified to pH 1 with 3N hydrochloric acid and extracted with three portions of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate, and evaporated in vacuo to give the product, which was used in the next step directly.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[C:16]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=2)=[N:15][N:14]=1>C(O)C>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[C:16]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[CH:27][CH:26]=2)=[N:15][N:14]=1
Reactant: COc1ccc2c(-c3ccc(CCl)cc3)nnc(Cl)c2c1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN(CC)Cc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
280 mg (2 mmol) of potassium carbonate and 0.3 mL of diethylamine are added to a solution of 319 mg (1 mmol) of 1-chloro-4-(4-chloromethylphenyl)-7-methoxyphthalazine (synthesized in 30.3) in 3 mL of ethanol. The mixture is stirred at 85° C. for 4 hours. The ethanol is evaporated off and the residue is taken up in water and extracted with dichloromethane. The organic extracts are washed with brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (solvent: 95/5 to 85/15 (v/v) dichloromethane/methanol). 287 mg of product are obtained (80% yield).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]3[S:25][C:24]([CH2:26][O:27][N:28]=[C:29]([CH3:31])[CH3:30])=[N:23][C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=1>C(Cl)(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]3[S:25][C:24]([CH2:26][O:27][N:28]=[C:29]([CH3:31])[CH3:30])=[N:23][C:18]=3[CH:19]=[N+:20]([O-:9])[C:21]=2[CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)=NOCc1nc2cnc3cc(Br)ccc3c2s1
Solvent: ClC(Cl)Cl
Product: CC(C)=NOCc1nc2c[n+]([O-])c3cc(Br)ccc3c2s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
mCPBA (5.50 g of 77% purity, 24.6 mmol) was added to a solution of acetone O-(7-bromo[1,3]thiazolo[4,5-c]quinolin-2-ylmethyl)oxime (3.44 g, 9.82 mmol) in chloroform (100 mL), and the reaction was stirred for 1.5 hours at room temperature and subsequently washed with aqueous sodium carbonate (100 mL of 10% w/w). The organic layer was dried over magnesium sulfate and filtered to provide a solution of acetone O-(7-bromo-5-oxido[1,3]thiazolo[4,5-c]quinolin-2-ylmethyl)oxime in chloroform.
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.O.[C:15]1(O)([CH3:24])[CH2:20][CH2:19][CH:18]([C:21]([CH3:23])=[CH2:22])[CH:17]=[CH:16]1>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[CH:12]=[C:1]([OH:13])[C:2]([C@@H:17]2[C@@H:18]([C:21]([CH3:23])=[CH2:22])[CH2:19][CH2:20][C:15]([CH3:24])=[CH:16]2)=[C:3]([OH:4])[CH:5]=1
Reactant: C=C(C)C1C=CC(C)(O)CC1
Reactant: CCCCCc1cc(O)cc(O)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: C=C(C)[C@H]1CCC(C)=C[C@@H]1c1c(O)cc(CCCCC)cc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
A mixture of olivetol (3.6 g, 20 mmol), zinc chloride (3.5 g, 26 mmol), water (3.5 mL, 19 mmol) and dichloromethane (35 mL) was refluxed for 1 hour. A solution of (−)-p-mentha-2,8-dien-1-ol (3.0 g, 20 mmol) in dichloromethane (10 mL) was added drop-wise over 0.75 hour to the refluxing mixture, and the resultant reaction mixture was mixed for 0.5 hours at reflux. The mixture was cooled to 25° C., ice water (50 mL) was added, and the resultant biphasic mixture stirred for 20 minutes at 0° C. The resultant organic phase was collected, washed with water (2×20 mL) and 5% NaHCO3 (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 6.0 g of first crude (+)-CBD residue. Analysis (GC) of the first crude (+)-CBD residue indicated that it contained (+)-CBD (46.9%) and abn-(−)-CBD (19.7%). The first crude (+)-CBD residue was purified by column chromatography on silica gel (eluent MTBE/hexane) to provide 2.4 g of a second crude (+)-CBD residue.
Reaction SMILES: [S:1]([OH:5])(O)(=O)=O.S1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:13]=2)[CH2:8][CH2:7]1.S1CCN(C2C3C(=C(OC)C=CC=3)C=C(N3CCNCC3)N=2)CC1.OO.O.O.O.Cl.C(O)(C)C>S(=O)(=O)(O)O>[O:5]=[S:1]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[N:13]=2)[CH2:8][CH2:7]1
Reactant: O=S(=O)(O)O
Reactant: COc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Agent: Cl
Agent: OO
Solvent: CC(C)O
Solvent: O
Product: COc1cccc2c(N3CCS(=O)CC3)nc(N3CCNCC3)cc12
Yield: 36 %

Procedure:
1-(1-Oxido--thiomorpholino)-3-piperazino-5-methoxy-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-5-methoxy-isoquinoline hemisulfate by oxidation with hydrogen peroxide in dilute sulfuric acid. M.p. of its hydrochloride trihydrate: 151°-153°C (decomposition; from isopropanol). Yield: 36% of theory.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([CH:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C[Si]([C:25]#[N:26])(C)C>>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:19]=[CH:18][C:7]([CH:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[C:25]#[N:26])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C#N
Reactant: CSc1ccc(N=Cc2ccc(OC(F)F)cc2)cc1
Product: CSc1ccc(NC(C#N)c2ccc(OC(F)F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-difluoromethoxybenzaldehyde and 4-methylthioaniline as starting materials, N-(4-difluoromethoxybenzylidene)-4-methylthioaniline was obtained in a yield of 91%. This aniline compound and trimethylsilyl cyanide were then reacted together in a similar manner to that described in Example 1(ii), to give the title compound as a slightly yellow powder (yield 80%).
Reaction SMILES: [NH3:1].C(O[C:5](=[N+:13]1[CH2:21][CH:20]2[CH:15]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:18][C:19]2=[O:22])[CH2:14]1)[CH2:6][C:7]1[CH2:12][CH:11]=[CH:10][CH2:9][CH:8]=1)C>C(O)C.ClCCl>[C:7]1([CH2:6][C:5]([N:13]2[CH2:21][CH:20]3[CH:15]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:17][CH2:18][C:19]3=[O:22])[CH2:14]2)=[NH:1])[CH2:12][CH:11]=[CH:10][CH2:9][CH:8]=1
Reactant: N
Reactant: CCOC(CC1=CCC=CC1)=[N+]1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Solvent: ClCCl
Solvent: CCO
Product: N=C(CC1=CCC=CC1)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Temperature: -15 °C
Reaction time: 20 h

Procedure:
A 5.4N solution (0.7 cc) of ammonia in ethanol is added to a stirred suspension of (3aRS,7aRS)-2-[1-ethoxy-2-(cyclohexa-1,4-dien-1-yl)-ethylidene]-4-oxo-7,7-diphenyl-perhydroisoindolium tetrafluoborate (2 g) in anhydrous dichloromethane (30 cc), which is cooled to -15° C. After the temperature has returned to ambient temperature, the reaction mixture is stirred for 20 hours and then washed with a 20% aqueous potassium carbonate solution (2×35 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (5 cc). The crystals obtained are drained, washed with acetonitrile and dried. (3aRS,7aRS)-2-[-2-(cyclohexa-1,4-dien-1-yl)-1-iminoethyl]-7,7-diphenyl-4-perhydroisoindolone (0.6 g) is obtained in the form of white crystals. m.p.=190° C.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]3[N:15]=[C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][N:17]4[C:18](=[O:21])[C:19]=3[CH3:20])=[CH:10][CH:9]=2)=[O:7])=[CH:4][N:3]=1.[N:30]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>N1C=CC=CC=1>[CH3:20][C:19]1[C:18](=[O:21])[N:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=[N:15][C:14]=1[O:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]2[CH:28]=[CH:29][C:2]([N:39]3[CH2:40][CH2:41][CH:36]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:37][CH2:38]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1c(OCc2ccc(C(=O)c3ccc(Cl)nc3)cc2)nc2ccccn2c1=O
Solvent: c1ccncc1
Product: Cc1c(OCc2ccc(C(=O)c3ccc(N4CCC(N5CCCCC5)CC4)nc3)cc2)nc2ccccn2c1=O

Procedure:
A solution of 2-[4-(6-chloronicotinoyl)benzyloxy]-3-methylpyrido[1,2-a]pyrimidin-4-one (0.49 g, 1.21 mmol) and 4-piperidinopiperidine (0.402 g, 2.39 mmol) in pyridine (15 ml) was stirred at 90° C. overnight. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (isopropyl ether: methylene chloride: methanol: ammonia=5:5:1:0.1) to provide a light-yellow oil.
Reaction SMILES: O.[CH2:2]([NH:9][C:10](=[O:19])[CH2:11][N:12]1[CH:15]([S:16][CH3:17])[CH2:14][C:13]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:24]O)(C)(C)C>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:2]([NH:9][C:10](=[O:19])[CH2:11][N:12]1[CH:15]([S:16]([CH3:17])=[O:24])[CH2:14][C:13]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OO
Reactant: CSC1CC(=O)N1CC(=O)NCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)C1CC(=O)N1CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4RSR-(-)-N-Benzyl-(4-methylsulphinyl-2-oxoazetidin-1-yl )acetamide A solution of S(-)1,1'-bi-2-napthol (0.012 g, 4.2 μmol) in toluene (2 ml) was treated with titanium isopropoxide (0.012 g, 21 μmol) in water (6 mg, 0.033 mmol). The resulting mixture was stirred at room temperature for 1 h. A solution of (-)-N-Benzyl (4-methylthio-2-oxoazetidin-1-yl)acetamide (0.2 g, 0.76 mmol) in toluene was added. After 30 mins t-butylhydroperoxide (136 mg, 1.5 mmol) was added and the mixture stirred for 3h. After evaporation to dryness, the residue was purified by flash chromatography on silica (EtOAc/EtOH 6:1 to 3:1) to give (-)-N-benzyl-(4-methylsulphinyl-2-oxoazetidin-1-yl)acetamide as a solid, 70 mg, 33% m.p. 138-140° C, [α]D25 =-237° (c=1.35, EtOH).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[Cl:13][C:14]1[C:15]([CH:20]=O)=[N:16][N:17]([CH3:19])[CH:18]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:20][C:15]1[C:14]([Cl:13])=[CH:18][N:17]([CH3:19])[N:16]=1
Reactant: Cn1cc(Cl)c(C=O)n1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: Cn1cc(Cl)c(C=NNC(=S)NC2CC3C=CC2C3)n1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (35 mg, 0.21 mmol) and 4-chloro-1-methylpyrazole-3-carboxaldehyde (41 mg, 0.287 mmol) similar to Example 3 and isolated as a white solid (15 mg, 24%). 1H NMR (CDCl3): 11.91 (s, 1H), 7.24 (s, 1H), 7.45 (s, 1H), 7.35 (s, 1H), 6.10 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 4.26 (t, J=7.5 Hz, 1H), 3.99 (s, 3H), 3.02 (s, 1H), 2.93 (s, 1H), 1.88 (ddd, J=8.4, 7.0, 2.7 Hz, 1H), 1.61 (m, 1H), 1.52-1.38 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.C[O:15][C:16](=[O:45])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32]C3C=CC(C(F)(F)F)=CC=3Br)[CH:27]=2)=[CH:21][C:20]=1[CH3:44]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([O:32][C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=2)[O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:45])=[O:15])=[C:20]([CH3:44])[CH:21]=2)=[C:5]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:8]=2)[CH:4]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3cccc(C(F)(F)F)c3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 3-trifluoromethylphenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 112 mg (63%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H22O4F6 560, found 561 (M+1, 100%).
Reaction SMILES: [CH3:1][C:2]([NH2:7])([CH2:5][CH3:6])[CH2:3][CH3:4].Cl[CH2:9][CH2:10][O:11][CH:12]([OH:14])[CH3:13].[OH-].[K+]>COCCO>[CH3:1][C:2]([NH:7][CH2:9][CH2:10][O:11][CH:12]([OH:14])[CH3:13])([CH2:5][CH3:6])[CH2:3][CH3:4]
Reactant: CC(O)OCCCl
Reactant: CCC(C)(N)CC
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Product: CCC(C)(CC)NCCOC(C)O

Procedure:
A solution of 124.7 g of 1-methyl-1-ethylpropylamine and 76.9 g of 2-chloroethoxyethanol in 300 ml of ethylene glycol monomethylether was refluxed overnight. The reaction mixture was treated with a stoichiometric excess of KOH and refluxed for one hour, filtered, and distilled. The product had a b.p. of 153° C. (2 mm). Analysis calculated for C10H23NO2 :% N, 7.4, found %N, 7.15.
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:20]3[C:14](=[C:15]([N+:17]([O-])=[CH:18][N:19]=3)[NH2:16])[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[OH-].[Na+].[NH4+].N1C=CC=CC=1.C(=S)=[S:32]>>[CH:12]1[N:11]([C@@H:2]2[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]2[OH:4])[C:20]2[C:14](=[C:15]([NH2:16])[NH:17][C:18]([N:19]=2)=[S:32])[N:13]=1
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Reactant: S=C=S
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 98 %

Procedure:
In the same manner as described in Example 11, 9.6 g of adenosine 1-oxide monohydrate was treated with a 5N sodium hydroxide aqueous solution and Diaion SK-1B (ammonium-type) to obtain a residue. 200 ml of pyridine and then 60 ml of carbon disulfide were added to the above residue, and the resulting mixture was allowed to react in an autoclave at 120° C for 5 hours under autogenous pressure (about 10 Kg/cm2). The reaction mixture was concentrated to dryness, and the residue was worked up in the same manner as described in Example 11 to obtain 9.35 g of 2-thioadenosine as crystals having a melting point of 197° C (with decomposition) in a 98% yield.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.[CH2:19](O)[CH3:20]>OS(O)(=O)=O.C1(C)C=CC=CC=1>[OH:1][N:2]=[C:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(CC2CCCC2=NO)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(CC2CCCC2=NO)cc1

Procedure:
Another method is also possible: a mixture of 5.8 g of 4-[(2-hydroxyiminocylcopentyl)methyl]-benzeneacetic acid, 4.1 ml of ethanol 98° and 2 drops of concentrated H2SO4 in 20 ml of toluene is refluxed for 6 hours, in a reactor above which there is a Dean-Stark separator. After cooling, the toluene is washed with a solution of NaHCO3, then with H2O. The organic phase is dried over Na2SO4 and is concentrated. The product obtained is in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[O:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=2)[NH:4][N:3]=1.CC(C)([O-])C.[Na+].[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>C1COCC1>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[O:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=2)[N:4]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[N:3]=1
Reactant: Clc1n[nH]c2ccc(C3OCCCO3)cc12
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(Cl)c2cc(C3OCCCO3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2.7 g (11.3 mmol) 3-chloro-5-(1,3-dioxan-2-yl)-1H-indazole (Example 44A) in anhydrous THF (60 ml) were added 1.31 g (13.6 mmol) sodium tert-butoxide at room temperature. The solution was cooled to 0° C., and 2.26 g (13.6 mmol) 2-(trimethylsilyl)ethoxymethyl chloride were added at this temperature. The resulting mixture was stirred at 0° C. for 1 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and with brine. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography (silica gel; cyclohexane/ethyl acetate 5:1 v/v) to give 1.73 g (41% of th.) of the title compound.