Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[CH:8])(C)(=O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([OH:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:5]([N:19]1[CH2:18][CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)([OH:22])[CH2:21][CH2:20]1)[CH2:6][C:7]#[CH:8]
Reactant: C#CCCS(C)(=O)=O
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Yield: 87.2 %

Procedure:
A mixture of 1-mesylbut-3-yne (1.48 g, 10.0 mmol), 4-(4-chlorophenyl)-4-hydroxypiperidine (2.54 g, 12.0 mmol) and K2CO3 (4.14 g, 30.0 mmol) in CH3CN (25 mL) is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×30 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a colorless solid (2.30 g, 87%): mp 98-100° C.; 1H NMR (CDCl3) 1.55 (s, 1 H), 1.74 (m, 2 H), 1.99 (m, 1 H), 2.10 (m, 2 H), 2.42 (m, 4 H), 2.65 (m, 2 H), 2.79 (m, 2 H), 7.32 (d, J=7.2 Hz, 2 H), 7.42 (d, J=7.2 Hz, 2 H).
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2)[CH2:5]1.CN1CCOCC1.[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](Cl)=[O:47]>C(Cl)Cl>[ClH:43].[CH3:2][N:3]([CH:4]1[CH2:8][CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2)[CH2:5]1)[C:46]([C:45]1[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=1[Cl:43])=[O:47]
Reactant: CCCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(NC)CC2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(N(C)C(=O)c3ccccc3Cl)CC2c2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 1-(RS)-(methylamino)-3-(SR)-((4-(N-(benzyloxycarbonyl)-N-(propyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane hydrochloride from Step A (5.5 mg, 0.012 mmol) in methylene chloride (1 mL) was added N-methyl morpholine (0.005 mL, 0.035 mmol) and 2-chlorobenzoyl chloride (4 mg, 0.024 mmol). After 16 h, the reaction was concentrated and the residue purified on Prep TLC to afford the free amine of the title compound. This was taken up in ether and excess 1N hydrogen chloride in ether was added. The volatiles were removed under a stream of nitrogen and evaporated to dryness under vacuum.
Reaction SMILES: [C:1](#N)C.[F:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:16][CH3:17])[C:14]=1F)[N:11]([C@@H:18]1[CH2:20][C@@H:19]1[F:21])[CH:10]=[C:9]([C:22]([OH:24])=[O:23])[C:8]2=[O:25].Cl.Cl.C([CH:35]1[C:37]2([C@:41]([CH3:43])([NH2:42])[CH2:40]N[CH2:38]2)[CH2:36]1)C1C=CC=CC=1>C(N(CC)CC)C>[OH2:16].[OH2:16].[NH2:42][C@:41]1([CH3:43])[C:37]2([CH2:36][CH2:35]2)[CH2:38][CH:1]([C:14]2[C:13]([O:16][CH3:17])=[C:12]3[C:7]([C:8](=[O:25])[C:9]([C:22]([OH:24])=[O:23])=[CH:10][N:11]3[C@@H:18]3[CH2:20][C@@H:19]3[F:21])=[CH:6][C:5]=2[F:4])[CH2:40]1
Reactant: C[C@@]1(N)CNCC12CC2Cc1ccccc1
Reactant: CC#N
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1c(C2CC3(CC3)[C@@](C)(N)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Product: O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
An acetonitrile solution (800 mL) containing 6,7-difluoro-1,4-dihydro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-3-quinolinecarboxylic acid (90 g), benzyl-(7S)-7-methyl-5-azaspiro[2.4]heptan-7-amine dihydrochloride (90 g), triethylamine (39.9 mL), and boron trifluoride-tetrahydrofuran complex (63.4 mL) was stirred at room temperature for 30 minutes. Boron trifluoride-tetrahydrofuran complex (6.3 mL) was further added to the solution, followed by stirring for one hour at the same temperature. Triethylamine (159.5 mL) was further added to the reaction mixture, followed by stirring at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and methanol (900 mL) was added to the residue. The mixture was refluxed for 6 hours. After cooling to room temperature, the mixture was stirred at 40° C. for 5 hours under hydrogen in the presence of 5% Pd—C (4.5 g). Subsequently, triethylamine (90 mL) and water (225 mL) were added to the thus-obtained reaction mixture, followed by stirring at 40° C. for one hour. Pd—C was removed through filtration, and the filtrate was concentrated under reduced pressure. Water (720 mL) and methanol (180 mL) were added to the residue, and the pH of the product was adjusted to 8 by use of 5N aqueous sodium hydroxide solution. The thus-obtained mixture was stirred at 60° C. for 40 minutes, and the pH of the product was adjusted to 7 by use of 5N aqueous sodium hydroxide solution, followed by stirring at room temperature for one hour. The thus-produced crystals were recovered through filtration and dried, to thereby yield 120.9 g of the title compound as pale brown crystals (yield: 91%).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:12](=[O:14])O[C:10]([CH3:15])=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].CO>N1C=CC=CC=1>[CH3:15][C:10]1[N:17]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[C:12](=[O:14])[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 170 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
Step 4: Two vials each with a suspension of 5-nitro-2-methyl-benzo[d][1,3]oxazin-4-one (0.60 g, 2.91 mmol) and 3-amino-piperidine-2,6-dione hydrogen chloride (0.48 g, 2.91 mmol) in pyridine (15 mL) were heated at 170° C. for 10 minutes in a microwave oven. The suspension was filtered and washed with pyridine (5 mL). The filtrate was concentrated in vacuo. The resulting mixture was stirred in HCl (30 mL, 1N), ethyl acetate (15 mL) and ether (15 mL) for 2 hrs. The suspension was filtered and washed with water (30 mL) and ethyl acetate (30 mL) to give a dark brown solid, which was stirred with methanol (50 mL) at room temperature overnight. The suspension was filtered and washed with methanol to give 3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a black solid (490 mg, 27% yield). The solid was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[CH2:50]([C:52]1[N:57]=[C:56]([NH2:58])[CH:55]=[CH:54][CH:53]=1)[CH3:51]>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([NH:58][C:56]3[CH:55]=[CH:54][CH:53]=[C:52]([CH2:50][CH3:51])[N:57]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Reactant: CCc1cccc(N)n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)OC(C)(C)C)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.28 mL, 2.5 mmol). The reaction mixture was stirred for 2 hours. After this time, 6-ethyl-2-pyridinamine (159 mg, 1.3 mmol) was added to the mixture, which was then allowed to warm to room temperature and stirred for 3 hours. The solvent was removed under reduced pressure, and water (5 mL) and DCM (15 mL) were added to the resulting residue. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organic phases were dried over sodium sulfate and concentrated. The crude product residue was purified by Combiflash silica gel chromatography (0-100% EtOAc in hex) to provide 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (359 mg, 0.79 mmol, 79% yield) as a clear oil. MS: 457 ([M+H]+).
Reaction SMILES: C(=O)C1C=CC=CC=1.[O:9]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.COC1C=CC(/C=[C:42]2/[C:43]([NH:45][C:46]([S:48]/2)=[NH:47])=[O:44])=CC=1OC1CCCC1>>[O:9]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[C:42]4[S:48][C:46](=[NH:47])[NH:45][C:43]4=[O:44])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Solvent: O=Cc1ccccc1
Product: N=C1NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)cc2)S1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde benzaldehyde (Taylor, E. C., Strotnicki, J. S. Synthesis, 1981, 606) and pseudothiohydantoin according to the procedure of Example 35 as an orange solid; 1H NMR (300 MHz, DMSO-d6) δ 1.68 (t, J=5.6 Hz, 4 H), 3.43 (t, J=5.6 Hz, 4 H), 3.91 (s, 4 H), 7.06 (d, J=8.9 Hz, 2 H), 7.41 (d, J=8.9 Hz, 2 H), 7.48 (s, 1 H), 8.99 (brs, 1 H), 9.33 (brs, 1 H); MS (ES) m/z: 345.9 (MH+); HRMS Calcd. for C17H20N3O3S (MH+): 346.1226. Found: 346.1205. Anal. Calcd. for C17H19N3O3S: C, 59.11; H, 5.54; N, 12.16. Found: C, 58.80; H, 5.71; N, 12.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[CH3:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:20]([C:26]([C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[O:27])[CH:19]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1

Procedure:
[5-(2,6-Dimethyl-4-nitro-phenoxy)-2-methoxy-phenyl]-(4-fluoro-phenyl)-methanone was prepared by titanium tetrachloride-catalyzed Friedel-Crafts acylation of 4-(4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene with p-fluorobenzoyl chloride according to the procedure described in the J. Med. Chem., 1995, 695-707.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N+:23]([O-])=O.[H][H]>C(N(CC)CC)C.CN(C)C=O.[OH-].[Pd+2].[OH-]>[NH2:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3[N+](=O)[O-])c2cc1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(C)cc3N)c2cc1OC
Yield: 54.8 %

Procedure:
6,7-Dimethoxy-4-(4-methyl-2-nitrophenoxy)quinoline (480 mg) was dissolved in triethylamine/N,N-dimethylformamide (2 ml/10 ml), and palladium hydroxide (1.2 g) was added to the solution. The mixture was stirred at room temperature in a hydrogen gas atmosphere overnight. The reaction solution was filtered through Celite, and the solvent was removed therefrom by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 4-(2-amino-4-methylphenoxy)-6,7-dimethoxyquinoline (240 mg, yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:6]([C:5]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[C:4]=2[N+:16]([O-:18])=[O:17])=[O:8])=[N:27][CH:28]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2ccc(Br)cn2)c([N+](=O)[O-])c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4,5-trimethoxy-2-nitrobenzoic acid (0.5 g, 1.95 mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.34 ml, 3.9 mmol) and a few drops of dimethylformamide. The mixture was stirred at r.t. for 2 hrs. After the evaporation of the solvent, the residue was dissolved in dichloromethane (5 ml). 2-amino-5-bromopyridine (0.81 g, 4.7 mmol) and pyridine (0.94 ml, 11.7 mmol) were added to the solution. The mixture was stirred at r.t. overnight. After the evaporation of the solvent, the crude residue was purified by silica gel column chromatography using solvent system 25% ethyl acetate in hexane as eluent to give N-(5-bromo(2-pyridyl))(3,4,5-trimethoxy-2-nitrophenyl)carboxamide as a solid (790 mg; 98%). MS found for C15H14BrN3O6 M+=412, (M+2)+=414.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC(O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH:26]([OH:25])[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: OC1CCNC1
Product: CC(C)(C)c1nc(N2CCC(O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and pyrrolidin-3-ol and isolated as colorless foam. MS (m/e): 387.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)[CH:3]=1.C(N(CC)CC)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)[CH:3]=1)=[C:28]=[O:30]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C=Nc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 4-(4-amino-pyridin-2-ylmethyl)-2H-phthalazin-1-one (21) (0.40 g, 1.48 mmol) in anhydrous DCM (160 mL) and triethylamine (0.46 mL, 4.09 mmol), was added a dropwise preformed solution of triphosgene (0.27 g, 0.93 mmol) in anhydrous DCM (30 mL). The reaction was stirred for 6 hrs at room temperature. The reaction mixture was then concentrated to dryness in vacuo yielding a grey solid. Single peak in LC-MS analysis, (yield taken to be quantitative) no purification performed. m/z (LC-MS, ESP), RT=3.79 mins, (M+MeOH) 329.0.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([C:14]([F:17])([F:16])[F:15])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22]>C(OCC)C>[F:18][C:4]([F:3])([C:14]([F:15])([F:16])[F:17])[C@H:5]([O:6][S:21]([C:20]([F:26])([F:25])[F:19])(=[O:23])=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O[C@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(O[C@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 60% suspension of NaH in oil (2.35 g, 58.8 mmol) was washed several times with hexanes and after suspending it in anhydrous ethyl ether (100 mL), (R)-2,2,3,3,3-pentafluoro-1-(4-fluoro-phenyl)propan-1-ol (12.0 g, 49 mmol) in ether (20 mL) was added slowly at room temperature. After stirring for 15 min, the reaction mixture was cooled at 0° C. and trifluoromethylsulfonyl chloride (12.38 g, 73.7 mmol) was added. The reaction mixture was stirred for 1:30 h at 0° C., then concentrated under reduced pressure and the residue was diluted with hexane (100 mL). The reaction mixture was washed with sat. sol. NaHCO3, brine and dried over magnesium sulfate. After removing the solvent on rotovapor, trifluoro-methanesulfonic acid (R)-2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)propyl ester was obtained as a colorless oil (16.0 g).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][C:5]1[CH2:10][CH:9]=CC[CH:6]=1.[C:12]([OH:15])(=O)[CH3:13].II.C(OCC)(=[O:20])C>C([O-])(=O)C.[Ag+]>[CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][C:5]1[CH2:10][C@@H:9]([OH:20])[C@H:12]([OH:15])[CH2:13][CH:6]=1
Reactant: CCOC(C)=O
Reactant: CN(C)CCC1=CCC=CC1
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Agent: II
Product: CN(C)CCC1=CC[C@@H](O)[C@H](O)C1

Procedure:
A solution of 45 g. (0.3 moles) of 1-[2-(dimethylamino)-ethyl]-1,4-cyclohexadiene from Example 3(a) in 1.5 l. of dry glacial acetic acid is treated with 100 g. of silver acetate and 75 g. of iodine. The mixture is stirred until most of the iodine dissolves and is then heated for two hours at 95°. The reaction solution is cooled, filtered and evaporated in vacuo to give an oil. The oil is taken up in ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic phase is dried (MgSO4) and evaporated to an oil. The oil is taken up in ethyl acetate and treated with HCl in isopropanol. The resulting crude solid is removed by filtration and recrystallized from acetonitrile-ether to yield dl-trans-4-[2-(dimethylamino)-ethyl]-4-cyclohexene-1,2-diol, diacetate ester, hydrochloride salt.
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:13]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]([P:4](=[O:3])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[O:13])=[CH:16][CH:17]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Product: CCOP(=O)(OCC)C(=O)Oc1ccc(Cl)cc1

Procedure:
From 20 g (0.12 mole) of triethylphosphite and 19.1 g (0.10 mole) of 4-chlorophenyl chloroformate (prepared according to M. J. Zabik and R. D. Scheutz J. Org. Chem. 32 (1967) 300). (125° C., 2 hours). Yield 26.3 g (90%). Bp0.01 153°-6° C., nD21 1.4980.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[C:12]([C:13](=O)[CH3:14])=[CH:11][CH:10]=[CH:9][N:8]=1.[ClH:16].NO.C[N:20]([CH3:23])C=O>>[Cl:16][C:13]([C:12]1[C:7]([Cl:6])=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:14][C:23]#[N:20]
Reactant: Cl
Reactant: CN(C)C=O
Reactant: CC(=O)c1cccnc1Cl
Agent: NO
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC=C(Cl)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
100 ml of dimethyl formamide (DMF) were cooled to 0° C. and POCl3 (35.47 g, 231 mmol, 3 eq.) added dropwise. The reaction was stirred 30 min at 0° C. and a solution of 2-chloro-3-acetyl-pyridine (12 g, 77.12 mmol, 1 eq.) in 15 ml of dimethyl formamide (DMF) was added. Once all added the reaction was warmed to 50° C. and stirred for 8 h. The mixture was cooled to 0° C. and hydroxylamine hydrochloride (21.43 g, 308 mmol, 4 eq.) was added by portions very carefully (exothermic). Once all added the reaction was stirred at room temperature for 2 h and quenched with water. The medium was basified until pH 2-3 was reached with 1N aqueous NaOH and extracted with ethylacetate. The organic layer was washed with brine and dried over MgSO4. Removal of all volatiles under reduced pressure afforded 3-chloro-3-(2-chloropyridin-3-yl)acrylonitrile (13.21 g, 81% yield) as a mixture of isomers which was used without further purification.
Reaction SMILES: [I-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:52][C:53]([F:65])([C:58]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=1)[CH:54](OC)O>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([CH:15]=[CH:54][C:53]([F:65])([F:52])[C:58]2[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: COC(O)C(F)(F)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(F)(F)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (500 mg, 0,92 mmol) from Step C in THF (7.2 mL) was stirred at rt for 30 min. A 0.5 M toluene solution of potassium bis(trimethylsilyl)amide (1.8 mL, 0.90 mmol) was added over 3 min., giving an orange suspension. After 30 min., crude 2,2-difluoro-2-(4-fluorophenyl)-1-methoxyethanol (95 mg, 0.46 mmol) was added in THF (1.0 mL). After an additional 30 min, the mixture was quenched by the addition of saturated aq. NH4Cl (2 mL). The mixture was partitioned between ethyl acetate (50 mL) and water (75 mL), and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were washed in succession with saturated aq. brine (25 mL), dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 10% ether in hexane to give 117 mg of the title compound as a 95:5 mixture of cis and trans isomers, respectively.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:19]=[C:20]([C:24]4([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:21]=[CH:22][CH:23]=3)=[CH:13][CH:12]=2)[N:7]=[C:6]1[CH3:32])[CH3:4]>C(O)(C)C.CO>[CH2:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:19]=[C:20]([C:24]4([C:30]([NH2:31])=[O:1])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:21]=[CH:22][CH:23]=3)=[CH:13][CH:12]=2)[N:7]=[C:6]1[CH3:32])[CH3:4]
Reactant: CCn1c(C)nn(-c2ccc(Sc3cccc(C4(C#N)CCOCC4)c3)cc2)c1=O
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)O
Product: CCn1c(C)nn(-c2ccc(Sc3cccc(C4(C(N)=O)CCOCC4)c3)cc2)c1=O
Temperature: 95 °C

Procedure:
Solid potassium hydroxide (0.035 g, 0.6333 mmol) was added to a solution of 4-(3-{[4-(4-ethyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carbonitrile (0.070 g, 0.166 mmol) (example 9) in isopropyl alcohol and methanol mixture (3 mL). The reaction mixture was heated at about 90-100° C. for about 12-15 hours. The solvent was evaporated under vacuum and water was added. A white solid separated out, which was filtered and dried under vacuum to afford the title compound. Yield: 0.045 g.