Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>ClCCCl>[N:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][C:5]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: c1ccc(Oc2ccncc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCCl
Product: O=S(=O)(O)c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a vigorously stirred solution of 1.00 kg (5.85 mol) of 4-phenoxypyridine (Tetrahedron, 1978, 34, 2069-2076) in dry 1,2-dichloroethane (3000 L) at -10° C. under a stream of argon was added chlorosulfonic acid (974 mL) at a rate so as to maintain the reaction temperature below 0° C. After half of the chlorosulfonic acid was added, the exotherm stopped. The cooling bath was removed and the addition of chlorosulfonic acid continued over 3 hours while the reaction solution warmed to room temperature. While continually purging with argon, the vigorously stirred reaction mixture was heated to 45° C. After 20 hours, the reaction mixture was cooled to room temperature and slowly poured into vigorously stirred ice cold water (5 L). Potassium phosphate tribasic (212 g) was added as a solid to the mixture and this was stirred for 10 minutes followed by addition of sodium hydroxide (2M) to pH 2. After stirring for 1 hour, the pH was changed to 7 by the addition of sodium hydroxide (2M). Agitation was continued for 5 minutes; then the organic layer was drained off and discarded. The mixture was extracted a second time with dichloromethane (2 L), and the organic layer drained off and discarded. The remaining aqueous phase was extracted with tetrabutylammonium bromide (940 g) in dichloromethane (6L), adjusting the aqueous phase to pH 7 with 2M aq. sodium hydroxide as necessary. The extraction was repeated two more times and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved with 20% ethanol in ethyl acetate (8 L, dry), and hydrogen chloride gas added to achieve a pH of 1. The solid was filtered off, and the filter cake was rinsed with the precipitation solvent mixture (20% ethyanol in ethyl acetate, 2 L). The solid was dried under vacuum at 45° C. for 15 hours to yield 4-(pyrid-4-yl)oxybenzenesulfonic acid (1.3 kg) as a white powdery solid.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1.[Xe](F)[F:21]>C(#N)C.C(OCC)(=O)C>[F:21][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[C:8]1[C@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:13][C:7]=1[CH:6]=[CH:5]2
Reactant: CC(=O)NCC[C@@H]1CCc2ccc3nn(C)cc3c21
Reactant: F[Xe]F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)NCC[C@@H]1CCc2ccc3nn(C)c(F)c3c21
Reaction time: 18 h
Yield: 8 %

Procedure:
To a solution of N-{2-[(8S)-2-methyl-2,6,7,8-tetrahydrocyclopenta[e]indazol-8-yl]ethyl}acetamide (1.01 g, 3.91 mmol) in acetonitrile (39.2 mL) was added xenon difluoride (728 mg, 4.30 mmol) under ice-cooling, and the mixture was stirred for 18 hr. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=50/50→100/0) and preparative TLC (methanol/ethyl acetate=10/90) to give the title compound (86.4 mg, yield 8.0%).
Reaction SMILES: [Na].[F:2][C:3]([F:10])([F:9])[C:4]([O:6]CC)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1>C(O)C>[F:10][C:3]([F:2])([F:9])[C:4]([CH:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)[C:19]#[N:20])=[O:6]
Reactant: CCOC(=O)C(F)(F)F
Reactant: N#CCc1ccc(F)cc1
Agent: [Na]
Solvent: CCO
Product: N#CC(C(=O)C(F)(F)F)c1ccc(F)cc1
Yield: 90.6 %

Procedure:
Dry ethanol (15 ml) was added to sodium metal (1.22 g, 0.0530 mole) and the mixture was heated under reflux to dissolve sodium metal perfectly. A mixture of ethyl trifluoroacetate (7.53 g, 0.0530 mole) and p-fluorophenylacetonitrile (6.76 g, 0.0500 mole) was added dropwise over 30 minutes. The mixture, after being heated under reflux for 10 hours, was extracted with methylene chloride to remove neutral and basic components. To the mixture was then added 36% hydrochloric acid to adjust below pH 2 and the mixture was extracted with diethyl ether again. After being dried, the solvent was distilled off under reduced pressure to give the crude title compound (10.47 g, 84.0%). The product showed a single spot on thin-layer chromatography. The product was recrystallized from benzenecyclohexane to recover the monohydrate of the title compound (8.97 g, 77.0%) as pale yellow prisms. The structure of this compound was confirmed by IR and NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:31]1([Mg]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CO.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[OH:23])[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(O)c3ccccc3)n2)ccc1-n1cnc(C)c1

Procedure:
2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine-4-carbaldehyde (0.10 g, 0.24 mmol) was dissolved in THF (5 mL). The mixture was cooled on an ice bath and phenylmagnesium bromide (3 M, 0.79 mL, 2.37 mmol) was added over 30 min. MeOH and ammonium chloride (aq, sat) were added. The mixture was extracted with EtOAc (×2). The organic phase was filtered through a pad of silica and sodium sulfate. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a dry film, 50 mg (22%).
Reaction SMILES: O1CCCC1.CS(C)=O.[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[N+:25]([O-:27])=[O:26])=[CH:19][CH:18]=1.C(O)(=O)C.[BH4-].[Na+]>O>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N+:25]([O-:27])=[O:26])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(CCC2CCCO2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(CCC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To a mixed tetrahydrofuran-dimethyl sulfoxide (1:1, 10 mL) solution of 4-(2-(tetrahydrofuran-2-yl)-ethyl)-((E)-2-nitro-vinyl)-benzene (646 mg, 2.61 mmol) described in Manufacturing Example 82-1-4 and acetic acid (0.6 mL) was added sodium borohydride (148 mg, 3.92 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Water was added dropwise into the reaction mixture at room temperature while cooling appropriately. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate:heptane=2:8) to obtain the title compound (421 mg, 65%).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH:7]([N:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=[N:10]1)[CH3:8])(C)(C)C.Cl>O1CCOCC1>[CH3:17][O:16][C:14]([C:13]1[N:9]([CH:7]([CH3:8])[C:6]([OH:18])=[O:5])[N:10]=[N:11][CH:12]=1)=[O:15]
Reactant: COC(=O)c1cnnn1C(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cnnn1C(C)C(=O)O
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a stirred solution of 0.40 g (1.6 mmol) of methyl 1-(2-tert-butoxy-1-methyl-2-oxoethyl)-1H-1,2,3-triazole-5-carboxylate from step A above in 3 mL of anhydrous 1,4-dioxane was added 2.7 mL (11 mmol) of a 4.0 M hydrogen chloride solution in 1,4-dioxane. The resulting mixture was stirred for 1 h and then evaporated to dryness to afford the title compound as an off-white solid (0.27 g, 87%). LC-MS: m/z (ES) 200 (MH)+.
Reaction SMILES: COC(=O)C([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)NC(=O)CN(S(C1C=CC(C)=CC=1)(=O)=O)C.[Na].[C:30]([NH:33][CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])[CH3:31].Cl.N1C=CC(CCl)=CC=1>CCO>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:34]([NH:33][C:30](=[O:32])[CH3:31])([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: COC(=O)C(Cc1ccncc1)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: ClCc1ccncc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccncc1)(NC(C)=O)C(=O)OCC

Procedure:
N-(Toluene-4-sulfonyl)sarcosyl-β-(pyrid-4-yl)-D,L-alanine methyl ester was employed in this reaction and was prepared as follows. Sodium metal (2 eq.) was dissolved in EtOH containing diethyl acetamidomalonate (1 eq.) and 4-picolylchloride hydrochloride (1 eq.). The mixture was heated to reflux for 6 hr, and then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture was taken up into saturated aq NaHCO3 and extracted with EtOAc. The solvent was removed and the residue purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to give diethyl 2-(4-pyridylmethyl)-2-acetamidomalonate.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[CH2:18]([C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
A mixture of ethyl isonipecotate (65 mmol; 10.2 g), anhydrous potassium carbonate (195 mmol; 26.9 g) and benzyl bromide (78 mmol; 13.36 g) in anhydrous N,N-dimethylformamide (100 ml) was stirred at 70° C. for 18 hours. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with saturated NaCl solution (3×100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with chloroform) to give 13.84 g (86%) of pure product as a yellow oil.
Reaction SMILES: C(C1SC=CC=1)(=O)C.[CH3:9][CH2:10][CH2:11][CH2:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].CCCCCCCCCCCCCCCCCC(CCCCCCCCCCCCCCCCC)=O.Cl[Si](CC)(CC)CC.[F:63]OC(F)(F)F>>[F:63][CH:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10][CH3:9]
Reactant: CCCCC(=O)CCCC
Reactant: FOC(F)(F)F
Agent: CC(=O)c1cccs1
Agent: CCCCCCCCCCCCCCCCCC(=O)CCCCCCCCCCCCCCCCC
Agent: CC[Si](Cl)(CC)CC
Product: CCCCC(=O)C(F)CCC

Procedure:
Similarly, 2-acetylthiophene, 5-nonanone and stearone give, for example, by treatment with chlorotriethylsilane, the corresponding siloxy compounds which, upon reaction with trifluoromethyl hypofluorite, give 2-β-fluoroacetylthiophene, 4-fluorononane-5-one and α-fluorostearone, respectively.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH3:9].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH:25][CH:26]1[CH2:27][CH2:28][N:29]([CH2:3][C:4]2[NH:8][CH:7]=[N:6][C:5]=2[CH3:9])[CH2:30][CH2:31]1
Reactant: Cc1nc[nH]c1CCl
Reactant: c1coc(Cn2c(NC3CCNCC3)nc3ccccc32)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1CN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Temperature: 70 °C
Yield: 60.2 %

Procedure:
A mixture of 3.4 parts of 5-(chloromethyl)-4-methyl-1H-imidazole monohydrochloride, 6 parts of 1-(2-furanylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 4.25 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred and heated for 3 hours at 70° C. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and methanol, yielding 4.7 parts (60.2%) of 1-(2-furanylmethyl)-N-[1-[(4-methyl-1H-imidazol-5-yl)methyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 242.1° C. (compound 1).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([CH:19]4[CH2:23][CH2:22][CH2:21][NH:20]4)[CH:18]=2)[O:15][C:14]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:13][C:12]3=[O:30])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Br[C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[F:63][C:60]1[CH:61]=[CH:62][C:57]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[C:17]2[CH:18]=[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:13][C:12]3=[O:30])=[CH:58][CH:59]=1
Reactant: O=C(c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Reactant: Fc1ccc(Br)cc1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(c1cc(C2CCCN2c2ccc(F)cc2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Temperature: 100 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
Diacetoxypalladium (6.79 mg, 0.03 mmol) was added to a stirred mixture of 6-(morpholine-4-carbonyl)-2-morpholino-8-(pyrrolidin-2-yl)-4H-chromen-4-one (250 mg, 0.60 mmol), biphenyl-2-yldicyclohexylphosphine (21 mg, 0.06 mmol), 1-bromo-4-fluorobenzene (0.083 ml, 0.76 mmol) and cesium carbonate (296 mg, 0.91 mmol) dissolved in 1,4-dioxane (5 mL). The resulting suspension was degassed with argon and then stirred at 100° C. for 15 h. The reaction mixture was purified by preparative HPLC. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (140 mg, 46%) as a gum.
Reaction SMILES: C(OC(N=NC(OCC)=O)=O)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.O[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1
Reactant: OC1CCOCC1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc(OC2CCOCC2)cc1
Reaction time: 72 h

Procedure:
A mixture of 4.0 mL of diethyl-azodicarboxylate in 20 mL of dry tetrahydrofuran was added at 5° C. to a stirred solution of 3.5 g of 4-bromo-phenol, 2.4 mL of 4-hydroxy-tetrahydropyran and 6.6 g triphenylphosphine in 75 mL of tetrahydrofuran within 30 minutes. Stirring was continued at room temperature for 72 hours. The solvent was evaporated in vacuo and the residue chromatographed on silica gel (ethyl acetate) yielding 5.6 g of 4-(4-bromo-phenoxy)-tetrahydropyran as a white solid. M.p. 53-55° C., EI-MS: 256 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([CH:8]1[CH:13]([C:14](O)=[O:15])[CH2:12][CH:11]=[CH:10][CH2:9]1)=O.O.[NH2:23][NH2:24]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH:8]3[CH:13]([CH2:12][CH:11]=[CH:10][CH2:9]3)[C:14](=[O:15])[NH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C(=O)C2CC=CCC2C(=O)O)cc1OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNC(=O)C3CC=CCC23)cc1OC
Temperature: 25 °C

Procedure:
A mixture of 6-(3,4-dimethoxy-benzoyl)-cyclohex-3-enecarboxylic acid (112 mg, 0.39 mmol, 1.0 eq) and hydrazine hydrate (31 mg, 0.96 mmol, 2.5 eq) in EtOH (3 mL) was refluxed for 4 hr. The reaction was then cooled to room temperature and then concentrated under reduced pressure to oil. The oil was dissolved in EtOAc and washed with water followed by brine. The organic layer was then dried over Na2SO4, filtered through paper, and concentrated under reduced pressure to oil. The product was recrystallized in EtOH to yield a white solid.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=CN=[CH:5][CH:4]=1.COC1CCC(OC)O1.[CH3:18][C:19]1[C:20]([NH2:28])=[C:21]([C:24]([O:26][CH3:27])=[O:25])[S:22][CH:23]=1>O1CCOCC1>[CH3:18][C:19]1[C:20]([N:28]2[CH:5]=[CH:4][CH:3]=[CH:8]2)=[C:21]([C:24]([O:26][CH3:27])=[O:25])[S:22][CH:23]=1
Reactant: Clc1ccncc1
Reactant: COC(=O)c1scc(C)c1N
Agent: COC1CCC(OC)O1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1scc(C)c1-n1cccc1
Yield: 91 %

Procedure:
43.8 g (0.292 mol) of 4-chloropyridine hydrochloride and 38.59 g (0.292 mol) of 2,5-dimethoxytetrahydrofuran are stirred for 10 minutes at room temperature in 600 ml of dioxane. 50 g (0.292 mol) of methyl 4-methyl-3-aminothiophene-2-carboxylate are added and the suspension is heated at reflux for 3 hours. The dioxane is removed under reduced pressure, and the residue is taken up in 1 liter of water and then extracted with 1 liter of diethyl ether. The ethereal phase is washed with water, decanted off, dried over magnesium sulfate, rendered colourless with animal charcoal and concentrated under reduced pressure to yield the title compound.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].[Li]CCCC.[P:13](Cl)([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:16]([O:15][P:13]([CH2:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3])([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOS(C)(=O)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A solution of ethyl methanesulfonate (4.27 mL, 40.3 mmol) in 100 mL of dry THF was treated at -78° C. with 19.3 mL (44.4 mmol) of n-BuLi in hexane. After 15 min. diethyl chlorophosphate (3.30 ml, 22.2 mmol) was added. The solution was kept at -78° C. for 0.5 h and allowed to stay at -50° C. for 1 h. Saturated ammonium chloride (75 mL) was added to the solution and the mixture warmed to room temperature. The mixture was concentrated (THF removed), diluted with water and extracted with methylene chloride (3×70 mL). The combined organic fractions were dried (MgSO4), concentrated and purified by distillation to yield 3.86 g (70%) of title compound.
Reaction SMILES: [Cl:1]C1C=C([C@H]2[C@@H](C3C=CC=CC=3)CCNC2)C=CC=1.[C:20]1([S:26](N2CC[C@H](C3C=CC=CC=3)[C@H](C3C=CC=C(Cl)C=3)C2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26]([Cl:1])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1cccc([C@@H]2CNCC[C@@H]2c2ccccc2)c1
Reactant: O=S(=O)(c1ccccc1)N1CC[C@H](c2ccccc2)[C@H](c2cccc(Cl)c2)C1
Product: O=S(=O)(Cl)c1ccccc1

Procedure:
In analogy to Example 38, from rac-cis-3-(m-chlorophenyl)-4-phenylpiperidine (CAS Reg. No.: [735259-16-2]) and benzenesulfonyl chloride was prepared cis-1-benzenesulfonyl-3-(3-chloro-phenyl)-4-phenyl-piperidine as colorless oil, MS: 412.2 (M+H, 1Cl)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([OH:38])[CH2:36][OH:37])=[CH:31][C:30]=2[N:39]2[CH:43]=[CH:42][C:41]([CH3:44])=[N:40]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([OH:38])[CH2:36][OH:37])=[CH:31][C:30]=2[N:39]2[CH:43]=[CH:42][C:41]([CH3:44])=[N:40]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C(O)CO)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(C(O)CO)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of (3S)-ethyl 8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provides the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>CN(C)C=O>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:15]2[CH:14]=[CH:13][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH2:5][CH2:6]1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To dried dimethylformamide (20 ml) solution in which 4-(2-hydroxyethyl)morpholine (1 g, 7.62 mmol) was dissolved, sodium hydride (201.2 mg, 8.38 mmol) was slowly added under nitrogen at room temperature. The mixture was stirred for 30 minutes at room temperature, and 4-fluorobenzaldehyde (1.1 g, 8.86 mmol) in dried dimethylformamide (5 ml) was added over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours until the initial reaction product disappeared. Subsequently, 20 ml of ice water was added to the resulting mixture, and the mixture was extracted with ethyl acetate and water. The organic layer was washed with water several times, dried over anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to afford the intermediate compound 4-(2-(morpholinoethoxy)benzaldehyde (1.42 g, 79%).
Reaction SMILES: C(OCC)(=O)CC(OCC)=O.[CH2:12]([CH:16]([C:22]([O:24]CC)=[O:23])[C:17]([O:19]CC)=[O:18])[CH:13]([CH3:15])[CH3:14].[OH-].[K+]>CO.O>[CH2:12]([CH:16]([C:22]([OH:24])=[O:23])[C:17]([OH:19])=[O:18])[CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(=O)CC(=O)OCC
Product: CC(C)CC(C(=O)O)C(=O)O
Yield: 83.9 %

Procedure:
To a solution of sodium ethoxide obtained from 46.0 g (2.00 mol) of sodium lump and 1000 cm3 of anhydrous ethanol 320 g (2.00 mol) of diethyl malonate was added at room temperature. The obtained mixture was stirred for 30 min at this temperature, and then 274 g (2.00 mol) of isobutylbromide was added. The resulting mixture was refluxed for 5 h, and then ethanol was distilled off. To the cooled residue 1500 ml of cold water and 500 ml of ethyl acetate were added. The organic layer was separated, dried over Na2SO4 and then evaporated to dryness. Fractional rectification of the residue gave 357 g of colorless liquid, bp 177-187° C./220 mm Hg. This product contained ca. 10% of diethyl malonate. To a solution of 117.3 g (542 mmol) of diethyl isobutylmalonate in 500 ml of methanol a solution of 125 g of potassium hydroxide in 1000 cm3 of water was added. The resulting mixture was refluxed for 5 h, then ethanol and methanol were distilled off. Further on, 1000 cm3 of water was added, and then this mixture was acidified by 12 M HCl to pH 1.0. Isobutylmalonic acid was extracted by 4×500 ml of ether. The combined extract was evaporated to dryness. To the residue 300 ml of toluene was added. Again, the obtained mixture was evaporated to dryness to remove moisture. To a solution of the residue in 150 ml of toluene 500 ml of hexanes was added. The formed precipitate was filtered off, washed by 50 ml of hexanes and dried in vacuum. This procedure gave 72.8 g (84%) of the title product as white crystalline solid.