Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:25]C1CCCCO1)([CH2:20][CH2:21][C:22]#[C:23][CH3:24])/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][CH2:6]1>C(O)(=O)C.O.C1COCC1>[OH:25][C:2]([CH3:1])([CH2:20][CH2:21][C:22]#[C:23][CH3:24])/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][CH2:6]1
Reactant: CC#CCCC(C)(/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC#CCCC(C)(O)/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
300 mg. of (5Z,13E)-(15RS)-15-methyl-9-oxo-15-(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid is agitated for 16 hours at room temperature with 8 ml. of a mixture of glacial acetic acid/water/THF (65/35/10); the mixture is then evaporated under vacuum, and the residue is purified by chromatography on silica gel. With methylene chloride/5% methanol, 205 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH:12]=[CH2:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:6]([CH2:7][OH:8])[C:5]([CH:12]=[CH2:13])=[N:4][CH:3]=1
Reactant: C=Cc1ncc(Cl)cc1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: C=Cc1ncc(Cl)cc1CO
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
A solution of methyl 5-chloro-2-vinylnicotinate (0.21 g, 1.06 mmol) in DCM (5 ml) was cooled to −45° C. A solution of diisobutylaluminum hydride (1M in hexane, 1.6 ml, 1.59 mmol, Aldrich) was added dropwise. After 15 min, the reaction mixture was quenched by the addition of a saturated aqueous solution of potassium sodium tartrate (3 mL). DCM was added, followed by water. The organic phase was separated, washed with water and dried over MgSO4. The filtrate was concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography, eluting with a gradient of 5% to 55% EtOAc in hexane, to provide the title compound (77 mg) as a white solid. LC/MS m/z=170.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16]/[CH:17]=[C:18](\[CH2:21][C:22]#[N:23])/[C:19]#[N:20])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O-]CC.[K+].O>O1CCCC1.C(O)C>[NH2:23][C:22]1[N:16]([CH:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:17]=[C:18]([C:19]#[N:20])[CH:21]=1
Reactant: N#CC/C(C#N)=C\NC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc(N)n(C(c2ccc(F)cc2)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-2-({[bis(4-fluorophenyl)methyl]amino}methylene)butanedinitrile (13.9 g, 45.1 mmol) in tetrahydrofuran (48 ml) and ethanol (48 ml) was slowly added potassium ethoxide (6.67 g, 79.2 mmol), which was stirred at room temperature for 1 hour and poured into iced water. The product was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the objective product as oily matter.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[NH:44][CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].[F:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[CH:54]=O.C(O)(=O)C>CN(C)C=O>[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[N:44]([CH2:54][C:53]4[CH:56]=[CH:57][CH:58]=[C:51]([F:50])[CH:52]=4)[CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Reactant: O=Cc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.012 g) was added to a mixture of 1-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (916 mg, Example 121), 3-fluorobenzaldehyde (474 mg) and acetic acid (229.4 mg) in dimethylformamide (15 mL). The reaction was stirred under nitrogen at room temperature for 2 hours. The reaction was quenched by the addition of saturated NH4Cl solution (2 mL), followed by the addition of H2O (10 mL). The resulting solution was diluted with 120 mL of H2O to precipitate product. The solution was neutralized with saturated NaHCO3 solution to pH=7 to produce additional precipitate. The mixture was filtered thru a celite pad. The collected solid was rinsed by water (35 mL×2). The solid was dissolved in EtOAc (50 mL) and then eluted from the celite pad. The filtrate (EtOAc solution) was washed with H2O (15 mL×2) and brine (15 mL×1), dried over Na2SO4 and concentrated to give crude product, which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 1-{3-[(R)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester as light pink solid (675 mg; 60%). 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 2H), 7.25 (m, 3H), 7.06 (m, 3H), 6.90 (m, 1H), 6.64 (m, 3H), 5.03 (s, 1H), 4.50 (m, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.91 (d, J=13.5 Hz, 1H), 3.70 (m, 1H), 3.18 (d, J=13.5 Hz, 1H), 3.02 (m, 2H), 2.60 (m, 5H), 2.01 (m, 3H), 1.72 (m, 3H), 1.26 (t, J=7.0 Hz, 3H), 1.05 (m, 6H).
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][C:16]([CH3:21])([N+:18]([O-:20])=[O:19])[CH3:17].[OH-].[K+]>CN(C=O)C>[CH3:1][N:8]1[C:4]([CH3:3])=[C:5]([CH2:15][C:16]([CH3:21])([N+:18]([O-:20])=[O:19])[CH3:17])[N:6]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1[nH]c(-c2ccccc2)nc1CC(C)(C)[N+](=O)[O-]
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1c(CC(C)(C)[N+](=O)[O-])nc(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
Methyliodide (1.4 g) was added dropwise to a stirred mixture of 5-methyl-4-(2-methyl-2-nitro-propyl)-2-phenyl-1H-imidazole (2.0 g) and fine powdered potassium hydroxide (2.0 g) in DMF (30 ml) at 10-20° C. The reaction mixture was stirred at RT for 2 h, quenched with ice/water and extracted with ethyl acetate. The organic phase washed with water and brine, dried over magnesium sulphate and concentrated. The residue was purified on silica gel using methylene chloride/methanol 2 and 5% as eluent. to obtain the desired product (0.98 g) as a light yellow amorphous compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[C:23]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[CH:28][C:27]=1[O:37][CH3:38])(=[O:25])[CH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:33][CH2:32][CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:26]([C:23](=[O:25])[CH3:24])=[C:27]([O:37][CH3:38])[CH:28]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc(OCCCCl)ccc1C(C)=O
Product: COc1cc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)ccc1C(C)=O

Procedure:
Following the procedure of Examples 1 and 66, [α,α-bis (p-fluorophenyl)]-4-piperidinemethanol and 3-(p-acetyl-m-methoxyphenoxy)propyl chloride are reacted to give the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[C:9]([N:17]1[CH2:22][CH2:21][C:20]2([S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[S:1]2)[CH2:19][CH2:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: Sc1ccccc1S
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC2(CC1)Sc1ccccc1S2
Reaction time: 15 h

Procedure:
500 mgs (3.52 mmol) of 1,2-dimercaptobenzene and 610 mgs (3.00 mmol) of N-benzoyl-4-piperidone were stirred in CH2Cl2 while anhydrous HCl gas was introduced Na2SO4 (2 grams) was added and the mixture stirred 15 hours. The mixture was diluted with CH2Cl2 filtered and washed with H2O, and 10% NaOH. The organics were dried (Na2SO4) and concentrated to a solid (yield 740 mgs).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23][CH3:24])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH:25]=[O:26])=[N:8]2)=[CH:4][CH:3]=1.[CH3:29][Mg]Br.C(OCCCC)CCC.Cl>COCCOC.ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23][CH3:24])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH:25]([OH:26])[CH3:29])=[N:8]2)=[CH:4][CH:3]=1
Reactant: COc1c2n(c3c(C=O)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCCCOCCCC
Solvent: ClCCl
Solvent: COCCOC
Product: COc1c2n(c3c(C(C)O)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(4-fluorobenzyl)-8-methyl-10-methoxy-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-carboxaldehyde (42 mg, 0.11 mmol) in anhydrous DME (10 mL), a solution of methyl magnesium bromide in butyl ether (0.26 mL, 0.26 mmol; 1 M) was added. After stirring at room temperature for 5 minutes, the reaction mixture was treated with dilute hydrochloric acid, and diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound as yellow solid. ES MS M+1=401
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][CH2:13][C@H:14]([S:16][CH2:17][C:18]2[N:19]=[CH:20][NH:21][C:22]=2[CH3:23])[CH3:15])=[NH:11])[N:3]=[CH:2]1.C(NC(N)=N)#N.[Cl-:30].[NH4+]>>[ClH:30].[ClH:30].[ClH:30].[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][CH2:13][C@H:14]([S:16][CH2:17][C:18]2[N:19]=[CH:20][NH:21][C:22]=2[CH3:23])[CH3:15])=[NH:11])[N:3]=[CH:2]1
Reactant: [Cl-]
Agent: Cc1[nH]cnc1CS[C@H](C)CNC(=N)NCCCc1c[nH]cn1
Agent: N#CNC(=N)N
Agent: [NH4+]
Product: Cl

Procedure:
(R)-(+)-N-[3-(imidazol-4-yl)propyl]-N'-[2-[(5-methylimidazol-4-yl)methylthio]-1-propyl]-guanidine ##STR95## prepared by a method analogous to that of Example 39 from 0.63 g (1.7 mmol) of the previously prepared cyanoguanidine. 0.85 g of a hygroscopic foam composed of equimolar quantities of ammonium chloride and (R)-(+)-N-[3-(imidazol-4-yl)propyl]-N'-[2-[(5-methylimidazol-4-yl) methylthio]-1-propyl]guanidine trihydrochloride is obtained as residue.
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:6][O:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:13][CH:12]=1)([OH:5])=[O:4].Cl>CO>[C:22]([CH2:21][O:20][CH2:19][C:18]#[C:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]#[C:9][CH2:8][O:7][CH2:6][C:3]([OH:5])=[O:4])=[CH:16][CH:15]=1)([OH:24])=[O:23]
Reactant: COC(=O)COCC#Cc1ccc(C#CCOCC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COCC#Cc1ccc(C#CCOCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
An aqueous 2 N NaOH solution (10 ml) is added dropwise to a solution of methyl {3-[4-(3-carboxymethoxyprop-1-ynyl)phenyl]prop-2-ynyloxy)acetate (A31; 0.88 g, 2.7 mmol) in methanol (50 ml), and the mixture is stirred at RT for 2 h. The pH of the reaction solution is then adjusted to pH 2 using an aqueous 2 N HCl solution. The solution is extracted with ethyl acetate (30 ml, 2×) and washed with a saturated NaCl solution (30 ml). The combined organic phases are dried over MgSO4, filtered off and concentrated under reduced pressure. This gives the title compound (0.75 g) as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH3:11])=[CH:4][N:3]=1.[O:12]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O>[CH3:11][O:10][C:5]1[C:6](=[O:9])[N:7]([CH3:8])[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COc1cnc(Cl)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc(-c2ccc(Oc3ccccc3)cc2)n(C)c1=O
Temperature: 120 °C
Yield: 100.3 %

Procedure:
To a solution of 750 mg (4.30 mmol) 2-chloro-5-methoxy-3-methylpyrimidin-4(3H)-one in 20 ml THF was added 314 mg (0.430 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(H)dichloride dichloromethane adduct, 1.83 g (8.59 mmol) 4-phenoxyphenylboronic acid, and 4.30 ml (4.30 mmol) 1 M aq Cs2CO3. The reaction mixture was heated to 120° C. for 15 min in the microwave, then diluted with 10 ml water, extracted with 50 ml EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo to give 1.33 g (100% yield) of crude 5-methoxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22]C1C=CC=CC=1B(O)O>>[CH3:21][O:22][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 2-methoxyphenylboronic acid (189 mg, 1.24 mmol) were coupled to yield 2-(2-methoxy-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 177 mg (53%) as a brown solid: m.p. 254-255° C.; 1H NMR (300 MHz, d6-DMSO) DMSO) δ 2.81 (m, 2H), 3.36 (m, 2H), 3.83 (s, 3H), 7.08 (app t, J=7.5 Hz, 1H), 7.17 (m, 2H), 7.43 (m, 2H), 7.54 (dd, J=7.8, 0.6 Hz, 1H), 7.67 (dd, J=7.5, 0.6 Hz, 1H), 8.03 (br t, 1H), 11.27 (br s, 1H). MS (FAB, MH+) 293. Anal. (C18H16N2O2.0.3 H2O) C, H, N.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CS(C)=O.[Br:11][C:12]1([C:15]([NH:17][CH2:18][CH2:19][CH2:20]CO)=[O:16])[CH2:14][CH2:13]1.[Cl-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Br:11][C:12]1([C:15]([NH:17][CH:18]([CH:2]=[O:3])[CH2:19][CH3:20])=[O:16])[CH2:13][CH2:14]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(NCCCCO)C1(Br)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C=O)NC(=O)C1(Br)CC1
Reaction time: 0.5 h

Procedure:
2.23 ml of oxalyl chloride in 102 ml of methylene chloride is mixed drop by drop at −78° C. under nitrogen with 3.6 ml of dimethylsulfoxide in 41 ml of methylene chloride. Then, 5.43 g of amide alcohol 78 in 41 ml of methylene chloride and, after 15 minutes, 14.3 ml of triethylamine are added in drops at −78° C. After another 30 minutes, sodium chloride solution is added, extracted with methylene chloride, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 3.4 g of 1-bromo-N-[(1-formyl)propyl]-cyclopropane-1-carboxamide 79 is obtained as a yellow oil, which is converted into title compound 80 analogously to the reaction of amide 76.
Reaction SMILES: [CH2:1]([NH:8][S:9](=[O:12])(=O)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][S:9]([Cl:14])(=[O:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)NCc1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)NCc1ccccc1

Procedure:
A stirred mixture of benzylsulfamic acid (73 g), PCl5 (81 g) in toluene (540 ml) is heated to 40°-50° C. for one hour and refluxed for about 3 hours. The cooled mixture is filtered through Celite and the filtrate concentrated in vacuo to remove the toluene affording the desired product as a liquid.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:25])[O:19][CH2:20][C:21]#CCO)[CH:14]=[CH:15][CH:16]=1>C(Cl)CCl>[CH:15]1[CH:16]=[C:11]([Cl:10])[CH:12]=[C:13]([NH:17][C:18]([O:19][C:20]#[C:21][Cl:3])=[O:25])[CH:14]=1
Reactant: O=C(Nc1cccc(Cl)c1)OCC#CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Cl)c1)OC#CCl

Procedure:
In another preparation on the same scale, the thionyl chloride and dimethylformamide in 25 ml of EDC were stirred at 65° while a warm solution of 4-hydroxy-2-butynyl N-(3-chlorophenyl)carbamate in 75 ml of EDC was added dropwise over 60 minutes. Barban (6.5 g) was obtained by evaporation of the solvent after 17 hours at 65° and analyzed by HPLC: barban 97.6% (w/w); biscarbanate -- 2.2% (w/w); bisurea -- 1.6% (w/w).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[CH:4][C:3]=1[F:11].P([O-])([O-])([O-])=[O:13].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[F:11][C:3]1[CH:4]=[C:5]([C:8]2([CH3:10])[CH2:9][O:13]2)[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: C=C(C)c1ccc(F)c(F)c1
Reactant: O=P([O-])([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(c2ccc(F)c(F)c2)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a biphasic solution of 1,2-difluoro-4-isopropenyl-benzene (0.81 g, 5.1 mmol) in CH2Cl2 (50 mL) and 50 mL of phosphate buffer (made by dissolving 0.3 g of NaHPO4 and 0.35 g of NaH2PO4 in 50 mL water, pH=8) at 0° C., was added a solution of 3-chloroperoxybenzoic acid (approx. 75% solid, 3.32 g, 10.2 mmol) via a dropping funnel fitted with a cotton plug dropwise in two batches. The solution was stirred at room temperature overnight. It was extracted with CH2Cl2, washed with sat. Na2S2O4 solution followed by water. The organic layer was finally washed with sat. NaHCO3, separated, dried over Na2SO4, filtered and solvent was removed in vacuo. 2-(3,4-Difluorophenyl)-2-methyl-oxirane was obtained as a pale yellow oil (0.65 g, 74% yield). It was used in the next step without purification.
Reaction SMILES: ClC1N=C(Cl)N=C(Cl)N=1.O[N:11]=[C:12]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[CH2:13]1.[OH2:36]>CN(C=O)C>[O:36]=[C:12]1[CH2:13][C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:18][CH2:19]2)[C:30]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:11]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=NO)c1ccccc12
Reactant: O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
2,4,6-trichloro-[1,3,5]-triazine (1.32 g, 7.16 mmol) was added to DMF (9.6 mL) maintained at 25° C. The reaction was monitored by TLC until TCT was consumed. Then benzyl 3-(hydroxyimino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (1.6 g, 4.77 mmol) in DMF (17 mL) was added. After the addition, the mixture was stirred at room temperature overnight. Water was added. The mixture was extracted with EtOAc. The combined organic layers were washed with sat. Na2CO3, followed by 1N HCl and brine, dried over Na2SO4 and concentrated. The residue was purified by prep HPLC to obtain benzyl 2′-oxo-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1-carboxylate (260 mg, yield 16%).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C.O.[OH-].[Li+]>CO.C1COCC1.O>[C:19]([O:18][C:16]([NH:15][CH2:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:23])=[O:3])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)COc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1OCC(=O)O

Procedure:
The product from Step D was suspended in 1:1:1 methanol/THF/water (9 ml) and lithium hydroxide hydrate (126 mg, 3.0 mmol) was added. After 16 h the volatiles were removed in vacuo and the solution was diluted with water and was washed with ethyl acetate, adding sufficient brine to disperse the emulsion. The aqueous layer was acidified with 5% KHSO4 solution and was extracted with methylene chloride which was then dried (Na2SO4) and evaporated in vacuo to give the title compound as a solid:
Reaction SMILES: [C:1]([C:6]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH:19]1([C:6]2([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(=O)C1(C2CCCCC2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.5 %

Procedure:
2.5 g (7.4 mmol) of tert-butyl 4-butyryl-4-cyclohexylpiperidine-1-carboxylate (cf. preparation 17-1-4) are diluted in a mixture comprising 40 mL of dichloromethane and 8 mL of trifluoroacetic acid. The mixture is stirred at room temperature for 2 hours and the reaction is then stopped by adding aqueous 1N NaOH solution and the organic compounds are extracted with dichloromethane. The organic phase is dried and then concentrated. 2.1 g of 1-(4-cyclohexylpiperidin-4-yl)butan-1-one in the form of a colourless oil are obtained in a yield of 100%.
Reaction SMILES: C([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:8])(C)(C)C>FC(F)(F)C(O)=O>[OH:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:8]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCOC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCOC[C@]3(C)C(=O)NO)cc2)c2ccccc2n1
Reaction time: 0.25 h
Yield: 30 %

Procedure:
The (3R,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)-tetrahydro-2H-pyran-3-carboxamide (0.52 g, 0.96 mmol) from Step 10 was stirred in neat trifluoroacetic acid (3 mL) at 40° C. for 3.5 h. The reaction mixture was then concentrated in vacuo and chased with methanol. The residue was then stirred in ethyl acetate (100 mL) and saturated NaHCO3 (50 mL) for 15 min. The organic layer was washed with water (50 mL), then with brine (50 mL), dried over MgSO4, and concentrated. The residue was purified by chromatography on silica eluting with 5-8% MeOH/CH2Cl2 to yield 140 mg (30%) of (3R,4R)-N-hydroxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)-tetrahydro-2H-pyran-3-carboxamide as an off-white solid. In addition, 35% of the starting material was recovered. HRMS: calcd for C24H27N3O6S+H+, 486.16933; found (ESI-FT-MS, [M+H]+1), 486.1695