Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:15]=[CH:16][CH2:17][CH3:18])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)=[CH:16][CH2:17][CH3:18]
Reactant: CCC=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-(1-butenyl)-6-methylpiperidine (1.80 g, 7.65 mmol) in 15% trifloroacetic acid (38 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-(1-butenyl)-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid that was homogeneous by TLC analysis. mp 167-169.0° C.; 1H NMR (250 MHz) δ 9.4 (s, 2H), 5.71-5.58 (m, 2H), 4.17 (s, 1H), 3.54 (s, 1H), 2.2-1.4 (m, 11H), 0.98 (t, 3H); 13C NMR (62.7 MHz) δ 138.5 (s), 122.4 (s), 48.2 (s), 47.9 (s), 28.74 (s), 28.45 (s), 21.3 (s), 17.6 (s), 16.9 (s), 13.8 (s). FT-IR (neat): 3425, 3183, 3072, 2961, 2915, 1656, 1585, 1463, 1443, 1407, 1107, 1075, 960, 883, 803. Elemental Analysis for C10H20NCl: C, 63.29%; H, 10.65%; N, 7.38%. Found: C, 63.14%; H, 10.58%; N, 7.32%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:25][C:24]4[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:22]([O:21][CH3:20])[CH:23]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc(OC)c1OC

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,4,5-trimethoxyaniline were reacted to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 1H NMR (DMSO-d6): δ 8.08 (d, 1H, J=4.8 Hz), 7.29 (d, 1H, J=2.4 Hz), 7.15 (dd, 1H, J=3.0 and 9.0 Hz), 6.91 (s, 1H), 6.76 (d, 1H, J=8.7 Hz), 4.20 (s, 4H), 3.61 (s, 6H), 3.59 (s, 3H); LCMS: purity: 97%; MS (m/e): 429 (MH+).
Reaction SMILES: OCCC[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].N1CCCC([CH2:27][CH2:28][OH:29])C1>>[OH:29][CH2:28][CH2:27][CH:8]1[CH2:9][CH2:10][CH2:5][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7]1
Reactant: OCCC1CCCNC1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCO
Product: O=C(OCc1ccccc1)N1CCCC(CCO)C1

Procedure:
Prepared similarly to Intermediate 29 from 2-(3-piperidinyl)ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.CO.C(N(CC)CC)C.Cl.[NH2:26][C@H:27]([CH3:31])[C:28]([NH2:30])=[O:29]>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:26]([C@H:27]([CH3:31])[C:28]([NH2:30])=[O:29])[CH:6]=[CH:5]2
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 55 °C

Procedure:
A round bottom flask was charged with 6-chloro-5-nitro-1H-isochromen-1-one (950 mg, 0.0042 mol), methanol (30 mL, 0.7 mol), triethylamine (0.64 mL, 0.0046 mol) and (R)-2-aminopropanamide hydrochloride (0.58 g, 0.0046 mol) and the reaction heated to 55° C. overnight. The reaction went to 90% completion. The solvent was removed and the residue purified by flash chromatography (40 g silica gel, 0-10% MeOH/DCM) to obtain the pure product as a light yellow solid. MS m/z=296.4 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[N:11]1([CH2:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
To a stirred solution of of 3-cyanobenzaldehyde (15 g, 114.4 mmol) in THF (150 ml) was added pyrrolidine (9.76 g, 137.2 mmol, 1.2 eq.), acetic acid (8,24 g, 137.2 mmol, 1.2 eq.) and sodium triacetoxyborohydride (36.3 g, 171.6 mmol, 1.5 eq.). The resulting suspension was vigorously stirred at r.t. for 24 hrs. under Ar. 5% NaHCO3 was then added and the mixture stirred for a further 10-15 min. The mixture was then extracted with ethylacetate. The organic phase was washed with brine, then dried with Na2SO4. After removal of the solvent the yellow liquid was distilled over a Vigreux column to afford the title compound as a colorless liquid (19 g, 102 mmol, 89% yield). MS: m/e=186 (M+)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24]C(=O)OC(C)(C)C)[C:10]2=[O:32])=[CH:5][C:4]=1[C:33]([F:36])([F:35])[F:34])#[N:2].[ClH:37]>C(OCC)(=O)C.C(OCC)C>[ClH:37].[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:11]1[C:12]([CH3:15])([CH3:16])[C:13](=[O:14])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:5]=2)[C:10]1=[O:32]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.369 g of compound 68.2 were dissolved in 3.7 ml of ethyl acetate and admixed with 1.47 ml of a 2 molar solution of HCl in diethyl ether, and stirred at room temperature for 24 h. 4 equivalents in each case of ethereal HCl solution were added twice more and the solution was left to stand for 24 h each time. For workup, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile/water and freeze-dried. 4-[3-(2-Aminobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile hydrochloride was obtained in quantitative yield. Molecular weight (free base) 402.13 (C20H17F3N4O2); retention time Rt=1.59 min. [B]; MS (ESI): 403.14 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[C:6]2[N+:18]([O-])=O.[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.[Fe]>[NH2:18][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]=1[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13]
Reactant: COc1ccc2[nH]c(C(=O)N(C)OC)c([N+](=O)[O-])c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(C(=O)N(C)OC)c(N)c2c1

Procedure:
A mixture of 5-methoxy-2-(N-methoxy-N-methylamino)carbonyl-3-nitroindole (step 2, 110 mg, 0.39 mmol), ammonium chloride (11 mg, 0.20 mmol) and iron powder (115 mg, 1.97 mmol) in 70% aqueous ethanol (10 ml) was heated at reflux for 2 h, and then cooled and filtered through a pad of Celite. The pad was washed copiously with a mixture of ethanol/ethyl acetate (1:1 v/v) and the combined washing evaporated. The residue was diluted with ethyl acetate (50 ml), washed with saturated aqueous sodim bicarbonate (30 ml) and dried (Na2SO4). Removal of solvent gave product as an oil. tlc: Rf=0.5 (50% ethyl acetate in hexanes)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O=S(Cl)Cl>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([O:6][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: COc1cc(O)c(C(=O)O)cc1OC
Reactant: Oc1ccccc1
Solvent: Cc1ccccc1C
Solvent: O=S(Cl)Cl
Product: COc1cc(O)c(C(=O)Oc2ccccc2)cc1OC
Yield: 63.6 %

Procedure:
In 10 g of xylene were suspended 1.0 g of compound (2a) and 522 mg of phenol, to which 460 μL of SOCl2 was then added dropwise before heating to reflux for 3 hours, followed by further adding 184 μL of SOCl2 and additionally heating to reflux for one hour. The reaction solvent was distilled off, followed by adding methanol to the residue before stirring. The precipitated crystal was collected by filtration to provide 880 mg of phenyl 2-hydroxy-4,5-dimethoxybenzoate (3a) at a yield of 64%.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:37])=[C:24]([C@@:26]2([CH:34]([F:36])[F:35])[C@H:32]3[C@H:30]([CH2:31]3)[O:29][C:28]([NH2:33])=[N:27]2)[CH:25]=1.[Cl:38][C:39]1[CH:40]=[C:41]([O:48][CH3:49])[C:42]([C:45](O)=[O:46])=[N:43][CH:44]=1>C([O-])(O)=O.[Na+]>[NH2:33][C:28]1[O:29][C@H:30]2[C@@H:32]([C@:26]([C:24]3[CH:25]=[C:20]([NH:19][C:45](=[O:46])[C:42]4[C:41]([O:48][CH3:49])=[CH:40][C:39]([Cl:38])=[CH:44][N:43]=4)[CH:21]=[CH:22][C:23]=3[F:37])([CH:34]([F:35])[F:36])[N:27]=1)[CH2:31]2
Reactant: COc1cc(Cl)cnc1C(=O)O
Reactant: NC1=N[C@](c2cc(N)ccc2F)(C(F)F)[C@@H]2C[C@@H]2O1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@@]2(C(F)F)N=C(N)O[C@@H]3C[C@@H]32)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
A solution of 1-propanephosphonic acid cyclic anhydride (50 wt % in EtOAc, 0.352 ml, 0.553 mmol) was added to a solution of (1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (16g-B, 0.075 g, 0.277 mmol) and 5-chloro-3-methoxypicolinic acid (0.062 g, 0.332 mmol) in EtOAC (2 mL) at room temperature. The reaction mixture was stirred at rt for 12 h, diluted with aqueous saturated NaHCO3 solution and extracted with EtOAC. The organic phase dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using (0-100% EtOAc/heptane) to give the title compound (0.082 g, 0.186 mmol, 67.3% yield). MS m/z=441.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[C:11]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:5]([NH2:6])=[C:4]([F:22])[CH:3]=1.[F:23][C:24]([F:34])([F:33])[C:25](=[O:32])[CH2:26][C:27](OCC)=[O:28].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:8]([O:9][C:10]2[C:11]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:5]([NH:6][C:27](=[O:28])[CH2:26][C:25]([C:24]([F:34])([F:33])[F:23])=[O:32])=[C:4]([F:22])[CH:3]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(N)c(F)cc1Cl
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)COc1ncccc1Oc1cc(NC(=O)CC(=O)C(F)(F)F)c(F)cc1Cl
Yield: 100.5 %

Procedure:
A mixture of 0.50 g of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline, 0.28 g of ethyl trifluoroacetoacetate and 10 ml of toluene was subjected to azeotropic reaction with removing ethanol by passing through molecular sieves 5A for 3 hours. After cooling, the reaction solution was concentrated to obtain 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]trifluoroacetoacetamide.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[C:13]3=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]3[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)c1ccc(CCc2cccnc2N)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(CCC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A mixture of 3-{2-[4-(1-methylethyl)phenyl]ethyl}pyridin-2-amine (150 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 125 mg) and 2-chloroethanesulfonyl chloride (305 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (149 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].O.[BH4-].[Na+].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)[C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(O)CC1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (1 eq.) is dissolved in THF. Water is added to the reaction mixture and cooled to −25° C. NaBH4 (0.5 eq.) is added portion wise maintaining the temperature below −20° C. The mixture is stirred for 2 h at −25° C., 2N HCl is then added and the solution is warmed to room temperature. The phases are separated and the aqueous layer is washed with EtOAC. The organic phases are combined and washed with brine and dried over Na2SO4 and concentrated to dryness to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a 93:7 mixture of isomers. The crude cis/trans mixture is recrystallized in methanol to obtain >99% the trans isomer.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH2:24]([C:26]1[O:30][N:29]=[C:28]([CH3:31])[C:27]=1[C:32](O)=[O:33])[CH3:25]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:32]([C:27]3[C:28]([CH3:31])=[N:29][O:30][C:26]=3[CH2:24][CH3:25])=[O:33])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: CCc1onc(C)c1C(=O)O
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: CCc1onc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 5-ethyl-3-methyl-isoxazole-4-carboxylic acid. LC-MS (basic): tR=0.80 min; [M+H]+=470.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:20]([O-])=O)=[CH:4][C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN(C)C=O>[NH2:20][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])[CH:4]=1
Reactant: COc1cccc(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc(Cl)c(N)cc1OCc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 5-chloro-2-(2-fluoro-6-methoxybenzyloxy)-4-nitrophenol (5 g) and potassium carbonate (3.16 g) in N,N-dimethylformamide (15 mL) was added ethyl bromoacetate (2.2 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (75 mL). To the solution were added methanol (75 mL) and nickel(II) bromide (0.17 g). To the mixture was added sodium borohydride (1.73 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−2/1) to give the title compound (4.11 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-])=O)=[C:6]([CH:26]=1)[CH2:7][C:8]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1>[Pd].CCO>[NH2:27][C:5]1[CH:4]=[CH:3][CH:2]=[CH:26][C:6]=1[CH2:7][C:8]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:10][CH2:9]1
Reactant: CCOC(=O)C1(Cc2cc(Cl)ccc2[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccccc2N)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 24 h
Yield: 94.2 %

Procedure:
10% Palladium on carbon (200 mg) was added to a solution of 1-tert-butyl 4-ethyl 4-(5-chloro-2-nitrobenzyl)piperidine-1,4-dicarboxylate (250 mg, 0.586 mmol) in EtOH (15 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (55 psi). After 24 h, the mixture was filtered though celite and concentrated to give the title compound (0.20 g). MS: m/z=363.1 (M+1).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C@H:10]1[CH3:27])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[OH:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=2)[C@H:10]1[CH3:27]
Reactant: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.5 %

Procedure:
To a solution of 4-[(2S,3S)-3-(tert-butyldimethylsilyloxy)-2-methyl-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (5.61 g) in THF (50 mL) was added tetrabutylammonium fluoride-THF solution (20.0 mL, 1 mol/L), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give the title compound as a colorless oil (yield: 1.42 g, 35%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](O)=[O:7])#[N:2].Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)C(C)C)(C)C.P(C#N)(OCC)(OCC)=O>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:18]([O:19][CH3:20])[CH3:17])=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNOC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of 3-cyano-5-(trifluoromethyl)benzoic acid (200 mg, 0.93 mmol) in tetrahydrofuran (2 mL) stirred on an ice bath was added N,O-dimethylhydroxyamine hydrochloride (145 mg, 1.49 mmol), N,N-diisopropylethylamine (470 mg, 3.64 mmol) and diethyl cyanophosphate (DEPC, 227 mg, 1.39 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with 1 M hydrochloric acid (0.5 mL), and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 3-cyano-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (196 mg, 82%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.S([O-])([O-])(=O)=O.[Mg+2].[CH:17](=O)[CH3:18]>ClCCl>[CH3:17][CH:18]1[NH:1][CH2:2][C:3]2([CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[O:10]1
Reactant: CN1CCC(O)(CN)CC1
Reactant: CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC1NCC2(CCN(C)CC2)O1
Temperature: 0 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
To a solution of 4-aminomethyl-1-methyl-piperidin-4-ol (2.127 g, 14.77 mmol) in dichloromethane (15 ml) was added anhydrous magnesium sulfate (2.9 g). The resulting mixture was cooled to 0° C. and freshly distilled acetaldehyde (835 μl, 14.78 mmol) was added. After 6 h of stirring at room temperature, the mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound (2.16 g) as an almost colorless liquid. 1H NMR (CDCl3, 500 MHz) δ 4.60 (q, J=5.40 Hz, 1H, CHCH3), 3.01 (d, J=12 Hz, 1H, CHHNH), 2.76 (d, J=12 Hz, 1H, CHHNH), 2.55-2.31 (m, 4H, CH2N), 2.28 (s, 3H, NCH3), 1.77-1.58 (m, 4H, CH2CO), 1.36 (d, J=5.40 Hz, 3H, CH3CH) ppm; 13C NMR (CDCl3, 300 MHz) δ 87.57 (CH), 57.19 (CH2), 53.14 (C), 52.96 (CH2), 46.15 (CH3), 37.28 (CH2), 35.73 (CH2), 20.32 (CH3) ppm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(Cl)cc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2,4-dichlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.