Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][C:6]#[N:7].[H-].C([Al+]CC(C)C)C(C)C.[C:22]1([CH:32](N)[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+]>ClCCl.CO.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH2:6][NH:7][C@@H:32]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:33]
Reactant: CC(N)c1cccc2ccccc12
Reactant: N#CCCc1ccccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@@H](NCCCc1ccccc1Cl)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A stirred solution of 2-chlorohydrocinnamonitrile (Aldrich Chemical Co., 1.66 g, 10 mmol) in dichloromethane (100 ml) was cooled to −78° C. and treated dropwise with diisobutylaluminum hydride (1.42 g, 10 mmol). The reaction was stirred 1 hr at rt, cooled to −78° C. and treated with a solution of 1-(1-naphthyl)ethylamine (1.71 g, 10 mmol) in dichloromethane (25 ml). The reaction was transferred to an ice bath and stirred 2 hr. After this time the reaction was poured directly into a stirred solution of ethanolic sodium borohydride (50 ml of 0.2 M, 10 mmol). The mixture was stirred 30 min at rt and the excess sodium borohydride quenched by the addition of 10% HCl. The solution was then made basic by the addition of 10 N NaOH and transferred to a separatory funnel washing with diethyl ether (300 ml). The aqueous phase was removed and the remaining organic layer washed with 1 N NaOH (3×100 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to an oil. Chromatography of this material through silica gel using a gradient of chloroform to 10% methanol-chloroform afforded 2.34 g (72% yield) of (R)-N-[3-(2-chlorophenyl)propyl]-1-(1-naphthyl)ethylamine, 12Z, as a clear oil; m/z (rel. int.) 323 (M+, 2), 308 (63), 288 (7), 196 (5), 184 (5), 155 (100), 125 (24), 115 (8), 103 (4), 91 (3), 77 (7).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH2:23]([O:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44](O)=[O:45])[C:39](=[O:47])[N:38]=1)=[O:35])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:44](=[O:45])[CH2:43][N:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]([O:33][CH2:23][C:24]2[CH:32]=[CH:31][C:30]3[O:29][CH2:28][O:27][C:26]=3[CH:25]=2)=[O:35])=[N:38][C:39]1=[O:47])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Yield: 85.9 %

Procedure:
The title compound (2.89 g, 86%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [4-N-(piperonyloxycarbonyl)-cytosin-1-yl]-acetic acid (1.74 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.65 (s, 1H), 8.80 (brs, 0.6H), 8.68 (brs, 0.4H), 8.19(d, 1H), 8.11 (d, 1H), 7.81 (d, 0.6H), 7.75 (d, 0.4H), 7.62˜7.54 (m, 2H), 6.92 (t, 1H), 6.90 (s, 1H), 6.82 (s, 2H), 5.93 (s, 2H), 5.00 (s, 2H), 4.72 (s, 1.2H), 4.54 (s, 0.8H), 4.26 (s, 0.8H), 4.01 (q, 0.8H), 4.00 (s, 1.2H), 4.96 (q, 1.2H), 3.51 (t, 1.2H), 3.35˜3.30 (m, 2H), 3.13 (t, 0.8H), 1.12 (t, 1.2H), 1.06 (t, 1.8H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CC([O:18][B:19](OC(C)C)[O:20]C(C)C)C>C1COCC1.[OH-].[Na+]>[F:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:20])[OH:18])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1B(O)O
Temperature: -78 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a solution of 1-bromo-4-fluoro-2-methylbenzene (5 g, 26.45 mmol) in THF (100 mL) was added n-butyllithium (12.7 mL) dropwise at −78° C. Tris(propan-2-yl)borate (10 g, 53.17 mmol) was added dropwise and the reaction was stirred overnight at −78° C. in a liquid nitrogen bath. The resulting solution was diluted with aqueous sodium hydroxide (1N, 30 mL) and extracted with ether (2×50 mL). The aqueous layers were combined and adjusted to pH 3 with HCl (3N), extracted with ethyl acetate (3×50 mL), and the organic layers were combined and concentrated in vacuo to give (4-fluoro-2-methylphenyl)boronic acid as a white solid (2.1 g, 52%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][Cl:7].[S:8](Cl)(Cl)(=[O:10])=[O:9]>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][Cl:7])[SH:8](=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: ClCCNCCCl
Solvent: c1ccncc1
Product: O=[SH](=O)N(CCCl)CCCl

Procedure:
N,N-bis(2-chloroethyl)arylsulfonamide can be prepared from bis(2-chloroethyl)amine (10 mmol) and the corresponding sulfonyl chloride (10 mmole) in 50 ml dry pyridine at ambient temperature for 2 hours. Pyridine can be removed and the mixture can be extracted with EtOAc and water. The organic layer can be acidified with 0.1 N HCl, washed with water and dried. The desired N,N-bis(2-chloroethyl)sulfonamide is obtained in the form of an oil.
Reaction SMILES: C1COCC1.[Br-].[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:36]([N:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>C1(C)C=CC=CC=1>[CH2:36]([N:43]1[CH2:48][CH2:47][C:46](=[CH:16][CH2:15][CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: c1ccc(CCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C(CCCc1ccccc1)=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A 0.62M solution of potassium bis(trimethylsilyl)aride in THF (180 mL, 112 mmol) in toluene (250 mL) was added to a mixture of (4-phenylbut-1-yl)triphenylphosphonium bromide from Step B (53 g) in toluene (250 mL) in an ice bath over 15 min with stirring under nitrogen. After stirring for a further 15 min, a solution of 1-benzyl4-piperidone (16.9 g) in toluene (100 mL) was added over 30 min with stirring. The reaction mixture was allowed to warm to rt over 15 h. The reaction mixture was then poured into cold 1N HCl (400 mL) and the layers were separated. The organic layer was extracted with two more portions of 1N HCl. The combined cloudy HCl solution and an oil layer in between were washed with toluene (200 mL) before the aqueous layer was basified by the addition of potassium hydroxide (30 g). The aqueous layer was extracted with ether (3×150 mL) and the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by FC (10-15% ethyl acetate in hexanes having 4% (v/v) TEA) to give the title compound (16 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([O:18]CC4C=CC=CC=4)=[O:17])=[CH:12][C:10]=32)[C:6](=[O:26])[NH:5][CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:27])[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:10]=32)[C:6](=[O:26])[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCNC(=O)c2nc3ccc(C(=O)OCc4ccccc4)cc3n21
Agent: [Pd]
Solvent: CO
Product: CC1(C)CCNC(=O)c2nc3ccc(C(=O)O)cc3n21
Yield: 63.2 %

Procedure:
A suspension of benzyl 5,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylate (88 mg, 0.22 mmol) in methanol (2 mL) is hydrogenated over 10% palladium on carbon (23 mg) under balloon pressure for 3 h. The catalyst is removed by filtration, and the filtrate concentrated to afford the title compound (38 mg, 63%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][O:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1)#[CH:2]
Reactant: CS(=O)(=O)Cl
Reactant: C#Cc1ccc(-n2ccc3cc(C#CCCCO)ccc32)cc1
Product: C#Cc1ccc(-n2ccc3cc(C#CCCCOS(C)(=O)=O)ccc32)cc1

Procedure:
In analogyto example 5.4, 5-[1-(4-Ethynyl-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol and methanesulfonyl chloride were converted to yield Methanesulfonic acid 5-[1-(4-ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester as orange oil, MS: 377 (M).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]=O>C(O)=O>[CH3:14][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10]
Reactant: C[C@H](NCc1ccccc1)C(=O)O
Reactant: C=O
Solvent: O=CO
Product: C[C@@H](C(=O)O)N(C)Cc1ccccc1

Procedure:
The N-benzylalanine (1), (67 g, 0.374 mole) was taken up in formic acid (41 mL, 88%) and formaldehyde (37 mL, 38%) added. The resulting solution was heated on a steam bath for 11/2 hours. After this period the clear solution was cooled and as much of the solvent as possible removed under reduced pressure. Removal of the water was aided by co-evaporation with methanol. To the residual oil was added methanol (200 mL) and the solution diluted with ether yielding the product as a fine white powder, 63.7 g (88%).
Reaction SMILES: Cl.C([O:4][C:5](=[O:24])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:20]2[S:21][CH:22]=[N:23][C:19]=2[CH2:18][CH2:17][NH:16]1)C.CCN(CC)CC.[CH3:32][O:33][C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[CH2:36][N:37]=[C:38]=[S:39].[OH-].[Na+]>CC#N.C(O)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([OH:4])=[O:24])=[C:9]([CH:15]2[C:20]3[S:21][CH:22]=[N:23][C:19]=3[CH2:18][CH2:17][N:16]2[C:38](=[S:39])[NH:37][CH2:36][C:35]2[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=2[O:33][CH3:32])[CH:10]=1
Reactant: COc1ccccc1CN=C=S
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ncsc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccccc1CNC(=S)N1CCc2ncsc2C1c1cc(Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (50 mg, 0.13 mmol, 1.00 eq.) and NEt3 (54 μL, 0.39 mmol, 3.00 eq.) in MeCN (1 mL), 2-methoxybenzyl isothiocyanate (24 mg, 0.14 mmol, 1.05 eq.) in MeCN (1 mL) was added. The mixture was stirred at r.t. for 18 hours. 1M aq. NaOH (0.5 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid, purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions), and concentrated in vacuo to give the desired acid as a white solid.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:14]#[N:15])[C:12]#[N:13])=[CH:7][C:6]=1[CH3:16]>C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:14]([NH2:15])=[N:2][NH:3][C:12]=2[NH2:13])=[CH:7][C:6]=1[CH3:16]
Reactant: NN
Reactant: Cc1cc(C(C#N)C#N)ccc1Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(-c2c(N)n[nH]c2N)ccc1Cl
Temperature: 70 °C

Procedure:
Hydrazine monohydrate (0.312 mL, 6.4 mmol) was added to a solution of the product from Example 47A (512 mg, 2.69 mmol) in CHCl3 (25 mL). The reaction flask was evacuated and purged with nitrogen (3 cycles) and the mixture was heated at 70° C. under nitrogen for 22 hours, then cooled to room temperature. The mixture was concentrated under vacuum to provide the title compound as a beige solid. MS (DCI/NH3) m/z 223/225 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:18][C:17]=1[CH3:30].O>CN(C)C(=O)C.CCCCCC.C(OCC)C.ClCCl>[C:20]([C:19]1[CH:28]=[CH:29][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:17]([CH3:30])[CH:18]=1)(=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(C(=O)c2ccccc2)ccc1N
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)c2ccccc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Temperature: -12.5 °C
Reaction time: 1 h

Procedure:
To a solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.11 g) in N,N-dimethylacetamide (15 mL) at -20° C. was added thionyl chloride (0.84 g) and the mixture was allowed to stir at -10 to -15° C. for 1 hour. 4-Amino-3-methylbenzophenone (1.00 g) was added in one portion and the reaction mixture was stirred at room temperature overnight. The mixture was poured into water and the resultant gummy solid was collected by filtration. The solid was dissolved in methylene chloride, dried and evaporated to give a brown oil. Chromatography, with diethyl ether:dichloromethane (2:98) as the eluent, gave a white foam which was stirred with hexane for two hours. The title compound was collected by filtration as a white solid (1.04 g); mp 123-124° C.; MS: m/z=352(M+1); NMR: 1.61 (s,3), 2.28 (s,3), 7.54-7.61 (m,3) 7.66-7.74 (m,6) 9.73 (s,1). Analysis for C18H16F3NO3 : Calculated: C, 61.54; H, 4.59; N, 3.99; Found: C, 61.53; H, 4.73; N, 4.01.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[CH3:10][N:11]([CH3:42])[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C@H:22]([C:27]([NH:29][C:30](=O)[C@H:31](CCC2C=CC=CC=2)[NH2:32])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[C:43]([C:46]#N)([CH3:45])=O.O>CN(C=O)C>[C:31]([C@@H:30]([NH:29][C:27](=[O:28])[C@@H:22]([NH:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([N:11]([CH3:10])[CH3:42])=[CH:17][CH:16]=1)(=[O:20])=[O:19])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:45][CH2:43][C:46]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)#[N:32]
Reactant: CC(C)C[C@H](NS(=O)(=O)c1ccc(N(C)C)cc1)C(=O)NC(=O)[C@@H](N)CCc1ccccc1
Reactant: CC(=O)C#N
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(N(C)C)cc1)C(=O)N[C@H](C#N)CCc1ccccc1
Yield: 57 %

Procedure:
Cyanuric chloride (33 mg, 0.18 mmol) was added to a solution of N-[N-((4-dimethylaminophenyl)sulfonyl)-L-leucinyl]-L-homophenylalaninamide (80 mg, 0.18 mmol) in DMF (2 mL) at 0° C. After stirring for 2h, the reaction was quenched by addition of satd. NaHCO3, filtered, diluted with EtOAc, washed sequentially with H2O (×5), brine, dried over Na2SO4, and concentrated giving a yellow foam. The crude residue was fractionated by preparative HPLC (65% AcCN/H2O/0.1% TFA) giving the title compound (47 mg, 57%) as a white solid, m.p. 46-48° C. 1H NMR (400 MHz, CDCl3): δ: 7.74(2H, d, J=9), 7.37-7.34 (2H, m), 7.30-7.26 (2H, m), 7.23-7.21 (3H, m), 6.79 (1H, d, J=8.5), 4.91 (1H, bs), 4.70 (1H, ddd, J=8, 8, 8), 3.68-3.73 (1H, m), 3.06 (3H, s), 2.84-2.76 (2H, m), 2.16-2.09(2H, m), 1.63-1.56 (2H, m), 1.42-1.37 (1H, m), 0.88 (3H, d, J=6), 0.71 (3H, d, J=6).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[N:4][CH:3]=1.Cl.C(O)C>C(Cl)(Cl)Cl>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A solution of 0.59 g of tert-butyl (1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 30 mL of a 2 mol/L hydrogen chloride/ethanol was stirred at room temperature for 18 hours. To the reaction mixture, 2 mL of chloroform was added, and the mixture was stirred at 40° C. for 4 hours, and stirred at room temperature for 18 hours. In the reaction mixture, the solvent was distilled off under reduced pressure, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and then the solvent was distilled off under reduced pressure. The resultant residue was washed with ethanol and, in the mother liquid, the solvent was distilled off under reduced pressure, and the resultant residue was purified with silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd. and an eluent of chloroform:methanol=10:1 to obtain 421 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[C:2]=1[C:11]([O:13][CH3:14])=[O:12].C[Si]([C:20]#[N:21])(C)C.CN(C)C(Cl)=O.C([O-])(O)=O.[Na+]>COCCOC>[C:20]([C:6]1[N:1]=[C:2]([C:11]([O:13][CH3:14])=[O:12])[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:5]=1)#[N:21]
Reactant: COC(=O)c1ccc[n+]([O-])c1C(=O)OC
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(C#N)nc1C(=O)OC
Temperature: 0 °C

Procedure:
To a solution of dimethyl pyridine-2,3-dicarboxylate 1-oxide [Niiyami et al. (2002) Bioorg. Med. Chem. Lett. 12, 3041] (15.3 g, 72.5 mmol) and trimethylsilyl cyanide (15.7 mL, 117 mmol) in DME (161 mL) was added dimethylcarbamoyl chloride (10.5 mL, 114 mmol). The reaction mixture was heated at reflux for 72 h, and then cooled to 0° C. Saturated aqueous NaHCO3 (800 mL) was added slowly and the quenched mixture was extracted with EtOAc (2×1 L). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=221 (M+1).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CO.O.O>[OH:3][CH:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:1]([O:9][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:8]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COc1ccc(COC(=O)C(O)CC(C)C)cc1
Reaction time: 8 h

Procedure:
To D/L-leucic acid (7.58 g, 57.36 mmol) in MeOH/H2O (9:1, 100 mL) was added a 20% solution of Cs2CO3 in water until the pH reached 7.0. The reaction mixture was concentrated in vacuo to dryness, DMF was added and concentrated in vacuo to dryness again. The solid was suspended in DMF (100 mL) at 0° C., 4-methoxybenzyl chloride (7.8 mL, 51.6 mmol) was added dropwise and the reaction mixture stirred overnight. The mixture was added to water and the product extracted with Et2O, dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8, then 3/7) to afford 4-methoxybenzyl 2-hydroxy-4-methylpentanoate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:18]([C@@H:25]1[NH:30][CH2:29][CH2:28][N:27]([S:31]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)(=[O:33])=[O:32])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:18]([C@H:25]1[CH2:26][N:27]([S:31]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:33])[CH2:28][CH2:29][N:30]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(c1cccs1)N1CCN[C@@H](Cc2ccccc2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C1
Temperature: 100 °C
Yield: 13.7 %

Procedure:
2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.22 g, 0.68 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), (3S)-3-benzyl-1-(2-thiophenylsulfonyl)piperazine (0.20 g, 0.62 mmol), sodium tert-butoxide (0.19 g, 1.9 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.058 g, 0.12 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.057 g, 0.062 mmol, Strem Chemical Inc, Newburyport, Mass.), and toluene (2.5 mL) were added to a high-pressure reaction vessel under a nitrogen atmosphere. The vessel was sealed and was heated at 100° C. for 29 h. Then the mixture was allowed to cool to room temperature and then partitioned between EtOAc (15 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated and the organic material was washed sequentially with saturated aqueous sodium bicarbonate (25 mL) and brine (15 mL), dried (Na2SO4) and filtered. The filtrate was concentrated, and the solution, and the volatiles were removed in vacuo. The residue was subjected purified via column chromatography using silica gel (twice, 100% CH2Cl2, then 25% EtOAc in hexanes) to give of 2-(4-((2S)-2-benzyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.048 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.72-7.54 (m, 4H), 7.33-7.14 (m, 6H), 6.94 (d, J=7.2 Hz, 2H), 4.04 (d, J=8.2 Hz, 1H), 3.91 (d, J=9.4 Hz, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.54 (d, J=11.2 Hz, 1H), 3.42 (t, J=10.9 Hz, 1H), 3.31 (br. s., 1H), 3.21 (t, J=11.7 Hz, 1H), 2.67-2.48 (m, 3H); m/z (ESI, +ve ion) 565.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.308 μM; GK-GKRP EC50 (LC MS/MS)=0.772 μM.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:24]([N:16]1[CH2:17][CH2:18][C:5]2([O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]3[CH:1]=[CH:2][CH:3]=[C:4]23)[CH2:14][CH2:15]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(CN2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1
Yield: 55.5 %

Procedure:
To a 0° C. solution of spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (HCl salt) (1.0 g, 3.6 mmol) in dry acetonitrile (10 mL), under nitrogen, was added NaHCO3 (1.5 g, 18 mmol) followed by dropwise addition of benzyl bromide (560 μL, 4.7 mmol). The cooling bath was removed. Water (25 ml) was then added, and the organic solvent was removed under vacuum. The product was extracted from the aqueous solution with EtOAc (3×150 mL). The organic phases were combined, washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (silica gel: 5-70% EtOAc in hexanes) to give 1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] 660 mg, 55%). ESI-MS m/z calc. 330.4. found 331.5 (M+1)+; Retention time: 1.23 minutes (3 min run).