Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:45]=[CH:44][C:19]([CH2:20][NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:25]=[C:24]([NH:34][C:35]3[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=3)[N:23]=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:46][CH:47]([CH:52]1[CH2:57][CH2:56][CH2:55][N:54]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:53]1)[C:48]([O:50][CH3:51])=[O:49].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:45]=[CH:44][C:19]([CH2:20][NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]([F:31])([F:32])[F:33])[N:25]=[C:24]([NH:34][C:35]3[CH:43]=[CH:42][C:38]([C:39]([NH:46][CH:47]([CH:52]4[CH2:57][CH2:56][CH2:55][N:54]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:53]4)[C:48]([O:50][CH3:51])=[O:49])=[O:40])=[CH:37][CH:36]=3)[N:23]=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(N)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCCCCNC(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
To a solution of 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (100 mg), tert-butyl 3-(1-amino-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (51.5 mg) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (60.7 mg) was added iPr2NEt (0.055 mL). The mixture was stirred at room temperature for 4 hours. The mixture was purified by preparative HPLC to give tert-butyl 3-(1-(4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (80 mg).
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:23])[CH2:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)=[O:10])C>CO.C1COCC1.O>[C:17]1([C:15]2[N:16]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:7]([OH:23])=[O:6])[S:13][CH:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(=O)Nc1nc(-c2ccccc2)cs1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
LiOH.H2O (85 mg, 2.0 mmol) was added to a solution of N-(4-phenyl-thiazol-2-yl)-malonamic acid ethyl ester (292 mg, 1.0 mmol) in methanol (1.0 mL), THF (1.5 mL) and H2O (1 mL). The resulting mixture was stirred for 1 hour at room temperature then concentrated. The residue was diluted with water, acidified with concentrated HCl and extracted with ethyl acetate. The organics were washed with brine, dried over Na2SO4 and concentrated to afford 230 mg (87%) of N-(4-Phenyl-thiazol-2-yl)-malonamic acid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=2[CH3:16])[N:17]=1
Reactant: NC(N)=S
Reactant: CC(=O)Nc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: CC(=O)Nc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 86.5 %

Procedure:
A mixture of N-(4-(2-bromoacetyl)-3,5-dimethylphenyl)acetamide (7.34 g, 25.8 mmol) and thiourea (1.97 g, 25.9 mmol) in 95% EtOH (36.9 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (50 mL). The solids were filtered and dried under vacuum to give N-(4-(2-aminothiazol-4-yl)-3,5-dimethylphenyl)acetamide (5.83 g) as yellow solids in 86% yield: 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.26 (s, 2H), 6.90 (bs, 2H), 6.30 (s, 1H), 2.06 (s, 6H), 2.02 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12]1>[Pd]>[O:14]1[C:13]2([CH2:18][CH2:19][N:11]([C:3]3[CH:4]=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=3[F:1])[CH2:12]2)[O:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Agent: [Pd]
Product: Nc1ccc(N2CCC3(C2)OCCO3)c(F)c1

Procedure:
According to Method F, 7-(2-fluoro-4-nitro-phenyl)-1,4-dioxa-7-aza-spiro[4.4]nonane was reduced using Pd/C. In this way the product was obtained with molecular weight 238.26 (C12H15FN2O2); MS (ESI): 239 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:26]([CH:29]=1)[C:27]#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:27]([C:26]1[CH:29]=[C:22]([CH:23]=[CH:24][C:25]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:28]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: N#Cc1cc(CCl)ccc1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCCC4)c(C#N)c3)cc21
Temperature: 25 °C
Reaction time: 41 h
Yield: 64.5 %

Procedure:
To a solution of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (166.0 mg, 0.641 mmol) and 5-(chloromethyl)-2-cyclohexylbenzonitrile (147.0 mg, 0.629 mmol) in N,N-dimethylformamide (15 mL) was added cesium carbonate (246.0 mg, 0.755 mmol). The mixture was stirred at room temperature for 41 h. The mixture was diluted with ethyl acetate, filtered through Celite®, concentrated under reduced pressure and purified by silica gel column chromatography to provide the title compound as a yellow foam (185.3 mg). LCMS m/z=457.5 [M+H]+; NMR (400 MHz, CDCl3) δ ppm 1.18-1.28 (m, 1H), 1.30 (t, J=7.20 Hz, 3H), 1.41-1.52 (m, 4H), 1.79 (dd, J=12.82, 1.33 Hz, 1H), 1.85-1.93 (m, 4H), 2.06-2.15 (m, 1H), 2.50 (dd, J=16.80, 11.24 Hz, 1H), 2.68-2.86 (m, 4H), 2.94-3.04 (m, 1H), 3.49-3.61 (m, 1H), 4.16-4.25 (m, 2H), 5.06 (s, 2H), 6.82 (dd, J=8.78, 2.46 Hz, 1H), 6.97 (d, J=2.53 Hz, 1H), 7.21 (d, J=8.72 Hz, 1H), 7.37 (d, J=8.21 Hz, 1H), 7.62 (dd, J=8.15, 1.71 Hz, 1H), 7.71 (d, J=1.52 Hz, 1H), 8.47 (bs, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:16])[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[S:6][C:5]([C:7](=[O:16])[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCCC(=O)c1ccc(Br)s1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOC(=O)CCCC(=O)c1ccc(-c2ccc(C)cc2)s1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Under argon atmosphere, a solution of ethyl 5-(5-bromothiophen-2-yl)-5-oxovalerate (10.09 g), 4-methylphenyl borate (5.39 g) and potassium carbonate (9.14 g) in toluene-ethanol-water (320-32-32 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphinepalladium (1.14 g), and the mixture was refluxed for 8 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:4→1:3→1:2→1:1) to give ethyl 5-[5-(4-methylphenyl)thiophen-2-yl]-5-oxovalerate (10.23 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>CN(C=O)C>[CH:18]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH:12]=3)[N:9]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: Fc1ccc(CBr)cc1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccc(F)cc4)c3)c12
Temperature: 40 °C
Reaction time: 12 h

Procedure:
An anhydrous DMF (2 mL) solution of 3-(8-amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (50 mg, 0.179 mmol) and K2CO3 (27 mg, 0.197 mmol) was charged with 1-bromomethyl-4-fluoro-benzene (7) (24 μL, 0.197 mmol) and stirred 12 h at 40° C. The reaction mixture was partitioned between CHCl3 and H2O and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were washed with H2O (1×), brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The crude mixture was purified by MDP resulting in a light tan/waxy solid; 1H NMR (CDCl3, 400 MHz) δ 1.99-2.08 (m, 1H), 2.11-2.25 (m, 1H), 2.44-2.55 (m, 2H), 2.58-2.70 (m, 2H), 3.75-3.88 (m, 1H), 5.06 (brs, 2H), 5.10 (s, 2H), 6.98-7.15 (m, 5H); 7.20-7.34 (m, 3H), 7.35-7.47 (m, 3H); MS (ES+): m/z 389.14.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[CH:4]=1.[CH:12]1([N:15]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:14][CH2:13]1>>[CH:12]1([N:15]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[CH:4]=3)[CH2:27][CH2:26]2)[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:14][CH2:13]1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Reactant: COc1ccc(CBr)cc1C
Product: COc1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3ccccc3)CC2)cc1C

Procedure:
N-Cyclopropyl-N-[1-(3-methyl-4-methoxybenzyl)piperidin-4-yl]benzenesulfonamide was prepared from 4-bromomethyl-1-methoxy-2-methylbenzene and N-cyclopropyl-N-piperidin-4-yl-benzenesulfonamide according to the above procedure. LC: 100%. MS: m/z=415.2, 416.2 (M+H+). 1H NMR (400 MHz, CDCl3): δ 7.82 (2H, d, J=8.0 Hz), 7.60 (1H, m), 7.52 (2H, m), 7.29 (1H, m), 7.21 (1H, s), 6.85 (1H, d, J=8.8 Hz), 4.13 (2H, s), 4.05 (1H, s), 3.85 (3H, s), 3.54 (2H, m), 2.63 (4H, m), 2.22 (3H, s), 1.75 (3H, m), 0.93 (2H, m), 0.86 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][C:9]=1[OH:10])=[O:4].[CH2:15](I)[CH3:16]>C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([F:14])([F:12])[F:13])=[CH:8][C:9]=1[O:10][CH2:15][CH3:16])=[O:4]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)sc1C(=O)OC

Procedure:
3-Ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (mp.: 93.6° C.) was prepared from the known 3-hydroxy-5-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (Synthesis 2000, No. 8, 1078-1080) by alkylation with ethyl iodide in the presence of cesium carbonate in DMF as solvent.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[CH3:15][O:16]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[CH:8][C:7]([O:13][CH3:14])=[C:6]2[CH:15]=[O:16])=[CH:11][CH:12]=1)#[N:2]
Reactant: COc1ccc2ccc(C#N)cc2c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc2ccc(C#N)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 3.7 g of 2-cyano-7-methoxynaphthalene was dissolved in 40 ml of dichloro-methane, and 6.6 ml of titanium tetrachloride and 4.6 ml of dichloromethyl methyl ether were added dropwise into the resulting solution at 0° C. in this order. The resulting mixture was stirred at room temperature for 30 minutes and cooled to 0° C. again. Water was added to the resulting mixture to cease the reaction, and the resulting mixture was extracted with dichloromethane (100 ml×2). The organic layers were combined, washed with water, a saturated aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the resulting crude crystal was washed with ether and dried to give 3.3 g of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH3:22])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[CH3:14])[N:6]=1.[C:23]([Cu])#[N:24]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([C:23]#[N:24])[S:3][C:4]=2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH3:22])=[C:8]([CH3:14])[CH:9]=1
Reactant: Cc1cc(Cl)ccc1-c1nc(Br)sc1-c1ccc(Cl)cc1C
Reactant: N#C[Cu]
Product: Cc1cc(Cl)ccc1-c1nc(C#N)sc1-c1ccc(Cl)cc1C
Temperature: 150 °C
Yield: 88.8 %

Procedure:
A round-bottomed flask was charged with 2-Bromo-4,5-bis(4-chloro-2-methylphenyl)thiazole (196 mg, 0.47 mmol) and CuCN (84.2 mg, 0.94 mmol). After degassed, 3 mL of DMF was added. The reaction mixture was heated to 150° C. overnight. After cooled to room temperature, the reaction was quenched with 25 mL of water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography to afford 150 mg of product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25]CC1C=CC=CC=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1O
Yield: 95.7 %

Procedure:
A mixture of 22.52 g (47.05 mmol) (S)-3-(2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester, 1 g 20% Pd on charcoal, 250 mL tetrahydrofuran and 250 mL ethanol was shaken under a 50 psig. hydrogen atmosphere for 26 h. The mixture was filtered through a pad of celite and concentrated. The residue was passed through a 100 g plug of silica eluting with 6:4 ethyl acetate:hexanes to give 17.5 g (45.05 mmol, 95.7%) of (S)-3-(2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a thick colorless oil. MS (APCI) m/z 387.0 (M−1).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=[O:17]>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=[O:17]
Reactant: O=c1ccccn1CCCOC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccccn1CCCO
Yield: 98.7 %

Procedure:
A solution of 1-(3-(2-tetrahydropyranyloxy)propyl)-1,2-dihydro-2-pyridone (1.0 g, 4.5 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50° C. for 4 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene to give 1-(3-hydroxypropyl)-1,2-dihydro-2-pyridone (680 mg, 99%) as an off-white solid.
Reaction SMILES: C(O)(=O)CCCCC(O)=O.[CH2:11]([NH2:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:21]([N:30](CCCCCCCCC)[C:31](=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][C:36](N)=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[OH-].[Na+]>O>[CH2:11]([NH:20][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][C:31]([NH:30][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCN
Reactant: CCCCCCCCCN(CCCCCCCCC)C(=O)CCCCC(N)=O
Agent: O=C(O)CCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCNC(=O)CCCCC(=O)NCCCCCCCCC
Temperature: 160 °C
Reaction time: 3 h

Procedure:
Into a 1 L flask equipped as described as above in Example 1 were added 350.9 grams (2.4 moles) of adipic acid. This acid was heated to 160° C. with agitation until melted. After all of the adipic acid was melted, there were added 28.6 g (0.2 mole) of nonylamine over a period of about 15 minutes. The reaction mixture was held at 170° C. with agitation for an additional 3 hours under nitrogen. The reaction mixture was then gradually poured into 2 L of hot (70° C.) water, with agitation to dissolve the unreacted adipic acid. The mixture was filtered and the wetcake was washed with hot water to obtain a mixture of monoamido adipic acid and N,N1 -dinonyl adipamide. The wetcake was reslurried in a caustic solution (16 g of 50% sodium hydroxide and 200 g of water) whereby the acid dissolved leaving the insoluble N,N'-dinonyl adipamide as an insoluble which was removed by filtration. After drying overnight at 70° C., the amount of dinonyl amido adipamide was found to be 1.78 g (0.0045 mole). This amount of diamide represents a molar selectivity of 4.5% based upon the amine reactant. The alkaline solution was then acidified with an equivalent of sulfuric acid to precipitate the desired monoamido adipic acid which precipitated and was collected by filtration. After drying in an oven overnight at 70° C., the amount of monoamido adipic acid obtained was found to be 49 g (0.1808 mole) having a purity of 99.9% by HPLC. This amount of monoamido adipic acid represents a molar selectivity of 90% based upon the amine reactant. A sample of the acid was subjected to melting point determination which was found to be in the range of 108° C.-110° C. The filtrate containing dissolved adipic acid was cooled to room temperature, whereupon the adipic acid precipitated and was recovered by filtration. The solid collected from this filtration contained mostly adipic acid and a small amount of monoamido adipic acid. After removal of residual water, the adipic acid, containing small amounts of monoamido adipic acid, was ready to be used as starting material for further reaction with an amine. The filtrate obtained from the recovery of the adipic acid contained about 2% adipic acid and was used as the water source to dissolve further unreacted adipic acid from the next batch in the further production of monoamido adipic acid by the reaction of nonylamine with adipic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.Br[CH2:26][C:27]#[C:28][CH3:29]>>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:26][C:27]#[C:28][CH3:29])[CH:18]=2)=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Reactant: CC#CCBr
Product: CC#CCn1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccc1=O

Procedure:
The title compound was synthesized in a similar manner to Example 66 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and 1-bromo-2-butyne.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][C@H:11]1[C@:6]2([NH:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10]1.[NH4+].[OH-:20]>Br>[CH3:18][NH:17][C@@:6]12[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:3]=[CH:4][C:5]2=1
Reactant: [OH-]
Reactant: CN[C@]12CCCC[C@H]1CCc1ccc(OC)cc12
Agent: Br
Agent: [NH4+]
Product: CN[C@@]12CCCC[C@@H]1CCc1cc(O)ccc12
Yield: 74 %

Procedure:
A solution of the product from Example 133 (150 mg) in 48% aqueous HBr was heated at reflux for 2.5 hours. The reaction mixture was poured into cold aqueous NH4OH solution. The resulting solution was extracted with ethyl acetate (3×25 ml), dried (MgSO4) and filtered. Evaporation of the solvent and drying in vacuo afforded the title compound as a tan solid (90 mg, 74%), mp 191° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[OH:12]O>C(O)=O>[C:6]12[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:1][C:2](=[O:12])[O:3][C:4]2=[O:5]
Reactant: OO
Reactant: O=C1Nc2ccccc2C1=O
Solvent: O=CO
Product: O=c1[nH]c2ccccc2c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.7 parts of isatin are suspended in 80 parts of formic acid. 20 parts of 30 percent strength hydrogen peroxide solution are added dropwise, with slight cooling. The mixture is then stirred for 60 minutes at 25° C., after which it is worked up in a conventional manner. 13.2 parts of isatoic anhydride are obtained; melting point 252°-253° C., with decomposition.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1[N:25]=[C:24]([C:26]2[C:27]([CH3:33])=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[O:23][N:22]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:32][C:29]1[N:28]=[C:27]([CH3:33])[C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][CH2:19][OH:18])[N:25]=2)=[CH:31][CH:30]=1
Reactant: Cc1nc(Cl)ccc1-c1nc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(Cl)ccc1-c1nc(CCO)no1
Temperature: 50 °C

Procedure:
3-[3-(2-{[tert-Butyl(diphenyl)silyl]oxy}ethyl)-1,2,4-oxadiazol-5-yl]-6-chloro-2-methylpyridine (210 mg, 0.44 mmol) was taken up in tetrahydrofuran (2.2 ml) and tetrabutylammonium fluoride (0.44 ml of 1.0 M in THF, 0.44 mmol) was added. The solution was heated to 50° C. for 2 hours, cooled to room temperature, concentrated under reduced pressure, and directly purified via silica gel chromatography (0-100% ethyl acetate in hexane) to afford the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:31]>CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([N:21]([CH3:31])[CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CI
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NC3CCOCC3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1nc(-c2ccc(S(C)(=O)=O)cc2)cc(C(F)(F)F)n1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[4-(methylsulfonyl)phenyl]-N-tetrahydro-2H-pyran-4-yl-6-(trifluoromethyl)pyrimidin-2-amine (0.05 g) in dry dimethylformamide (2 ml) was treated with sodium hydride (0.007 g, 60% in mineral oil) and the mixture stirred at ambient temperature for 30 minutes. Iodomethane (0.01 ml) was added and the mixture stirred overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer was purified by passing through a silica bond elute column and eluting with dichloromethane. Concentration of the eluent gave the title compound as a yellow solid (0.031 g).