Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH2:24][C@H:25]([NH:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH2:38][CH3:39])[CH3:26])=[CH:19][C:20]=2[C:22]#[N:23])[CH2:15][CH2:14]1)(=O)C1C=CC=CC=1.[OH-].[K+]>CO.O>[CH2:38]([O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][CH2:29][CH2:28][NH:27][C@H:25]([CH3:26])[CH2:24][C:18]1[CH:17]=[C:16]2[C:21](=[C:20]([C:22]#[N:23])[CH:19]=1)[N:13]([CH2:12][CH2:11][CH2:10][OH:9])[CH2:14][CH2:15]2)[CH3:39]
Reactant: CCOc1ccccc1OCCN[C@H](C)Cc1cc(C#N)c2c(c1)CCN2CCCOC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1ccccc1OCCN[C@H](C)Cc1cc(C#N)c2c(c1)CCN2CCCO
Yield: 104.4 %

Procedure:
(R)-3-[7-Cyano-5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-2,3-dihydro-1H-indol-1-yl]propyl benzoate (7.23 g) was dissolved in methanol (46 ml) and the solution was added to a solution of potassium hydroxide (1.54 g) in distilled water (9.2 ml). After being heated under reflux for 1 hour, the reaction mixture was concentrated in vacuo. Distilled water (100 ml) was added to the residue and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was dissolved in toluene(30 ml) and the toluene was removed in vacuo to give (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carbonitrile(6.06 g) as a pale brown oil.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1.C1CCN2C(=NCCC2)CC1>>[C:1]1([CH:7]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: COC(=O)/C=C/c1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A solution of methyl (2E)-3-phenylacrylate (500 mg, 0.003 mol) in ACN (2 mL, 0.04 mol) was slowly added to a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 μL, 0.003 mol). The reaction was stirred at room temperature over the weekend. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated sodium chloride, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel using EtOAc/Hexane (1:2 to 1:1) gave methyl 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate (500 mg, 70%) as a semisolid residue.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:26](=[O:30])/[CH:27]=[CH:28]/[CH3:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH:28]([CH3:29])[CH2:27][CH:26]=[O:30])=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: C/C=C/C=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(CC=O)P(=O)(O)CCCCc1ccccc1

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.5 g, 0.0025 mole) in chloroform (15 ml) was added triethylamine (0.77 ml, 0.005 mole), trimethyl silylchloride (0.70 ml, 0.005 mole) and crotonaldehyde (0.23 ml, 0.0025 mole). The reaction mixture was stirred at reflux temperature for 18 hours. The chloroform was removed in vacuo. The residue was diluted with ether and extracted with 5% NaHCO3 solution. The aqueous layer was acidified with concentrated HCl and extracted twice with ether and once with EtOAc. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a solid which was dissolved in CH3OH; ether and hexane were added until turbidity. The mixture was kept in a freezer overnight, yield 0.099, m.p. 138° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=O)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:9])=[O:8]
Reactant: COc1ccc(C(=O)O)c(C=O)c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)O)c(C=C2SC(=S)NC2=O)c1

Procedure:
To a stirred hot solution of 4.23 g. (23.5 mM) of 4-methoxyphthalaldehydic acid and 3.13 g. (23.5 mM) of rhodanine in 16.5 ml. of acetic acid is added 6.33 g. (77.2 mM) of anhydrous sodium acetate. The resulting hot solution is refluxed for 0.5 hour, whereupon a solid yellow mass forms. The mixture is cooled, poured into water, to yield 5-(2-carboxy-5-methoxybenzylidene)rhodanine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([N:11]3[CH2:13][CH:12]3[CH3:14])=[N:8][C:7]([CH:15]([CH3:17])[CH3:16])=[N:6][C:5]=2[C:4]([CH3:18])=[N:3]1.[I-].[Na+]>CC(C)=O>[CH:15]([C:7]1[N:8]2[CH2:14][CH:12]([CH3:13])[N:11]=[C:9]2[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:18])[C:5]=2[N:6]=1)([CH3:16])[CH3:17]
Reactant: Cc1nn(C)c2c(N3CC3C)nc(C(C)C)nc12
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nn(C)c2c1N=C(C(C)C)N1CC(C)N=C21
Yield: 54.4 %

Procedure:
The aziridine (6.7 g, 0.027 mol) in 100 ml of acetone is refluxed two hours with 4.5 g (0.03 mol) of sodium iodide and the mixture is evaporated in vacuo. The residue is partitioned in 100 ml of methylene dichloride and 50 ml of saturated sodium bicarbonate solution. The organic layer is separated, dried over magnesium sulfate, and evaporated in vacuo. The oil is crystallized from pet ether to give 3.6 g (54%) mp 96°-97° C. of 7,8-dihydro-5-isopropyl-1,3,8-trimethyl-1H-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=O)[CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([NH2:22])=[O:19])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reaction time: 12 h

Procedure:
6-Chloro-3-[(2-fluoro-4-iodophenyl)amino]pyridazine-4-carboxylic acid (144 mg, 0.37 mmol.) and 1,1′-carbonylbis(1H-imidazole) (119 mg, 0.73 mmol) were suspended in N,N-dimethylformamide (1.00 ml). The mixture was stirred over night (12 hr). Solid ammonium acetate (31 mg, 0.40 mmol) then added. The reaction was stirred for another 5 h. Water (0.5 mL) was then added into the mixture. The desired product was precipitated and was collected by vacuum filtration. LC/MS [7.39 min; 393 (M+1)].
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:22][CH2:23][N:24]([C:2]3[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=3[N+:10]([O-:12])=[O:11])[CH2:25][CH2:26]2)=[CH:17][CH:16]=1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1 074 549 A2) was treated with the 4-(4-fluoro-phenyl)-piperidine hydrochloride in N,N-dimethylformamide in the presence of N-ethyldiisopropylamine at room temperature to yield the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one as yellowish solid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:21][CH3:22])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4.[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:23]1([CH2:26][N:19]2[CH2:18][CH2:17][C@@:14]34[C:15]5[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[CH2:7][C@@H:8]2[C@:9]3([O:21][CH3:22])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)[CH2:25][CH2:24]1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)CCC(=O)C3
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(OC)CCC(=O)C3
Temperature: 110 °C

Procedure:
A mixture of 3,14-dimethoxymorphinan-6-one (6a) (4.491 g, 14.9 mmol), cyclopropylmethyl bromide (3.017 g, 22.35 mmol) and NaHCO3 (7.50 g, 89.4 mmol) in DMF (50 ml) was refluxed under nitrogen for 16 hours at 110° C. The mixture was filtered and the DMF removed by distillation under reduced pressure. The residue was taken up in methylene chloride (150 ml) and 150 ml of water. The two layers were separated and the aqueous layer re-extracted with methylene chloride (2×100 ml). The organic solutions were combined, washed with water (100 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting yellow solid was chromatographed on Florisil using graded methanol/chloroform as the eluant to give 17-cyclopropylmethyl-3,14-dimethoxymorphinan-6-one as a yellow oil which crystallized after drying the give 4.132 g (78% theory) of yellow solid. Recrystallization from ethanol gave 3.443 g (65%) of the title compound (8) (TR-5400) as colorless needles. A portion of 8 was converted to the hydrochloride salt (TR-5305) by treatment with ethereal hydrogen chloride to give a white solid, m.p. 215°-128° C.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O>>[CH:19]1[C:18]2[C:12]3[CH:11]=[CH:10][CH:9]=[C:4]4[C:5]([O:14][C:1](=[O:13])[C:2]([C:3]=34)=[CH:21][C:17]=2[O:16][CH:20]=1)=[O:7]
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Reactant: O=Cc1ccco1
Product: O=C1OC(=O)c2cc3occc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and 2-furaldehyde:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:40]=2[CH:41]=[N:42][NH:43]3)O1>>[NH:43]1[C:44]2[C:40](=[C:39]([C:2]3[N:3]=[C:4]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([C:17]([N:19]6[CH2:24][CH2:23][O:22][CH2:21][CH2:20]6)=[O:18])[CH:14]=[CH:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:47]=[CH:46][CH:45]=2)[CH:41]=[N:42]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C(c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1)N1CCOCC1
Product: O=C(c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1)N1CCOCC1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (49 mg) was reacted with morpholine via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(morpholino)methanone. Crude 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(morpholino)methanone (58 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 23.7 mg of 337. MS (Q1) 527.2 (M)+
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[NH:8][C:7](=O)[N:6]=[C:5]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:4]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:7]1[N:8]=[C:3]([CH:2]([F:20])[F:1])[CH:4]=[C:5]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc(C(F)(F)F)nc2)cc(C(F)F)[nH]1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1

Procedure:
The title compound was prepared from 6-difluoromethyl-4-(6-trifluoromethyl-pyridin-3-yl)-1H-pyrimidin-2-one (6.37 g, 0.022 mol) and phosphoroxychloride (34 ml) according to the general procedure I. Obtained as a brown oil (6.65 g, 98%). MS (ISP) 310.2 [(M+H)+].
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)=[CH:3][CH:2]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>CC#N.FC(F)(F)C(O)=O>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:11]1[C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=2)=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10]1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)[nH]n1
Reactant: C1=COCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccc(C)cc2)n(C2CCCCO2)n1
Yield: 117.3 %

Procedure:
A mixture of methyl 5-p-tolyl-1H-pyrazole-3-carboxylate (224 mg, 1.03 mmol), 3,4-dihydro-2H-pyran (190 μL, 2.07 mmol) and trifluoroacetic acid (2 μL, 0.02 mmol) in anhydrous MeCN (3 mL) was refluxed for 2 hrs. The solvent was evaporated. The residue was resuspended in CH2Cl2 (50 mL) and was washed with H2O and brine. After drying with Na2SO4, solvent evaporation and silica gel column chromatography (PE-EtOAc, 6:4) methyl 1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazole-3-carboxylate (363 mg, 68%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH:13]([N:16]([CH:19]([CH3:21])C)CC)([CH3:15])C.N1CCCC1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:16]2[CH2:13][CH2:15][CH2:21][CH2:19]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (0.83 g, 2.73 mmol) in tetrahydrofuran (10 mL) under argon was added diisopropylethylamine (0.525 mL, 3.00 mmol) followed by pyrrolidine (0.183 mL, 2.73 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between diethyl ether and aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was triturated with diethyl ether/heptane at −20° C. to provide the title compound (0.56 g, 67% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:6]2.Cl.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:33][C:19]([F:18])([F:32])[C:20]1[CH:21]=[C:22]([C:26]2[CH2:31][CH2:30][N:29]([C:14](=[O:16])[CH2:13][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)[CH2:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: COc1ccc2cc(CC(=O)O)ccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2cc(CC(=O)N3CC=C(c4cccc(C(F)(F)F)c4)CC3)ccc2c1
Yield: 81 %

Procedure:
A solution of 6-methoxy-2-naphthylacetic acid (1.8 g, 0.009 mol), 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (2.4 g, 0.009 mol), triethylamine (2.4 ml, 0.018 mol), and BOP (3.7 g, 0.009 mol) in methylene chloride (40 ml) is stirred at room temperature for 5 hours. Then it is concentrated to dryness, the obtained residue is dissolved in a mixture ethyl ether/water, the organic phase is separated, and washed sequentially with 1N HCl, water, 5% NaOH, and water. The reaction mixture is then filtered over silica and the filtrate is concentrated to dryness affording 1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-1-oxo-2-(6-methoxy-naphth-2-yl)ethane (3.1 g). M.p. 102°-105° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[Na+].[Na+].[O:13]=[CH:14][CH2:15][CH2:16][C:17](OCC)=O>O>[CH2:16]1[CH:17]2[NH:6][C:4]([CH2:3][N:2]2[C:14](=[O:13])[CH2:15]1)=[O:5]
Reactant: NCC(N)=O
Reactant: CCOC(=O)CCC=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CN2C(=O)CCC2N1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
A solution of 2.56 g (22.7 mmol) of glycinamide hydrochloride (purity 98%) in 200 ml of water is heated to 95° C. and the pH adjusted to 6.6 with Na2CO3 20% w/v in water. Then ethyl 4-oxobutanoate (purity 97%) (7.60 g, 56.6 mmol) are added dropwise during four hours maintaining the temperature at 95° C. and the pH at 6.6 by automated addition (pHstat) of Na2CO3 20% w/v in water. The solution is stirred at 95° C. for 1.5 hours and then concentrated to a small volume under vacuum. The obtained suspension is treated with 50 ml of isopropanol and the solvent is evaporated at atmospheric pressure. This operation is repeated once again. The residue is diluted with 50 ml of isopropanol and the resulting suspension heated to 60° C. and then filtered. The filtrate is concentrated to about 15 ml, cooled to room temperature and stirring continued for about 2 hours. The white precipitate is collected by suction filtration, washed with 4 ml of isopropanol and dried under vacuum at 60° C. for 12 hours, resulting in 1.8 g of crude dimiracetam (12.8 mmol, 55.5%). Recrystallization from isopropanol (10 volumes) affords 1.6 g (50%) of pure dimiracetam (>99.5% as determined from area % HPLC). Melting point: 154° C.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Product: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)acetic acid and t-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [O:1]=[C:2]1[N:11]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[O:1]=[C:2]1[N:11]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:15])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: CC(C)C[C@@H](C(=O)O)n1c(=O)[nH]c2ccccc2c1=O
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)Nc1nccs1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1 (187 mg, 0.7 mmol), 2-aminothiazole (70 mg, 0.7 mmol), HBTU (303 mg, 0.8 mmol) and 0.2 mL of Et3N in DMF (5 mL) was stirred at room temperature for 2 hours to provide the title compound, which purified by HPLC. 1H NMR (400 MHz, CD3OD) δ: 8.03 (dd, J=1.2, 8.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.42 (d, J=4.0 Hz, 1H), 7.27-7.17 (m, 2H), 7.15 (d, J=4.0 Hz, 1H), 5.76 (dd, J=4.8, 9.2 Hz, 1H), 2.29-2.20 (m, 1H), 2.11-2.01 (m, 1H), 1.61-1.49 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H). [M+H] calc'd for C17H18N4O3S, 359; found, 359.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+]>CO>[CH2:11]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NCC(O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CNCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 2-amino-1-phenyl-ethanol (12.0 g, 87.48 mmol) in methanol (60 mL) was added benzaldehyde (9.3 g, 8.9 mL, 87.48 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was then cooled to 0° C. and sodium borohydride (3.3 g, 87.48 mmol) was added. The reaction mixture was gradually allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo, diluted with water, and filtered. The residue was rinsed with cold isopropanol (3×), then dried in vacuo to give 2-(benzylamino)-1-phenylethanol as white crystals (14.0 g, 70%). ESI-MS m/z calc. 227.1. found 228.2 (M+1)+; Retention time: 0.8 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 7.37-7.27 (m, 8H), 7.27-7.19 (m, 2H), 4.78 (dd, J=8.5, 4.5 Hz, 1H), 3.77 (q, J=13.0 Hz, 2H), 2.82-2.68 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:22]=[C:21]([NH:32][CH3:33])[N:20]=1>CC#N>[CH3:33][NH:32][C:21]1[N:22]=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:24]=[C:19]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]2)[N:20]=1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNc1nc(Cl)nc(N2CCN(C)CC2)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Temperature: 80 °C

Procedure:
trans-4-Aminocyclohexylcarboxylic acid (472 mg, 3.30 mmol, 8 equivalents) and triethylamine (0.46 ml, 3.30 mmol, 8 equivalents) was added to the solution of 4-Chloro-N-methyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (100 mg, 0.412 mmol, 1 equivalent) in CH3CN (8 ml). The reaction mixture was heated at 80° C. for 16 hours. The solvent was evaporated and the crude product was purified with RP-HPLC (Luna 5μ, C8(2), 100×21 mm, 2-45% CH3CN/H2O, 0.1% TFA, 25 min) to give the product (18.4 mg, 10%). MS (ES+): m/e 350.13 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>[OH-].[Na+]>[CH:14]1([C:20]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:10][C:20]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:21])=[CH:8][CH:9]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](Cc1ccc(OC(=O)C2CCCCC2)cc1)C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
(L)-Tyrosine (61.6 g., 0.34 mole) was dissolved in 190 mL of 2 N sodium hydroxide. Cyclohexanoyl chloride (49.32 mL, 0.34 mole) was added dropwise to the mixture. Additional aqueous 2 N sodium hydroxide was added, and the reaction mixture was allowed to stir at room temperature for 2 hours. The mixture was then acidified to pH 9.5 with aqueous (4:1) hydrochloric acid. A precipitate formed which was separated by vacuum filtration. The solids were dissolved in 2 N sodium hydroxide and dried by lyophilization to furnish 33.5 g of N,O-dicyclohexanoyl-(L)-tyrosine. The product was purified by column chromatography on silica gel using butanol/acetic acid/water as the eluent system. The pure product was a white solid.