Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](O)=[O:12]>CN(C=O)C.C(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([Cl:4])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(CCCl)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.56 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-phenylbutyric acid (2.28 g) in methylene chloride (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid chloride. A solution of 4-chloro-2-phenylbutyric acid chloride in THF (10 mL) was added to a solution of tert-butyl carbazate (1.5 g) and triethylamine (7.8 mL) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). A solution of 4 N hydrogen chloride in ethyl acetate (50 mL) was added to tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g). A solution of 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g) and triethylamine (5.7 mL) in ethanol (40 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (3.00 g) and triethylamine (6.0 mL) in ethanol (50 mL) at room temperature, and the reaction solution was stirred at 80° C. for 24 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 231 mg of the racemic title compound. The property values of the compound are as follows.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[OH:12].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[N:15]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:13][C:14]1[N:15]=[C:16]([Cl:24])[C:17]([CH:21]([CH3:23])[CH3:22])=[C:18]([O:12][C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[C:9]([CH3:10])[C:4]=2[CH3:3])[N:19]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C)c(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
Sodium hydride (60%, 59 mg, 1.44 mmol. 1.1 eq.) was added to 2,3,5-trimethyl-phenol (179 mg, 1.31 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 15 minutes and then added to 2,4,6-trichloro-5-isopropyl-pyrimidine (296 mg, 1.31 mmol) in 1 mL DMF. The reaction was stirred at room temperature for 4 hours. Ethyl acetate was added and washed with brine. The organic layer was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) to give white solid (400 mg, 94%). LC-MS shows 325.2 (M+1). 1H NMR (300 MHz, CDCl3): δ 6.94 (s, 1H), 6.63 (s, 1H), 3.61 (m, 1H), 2.32 (s, 6H), 2.02 (s, 3H), 1.42 (d, 6H).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([N+:15]([O-])=O)=[C:10]3[S:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:21][C:20]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2]>[Ni].CO>[NH2:15][C:11]1[CH:12]=[CH:13][C:14]2[N:6]([CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:33][CH3:34])[N:7]=[C:8]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:23]=[CH:24][C:19]=4[S:18][C:10]=1[C:9]=23
Reactant: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Sc1ccc(OCc3ccccc3)cc1-2
Agent: [Ni]
Solvent: CO
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccc(OCc3ccccc3)cc1-2

Procedure:
A mixture of 0.47 g (0.001 mol) of N,N-diethyl-5-nitro-9-phenylmethoxy-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine, 0.5 of Raney nickel, and 100 ml of MeOH was hydrogenated in a Parr shaker at 25° C. and an initial pressure of 50.0 psi. The mixture was filtered and the filtrate was concentrated to dryness. Crystallization of the residue from the appropriate solvent furnished the product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C@@H:13]([CH2:16][CH3:17])[CH2:14]O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][C@@H:13]([CH3:14])[CH2:16][CH3:17])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CC[C@H](C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC[C@H](C)COC(=O)c1ccc(O)cc1Cl
Temperature: 25 °C
Yield: 98.1 %

Procedure:
2-Chloro-4-hydroxybenzoic acid (17.2 g: 100 mmols), 10.5 g (120 mmols) of (S)-2-methylbutanol and 0.17 g (1 mmol) of p-toluenesulfonic acid were refluxed in 100 ml of toluene on heating. Azeotropic water was removed with a Dean Stark trap. After water was no longer distilled off, the residue was left to cool up to room temperature. The resulting product was washed with a sodium bicarbonate aqueous solution until the aqueous phase became alkaline. The product was further washed with water and then with saturated sodium chloride aqueous solution, and dried with anhydrous sodium sulfate. Excess toluene and (S)-2-methylbutanol were mostly distilled off under reduced pressure and the residue was recrystallized from n-hexane to obtain 23.8 g of (S)-2-methylbutyl 2-chloro-4-hydroxybenzoate as a white crystal.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[C:8](=[O:15])[N:9]2[C:13]=1[CH2:12][CH2:11][CH:10]2[CH3:14])=[O:4].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.CCO>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:7]1[C:8](=[O:15])[N:9]2[C:13](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=1)[CH2:12][CH2:11][CH:10]2[CH3:14]
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c(=O)n2c1CCC2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1CCc2c(C(=O)O)cc(-c3ccccc3F)c(=O)n21
Yield: 53.6 %

Procedure:
To a microwave tube was added methyl-3-methyl-5-oxo-6-(trifluoromethylsulfonyloxy)-1,2,3,5-tetrahydroindolizine-8-carboxylate (94 mg, 0.26 mmol), 2-fluorophenylboronic acid (37 mg, 0.26 mmol, Aldrich), and 2 M sodium carbonate (0.65 mL, 1.30 mmol). To this was added 4 mL of toluene, 0.25 mL of EtOH, and Pd(PPh3)4 (20 mg, 0.17 mmol, Aldrich). The tube was sealed and treated in Emry's optimizer for 15 min at 160° C. The aqueous phase was separated and acidified to pH 2 with 2 N HCl and extracted with EtOAc (3×). The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give 40 mg (53%) of the title compound as a light brown residue. MS m/z: 288.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.Cl.[NH2:24][C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:24][C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 73.5 %

Procedure:
In 500 ml of a mixture of chloroform-tetrahydrofuran (2:1), were dissolved 29.9 g of N-(4-methoxybenzoyl)-phenylalanine, 23.2 g of methyl tyrosinate hydrochloride, 10.1 g of trethylamine and 11.6 g of H-hydroxysuccinimide and the mixture was cooled with ice. To the cold solution was added 20.6 g of N,N'-dicyclohexylcarbodiimide. The mixture was stirred for two hours and then allowed to sit at room temperature overnight. The precipitates were removed by filtration and the filtrate was concentrated. The residue was extracted with ethyl acetate. The extract was washed with 2% hydrochloric acid, 4% sodium bicarbonate and water, then dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 35 g of methyl N-(4-methoxybenzoyl)-phenylalanyltyrosinate with a mp. 195°-197° C in a yield of 74%. Analysis, calculated for C27H28O6N2C 68.05, H 5.92, N 5.88, found C 67.84, H 5.92, N 5.57.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[CH2:18][CH2:17][C:11]3[N:12]=[N:13][C:14](Cl)=[CH:15][C:10]=3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[CH2:18][CH2:17][C:11]3[N:12]=[N:13][C:14]([NH:22][NH2:23])=[CH:15][C:10]=3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(Br)cc1)N1CCc2nnc(Cl)cc2C1
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccc(Br)cc1)C2

Procedure:
10.2 g of 6-(p-bromobenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 55 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 2 hours. The title compound has a M.P. of 192°-195° (decomp., from absolute ethanol/methanol 3:1).
Reaction SMILES: [Na].[Cl-].[C:3]([CH2:6][O:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH3+:14])([OH:5])=[O:4].[C:15]1([N:21]=[C:22]=[S:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([NH:21][C:22](=[S:23])[NH:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]2[O:7][CH2:6][C:3]([OH:5])=[O:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: S=C=Nc1ccccc1
Reactant: [NH3+][C@@H]1CCCC[C@H]1OCC(=O)O
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: O=C(O)CO[C@@H]1CCCC[C@H]1NC(=S)Nc1ccccc1
Yield: 30 %

Procedure:
To a solution of sodium ethoxyde prepared from Na (0.046 g, 2 mmoles) and ethanol (10 ml), there were added trans-2-carboxymethoxy-cyclohexyl ammonium chloride (0.419 g, 2 mmoles) and phenylisothiocyanate (0.270 g, 2 mmoles). The mixture was refluxed for 1 hour, evaporated and the residue was dissolved in 1N NaOH (25 ml). The solution was extracted with diethyl ether (2×20 ml), the aqueous phase was acidified with HCl 18% to pH 2 and reextracted with diethyl ether (3×20 ml). The organic phase was dried with MgSO4, the drying agent was filtered off and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of ethanol/ether. Thus, there were obtained 0.185 g (30%) of the title compound in the form of white crystals, melting point 147°-149° C.
Reaction SMILES: [NH2-:1].[Li+].N.[Li].[NH2:5][C:6]1[C:7]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[C:11](OC)=[O:12]>O1CCCC1>[NH2:5][C:6]1[C:7]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[C:11]([NH2:1])=[O:12]
Reactant: [NH2-]
Reactant: COC(=O)c1sc2cccc(OC)c2c1N
Agent: N
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cccc2sc(C(N)=O)c(N)c12
Yield: 58 %

Procedure:
Lithium amide in liquid ammonia is prepared as described by Unangst P. C., Carethers M. E., J. Heterocyclic. Chem. 21, 709 (1984), from lithium metal ribbon (0.16 g, 23 mmol). A solution of methyl 3-amino-4-methoxybenzo[b]thiophene-2-carboxylate (1.3 g, 5.5 mmol) [Beck J. R., supra] in 10 mL of tetrahydrofuran is added dropwise. The mixture is stirred for 18 hours as the excess ammonia is permitted to evaporate. The residue is treated with 250 g of ice and water. The solid product is filtered, washed with water, and recrystallized from aqueous ethanol to yield 0.70 g (58%) of product; mp=151°-153° C.
Reaction SMILES: [C:1](=[O:38])([O:3][C:4]([CH3:37])([CH3:36])[CH2:5][C@@H:6]([CH2:17][C:18]([N:21]1[CH2:25][CH2:24][C@H:23]2[CH2:26][N:27]([C:29]([C:31]3([C:34]#[N:35])[CH2:33][CH2:32]3)=[O:30])[CH2:28][C@@H:22]12)=[C:19]=[O:20])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[NH2:2].OO.C(=O)([O-])[O-:42].[K+].[K+].O>CS(C)=O>[C:1](=[O:38])([O:3][C:4]([CH3:36])([CH3:37])[CH2:5][C@@H:6]([CH2:17][C:18]([N:21]1[CH2:25][CH2:24][C@H:23]2[CH2:26][N:27]([C:29]([C:31]3([C:34]([NH2:35])=[O:42])[CH2:32][CH2:33]3)=[O:30])[CH2:28][C@@H:22]12)=[C:19]=[O:20])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[NH2:2]
Reactant: CC(C)(C[C@@H](CC(=C=O)N1CC[C@H]2CN(C(=O)C3(C#N)CC3)C[C@H]21)Cc1cc(F)c(F)cc1F)OC(N)=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C[C@@H](CC(=C=O)N1CC[C@H]2CN(C(=O)C3(C(N)=O)CC3)C[C@H]21)Cc1cc(F)c(F)cc1F)OC(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
(R)-4-((3aS,6aS)-5-(1-cyanocyclopropylcarbonyl)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4-carbonyl-1-(2,4,5-trifluorophenyl)butan-2-yltertbutyl carbamate 17a (300 mg, 0.58 mmol) was dissolved in DMSO (5 mL), added 30% of hydrogen peroxide (0.5 mL) and potassium carbonate (160 mg, 1.16 mmol) at 0° C., the temperature of reaction solution was raised to room temperature and stirred for 5 minutes, added water (20 mL), extracted by dichloromethane, dried by anhydrous sodium sulfate, concentrated, residues was purified by column chromatography to give (R)-4-((3aS,6aS)-5-(1-aminocarbonylcyclopropylcarbonyl)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4-carbonyl-1-(2,4,5-trifluorophenyl)butan-2-yltertbutyl carbamate 28a (265 mg, 85%) as white foamy solid. MS m/z (ESI): 539.2 (M+1).
Reaction SMILES: C(N(CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CC[O:11][CH2:10]1)C1C=CC=CC=1.O1C=CC(N)=[N:48]1>>[O:39]=[S:30]1(=[O:38])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:16]([NH:15][C:14]3[CH:9]=[CH:10][O:11][N:48]=3)[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: Nc1ccon1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Nc3ccon3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 4,6-dibromoquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 1,2-oxazol-3-amine. MS obsd. (ESI+) [(M+H)+] 421, 1H NMR (400 MHz, CD3OD) δ ppm 8.72 (s, 1 H), 8.20 (s, 2 H), 8.14 (d, J=7.2 Hz, 1 H), 8.07 (d, J=7.6 Hz, 1 H), 7.83 (d, J=8.8 Hz, 1 H), 7.63-7.68 (m, 2 H), 7.56 (t, J=7.6 Hz, 1 H), 6.65 (s, 1 H), 5.29 (s, 2 H), 4.61 (s, 2 H), 3.79 (s, 2 H), 2.54 (s, 3 H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]([I:1])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Product: Cc1cc(Br)c(C(=O)O)cc1I
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
N-Iodosuccinimide (19.1 g) is added in portions to an ice-cold solution of 2-bromo-4-methyl-benzoic acid (18.4 g) dissolved in sulphuric acid (20 mL). The resulting mixture is stirred at 5-10° C. for 3 h before warming to room temperature overnight. Then, the mixture is poured on crushed ice and the resultant solution is extracted with ethyl acetate. The combined extracts are washed in succession with aqueous 10% Na2S2O3 solution (2×), water (3×), and brine (1×). After drying (MgSO4), the organic solvent is evaporated under reduced. The remaining solid is taken up in water and the resulting slurry is stirred at 70° C. for 5 min. The non-dissolving part is separated by filtration and dried to give the desired product.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[CH3:28])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O>[CH3:28][C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:32][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1C
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 55.1 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (6.28 g, 15.12 mmol) was dissolved in MeOH (60 mL) and cooled to −40° C. 3.8 M NaOH (3.98 mL, 15.12 mmol) was dissolved in water (6 mL) and added to the mixture and the reaction stirred at −40° C. for 40 min. Hydroxylamine (50% by weight in water, 0.926 mL, 15.12 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a preheated 80° C. warm solution of 6 M HCl (76 mL, 453.53 mmol) and stirred for 20 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM and the combined organic phase was dried and evaporated. The compound was purified in two runs by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (3.2 g, 55%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.81-1.93 (m, 2H), 2.21-2.42 (m, 2H), 2.44 (s, 3H), 3.03-3.13 (m, 1H), 3.59 (s, 3H), 3.63-3.75 (m, 1H), 4.12-4.20 (m, 1H), 5.02 (dd, 1H), 5.65 (s, 1H), 7.30 (d, 1H), 7.37-7.44 (m, 2H). MS m/z 383 (M−H)−
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: ClCC1CO1
Reactant: Oc1cc(-c2ccccc2)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2cc(OCC3CO3)no2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
To a solution of 10.00 g of 3-hydroxy-5-phenylisoxazole dissolved in hexamethylphosphoroamide (50 ml) were added 10.28 g of anhydrous Potassium carbonate and 6.89 g of epichlorohydrin, and the mixture was stirred at room temperature for 24 hours. After insoluble materials in the reaction mixture were removed by filtration, the filtrate was diluted with ethyl acetate (200 ml) followed by washing with an aqueous 10% sodium chloride solution (200 ml ×2). After the organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was freed from the solvent by distillation under reduced Pressure. The residue was purified by column chromatography through silica gel (developing solvent: a 4:1 mixture of cyclohexane and ethyl acetate) to afford 11 00 g (82.0%) of the title compound with melting point 98° to 99° C. as colorless needles.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([N:14]=[C:15]=[S:16])[CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([NH:14][C:15](=[S:16])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:13]=1
Reactant: NCC(N)=O
Reactant: Cc1ccc(F)cc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(F)cc1NC(=S)NCC(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
A mixture of glycinamide hydrochloride (4.42 g), 5-fluoro-2-methylphenyl-isothiocyanate (6.68 g), triethyl amine (4.1 g), and chloroform (150 mL) was stirred at ambient temperature for 18 hours. The precipitate was collected by filtration, washed with chloroform and air dried to give 2-[3-(5-Fluoro-2-methylphenyl)-thioureido]-acetamide (7.6 g), m.p. 172°-174° C. (dec.). This compound was used without further purification in the next paragraph.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1>CC(O)=O>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[N:17]([C:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: Cc1cc(=O)c(OCc2ccccc2)co1
Solvent: CC(=O)O
Product: Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Temperature: 160 °C

Procedure:
To a suspension of 6.6 g (30.5 mmol) 5-(benzyloxy)-2-methyl-4H-pyran-4-one in 150 ml 30% AcOH was added 7.5 g (45.8 mmol) m-aminobiphenyl. The reaction mixture was heated at 160° C. for 18 h, then cooled to rt, extracted with 300 ml EtOAc, washed with brine, and concentrated in vacuo. Purification by flash chromatography (330 g silica gel, 0-20% MeOH:EtOAc) afforded 5-(benzyloxy)-1-biphenyl-3-yl-2-methylpyridin-4(1H)-one. LCMS (M+H)+=368.3.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1>CC(C)=O>[F:10][C:11]([F:21])([F:22])[C:12]1[CH:13]=[C:14]([NH:18][C:19]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 250 ml. dry acetone, 13.6 g. valeramidine hydrochloride, and 18.7 g. 3-(trifluoromethyl)phenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from acetonitrile 17.9 g. of the hydrochloride of 1-[3-(trifluoromethyl)phenyl]-3-(pentanimidoyl)urea; m.p. 167°-169°C.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)=[C:2]=[O:3].Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>O1CCCC1>[NH2:33][C:19]1[N:20]=[C:21]([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([C:2]([NH:1][CH:4]4[CH2:8][CH2:7][CH2:6][CH2:5]4)=[O:3])[CH2:30]3)=[CH:25][CH:24]=2)[CH:22]=[C:17]([N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)[N:18]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=NC1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCCC3)CC4)nc(N)n2)CC1
Reaction time: 0.5 h

Procedure:
Isocyanatocyclopentane (0.030 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (16 μL, 0.12 mmol) in tetrahydrofuran (0.3 mL). After 30 minutes, the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=436.5.