Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.Cl>C(O)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:4]3[C:5]4[C:10]([CH2:11][C:3]=3[CH:2]=[N:22]2)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:17][CH:16]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C1C(=CO)Cc2ccccc21
Agent: Cl
Solvent: CCO
Product: Fc1ccc(-n2ncc3c2-c2ccccc2C3)cc1

Procedure:
2-Hydroxymethylene indan-1-one, (Example 1(ii) (a) (4.004 g; 250 mmol), p-fluorophenyl hydrazine hydrochloride (Aldrich) (4.106 g; 25.25 mmol) 10M hydrochloric acid (1 cm3) and ethanol (30 cm3), were heated under reflux for 19 hours. After cooling, the solvent was evaporated under reduced pressure, then taken up in dichloromethane and washed with 2M NaOH. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. Purification by Kugelrohr distillation (140° C.; 0.01 mmHg) afforded a yellow solid, m.p. 104-105° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]#[C:22][CH3:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[C:21]#[C:22][CH3:23]
Reactant: CC#CCBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylxanthine (1.1 g) was dissolved in N,N-dimethylformamide (15 ml), and potassium carbonate (1.0 g) and 1-bromo-2-butyne (0.64 ml) were added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.3 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione (1.3 g) was dissolved in N,N-dimethylformamide (15 ml), and N-chlorosuccinimide (0.89 g) was added while cooling on ice. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.1 g of 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione. The resulting 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (1.4 g) and 1-piperazine carboxylic acid tert-butyl ester (2.8 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, then the organic layer was washed with water and saturate brine, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17]>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:20][CH:16]([CH2:18][CH3:19])[CH3:17]
Reactant: CCC(C)N
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Solvent: CCO
Product: CCC(C)NCCOc1cc(F)cc(S(C)(=O)=O)c1
Yield: 70.4 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and sec-butylamine 1.37 ml, 13.46 mmol) in ethanol (5 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (342 mg, 70%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 166.5° C. MS m/z (relative intensity, 70 eV) 289 (M+, 1), 261 (25), 260 (bp), 86 (49), 70 (12).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][CH2:24]N5CCCCC5)[C:18](=[O:31])[CH:17]=4)=[CH:15][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.FC(F)(F)C(O)=[O:39]>O>[O:31]=[C:18]1[CH:17]=[C:16]([C:14]2[CH:13]=[CH:12][N:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][N:9]=[C:10]3[CH:15]=2)[CH:21]=[CH:20][N:19]1[CH2:22][CH2:23][CH:24]=[O:39]
Reactant: O=c1cc(-c2ccn3c(-c4ccccc4)cnc3c2)ccn1CCCN1CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=CCCn1ccc(-c2ccn3c(-c4ccccc4)cnc3c2)cc1=O

Procedure:
To a solution of 4-(3-phenylimidazo[1,2-a]pyridin-7-yl)-1-(3-piperidin-1-ylpropyl)pyridin-2(1H)-one (0.210 g, 0.503 mmol) in 5.0 mL of a 2:1 solution of chloroform: (50% trifluoracetic acid:water) at 0° C. After 1 hour solvent was removed under reduced pressure to give 3-[2-oxo-4-(3-phenylimidazo[1,2-a]pyridin-7-yl)pyridin-1(2H)-yl]propanal. 1H NMR (CDCl3) δ 8.94 (s, 1H), 8.90 (d, 1H, J=6.84 Hz), 8.05 (s, 1H), 7.73–7.64 (m, 6H), 7.60 (m, 4H), 4.90 (t, 2H, J=5.13 Hz), 2.60 (m, 2H). LCMS m/z (M+1) Calc: 344.1, found 344.0
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:8][CH2:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:3][CH:4]1[CH2:8][CH2:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CCC(OCc2ccccc2)C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Sodium hydride (60% oil dispersion, 2.1 g, 53 mmol) was added in portions to a solution of diethyl 3-hydroxycyclopentane-1,1-dicarboxylate 27 (11 g, 48 mmol), benzyl bromide (9.7 g, 53 mol), and n-tetrabutylammonium iodide (100 mg) in dry DMF (50 mL) at 25° C. (Step 25). The mixture was stirred for 1 hr at 65° C., poured onto ice and then extracted with ether (2×50 mL). The combined either extract was washed with water (3×50 mL) and driedover MgSO4. Chromatography on silica gel (10:90 ethyl acetate/hexane, Rf=0.38) afforded 11.6 g (75%) of the benzyl ether 28; 1H NMR (CDCl3) δ1.3 (t, J=7.2 Hz, 6H, CH3), 1.7-2.7 (m, 6H, CH2), 4.2 (q, J=7.2 Hz, 4H, O=COCH2), 4.1 (m, 1H, O--CH), 4.6 (s, 2H, O--CH2), 7.3 (s, 5H, phenyl).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13].I[CH3:15]>CN(C=O)C>[CH3:15][O:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[NH2:3]
Reactant: CI
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
85% potassium hydroxide solution (11.7 g, 0.179 mol) is added to a solution of 25 g (0.162 mol) 2-amino-3-nitro-phenol in 200 mL DMF. Then 11.1 mL (0.178 mol) iodomethane are added dropwise and the mixture is stirred overnight at ambient temperature. The reaction mixture is poured onto ice and stirred for one hour. The precipitated product is filtered off, washed with water and dried.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9]([NH:12][C@H:13]([C:21](O)=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:11])[CH3:10].CN1CCOCC1>ClCCl>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][C:21](=[O:22])[C@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:12][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: -10 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
0.1 g of L-alanine methyl ester hydrochloride (0.7 mmol), 0.2 g of N-acetyl-L-phenylalanine (1 mmol) and 0.55 ml of N-methylmorpholine (5 mmol) are dissolved in 50 ml of dichloromethane and cooled to −10° C. 0.5 g of CPA from example 1 (50% in CH2Cl2; 0.8 mmol) is added slowly, and the mixture is stirred under cold conditions for 3 h and at room temperature for 72 h. The solution is concentrated by evaporation and extracted with ethyl acetate and 1 N HCl solution, sat. NaHCO3, sat. NaCl and dist. water. The organic phase is dried over magnesium sulfate, filtered off and concentrated by evaporation. 0.18 g of the white N-acetyl-L-phenylalaninyl-L-alanine methyl ester is obtained (88%).
Reaction SMILES: Cl.[C:2]([C:6]1[C:7]2[CH2:8][C:9]([CH3:22])([CH3:21])[NH:10][C:11]=2[C:12]([CH3:20])=[C:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][C:14]=12)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])O.[Na+].C(N(CC)CC)C.[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>C1COCC1>[C:2]([C:6]1[C:7]2[CH2:8][C:9]([CH3:22])([CH3:21])[N:10]([C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([F:35])=[CH:37][CH:38]=3)[C:11]=2[C:12]([CH3:20])=[C:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][C:14]=12)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c2c(c(C(C)(C)C)c3c1NC(C)(C)C3)OC(C)(C)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c2c(c(C(C)(C)C)c3c1N(C(=O)c1ccc(F)cc1)C(C)(C)C3)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
8-tert-Butyl-3, 5, 6, 7-tetrahydro-2,2,4,6,6-pentamethyl-2H-furo[2,3-f]indole hydrochloride (715.8 mg, 2.21 mmol) was suspended in THF (20 ml). To the mixture was added a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and stirred for 1 hour at room temperature. After extracting with isopropyl ether followed by drying over magnesium sulfate, the solvent was removed under reduced pressure. The residue was dissolved in THF (20 ml). To the solution were added triethylamine (0.35 ml, 2.51 mmol) and p-fluorobenzoyl chloride (371.8 mg, 2.34 mmol) and stirred at room temperature for 5 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain 417 mg of the title compound as an amorphous powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH2:19][CH3:20])=[C:6]([CH:12]([C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)O)[C:7]([CH2:10][CH3:11])=[CH:8][CH:9]=1)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]1[C:5]([CH2:19][CH3:20])=[C:6]([C:7]([CH2:10][CH3:11])=[CH:8][CH:9]=1)[CH2:12][C:14]1[NH:18][CH:17]=[CH:16][N:15]=1)[CH3:2]
Reactant: CCOc1ccc(CC)c(C(O)c2ncc[nH]2)c1CC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(CC)c(Cc2ncc[nH]2)c1CC

Procedure:
2-(3-Ethoxy-2,6-diethyl-benzyl)-1H-imidazole was prepared from rac-(3-ethoxy-2,6-diethyl-phenyl)-(1H-imidazol-2-yl)-methanol, triethylsilane and trifluoroacetic acid in analogy to Example 191e): light yellow crystals; MS (ISP): 259.3 ([M+H]+, 100%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:15]([F:16])=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[Na+].O.CN([CH:23]=[O:24])C>>[CH:23]([C:11]1[C:10]2[C:14](=[C:15]([F:16])[C:7]([Cl:6])=[CH:8][CH:9]=2)[NH:13][CH:12]=1)=[O:24]
Reactant: Fc1c(Cl)ccc2cc[nH]c12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2c(F)c(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Add phosphorus oxychloride (0.94 g, 6.16 mmol) to DMF (12 mL, cooled in an ice bath) with vigorous stirring. After about 10 minutes, add 6-chloro-7-fluoro indole (0.93 g, 5.6 mmol) in anhydrous DMF (4 mL), stir at 0° C. for 1 hour, warm to room temperature and stir overnight at room temperature (˜16 hrs). Treat with 14.0 mL of 2N NaOH (4 eq.) with vigorous stirring. Heat the reaction to 80° C. for half an hour then cool. Pour the reaction into cold water with vigorous stirring to give a solid. Collect the solid by filtration and dry overnight in a vacuum oven at room temperature, to give the title compound: 1H NMR (300 MHz, CD3COCD3/CDCl3) 7.09 (t, 1H, J=7.7 Hz), 7.83–7.86 (m, 2H), 9.89 (s, 1H). By the method of Example 316 the following compounds were prepared: a) 3-Formyl-5,7-difluoro-1H-indole: 1H NMR (300 MHz, CD3COCD3) 6.98–7.06 (m, 1H), 7.71–7.75 (m, 1H), 8.35 (s, 1H), 10.04 (s, 1H);
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]#[N:14])([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(N(C)C)=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:13]#[N:14])=[N:8]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: Cn1nc(C#N)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
5-nitro-1H-indazole-3-carbonitrile (150 mg, 0.797 mmol) was taken up in DMA (4 mL) and K2CO3 (331 mg, 2.392 mmol) was added, followed by drop wise addition of MeI (0.060 mL, 0.957 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was quenched with a saturated solution of NaHCO3 and Na2S2O3, and then diluted with EtOAc. The organic layer was washed with saturated NaHCO3, then brine, and dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography eluting with 0%-50% EtOAc/Hex. 1-methyl-5-nitro-1H-indazole-3-carbonitrile (134 mg) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:40][CH2:41][CH3:42])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[O:30])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:39])[CH3:2]>C(O)C.[Pd]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[NH:15][C:8]2([CH2:28][C:29]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=3)=[O:30])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]([CH2:5][CH:4]([O:40][CH2:41][CH3:42])[O:3][CH2:1][CH3:2])[C:7]2=[O:39])=[CH:24][CH:23]=1
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc([N+](=O)[O-])cc2)c2ccccc21)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(N)cc2)c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
A suspension of 0.62 g of (RS)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-nitrophenyl)ureido)indolin-2-one and 20 mg of 5% Pd/C in 100 ml of ethanol was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered through Cerite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 0.33 g (57%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([CH:19]([N:26]1[C:34]2[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37](O)=[O:38])=[CH:32][CH:33]=2)[CH:28]=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18]>>[CH2:17]([CH:19]([N:26]1[C:34]2[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:38])=[CH:32][CH:33]=2)[CH:28]=[CH:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:18]
Reactant: CCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
73 mg of compound 40 was obtained in a similar manner to those described in Examples 1 and 2 using 465 mg of ethyl 4-(2-aminophenoxy)butyrate and 333 mg of 3-[1-(α-ethylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH2:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH2:10]=O>O>[CH3:4][C:3]1([CH3:5])[S:6][CH2:10][NH:1][CH:2]1[C:7]([NH2:9])=[O:8]
Reactant: CC(C)(S)[C@H](N)C(N)=O
Reactant: C=O
Solvent: O
Product: CC1(C)SCNC1C(N)=O
Temperature: 50 °C
Yield: 94 %

Procedure:
Penicillaminamide (74.0 g, 0.50 mol) was dissolved in distilled water (800 ml) and added with 37% formalin (60.8 g, 0.75 mol). The mixture was heated with stirring at 50° C. under normal pressure, allowed to react for 2 hours and cooled. Subsequently, water was evaporated by using an evaporator. The residue was washed with acetone to obtain white crystals of 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid amide (75.5 g, 0.47 mol). The yield to penicillaminamide was 94.4 mole %.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]([CH3:15])([CH3:14])[CH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.CN([CH:19]=[O:20])C>>[CH3:6][C:7]([CH3:15])([CH3:14])[CH2:8][N:9]1[CH:13]=[C:12]([CH:19]=[O:20])[CH:11]=[N:10]1
Reactant: CC(C)(C)Cn1cccn1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)Cn1cc(C=O)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask charged with anhydrous DMF (400 mL) was cooled to 0° C., to which phosphorous oxychloride (114 g, 0.74 mol) was added dropwise, and the temperature was kept below 10° C. The stirring was continued for 1 h and it was allowed to rise to room temperature. Then it was cooled to 0° C. again, and a solution of 1-(2,2-dimethyl-propyl)-1H-pyrazole (51.1 g, 0.37 mol, CAS registry 725746-83-8) in DMF (100 mL) was added dropwise. Then it was heated to 100° C. overnight. After cooling, the reaction was quenched by slow addition of cold water, and it was neutralized with aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The resulting residue was purified by column chromatograph on silicagel (petroleum ether-EtOAc 10:1) to give the title compound as light yellow oil: ESIMS [M+H]+=167; 1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.42 (s, 1H), 7.98 (s, 1H), 3.99 (s, 2H), 0.90 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:40])[O:15][CH2:16][C@@H:17]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=3[Cl:38])=[O:28])[CH2:18][C:19]([F:25])([F:24])[CH2:20][N:21]=[N+]=[N-])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:40])[O:15][CH2:16][C@@H:17]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=3[Cl:38])=[O:28])[CH2:18][C:19]([F:24])([F:25])[CH2:20][NH2:21])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2cccc(F)c2)no1)CC(F)(F)CN=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2cccc(F)c2)no1)CC(F)(F)CN
Reaction time: 0.17 h
Yield: 53.8 %

Procedure:
To a mixture of (S)-5-azido-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-difluoropentyl 3-(3-fluorophenyl)isoxazol-5-ylcarbamate (0.35 g, 0.6 mmol) in MeOH (2 mL), was added 10% Pd/C (0.1 g). The mixture was transferred to an autoclave reactor, charged with 10 psi of hydrogen, and stirred for 10 min. The catalyst was filtered off and the filtrate was concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and H2O with 0.1% TFA. The elute was washed with saturated NaHCO3. The organic layer was concentrated to give (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-difluoropentyl 3-(3-fluorophenyl)isoxazol-5-ylcarbamate (0.18 g, 54%) as a white solid. LRMS (M+H+) m/z 558.1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[S:4][C:5]([CH3:12])=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.O[CH2:16][CH2:17][NH:18][CH:19]([CH3:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:29]([CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:19]([N:18]2[CH2:17][CH2:16][O:11][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:14])([F:13])[F:1])[S:4][C:5]=3[CH3:12])[CH2:9]2)[CH3:33])=[CH:22][CH:23]=1)([O:31][CH3:32])=[O:30]
Reactant: Cc1sc(C(F)(F)F)nc1C(=O)CBr
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3nc(C(F)(F)F)sc3C)C2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Prepared by analogy to Example 32 by reaction of 4.2 g (0.0146 mol) of 2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole with 8 g (0.03 mol) of N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine in methylene chloride by stirring at room temperature for 20 hours and heating under reflux for 2 hours. The reduction is carried out in 28 ml of trifluoroacetic acid using 2.4 g (0.02 mol) of triethylsilane. The crude product is purified on a silica gel column using toluene/ethyl acetate=7:3 as eluant.
Reaction SMILES: [ClH:1].[C:2]1(=O)[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)N.CO>Cl>[ClH:1].[CH3:13][N:14]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:3]2[CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]3)[C:2]1=2
Reactant: O=C1CCCC12CCNCC2
Reactant: CN(N)c1ccccc1
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccccc31)CCC21CCNCC1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution of 8-azaspiro[4,5]decane-1-one hydrochloride (5.2 g) in 95% ethanolic hydrochloric acid (30 ml) and 1-methyl-1-phenylhydrazine (5 g) was heated overnight on a steam bath, under nitrogen. The reaction mixture was cooled to ambient temperature, methanol was added and the mixture was concentrated in vacuo. The residue was flash chromatographed (silica gel) eluting with 10% methanol/dichloromethane. The appropriate fractions were collected and concentrated to afford 7.4 g (95%) of product, mp>270° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CC(O)C>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Yield: 88.9 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (300 mg, 1.43 mmol) and 3-(trifluoromethyl)aniline (461 mg, 2.86 mmol) in iPrOH (1.5 mL) was heated in a sealed tube at 120° C. for 2 h. Then the reaction mixture was concentrated and purified by triturating in Et2O to afford 425 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.52 (br s, 1H), 8.88 (d, J=7.8 Hz, 1H), 8.75 (s, 1H), 8.42 (d, J=7.2 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=6.9 Hz, 1H), 7.87-7.81 (t, J=8.4 Hz, 1H), 7.71-7.65 (t, J=7.8 Hz, 1H), 7.56-7.30 (d, J=7.8 Hz, 1H); MS (m/z): 335.19 (M+H)+.