Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14]([O:21][C:22]([CH:24]1[CH2:36][C:35]2[C:34]3[C:29](=[C:30]([Cl:37])[CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]=2[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:21][C:22]([CH:24]1[CH2:36][C:35]2[C:34]3[C:29](=[C:30]([Cl:37])[CH:31]=[CH:32][CH:33]=3)[N:28]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:27]=2[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OCc1ccccc1)C1CCc2[nH]c3c(Cl)cccc3c2C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cccc(Cl)c31)CC(C(=O)OCc1ccccc1)CC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
Cesium carbonate (6.32 g, 19.2 mmol) and ethyl bromoacetate (1.16 ml, 10.2 mmol) are added to a stirred solution of 8-chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid benzyl ester (2.17 g, 6.4 mmol) in dry DMF (20 ml). The reaction mixture is stirred at 60° C. for 3 h. The precipitate is filtered off and rinsed thoroughly with acetone. The filtrate is concentrated and the residue is purified by flash chromatography on silica gel (heptane/EtOAc 4:1) to afford pure title compound as a yellow solid (2.54 mg) in 93% yield. tR (LC-5) 1.14 min; ESI-MS (positive ion): m/z 426.16 [M+H]+ (calcd 425.91 for C24H24NO4Cl). 1H-NMR (CDCl3): 1.25 (t, J=7.0 Hz, 3H); 2.07 (m, 1H); 2.37 (m, 1H); 2.69 (m, 2H); 2.89 (m, 2H); 3.07 (dd, J=14.4, 4.4 Hz, 1H); 4.22 (q, J=7.3 Hz, 2H); 5.07 (d, J=18.2 Hz, 1H); 5.18 (s, 2H); 5.19 (d, J=18.5 Hz, 1H); 6.97 (t, J=7.9 Hz, 1H); 7.08 (dd, J=7.6, 0.9 Hz, 1H); 7.34 (m, 6H).
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([N:11]=CN(C)C)=[N:6][CH:7]=[C:8]([I:10])[N:9]=1)#[N:3]>>[NH2:11][C:5]1[C:4]([C:2]#[N:3])=[N:9][C:8]([I:10])=[CH:7][N:6]=1
Reactant: CN(C)C=Nc1ncc(I)nc1C#N
Agent: Cl
Product: N#Cc1nc(I)cnc1N
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
77 ml (77 mmol) of 1 M hydrochloric acid solution is added to 7.7 g (25.6 mmol) of N′-(3-cyano-5-iodopyrazin-2-yl)-N,N-dimethylformimidamide. The reaction medium is heated at 50° C. for 4 hours and then stirred at room temperature overnight. The precipitate formed is filtered, rinsed with water and dried at 50° C. to yield 6 g (95%) of 3-amino-6-iodopyrazine-2-carbonitrile in the form of a beige solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]=2/[CH:27]=[CH:28]\[CH3:29])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2/[CH:27]=[CH:28]\[CH3:29])[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C\c1cc(C(=O)OC)ccc1N1CCN(CCOCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C=C\c1cc(C(=O)O)ccc1N1CCN(CCOCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
Methyl (Z)-4-{4-[2-(benzyloxy)ethyl]piperazin-1-yl}-3-(prop-1-en-1-yl)benzoate (20 mg, 0.0507 mmol) was dissolved in methanol (1.0 mL). Under ice-cold conditions, 4N aqueous solution of sodium hydroxide (50 μL) was added and stirred at 50° C. overnight. The reaction solution was added 4N aqueous solution of hydrochloric acid under ice-cold conditions, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (13 mg (yield 65%)) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7](Br)[O:6]1)=[O:4].[OH:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[O:6]1)=[O:4]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)[C@H]1O[C@@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc(C=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 72.1 %

Procedure:
44.1 g (111 mmol) of (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-bromo-tetrahydro-pyran-2-carboxylic acid methyl ester is reacted analogously to Example LE1a with 14 g of 4-hydroxy-benzaldehyde, and after working-up and purification, 35.1 g (80 mmol, 72%) of the title compound is isolated.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[CH3:30])=[CH:11]/[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:27][CH2:28][CH3:29])[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1>C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7](/[C:10](/[CH3:30])=[CH:11]/[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:27][CH2:28][CH3:29])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(Br)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(Br)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydroxide (1M, 1.10 ml, 1.10 mmol) was added to a solution of (E)-(S)-ethyl 3-{4-[3-(4-bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (example 50) (0.245 g, 0.548 mmol) in ethanol (10 ml) and the mixture stirred at room temperature for 18 h. The resulting mixture was partitioned between water (50 ml) and ethyl acetate (50 ml) and the aqueous layer acidified to pH1 by addition of 1N HCl. The aqueous layer was separated and further extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine, dried (MgSO4), evaporated and vacuum dried at 40° C. for 18 h, to give (E)-(S)-3-{4-[3-(4-bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid as a colourless gum which contained 0.1 molar equivalents of ethyl acetate; 0.22 g (96%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.[Br-].[CH3:25][C:26]1[N:31]=[C:30]([Zn+])[CH:29]=[CH:28][CH:27]=1.C1COCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:4]3[S:5][CH:6]=[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=4)[C:3]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: Cc1cccc([Zn+])n1
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3scc(-c4cccc(C)n4)c3C)c(C)nc12
Temperature: 65 °C
Yield: 31 %

Procedure:
To a flask containing 3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (below) (0.25 g, 0.64 mmol) and PdCl2(dppf) (0.023 g, 0.032 mmol) is added a solution of 0.5 M 6-methyl-2-pyridylzinc bromide in THF (2.5 mL, 1.27 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (25 mL), washed with sat. NH4Cl (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (15%-20% EtOAc gradient) and is chromatographed (50×250 C18 Symmetry column, 10-70% water: 0.1% TFA/ACN: 0.1% TFA gradient). The residue is dissolved in Et2O (20 mL), washed with sat. NaHCO3 (15 mL) dried over MgSO4, filtered and concentrated to furnish the title compound (0.066 g, 1.57 mmol, 31%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.20 (s, 3H), 2.47 (s, 3H), 2.49 (s, 3H), 2.61 (s, 3H), 3.29-3.38 (m, 1H), 6.66 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.54 (dd, J=7.5, 7.8 Hz, 1H), 7.72 (s, 1H). LC/MS (m/z): calcd. for C24H28N4S (M+H)+: 405.2; found: 405.3.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH3:2].N1C(C)=CC=CC=1C.[Cl:22][C:23]([Cl:28])([Cl:27])[C:24](Cl)=[O:25].O>C(Cl)(Cl)Cl>[CH2:12]([O:11][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:24](=[O:25])[C:23]([Cl:28])([Cl:27])[Cl:22])[CH3:13]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOC(Cn1cccc1)OCC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CCOC(Cn1cccc1C(=O)C(Cl)(Cl)Cl)OCC
Temperature: 25 °C
Yield: 60 %

Procedure:
To a refluxing solution of 1-(2,2-diethoxyethyl)pyrrole (31.6 g, 172.5 mmol) and 2,6-lutidine (20.3 g, 189.8 mmol) in 90 mL of chloroform over a period of 16 hours was added trichloroacetyl chloride (34.5 g, 189.8 mmol) in 90 mL of chloroform. The reaction mixture was refluxed for an additional 4 hours. The reaction mixture was allowed to cool to room temperature and then poured into a mixture of water and chloroform (1:1). The phases were separated, washed with a saturated solution of NaCl, dried over MgSO4, and then evaporated. Purification of the product by column chromatography [hexane:ether (9.9:0.1)] gave the title compound, 1-(2,2-diethoxyethyl)-2-trichloroacetylpyrrole, in 60% yield, ms 327 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:25])[C:16]([CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)[CH:14]=1.[NH3:26]>[Cu].[Cu](I)I>[NH2:26][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:25])[C:16]([CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)[CH:14]=1
Reactant: N
Reactant: O=c1c(Cc2cccnc2)cn2c3ccccc3c3cc(Br)cc1c32
Agent: I[Cu]I
Agent: [Cu]
Product: Nc1cc2c(=O)c(Cc3cccnc3)cn3c4ccccc4c(c1)c23
Temperature: 185 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
2-bromo-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (555 mg) produced in Example 178, copper (20 mg), and copper iodide (10 mg) were suspended in aqueous ammonia (28%, 30 ml) in a pressure-resistant microbomb, and the suspension was heated to 180 to 190° C. in an oil bath and stirred for 8 hours. The reaction mixture was then allowed to cool and brought back to normal pressure, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate), and the crude purification product was recrystallized from ethanol to obtain the title compound (120 mg; 26%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([CH:28]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1-c1ccc(F)cc1

Procedure:
172 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (105 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Product: CC(=O)c1cc(C(=O)NC[C@H](C)n2ccc(-c3cc(F)c(C#N)c(F)c3)n2)[nH]n1

Procedure:
The title compound was synthesized from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (380 mg, 1.45 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (229 mg, 1.48 mmol) using the method of Example 34(d). Yield 249 mg. 1H NMR (400 MHz; d6-DMSO): δ 1.49 (d, 3H), 2.48 (s, 3H), 3.62 (m, 2H), 4.67 (m, 1H), 6.98 (d, 1H), 7.25 (bs, 1H), 7.76 (m, 2H), 7.89 (d, 1H), 8.52 (bs, 1H), 14.18 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C1C=CC(C2(CO)CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1(c2cccc(Cl)c2)CCCC1
Agent: OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: OCC1(c2cccc(Cl)c2)CCCC1

Procedure:
(1-(3-Chlorophenyl)cyclopentyl)methanol (496) was synthesized from 1-(3-chlorophenyl)phenyl)cyclopentanecarbaldehyde (495) following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentane-methanol (239).
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C:8]([C:10]1[CH:37]=[CH:36][C:13]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]3[CH2:23][CH2:24][CH:25]([C:27]([O:29][CH3:30])=[O:28])[O:26][C:21]=3[C:20]=2[CH2:33][CH2:34][CH3:35])=[C:12]([CH2:38][CH2:39][CH3:40])[C:11]=1[O:41][CH3:42])=O)(=O)=O.[CH:45]([NH2:47])=O.CN(C)C=O>C(OCC)(=O)C.O>[CH3:42][O:41][C:11]1[C:12]([CH2:38][CH2:39][CH3:40])=[C:13]([CH:36]=[CH:37][C:10]=1[C:8]1[N:47]=[CH:45][O:6][CH:7]=1)[O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]2[CH2:23][CH2:24][CH:25]([C:27]([O:29][CH3:30])=[O:28])[O:26][C:21]=2[C:20]=1[CH2:33][CH2:34][CH3:35]
Reactant: NC=O
Reactant: CCCc1c(OCCCOc2ccc(C(=O)COS(=O)(=O)C(F)(F)F)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(-c3cocn3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2

Procedure:
The compound of Example 3 (0.10 g, 0.155 mmol) was stirred with 0.5 ml of formamide and 0.2 ml of dimethyl formamide (DMF) for 1.5 hours at 170° C. The reaction mixture was cooled and poured into ethyl acetate/water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was flash chromatographed on silica gel using 10:1 to 4:1 hexane/ethyl acetate eluant to give the product, 0.057 g (0.109 mmol), 35%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19].[ClH:36]>>[ClH:36].[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CCCN4CCOCC4)cc3)c(C)o2)cc1
Agent: Cl
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(CCCN2CCOCC2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of methyl 4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate (2.0 g, 4.02 mmol, 1.00 equiv) in 6N hydrochloric acid (80 mL) was refluxed overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum to give 2.0 g (96%) of 4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid hydrochloride as a white solid. LC-MS: (ES, m/z): 485 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1>C1(C)C=CC=CC=1.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:33][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][N:17]2[C:9]3=[N:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][C@H:16]2[C:18]([F:20])([F:21])[F:19])[CH:32]=[CH:31][CH:30]=1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Clc1cccc(CCBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2CCc1cccc(Cl)c1
Reaction time: 44 h
Yield: 19.2 %

Procedure:
The product is prepared according to the procedure described in Example 40, using 150 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one in 2.5 ml of toluene are added 296 mg of sodium hydroxide in 2.5 ml of water, 33 mg of tetrabutylammonium hydrogen sulphate and 216 mg of 1-(2-bromoethyl)-3-chlorobenzene. After 44 hours at 60° C. After cooling, the reaction mixture is diluted with ethyl acetate. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated to dryness under reduced pressure and the residue is purified by preparative HPLC/MS (Method D). 42 mg of (8S)-9-[2-(3-chloro-phenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one are thus obtained, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].[C:25](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>O1CCCC1.O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[N:15]([CH3:25])[C:14]2=[O:24])=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 2′-chloro-5′-[3,6-dihydro-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4′-fluoroacetanilide (0.85 g, 2.3 mmol), potassium carbonate (0.32 g, 2.3 mmol) and dimethylsulfate (0.22 mL, 2.3 mmol) in tetrahydrofuran is refluxed for 90 minutes, cooled to room temperature, and diluted with water and chloroform. The resultant mixture is concentrated in vacuo to obtain an aqueous suspension which is filtered to give the title product as an off-white solid (0.75 g, mp 257-258.5° C.).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3]1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:25][S:26]([O:1][CH:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)C2
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OS(C)(=O)=O)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (392 mg, 1.62 mmol, 1.0 equiv) was dissolved in DCM (6.0 mL). The solution was cooled to 0° C. with an external ice-bath. Et3N (237 μL, 1.706 mmol, 1.05 equiv)) and DMAP (2.0 mg, 1 mol %) were added. Methanesulfonyl chloride (132 μL, 1.706 mmol, 1.05 equiv) was then added dropwise by a syringe. The solution was stirred at 0° C. for 2.0 hrs, was then allowed to warm to room temperature and stirred at room temperature for 18 hrs. Et3N (23 μL, 0.1 equiv) and methanesulfonyl chloride (13 μL, 0.1 equiv) were added and the mixture was stirred for another 6 h. A saturated solution of NH4Cl (20 mL) was added and stirred at room temperature for 10 min. The layers were separated. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phase were washed with HCl (1N, 20 mL) and water (20 mL) and were dried over anhydrous Na2SO4, concentrated in vacuo to afford 482 mg (yield 93%) of tert-butyl 2-(methylsulfonyloxy)-7-azaspiro[3.5]nonane-7-carboxylate as a white solid.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:52]([O:59][C:60]([N:62]1[CH2:66][CH:65]([C:67]2[C:75]3[C:70](=[CH:71][C:72]([F:76])=[CH:73][CH:74]=3)[NH:69][CH:68]=2)[CH:64]2[NH:77][CH2:78][CH2:79][CH:63]12)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:52]([O:59][C:60]([N:62]1[CH2:66][CH:65]([C:67]2[C:75]3[C:70](=[CH:71][C:72]([F:76])=[CH:73][CH:74]=3)[NH:69][CH:68]=2)[CH:64]2[N:77]([C:9](=[O:11])[CH:2]([NH:1][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:78][CH2:79][CH:63]12)=[O:61])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: O=C(OCc1ccccc1)N1CC(c2c[nH]c3cc(F)ccc23)C2NCCC21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution containing Boc-Chg-OH (600 mg, 2.3 mmol) in anhydrous NMP (6 mL) was cooled to 0° C. HATU (865 mg, 2.3 mmol) and DIPEA (0.67 g, 5.2 mmol) were added followed by the addition of crude 42 (900 mg, 2.4 mmol) in anhydrous NMP (6 mL). The reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with EtOAc and washed successively with 1M HCl, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.5 g of crude 48 as a light brown-colored foam which was used without further purification. 1H NMR (300 MHz, CDCl3), mixture of rotamers: δ8.38 (s, 0.5H), 8.31 (s, 0.5H), 8.19 (dd, J=5.4, 8.7 Hz, 0.5H), 8.12 (dd, J=5.4, 8.7 Hz, 0.5H), 7.44-7.35 (m, 5H), 7.00-6.88 (m, 2H), 6.78 (s, 0.5H), 6.61 (s, 0.5H), 5.38-5.28 (m, 1H), 5.22-5.12 (m, 2H), 4.65 (d, J=4.8 Hz, 0.5H), 4.58 (d, J=5.1 Hz, 0.5H), 4.39-4.31 (m, 2H), 4.23 (d, J=11.7 Hz, 0.5H), 4.16-4.02 (m, 2H), 3.92 (d, J=5.4 Hz, 1H), 3.54-3.43 (m, 2H), 2.47-2.37 (m, 0.5H), 2.29-2.23 (m, 0.5H), 1.93-1.70 (m, 7H), 1.43 (s, 9H), 1.19-1.12 (m, 2H) ppm. Mass spectrum, m/z [619.5] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([SH:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([S:13][CH2:15][C:16]([OH:18])=[O:17])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Sc1nc(-c2ccc(Cl)cc2)no1
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CSc1nc(-c2ccc(Cl)cc2)no1
Yield: 67 %

Procedure:
A mixture of 3-(p-chlorophenyl)-5-mercapto-1,2,4-oxadiazole (106 parts), chloroacetic acid (48 parts), potassium carbonate (75 parts) and water (100 parts) was heated at reflux for one hour. The solution was filtered hot, cooled, acidified and the solid separated to give [3-(p-chlorophenyl)-1,2,4-oxadiazol-5-ylthio]acetic acid (91 parts, 67% yield), melting point 112°-114° C. (as monohydrate).