Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29]N.S>C(O)C>[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29][NH:25][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[O:24]
Reactant: CC(C)CCN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=O)cc21
Agent: S
Solvent: CCO
Product: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 16 h

Procedure:
A solution of 10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (6 g), and 3-methylbutylamine (18.9 cc) in absolute ethanol (90 cc) is saturated with hydrogen sulphide and brought for 16 hours to a temperature in the region of 105° C. After cooling, the reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oily brown residue is purified by chromatography on a column (height: 40 cm, diameter: 4 cm) of silica gel (0.02-0.063 mm), eluting with methylene chloride (1 liter) and then with a mixture (1.5 liters) of methylene chloride and methanol (95:5 by volume) and collecting 80-cc fractions. Fractions 23 to 36 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-(3-Methylbutyl)-10-[1-(1-pyrrolidinyl) -2-propyl]-2-phenothiazinecarboxamide, L series (6.76 g), is thereby obtained in the form of an orange-colored oil.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:22][C:21]=2[O:34][CH2:35][C@@H:36]2[CH2:38][O:37]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:22][C:21]=2[O:34][CH2:35][C@@H:36]([OH:37])[CH2:38]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCc4ccccn4)cc3OC[C@@H]3CO3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1cc(OCc2ccccn2)ccc1-3
Yield: 62 %

Procedure:
Methyl 3-cyclohexyl-2-[2-[(2S)-oxiran-2-ylmethoxy]-4-(pyridin-2-ylmethoxy)phenyl]-1H-indole-6-carboxylate was dissolved in DMF (0.1 M) and the solution was added slowly to a suspension of Cs2CO3 (0.5 eq) in DMF at 65° C. After 1 h the mixture was diluted with Et2O. The solution was extracted with H2O, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo to leave an orange amorphous solid. The product was purified by FC (PE:EtOAc, 1:1+1% NEt3 to wash away remaining starting material, then EtOAc:MeOH, 9:1+1% NEt3). The product was obtained as a yellowish amorphous solid (62%). (ES+) m/z 513 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:8]=2[C:4]2[CH:3]=[C:2]([O:1][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:7]=[CH:6][CH:5]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2-c2cccc(O)c2)cc1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2-c2cccc(OCCCN3CCCCC3)c2)cc1
Yield: 92.4 %

Procedure:
In a manner similar to that used in Example 2, 1.04 g (2.9 mmol) of 1-(3-hydroxyphenyl)-2-(4-methoxyphenyl)-6-methoxynaphthalene, 0.86 g (4.35 mmol) of 1-(3-chloropropyl)piperidine hydrochloride, and 2 g (14.4 mmol) of K2CO3 were converted to 1.29 g of the title compound, isolated as a brown oil.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:23]1[CH:36]=[CH:35][C:26]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]([O:17][C:15]([NH:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:32]2[CH:33]=[CH:34][C:29]([C:27](=[O:28])[C:26]3[CH:35]=[CH:36][CH:23]=[CH:24][CH:25]=3)=[CH:30][CH:31]=2)=[CH:8][CH:9]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 42 h
Yield: 102.8 %

Procedure:
A mixture of Boc-Tyr-OMe (0.80 g, 2.7 mmol), 4-fluorobenzophenone (0.80 g, 4.0 mmol) and potassium carbonate (1.11 g, 8.0 mmol) in DMF (30 mL) was heated to 100° C. After 42 h, the reaction mixture was allowed to cool to rt. DMF was removed in vacuo and the remaining material was partitioned between EtOAc (50 mL) and water (50 mL). This gave an emulsion that was allowed to sit overnight. The following day the layers had mostly separated and so the organic layer was concentrated in vacuo to give 1.32 g of material. This material was purified by chromatography (4:1 hexane/ethyl acetate) to give 0.69 g of product. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 2.98-3.19 (m, 2H), 3.74 (s, 3H), 4.60 (q, J=6.8 Hz, 1H), 5.03 (br d, J=7.6 Hz, 1H), 6.98-7.05 (m, 4H), 7.14-7.19 (m, 2H), 7.45-7.51 (m, 2H), 7.55-7.61 (m, 1H), 7.75-7.84 (m, 4H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([C:20](Cl)=[O:21])[CH2:18][CH3:19]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:10][C:20](=[O:21])[CH2:17][CH2:18][CH3:19])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C(c1ccccc1)c1ccccc1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 205° C. and MS: m/e=281 (M+) was prepared in accordance with the general method of example 39 from 2,2-diphenylacetamide and propanecarboxylic acid chloride.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=S)[NH:11][NH2:12])[CH:6]=[CH:7][CH:8]=1.Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[CH3:23][C:21]1[NH:12][N:11]=[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CSc1cccc(NC(=S)NN)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2cccc(SC)c2)n[nH]c1C
Temperature: 25 °C

Procedure:
A suspension of 10.0 g (0.046 mole) of 4-(3-methythiophenyl)-3-thiosemicarbazide and 7.72 g (0.0469 mole) of ethyl 2-chloroacetoacetate in 150 mL of absolute ethanol was stirred at room temperature for ~16 hr. Ethanolic hydrogen chloride (2N, 50 mL) was added, the mixture refluxed for 1.0 hr, the solution filter while hot, and the filtrate evaporated under reduced pressure to give a crystalline residue which was recrystallized three times from absolute ethanol to give 6.3 g produce, mp 191.5°-194° C. The sample was dried at 56° C./4 hr/0.1 mmHg then 2 hr/25° C./0.1 mmHg.
Reaction SMILES: CS(O[CH:6]([C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)[CH2:7][N:8]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])(=O)=O.[N-:52]=[N+:53]=[N-:54].[Na+]>CN1C(=O)N(C)CCC1.CCOC(C)=O>[C:34]([O:33][C:31](=[O:32])[N:8]([CH2:7][CH:6]([N:52]=[N+:53]=[N-:54])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:49])([F:50])[F:51])[CH:39]=1)[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:27])[CH3:28])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])([CH3:36])([CH3:37])[CH3:35]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The 1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl methanesulfonate from the previous reaction was dissolved in DMPU (15 mL) and treated with NaN3 (140 mg, 2.15 mmol). The reaction was stirred at room temperature for 15 hours and then diluted with EtOAc (75 ml). The solution was washed with H2O (5×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified with 20% EtOAc/hexanes to afford tert-butyl{2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.52 (15% EtOAc/hexanes). LCMS=605.3 (M+1−BOC)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.80 (s, 1H), 7.67 (s, 1H), 7.48 (s, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.01-7.11 (m, 2H), 6.89 (m, 1H), 6.64 (d, J=8.6 Hz, 1H), 4.22-4.69 (m, 3H), 3.28 (s, 3H), 2.61-3.16 (m, 3H), 1.34 (s, 9H), 1.13-1.18 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:9][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[F:8])[CH:14]=[CH2:13]
Reactant: O=[N+]([O-])c1cc(Br)cc(F)c1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1c(F)cc(Br)cc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-6-fluoro-2-nitrophenol (2 g, 8.49 mmol), allyl bromide (0.88 mL, 10.07 mmol) and K2CO3 (2.34 g, 16.98 mmol) in DMF (20 mL) was stirred at 45° C. overnight. Inorganic salts were filtered off, and the filtrate was concentrated to provide the crude product, which was directly used for next step without further purification. MS (DCI/NH3) m/z 245.92 (M+H)+; 1H NMR (400 MHz, DMSO-D6) δ ppm 4.70 (d, J=6.14 Hz, 2 H) 5.27 (d, J=10.43 Hz, 1 H) 5.37 (dd, J=17.18, 1.53 Hz, 1 H) 5.92–6.02 (m, 1 H) 8.03–8.06 (m, 2 H).
Reaction SMILES: [CH2:1]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:5]=1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:42]=[CH:41][C:30]([CH:31](Cl)[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH:31]([N:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=3)[N:5]=[C:4]2[CH2:1][CH2:2][CH3:3])[C:30]2[CH:41]=[CH:42][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(C(Cl)c2ccc(OC)cc2)cc1
Reactant: CCCc1nc2ccc([N+](=O)[O-])cc2c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 48 h
Yield: 83.7 %

Procedure:
To a suspension of 10.0 g (45 mmol) of 2-propyl-6-nitro-quinazolin-4(3H)-one in 160 ml of dry CH2Cl2 was added 9.5 ml (67 mmol) of triethylamine followed by 12.9 g (49 mmol) of 4,4'-dimethoxybenzhydryl chloride. The reaction mixture was stirred for 48 hours and then washed with 10% citric acid (2×20 ml), water (1×20 ml), saturated NaHCO3 (2×20 ml) and brine (1×20 ml). The solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was recrystalised from EtOAc to give 17.3 g of white solid. 85% yield. 1H-NMR (CDCl3): 0.87 (t, 3H, J=7.3 Hz), 1.58 (bm, 2H), 2.72 (t, 2H, J=7.8 Hz), 3.80 (s, 6H), 6.88 (d, 4H, J=9 Hz), 7.19 (d, 4H, J=9.0 Hz), 7.73 (d, 1H, J=8.9 Hz), 8.48 (dd, 1H, J=2.8, 9.0 Hz), 9.08 (d, 1H, J=2.8 Hz).
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH2:6][CH2:7][C:8](=[O:14])[NH:9]3)[CH2:3][CH2:2]1.[Br:15]N1C(=O)CCC1=O>CN(C)C=O>[Br:15][C:13]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: O=C1CCc2c(cccc2C2CC2)N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C1CCc2c(ccc(Br)c2C2CC2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 5-cyclopropyl-3,4-dihydroquinolin-2(1H)-one (147-5; 0.5 g, 0.00267 mol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (0.47 g, 0.0026 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 4 h. The reaction mixture was concentrated and diluted with ice cold water (100 mL) with constant stirring, the solid residue obtained was filtered and dried to obtain the title compound. MS (M+1): 266.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.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>[C:35]([CH2:34][CH2:33][C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:4]2[CH:3]=[C:2]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:37])=[O:36]
Reactant: OB(O)c1ccccc1
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
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: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccccc2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (100 mg, 0.17 mmol) in EtOH (4 mL)/H2O (1 mL) were added phenylboronic acid (50 mg, 0.35 mmol), potassium carbonate (100 mg, 0.7 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate was concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([CH:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)[O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.Cl>ClCCl>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:16]2[CH2:17][CH2:18][O:19][CH:14]([C:12]3[O:11][N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)[N:13]=3)[CH2:15]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(-c2noc(C3CNCCO3)n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCOC(c2nc(-c3ccc(F)cc3)no2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a suspension of 2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine hydrochloride (0.15 g, 0.53 mmol) in anhydrous dichloromethane (6 mL), under nitrogen atmosphere, triethylamine (155 mL, 1.1 mmol) and 4-fluorobenzoyl chloride (62 mL, 0.53 mmol) were subsequently added at 0° C. The reaction mixture was allowed to warm at room temperature and stirred overnight. HCl 1N (6 mL) was added and the phases were separated. The organic layer was washed sequentially with HCl 1N (6 mL), NaOH 1N (6 mL×2 times) and with water, then was dried over sodium sulphate and evaporated under reduced pressure. The crude was purified by flash chromatography (silica gel, eluent: hexane/ethyl acetate 7/3) to afford 120 mg of (4-fluoro-phenyl)-{2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholin-4-yl}-methanone as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:6]3[NH:5][C:4]=2[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:6]3[N:5]([CH3:17])[C:4]=2[CH:3]=1
Reactant: Cc1cc2[nH]c3cc(Cl)ncc3c(=O)n2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc2n(C)c3cc(Cl)ncc3c(=O)n2n1
Reaction time: 24 h

Procedure:
23.5 g. of 6-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 3 are suspended in 200 ml. of dimethylformamide. 20 g. of potassium carbonate and 16 g. of methyl iodide are added. The mixture is stirred at 80° for 24 hours. After this time, the mixture is cooled and the precipitate filtered off. The crystalline product, 6-chloro-2,4-dimethylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is washed several times with water and then recrystallized from dimethylformamide, yield: 18 g. (72%); m.p. >300°.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(O)(=O)C.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 110 °C
Yield: 53.7 %

Procedure:
A mixture of 1.7 g (10 mmol) 2-chloro-1,3-benzothiazole and 2.6 g (10 mmol) 4-chloroaniline in 20 ml acetic acid was heated to 110° C. for 3 h. The reaction mixtures was diluted with 200 ml water and the resulting mixture was extracted with 3×150 ml ethyl acetate. The combined organic phases were washed with 2×100 ml water, dried with MgSO4, filtered and evaporated to dryness. The residue was recrystallysed from a mixture of hexane/ethyl acetate to yield 1.4 g (54%) of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[N:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:31][N+:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[S:34][C:33]=1SC>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[C:33]2[N:32]([CH3:31])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[S:34]2)[S:7][C:6]1=[N:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)CSC1=Nc1cccc(C#N)c1
Reactant: CSc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: CCCCN1C(=O)C(=C2Sc3ccccc3N2C)SC1=Nc1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
To a 8 mL vial was added 3-(3-butyl-4-oxothiazolidin-2-ylideneamino)benzonitrile (55 mg, 0.20 mmol), 3-methyl-2-(methylthio)benzothiazol-3-ium p-toluenesulfonate (73 mg, 0.20 mmol), anhydrous MeCN (2 mL) and TEA (70 μL, 0.50 mmol). The reaction mixture was first warmed to 50° C. and the resulting solution was allowed to stir at room temperature for 16 h. The product mixture was concentrated under reduced pressure, chromatographed (silica gel, 1:99 MeOH/DCM) and then recrystallized from MeCN to give the title product (11.8 mg) as a yellow solid.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].[Cl-].[NH4+]>O1CCCC1>[CH3:6][C:7]1[N:8]=[C:9]([C:14](=[O:15])[C:13]([F:20])([F:19])[F:12])[S:10][CH:11]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1cscn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1csc(C(=O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 40.4 ml) was added dropwise to a stirred solution of 4-methylthiazole (l10 g) in anhydrous tetrahydrofuran at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, ethyl trifluoroacetate (12 ml) was added dropwise. After a further 2 hours the mixture was allowed to warm to room temperature and was, then left stirring overnight. Saturated aqueous ammonium chloride solution was added and the organic phase was separated, dried and evaporated to dryness. The residue was purified by flash chromatography to give the hydrate corresponding to the title compound as a white solid. M.p. 77°-81° C. 13C Nmr (d6 -DMSO) 16.4, 91.1 (q J 32 Hz), 116.3, 122.2 (q, J 287 Hz), 152.0 and 166.6 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[C:5]#[N:6].N1C=CC=CC=1.[Cl:18][CH2:19][O:20][C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([Br:11])[C:9]=1[O:10][C:21](=[O:22])[O:20][CH2:19][Cl:18]
Reactant: O=C(Cl)OCCl
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(Br)c(OC(=O)OCCl)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
To a suspension of 3,5-dibromo-4-hydroxybenzonitrile (10.0 g, 36.1 mmol) in 180 mL of chloroform was added pyridine (2.92 ml, 36.1 mmol). Chloromethylchloroformate (5.2 mL 60 mmol) was then added over 5 min. The mixture was allowed to stir at room temperature for 12 h. The reaction was then washed with 1% HCl aq, water, and brine. The organic layer was then dried over sodium sulfate, filtered, and evaporated to afford a white solid (12.5 g) in 94% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.87 (d, 2H), 7.90 (s, 2H). 13C-NMR (300 MHz, CDCl3) δ (ppm): 73.58, 113.87, 115.68, 119.01, 136.40, 149.53, 149.71. Mp=83-85° C.
Reaction SMILES: [OH:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[C:14](#[N:18])[CH2:15][C:16]#[N:17].C(NCC)C>C(O)C>[NH2:18][C:14]1[O:1][C:2]2[CH2:3][N:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=2[C:15]=1[C:16]#[N:17]
Reactant: N#CCC#N
Reactant: CCOC(=O)N1CCC(=O)C(O)C1
Solvent: CCNCC
Solvent: CCO
Product: CCOC(=O)N1CCc2c(oc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
Ethyl 3-hydroxy-4-oxopiperidine-1-carboxylate from Example 35A (4.00 g, 21.4 mmol) was dissolved in ethanol (10 mL), and propanedinitrile (1.41 g, 21.4 mmol) was added. Within 10 min, diethylamine (1.56 g, 21.4 mmol) was added dropwise, whilst the temperature was kept below 35° C. Subsequently, the reaction mixture was stirred for 20 h at rt. The precipitate was collected by suction filtration and washed with ethanol and diethyl ether to yield 2.00 g (39%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br>C1COCC1>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: BrCc1cccc(Br)c1
Solvent: C1CCOC1
Product: CN1CCN(Cc2cccc(Br)c2)CC1
Reaction time: 2 h

Procedure:
0.30 g 1-Methylpiperazine in 2 ml THF were treated dropwise at RT with a solution of 0.5 g 3-bromobenzyl bromide in 3 ml THF. After stirring for 2 hrs, the mixture was heated to 60 C for 30 min. The solvent was evaporated and the residue chromatographed on silica using a gradient from heptane to heptane/dichloromethane/concentrated ammonia (4/6/0.5).