Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[NH:15][CH2:14][CH2:13]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[CH:19][CH:20]=2)[NH:15][CH2:14][CH2:13]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)NCCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1ccc2c(c1)NCCN2c1ccc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h

Procedure:
1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (INTERMEDIATE V, 0.068 g, 0.108 mmol) was dissolved in 1 mL of DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 10 minutes. The material was concentrated, dissolved in acetonitrile and loaded onto an ion exchange column (pre-wetted with acetonitrile). The column was flushed several times with acetonitrile, then the product was liberated by flushing the column several times with about 1M HCl solution in MeOH/EtOAc (made by adding acetyl chloride to a MeOH/EtOAc mixture). The second filtrate was concentrated to afford 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a purple solid. 1H NMR (400 MHz, DMSO-d6) δ=8.42 (s, 1 H), 7.99 (s, 1 H), 7.80 (d, J=8.1 Hz, 1 H), 7.63 (d, J=8.0 Hz, 1 H), 7.01 (d, J=2.1 Hz, 1 H), 6.80 (dd, J=1.9, 8.3 Hz, 1 H), 6.08 (d, J=8.4 Hz, 1 H), 3.61 (t, J=4.0 Hz, 2 H), 3.40 (t, J=4.4 Hz, 2 H). m/z (ESI) 475.8 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([N:32]2[CH2:33][C:30]([F:34])([F:29])[CH2:31]2)=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: FC1(F)CNC1
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)N2CC(F)(F)C2)C1(C)C

Procedure:
The product from Example 173 and 3,3-difluoroazetidine hydrochloride (Oakwood) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.51 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.22 (s, 3H), 1.25 (s, 3H), 1.26-1.36 (m, 2H), 1.39-1.48 (m, 1H), 1.57 (s, 9H), 1.57-1.78 (m, 3H), 1.93-2.05 (m, 1H), 2.62-2.67 (m, 2H), 2.73-2.83 (m, 1H), 2.88-2.94 (m, 1H), 4.14-4.37 (m, 2H), 4.41-4.53 (m, 1H), 4.74-4.86 (m, 1H), 8.51 (s, 1H). (ESI+) m/z 470 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:22]4[CH2:24][CH2:23]4)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C1COCC1>[CH:22]1([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:21])[CH2:23][CH2:24]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(C4CC4)cc3c(=O)[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3ccc(C4CC4)cc3c(=O)[nH]2)c1
Reaction time: 18 h
Yield: 85 %

Procedure:
A mixture of 1-(6-cyclopropyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.045 g, 0.139 mmol), 1M aq. KOH (0.694 mL) and THF (0.694 mL) was stirred for 18 h. The mixture was concentrated to remove the THF and the aqueous residue was acidified with 6 M aq. HCl at 0° C. The resulting precipitate was collected by filtration to provide the titled compound (0.035 g, 85%). MS (ESI/Cl): mass calcd. for C16H12N4O3, 296.1; m/z found, 297.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.92 (s, 2H), 8.93 (d, J=0.5 Hz, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.65-7.50 (m, 2H), 2.22-2.04 (m, 1H), 1.14-0.94 (m, 2H), 0.85-0.68 (m, 2H).
Reaction SMILES: C(OC([NH:8][C:9]([C:11]1[CH:53]=[CH:52][C:14]([C:15]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH:26]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)[CH2:27][C:28]([O:30]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:29])[C:22](=[O:50])[C:21]2=[O:51])=[O:16])=[CH:13][CH:12]=1)=[NH:10])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH:26]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)[CH2:27][C:28]([OH:30])=[O:29])[C:22](=[O:50])[C:21]2=[O:51])=[O:16])=[CH:52][CH:53]=1)(=[NH:8])[NH2:10]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(C(=O)NCCN2CCN(C(CC(=O)OC(c3ccccc3)c3ccccc3)c3cccnc3)C(=O)C2=O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(C(=O)NCCN2CCN(C(CC(=O)O)c3cccnc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
To a mixture of 0.1 g of diphenylmethyl 3-[4-[2-(4-tert-butoxycarbonylamidinobenzoyl)aminoethyl]-2,3-dioxopiperazin-1yl]-3-(pyridin-3-yl)propionate and 1 ml of anisole was added 2 ml of trifluoroacetic acid, and the resulting mixture was stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure and 2 ml of ethyl acetate, 1 ml of water and 1 ml of acetonitrile were added to the residue. To the resulting mixture was added 0.023 g of sodium hydrogencarbonate, followed by stirring at room temperature for 10 minutes. Thereafter, the aqueous layer was separated and then concentrated to a volume of about 0.5 ml under reduced pressure. The resulting concentrate was purified by a reversed phase column chromatography (eluent: a 10% aqueous acetonitrile solution) to obtain 0.02 g of 3-[4-[2-(4-amidinobenzoyl) aminoethyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl) propionic acid as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]O)=[N:4][C:3]=1[CH2:9][CH3:10].S(Cl)([Cl:13])=O>C1COCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][Cl:13])=[N:4][C:3]=1[CH2:9][CH3:10]
Reactant: CCc1nc(CO)sc1Br
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCc1nc(CCl)sc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a solution of (5-bromo-4-ethylthiazol-2-yl)methanol (313 mg 1.41 mmol) in THF (15 ml) under nitrogen at room temperature was added thionyl chloride (0.206 ml 2.82 mmol) and stirred overnight. LCMS indicated the completion of the reaction. A saturated ice cold aqueous NaHCO3 solution was added to the reaction solution with gas evolution. The mixture was extracted with EtOAc (4×20 ml), dried over sodium sulfate and concentrated to give a brown oil 301 mg, 89% which was used for the next step without further purification.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]2[CH:16]=[C:15]([CH:17]3[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]3)[S:14][C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)(=O)=O.Cl.[NH:26]1[CH2:30][C@H:29]([OH:31])[C@H:28]([OH:32])[CH2:27]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:23][C:20]1([CH3:24])[CH2:21][CH2:22][CH:17]([C:15]2[S:14][C:9]3[N:10]=[C:11]([CH3:13])[N:12]=[C:7]([CH2:6][N:26]4[CH2:30][C@H:29]([OH:31])[C@H:28]([OH:32])[CH2:27]4)[C:8]=3[CH:16]=2)[CH2:18][CH2:19]1
Reactant: O[C@@H]1CNC[C@@H]1O
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CN2C[C@@H](O)[C@@H](O)C2)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 50 °C
Reaction time: 12 h
Yield: 8.8 %

Procedure:
A suspension of [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (100 mg), cis-pyrrolidine-3,4-diol hydrochloride (57 mg), and K2CO3 (75 mg) in DMF (3 mL) was stirred at 50° C. for 12 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH). The obtained purified product was suspended in IPE, and the precipitate was collected by filtration to obtain cis-1-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}pyrrolidine-3,4-diol (9 mg).
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([CH2:17][C:18]3[N:28]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]4[N:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:20]=4[CH:19]=3)[C:13](=[O:34])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:29][N:28]1[C:21]2[N:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH2:17][N:14]1[C:13](=[O:34])[CH2:12][C:11]2([CH2:10][CH2:9][NH:8][CH2:36][CH2:35]2)[C:15]1=[O:16]
Reactant: CC(C)(C)Cn1c(CN2C(=O)CC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc2cnc(C#N)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)Cn1c(CN2C(=O)CC3(CCNCC3)C2=O)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-1,3-dioxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.5 g, 3.1 mmol) in dichloromethane (20 ml), TFA (5 ml) is added at 0° C. The reaction mixture is stirred at room temperature for 2 h. After removal of the solvent, saturated sodium bicarbonate is added to the residue and the mixture is extracted with dichloromethane. The combined extracts are washed with H2O, brine, dried over magnesium sulfate and concentrated under vacuum to give desired product, 7-(2,2-dimethyl-propyl)-6-(1,3-dioxo-2,8-diaza-spiro[4.5]dec-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C>C(#N)C>[N:16]1[C:17]2[C:12](=[CH:11][C:10](/[CH:9]=[C:5]3/[C:6](=[O:8])[N:7]=[C:3]([NH:26][CH2:25][C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)[S:4]/3)=[CH:19][CH:18]=2)[CH:13]=[N:14][CH:15]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Reactant: NCc1cccs1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2cccs2)S/C1=C\c1ccc2ncncc2c1
Temperature: 145 °C

Procedure:
The suspension of 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one (example 1c, 58 mg, 0.2 mmol), thiophene methyl amine (45.3 mg, 0.4 mmol) and diisopropylethylamine (DIEA) (70 uL, 0.4 mmol) in acetonitrile (1 mL) was heated to 145° C. by microwave for 20 min. After cooling to room temperature, the solid was collected by filtration, washed with a small amount of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a light yellow solid: LC-MS m/e 353 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:3]=1[C:30]1[C:31]([O:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:37][O:36][C:31]1[C:30]([C:3]2[N:4]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:5]3[C:10]([C:2]=2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:9][C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:7][CH:6]=3)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ncccc1-c1c(Br)c2cc(C(=O)NCCCN3CCOCC3)ccc2n1C(=O)OC(C)(C)C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1c(-c2ccccc2)c2cc(C(=O)NCCCN3CCOCC3)ccc2n1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 3-bromo-2-(2-methoxypyridin-3-yl)-5-(3-morpholinopropylcarbamoyl)-1H-indole-1-carboxylate (0.38 mmol), phenylboronic acid (69 mg, 0.57 mmol), Cs2CO3 (0.18 g, 0.57 mmol) in dioxane (3 ml) and water (1 ml) was added Pd(PPh3)4 (43 mg, 0.038 mmol). The reaction mixture was heated at 100° C. for up to 3 h. The reaction mixture was quenched by adding ethyl acetate (15 ml) and saturated NaHCO3 (10 ml). The ethyl acetate layer was separated and washed with brine (10 ml), dried with Na2SO4, filtered and concentrated to give a crude product. The crude product was purified using flash column chromatography (SiO2, 5% EtOAc in hexanes to 10% EtOAc in hexanes). The desired product, tert-butyl 2-(2-methoxypyridin-3-yl)-5-(3-morpholinopropylcarbamoyl)-3-phenyl-1H-indole-1-carboxylate was obtained as a light yellow solid (0.017 g, 47%); 400 MHz 1H NMR (DMSO-d6) δ: 8.57 (t, J=5.2 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.17 (dd, J=1.2 Hz, 4.4 Hz, 1H), 8.10-7.98 (m, 1H), 7.92 (dd, J=1.2 Hz, 8.4 Hz, 1H), 7.45 (dd, J=1.6 Hz, 7.6 Hz, 1H), 7.40-7.23 (m, 3H), 7.23-7.19 (m, 1H), 6.94-6.89 (m, 1H), 3.87 (s, 3H), 3.57-3.50 (m, 4H), 3.34-3.25 (m, 2H), 2.35-2.28 (m, 6H), 1.71-1.62 (m, 2H), 1.24 (s, 9H); LCMS: 571 [M+H]. Hydrolysis as described in example 33 provides compound 1 in Table 2.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[CH:15]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH3:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[CH3:20])[C:13]([C:4]1[C:3](=[O:23])[C:8]2[C:7](=[CH:12][CH:11]=[N:10][CH:9]=2)[NH:6][CH:5]=1)=[O:22]
Reactant: COC(=O)C(=CNc1ccncc1)C(=O)c1ccc(C)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1ccc(C(=O)c2c[nH]c3ccncc3c2=O)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.6 %

Procedure:
273 g (0.88 mmol) of 2-(3,4-Dimethyl-benzoyl)-3-(pyridine-4-ylamino)-acrylic acid methyl ester 2f was dissolved in 30 mL of diphenyl ether and the resultant solution was heated at 250° C. After 2.5 h, the reaction solution was cooled to room temperature and diluted with 50 mL of hexane. The crude product precipitated out of solution and was isolated by filtration. The crude product was purified by washing with hexane to yield 119 mg of 3-(3,4-Dimethyl-benzoyl)-1H-[1,6]napthyridin-4-one 10a as white crystals.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH2:31]([NH:33][CH2:34][CH2:35][OH:36])[CH3:32]>C(O)C>[CH2:31]([N:33]([CH2:34][CH2:35][OH:36])[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1)[CH3:32]
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: CCNCCO
Solvent: CCO
Product: CCN(CCO)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 2.25 ml of ethanol were added 601 mg (6.74 mmol) of 2-(ethylamino)ethanol, and then the reaction mixture was stirred in the microwave at 80 for 2 h. Another 601 mg (6.74 mmol) of 2-(ethylamino)ethanol were added and the mixture was stirred in the microwave at 100 for a further 7 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 28.3 mg (17% of theory)
Reaction SMILES: BrC1C=CC([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=C(F)C=1.C(=O)([O-])O.[Na+]>Cl>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])[N:10]=[CH:9][NH:8][C:7]2=[O:6]
Reactant: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCN(C)S(C)(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN(C)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 104 %

Procedure:
4-(4-Bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methyl N-methylsulphonylamino)propoxy)quinazoline (4.70 g, 9.1 mmol) was dissolved in 2N aqueous hydrochloric acid solution (85 ml) and heated at reflux for 1 hour. After cooling, the solution was carefully poured into saturated aqueous sodium hydrogen carbonate solution (to pH8) and stirred vigorously for 30 minutes. The resulting precipitate was filtered and dried. The filter cake was then taken up as a suspension in acetone, filtered, washed with diethyl ether and dried to give 6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazolin-4-one (3.23 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[C:14]([Cl:25])[C:13]=1[N+:26]([O-:28])=[O:27].CC([O-])(C)C.[K+].C(O)(=O)C>CS(C)=O>[Cl:25][C:14]1[C:13]([N+:26]([O-:28])=[O:27])=[C:12]([N:6]2[C:7]([O:8][CH3:9])=[C:2]([NH2:1])[C:3]([Cl:10])=[N:4][CH2:5]2)[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]=1[C:21]([F:23])([F:24])[F:22]
Reactant: COc1ncnc(Cl)c1N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COC1=C(N)C(Cl)=NCN1c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 103.2 %

Procedure:
2.84 g (17.8 mmoles) of 5-amino-4-chloro-6-methoxypyrimidine are dissolved in 20 ml of dimethylsulfoxide. With stirring, a solution of 6.24 g (20.5 mmoles) of 1,3-dichloro-2,6-dinitro-4-trifluoromethylbenzene in 15 ml of dimethylsulfoxide and a solution of 2.30 g (20.5 mmoles) of potassium tert-butylate in 15 ml of dimethylsulfoxide are added simultaneously dropwise at 15° C. The dark red solution so obtained is stirred for 1 hour at 15°-20° C. and then poured into ice-water, neutralised with acetic acid and extracted three time with chloroform. The extracts are dried over sodium sulfate and the solvent is removed by rotary evaporation, affording 7.9 g of an oil. This crude product is purified by chromatography through a column of silica gel affording 3.19 g of a crystalline product. Recrystallisation from a mixture of 2 ml of toluene and 8 ml of cyclohexane yields 2.52 g of yellow crystals of m.p. 114°-116° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH3:30])C>CS(C)=O>[CH2:27]([C:26]1[N:15]2[CH2:14][C@@H:13]([CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=3)[O:17][C:16]2=[N:18][C:24](=[O:23])[CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCCCC#CC(=O)OCC
Solvent: CS(C)=O
Product: CCCCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and hept-2-ynoic acid ethyl ester employing the procedure described in Example 99. [α]D25 +8.40 (c 0.5, DMSO)
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15][CH3:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4].[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]([NH:5][C:6]2[C:7]([S:15][CH3:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=2[S:12][CH3:13])=[O:4])[CH2:22][CH2:21]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 97 %

Procedure:
To a solution of 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (6.41 g, 0.02 mol) in acetonitrile (120 ml) was added 1-(2-hydroxyethyl)piperazine(3.53 g, 0.027 mol), and then added potassium carbonate (3.75 g, 0.027 mol) with ice-cooling and the mixture was stirred at room temperature for 23 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was recrystallized from ethanol-ether to provide 7.19 g (yield 97%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide as colorless needles.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][O:18][C:19]1[C:20](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:15])=O)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][O:18][C:19]1[C:20](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:15]
Reactant: CCOC(=O)c1ccccc1OCNC(=O)CCCCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1OCNC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Ethyl (N-tert-butoxycarbonyl-6-aminohexanoyl)aminomethylsalicylate (0.58 & 1.41 mmoles) was dissolved in dichloromethane (5 mL) and the solution was cooled in an ice/water bath. Trifluoroacetic acid (5 mL) was added, and the reaction was allowed to warm to room temperature. After 2 hours, the reaction mixture was evaporated to dryness to give. the product as an oil, which was dried in vacuo over potassium hydroxide pellets to afford 0. 59 g (99% yield) of ethyl (6-aminohexanoyl)aminomethylsalicylate trifluoroacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([CH:11]=[CH:12][O:13]C)=[C:4]2[CH:3]=1.Cl.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10]([CH2:11][CH:12]=[O:13])=[C:4]2[CH:3]=1
Reactant: COC=Cc1c(-c2ccc(OC)cc2)nn2ccc(Br)cc12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nn3ccc(Br)cc3c2CC=O)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 5-bromo-2-(4-methoxyphenyl)-3-(2-methoxyvinyl)pyrazolo[1,5-a]pyridine (160 mg, 0.45 mmol) in THF (7.3 ml) was added a 4N HCl solution in water (2.45 ml, 9.8 mmol). Heated to 50° C. and stirred for 4 h at which time monitoring the reaction by LC indicated all starting material had converted to the title compound. The solution was cooled to 20° C. and a saturated solution of sodium bicarbonate (10 mL) and ethyl acetate (15 mL) were added The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness to afford a residue that was purified by automated ISCO chromatography (ethyl acetate/dichloromethane; 7/93). The title compound was obtained as a tan solid (43 mg, 28%). LCMS m/z 345.0, 347.0 (M+H)+, ret. time=2.02, 2.12 min. Peak at 2.01 is hydrate of the aldehyde LCMS m/z 363.1, 365.1 (M+H)+ and peak at 2.12 is methyl hemiacetal of the aldehyde LCMS m/z 377.1, 379.1 (M+H)+ both formed under LCMS conditions.