Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](O)(=[O:34])[C:25]1[CH:33]=[CH:32][C:31]2[O:30][CH2:29][O:28][C:27]=2[CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24]([C:25]5[CH:33]=[CH:32][C:31]6[O:30][CH2:29][O:28][C:27]=6[CH:26]=5)=[O:34])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc5c(c4)OCO5)nc3cc21

Procedure:
Benzo[1,3]dioxole-5-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and piperonylic acid (147 mg, 0.89 mmol). The title compound was obtained as grey powder (150 mg, 40%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][N:27]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 2-amino-5-bromopyridine (43 mg, 0.25 mmol) according to general procedure II. Obtained as an orange solid (9 mg, 9%). MS (ISP) 420.2 [(M+H)+]; mp 228-231° C.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+].C(OC)=O.CO>O>[O:1]([CH2:8][CH:9]([OH:10])[CH2:11][N:12]=[N+:13]=[N-:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(OCC2CO2)cc1
Agent: [Na+]
Solvent: CO
Solvent: COC=O
Solvent: O
Product: [N-]=[N+]=NCC(O)COc1ccccc1
Yield: 101 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 1.00 g of phenoxymethyloxirane, 1.94 g of sodium azide, 10 ml of methyl formate and 45 ml of an 8:1 by volume mixture of methanol and water were used, to give 1.30 g of the title compound as a pale yellow oil having an Rf value of 0.26 (on silica gel thin gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)C=CC=CC=1.[Li]CCCC.[Br:37][C:38]1[CH:43]=[C:42]([CH:44]=O)[CH:41]=[CH:40][N:39]=1.[NH4+].[Cl-]>C1COCC1.O>[Br:37][C:38]1[CH:43]=[C:42]([CH:44]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH:41]=[CH:40][N:39]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: FC(F)(F)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1cccc(C=Cc2ccnc(Br)c2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
Triphenyl-(3-trifluoromethyl-benzyl)-phosphonium bromide (808 mg, 1.61 mmol) is dissolved in THF (15 mL) and it is cooled down to −78° C. Then 1.6 M n-BuLi (2.0 mL, 3.2 mmol) is added and the reaction mixture is stirred for 15 min at −78° C. before it is warmed up to room temperature for 30 min. The mixture is cooled down to −78° C. again and 2-bromo-pyridine-4-carbaldehyde (300 mg, 1.61 mmol) is added. The mixture is stirred for 20 min at −78° C. before it is warmed up to room temperature for another 30 min. Saturated NH4Cl aqueous solution (20 mL) is added along with water (45 mL). The mixture is extracted with EtOAc (3×40 mL) and the organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 6%) affords 289 mg of the desired product.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:11]#[N:12])=[CH:7][NH:8][C:9]=1[CH3:10])[CH2:2][CH2:3][CH3:4].[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([N:8]2[CH:7]=[C:6]([C:11]#[N:12])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:9]2[CH3:10])=[CH:19][CH:18]=1)[CH3:14]
Reactant: CCCCc1c(C#N)c[nH]c1C
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1c(C#N)cn(-c2ccc(C(=O)OCC)cc2)c1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A suspension of 4-butyl-5-methyl-1H-pyrrole-3-carbonitrile (0.081 g), 4-fluoro-benzoic acid ethyl ester (0.10 g) and cesium carbonate (0.21 g) in N,N-dimethylformamide (3 mL) was stirred at 70° C. overnight. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/6) to give the title compound (0.032 g).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]([C:22]1[CH:23]=[C:24]([CH2:33][CH2:34][C:35](O)=[O:36])[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:21])([CH3:20])[CH3:19]>C1(C)C(C)=CC=CC=1>[C:29]([C:26]1[CH:25]=[C:24]([CH2:33][CH2:34][C:35]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)=[O:36])[CH:23]=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[C:27]=1[OH:28])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccc(N2CCN(C(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1

Procedure:
A mixture of 23.4 g. (0.1 mole) ethyl 4-(piperazin-1-yl)-benzoate (base), 600 ml. xylene and 27.8 g. (0.1 mole) 3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionic acid is boiled under a water separator for 28 hours, then evaporated to dryness in a vacuum and the residue is taken up with diethyl ether. For the removal of unreacted ethyl 4-(piperazin-1-yl)-benzoate, the ether solution is extracted with 1N hydrochloric acid, washed with water and aqueous sodium bicarbonate solution, dried with anhydrous sodium sulphate and mixed with hydrogen chloride-containing diethyl ether, whereby the hydrochloride precipitates out. This is washed with diethyl ether and recrystallised from ethanol to give 32.0 g. (60% of theory) of the desired product as colourless crystals; m.p. 196°-198° C.
Reaction SMILES: [CH3:1][Si](C)(C)N[Si](C)(C)C.[Na].[CH:11]([C@@H:13]1[C@@H:22]2[C@@H:16]([O:17][CH2:18][C@@H:19]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:20][CH2:21]2)[CH2:15][C@H:14]1[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)=O.Cl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[O:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]1[O:32][C@@H:14]1[CH2:15][C@@H:16]2[O:17][CH2:18][C@@H:19]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:20][CH2:21][C@@H:22]2[C@H:13]1[CH:11]=[CH2:1]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@@H]2OC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C[C@@H]1[C@H]2CC[C@H](CCCC(=O)OC(C)C)CO[C@H]2C[C@H]1OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (2.60 g) was suspended in THF (10 mL), and followed by cooling to 0° C. Sodium hexamethyldisilazane (7.0 mL, 1 mol/L THF solution) was added, followed by stirring at the same temperature for 30 minutes. A THF (1 mL) solution of the compound (1.0 g) produced in Example 13 was added dropwise, followed by stirring at the same temperature for 1 hour. An extract obtained by pouring the reaction solution to 1 N hydrochloric acid cooled to 0° C. and extracting with ethyl acetate was washed with water, an aqueous saturated sodium bicarbonate solution and a saturated saline; dried with anhydrous magnesium sulfate; and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a titled compound (967 mg) having the following physical property values.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[F:24]>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Fc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2ccc(F)c(F)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 0.5 M 3,4-difluorophenylmagnesium bromide in THF (0.6 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(3,4-difluoro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])[CH2:5]Br.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:4](=[N:3][O:2][CH3:1])[CH2:5][N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CON=C(CBr)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To 2.17 g of 2-bromo-1-(2,4-dichlorophenyl)ethanone-O-methyloxime in 20 ml of N,N-dimethylformamide, 3.03 g of potassium phthalimide and 1.61 g of potassium carbonate were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 40 ml of water and extracted with ethyl acetate (50 ml×1), the resulting organic layer was washed with water (20 ml×1) and then dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 2.10 g of the desired product as pale yellow crystals.
Reaction SMILES: O=[C:2]1[CH:8]([CH2:9][C:10]([OH:12])=O)[CH2:7][CH2:6][S:5][C:4]2[S:13][CH:14]=[CH:15][C:3]1=2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:10](=[O:12])[CH2:9][CH:8]3[CH2:7][CH2:6][S:5][C:4]4[S:13][CH:14]=[CH:15][C:3]=4[C:2]3=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C(O)CC1CCSc2sccc2C1=O
Reactant: NNc1ccc(Cl)cc1
Solvent: CCO
Product: O=C1CC2CCSc3sccc3C2=NN1c1ccc(Cl)cc1
Yield: 31.9 %

Procedure:
A solution of 3.7 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetic acid and 2.6 g of 4-chlorophenylhydrazine in 50 ml of ethanol is refluxed under heating for 6.5 hours. Then, the reaction mixture is concentrated under reduced pressure. The resulting residue is dissolved in 40 ml of acetic acid and the solution is refluxed under heating for 1.5 hours. After cooling, the reaction mixture is concentrated under reduced pressure, the residue is subjected to column chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 1.7 g of 2-(4-chlorophenyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as pale brown crystals, melting at 134°-135° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][OH:14])[CH:2]=1.[C:15]([O:22]C(OC(C)(C)C)=O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[OH-].[Na+]>O.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][OH:14])[CH:2]=1.[C:18]([O:17][C:15](=[O:16])[O-:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: OCC#Cc1cnc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[O-]
Reaction time: 4 h

Procedure:
To a dry 1-L three-necked round-bottom flask equipped with a nitrogen inlet and overhead stirrer was charged 3-(3-quinolyl)-2-propyn-1-ol (15.81 g, 86.39 mmol), di-tert-butyl dicarbonate (22.48 g, 103 mmol, 1.19 equiv), n-tetrabutyl ammonium hydrogen sulfate (0.86 g, 2.54 mmol, 0.029 equiv) and methylene chloride (300 mL). The resulting suspension was mechanically stirred while a 25% w/w aqueous NaOH solution (38 g) was added in over a period of 5 minutes. The biphasic mixture which resulted was stirred for 4 hours after which time the reaction was found to be complete by HPLC and TLC. The mixture was diluted with water (200 mL) and methylene chloride (100 mL). After stirring for 10 minutes and settling for 15 minutes the layers were separated. The organic layer was washed with water (1×200 mL) and 20% aq., NaCl (1×200 mL). The organic was then stirred with 15 g of sodium sulfate, filtered and then stripped to an oil under reduced pressure. The residual oil was taken up in isopropyl acetate/hexane (1:1, 100 mL) and passed through a small pad of silica gel (8 g). The pad was rinsed with the same eluent (100 mL). The combined filtrates were concentrated under reduced pressure and rigorously dried in a vacuum oven to yield the 3-(3-quinolyl)-2-propyn-1 ol t-butyl carbonate as a light orange-yellow colored oil: 24.50 g, 100%.
Reaction SMILES: [S:1]([C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)[C:2]#[N:3].[N+:21]([O-])([OH:23])=[O:22].O>C(O)(=O)C>[N+:21]([C:6]1[CH:5]=[C:4]([S:1][C:2]#[N:3])[CH:20]=[CH:19][C:7]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([O-:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(SC#N)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(SC#N)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
4′-Thiocyano-p-toluenesulfonanilide (19.2 g (63.2 mmol)) was dissolved in acetic acid (60 ml). To this, fuming nitric acid (3.04 ml (75.9 mmol)) was added dropwise with stirring at room temperature. Then, the mixture was stirred at 50° C. for 4 hours, poured into water, and the crystals separated were filtered and washed with water. The resulting crystals were dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 21.8 g (99%) of 2′-nitro-4′-thiocyano-p-toluenesulfonanilide as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:24]=1.[ClH:26]>>[ClH:1].[Cl:1][C:2]1[C:3]([CH3:25])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1.[ClH:26]
Reactant: Cc1cc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2cc1Cl
Agent: Cl
Product: Cc1cc2[nH]c(=O)n(C3CCNCC3)c2cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1,1-Dimethylethyl 4-(6-chloro-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D8) (0.270 mmol, 100 mg) was treated with 8 ml of HCl (4M solution in 1,4-dioxane) at room temperature; the mixture was stirred at room temperature for 5 hours. Solvent was evaporated to afford the title compound, mono hydrochloride salt, 60 mg, 90%, M++H=266.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:13]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CC#N.O>[Cl:13][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]([OH:12])=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc2[nH]nc(Cl)c2c1
Yield: 83.2 %

Procedure:
To a suspension of 1H-indazole-5-carboxylic acid (155 mg, 0.96 mmol) in CH3CN (8 mL) was added N-chlorosuccinimide (142 mg, 1.06 mmol). The mixture was heated at reflux overnight before concentration. The solid was suspended in water and aqueous sodium thiosulfate solution, acidified with 1 N HCl and the solids were isolated by filtration. The solids were then washed with water and dried under vacuum at 50° C. to provide the title compound as an off-white solid (157 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[F:32][C:23]([F:22])([F:31])[C:24]1[CH:28]=[C:27]([CH2:29][NH:30][C:19]([C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[CH:12][N:11]=2)=[O:21])[O:26][N:25]=1
Reactant: O=C(O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1cc(C(F)(F)F)no1
Product: O=C(NCc1cc(C(F)(F)F)no1)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid (example T) and 3-trifluoromethyl-isoxazol-5-methanamine (example BA) as starting materials; MS: 453.1 (M+H)+.
Reaction SMILES: CC(C)CCN.[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)=[O:19])=[CH:12][C:11]=12.[N+:29]([C:32]1C=[CH:39][C:35](C(O)=O)=[CH:34][CH:33]=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:19])[C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:29]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:39]4)=[O:26])=[CH:27][CH:28]=3)=[CH:12][C:11]=12
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccn3ccnc3c2)cc1
Agent: CC(C)CCN
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C(=O)N2CCCCC2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting piperidine for 3-methylbutan-1-amine and 4-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)benzoic acid for 4-nitrobenzoic acid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.18 (t, J=5.9 Hz, 1H), 8.49 (d, J=7.0 Hz, 1H), 7.96 (m, 2H), 7.89 (s, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.47 (m, 2H), 7.40 (s, 1H), 6.86 (dd, J=7.0, 1.7 Hz, 1H), 4.52 (d, J=5.9 Hz, 2H), 3.59 (m, 2H), 3.24 (m, 2H), 1.66-1.38 (m, 6H); MS (ESI(+)) m/e 363 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[O:5][N:4]=1.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[OH:9][CH2:8][C:6]1[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=1
Reactant: CCOC(=O)c1cc(OC)no1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7.0 g 3-methoxy-5-carbethoxy-isoxazole in 80 ml tetrahydrofuran a 2m solution of lithiumborohydride in tetrahydrofuran was added at 15°-20° C. The reaction mixture was stirred for 2 h at room temperature, then poured into saturated ammoniumchloride solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated togive 4.87 g alcohol.
Reaction SMILES: CS[C:3]1[N:12]=[C:11]([NH2:13])[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([Cl:14])[CH:9]=2)[N:4]=1.[CH2:19]([CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)CC(C)C>[CH2:19]([CH:25]1[CH2:29][CH2:28][N:27]([C:3]2[N:12]=[C:11]([NH2:13])[C:10]3[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([Cl:14])[CH:9]=3)[N:4]=2)[CH2:26]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCC1CCNC1
Reactant: COc1c(Cl)cc2c(N)nc(SC)nc2c1OC
Solvent: CC(C)CCO
Product: CCCCCCC1CCN(c2nc(N)c3cc(Cl)c(OC)c(OC)c3n2)C1

Procedure:
A mixture of 0.1 mole of 2-methylmercapto-4-amino-6-chloro-7,8-dimethoxyquinazoline and 0.12 mole of 3-n-hexylpyrrolidine in isoamyl alcohol is heated at reflux for 16 hours, cooled, washed with water and the organic phase is concentrated in vacuo. Hexane is slowly added to the residue and the solid title compound is collected and purified, if desired by silica gel column chromatography.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH2:19]=O>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:16]=[CH:15][C:14]2[O:17][CH2:19][N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[O:6])[C:4]=2[C:3]=1[CH3:18]
Reactant: Cc1c(Br)ccc(O)c1C(=O)Nc1ccccc1
Reactant: C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)ccc2c1C(=O)N(c1ccccc1)CO2
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of 3-bromo-6-hydroxy-2-methyl-N-phenylbenzamide (Intermediate 16-1, 40 mg, 0.131 mmol) and paraformaldehyde (11.77 mg, 0.392 mmol) in TFA (1 mL) was heated at 100° C. for 4 h. The TFA was removed under vacuum, and the residue was diluted with EtOAc (80 mL), washed with NaHCO3 (aq) (10 mL), water (10 mL) and brine (10 mL), and dried and concentrated. The residue was purified by column chromatogaphy (eluting with a gradient from 95:5 to 70:30 hexane-EtOAc) to give 6-bromo-5-methyl-3-phenyl-2H-benzo[e][1,3]oxazin-4(3H)-one (25 mg, 45%). 1H NMR (400 MHz, chloroform-d) δ 7.63 (1 H, d, J=8.80 Hz), 7.37-7.50 (3 H, m), 7.29-7.35 (2 H, m), 6.81 (1 H, d, J=8.80 Hz), 5.48 (2 H, s), 2.80 (3 H, s). Mass spectrum m/z 318, 320 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:25][N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][N:28]=[CH:27]1.Cl.CN(C)CCCN=C=NCC.SC1SC2C=CC=CC=2N=1.C(N(CC)CC)C>C(#N)C>[C:12]1([S:9]([N:8]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:4]2[CH:3]=[C:2]([NH:1][C:31]([C:30]3[N:26]([CH3:25])[CH:27]=[N:28][CH:29]=3)=[O:32])[CH:7]=[CH:6][CH:5]=2)(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1cncc1C(=O)O
Reactant: Nc1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Sc1nc2ccccc2s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1cncc1C(=O)Nc1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1

Procedure:
A solution of N-(3-amino-phenyl)-N-benzyl-benzene sulfonamide (25 mg, 0.07 mmol), 3-methyl-3H-imidazole-4-carboxylic acid (14 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.08 mmol), mercaptobenzothiazole (2 mg, 0.007 mmol) and triethylamine (25 μl, 0.18 mmol) in dry acetonitrile (1 ml) were stirred at room temperature for 15 hrs. The reaction mixture was quenched with water (10 ml), extracted with dichloromethane (3×7 ml) and the combined organics concentrated in vacuo. The crude residue was purified by preparative TLC (SiO2) eluting with ethyl acetate/dichloromethane (1:1) to afford the title compound as an off white solid (2.8 mg, 8%). HPLC retention time 5.6 min. Mass spectrum (ES+) m/z 447 (M+H).