Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:16]([Mg]Cl)([CH3:18])[CH3:17].C1([Mg]Br)CC1>C1COCC1>[CH:16]1([C:4](=[O:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:18][CH2:17]1
Reactant: CC(C)[Mg]Cl
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)C1CC1
Temperature: 10 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of tert-butyl N-[2-(methoxy(methyl)amino)-2-oxo-ethyl]carbamate (2,455.3 g, 11.25 mol) in THF (9.0 L) is added 2.0M isopropylmagnesium chloride in THF (5.34 L, 10.69 mol) at −30° C. via an addition funnel over a period of 60 min such that the internal temperature does not exceed 0° C. The mixture is then warmed slowly to 10° C. and 0.5M cyclopropylmagnesium bromide in THF (27.0 L, 13.50 mol) is added via an addition funnel over a period of 1 h. The mixture is stirred at room temp 24 h. The mixture is cooled to 0° C. and quenched with 1.0M HCl to pH 5-6, then warmed to room temp and extracted with EtOAc (12 L and 10 L). The combined organic phase is washed successively with water (10 L) and brine (8 L), dried over Na2SO4, and filtered. The filtrate is evaporated under reduced pressure to afford 2.24 kg (100% yield) of the title compound as a light yellow oil which is used directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C=O)C>[CH2:35]([N:14]1[CH:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])[C:11](=[O:26])[C:12]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:16][C:13]1=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added benzylbromide (130 μL). The reaction mixture is allowed to stir at room temperature for 18 h. The resulting suspension is poured into water (10 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 400 mg (79%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)[C:7]=1[CH3:8].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:7]1[N:6]2[C:9]([CH:12]=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=[CH:3][C:2]=1[C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(Br)ccc2ncc(C=O)n12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)ccc2ncc(C=O)n12
Yield: 40 %

Procedure:
6-bromo-5-methylimidazo[1,2-a]pyridine-3-carbaldehyde (125 mg, 0.523 mmol), Pyridine-3-boronic acid (77.5 mg, 0.603 mmol), dichlorobis(triphenylphosphine) palladium (II) (36.7 mg, 0.05 mmol) and 2M aqueous Na2CO3 (2 ml) were dissolved in DMF (3 ml) and refluxed for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was evaporated to obtain crude product, which was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to obtain the title compound. Yield: 40%; 1H NMR (DMSO-d6; 300 MHz): 69.90(s, 1H), 8.39 (s, 1H), 7.73 (d, 1H, J=9.6 Hz), 7.56 (d, 1H, J=9.3 Hz), 3.11 (s, 3H); MS: m/z 238 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:5]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6][C:7]=1[CH3:8])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH:25]([N:28]=[C:29]=[S:30])([CH3:27])[CH3:26]>CC(C)=O>[C:1]([C:3]1[C:4]([S:15]([NH:18][C:29]([NH:28][CH:25]([CH3:27])[CH3:26])=[S:30])(=[O:16])=[O:17])=[C:5]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6][C:7]=1[CH3:8])#[N:2]
Reactant: CCOC(=O)Nc1sc(C)c(C#N)c1S(N)(=O)=O
Reactant: CC(C)N=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Nc1sc(C)c(C#N)c1S(=O)(=O)NC(=S)NC(C)C
Temperature: 55 °C

Procedure:
A mixture of 4-cyano-2-ethoxycarbonylamino-5-methyl-thiophene-3-sulfonamide (0.50 g), potassium carbonate (0.36 g) and isopropyl isothiocyanate (300 μl) in 10 ml of dry acetone was heated at 55° C. for 18 h and then evaporated to dryness. The residue was dissolved in 10 ml of water, and pH was adjusted to 2 by dropwise addition of 1M hydrochloric acid. The precipitate was filtered off, rinsed with a small amount of water and dried to give 0.34 g of the title compound; m.p. 169-171° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:33]([O:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(N)CC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-(4-aminopiperidin-1-yl)-benzoic acid ethyl ester (15.7 g, 63.2 mmol) obtained in Example 7(1) was dissolved in THF (200 ml), and a 2M sodium carbonate aqueous solution (63 ml) was added thereto. Subsequently, benzyloxycarbonyl chloride (11.7 ml, 82.2 mmol) was added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solid obtained by evaporation under reduced pressure was collected by filtration and dried under reduced pressure, thereby obtaining 4-(4-benzyloxycarbonylaminopiperidin-1-yl)-benzoic acid ethyl ester (18.0 g, 74%) as a white solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[Br:13][C:14]1[CH:22]=[C:18]([C:19](O)=[O:20])[C:17]([NH2:23])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:22]=[C:18]2[C:17](=[CH:16][CH:15]=1)[N:23]=[C:2]1[NH:3][C:4]3[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=3[N:6]1[C:19]2=[O:20]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: Cc1cc2nc(Cl)[nH]c2cc1C
Product: Cc1cc2[nH]c3nc4ccc(Br)cc4c(=O)n3c2cc1C

Procedure:
2-Bromo-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)-one is prepared with 2-chloro-5,6-dimethylbenzimidazole and 5-bromoanthranilic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[S:34]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.77 (d, 1H), 8.04 (m, 1H), 7.87 (d, 1H), 7.68 (d, 1H), 7.54 (m, 2H), 7.42 (m, 1H), 7.14 (m, 3H), 7.07 (m, 1H), 6.88 (d, 1H), 6.83 (s, 1H), 6.44 (dd, 1H), 4.36 (s, 2H), 4.32 (s, 2H), 3.62 (s, 3H), 2.79 (t, 2H), 2.49 (t, 2H); MS 491 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.CN1CCCC1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH2:11][Cl:10])=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: CN1CCCC1
Solvent: Cc1ccccc1C
Product: O=C(Oc1ccc(Cl)cc1Cl)c1ccc(CCl)cc1

Procedure:
81.5 g (0.5 mole) of 2,4-dichlorophenol was dissolved in 100 ml of absolute xylene, mixed with a solution of 95 g (0.5 mole) of p-chloromethylbenzoyl chloride in 80 ml of xylene, and after the addition of 0.5 ml of N-methylpyrrolidine the mixture was refluxed for 6 to 7 hours in a weak current of nitrogen.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][C:45](=[O:57])[C:46]2[CH:51]=[CH:50][C:49]([O:52][C:53]([F:56])([F:55])[F:54])=[CH:48][CH:47]=2)[CH:41]=[CH:40][C:39]=1[C:58]1[CH:66]=[C:65]2[C:61]([CH2:62][N:63]([C@@H:68]([CH:73]([CH3:75])[CH3:74])[C:69]([O:71]C)=[O:70])[C:64]2=[O:67])=[CH:60][CH:59]=1>>[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][C:45](=[O:57])[C:46]2[CH:47]=[CH:48][C:49]([O:52][C:53]([F:54])([F:55])[F:56])=[CH:50][CH:51]=2)[CH:41]=[CH:40][C:39]=1[C:58]1[CH:66]=[C:65]2[C:61]([CH2:62][N:63]([C@@H:68]([CH:73]([CH3:75])[CH3:74])[C:69]([OH:71])=[O:70])[C:64]2=[O:67])=[CH:60][CH:59]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3Cl)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3Cl)cc2C1=O
Yield: 72 %

Procedure:
The compound of example 488 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 487.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=O)[C:10]2=[O:11])=[CH:5][CH:4]=1.[OH-:20].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:5](=[C:12]([C:10]([OH:20])=[O:11])[C:14]3[C:19]([N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:4]=1
Reactant: COc1ccc(N2C(=O)C(=O)c3ccccc32)cc1
Reactant: [OH-]
Agent: [K+]
Product: COc1ccc2nc3ccccc3c(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The isatin from step (a) was refluxed with 150 mL of 10% potassium hydroxide under a nitrogen atmosphere. After 4 hours, the reaction was cooled to room temperature and filtered. The filtrate was diluted with water (150 mL) and ice. This solution was then acidified with concentrated HCl. A yellow precipitate separated out which was collected by filtration and rinsed with cold water and ether. After air drying, the precipitate was transferred to a round-bottom flask with methanol and evaporated to dryness. The resulting residue was evaporated to dryness twice from toluene and was obtained as a yellowish brown powder. Yield=1.15 g (26%).
Reaction SMILES: [OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C.Br[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[F:45].C(OCC)(=O)C>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.O>[OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: C#CCN1CC[C@@H](CCC(O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Reactant: Fc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)ccc2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.1 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate, 11 cm3 of triethylamine, 0.16 cm3 of tetrakis(triphenylphosphine)palladium, 0.053 g of cuprous iodide, and 0.47 cm3 of 1-bromo-2,5-difluorobenzene was stirred for 3 hours 15 minutes under an inert atmosphere at a temperature in the region of 80° C. After cooling to approximately 20° C., the reaction mixture had 30 cm3 of ethyl acetate and 30 cm3 of water added with stirring. The organic phase was separated, while the aqueous phase was extracted with 2 times 30 cm3 of ethyl acetate. The organic extracts were combined, washed with 3 times 25 cm3 of water, dried over sodium sulfate, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. A product was obtained, which product was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3.3 cm; 50 g), elution was carried out with ethyl acetate, and a fraction of 300 cm3 first was collected, followed by 32-cm3 fractions. Fractions 7 to 22 were combined and then concentrated under the above conditions. 0.91 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate was obtained in the form of a foam with an off-white color.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:16]=[C:15]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:14]=1)[C:3]([OH:25])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2cccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Chill a solution of N-methyl-N-propyl-5-(pyridine-3-carbonyl)-isophthalamic acid methyl ester (0.070 g, 0.206 mmol) in MeOH (1 mL) and THF (1 mL) in an ice bath. Add 1 N NaOH (0.62 mL, 0.62 mmol) and stir at room temperature for 2 h. Acidify the solution to about pH=2 and concentrate to one half of the solvent. Partition the residue between ethyl acetate and H2O. Extract the aqueous layer with ethyl acetate (2×15 mL). Wash the combined organic extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (72%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].O[CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C>>[NH2:20][CH2:19][CH2:18][N:15]1[CH:14]=[CH:13][C:12]([C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=2)=[N:16]1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Product: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Yield: 63.6 %

Procedure:
The title compound was prepared from 2-nitro-4-(1H-pyrazol-5-yl)benzonitrile (0.828 g, 3.87 mmol) and tert-butyl 2-hydroxyethylcarbamate (0.748 g, 4.64 mmol) using the method of Example 34(c) affording 0.633 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.21-3.29 (m, 2H), 4.02-4.04 (m, 2H), 7.02 (d, 1H), 7.88 (d, 1H), 8.13 (d, 1H), 8.29 (m, 1H), 8.50 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[C:7]([S:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:6][CH:5]=[CH:4][C:3]1=2.CC1(C)CCC(C)(C)C2C=C(SC3C=CC(C(OCC)=O)=CC=3)C=CC1=2.[Li+].[OH-].CO>O1CCCC1>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[C:7]([S:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(Sc2cccc3c2C(C)(C)CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(Sc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2c(Sc3ccc(C(=O)O)cc3)cccc21
Temperature: 55 °C
Yield: 62 %

Procedure:
To a solution of 70 mg (0.19 mmol) of ethyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthylthio)benzoate (Compound 1) in 4.0 mL of tetrahydrofuran was added 1.0 mL of LiOH (1.9N aqueous solution) and 1.5 mL of MeOH. The solution was heated at 55° C. for 3 h, cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted with hexane. The aqueous layer was acidified to pH=l using 10% HCl and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvents removed in vacuo. Purification of crude product by flash chromatography on silica gel (7:3/hexane:ethyl acetate) gave the title compound as a white solid (40 rag, 62%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]2=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:29]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C:11](=[O:28])[N:12]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]2=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cn1c(=O)c2cc(C)ccc2n(Cc2ccc(Cl)c(Cl)c2)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cn1c(=O)c2cc(CBr)ccc2n(Cc2ccc(Cl)c(Cl)c2)c1=O
Yield: 48.1 %

Procedure:
In 30 ml of carbon tetrachloride were refluxed 3.5 g of ethyl 1-(3,4-dichlorophenyl)methyl-1,4-dihydro-2,4-dioxo-6-methyl-3(2H)-quinazolineacetate, 1.66 g of N-bromosuccinimide and calalytic amount of benzoyl peroxide for 2 hours. The insolubles were filtered off and the filtrate was concentrated. Ether was added to the residue for crystallization and the crystals thus obtained were recrystallized from acetonitrile to obtain 2.0 g of ethyl 6-bromomethyl-1 -(3,4-dichlorophenyl)methyl-1,4-dihydro-2,4-dioxo-3(2H)-quinazolineacetate. m.p. 128°-129° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)O1.Br[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:21]([C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1)=[O:22]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(-c2ccccc2C=O)cn1
Temperature: 100 °C
Yield: 72 %

Procedure:
In a microwave vial, 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile (279 mg, 1.51 mmol), 2-bromo-benzaldehyde (230 mg, 1 mmol) and 2 ml of actonitrile were mixed. Then, 2 ml of 1N aqueous sodium carbonate was added, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 100° C. for 10 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water and dried over sodium sulfate. The organic solvent was evaporated to give crude product which was purified by ISCO to give 150 mg of 5-(2-formyl-phenyl)-pyridine-2-carbonitrile, yield 72%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[N:9](COCC[Si](C)(C)C)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38](Cl)=[O:39])=[CH:28][CH:27]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:39])=[CH:30][CH:31]=1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: C[Si](C)(C)CCOCn1c(CC2CCCCN2)cc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3[nH]2)c(-c2ccc(F)cc2)s1

Procedure:
(RS)-1-[5-(4-Fluoro-phenyl)2-methyl-thiazol-4-yl]-1-{2-[1-(2-trimethylsilanyl-oxymethyl)-1H-indol-2-ylmethyl]-piperidin-1-yl}-methanone (130 mg) was prepared from (RS)-2-piperidin-2-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole, D68 (520 mg) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (512 mg) according to a procedure similar to that for Example 1. A stirring solution of the above amide (125 mg) in dry THF (5 ml) was treated with a solution of tetrabutylammonium fluoride (2.2 mmol) in THF (5 ml). Once tlc indicated the reaction had gone to completion, the reaction mixture was poured into water and the product extracted with ethyl acetate. The combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-100% pentane-ethyl acetate followed by preparative tlc, 40% ethyl acetate-pentane) afforded the title compound as a white solid (2.5 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[C:15]([CH2:18]Cl)=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4].[CH3:20][OH:21]>C[O-].[Na+].O>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[C:15]([CH2:18][O:21][CH3:20])=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCn1c2nc[nH]c2c(=O)n2c(CCl)nnc12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCCCn1c2nc[nH]c2c(=O)n2c(COC)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.1 %

Procedure:
The mixture of 9-butyl-3-(chloromethyl)-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (35 mg, 125 mmol) in 4 M of sodium methoxide in methanol (0.5 mL, 2 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo to yield the desired product (6 mg, 17.42%). LCMS calculated for C13H19N6O2 (M+H): 290.2. found 290.2.