Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27].[I-].[K+]>>[C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[O:14][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(C)=O)c(O)cc1O
Reactant: N#CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(=O)c1cc(C(C)=O)c(OCCCCC#N)cc1O
Yield: 24.2 %

Procedure:
A mixture of 582 mg of 4,6-diacetylresorcinol, of potassium carbonate, 530 mg of 5-bromopentanenitrile and 0.2 g of potassium iodide was heated at reflux overnight. The mixture was concentrated in vacuo and partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer raphy on silica gel eluting with 40% ethyl etate in hexane to provide 200 mg of the desired title product, m.p. =105°-106° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:19])[C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH3:18])=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][N:14]1[C:13]([CH3:18])=[C:12]2[C:16]([CH:17]=[C:9]([N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH3:19])[CH:10]=[CH:11]2)=[N:15]1
Reactant: Cc1n[nH]c2cc(N(C)c3ccnc(Cl)n3)ccc12
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2ccc(N(C)c3ccnc(Cl)n3)cc2nn1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-1H-indazol-6-amine (2 g, 7.31 mmol) was dissolved in DMF (15 ml), and Cs2CO3 (2 g, 14.6 mmol) and 3-chlorobenzyl bromide (1.25 ml, 9.5 mmol) were added at room temperature. Mixture was stirred at rt for overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated. The aqueous layer was thoroughly extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated to give 2-(3-chlorobenzyl)-N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-2H-indazol-6-amine as an off-white solid. 1H NMR (300 MHz, d6DMSO) δ 7.94 (d, J=6.0 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.56 (d, J=1.3 Hz, 1H), 7.36-7.38 (m, 2H), 7.32 (br s, 1H), 7.16 (m, 1H), 6.91 (m, 1H), 6.28 (d, J=6.1 Hz, 1H), 5.65 (s, 2H), 3.42 (s, 3H), 2.63 (s, 3H). MS (ES+, m/z) 398 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([C:6]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C[O-].[Na+].[CH3:24]N(C=O)C.COS(OC)(=O)=O>O>[OH:1][C@@H:2]([C:6]([O:19][CH3:20])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH3:24])=[O:4]
Reactant: COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)O
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@@H](O)C(OC)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
54.4 g (200 mmol) of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were introduced with 10.8 g (200 mmol) of sodium methoxide into 300 ml of DMF. 21 ml (210 mmol) of dimethylsulfate were added dropwise to this suspension over 15 minutes, during which the temperature rises to 50° C. and the suspension becomes mobile. The mixture was stirred overnight and then added to 1.5 l of water and ice. The aqueous phase was extracted twice with 500 ml of ether, and the ether phase was in turn washed with 200 ml of water twice. The organic phase was dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off. 55.8 g of an oil were isolated and were immediately processed further.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH:32]1([CH:35]([C:37]2[CH:42]=[C:41]([F:43])[C:40](B3OC(C)(C)C(C)(C)O3)=[C:39]([F:53])[CH:38]=2)[OH:36])[CH2:34][CH2:33]1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:40]3[C:39]([F:53])=[CH:38][C:37]([CH:35]([CH:32]4[CH2:34][CH2:33]4)[OH:36])=[CH:42][C:41]=3[F:43])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CC1(C)OB(c2c(F)cc(C(O)C3CC3)cc2F)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cc(C(O)C4CC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with cyclopropyl(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (Intermediate 140) gave 275, which was isolated as a mixture of diastereomers. LCMS (ES+) m/z 522 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:16][CH2:17]CC.[Li]C(C)(C)C.C(I)C>C1COCC1>[CH2:16]([C:11]1[C:12]2[NH:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1)[CH3:17]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Li]C(C)(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cccc2c1Nc1ccccc1S2
Temperature: 25 °C

Procedure:
This compound was prepared according to a procedure by A. R. Katritzky et al., Synthesis, 1988, 215-217. To a solution of phenothiazine (10.0 g, 50.18 mmol) in anhydrous THF (200 mL) and cooled to −78° C. was added a solution of n-BuLi (24.1 mL, 60.2 mmol, 2.5 M in hexanes) dropwise. The mixture is stirred until a yellow precipitate forms and then allowed to warm to room temperature, until a clear yellow solution results. the solution is again cooled to −78° C. and CO2 gas is bubbled through the mixture for 5 min. The resulting solution is allowed to warm to RT and the solvent was evaporated to give a residue. The residue was again dissolved in anhydrous THF (200 mL) and cooled to −78° C., before t-BuLi (50 mL, 85 mmol, 1.7 M in pentane) was added dropwise. The resulting mixture was allowed to warm to −20° C. and was stirred at this temperature for 2 h. The reaction mixture was again cooled to −78° C. and a solution of ethyl iodide (100.0 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at this temperature for 1 hour then allowed to warm to −20° C. and stirred for 2 h. The reaction mixture was quenched with ice cold 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give a residue. The residue was purified by flash silica gel chromatography to give the desired product.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:37])[CH2:35][CH3:36]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.Cl.[CH2:16](O)[CH3:17]>O1CCOCC1>[CH2:16]([O:9][C:8](=[O:10])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)[CH3:17]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(CC(=O)O)cc1

Procedure:
A solution of the diester from preparation 9 (11.8 g,•47.0 mmol) and 2,2′-(1,4-phenylene)diacetic acid (15.73 g, 81.0 mmol) in ethanol (6.14 ml) and dioxan (75 ml) was treated dropwise with 12M hydrochloric acid (1.57 ml, 18.8 mmol). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated to low volume. The reaction mixture was diluted with toluene (125 ml) and the resulting slurry filtered. The filtrate was concentrated in vacuo and the residue taken up in water and basified with sodium bicarbonate until pH neutral. The mixture was diluted with ethyl acetate (200 ml) and the organic layer was separated and washed with sodium bicarbonate solution (5×30 ml) and sat. aq. sodium chloride (50 ml). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with ether (3×30 ml). The organics were combined, dried (magnesium sulphate) and concentrated in vacuo. The residue was triturated with pentane giving the title compound as a colourless solid 10.8 g.
Reaction SMILES: C[Si](C)(C)[C:3]1[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:5][O:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9].[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[Br:20][C:3]1[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:5][O:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C[Si](C)(C)c1onc(-c2cccnc2)c1[Si](C)(C)C
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)c1onc(-c2cccnc2)c1Br
Temperature: 40 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of anhydrous CCl4 (80 ml) containing compound 62 (4.45 g, 15.4 mmol) was added (1.1 eq, 1.04 ml) Br2. After the addition, the resulting solution was stirred for 18 hours at 40° C. The reaction mixture was cooled and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether) afforded 3-(4-bromo-5-trimethylsilanyl-isoxazol-3-yl)-pyridine (63) as an oil (4.5 g, ˜100%). 1H-NMR (400 MHz, CDCl3) δ 9.08 (d, J=2 Hz, 1H), 8.73 (dd, J=5 Hz, 2 Hz, 1H), 8.14 (dt, J=8 Hz, 2 Hz, 1H), 7.46-7.41 (m, 1H), 0.40 (s, 9H).
Reaction SMILES: FC(F)(F)S(O[C:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]2=[O:14])(=O)=O.C([OH:19])C.O>>[C:7]12([C:8]([OH:14])=[O:19])[CH2:9][CH:10]([CH2:13]1)[CH2:11][CH2:12]2
Reactant: CCO
Reactant: O=C1CC2CCC1(OS(=O)(=O)C(F)(F)F)C2
Solvent: O
Product: O=C(O)C12CCC(C1)C2
Temperature: 130 °C
Yield: 45 %

Procedure:
A mixture of 2-oxobicyclo[2.2.1]heptan-1-yl trifluoromethanesulfonate (4.6 g, 18.1 mmol) in 600 mL ethanol/water (60% w/w) and TEA (3.7 g, 36.2 mmol) was heated at 130° C. for 100 h. The mixture was concentrated under reduced pressure and the residue was poured into aqueous hydrochloric acid solution (1 mol/L, 150 mL) and extracted with diethyl ether (3×100 mL). The combined extracts were washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give the crude product which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the desired product (1.00 g, 8.09 mmol, yield: 45%). 1H NMR (400 MHz, CDCl3) δ ppm 2.47-2.45 (m, 1H), 1.94-1.90 (m, 4H), 1.79-1.74 (m, 2H), 1.37-1.35 (m, 2H).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[N:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:23][C:24]1[CH:31]=[C:30]([NH:32][NH2:33])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>C(O)C>[Cl:23][C:24]1[CH:31]=[C:30]([N:32]2[CH:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[N:13][C:14]=4[CH2:15][CH2:16]3)=[N:33]2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: N#Cc1ccc(NN)cc1Cl
Reactant: COC(=O)c1ccc2c(n1)CCC(=CC1CCCC1)C2=O
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
In a dried reaction flask, methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylate (1.552 g, 5.44 mmol) and 2-chloro-4-hydrazinobenzonitrile hydrochloride (1.437 g, 7.04 mmol) were dissolved in ethanol (55 mL). In the protection from light and under the nitrogen atmosphere, the solution was stirred at 80° C. for 8 hr and at room temperature for 15 hr, and filtered to obtain a pale yellow solid (0.972 g) in 41.1% yield.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][NH2:25]>>[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: NNC(=O)Nc1ccccc1Br
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1Br

Procedure:
ninhydrin, 4-(2-bromophenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH2:1]([CH:10]1[C:15](=O)[CH2:14][CH2:13][S:12][CH2:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH2:22].C(O)C.[ClH:27]>Cl.CCOCC>[ClH:27].[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][N:22]1[C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][C:10]2[CH2:11][S:12][CH2:13][CH2:14][C:15]1=2
Reactant: CN(C)CCCN
Reactant: O=C(CC1CSCCC1=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCCn1c(-c2ccccc2)cc2c1CCSC2
Temperature: 25 °C

Procedure:
A solution of 3.0 g (0.013 mole) of 3-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one, 1.33 g of 3-dimethylaminopropylamine, 20 ml. of ethanol, and one drop of concentrated hydrochloric acid is heated under reflux under nitrogen for 1.5 hours, and then cooled to ambient temperature. The reaction mixture is treated with 4 ml. of saturated ethereal hydrogen chloride and diluted to the cloud point with ether. The solid which separates is collected and recrystallized from ethanol to provide colorless crystals of 1-(3-dimethylaminopropyl)-2-phenyl-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 225° to 227° C. dec.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([C@:10]1([OH:21])C(=O)[O:14][C:12](=[O:13])[C@:11]1(C(=O)C)[OH:17])(=[O:9])C>O1CCCC1>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:9])[CH:10]([CH:11]([C:12]([OH:14])=[O:13])[OH:17])[OH:21]
Reactant: NCCCCN
Reactant: CC(=O)[C@]1(O)C(=O)OC(=O)[C@@]1(O)C(C)=O
Solvent: C1CCOC1
Product: NCCCCNC(=O)C(O)C(O)C(=O)O
Reaction time: 2 h

Procedure:
13.225 Grams (150 mmoles) of putrescine (VI) was dissolved in 75 ml of tetrahydrofuran (THF), and a solution of 10.8 g (50 mmoles) of diacetyl-L-tartaric acid anhydride (VIII) in 50 ml of THF was gradually added dropwise thereto while cooling with ice under stirring. After addition, stirring was continued for 2 hours at room temperature, and after completion of the reaction, the solvent was removed by evaporation under reduced pressure. Thereafter, 50 ml of water was added, and the reaction solution was adjusted to pH 13 with 2N NaOH and stirred at room temperature for 2 hours to effect the hydrolysis of the acetyl group.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=2[CH3:27])=[N:14]1>>[NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])=[N:14]2)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)O)co1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3coc(N)n3)n2)ccc(C#N)c1Cl
Yield: 29 %

Procedure:
(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-amino-1,3-oxazole-4-carboxylic acid (0.196 g, 1.527 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.437 g, 1.272 mmol). The product was purified by Flash-chromatography. Yield 29.0%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.58 (s, 3H), 4.29 (dd, 1H), 4.39 (dd, 1H), 4.54 (m, 1H), 4.59 (s, 2H), 6.44 (d, 1H), 7.31 (d, 1H), 7.50 (d, 1H), 7.53 (dd, 1H), 7.58 (dd, 1H), 7.68 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([OH:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-(4-fluorophenoxy)benzaldehyde (9.00 g, 41.63 mmol) in CHCl3 (75 mL) was treated with m-chloroperbenzoic acid (46-85%, 15.80 g, 52.00 mmol) and stirred for 3 h at room temperature. The reaction was washed with sat. aq. NaHSO3, sat. aq. NaHCO3, and water. The organic layer is concentrated and the residual oil taken up in MeOH (10 mL) containing a few drops of conc. HCL and stirred for 1 h at room temperature. The solvent is removed in vacuo and the resulting oil was chromatographed on silica gel (20% ethyl acetate/hexane) to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.[H-].[Na+].O>C1COCC1>[N:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:15]=[C:14]([NH:13][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=3[N+:10]([O-:12])=[O:11])[CH:19]=[CH:18][CH:17]=2)=[N:21][CH:22]=1
Reactant: Nc1cccc(-c2ccncn2)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Nc2cccc(-c3ccncn3)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.6 %

Procedure:
To a mixture of 4-chloro-3-nitrobenzonitril (5.5 g, 30 mmol) and (58) (5.1 g, 30 mmol) in THF (120 ml) was added sodium hydride (2.3 g, 50% suspension in mineral oil). After stirring at room temperature for 2 days, the mixture was poured into water and extracted with CH2Cl2. The extract was concentrated under reduced pressure and the residue was triturated with diethylether to yield crystalline (59) (9.2 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]2[NH:16][C:15]3[CH:17]=[C:18]4[C:22](=[CH:23][C:14]=3[N:13]=2)[C:21]([CH3:25])([CH3:24])[C:20](=O)[C:19]4([CH3:28])[CH3:27])[C:4]=1[CH3:29].[CH3:30][O:31][NH3+:32].[Cl-]>CO>[CH3:30][O:31][N:32]=[C:20]1[C:21]([CH3:25])([CH3:24])[C:22]2[C:18](=[CH:17][C:15]3[N:16]=[C:12]([S:11][CH2:10][C:5]4[C:4]([CH3:29])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=4)[NH:13][C:14]=3[CH:23]=2)[C:19]1([CH3:28])[CH3:27]
Reactant: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: CO
Product: CON=C1C(C)(C)c2cc3nc(SCc4ncc(C)c(OC)c4C)[nH]c3cc2C1(C)C

Procedure:
5 g of 5,7-dihydro-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethyli ndeno[5,6-d]imidazol-6(lH)-one and 40 g of 0-methylhydroxylamine hydrochloride in 250 ml of methanol were boiled at reflux for 16 hours under argon. After removing the solvent in vacuo the residue was partitioned between methylene chloride and water and the aqueous phase was extracted three times with methylene chloride. The combined organic extracts were made neutral with saturated sodium bicarbonate solution in the presence of ice and under argon gasification. After repeated extraction with methylene chloride the organic phases were dried over sodium sulfate and evaporated in vacuo. A red impurity was removed by chromatography on silica gel with ethyl acetate. The separation of the reaction product from starting material was carried out on silica gel using toluene/methyl isobutyl ketone/pyridine (80:18:2) as the elution agent. The purity of the fractions was assayed by thin-layer chromatography using the system ethyl acetate/ methyl isobutyl ketone/pyridine (80:18:2). By crystallization from acetone/water there was obtained 5,7-dihydro-2-[[(4- methoxy-3,5-dimethyl -2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(lH)-one O-methyl oxime of melting point 110-112° .
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[CH2:11][OH:12])[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C(OCC)(=O)C>[CH2:15]([O:12][CH2:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[O:4][CH2:3][CH2:2][O:1]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CCCCC12OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(COCC2CCCCC23OCCO3)cc1
Reaction time: 1 h

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-6-ylmethanol (2.3 g, 13.3 mmol) in THF (20 mL) and cooled in an ice bath, was treated with a NaH (0.48 g, 20.0 mmol). The reaction mixture was stirred for 1 hour and then benzyl bromide (2.4 mL, 20 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at rt for 5 hours and then diluted with ethyl acetate (100 mL). The organic layer was washed with water, brine and dried over sodium sulfate and concentarted. Purification by silica chromatography using hexane-Et2O 20% linear gradient afforded the title compound as pale yellow solid. MS m/z 263.2 (M+1).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.[Pd]>[OH:32][CH:29]([CH2:30][OH:31])[CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(OCC(O)CO)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OCC(O)COc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(RS)-(2,3-dihydroxypropyl)oxy]quinazoline (930 mg) in methanol (10 ml) is added 10% palladium/carbon (280 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 15 hours. To the reaction mixture is added chloroform (30 ml), and the mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in methanol-chloroform, and the solution is filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in acetone, and the solution is allowed to stand at room temperature, and the precipitated crystals are separated by filtration to give 4-[(RS)-(2,3-dihydroxypropyl)oxy]-2-(1-piperazinyl)quinazoline (355 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloroaniline (5.0 g, 39.2 mmol) in 25 mL pyridine was added 5.3 mL (43.1 mmol) of pivaloyl chloride and the reaction mixture stirred overnight at room temperature. The mixture was poured into vigorously stirring 6M HCl, and the solids were collected by vacuum filtration, washed well with H2O, and dried in vacuo to yield the title compound. 1H NMR (CDCl3) δ 7.47 (d, J=9.2 Hz, 2H) 7.30 (s, 1H) 7.27 (d, J=8.8 Hz, 2H) 1.32 (s, 9H) MS (ES) m/z=212.1