Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[CH:28]1([C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=3)[CH2:35][CH2:34]2)=[O:32])[CH2:30][CH2:29]1>>[CH:28]1([C:31]([N:33]2[CH2:34][CH2:35][N:36]([C:39]3[CH:40]=[CH:41][C:42]([C:43]4[NH:25][C:24]5[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]6[CH:14]=[CH:13][C:12]([N:15]7[CH2:20][CH2:19][O:18][CH2:17][CH2:16]7)=[CH:11][CH:10]=6)=[CH:5][C:4]=5[N:1]=4)=[CH:45][CH:46]=3)[CH2:37][CH2:38]2)=[O:32])[CH2:29][CH2:30]1
Reactant: O=Cc1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCN(C(=O)C5CC5)CC4)cc3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 415 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 4-(4-cyclopropanecarbonylpiperazinyl)benzaldehyde. [M+H]+ calcd for C32H34N6O3: 551.27; found: 551.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH2:22]O)[C:13]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[N:6][CH:7]=1.C(P(CCCC)CCCC)CCC.[O:42]1[CH2:46][CH2:45][NH:44][C:43]1=[O:47].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH2:22][N:44]3[CH2:45][CH2:46][O:42][C:43]3=[O:47])[C:13]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)CCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(Br)c1
Reactant: O=C1NCCO1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)CCCc1c(CN2CCOC2=O)nn2c(CC)ccc2c1-c1cncc(Br)c1
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
To a solution of ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate (70.0 mg) in toluene (1 mL) was added tributylphosphine (0.098 mL), 1,3-oxazolidin-2-one (34.1 mg) in that order in an ice bath. After stirring for 5 minutes, to the mixture was added 1,1′-(azodicarbonyl)dipiperidine (98.9 mg). The mixture was stirred for 10 minutes in the bath, and 8 hours at room temperature. Hexane (5 mL) was added, and the mixture was filtered. The filtrate was evaporated. Preparative thin layer chromatography (ethyl acetate-hexane=1-1) afforded ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate as an yellow gum (25.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([NH:27][C:28](=[O:42])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:21][CH3:22])[CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:26]=[C:25]([NH:27][C:28](=[O:42])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][C:32]=2[Cl:41])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:21][CH3:22])[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CCN(CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.180 g (0.284 mmol) of tert.butyl 4-[(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-ethyl-amino]-piperidine-1-carboxylate (from Example 97) were dissolved in 5.0 mL dichloromethane. After the addition of 0.44 mL (5.680 mmol) of trifluoroacetic acid the mixture was stirred for 2 hours at RT. The reaction solution was evaporated down i. vac. and the residue combined with sat. aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with EtOAc. The org. phase was dried over magnesium sulphate, filtered and evaporated down i. vac. Further purification was carried out by column chromatography.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.CN([CH:27]=[O:28])C>>[C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([Cl:13])=[CH:11][C:12]=1[CH:27]=[O:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)s1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Product: CC(C)(C)NC(=O)c1sc(Cl)cc1C=O
Temperature: -75 °C
Reaction time: 1.5 h
Yield: 102.8 %

Procedure:
A 1 L three-neck flask was charged with N-tert-butyl-5-chlorothiophene-2-carboxamide (10.0 g, 45.9 mmol) and thoroughly flushed with nitrogen gas. The flask was charged with THF (400 ml) by cannulation, then cooled to −75° C. Tert-butyllithium, 1.7 m solution in pentane (68.4 ml, 116 mmol) was added by syringe pump over 45 min, keeping the temperature less than −70° C. After stirring at −75° C. for 90 min, the reaction was gradually warmed to −60° C. and stirred for 1 hr. The mixture was again cooled to −75° C. and DMF (14.2 ml, 184 mmol) was added dropwise, ensuring the temperature remained below −70° C. The mixture was stirred at −75° C. for 1 hr. The reaction was quenched with 200 ml sat. aq. NH4Cl, then allowed to warm to RT. Water was added to the solution to dissolve solids and the mixture was extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered and concentrated to give the title compound as a tan solid (11.6 g.). MS (ESI, pos. ion) m/z: 246 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]([OH:17])=O)[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]([N:31]1[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]1)=[O:17])[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1
Reactant: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CC(=O)O)c2cc1OC
Reactant: OC1CCNCC1
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CC(=O)N3CCC(O)CC3)c2cc1OC
Yield: 38.8 %

Procedure:
2-[5,6-Dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone is prepared by following the procedure described in example 93, but using 0.2 g of 2-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]acetic acid and 0.07 g of 4-hydroxypiperidine. After purification by flash-pack chromatography (silica, 98/02 by volume dichloromethane/methanol as eluents), 0.096 g of 2-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone is obtained, the characteristics of which are as follows:
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O-]CC.[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:34]([C:35](=O)[C:36]#[CH:37])=[C:25]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][N:24]3[N:23]=2)=[CH:18][CH:17]=1>C(O)C.O>[CH:2]1([NH:7][C:8]2[N:10]=[C:35]([C:34]3[C:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)=[N:23][N:24]4[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=34)[CH:36]=[CH:37][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a suspension of N-cyclopentylguanidine hydrochloride (2.20 g, 13.5 mmol) in ethanol (70 mL) was added sodium ethoxide (4.5 mL, 3 M in ethanol, 14 mmol). The mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. To this mixture was added 1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin -3-yl]-2-propyn-1-one (3.44 g, 10.4 mmol) portionwise The reaction mixture was stirred at 0° C. for 30 minutes, followed by room temperature for 15 hours. The reaction mixture was diluted with water (400 mL). The solid precipitate was collected on a filter to provide N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (4.48 g, 98%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.51 (d, 1H), 8.11 (d, 1H), 7.64 (dd, 2H), 7.44 (dd, 1H), 7.17 (t, 2H), 6.33 (d, 1H), 5.17 (d, 1H), 4.34(m, 1H), 2.15–2.06 (m, 2 H), 1.84–1.52 (m, 6H); 19F NMR (CDCl3): δ−62.70, −112.25 MS m/z 442 (M+1); mp 155–156° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39])=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1[CH:34]=[C:35]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:12])[F:13])=[C:4]([Cl:27])[CH:3]=2)[CH:36]=[CH:37][C:38]=1[F:39])=[O:32])[CH3:29]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
The title compound was prepared in analogy to Example 117 from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 116, step 8) by Suzuki coupling with 3-ethoxycarbonyl-4-fluoro-phenylboronic acid [CAS Reg. No. 874219-36-0]. MS (m/e)=552.3 [M+H+], MS (m/e)=506.1 [(M−CH3CH2O−)+].
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][S:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])=[O:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:31][CH2:32][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[C:29]4=[O:33])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CS(=O)(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(S(C)(=O)=O)C4=O)nc3)CC2)c(C)c1
Yield: 74.2 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 127 and 1-methanesulfonylimidazolidin-2-one (82 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (170 mg) was obtained.
Reaction SMILES: [CH:1]([O:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH2:2].O>CO>[CH:1]([O:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH2:2]
Reactant: C=CO[C@@H]1CCCC[C@@H]1C(C)(C)C
Solvent: O
Solvent: CO
Product: C=COC1CCCCC1C(C)(C)C
Temperature: 20 °C
Reaction time: 11 h

Procedure:
1.09 g (6.00 mmol) of cis-2-tert-butylcyclohexyl vinyl ether and 199 mg (0.30 mmol) of Co(OAc) (L3) were dissolved in 6.0 ml of methanol under the atmosphere and 540 μL (30 mmol) of water was added to the mixture and the mixture was then stirred at 20° C. After 11 hours, the reaction solution was analyzed by GC, to find that 23% of the cis-2-tert-butylcyclohexyl vinyl ether was left with an optical purity of 92% ee and comprised (1R, 2R) isomers. Further, the reaction solution was purified by silica gel column chromatography to isolate the reaction substrate 2-tert-butylcyclohexyl vinyl ether and the reaction product 2-tert-butylcyclohexanol in a ratio of 22% and 77% respectively. Also, the kre1 value showing the selectivity of reactions at this time was 4.9.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)#[N:23]>>[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])#[N:23]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cccc(C#N)c2)c1
Yield: 55.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (222 mg, yield: 55.3%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(Br)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a 500 mL flask, ethyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate (22.00 g, 83%, 55.23 mmol) and ethanol (100 mL) were added. The sodium hydroxide solution (2.20 g, 55.23 mmol, dissolved into water (100 mL)) was added dropwise. After being stirred for 2 hours at room temperature, the reaction mixture was concentrated by rotary evaporator to remove ethanol. The residue was extracted with ethyl acetate (30 mL) and the aqueous layer was acidified with concentrated hydrochloric acid to pH=3. Then the aqueous solution was extracted with ethyl acetate (3×100 mL) again. The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give the product (15.51 g) as a light yellow solid in 91% yield. HPLC area normalization method content is 98%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[N:13]1[C:17](=[O:18])[CH2:16][NH:15][C:14]1=[O:19].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:1]([N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[F:5])[C:14]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C1CNC(=O)N1c1cc(F)ccc1F
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(=O)N(c2cc(F)ccc2F)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (1.05 equivalent) in methylene chloride (50 mL) was added dropwise to a solution of 3-(2,5-difluorophenyl)imidazolidine-2,4-dione (50 mmol) in methylene chloride (150 mL) containing triethylamine (1.1 equivalent) and a catalytic amount of dimethylaminopyridine. The solution was allowed to stir overnight at room temperature, then was diluted with methylene chloride, and washed with 10% HCl, with water and with brine (saturated), dried (MgSO4), filtered and concentrated to give N-acetyl-3-(2,5-difluorophenyl)imidazolidine-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[C:11]([OH:14])(=S)[CH3:12]>C([O-])([O-])=O.[K+].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:11](=[O:14])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(O)=S
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1ccc(Cl)cc1
Temperature: 150 °C
Yield: 90.5 %

Procedure:
In one example, under nitrogen gas, a stirred mixture of 4-Chloro-1-nitrobenzene (e.g., about 1 g, 6.35 mmol), thioacetic acid (e.g., about 1.93 g, 25.39 mmol), K2CO3 (e.g., about 0.050 g, 0.36 mmol), and dry Triton-X 405 (e.g., about 0.010 g) were heated at about 150° C. The progress of the reaction was monitored by HPLC and GC. After four hours the reaction was cooled to room temperature, and acetone (e.g., about 8 mL) was added and filtered through a sintered glass funnel. Evaporation of the acetone produced about 0.975 g of N-(4-Chloro-phenyl)-acetamide (e.g., about 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[C:13]([N:16]1[CH:21]([CH3:22])[CH2:20][N:19]([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:18][CH:17]1[CH3:31])(=[O:15])[CH3:14].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[C:13]([N:16]1[CH:21]([CH3:22])[CH2:20][N:19]([C:23]2[CH:24]=[CH:25][C:26]([C:27]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([F:11])=[CH:8][C:7]=4[F:12])[N:1]=3)=[CH:29][CH:30]=2)[CH2:18][CH:17]1[CH3:31])(=[O:15])[CH3:14]
Reactant: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Reactant: NC(=O)c1c(N)cc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)N1C(C)CN(c2ccc(-c3nc4cc(F)cc(F)c4c(=O)[nH]3)cc2)CC1C
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-amino-4,6-difluoro-benzamide (0.66 g, 3.84 mmol) and 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde (1.00 g, 3.84 mmol) in N,N-dimethyl acetamide (20 mL), was added sodium hydrogen sulfite (58.5 wt %, 1.04 g, 5.76 mmol) and p-toluenesulfonic acid monohydrate (0.88 g, 4.61 mmol) and the reaction mixture was stirred at 115° C. for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered off, to give 2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-5,7-difluoro-3H-quinazolin-4-one as a yellow solid, which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][C:14]1([CH3:26])[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[N:15]1[CH2:22][CH2:23][CH2:24][NH2:25]>>[CH3:26][C:14]1([CH3:13])[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[N:15]1[CH2:22][CH2:23][CH2:24][NH:25][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CC1CC(C)N(CCCN)C(C)(C)C1
Product: CC1CC(C)N(CCCNC(=O)CN2CCCC2=O)C(C)(C)C1

Procedure:
From 8.5 g. of ethyl 2-oxo-1-pyrrolidineacetate and 14 g. of 3-(2,2,4,6-tetramethyl-1-piperidinyl)propylamine (U.S. Pat. No. 3,446,811), following the procedure of Example 9, there is obtained N-[3-(2,2,4,6-tetramethyl-1-piperidinyl)propyl]-2-oxo-1-pyrrolidineacetamide; m.p. 85°-87° C. after recrystallization from ethyl ether.
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]=[C:23]=[O:24]>C(N(CC)CC)C>[CH3:21][NH:22][C:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:24]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)OCCCCC/C=C(\c1ccccc1)c1cccnc1
Yield: 91.6 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.0 g, 7.4 mmoles) was reacted with methyl isocyanate (500 mg, 8.8 mmoles) in the presence of triethylamine in the same manner as Example 9 to give 1-methylaminocarbonyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (2.2 g) (Compound Id-24) as an oil. This compound forms a crystalline salt of oxalic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21]C)=O)[CH:15]=2)[CH2:10]1)=[O:8].[K].[NH2:24][OH:25].C(O)(=O)C>CO>[OH:25][NH:24][C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:8])[CH2:18][CH2:17]2)=[O:21]
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)c1cccn1C)C2
Agent: [K]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cccc1C(=O)N1CCc2cc(C(=O)NO)ccc2C1
Yield: 16.2 %

Procedure:
Methyl 2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate in a vial was dissolved in MeOH (1 mL) and hydroxylamine potassium salt (0.682 mL, 1.2 mmol; 1.76 M in MeOH) was added. The solution was shaken at rt for 2 h before acetic acid (0.0682 mL, 1.2 mmol) was added to neutralize the reaction. The solvent was then completely evaporated and to the residue was added DMSO (1.2 mL). After filtration, the solution was purified by prep-HPLC to yield N-hydroxy-2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (0.0073 g, 16.2%). LC-MS: (AA) ES+ 301; 1H NMR (Methanol-d4, 400 MHz) δ 7.87 (d, J=8.0 Hz, 1 H), 7.72 (d, J=8.0 Hz, 1 H), 6.86 (t, J=1.8 Hz, 1 H), 6.52 (dd, J=3.8, 1.5 Hz, 1 H), 6.12 (dd, J=3.8, 2.5 Hz, 1 H), 4.96 (s, 2 H), 4.07 (t, J=5.8 Hz, 2 H), 3.74 (s, 3 H), 3.11 (t, J=6.0 Hz, 2 H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])C.[OH-].[Na+].CCOCC>ClC1C=CC=CC=1>[Br:13][C:8]1[C:7]2[O:6][CH:5]=[CH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(COc1ccccc1Br)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: Brc1cccc2ccoc12
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A stirred mixture of polyphosphoric acid (˜5 g) and chlorobenzene (8 mL) was heated at reflux and a solution of 1-(2,2-diethoxyethoxy)-2-bromobenzene (2.62 g, 9.0 mmol) in chlorobenzene (3 mL) was added dropwise over 10 min. The mixture was heated at reflux for 1.5 h. The mixture was allowed to cool to rt and 1M aq NaOH (20 mL) was added, followed by ether (175 mL). The mixture was washed with water (2×20 mL) and brine (20 mL), and dried over MgSO4. Evaporation of the solvent left a residue which was purified by a chromatography on a 140-g silica cartridge eluted with hexanes and a 0-10% EtOAc in hexanes gradient. Appropriate fractions were pooled and concentrated to afford 7-bromobenzofuran (0.65 g, 38% from 2-bromophenol) as a clear colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([OH:23])[C@H:5]([C:10](=[O:22])[C@H:11]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH:12]([CH3:14])[CH3:13])[C:6]([O:8]C)=[O:7].COCCOC.Cl>O>[OH:23][C@H:4]([C@H:5]([C:10](=[O:22])[C@H:11]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH:12]([CH3:14])[CH3:13])[C:6]([OH:8])=[O:7])[C:3]([OH:24])=[O:2]
Reactant: COC(=O)[C@@H](C(=O)[C@H](c1ccc(Cl)cc1)C(C)C)[C@@H](O)C(=O)OC
Agent: Cl
Solvent: O
Solvent: COCCOC
Product: CC(C)[C@H](C(=O)[C@H](C(=O)O)[C@@H](O)C(=O)O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 2(R)-hydroxy-3(R)-[2(S)-(4-chlorophenyl)-3-methylbutanoyl]-butanedioic acid dimethyl ester (diastereoisomer K) (1 g, 2.6 mmol), 1,2-dimethoxyethane (18.3 ml) and of conc HCl (18.3 ml) was heated, under stirring, at 70° C. for 1 hour. The reaction mixture was cooled at room temperature, poured into water (50 ml) and extracted with dichloromethane (2×50 ml). The organic phase was extracted with a 10% aqueous solution of sodium bicarbonate (4×50 ml). The aqueous phase was acidified with conc HCl to pH 1 and extracted with dichloromethane (3×50 ml). The combined organic phase was washed with water, anhydrified over sodium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:27][CH:28]=2)O1>>[C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:27]3[CH:26]=[C:25]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=[CH:23][CH:28]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(C)(C)c1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-tert-butylimidazo[1,2-a]pyrimidine was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-tert-butylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white powder: Found C, 77.17; H, 5.79; N, 15.78. C23H20N4.0.3(H2O) requires C, 77.21; H, 5.80; N, 15.66; δH (400 MHz, CDCl3) 1.44 (9H, s), 7.05 (1H, d, J 7), 7.48-7.76 (7H, m), 7.83 (1H, dd, J 8 and 1), 7.86 (1H, s), 8.88 (1H, d, J 7); m/z (ES+) 353 (M++H).