Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2](/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([O:20][CH3:21])[CH:19]=1)=[O:11])[CH3:3].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].P(O)([O-])([O-])=O.[Na+].[Na+].Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45]>CC(C)=O>[CH3:47][O:46][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:22][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH:2]([CH3:1])[CH3:3])=[CH:19][C:18]=1[O:20][CH3:21]
Reactant: COc1cc(CNC(=O)CCCC/C=C/C(C)C)ccc1O
Reactant: COC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])O
Agent: [I-]
Solvent: CC(C)=O
Product: COC(=O)CCCCCOc1ccc(CNC(=O)CCCCC=CC(C)C)cc1OC
Yield: 52.7 %

Procedure:
To a mixture of Capsaicin (2 g, 6.56 mmol), anhydrous K2CO3 (3 g, 22 mmol), sodium iodide (2 g, 13.3 mmol) and disodium phosphate (2 g, 14.2 mmol) in anhydrous acetone (50 ml) was added methyl 6-bromohexanoate (2 g, 9.6 mmol) and refluxed for 24 hours. Acetone was distilled off and water (15 ml) was added. Crude 12 was filtered, dried and purified by column chromatography on silica gel using benzene:ethyl acetate (9:1) to give pure 12 (1.5 g, 52.8%) as a pale white powder. The melting point was found to be 69.2-70.8° C.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]2[CH2:30][O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[S:15][CH:16]=1)=[O:11]>CO>[ClH:1].[ClH:1].[CH3:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[CH2:30][O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[S:15][CH:16]=1)=[O:11]
Reactant: CNC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNC(=O)c1csc(N2CCNCC2COc2cccnc2)n1
Reaction time: 1 h
Yield: 97 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4-(methylcarbamoyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (35 mg, 0.081 mmol) in MeOH (1 mL). After stirring for 1 h, the reaction mixture was concentrated under reduced pressure, yielding 31.9 mg (97%) of the title compound. LC-MS: RT=1.37 min, (M+H)+=334.2.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:28]([N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)=[CH2:29].CN(C)CCN(C)C>CCCCCC>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]([C:8]2[CH:21]=[CH:22][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)([C:31]2[N:30]([CH:28]=[CH2:29])[CH:34]=[CH:33][N:32]=2)[OH:10])=[CH:16][CH:15]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C=Cn1ccnc1
Reactant: CC(C)(C)c1ccc(C(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=Cn1ccnc1C(O)(c1ccc(C(C)(C)C)cc1)c1ccc(C(C)(C)C)cc1

Procedure:
This compound was prepared by the procedure indicated in Example XXII A, using the following materials: 10 g. (0.03 mol) of 4,4'-di-tert.-butylbenzophenone, 19.5 ml. (0.04 mol) of 20% butyllithium in n-hexane, 3 g. (0.03 mol) of 1-vinylimidazole and 4.9 g. (0.04 mol) of N,N,N', N'-tetramethylethylenediamine. The product was crystallised from ethyl acetate. Melting point 169°-170° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:24])[N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])C.C(O)C.[OH-].[Na+]>O>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:24])[N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(N2CCN(C(=O)N(CC)CC)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reaction time: 3.5 h
Yield: 49.1 %

Procedure:
To 3.3 g (0.01 mole) of 1-(4-ethoxycarbonylphenyl)-4-diethylcarbamoylpiperazine obtained in Example 6 were added 90 ml of ethanol, 10 ml of water and 1.0 g of sodium hydroxide, and the mixture was heated and refluxed under stirring for 3.5 hours. The solvent was removed by distillation under reduced pressure, and 100 ml of water was added to the residue and the insoluble substance was removed. The pH value of the filtrate was adjusted to 3 by 2 N hydrochloric acid. The precipitate was recovered by filtration and dissolved in a dilute aqueous solution of sodium hydroxide, and the pH value was adjusted to 3 again by 2 N hydrochloric acid. The precipitate was recrystallized from methanol to obtain 1.5 g of 1-(4-carboxyphenyl)-4-diethylcarbamoylpiperazine having a melting point of 207° to 209.5° C. The elementary analysis values are as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: Nc1ccc(F)cc1Nc1cccnc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A mixture of 4-fluoro-N2-pyridin-3-ylbenzene-1,2-diamine (1.03 g, 5.07 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.05 g, 5.58 mmol), HOAt (759 mg, 5.58 mmol), 4-methylmorpholine (1.23 mL, 11.15 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.07 g, 5.58 mmol) in DCM (30 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM and a saturated solution of NaHCO3. A precipitate was present in the organic fraction which was filtered off to afford the title compound as a pale yellow solid (503 mg). The filtrate was dried (MgSO4) and concentrated in vacuo and the resulting residue was triturated with DCM to afford a second batch of the title compound as a yellow solid (765 mg; 67% yield for the combined batches). LCMS (Method C): RT 2.06 min [M+H]+ 375.3
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:27](=[S:36])[NH:26][CH:25]=2)([CH3:23])[CH3:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][S:36][C:27]1[N:28]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[C:24]([C:21]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)([CH3:23])[CH3:22])=[CH:25][N:26]=1
Reactant: COc1ccc(C(C)(C)c2c[nH]c(=S)n2-c2ccc(F)cc2)cc1OC
Reactant: Fc1cccc(Cl)c1CBr
Product: COc1ccc(C(C)(C)c2cnc(SCc3c(F)cccc3Cl)n2-c2ccc(F)cc2)cc1OC

Procedure:
In a manner similar to that described for Example 1, the title compound was prepared from 2-chloro-6-fluorobenzyl bromide and 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione. 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 7.17-7.10 (m, 2H), 6.92-6.88 (m, 1H), 6.75-6.71 (m, 2H), 6.65 (d, 1H), 6.52 (d, 1H), 6.47 (dd, 1H), 6.34 (m, 2H), 4.24 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 1.49 (s, 6H); MS (EI) m/z 515 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[CH2:15]([NH2:17])[CH3:16]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:17][CH2:15][CH3:16])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCN
Reactant: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Solvent: CCO
Product: CCNc1ccc(C(C)=O)cc1S(N)(=O)=O

Procedure:
A solution of 5-acetyl-2-fluorobenzenesulphonamide (6.0 g) and ethylamine (70% solution in water, 25 ml) in absolute ethanol (100 ml) was heated at 100° for 16 hours in a bomb. The resulting yellow solution was evaporated to small volume to deposit the title compound as an off-white crystalline solid, 6.0 g, m.p. 201°-204° (from ethanol).
Reaction SMILES: CB(O)O.[F-].[Cs+].[C:7]1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:37][C:38]1[C:43]([F:44])=[C:42](Cl)[N:41]=[C:40]([C:46]([O:48][CH3:49])=[O:47])[C:39]=1[Cl:50]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(N(CC)CC)C>[NH2:37][C:38]1[C:43]([F:44])=[C:42]([CH3:7])[N:41]=[C:40]([C:46]([O:48][CH3:49])=[O:47])[C:39]=1[Cl:50]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(C)c(F)c(N)c1Cl
Yield: 500 %

Procedure:
A solution of methylboronic acid (0.17 g, 2.93 mmol), cesium fluoride (0.95 g, 6.27 mmol), 1,4-bis(diphenylphosphino)butane (0.09 g, 0.21 mmol), methyl 4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylate (0.50 g, 2.09 mmol) and triethylamine (1 mL) in acetonitrile (20 mL) was purged for 15 minutes with nitrogen. Palladium acetate (0.05 g, 0.21 mmol) was then added and the reaction mixture heated under reflux overnight. After cooling, water was added and the mixture extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and concentrated. The residue was purified by column chromatography (33% ethyl acetate in hexane) to give methyl 4-amino-3-chloro-5-fluoro-6-methylpyridine-2-carboxylate (0.23 g, 1.05 mmol), mp 113-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:31][CH2:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: NCC1CCCCC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CNCC2CCCCC2)c1
Yield: 73.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-((cyclohexylmethylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), cyclohexylmethanamine (0.057 mL; 0.5 mmol), and sodium iodide (0.015 g; 0.1 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.045 g (73%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][C:58]([N:61]=[C:62]=[O:63])=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@H:47]1[CH2:51][CH2:50][N:49]([C:62]([NH:61][C:58]2[CH:59]=[CH:60][C:55]([F:54])=[CH:56][CH:57]=2)=[O:63])[CH2:48]1
Reactant: O=C(C[C@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1CCN(C(=O)Nc2ccc(F)cc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 73 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-fluoro-4-isocyanatobenzene as the starting materials in 73% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z=587.0.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[N-:22]=[N+:23]=[N-:24].[Na+].O>CS(C)=O>[N:22]([CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.65 g, 1.587 mmol) and sodium azide (0.114 g, 1.746 mmol) were combined in DMSO (7 mL) and stirred overnight at 25° C. Water was added to the reaction mixture to give a white precipitate. The reaction mixture was stirred for 15 min at room temperature, filtered, washed with water, and air dried to give 3-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.565 g, 1.521 mmol, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (d, J=2.20 Hz, 1H), 7.50-7.63 (m, 2H), 7.31 (d, J=1.74 Hz, 1H), 4.61 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([OH:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[I:12]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CC#N.CN(C=O)C>[I:12][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([OH:9])=[N:5][CH:6]=1
Reactant: Oc1ncccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Oc1ncc(I)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
3-trifluoromethyl-2-pyridinol (25 g, 153.3 mmol) is dissolved in anhydrous CH3CN (150 mL) and DMF (150 mL). N-iodosuccinimide (34.5 g, 153 mmol) is then added. The reaction mixture is stirred at 80° C. for 2 hours and cooled to room temperature. Aqueous 1 M NaHCO3 (150 mL) is then added to the cooled mixture. After stirring for 5 min, the solvents are evaporated to dryness. Water is added and the aqueous phase is extracted (×2) with dichloromethane. The organic phase is then evaporated and the desired product is recrystallized in water to afford 36.2 g (81%) of a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19]2[CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:28](O)=[O:29])=[CH:24][CH:25]=3)[C:20]2=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38])[CH3:33].Cl.CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CC#N.CCOC(C)=O>[CH2:32]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][C:28]([C:23]1[CH:22]=[C:21]2[C:26]([CH2:27][CH:19]([CH2:18][CH2:17][CH:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:16][CH2:15]3)[C:20]2=[O:31])=[CH:25][CH:24]=1)=[O:29])[CH3:33]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc2c(c1)C(=O)C(CCC1CCN(C(=O)OCc3ccccc3)CC1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CCNC(=O)c1ccc2c(c1)C(=O)C(CCC1CCN(C(=O)OCc3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A slurry of 1-4 (0.45 g, 1.2 mmol), β-alanine ethyl ester·HCl (Aldrich) (0.184 g, 1.2 mmol), in CH3CN (2 mL) was treated with N-methylmorpholine (0.4 mL, 3.6 mmol) and BOP reagent (0.8 g, 1.8 mmol) and stirred at room temperature for 24 h. The solution was diluted with EtOAc, washed with H2O, 10% KHSO4 and brine, dried (MgSO4), filtered, concentrated and chromatographed (30% EtOAc/Hexanes) to give 1-5 as a tan solid. Rf (30% EtOAc/Hexanes) 0.22 1H NMR (300 MHz, CDCl3) δ 8.14 (d, 1H), 8.03 (s, 1H), 7.59 (d, 1H), 7.3 (m, 5H), 6.92 (m, 1H), 5.12 (s, 2H), 4.2-4.1 (m, 4H), 3.75 (dd, 2H), 3.4 (m, 1H), 2.92 (dd, 1H), 2.78 (m, 2H), 2.17 (t, 2H), 2.41 (dd, 1H), 2.0 (m, 1H), 1.7 (m, 3H), 1.6- 11 (m, 6H), 1.3 (t, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5](=[O:14])[C:6]([CH3:13])([CH3:12])[CH:7]=[C:8]=[C:9]([CH3:11])[CH3:10])=[CH2:3].CC(CC(=O)C(C)(C)C=C=C)=C>>[C:9](=[C:8]1[CH2:3][C:2]2([CH3:1])[CH:7]1[C:6]([CH3:13])([CH3:12])[C:5](=[O:14])[CH2:4]2)([CH3:11])[CH3:10]
Reactant: C=C(C)CC(=O)C(C)(C)C=C=C(C)C
Agent: C=C=CC(C)(C)C(=O)CC(=C)C
Product: CC(C)=C1CC2(C)CC(=O)C(C)(C)C12

Procedure:
5.00 g (26.0 mmoles) of 3b were distilled through the same column as used for 3a. The reaction was monitored on GC. The main product 4b was separated by distillation on a good column (Fischer Spalt rohr, 60 theoretical plates) with >97% purity. The yield was 2.55 g (51%). Bp. 68° C./0.2 mm Hg.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[O:10][C:9]5[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=5[C:6]=4[N:7]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1ccc2c(c1)oc1c(N3CCOCC3)nc(-c3ccc4[nH]ccc4c3)nc12
Temperature: 90 °C
Yield: 34.2 %

Procedure:
Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 eq) and Indole-5-boronic acid pinacol ester (MW 243) (267 mg, 1.10 mmol, 4.0 eq) in 1,2 dimethoxyethan and 2 M Na2CO3 (3:1) (6 mL) for 5 min. dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (MW 732) (5.05 mg, 0.00690 mmol, 0.025 eq) was added and the reaction mixture was heated to reflux (90° C.) for 15 h, cooled and diluted with EtOAc (20 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc. 32 (% in water)=5:4:1 (9 mL), then NH4Cl (sat.) and brine (2×), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography (gradient from 100% hexane in EtOAc to 70% hexane) gave a colorless solid (35 mg, 34%).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14].C(=O)([O-])O.[Na+]>[N+](C)([O-])=O.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:13]([C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([CH3:9])[CH:11]=2)=[O:14])=[CH:3][CH:2]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: COc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2cccc(C)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
Commercially available anisole (541 mg) and 3-methylbenzoyl chloride (773 mg) were dissolved in nitromethane (5 ml) to prepare a solution. Scandium trifluoromethanesulfonate (49 mg) was added to the solution, and the mixture was stirred at 60° C. overnight. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane-acetone as a solvent to give (4-methoxyphenyl)(3-methylphenyl)methanone (633 mg, yield 56%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C:12](O)=[O:13])[CH2:6][CH2:5]2.B.C1COCC1.O.C([O-])(O)=O.[Na+]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][OH:13])[CH2:6][CH2:5]2
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CCc2cc(I)ccc2O1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, 19.5 mmol, 1.0 eq.) in THF (45 mL) at 10° C. was added dropwise a solution of borane-THF complex (1M in THF, 23.4 mmol, 1.2 eq). The resulting reaction mixture was stirred at 45° C. for 1.5 hours and was then cooled to 10° C. Next, water was added followed by saturated NaHCO3 solution. The resulting two-phase mixture was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated to afford the product as a white solid in quantitative yield that was used without further purification. GC-MS m/z 290 (M+)
Reaction SMILES: N1C=CC=CC=1.[O:7]=[C:8]1[N:13]([CH2:14][C:15]#[CH:16])[C:12]2[CH:17]=[C:18]([N:21]3[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[NH:23][C:22]3=O)[CH:19]=[CH:20][C:11]=2[O:10][CH2:9]1.P(Cl)(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[Cl:35][C:22]1[N:21]([C:18]2[CH:19]=[CH:20][C:11]3[O:10][CH2:9][C:8](=[O:7])[N:13]([CH2:14][C:15]#[CH:16])[C:12]=3[CH:17]=2)[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C#CCN1C(=O)COc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C#CCN1C(=O)COc2ccc(-n3c(Cl)nc(C(F)(F)F)cc3=O)cc21
Temperature: 100 °C

Procedure:
16.61 g of pyridine are added at 25° C. while stirring to a suspension of 25.55 g of 3-[3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (see Example 3) and 32.13 g of phosphorus oxychloride in 250 ml of toluene. The reaction mixture is heated to 100° C. for 6 hours, cooled to 25° C. and poured on to 500 g of ice. Subsequently, the aqueous mixture is extracted three times with 150 ml of ethyl acetate each time and the organic phase is washed neutral with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous product is purified by chromatography on a silica gel column with ethyl acetate/n-hexane (1:3) as the eluent. Finally, the product is recrystallized from diethyl ether/n-hexane. In this manner there is obtained 6-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one, m.p. 143°-145° C. (see Example 78).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[O:18]=[C:19]1[C:27]2([C:31]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=3[O:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:18]=[C:19]1[C:27]2([C:31]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=3[O:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: BrCc1ccccn1
Reactant: N#Cc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: Br
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile was obtained (89%) as a colorless solid: mp 151-153° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=3.9 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.34-6.84 (m, 9H), 5.19 (d, J=15.8 Hz, 1H), 5.07 (d, J=9.2 Hz, 1H), 4.97 (d, J=15.8 Hz, 1H), 4.79 (d, J=9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.3, 160.7, 155.1, 149.7, 142.3, 137.1, 134.8, 131.2, 129.5, 125.8, 124.6, 123.8, 122.9, 121.8, 118.5, 113.8, 113.3, 109.9, 80.21, 77.5, 57.9, 46.1; MS (ES+) m/z 353.9 (M+1).