Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]#[CH:10].[CH2:11]([O:13][C:14]([C:16]1[N:17]([CH3:23])[C:18](Br)=[N:19][C:20]=1[CH3:21])=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[N:17]([CH3:23])[C:18]([C:10]#[C:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:19][C:20]=1[CH3:21])=[O:15])[CH3:12]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1c(Cl)cccc1Cl
Product: CCOC(=O)c1c(C)nc(C#Cc2c(Cl)cccc2Cl)n1C

Procedure:
The title compound, MS: m/e=197.4 (M+H+) was prepared in accordance with the general method of example 1b from 1,3-dichloro-2-ethynyl-benzene and 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]12[CH2:15][CH:14]([CH3:16])[CH2:13][C:12](=[O:17])[CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH:18]([O:20][CH2:21][CH3:22])=[CH2:19].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCCCC.C(OCC)C>[CH2:18]([O:20][CH:21]([O:1][C:2]12[CH2:15][CH:14]([CH3:16])[CH2:13][C:12](=[O:17])[CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH3:22])[CH3:19]
Reactant: CC1CC(=O)C2CCCCCCCCC2(O)C1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCCCC
Solvent: CCOCC
Product: CCOC(C)OC12CCCCCCCCC1C(=O)CC(C)C2
Yield: 67.6 %

Procedure:
A mixture of 119 mg (0.5 mmol) of (30) and 384 μl (4 mmol) ethyl vinyl ether was stirred at 25° C. in the presence of 25 mg (0.1 mmol) pyridinium p-toluenesulfonate (PPTS) for 2 hours (94% conversion). Flash chromatography of the reaction mixture, using SiO2 (14 g) and n-pentane/diethyl ether=95:5 as eluent, afforded 105 mg (61%) of (31) as a ˜1:1 mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[OH:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH2:22][CH2:21][CH2:20][OH:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: NCCCO
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Product: OCCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 3-hydroxypropan-1-amine to afford 3-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)propan-1-ol (Preparation Hv). LC-MS (M+H)+=322.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.08 (2H, dd, J=8.55, 5.49 Hz), 6.97 (2H, t, J=8.70 Hz), 5.18 (1H, br. s.), 4.22-4.27 (1H, m), 3.66-3.75 (4H, m), 3.18 (1H, br. s.), 2.60-2.77 (3H, m), 2.02-2.12 (1H, m), 1.78-1.86 (2H, m)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:30])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[C:9]([O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]=2)=[O:4].[C:31]1([Mg]Cl)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[C:9]([O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:8]=2)=[O:4]
Reactant: COC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1(O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenylpropoxy)-1H-indene-2-carbonitrile (350 mg, 0.878 mmol) obtained in Step 1 was dissolved in THF, and phenylmagnesium chloride (0.483 mL, 0.966 mmol) was added thereto, followed by stirring for 3 hrs at 0° C. Upon the completion of the reaction, the mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 378 mg of the titled compound (yield: 90%).
Reaction SMILES: O[C:2]([CH3:26])([CH3:25])[C:3]#[C:4][C:5]1[CH:24]=[CH:23][C:8]2[N:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH2:11][C:12](=[O:14])[NH:13][C:7]=2[CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][C:2](=[CH2:25])[C:3]#[C:4][C:5]1[CH:24]=[CH:23][C:8]2[N:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH2:11][C:12](=[O:14])[NH:13][C:7]=2[CH:6]=1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C#Cc1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2
Yield: 67.6 %

Procedure:
Prepared from 3-[7-(3-hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 134) (50 mg, 0.15 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a sand solid (33 mg).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[Cl:10][C:11]([Cl:17])([Cl:16])[C:12](=[NH:15])OC>>[Cl:10][C:11]([Cl:17])([Cl:16])[C:12]([NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[NH:15]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=N)C(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NNC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A mixture of 2.9 g (0.025 mole) t-butyl carbazate and 10 ml (14.3 g, 0.08 mole) methyl 2,2,2-trichloroacetimidate was stirred 16 hours at room temperature. The solid that was left was washed with petroleum ether and dried to give 6.0 g (86% yield mp 150° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10]O)=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][Cl:14])=[CH:3][CH:2]=1
Reactant: OCCCCc1ccncc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCCCc1ccncc1
Temperature: 25 °C

Procedure:
A solution of 4-(4-pyridinyl)-1-butanol (Mayer J. M. and Testa, B., -Helv. Chim. Acta 65, pages 1868-1884 (1982) (4.20 g, 27.7 mmol) in 30 mL of chloroform is cooled to 0° C. and treated with thionyl chloride (6.60 g, 55.54 mmol) in 30 mL of chloroform. The reaction is allowed to warm to room temperature over 15 hours. The volatiles are removed in vacuo. The residue is cooled to 0° C. and treated with 50 mL of cold 10% sodium hydroxide solution and the mixture is extracted with three 100-mL portions of chloroform. The combined organic extracts are dried over sodium sulfate and the solvents are removed under reduced pressure to give 4.25 g of 4-(4-pyridinyl)-1-butylchloride as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][O:20][CH2:21][C:22](O)=[O:23])=[C:13]([C:26]([O:28]C)=[O:27])[CH:12]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][C:13]=2[C:26]([OH:28])=[O:27])=[O:25])[CH:8]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: Cc1ccc(Br)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 15-(i), 5-bromo-2-methylaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 2-[((2-[(5-bromo-2-methylphenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester (yield: 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17].C(O[C:27](=[NH:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])C.C(O)(=O)C>C(O)C>[NH2:34]/[C:27](/[N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17])[CH2:5][C:4]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:3]=1[O:2][CH3:1])=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: COc1ccc(CNCc2ccc(OC)cc2OC)c(OC)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)/C=C(\N)N(Cc1ccc(OC)cc1OC)Cc1ccc(OC)cc1OC
Yield: 156.7 %

Procedure:
A mixture of bis(2,4-dimethoxybenzyl)amine (8 g), ethyl 3-ethoxy-3-iminopropanoate (8.02 g), acetic acid (1.44 mL) and ethanol (420 mL) was refluxed overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (17 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[O:16][CH2:15][CH2:14][C:11]([C:12]#[N:13])([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCC(C#N)(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
4.6 g of 60% NaH are added in small portions to a solution of 36 g of the above 3,4-dichloro-α-[(2-tetrahydropyranyloxy)ethyl]benzeneacetonitrile (prepared according to PREPARATION II (a)) in 100 ml of dimethylformamide. The reaction mixture is stirred for 3 hours at room temperature and cooled to 0° C. and 22.4 g of ethyl 4-bromobutyrate in 40 ml of dimethylformamide are then added. The reaction mixture is stirred for 3 hours at room temperature, poured into water and extracted with ether and the extract is washed with a saturated solution of NaCl, dried over Na2SO4 and concentrated under vacuum. The residue obtained is purified by chromatography on silica gel using toluene as the eluent to give 24 g of the expected product.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH2:21][CH3:22].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:21]([C:3]1[S:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[C:10]=2[C:2]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1-c1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
Into a 25 ml sealed tube containing a solution of 4-N-[5-bromo-6-ethylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (100 mg, 0.26 mmol, 1.00 equiv) in dioxane (5 mL) was added 2-(tributylstannyl)pyridine (96 mg, 0.26 mmol, 1.00 equiv) and Pd(dppf)Cl2 (30 mg, 0.04 mmol, 0.16 equiv) at room temperature under nitrogen. The sealed tube was heated with stirring overnight at 100° C. The reaction mixture was cooled to room temperature and diluted with 20 mL of H2O, extracted with 3×50 mL of ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 49.0% in 27 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding 4-N-[6-ethyl-5-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (12 mg) as a light yellow oil. MS (ES, m/z): 382 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.75-8.41 (d, 1H), 7.90 (s, 1H), 7.89-7.84 (m, 1H), 7.46-7.38 (m, 2H), 6.73-6.71 (d, 1H), 3.95-3.89 (m, 1H), 2.89-2.81 (dd, 2, H), 2.29 (s, 6H), 2.25-2.04 (m, 3H), 1.90-1.86 (m, 2 H), 1.47-1.38 (m, 2H), 1.32-1.27 (m, 3H), 1.05-1.92 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][NH2:6])#[N:2].[Cl:30][CH2:31][CH2:32][CH2:33][S:34](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:36])=[O:35]>>[Cl:30][CH2:31][CH2:32][CH2:33][S:34]([NH:6][CH2:5][CH:4]([CH2:3][C:1]#[N:2])[CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:36])=[O:35]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)CC#N
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)CNS(=O)(=O)CCCCl

Procedure:
The crude 2-cyanomethyl-3-n-octadecylcarbamoyloxypropylamine IVn2 which was prepared above is allowed to react by the same procedure as described in (4). The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: Cl.[C:2]([NH2:6])(=[NH:5])[CH2:3][CH3:4].Cl[C:8](=[CH2:11])[C:9]#[N:10]>>[CH2:3]([C:2]1[N:6]=[C:9]([NH2:10])[CH:8]=[CH:11][N:5]=1)[CH3:4]
Reactant: C=C(Cl)C#N
Reactant: CCC(=N)N
Agent: Cl
Product: CCc1nccc(N)n1

Procedure:
This intermediate was made according to example 2, step A] via the alternative preparation method from propionamidine hydrochloride (1.45 g, obtained from propionitrile in analogy to Synth. Commun. 12 (13), 1982, 989-993 and Tetrahedron Lett. 31 (14), 1990, 1969-1972) and 2-chloro-acrylonitrile (1.17 mL). 2-Ethyl-pyrimidin-4-ylamine was obtained as a light brown solid (0.89 g): 1H NMR (δ, DMSO-d6): 7.96 (d, 1H), 6.68 (br s, 2H), 6.21 (s, 1H), 2.55 (q, 2H, 1.18 (t, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>O1CCOCC1>[NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:10](=[O:11])[C:9]3[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]2=[O:12])=[N:2]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc[nH]n1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Temperature: 25 °C

Procedure:
A mixture of 1H-pyrazol-3-amine (12 g, 144 mmol, Fluka Chemie AG) and phthalic anhydride (21.39 g, 144 mmol, Fluka Chemie AG) in 1,4-dioxane (200 ml) was heated at reflux for five days and allowed to cool to room temperature. The solid was filtered and washed with ether to give the title compound as an off white solid (22.44 g); LCMS: (System 3) MH+=214, tRET=0.67 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl:16]N1C(=O)CCC1=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[C:11]([Cl:16])[C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O)c(Cl)cc21
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a mixture of methyl((3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (10 g) in THF (dry) (192 mL) was added N-chlorosuccinimide (6.41 g) portionwise at 0° C. The mixture was stirred at room temperature over weekend. The mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (10.12 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:23]1[CH:24]=[CH:25][C:20]([CH:18]=[CH:19][C:2]2[CH:3]=[C:4]3[CH2:10][C@:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)=[CH:21][CH:22]=1
Reactant: C=Cc1ccncc1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C(=Cc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2)c1ccncc1
Temperature: 102.5 °C
Yield: 72 %

Procedure:
(R)-(-)-5'-Bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (295 mg, 1 mmol),4-vinylpyridine (0.135 mL, 1.25 mmol), palladium(II)acetate (7.2 mg,0.032 mmol), tri-o-tolylphosphine (38.7 mg, 0.127 mmol), and triethylamine (0.5 mL, 3.6 mmol) in anhydrous acetonitrile (0.5 mL) were combined in a heavy-walled threaded glass tube containing a magnetic stir bar, purged with argon and sealed with a Teflon plug and FETFE O-ring. The mixture was stirred and heated at 100 to 105° C. for 48 hours, cooled to room temperature, dissolved in chloroform (25 mL), washed with saturated aqueous sodium carbonate (2 mL), dried (MgSO4), and evaporated under reduced pressure. Purification by flash chromatography through silica gel (eluting with ammoniated chloroform/methanol, 95:5), followed by recrystallization from acetone afforded the title compound (230 mg, 0.72 mmol, 72%): electrospray MS (m/z, relative intensity) 320 ([MH]+, 100).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[N:13]([CH3:17])[C:12]3=[CH:18][C:19]([C:21]([NH2:23])=O)=[N:20][N:11]3[C:10](=[O:24])[C:9]=2[CH:8]=1>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[N:13]([CH3:17])[C:12]3=[CH:18][C:19]([C:21]#[N:23])=[N:20][N:11]3[C:10](=[O:24])[C:9]=2[CH:8]=1
Reactant: COc1ccc2c(c1)c(=O)n1nc(C(N)=O)cc1n2C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(=O)n1nc(C#N)cc1n2C
Temperature: 50 °C

Procedure:
Thionyl chloride (1.5 ml) is added slowly, with stirring to 50 ml of dimethylformamide at 0° C. To this solution is added 2.9 g of 4,9-dihydro-7-methoxy-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide and the mixture is stirred and heated at 50° C. for 18 hrs, then evaporated at reduced pressure. The residue is stirred with 600 ml of ice water and the resulting solid 4,9-dihydro-7-methoxy-4-methyl-9-oxo-pyrazolo-[5,1-b]quinazoline-2-carbonitrile is collected by filtration, washed with water and dried; mp 316°-320° C. after crystallization from dimethylformamide/ethanol.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21]Cl.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[Cl:18][C:12]1[CH:11]=[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:15]=[C:14]([CH3:16])[C:13]=1[O:17][CH2:19][O:20][CH3:21]
Reactant: COCCl
Reactant: Cc1cc(OC(=O)c2ccccc2)cc(Cl)c1O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(C)cc(OC(=O)c2ccccc2)cc1Cl
Temperature: 0 °C
Yield: 93.9 %

Procedure:
Then, 25 g of 4-benzoyloxy-2-chloro-6-methylphenol was dissolved in 250 ml of chloroform, to which 12 g of chloromethyl methyl ether was added, while stirring at 0° C., and 21 g of N-ethyldiisopropylamine was added dropwise. After heating under reflux for 1 hour, the chloroform layer was washed with water, and concentrated. The residue was subjected to silica gel chromatography, which afforded 27.4 g of 3-chloro-4-methoxymethoxy-5-methyl-1-benzoyloxybenzene (96% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:19])=[CH:13][CH:14]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2cccc(F)c2)cc1

Procedure:
Compound (104) was prepared from compound (20) and (3-fluoro-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.83 mins, m/z (ES−)=325 (M−H for C19H15FO4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=3)[C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:16])([F:17])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:42])[F:43])[CH:36]=3)[C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCNC(=O)C(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)CCNC(=O)C(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
78 mg (0.12 mmol) of the compound of Example 13 were dissolved in 2.3 ml of methanol, and 360 μl of a 1M aqueous lithium hydroxide solution (0.36 mmol) were added. The mixture was stirred at RT for 1 h and then adjusted to pH 2 by addition of 1N hydrochloric acid, diluted with a little DMSO and separated by preparative HPLC [Method 6]. This gave 67 mg (88% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].IC1C=C(C2O[CH2:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)C=CC=1>>[F:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[O:5][CH2:21][C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1
Reactant: Ic1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Reactant: O=C(Cl)c1cccc(I)c1F
Product: Fc1c(I)cccc1C1=N[C@H](c2ccccc2)CO1

Procedure:
4,5-Dihydro-2-(2-fluoro-3-iodophenyl)-4(R)-phenyloxazole was prepared from 2-fluoro-3-iodobenzoyl chloride in a similar manner to that of (+)-4,5-dihydro-2-(3-iodophenyl)-4(R)-phenyloxazole as described in Example 1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCc1ccc(OC)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CCC(=O)O)cc1OC1CCCC1
Reaction time: 16 h

Procedure:
To a stirring solution of 0.38 g (1.37 mmol) of methyl 3-(3-cyclopentoxy-4-methoxyphenyl)-n-propanoate in 20 mL of methanol was added dropwise 25 mL of a 1.0N solution of potassium hydroxide in water over a 5 minute period. The mixture precipitated immediately, but returned to a solution after a 16 hour period at which time the solution was concentrated, diluted with 20 mL of water and neutralized to pH 1.0 with concentrated hydrochloric acid. The analytically pure white solid which formed was collected, washed several times with cold water, and dried in vacuo.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18][C:19]([C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[CH:26][NH:27]4)=[CH:23][CH:22]=3)=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18][C:19]([C:21]3[CH:29]=[C:28]4[C:24]([CH2:25][CH2:26][NH:27]4)=[CH:23][CH:22]=3)=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3cc[nH]c3c2)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3c(c2)NCC3)cc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirring solution of N2-(4-t-butylbenzoyl)-N1-(6-indolylcarbonyl)-1,2-benzenediamine (0.1 g, 0.24 mmol) in acetic acid (1 mL) was added NaBH3CN (0.046 g, 0.73 mmol). After 2 h, the mixture was diluted with water (10 mL), the pH was basified with conc aq NaHCO3 and the aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate phase was washed with water and brine, then dried with MgSO4, filtered and concentrated in vacuo to give 70 mg (70%) of white solid.