Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@H:44]([CH2:51][CH2:52][CH3:53])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1.[OH-].[K+]>C(Cl)Cl.C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:43]([C@H:44]([CH2:51][CH2:52][CH3:53])[CH2:45][N:46]2[CH2:47][CH:48]([OH:50])[CH2:49]2)[CH3:42])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCC[C@H](CN1CC(O)C1)NC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCC[C@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
4-chlorobenzoic acid (0.527 g, 3.37 mmol) and DIPEA (1.176 mL, 6.73 mmol) were mixed in DCM (20 mL) at 0° C. After stirring for 10 min, TBTU (1.103 g, 3.43 mmol) was added to the reaction mixture. The mixture was stirred at 0° C. for 20 min. The above mixture was added in three portions to a solution of (R)-1-(2-(methylamino)pentyl)-azetidin-3-ol (Compound G2.5) (0.58 g, 3.37 mmol) in DCM (20 mL) within 10 min at 0° C. The mixture was stirred at 0° C. for 2.5 h, then warmed to rt and the mixture was stirred overnight. The mixture was concentrated to dryness. To the residue was added aq KOH (30 mL, 15.00 mmol) and methanol (15 mL)/THF (15 mL). The reaction mixture was stirred at rt for 2.5 h. The mixture was concentrated and extracted with DCM (30 mL×2). The DCM layers were combined, evaporated in vacuo to an oil residue. The crude was purified by preparative HPLC to afford the title compound (0.766 g, 73.2%). Mixture of rotamers:
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=1)[O:25][CH2:26][C:27]([O:29]C(C)C)=[O:28])=[O:20])=[CH:14][CH:13]=[CH:12]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C1COCC1>[CH2:3]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=1)[O:25][CH2:26][C:27]([OH:29])=[O:28])=[O:20])=[CH:14][CH:13]=[CH:12]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCc1ccc2c(C(=O)Nc3cccc(OCC(=O)OC(C)C)c3)cccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCc1ccc2c(C(=O)Nc3cccc(OCC(=O)O)c3)cccc2c1
Temperature: 60 °C
Reaction time: 40 h
Yield: 9.1 %

Procedure:
Aqueous 1 N lithium hydroxide (0.5 mL, 0.5 mmol) was added to a solution of isopropyl 2-(3-(6-hexyl-1-naphthamido)phenoxy)acetate (44 mg, 0.98 mmol) in THF (0.5 mL) in a scintillation vial. The vial was sealed and heated at 60° C. After 40 h, the reaction mixture was allowed to cool and the volatiles were evaporated under a stream of nitrogen. The residue was diluted with water (2 mL), acidified with 1 N aqueous HCl (2 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (10 mL), then dried (Na2SO4), filtered and concentrated in vacuo to afford 36 mg (90%) of the title compound.
Reaction SMILES: [C:1]1([O:11][CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13]2)[C:10]2[CH2:9][CH2:8]C[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24]1([OH:34])C2CCCCC=2C=CC=1>>[CH3:24][O:34][C:2]1[C:1]([O:11][C@H:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13]2)=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH2:6][CH2:8][CH2:9]2
Reactant: c1ccc(CN2CCC(Oc3cccc4c3CCCC4)C2)cc1
Reactant: Oc1cccc2c1CCCC2
Product: COc1ccc2c(c1O[C@H]1CCN(Cc3ccccc3)C1)CCC2

Procedure:
3-[(5,6,7,8-Tetrahydro-1-naphthalenyl)oxy]-1-(phenylmethyl)-pyrrolidine, M.S. (C.I.) (M/Z): 308 [M+H]+, starting from 5,6,7,8-tetrahydro-1-naphthol.
Reaction SMILES: [CH2:1](OS(C)(=O)=O)[C:2]#[CH:3].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:3]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:2]#[CH:1]
Reactant: C1COCCN1
Reactant: C#CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 120.3 %

Procedure:
A mixture of methanesulfonic acid prop-2-ynyl ester (3.44 g, 25.7 mmoles), prepared as described in example 136, morpholine (5.4 g) and Na2CO3 (3.3 g, 30.84 mmoles) in ethanol was stirred at room temperature for 6 hours. The solid was filtered off and the solution was concentrated and poured into water. The mixture was acidified with HCl, extracted with ethyl ether, alkalinised with NaHCO3 and extracted with ethyl acetate. The organic phase was anhydrified over Na2SO4 and dried to give 3.87 g of the title compound which was used as such in the subsequent step.
Reaction SMILES: C[CH2:2][O:3]C(C1N(C(OC(C)(C)C)=O)C2=NC=C(OC(=O)C3C=CC=CC=3)C=C2C=1)=O.[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@H:52]([O:54][CH3:55])[CH3:53])=[C:44](Br)[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@H:52]([O:54][CH3:55])[CH3:53])=[C:44]([CH:2]=[O:3])[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CO[C@H](C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Product: CO[C@H](C)c1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 15, intermediate c) from (4R,9aR)-7-bromo-6-(1-(R)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[O:13][CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1>O1CCOCC1>[ClH:1].[NH:17]1[CH2:18][CH2:19][CH:14]([O:13][N:4]2[C:3](=[O:2])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1OC1CCNCC1
Reaction time: 1 h
Yield: 94 %

Procedure:
Hydrogen chloride in 1,4-dioxane (4 M, 7.0 ml) was added to the solution of tert-butyl 4-(1,3-dioxoisoindolin-2-yloxy)piperidine-1-carboxylate (692 mg, 2.00 mmol) in 1,4-dioxane (4 ml) and stirred for 1 hour. The precipitated material was collected, washed with n-hexane (2 ml×2) and dried under reduced pressure at 80° C. to give 2-(piperidin-4-yloxy)isoindoline-1,3-dione hydrochloride (533 mg, 94%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.OS([O-])(=O)=O.[K+]>>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:13])=[O:12]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CNCCN1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: O=C(O)c1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 96.8 %

Procedure:
5-Chloro-2-nitro-benzoic acid (44 g) and piperizine (90 g, 4.8 eq.) were mixed without solvent and heated at 110° C. for 6 hours and then stirred at room temperature over night. At this time, the mixture had solidified. To this solid was added 10% KHSO4 (wt/vol, pH 4 to 5) aqueous solution and the mixture was sonicated. The supernatant was decanted and fresh 10% KHSO4 (wt/vol) aqueous solution was added. A total of 1.8 liters of 10% KHSO4 (wt/vol) aqueous solution was added and decanted in this manner. After stirring at room temperature, the solid was filtered and rinsed with water. The remaining solid was dried in a vacuum oven, leaving a yellow-orange solid (53.1 g). This material was carried forward to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]=[N+:15]=[N-:16])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: COc1cccc(N=[N+]=[N-])c1
Reaction time: 2 h

Procedure:
A solution of 9.26g. (0.08 mole) of 3-methoxyaniline in 40 ml. of water and 20 ml. of concentrated HCl was cooled to 0° C. There was then added a solution of 6.07g. (0.088 mole) of NaNO2 in 20 ml. of water, and the reaction mixture was aged for 1/2 hour. There was next added 70 ml. of hexane followed by dropwise addition of a solution of 5.72g. (0.088 mole) of NaN3 in 20 ml. of water. After addition was complete, the reaction mixture was aged for 2 hours at room temperature. The aqueous and organic components were separated and the aqueous component was extracted with 50 ml. of hexane. The hexane component and extract were dried over MgSO4 and concentrated under reduced pressure to 10.77g. (50.5%) of a yellow oil. Structure of the product as 3-methoxyphenylazide was confirmed by IR.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:29]C(=O)OC(C)(C)C)([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=3)[CH:9]=2)[CH2:4][O:3]1.CO.Cl.O>>[NH2:29][C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:14]=2)[CH:9]=1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(Oc4cccc(C(F)(F)F)c4)ccc3c2)COC(C)(C)OC1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(CO)(CO)c1ccc2cc(Oc3cccc(C(F)(F)F)c3)ccc2c1
Temperature: 50 °C
Yield: 90.2 %

Procedure:
tert-Butyl 2,2-Dimethyl-5-(6-(3-(trifluoromethyl)phenoxy)naphthalen-2-yl)-1,3-dioxan-5-ylcarbamate (35.0 mg, 0.0000676 mol) was dissolved in methanol (2 mL, 0.06 mol), followed by 2 M hydrogen chloride in water (2 mL, 0.004 mol). The reaction mixture was then heated at 50° C. for 3 hours. All solvents were removed to give a pure product (23 mg, 100%). 1H NMR (MeOD) δ: 8.00 (d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.54-7.64 (m, 2H), 7.42-7.48 (m, 2H), 7.24-7.37 (m, 3H), 4.05-4.13 (m, 2H), 3.94-4.03 (m, 2H). MS (M+1): 378.20.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[CH:18]=2)[C:13]([OH:15])=O)=[N:7][CH:8]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:13](=[O:15])[C:12]2[CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[CH:18]=[C:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:11]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cn3)cc(C(=O)O)c2)nc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Oc3ccc(C#N)cn3)cc(Oc3ccc(C#N)cn3)c2)CC1
Yield: 62.5 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoic acid 0.6 g (1.67 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.31 g, 1.67 mmol) were used to afford 0.55 g of the required product. 1HNMR (DMSO-d6): δ 1.42 (9H, s), 3.45 (6H, m), 3.56 (2H, m), 7.20 (2H, d), 7.27 (1H, t), 7.32 (2H, d), 8.37 (2H, dd), 8.70 (2H, d).
Reaction SMILES: FC(F)(F)C(O)=O.Cl.C(O[C:12]([C:14]1[N:15]([NH2:24])[CH:16]=[CH:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:13])C.[CH2:25]([N:27](CC)CC)[CH3:26]>CC#N>[CH2:22]([O:21][C:19]([C:18]1[CH:17]=[CH:16][N:15]2[C:14]=1[C:12](=[O:13])[NH:27][C:25]([CH3:26])=[N:24]2)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1ccn(N)c1C(=O)OCC
Reactant: CCN(CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1ccn2nc(C)[nH]c(=O)c12
Temperature: 85 °C
Yield: 54 %

Procedure:
Trifluoroacetic acid (0.45 ml, 5.85 mmol) was added to a solution of 1-amino-1H-pyrrole-2,3-dicarboxylic acid diethyl ester, hydrochloride salt in CH3CN (20 ml) and heated to 85° C. for 12 h. The reaction mixture was concentrated in vacuo, diluted with CH3CN (20 ml), treated with triethylamine (1.36 ml, 11.9 mmol), and heated to 85° C. for 6 h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and the organic layer washed with 1 N HCl (1×50 ml), saturated NaHCO3 (3×50 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a solid (0.20 g, 54%): 1H NMR (CDCl3) δ 7.27–7.32 (m, 1H), 7.01–7.02 (m, 1H), 4.32–4.38 (m, 2H), 2.41 (s, 3H), 1.90 (br m, 1H), 1.35–1.40 (m, 3H); MS (ESI+) 222 (M++H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.O=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](OCC)=[O:13].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:12]([OH:13])[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8][C:6]=2[N:7]=1
Reactant: Nc1ccc(Cl)nc1N
Reactant: CCOC(=O)C(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Oc1nc2ccc(Cl)nc2nc1-c1ccccc1
Reaction time: 72 h

Procedure:
To a stirred solution of 6-chloropyridine-2,3-diamine(8-1, Oguchi, et. al. J. Med. Chem. (2000), 43, 3052-3066; 15 g, 105 mmol) in DMF (53 mL) was added ethyl oxo(phenyl)acetate (23 mL, 160 mmol) and DIPEA (37 ml, 210 mmol). After 72 hours, the reaction was concentrated to dryness. The resulting material was suspended in ethyl acetate/water and filtered to give 8-2 as a solid. The organic phase was washed with water, NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated. The crude mixture was suspended in DCM (200 mL) and filtered to give another batch of 8-2 as a solid. MS calculated: 257.7; observed: 258.0.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[O:17].F[C:26]1[C:31]([CH:32]2[CH2:38][CH2:37][CH2:36][C:35](=[O:39])[CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][N:27]=1>CN1C(=O)CCC1>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:26]2[C:31]([CH:32]3[CH2:38][CH2:37][CH2:36][C:35](=[O:39])[CH2:34][CH2:33]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: O=C1CCCC(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C1CCCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 140 °C

Procedure:
A mixture of cesium carbonate (0.34 g, 1.03 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.25 g, 1.03 mmol), and 4-(2-fluoropyridin-3-yl)cycloheptanone (0.071 g, 0.343 mmol) in NMP (0.3 mL) under argon was heated to 140° C. for 36 h, then cooled to room temperature. The resulting mixture was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was washed 1N aqueous sodium hydroxide (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The oil was purified by silica gel chromatography to give 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cycloheptanone. MS (ESI, pos. ion) m/z: 426.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[Cl-].[Na+]>CN(C=O)C>[CH3:1][O:21][C:20]([C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([Cl:9])[CH:19]=1)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Cl)nc2ccccc12
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
Potassium carbonate (5.55 g, 40.2 mmol) and methyl iodide (1.88 mL, 30.2 mmol) were added to a DMF (25 mL) solution of commercially available 2-chloro-4-quinolinecarboxylic acid (4.17 g, 20.1 mmol), and the mixture was stirred overnight at room temperature in an argon atmosphere. The reaction solution was added to a saturated aqueous solution of sodium chloride, and the deposited crystal was collected by filtration, washed with water, and dried to obtain the title compound (3.53 g, 15.9 mmol) as a pale yellow solid.
Reaction SMILES: COC[C:4]([N:6](C)[C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1)=O.[OH-].[Na+].Cl>C(O)C.[Cl-].[Na+].O>[CH3:4][NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(N(C)C(=O)COC)c3)cs2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNc1cccc(-c2csc(Cn3cc(C(=O)O)cn3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
To a solution (6 mL) of the compound (500 mg, 1.2 mmol) obtained in Example 46a in ethanol was added 2N aqueous sodium hydroxide solution (2.4 mL, 4.8 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by HPLC and recrystallization (ethyl acetate-hexane) to give the title compound (193 mg, 39%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C(N(C(C)C)C(C)C)C>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cnc2ccccc2c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(Nc2cnc3ccccc3c2)n1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
50 g (0.34 mol) of 2,4-dichloropyrimidine and 50 g (0.35 mol) of 3-amino-quinoline are combined and kept at the boil under reflux for 50 h in 400 ml of 2-propanol with 100 ml of ethyldiisopropylamine. The reaction mixture is poured into 3 l of ice-water, the precipitate is filtered off with suction and washed with water. The residue is recrystallised from acetone, giving 60 g of pale-grey crystals (m.p.: 140-143° C.) (2-chloropyrimidin-4-yl)quinolin-3-ylamine.
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>CCCCCC.[Ti]>[CH3:1][C:2]1([CH3:3])[C:13]2[CH:14]=[CH:15][S:11][C:12]=2[C:6]([CH3:9])([CH3:7])[CH2:5][CH2:4]1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: c1ccsc1
Agent: [Ti]
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2sccc21
Temperature: 40 °C

Procedure:
90 g of 2,5-dimethyl-2,5-dichlorohexane and 195 ml of thiophene are dissolved in 400 ml of hexane. 54 ml of titanium tetrahcloride are slowly added dropwise thereto while cooling with ice, the mixture is warmed to 40° C. for 1.5 hours, again cooled with ice and the dark red mixture is treated cautiously with ice-water. The mixture is extracted three times with ether, the organic phase is washed with saturated sodium bicarbonate solution, dried and evaporated. The thus-obtained black oil is firstly filtered over silica gel (eluting agent hexane) and subsequently distilled in a water-jet vacuum. There are obtained 18.5 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thiophene as a colorless liquid, b.p. 95°-96° C./10 mm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:27]=[CH2:28])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Yield: 29.6 %

Procedure:
A solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.462 mmol), tributyl-vinyl-stannane (198 mg, 0.624 mmol), Pd2(dba)3 (23 mg, 0.005 mmol) and BINAP (6.84 mg, 0.011 mmol) in toluene (20 mL) was heated to reflux overnight. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 30%). 1H NMR (CDCl3): 0.81 (m, 2H), 1.07-1.28 (m, 5H), 1.53 (d, 3H), 1.83-1.97 (m, 4H), 2.22 (m, 3H), 2.83 (m, 1H), 3.55 (m, 2H), 5.09 (m, 1H), 5.21 (m, 1H), 5.58 (m, 1H), 6.63-6.77 (m, 2H), 7.04-28 (m, 13H), 7.43 (m, 2H), 7.68 (m, 1H).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[S:22][C:23]([Cl:26])=[CH:24][CH:25]=1.Cl>O1CCCC1>[Cl:26][C:23]1[S:22][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1cnoc1-c1ccc(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1cnoc1-c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a solution of diethyl malonate (10.1 g) in tetrahydrofuran (60 ml) was gradually added sodium hydride (60%, oil, 2.29 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(5-chloro-2-thienyl)isoxazole (6.70 g) in tetrahydrofuran (60 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was acidified by pouring into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was dissolved in a mixture of 6N hydrochloric acid (80 ml) and acetic acid (120 ml). The mixture was heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate to give a colorless prism (4.95 g, yield 67%) of 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionic acid. melting point: 138–139° C.
Reaction SMILES: O1CCCC1.Br[C:7](Br)([F:9])[F:8].CN(P(N(C)C)N(C)C)C.O=[C:22]([CH3:34])[CH2:23][CH2:24][O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)C>[C:26]([O:25][CH2:24][CH2:23][C:22]([CH3:34])=[C:7]([F:9])[F:8])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: FC(F)(Br)Br
Reactant: CC(=O)CCOC(=O)c1ccccc1
Agent: CN(C)P(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CCOC(=O)c1ccccc1)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
Reaction was carried out under nitrogen atmosphere. To 400 ml of tetrahydrofuran, 46.2 g (0.22 mol) of dibromodifluoromethane was dissolved, followed by drop-wise adding 70.2 g (0.43 mol) of tris (dimethylamino)phosphine at −10° C. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature for 1 hour, and 150 ml tetrahydrofuran solution dissolving with 19.2 g (0.10 mol) of 3-oxobutylbenzoate was further added drop-wise at −20° C. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature overnight. To this mixture, diethyl ether was added, followed by washing with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (diisopropyl ether:hexane=1:8) to obtain 16.4 g (yield: 72%) of 4,4-difluoro-3-methyl-3-butenyl benzoate.