Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]([Cl:24])[CH3:23])=[O:20]>ClCCl>[C:19](=[O:20])([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[O:21][CH:22]([Cl:24])[CH3:23]
Reactant: CCCCCCCCCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)OC(C)Cl
Reaction time: 8 h

Procedure:
To a stirred solution of decanol (6.0 g, 7.23 mmol) in dichloromethane (150 ml) was added dry pyridine (3.66 ml, 45.6 mmol). The solution was cooled in an ice bath. To this was added 1-chloroethyl chloroformate (6.5 g, 45.6 mmol) dropwise. The reaction mixture was allowed to proceed overnight, diluted with dichloromethane and washed with 0.5N HCl solution, twice with a saturated sodium bicarbonate solution and finally with distilled water. The solvent was dried over magnesium sulphate, filtered through silica and concentrated to dryness.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][Cl:6])[CH3:2].[CH3:8][CH2:9][O-:10].[Na+].[CH2:12]([OH:14])C>>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][C:12]([O:10][CH2:9][CH3:8])=[O:14])[CH3:2].[CH2:1]([O:3][C:4](=[O:7])[CH2:5][Cl:6])[CH3:2]
Reactant: CC[O-]
Reactant: CCO
Agent: [Na+]
Solvent: CCOC(=O)CCl
Product: CCOC(=O)CC(=O)OCC

Procedure:
As in Example 1, but in a pressure vessel with a capacity of 18 liters equipped with a pH measuring system, 3.06 kg (25 moles) of chloroacetic acid ethyl ester, 1 liter of ethanol and 125 g of Co2 (CO)8 are combined at 5 at. CO. At a reaction temperature of 55° C., 7.03 kg of 21.9% sodium ethylate (22.6 moles) is pumped in over a period of 51/2 hours, at a pH of 7.0. 3.43 kg of malonic acid diethyl ester is obtained (yield 95%) plus 290 g of chloroacetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(OCc2ccccc2)cc1
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(OCc2ccccc2)cc1
Yield: 84 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(benzyloxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(benzyloxy)phenyl)propanamide (160 mg, 84%).
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[F:42][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][N:33]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:34][CH2:35]3)[CH:21]3[CH2:22][CH2:23][N:24]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCNCC2)C2CCNCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCN(S(C)(=O)=O)CC2)C2CCN(S(C)(=O)=O)CC2)n1
Yield: 36 %

Procedure:
Reaction of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(1-piperazinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-amine with methanesulfonyl chloride in CH2Cl2 gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{3-[4-(methylsulfonyl)-1-piperazinyl]propyl}-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine in 36% yield; mp (CH2Cl2/MeOH) 246-250° C.; 1H NMR (DMSO-d6) (rotamers) δ 7.94 and 7.89 (2d, J=8.3 Hz, 1H), 7.73 and 7.70 (2t, JHF=53.0, 52.9 Hz, 1H), 7.44 and 7.40 (2t, J=8.4, 8.2 Hz, 1H), 6.97 (dd, J=8.0, 3.3 Hz, 1H), 4.68-4.51 (m, 1H), 3.98 (s, 3H), 3.81-3.69 (m, 10H), 3.59-3.48 (m, 2H), 3.12-3.10 (m, 2H), 3.06-3.02 (m, 2H), 2.94 and 2.92 (2s, 3H), 2.90-2.78 (m, 2H), 2.87 and 2.83 (2s, 3H), 2.55-2.39 (m, 6H), 1.92-1.75 (m, 6H); Anal. Calcd. for C30H44F2N10O6S2.0.25H2O: C, 48.2; H, 6.0; N, 18.7. Found: C, 48.1; H, 6.0; N, 18.7%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]#[N:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:27][OH:28]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]([NH2:18])=[N:27][OH:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1

Procedure:
Benzyl-(2S,4S)-2-cyano-4-fluoropyrrolidine-1-carboxylate dissolved in absolute ethanol was treated with triethyl amine (1.5 eq.) and hydroxylamine hydrochloride (1.3 eq.).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10][OH:11])=[CH2:9])[CH2:2][CH2:3][CH3:4].[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][O:25][C:26]2[CH:34]=[CH:33][C:29]([CH:30]=[N:31][OH:32])=[CH:28][CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>>[CH2:1]([O:5][C:6](=[O:12])[CH2:7][C:8]1([CH:10]=[O:11])[O:32][N:31]=[C:30]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([CH3:13])[CH:23]=3)=[CH:34][CH:33]=2)[CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(CO)CC(=O)OCCCC
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Product: CCCCOC(=O)CC1(C=O)CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 36 %

Procedure:
Following a procedure analogous to that used in step 1c, but using 3-hydroxymethyl-but-3-enoic acid butyl ester from step 3a and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude product was prepared. The product was purified by FCC on silica gel to give {5-formyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-acetic acid butyl ester (0.13 g, 36%) as an oil. MS found: (M+H)+=461.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CO>[C:23]1([NH:29][C:30]([N:14]2[CH2:15][CH:11]([NH:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH2:12][CH2:13]2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=S(=O)(NC1CCNC1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(Nc1ccccc1)N1CCC(NS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2S,4R)-2-[(E and Z)-5-carboxy-1-pentenyl]-4-phenylsulfonylaminopyrrolidine (169 mg), triethylamine (0.070 ml) and phenyl isocyanate (0.060 ml) in methanol (5 ml) was stirred at room temperature overnight and water was added to the solution. The solution was extracted with chloroform and organic phase was washed with brine. After the solution was dried over magnesium sulfate, the solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of chloroform and methanol (40:1) as an eluent to give (2S,4R)-2-[(E and Z)-5-carboxy-1-pentenyl]-1-phenylcarbamoyl-4-phenylsulfonylaminopyrrolidine (51 mg) as an oil.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:25][C:24](=O)[O:23][C:21](=[O:22])[CH2:20]2)=[CH:15][CH:14]=1.Cl.[O:28]1[CH2:33][CH2:32]OCC1>>[ClH:12].[C:33]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:24]([CH2:25][CH:19]([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[CH2:20][C:21]([OH:23])=[O:22])[NH:11][C:6]=2[CH:5]=1)(=[O:28])[C:32]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: C1COCCO1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Product: O=C(O)CC(Cc1nc2ccc(C(=O)c3ccccc3)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
The solution of commercial 4-nitro-1,2-phenylenediamine (0.31 g) and 3-(4-chlorophenyl)glutaric anhydride (0.45 g) in 1,4-dioxane (3 ml) was stirred under reflux for 0.75 h. 4M HCl in 1,4-dioxane (3 ml) was added and the solution is further heated to reflux for 1 h. After cooling to rt the precipitate is collected by suction filtration and washed with 1,4-dioxane and diethyl ether. The crude is recrystallised from acetic acid to give 4-(5-benzoyl-2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid HCl (0.59 g) as beige coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[NH:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH:22]3[CH2:26][N:27]([CH3:29])[CH3:28])[C:18]([Cl:20])=[CH:19][C:13]=2[N:12]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:4][C:3]=1[NH:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH:22]3[CH2:26][N:27]([CH3:29])[CH3:28])[C:18]([Cl:20])=[CH:19][C:13]=2[N:12]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(C)CC1CCCN1c1cc2[nH]c(Nc3cc(CN)ccc3Cl)nc2cc1Cl
Solvent: C1CCOC1
Product: CN(C)CC1CCCN1c1cc2[nH]c(Nc3cc(CNC(=O)C(C)(C)C)ccc3Cl)nc2cc1Cl

Procedure:
The title compound was prepared analogously to example 3 step (e) from 4-chloro-3-[5-chloro-6-(2-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine (30 mg), pivaloyl chloride (10 μL, 0.06 mmol) and TEA (70 μL, 0.54 mmol) in THF (2 mL).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:11])[CH3:10].[C:12]([CH2:16][Si:17](Cl)([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C>[C:12]([CH2:16][Si:17]([O:11][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:10])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(O)c1ccc(F)cc1F
Reactant: CC(C)(C)C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)CC(C)(C)C)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
2′,4′-difluoroacetophenone (5 g, 32 mmol) was reacted with sodium borohydride (1.21 g) in THF (20 mL) and methanol (10 mL) for 1 hr. The resultant mixture was evaporated to dryness and partitioned between methylene chloride and water. The organic layer was separated, dried, and evaporated to give 1-(2′,4′-difluorophenyl)-ethanol as a colorless oil (4.86 g, 96%). 1H NMR (300 MHz, CDCl3) δ 7.48 (m, 1H), 6.85 (m, 1H), 6.75 (m, 1H), 5.15 (q, 1H), 2.0 (s, 1H), 1.5 (d, 3H). 1-(2′,4′-difluorophenyl)-ethanol (5.384 g, 34 mmol), t-butyltrimethylsilyl chloride (6.148 g, 40.8 mmol) and imidazole (5.567 g, 81.8 mmol) in DMF (60 mL) were combined and stirred at rt overnight. The resultant mixture was evaporated to dryness in vacuo, and then the residue was partitioned between methylene chloride and water. The organic layer was separated, dried and evaporated to give 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether as a white solid (6.88 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.45 (q, 1H), 6.75 (m, 1H), 6.62 (m, 1H), 5.05 (q, 1H), 1.32 (d, 3H), 0.88 (s, 9H), 0.05 and 0.01 (each s, each 3H). A 1.6 M solution of n-butyl lithium in hexane (3.75 mL, 6 mmol) was added dropwise to a solution of 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether (1.362 g, 5 mmol) in THF (60 mL) at −50° C. and was stirred at the same temperature for 3 h. The reaction mixture was poured to dry ice; and then was evaporated to dryness. The residue was partitioned between methylene chloride and water, acidified with acetic acid. The organic layer was separated, dried, and evaporated to give 2,6-difluoro-3-(1-t-butyltrimethylsilyloxyethyl)-benzoic acid Compound 5A as white solid (1.57 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.70 (q, 1H), 7.00 (t, 1H), 6.00 (br, 1H), 5.15 (q, 1H), 1.40 (d, 3H), 0.90 (s, 9H), 0.12 and 0.05 (each s, each 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:19])=[CH:18][N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C(=O)N([I:27])C(=O)C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:19])=[C:18]([I:27])[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(-c2nn3cc(C)nc3s2)cc1OC
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(I)c(C)nc3s2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3,4-dimethoxyphenyl)-6-methylimidazo[2,1-b][1,3,4]thiadiazole (0.346 g, 1.257 mmol) was dissolved in DCM (4.2 mL), and NIS (0.283 mg, 1.257 mmol) was added. The reaction mixture was stirred at RT overnight, quenched with sat. aq. thiosulfate and extracted with DCM. The organic layers were combined and washed with sat. aq. NH4Cl, dried (MgSO4), filtered and concentrated. The residue was suspended in Et2O, and the solid was filtered off, washed with Et2O and dried in vacuo affording the desired product (brown solid (0.295 g, 58%). TLC (cyclohexane/EtOAc 1:1) Rf 0.46; HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.53 min, [M+H]+ m/z 402.0; 1H NMR (300 MHz, CDCl3) δ/ppm 7.37 (s, 1H), 7.32 (d, J=8.3, 1H), 6.86 (d, J=8.3, 1H), 3.91 (d, J=14.3, 6H), 2.31 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8]C(=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][C:11]([O:14][CH3:15])([O:16][CH3:17])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(OC)OC
Reactant: CC(=O)N1CCC(=O)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1(OC)CCN(C(C)=O)CC1
Yield: 89.2 %

Procedure:
A solution of 1-acetyl-4-piperidone (17.0 g, 121 mmol), trimethyl orthoformate (26.4 mL, 241 mmol) and para-toluenesulfonic acid monohydrate (80 mg, 0.42 mmol) in dry methanol (34 mL) was refluxed for one hour. Then 1.0 M methanolic NaOMe (0.42 mL, 0.42 mmol) and excess of methanol and trimethyl orthoformate were removed by distillation (atmospheric pressure). Further distillation under reduced pressure afforded 1-acetyl-4,4-dimethoxy-piperidine (20.2 g, 89%) 1H NMR (DMSO) δ 3.45-3.32 (m, 4H), 3.10 (s, 6H), 1.99 (s, 3H), 1.72-1.62 (m, 2H), 1.61-1.52 (m, 2H).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[C:38]([N:42]([CH3:47])[C:43](=O)[CH2:44]Cl)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([N:42]([CH3:47])[CH2:43][CH2:44][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CN(C(=O)CCl)C(C)(C)C
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN(C)C(C)(C)C)cc2)c1
Yield: 145.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and N-tert-butyl-2-chloro-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (15 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(O)=O>C1COCC1.O>[O:30]=[C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)Cc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.8 %

Procedure:
To a cooled solution (−78° C.) of ethyl 2-(pyridin-3-yl)acetate (1.842 mL, 12.11 mmol) in THF (12.2 mL) was added LiHMDS (12.11 mL, 12.11 mmol) and the mixture was stirred 15 min. A solution of benzoyl chloride (1.474 mL, 12.71 mmol) in THF (24.4 mL) was added slowly and the mixture was warmed to room temperature and stirred for 12 h. The reaction was quenched with AcOH (1.386 mL, 24.21 mmol), diluted with H2O (50 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a clear oil (1.82 g). LCMS m/z=270.2 [M+H]+.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][C:16]([CH:20]=O)([CH2:18][OH:19])[CH3:17].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:14][CH2:15][C:16]([CH3:20])([CH3:17])[CH:18]=[O:19])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)(C=O)CO
Reactant: CCCCCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCC(=O)OCC(C)(C)C=O

Procedure:
To a hot (80° C.) solution of lauric acid (70 g., 0.35 mole), and hydroxypivaldehyde (30.6 g., 0.3 mole) in 120 g. of toluene was added 1.75 g. of p-toluenesulfonic acid monohydrate (0.009 mole). The mixture was then heated at total reflux for 1.5 hrs. and water generated in the reaction mixture was removed by azeotropic distillation. The reaction mixture was cooled, washed with saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate, filtered, and evaporated in vacuo. GLC analysis of the product showed that it contained 90% of the desired laurate ester. Fractional distillation of the crude sample gave a product cut, b.p. 180° C./4.0 mm, of 95% purity (GLC, area %). NMR (CDCL3): 9.73 (s, 1H,--CHO), 4.2 (s, 2H, --CO2CH2 --), 2.3 (t, 2H, --CH2CO2 --), 0.9-1.9 (m, 23H, CH2 (CH2)10CH2CO 2 --), and 1.17 (s, 6H, --C(CH2)2.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[CH3:2].Cl[C:18]1[N:23]=[N:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:5]([CH:10]=1)[CH2:4][N:3]([C:18]1[N:23]=[N:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1)[CH2:1][CH3:2]
Reactant: NC(=O)c1ccc(Cl)nn1
Reactant: C=C(C)COc1ccc(Cl)cc1CNCC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(N)=O)nn1
Yield: 58 %

Procedure:
A mixture of N-ethyl-5-chloro-2-(2-methylprop-2-en-1-yloxy)benzylamine (reference example 16) (13.8 g, 50 mM), 6-chloropyridazine-3-carboxamide (7.9 g, 50 mM) and di-isopropylethylamine (20.0 ml, 115 mM) in DMF (50 ml) was stirred at reflux for 16 hours. The mixture was cooled and diluted with water (200 ml) giving an oil which was allowed to settle out (1 hour). The supernatant liquor was decanted and the residual brown gum dissolved in dichloromethane (250 ml) and washed with 2N hydrochloric acid (100 ml). The product was obtained by eluting the organic layer through silica, adjusting the solvent to dichloromethane/isopropanol (19:1) and collecting relevant fractions, which were combined and evaporated to give the title compound as a gum (10.5 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:13]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH2:29])[CH2:24]2)=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2
Reactant: Nc1cc2ccc(Br)cc2nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1cc2ccc(Br)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To a mixture of 3-amino-7-bromoquinoline-2-carboxylic acid (27.4 mg, 0.103 mmol), tert-butyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (31.4 mg, 0.107 mmol) and HATU (78.2 mg, 0.206 mmol), DMF (1.00 mL) was added, followed by DIPEA (83.6 mg, 0.647 mmol). The mixture was stirred at room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in DCM (2.0 mL); then TFA (1.0 mL) was added. The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to give the title compound as a yellow solid (10.1 mg, 22%). LCMS calc. for C20H22BrN6O (M+H)+: m/z=441.1. found 441.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[S:5][CH:6]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[CH:3]=[C:4]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])[S:5][CH:6]=2)[CH:21]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)cs1
Reactant: OB(O)c1cccnc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2cccnc2)cs1

Procedure:
The title compound was prepared by a method analogous to that described in Example 12 from (R)-3′-(4-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-3-boronic acid. The title compound (73 mg) was obtained as a pale solid, m/z 342 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[C:27]1([PH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[Cu]I.C1(C)C=CC=CC=1>[C:23]1([P:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([P:33]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCCC
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: c1ccc(P(c2ccccc2)c2ccc(-c3ccc(P(c4ccccc4)c4ccccc4)cc3)cc2)cc1
Temperature: 25 °C

Procedure:
In a three-necked flask, under a nitrogen atmosphere, there were placed 1.22 g (3 mmol) of 4,4′-diiodobiphenyl (product of Tokyo Kasei Kogyo Co., Ltd.), 0.11 g (0.6 mmol) of copper(I) iodide (product of Wako Pure Chemical Industries, Ltd.) and 3.26 g (12 mmol) of cesium carbonate (Wako Pure Chemical Industries, Ltd.). Next, 50 mL of dehydrated toluene (product of Wako Pure Chemical Industries, Ltd.) and 25 mL (9 mmol) of a hexane solution of diphenylphosphine (diphenylphosphine content: 10 mass %, product of Sterm) were added to the flask, and the mixture was heated to reflux for 24 hours. The reaction mixture was then cooled to room temperature and filtered with Celite. After filtration, the solvent was distilled off under reduced pressure and purified by silica gel column chromatography (silica gel, hexane:dichloromethane=2:1), to obtain 650 mg 4,4′-bis(diphenylphosphino)biphenyl represented by the following formula (1) (1.2 mmol, 42% yield), as a phosphine ligand.