Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]=2[F:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C([O-])([O-])=O.[Cs+].[Cs+]>CC(=O)CC.O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]=2[F:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(CNc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(C)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]phenol (100 mg, 0.30 mmol, 1.0 eq) and Na2CO3 (58 mg, 0.60 mmol, 2.0 eq) in 2-butanone (10 mL) was added ethyl bromoacetate (75.1 mg, 0.45 mmol, 1.5 eq). The mixture was stirred at room temperature for 3 h. TLC showed the reaction to be incomplete so Cs2CO3 (50 mg, 0.15 mmol, 0.5 eq) was added and the reaction stirred a further 3 h. TLC showed the reaction was still not finished so ethyl bromoacetate (0.2 mL) was added and the reaction stirred for a further 1 h. The solution was then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as a solid (100 mg, 81%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[C:9]([Cl:12])[CH:10]=2)[N:5]([C@@H:14]2[O:28][C@H:27]([CH2:29][O:30]C(C3C=CC(C)=CC=3)=O)[C@@H:16]([O:17]C(C3C=CC(C)=CC=3)=O)[CH2:15]2)[C:4]=1Cl)=[O:2].[CH3:41][O-:42].[Na+].CO.C(Cl)(Cl)Cl>CO>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[Cl:13])[N:5]([C@@H:14]1[O:28][C@H:27]([CH2:16][OH:17])[C@@H:29]([OH:30])[CH2:15]1)[C:4]([O:42][CH3:41])=[C:3]2[CH:1]=[O:2]
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3c(Cl)c(C=O)c4cc(Cl)c(Cl)cc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1c(C=O)c2cc(Cl)c(Cl)cc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
3-Formyl-2,5,6-trichloro-1-[3,5-di-O-(p-toluoyl)-2-deoxy-β-D-ribofuranosyl]indole (4.113, 198 mg, 0.33 mmol) was suspended in dry MeOH (10 mL) to which was added sodium methoxide (75 mg, 1.4 mmol). The suspension was stirred at room temperature for 16 h, after which time the solution clarified. The solvent was then removed under vacuum, and the residue was suspended in water (50 mL), and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO4, filtered and evaporated to yield a damp solid. The crude material was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid. The solid was recrystallized from warm MeOH to yield 82 mg (68%) of 4.114 as a white crystalline solid: mp 186-187° C.; Rf0.3 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 6.32 (dd, 1H), 5.37 (b, 1H, D2O exch.), 5.15 (b, 1H, D2O exch.), 4.43 (s, 3H), 4.41 (m, 1H), 3.83 (d, 1H), 3.68 (m, 2H), 2.53 (m, 1H), 2.11 (m, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 183.22, 159.16, 129.40, 125.04, 124.73, 124.66, 121.11, 114.24, 100.02, 87.29, 82.99, 70.07, 64.16, 61.03, 38.43. HRMS (EI) m/z calcd. for C15H15Cl2NO5 359.0327, found 359.0320. Anal calcd for C15H15Cl2NO5.½H2O: C, 48.80; H, 4.37; N, 3.79. Found: C, 48.48; H, 4.61; N, 3.61.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[OH:24][CH:25]([C:27]1[S:31][C:30]([CH:32]=[O:33])=[N:29][CH:28]=1)[CH3:26].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:32]([C:30]2[S:31][C:27]([CH:25]([OH:24])[CH3:26])=[CH:28][N:29]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: CC(O)c1cnc(C=O)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Yield: 81.8 %

Procedure:
A mixture of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.56 g), 5-(1-hydroxyethyl)-1,3-thiazole-2-carbaldehyde (0.30 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg), triethylamine (0.09 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was stirred with heating under reflux for 3 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate, and the fraction was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.66 g, yield 81%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate. MS: 514 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][C:27]([OH:29])=O)[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.CN(C(ON1N=NC2[CH:46]=[CH:47][CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1>O>[N:49]1([C:27](=[O:29])[CH2:26][N:24]2[CH:25]=[C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)[CH:22]=[N:23]2)[CH2:48][CH2:47][CH2:46][CH2:44]1
Reactant: O=C(O)Cn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: O
Product: O=C(Cn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1)N1CCCC1
Reaction time: 0.08 h
Yield: 15.7 %

Procedure:
To a solution of example 155 (0.056 g, 0.145 mmol) in DMF (0.5 ml) N-ethyldiisopropylamine (0.018 g, 0.145 mmol) and HATU (0.055 g, 0.145 mmol) were added and stirred for 5 min. Pyrrolidine (0.020 g, 0.290 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.010 g, 16%). M.P.: 136-138° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.87 (dd, J=2.7 Hz, 1H), 8.52 (d, J=8.7 Hz, 1H), 8.45 (s, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.99 (s, 1H), 7.83 (m, 2H), 7.52 (dd, J=8.3, 4.2 Hz, 1H), 6.11 (s, 2H), 5.11 (s, 2H), 3.52 (t, J=6.7 Hz, 2H), 3.33 (m, 2H), 1.93-1.77 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>ClCCl>[CH2:22]([NH:24][C:25]([NH:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:26])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of 500 mg (1.64 mmol) of the compound from Example 101A in 15 ml of dichloromethane was admixed at 0° C. with 260 μl (3.29 mmol) of ethyl isocyanate. The ice bath was removed and the reaction mixture was stirred for a further 1 h. Then all of the volatile constituents were removed on a rotary evaporator. The residue was purified by preparative HPLC [Method 23]. The product fraction was freed from the solvent on a rotary evaporator. Drying of the residue in an HV gave 546 mg (89% of theory) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].O=[C:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12.C([BH3-])#N.[Na+].[ClH:31]>C(#N)C.C(O)(=O)C>[ClH:31].[CH2:3]([N:2]([CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)[CH3:1])[CH3:4]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=O)=C21
Reactant: CCNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O

Procedure:
Compound No. 26 may also be prepared as follows: 8.5 ml of glacial acetic acid are added to the solution of 8.9 g of N-methyl-ethylamine in 100 ml of acetonitrile, followed by 7.5 g of 1-(2-oxo-propyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one and 1.7 g of sodium cyanoborohydride. The mixture is refluxed overnight, an additional1.7 g of sodium cyanoborohydride is added and refluxing is continued for an additional day. The mixture is cooled, acidified to pH=1 with hydrochloric acid and evaporated. Water is added to the residue, the mixture is washed with diethyl ether, filtered and the aqueous filtrate basified to pH=10-11 with 3 N aqueous sodium hydroxide. It is extracted with chloroform, the extract dried, evaporated and the residue is dissolved in the minimum amount of ethanol. The solution is combined with 2.15 ml of 8 N ethanolic hydrochloric acid, the precipitate collected and recrystallized from ethanol, to yield the 1-[2-(N-ethyl-N-methylamino)-propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one hydrochloride, melting at 256°-257°.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)=[O:12])[S:8][C:4]=2[CH:3]=1.[CH3:25][C:26](OC(C)=O)=[O:27].CCN(CC)CC>C(Cl)Cl>[N:13]1([C:11](=[O:12])[CH2:10][S:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][C:26](=[O:27])[CH3:25])[CH:24]=[CH:23][C:5]=3[N:6]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a 0° C. solution of compound 49 (0.16 g, 0.45 mmol) in dry CH2Cl2 (5 mL) was added Ac2O (0.25 mL, 2.70 mmol) followed by dropwise addition of Et3N (0.25 mL, 1.80 mmol). The reaction was stirred for 2 h under N2. The reaction mixture was diluted with CH2Cl2 (40 mL), washed with saturated NaHCO3 (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (EtOAc/hexanes 3:7) to afford 51 as a white solid (154 mg, 86%); MS m/z: 398 (M+H)+. Anal. Calcd. For, C20H19N3O2S2: C, 60.43; H, 4.82; N, 10.57; S, 16.13. Found: C, 60.54; H, 4.91; N, 10.41; S, 15.87.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([CH2:15][OH:16])[O:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:14]=[C:13]([CH2:15][OH:16])[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2cc(CO)on2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2cc(CO)on2)cc1

Procedure:
[3-(4-nitro-phenyl)-isoxazol-5-yl]-methanol (300 mg, 1.58 mmol) was placed in a 250-ml Parr reactor flask, to which were added 50 ml of ethanol and 10 wt % Pd/C. The mixture was reacted under 40 psi of hydrogen in the Parr reactor for about 1 hour. The completion of the reaction was confirmed by TLC, and then a filtrate by means of a celite placed was distilled under reduced pressure to obtain a yellow solid compound. This was recrystallized from ethyl acetate/hexane (1:2) to obtain [3-(4-amino-phenyl)-isoxazol-5-yl]-methanol in a yellow solid state.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.C(N(CC)C(C)C)(C)C.[C:40]([O:44][C:45](=[O:51])[NH:46][CH:47]1[CH2:50][NH:49][CH2:48]1)([CH3:43])([CH3:42])[CH3:41].O>CN1CCCC1=O>[C:40]([O:44][C:45](=[O:51])[NH:46][CH:47]1[CH2:50][N:49]([C:16]2[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=[C:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])[N:6]=3)[N:15]=2)[CH2:48]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NC1CN(c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc3c2C(C)(C)C(=O)N3)C1
Temperature: 150 °C
Yield: 69 %

Procedure:
150 mg (0.21 mmol, purity approx. 71%) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was dissolved, in a reaction vessel suitable for a microwave, in 1-methyl-2-pyrrolidone (3.1 ml), and 0.22 ml (1.24 mmol) of N,N-diisopropyl ethylamine and 143 mg (0.83 mmol) of tert.-butyl-azetidin-3-ylcarbamate were added. Then the reaction vessel was sealed with a septum and heated for 8 h at 150° C. in the microwave. Then 0.15 ml (0.82 mmol) of N,N-diisopropyl ethylamine and 107 mg (0.62 mmol) of tert.-butyl-azetidin-3-ylcarbamate were added again and the reaction mixture was heated for 3 h at 150° C. in the microwave. After cooling, water was added to the reaction mixture and it was purified by preparative HPLC (acetonitrile:water (+0.1% trifluoroacetic acid) gradient). 81 mg of the title compound was obtained (64% of theor.; purity 91%).
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[CH:5]=[N:6]2.C[Li].Cl[C:18]1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[CH3:18][C:5]1[C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[C:2]2[C:7](=[CH:8][CH:9]=[CH:10][N:1]=2)[N:6]=1
Reactant: c1ccc2c(c1)cnc1cccnc12
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]C
Solvent: C1CCOC1
Product: Cc1nc2cccnc2c2ccccc12
Temperature: -78 °C
Yield: 77.7 %

Procedure:
1.0 g benzo[c][1,5]naphthyridine (5.5 mmol) was dissolved in 30 mL tetrahydrofuran (THF) and then cooled to −78° C. under nitrogen with stirring. 4.4 mL methyl lithium (MeLi) (6.6 mmol, 1.5M) was added and reacted for 1 hr. After quenching the reaction by a saturated ammonium chloride (NH4Cl) solution, extraction by ethyl acetate, drying, and concentration, 30 mL THF and 1.87 g 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (8.2 mmol) were added and reacted for 8 hr. After extraction by ethyl acetate, drying, concentration, and purification by silicon-gel column, 0.83 g light yellow solid was obtained, with a yield of 77%.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O)[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C@@H:23]([CH2:44][C:45]1[N:46]=[CH:47][NH:48][CH:49]=1)[C:24]([NH:26][C@@H:27]([CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C@@H:28]([OH:36])[CH2:29][C@@H:30]([CH:33]([CH3:35])[CH3:34])[CH:31]=[CH2:32])=[O:25].C(N(CC)CC)C.CN(C([O:64]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:13][C:12]([CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH:22][C@@H:23]([CH2:44][C:45]2[N:46]=[CH:47][NH:48][CH:49]=2)[C:24]([NH:26][C@@H:27]([CH2:37][CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[C@@H:28]([OH:36])[CH2:29][C@@H:30]([CH:33]([CH3:34])[CH3:35])[CH:31]=[CH2:32])=[O:25])=[O:11])=[O:64])=[CH:16][CH:17]=1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(CC(Cc1ccccc1)C(=O)O)c1ccc(Cl)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)C(=O)Cc1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
0.17 g (0.56 mmol) of 2-(RS)-benzyl-4-(4-chlorophenyl)-4-oxo-butyric acid was dissolved in 10 ml of dimethylformamide and treated with 0.20 g (0.51 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide, 0.057 g (0.56 mmol) of triethylamine and 0.21 g (0.56 mmol) of HBTU and stirred at room temperature overnight. The mixture was subsequently evaporated in a high vacuum. The residue was dissolved in ethyl acetate and then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying the organic phase over sodium sulfate, the solvent was evaporated under reduced pressure and the residue, for purification, was chromatographed on silica gel using a 95:5 mixture of methylene chloride and methanol which contained 0.5% ammonium hydroxide. There were obtained 270 mg (78%) of (S)-α-[(RS)-α-(4-chlorophenylacetyl)hydrocinnamamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide in the form of a yellowish foam. MS: 675 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:20][Mn](=O)(=O)=O.[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][C:12]([C:13]([OH:20])=[O:14])=[CH:11][C:10]=1[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
4-Benzyloxy-3-ethyl-5-methyl-benzaldehyde (1.4 g, 5.5 mmol) is dissolved in acetone (20 mL) and is slowly added to a cold solution of KMnO4 (1.74 g, 11 mmol) in 20% aq. acetone (25 mL). The reaction mixture is stirred at rt for 3 h, and then acetone is evaporated. The remaining aq. phase is acidified with 10% citric acid (60 mL) and is extracted with DCM (80 mL, 60 mL, 60 mL). The combined org. extracts are washed with brine, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA (5:1 to 2:1) to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid (1.16 g) as an off-white solid; LC-MS: tR=0.56 min*; 1H NMR (CDCl3): δ 1.29 (t, J=7.5 Hz, 3H), 2.39 (s, 3H), 2.75 (q, J=7.5 Hz, 2H), 4.90 (s, 2H), 7.53-7.36 (m, 5H), 7.86 (s, 1H), 7.89 (s, 1H), 12.0 (s br, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOC(=O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
27.8 g (0.2 mol) of n-butyl hydroxyacetate (95% pure by GC) and 20.2 g (0.2 mol) of triethylamine are first introduced into 300 ml of dichloromethane at -5° C. 34.4 g (0.3 mol) of methanesulfonyl chloride in 50 ml of dichloromethane are slowly added dropwise at 0° to 5° C. Stirring of the batch at 0° C. is continued overnight, ice water is added, the phases are separated, and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried, and the solvent is removed on a rotary evaporator leaving a colorless oil which is subjected to incipient distillation in vacuo. n-Butyl methylsulfonyloxyacetate is isolated as an almost colorless oil (40.5 g, 96.3% of theory, GC content 91%).
Reaction SMILES: [OH2:1].C(Cl)Cl.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[O:22]=[C:23]([O-:34])[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Na+]>C(N(CC)CC)C>[CH3:14][C:12]([C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1)([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:13].[C:23]([OH:34])([OH:22])=[O:1]
Reactant: O
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)O
Reaction time: 1 h

Procedure:
To a reactor fitted with a mechanical agitator were charged 5.5 liters of deionized water, 10 liters of methylene chloride, 2280 grams (10 moles) of bisphenol-A, 28 milliliters of triethylamine, 3.4 grams of sodium gluconate, and 0.40 mole of chain terminating agent. Phosgene was introduced at the rate of 18 grams/minute and phosgenation is continued for 60 minutes. The pH was maintained at between 8.0 and 10.0 by the addition of 25% aqueous sodium hydroxide. After phosgenation has ceased 4 liters of methylene chloride were added, the brine layer separated by centrifuge and the resin solution washed with aqueous acid water. The resin was steam precipitated and dried. To this resin product were added minor amounts (about 0.03 parts by weight per hundred parts by weight of resin) of a phosphite and of an epoxy stabilizer. This resin product was then fed to an extruder operating at a temperature of about 500° F. to extrude the resin into strands and the extruded strands chopped into pellets. The pellets were then injection molded at about 570° F. into test samples measuring about 21/2"×1/2"×1/8".
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH3:9].[N:10]1[CH2:11][CH2:12][CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16](=[O:23])[C:15]=12.[Cl-].[NH4+]>BrCCCCOCC.CCOCC.ClCCCl>[OH:23][C:16]1([CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH3:9])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[N:14]2[CH2:13][CH2:12][CH2:11][N:10]=[C:15]12
Reactant: O=C1C2=NCCCN2c2ccccc21
Reactant: CCOCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCOCC
Product: CCOCCCCC1(O)C2=NCCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ether (10 ml) and a few drops 4-bromo-1-ethoxybutane were added to magnesium turnings (1.46 g). After the reaction started, the remainder of the 4-bromo-1-ethoxybutane (total 10.86 g) in ether (50 ml) was added dropwise over 20 minutes. The mixture was stirred under argon at room temperature for 30 minutes, cooled to 0° C. over 30 minutes and 3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.72 g) in dry 1,2-dichloroethane (20 ml) added dropwise over 20 minutes. The solution was stirred under argon at 0° C. for 1 hour, poured onto a swirling mixture of ice (100 ml) and saturated aqueous ammonium chloride (60 ml), and the mixture stirred for a further 20 minutes. The mixture was concentrated in vacuo and the aqueous residue extracted with chloroform (3×100 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. Ether (20 ml) was added and the product was filtered and recrystallised from ethyl acetate to give the title compound as the free base (2.99 g), m.p. 123°-124° C. The free base was acidified with ethereal HCl to give the title compound as the hydrochloride, m.p. 189°-190° C.