Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][O:68][C:69]1[CH:74]=[CH:73][C:72]([CH:75]=O)=[CH:71][CH:70]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:75]([C:72]3[CH:73]=[CH:74][C:69]([O:68][CH3:67])=[CH:70][CH:71]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cncnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cncnc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 52 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyrimidin-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.083 mmol, 12 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (19 mg, 52%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.64 (s, br, 4H, piperazine N(CH2)2), 3.64 (s, 2H, NCH2), 3.66 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.09 (d, J=8.9 Hz, 2H, methoxyphenyl H-2 & H-6), 8.13 (d, J=8.9 Hz, 2H, methoxyphenyl H-3 & H-5), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.80 (s, 2H, pyrimidine H-4 & H-6), 9.12 (s, 1H, pyrimidine H-2), 13.35 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[H][H].O>CO.[Pt]>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1cccnc1-c1ccccc1
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: O
Product: N[C@H]1CCCN[C@H]1c1ccccc1
Yield: 87.3 %

Procedure:
In a bottle were placed 2.65 g (15.6 mmol) of 3-amino-2-phenylpyridine, 10.6 g of 5% platinum/carbon and 106 mL of 1.5 M HCl in methanol. The mixture was shaken under an atmosphere (ca. 40 p.s.i.) of hydrogen for 2.5 hours. Water was added to the system, the mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ca. 700 mL of water. The filtrate was made basic with solid sodium hydroxide and extracted with two portions of dichloromethane. The combined organic fractions were washed with water, dried (sodium sulfate) and concentrated with a rotary evaporator to obtain 2.4 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH:8]=[C:7]([CH2:10][O:11]C(C)=O)[CH2:6][CH2:5]1)=[CH2:3].[OH-].[Na+]>>[CH3:3][C:2]([C@@H:4]1[CH2:5][CH:6]=[C:7]([CH2:10][OH:11])[CH2:8][CH2:9]1)=[CH2:1]
Reactant: C=C(C)C1CC=C(COC(C)=O)CC1
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)[C@@H]1CC=C(CO)CC1
Reaction time: 4 h
Yield: 97.7 %

Procedure:
Perillyl acetate (196 g.) derived from either of the examples mentioned and 30% aqueous sodium hydroxide (60 g.) were refluxed gently with stirring for 4 hours. The oil layer was separated and distilled under reduced pressure to give perillyl alcohol (150 g.) b.P. 80°/0.7 mm., αD20 + 102.5.
Reaction SMILES: CI.[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:18])[C:15]([OH:17])=[O:16])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:19]([O-])(O)=O.[Na+].O>CN(C=O)C>[CH3:19][O:16][C:15](=[O:17])[CH:14]([OH:18])[CH2:13][CH2:12][CH2:11][NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCCC(O)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(O)CCCNC(=O)OC(C)(C)C
Yield: 42.4 %

Procedure:
A solution of methyl iodide (11.5 mL, 0.189 mol) in DMF (50 mL) was added dropwise during 15 min. to a mixture of 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid (22.0 g, 94.4 mmol) and NaHCO3 (11.8 g, 141 mmol) in DMF (150 mL). After stirring over night, water was added and the mixture was extracted with ethyl acetate. The pooled organic phases were washed with water and brine, dried and concentrated under reduced pressure. The crude product was purified using chromatography (heptane/ethyl acetate, 1:1) to give 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid methyl ester 9.9 g, 42.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24])=[CH:15]2.[OH-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:15]2
Reactant: CCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 720.9 %

Procedure:
To a solution of methyl 2-({5-[3-(2-pyridylamino)propoxy]indolyl }methyl)pentanoate (0.015 g, 0.004 mmol), as prepared in the preceding step, in methanol (2.0 mL) was added a solution of NaOH (0.1 g, 2.5 mmol) in H2O (0.3 mL), and the reaction was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue is taken up in H2O (5 mL) and acidified to pH 4–5 with 10% HCl, and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (4% methanol in methylene chloride) to give the title compound as an oil (0.011 g, 85%). 1H-NMR (400 MHz, CDCl3) δ 8.28 (br s, 1H), 7.72 (d, J=4.5 Hz, 1H), 7.49 (m, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.06 (d, J=3.0 Hz, 1H), 6.99 (d, J=2.3 Hz, 1H), 6.78 (dd, J=8.9, 2.4 Hz, 1H), 6.5 (m, 2H), 6.27 (d, J=2.8 Hz, 1H), 4.25 (dd, J=14.1, 8.4 Hz, 1H), 3.97 (m, 3H), 3.33 (t, J=6.6 Hz, 2H), 2.87 (br s, 1H), 1.96 (m, 2H), 1.67 (m, 1H), 1.45 (m, 3H), 0.90 (t, J=6.8 Hz, 3H). Mass spectrum (LCMS, ESI pos.) Calcd. for C22H27N3O3 382.5 (M+H); Found: 382.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[O:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: OCCCCCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCCl
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a stirred solution of 6-chloro-1-hexanol (8.1 g, 60 mmol), triethylamine (9.2 g, 12.7 mL, 90 mmol), and DMAP (750 mg, 0.1 equiv., 6.1 mmol) in methylene chloride (100 mL) was added tert-butyldimethylchlorosilane (10.85 g, 1.2 equiv, 72 mmol). The reaction was allowed to proceed overnight under a nitrogen atmosphere. TLC analysis in ethyl acetate indicated complete disappearance of staring alcohol (Rf =0.43) and the appearance of a new spot (Rf =0.67). The organic solution was washed with water (2×30 mL) and saturated ammonium chloride solution (1×25 mL) and dried over MgSO4. Solvents were removed by rotary evaporation and the residue distilled to afford the title compound (12.03 g, 80%) as a colorless liquid: bp 70° C./0.1 Torr; 1H NMR (200 MHz, CDCl3) δ 3.58 (2 H, t, (J=6.26 Hz), 3.50 (2 H, t, (J=6.70 Hz), 1.86-1.69 (2 H), 1.60-1.28 (6 H), 0.86 (9 H, s), 0.02 (6 H, s); mass spectrum m/z (M+) calcd for C12H27CIOSi 250.1520, found 250.1396.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:26])=[C:6]([CH:25]=1)[C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:13]=2[CH:24]=1)=O.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>ClCCCl.CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:26])=[C:6]([CH:25]=1)[CH2:7][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[C:13]=2[CH:24]=1
Reactant: O=C(c1ccc2c(c1)N(C(=O)C(F)(F)F)CCO2)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCCl
Solvent: CC#N
Solvent: CCOCC
Product: O=C(N1CCOc2ccc(Cc3cc(Br)ccc3Cl)cc21)C(F)(F)F
Temperature: 50 °C
Yield: 61.9 %

Procedure:
To a stirred solution of 1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (1.0 g, 2.23 mmol) in 1:2 of 1,2-dichloroethane/MeCN (12 mL) was added Et3SiH (0.755 mL, 4.68 mmol) and BF3.OEt2 (0.34 mL, 2.90 mmol) simultaneously at 20° C. The reaction mixture was heated at 50° C. for 4 h and quenched by the addition of aq. NaHCO3 (10 mL). The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with dichloromethane (2×20 mL), washed with brine (5 mL), dried over sodium sulfate, concentrated and was purified by silica gel column chromatography to furnish 1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (0.60 g).
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6].C(=O)([O-])[O-].[K+].[K+].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>CC(C)=O>[C:20]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([O:16][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6])=[CH:22][CH:21]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: C=CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(C)(C)C(=O)COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
196.5 g (1.34 mol) of 5-chloro-3,3-dimethylpent-1-en-4-one were added dropwise to a mixture of 184.9 g (1.34 mol) of potassium carbonate and 227.8 g (1.34 mol) of 4-hydroxybiphenyl in 1,000 ml of boiling acetone, in the course of one hour. The mixture was heated to the boil after 5 hours, allowed to cool to room temperature, and filtered off from the precipitated potassium chloride. The oil which remained after the filtrate had been concentrated was taken up in 1,000 ml of ethyl acetate. The solution was washed twice with 150 ml each of 10% strength sodium carbonate solution and water, and dried over anhydrous sodium sulphate, and the solvent was distilled off. Residual amounts of solvent were stripped off at 0.13 mbar (bath temperature: 180° C.). 357.2 (95% of theory) of 5-(biphenyl-4-yloxy)-3,3-dimethylpent-1-en-4-one of melting point 42° to 44° C. were obtained in this manner.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([OH:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([C:37]3[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][C:29]([OH:31])=[O:30])=[CH:35][CH:36]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1cccc2c(-c3cccc(Br)c3)c(Cc3ccccc3)cnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)CCc1ccc(-c2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Yield: 67 %

Procedure:
To a solution of 3-benzyl-4-(3-bromophenyl)-8-(trifluoromethyl)quinoline (0.30 g, 0.7 mmol), 4-(2-carboxyethyl) benzene boronic acid (0.15 g, 0.75 mmol) in 15 ml DME under a nitrogen atmosphere is added terakistriphenyl phosphine palladium (0.08 g, 0.07 mmol) followed by sodium carbonate (0.22 g, 2.04 mmol) dissolved in 5 ml water. The reaction mixture was heated to reflux for 12 hr. The reaction was cooled, poured into 1N HCl and extracted with EtOAc. The organic layer was dried and concentrated to provide the title compound as a tan solid (0.24 g, 70%): MS (ES) m/z 509.9; HRMS: calcd for C32H24F3NO2+H+, 512.18319; found (ESI, [M+H]+), 512.1842;
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5]([CH2:14][CH3:15])(CC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(=O)([O-])[O-].[CH3:22][C:23]1[N:24]=C(C=O)[S:26][CH:27]=1>COCCOC.C(OCC)(=O)C>[CH3:22][C:23]1[N:24]=[C:15]([CH:14]=[CH:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:26][CH:27]=1
Reactant: Cc1csc(C=O)n1
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccccc1
Agent: O=[PH]([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1csc(C=Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 15.9 %

Procedure:
Sodium hydride (102 mg of a 60% suspension in mineral oil, 4.3 mmol) was slurried in dry 1,2-dimethoxyethane (DME) under argon, cooled to 0° C. in an ice bath, and diethylbenzyl phosphonate (0.89 mL, 4.3 mmol) was added dropwise to the suspension. Thirty minutes after the completion of the phosphonate addition, 4-methylthiazole-2-carboxaldehyde (120 mg, 0.94 mmol) was added as a solution in DME (5 mL). After stirring for 4 h, further NaH (40 mg of a 60% suspension in mineral oil, 1.0 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stir for 16 h. The reaction mixture was quenched by the addition of water (20 mL) and ethyl acetate (50 mL). The aqueous phase was extracted with ethyl acetate (2×30 mL), the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 90:10 hexane:ethyl acetate to afford 4-methyl-2-[2-phenylethenyl]-1,3-thiazole (30 mg, 16% yield) as an oil. 1H NMR analysis showed the material to be a 10:1 mixture of E and Z isomers (spectral data are reported for the major isomer). 1H NMR (CDCl3,300 MHz) δ: 7.54-7.51 (m, 2H) 7.42-7.23 (m, 5H) 6.80 (s, 1H) 2.47 (s, 3H). MS (ESI) (minor isomer) 202.2 (M++H), (major isomer) 201.6 (M+).
Reaction SMILES: [CH2:1]([C@@:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)[CH2:8][N:7]([CH3:9])[C@H:6]2[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:5]2[O:4]1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].CCOCC>C1(C)C=CC=CC=1>[CH2:1]([C@@:3]1([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[CH2:8][N:7]([CH3:9])[C@H:6]2[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:5]2[O:4]1)[CH3:2]
Reactant: CC[C@@]1(c2cccc(OC)c2)CN(C)[C@H]2CCCC[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC[C@@]1(c2cccc(O)c2)CN(C)[C@H]2CCCC[C@@H]2O1
Reaction time: 1 h

Procedure:
(2R*,4aS*,8aS*)-2-Ethyl-2-(3-methoxyphenyl)-4-methyloctahydro-2H-1,4-benzoxazine (0.5 g) in dry toluene (5 cm3) was added under nitrogen to di-isobutylaluminium hydride (20% in toluene, 1.2 M, 15 cm3) at room temperature. The mixture was then heated to reflux under nitrogen for 51/2 hr. The mixture was cooled in ice to 0° and treated cautiously with saturated Rochelle salt solution (75 cm3) and the mixture was stirred for 1 hr. Ether (30 cm3) was added and the phases were separated. The aqueous phase was then treated with an equal volume of saturated ammonium chloride solution and was extracted with further ether. The combined organic phases were dried (Na2SO4) and evaporated, leaving impure title compound base as a cloudy oil which crystallised to a pale yellow mass (0.45 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=O.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]2[C:8](=[O:10])[CH2:7][CH2:6][C:2]1=2
Reactant: O=C(O)CCc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CCc2sccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-thiophene-2-yl-propionic acid (Intermediate AC) (1.75 g, 0.01122 mol) in dichloromethane (50 mL) was added SOCl2 (1.67 mL, 0.02244 mol) and stirred at room temperature for 6 h. This solution was added dropwise to a suspension of AlCl3 (2.98 g, 0.02244 mol) in dichloromethane (50 mL) over 45 minutes. The resulting mixture was stirred at room temperature for 12 h. The system was quenched by dropwise addition of water (10 mL) and extracted with dichloromethane. The organics were dried with MgSO4 and the solvent was removed in vacuo. The title compound was purified by silica gel column chromatography using 4:1 Hexanes:ethyl acetate as the eluent. MS m/z 139.1 (M+H)+;
Reaction SMILES: [CH2:1]([C@@H:3]1[C@@H:5]([CH:6]=[O:7])[N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].[C-]#N.[Na+].[CH3:18][OH:19]>O=[Mn]=O>[CH2:1]([C@H:3]1[N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:5]1[C:6]([O:19][CH3:18])=[O:7])[CH3:2]
Reactant: CO
Reactant: CC[C@@H]1[C@@H](C=O)N1C(=O)OC(C)(C)C
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Product: CC[C@@H]1[C@@H](C(=O)OC)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The following step was run duplicate. To a 250 mL round-bottom flask equipped with a stir bar was added (2R,3S)-tert-butyl 2-ethyl-3-formylaziridine-1-carboxylate (one-half of the material isolated in step 1, assumed 20 mmol) as a solution in MeOH (100 ml). The solution was cooled to 0° C. To the solution was added sodium cyanide (1.96 g, 40.0 mmol). The solution was stirred for 10 minutes. To the solution was added oxidation-grade MnO2 (34.8 g, 400 mmol). The mixture was stirred for 10 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature with stirring for 18 hours. The reaction mixture was filtered through a pad Celite and the filter cake was extracted with EtOAc (100 mL). The filtrate was concentrated in vacuo and the resulting orange solid residue was dissolved in water (100 mL) and EtOAc (100 mL) and transfered to a 1 L separatory funnel where the mixture was further diluted with saturated aq. NaCl (“brine”, 100 mL) and EtOAc (100 mL). The mixture was shaken and the phases were separated. The aq. phase was extracted with EtOAc (100 mL). The combined organics were washed with brine (100 mL); dried over MgSO4; filtered; then concentrated in vacuo. The resulting residue was combined with the duplicate run and the combined material was subjected to silica gel chromatography (hexanes:EtOAc, 50:50 to 0:100) to afford (2S,3R)-1-tert-butyl 2-methyl 3-ethylaziridine-1,2-dicarboxylate as a yellow liquid (3.055 g, 33% over two steps).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([I:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.Cl[C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Cl:12][C:10]1[C:9]([I:13])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:11]=1
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Reactant: CCOC(=O)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1cc(Cl)c(I)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (8 g, 25.7 mmol) and pyridine (2.18 mL, 27 mmol) in dichloromethane (200 mL) was added ethyl 3-chloro-3-oxopropanoate (Aldrich, 3.45 mL, 27 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness, diluted with ethyl acetate, washed successively with water and brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in pentane, filtered and dried to give the title compound methyl 4-chloro-2-{[3-(ethyloxy)-3-oxopropanoyl]amino}-5-iodobenzoate (8.24 g, 19.36 mmol, 75% yield) as beige solid. LCMS: (M+H)+=426; Rt=3.78 min.
Reaction SMILES: [C:1]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:40]([O:47][C:48](=[O:65])[C@H:49]([CH3:64])[NH:50][C:51](=[O:63])[C@H:52]([CH3:62])[N:53]([C:55](=[O:61])[C@H:56]([CH:58]([CH3:60])[CH3:59])[NH2:57])[CH3:54])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[CH2:40]([O:47][C:48](=[O:65])[C@H:49]([CH3:64])[NH:50][C:51](=[O:63])[C@H:52]([CH3:62])[N:53]([C:55](=[O:61])[C@H:56]([CH:58]([CH3:60])[CH3:59])[NH:57][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:17])[CH3:54])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](N)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@H](C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 13.17 g (0.0537 mole) of Boc-N-methyl-L-leucine in 370 ml of dry dichloromethane was stirred and cooled at 0° C. as one-half of 13.15 g. (0.130 mole) of dry triethylamine was added, followed by 15.05 g (0.0591 mole) of BOP-Cl. This was stirred at 0° C. for 3 hours. The remainder of the triethylamine was added, followed by a solution of 13 g (0.0358 mole) of L-valyl-N-methyl-L-alanyl-L-alanine benzyl ester in 50 ml of dry dichloromethane. The reaction was stirred at ice temperature for 22 hours, then washed with 125 ml of a 10% solution of potassium bisulfate. The organic layer was further washed with 2×100 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, concentrated to a small volume, and chromatographed on silica gel eluting with 1:1 ether/hexane gradually increasing the ether to 2:1. The product weighed 15.8 g (75% of theory), and the FAB m.s. showed a molecular ion peak at 591.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[Cl:20][C:21]1[CH:45]=[CH:44][CH:43]=[CH:42][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)=[CH:26][N:25]=1>COCCOC>[Cl:20][C:21]1[CH:45]=[CH:44][CH:43]=[CH:42][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)=[CH:11][C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])=[CH:26][N:25]=1
Reactant: COc1ccc(C(=O)c2ccc(Oc3ccccc3Cl)nc2)cc1OC
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Oc3ccccc3Cl)nc2)cc1OC
Yield: 31.7 %

Procedure:
In 1,2-dimethoxyethane (10 ml) was suspended 60% sodium hydride (dispersion in paraffin) (132 mg). To the suspension was added dropwise, while stirring, a solution of diethylphosphonoacetic acid morpholide (688 mg) in 1,2-dimethoxyethane (5 ml). To the mixture was added 2-(2-chlorophenoxy)-5-(3,4-dimethoxybenzoyl)pyridine (800 mg), which was heated for 8 hours under reflux. The reaction mixture was concentrated and the residue was dissolved in ether, washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off to leave an oily substance, which was purified by means of a silica gel chromatography (eluted with ethyl acetate) to obtain 4-[3-(2-(2-chlorophenoxy)-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine (Compound No.1) (330 mg) as a resinous solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[N:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22][CH:21]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:24]3[CH:25]=[N:20][CH:21]=[N:22][CH:23]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1cncnc1
Product: Cc1c2n(c3c(-c4cncnc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, light yellow solid (19 mg, 24%), MS (ISP) m/z=318.6 [(M+H)+], mp 304° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).