Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:30]=[C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[N:32]1[CH2:41][CH2:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=O>>[Cl:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:3]([Cl:2])[C:4]=1/[CH:5]=[CH:47]/[C:46]1[CH:45]=[C:44]([CH2:43][CH2:42][CH2:41][N:32]2[C:33](=[O:40])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]2=[O:30])[CH:51]=[CH:50][CH:49]=1
Reactant: Clc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2c(Cl)cccc2Cl)c1

Procedure:
2,6-Dichlorobenzyltriphenylphosphonium bromide was coupled with phthalimide 29. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave (E)-2-(3-(3-(2,6-dichlorostyryl)phenyl)propyl)isoindoline-1,3-dione as a white solid. Yield (0.7041 g, 96%): 1H NMR (400 MHz, DMSO-d6) δ 7.78-7.86 (m, 4H), 7.51 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.27 (t, J=7.2 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.11 (d, J=16.4 Hz, 1H), 7.01 (d, J=16.8 Hz, 1H), 3.62 (t, J=6.8 Hz, 2H), 2.65 (t, J=7.4 Hz, 2H), 1.88-1.98 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14][CH2:13]1>C(#N)C.[Pd]>[CH3:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:17]2)=[N:3][CH:4]=1
Reactant: C1CCN(CCC2CCNCC2)CC1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC#N
Product: Cc1cnc(N2CCC(CCN3CCCCC3)CC2)c(N)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred solution of 0.086 g (0.50 mmol) of 2-chloro-5-methyl-3-nitro-pyridine in acetonitrile (5 mL) is added 0.098 g (0.50 mmol) of 1-(2-piperidin-4-yl-ethyl)-piperidine. The mixture is heated in a microwave reactor at 100° C. for 10 minutes then cooled to room temperature. To this solution is added 0.010 g (0.009 mmol) of 10% palladium on carbon. The mixture is placed under an atmosphere of hydrogen and stirred overnight at room temperature. The mixture is filtered and concentrated under reduced pressure to give 0.151 g (quant.) of 5′-methyl-4-(2-piperidin-1-yl-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl>[C:11]1([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(CCc1ccccc1)c1ccccc1
Reaction time: 96 h
Yield: 99.1 %

Procedure:
According to the general procedure, a solution of chalcone (50 mg, 0.24 mmol) and rac-32 (7.4 mg, 0.0047 mmol, 2.0 mol %) in CH2Cl2 (3 mL) was pressurized with H2 to 62 bar and stirred for 96 h. Filtration of the reaction mixture and evaporation of the solvent gave 41 as a colorless solid (50 mg, 99%). mp 69-70° C. (lit.2 70-72° C.); 1H NMR27 (300 MHz, CDCl3): δ 7.98 (d, 2H, J=7.2 Hz), 7.6-7.2 (m, 8H), 3.33 (t, 2H, J=7.8 Hz), 3.10 (t, 2H, J=7.2 Hz); 13C NMR (75.5 MHz, CDCl3): δ 199.3, 141.4, 136.9, 133.2, 128.7, 128.6, 128.5, 128.1, 126.2, 40.5, 30.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13](I)[C:11]=1[NH2:12]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:17][C:15]1[CH:14]=[C:13]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[C:11]([NH2:12])=[C:10]([F:9])[CH:16]=1
Reactant: Nc1c(F)cc(Cl)cc1I
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1c(F)cc(Cl)cc1C#Cc1cccnc1

Procedure:
To a mixture of 3-ethynylpyridine (1.13 g, 11 mmol) and 2-fluoro-4-chloro-6-iodoaniline (2.71 g, 10 mmol) in triethylamine (100 mL) is added PdCl2(PPh3)2 (175 mg, 0.25 mmol) and CuI (95 mg, 0.50 mmol) and the mixture is refluxed for 1 h. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 24:1) to give 4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine. MS (ESI) m/z 247 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](/[N:9]=[CH:15]/[N:16]([CH3:18])[CH3:17])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(OCC)N(C)C
Reactant: N#Cc1ccc(C(N)=O)cc1
Product: CN(C)/C=N/C(=O)c1ccc(C#N)cc1
Temperature: 120 °C
Reaction time: 1.17 h
Yield: 96.1 %

Procedure:
4-cyanobenzamide (327.0 mg, 2.237 mmol) and N,N-dimethylformamide diethyl acetal (0.53 ml, 3.09 mmol) were combined and heated to 120° C. A short path distillation apparatus was used to collect the ethanol that was liberated during the reaction. The reaction mixture was a dark purple solution that slowly turned lighter until it had become an amber solution. After 70 minutes, the reaction mixture solidified. The reaction mixture was cooled to room temperature and was placed under high vacuum overnight to give the title compound (432.7 mg, 2.150 mmol) as a yellow solid.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[N:22]=[C:21]([C:30]#[C:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:20]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1>C(Cl)Cl>[CH:24]1([N:23]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]([OH:12])=[CH:18][CH:17]=3)=[CH:20][C:21]([C:30]#[C:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:22]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C#Cc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C#Cc1cc(-c2ccc(O)cc2)n(C2CCCCC2)n1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A 1M solution of BCl3 in CH2Cl2 (1 ml, 1.00 mmol) was added to a solution of intermediate 7.3 (86 mg, 0.207 mmol) in 2 ml of CH2Cl2 at −50° C., and after being stirred at −50° C. for 15 min, the solution was quenched with MeOH, diluted with EtOAc, washed with H2O, sat. NaHCO3, brine, and dried (Na2SO4). Filtration through a 1″ pad of SiO2 and concentration provided 69 mg (100%) of 7.5. MS (ESI) 339.3 (MH+), 337.3 (MH−).
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C([Li])CCC.[P:12](Cl)([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13].[Li].C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C1COCC1.CO>[C:5]([P:12](=[O:13])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])#[CH:6]
Reactant: C#C[Si](C)(C)C
Reactant: CCOP(=O)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: C#CP(=O)(OCC)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
This known compound was synthesized according to the procedure of Acheson et al. in J. Chem. Reso; (Miniprint), 1986, 3001-3019 with some modifications. In a 100-mL round bottom flask equipped with a magnetic stir bar, trimethylsilylacetylene (2.9 mL, 21 mmol) was dissolved in dry THF (40 mL) at room temperature under argon atmosphere. The mixture was cooled to −78° C. and n-butyllithium (14 mL of 1.6M in hexane, 22 mmol) was added dropwise over 3 min In a separate round-bottom flask, diethyl chlorophosphate (10 mL) was dissolved in dry THF (10 mL) and was added to the solution of lithium trimethylsilylacetylide dropwise over 25 min via a cannula. The mixture was stirred at −78° C. for 1 h until trimethylsilylacetylene was consumed, as observed by TLC. Two new spots appeared on TLC (Rf=0.8 and 0.6 eluted with ethyl acetate, visualized with KMnO4 stain). The reaction mixture was warmed up to room temperature and saturated aqueous Na2CO3 (100 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL) and concentrated under reduced pressure to give dark brown syrup. This crude material was dissolved in methanol (20 mL) and Na2CO3 (500 mg) was added. Aqueous 1 N NaOH was then added dropwise until the pH the solution was 10 (by a pH paper). Within 30 min, the two spots on TLC converged into the lower Rf spot (Rf=0.6, eluted with ethyl acetate, visualized with KMnO4 stain). The reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined aqueous phases were dried over MgSO4 (s), filtered, and concentrated in vacuo. The crude product (pale yellow syrup) was purified by silica gel flash chromatography (30% ethyl acetate in hexane) to give 1.45 g of colorless syrup (yield=45%). The analytical data are identical with those reported by Acheson et al.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:26]=[CH:25][C:24]([O:28][CH2:29][CH3:30])=[O:27])=[C:3]([O:10][CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:4]=1)#[N:7]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(C#N)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C#N)cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
3.7 g (8.6 mmol) of 4-iodo-3-[(2R)-(1-t-butoxycarbonyl-pyrrolidine-2-ylmethoxy)]benzonitrile was dissolved in 40 ml of DMF. 4.68 ml (43 mmol) of ethyl acrylate , 6.1 ml (43 mmol) of triethylamine and 194 mg (0.85 mmol) of palladium acetate were added to the obtained solution, and they were stirred at 100° C. overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was treated with ethyl acetate as the extraction solvent in an ordinary manner to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: ON=[C:3]([C:8]1[CH:9]=[N:10][S:11][CH:12]=1)[C:4]([O:6]C)=[O:5].C=[O:14].Cl>O>[S:11]1[CH:12]=[C:8]([C:3](=[O:14])[C:4]([OH:6])=[O:5])[CH:9]=[N:10]1
Reactant: COC(=O)C(=NO)c1cnsc1
Reactant: C=O
Agent: Cl
Solvent: O
Product: O=C(O)C(=O)c1cnsc1
Reaction time: 7 h

Procedure:
A mixture of methyl 2-hydroxyimino-2-(isothiazol-4-yl)acetate (anti isomer) (3.41 g.), 36% aqueous solution of formaldehyde (24 ml.), conc. hydrochloric acid (12 ml.) and water (24 ml.) was stirred for 7 hours at 90° to 100° C. The reaction mixture was allowed to stand overnight in a refrigerator to precipitate crystals. The crystals were collected by filtration, washed with a small amount of ice-water and then dried to give 2-(isothiazol-4-yl)glyoxylic acid (2.09 g.). The mother liquor was extracted with ethyl acetate to give the same compound (0.34 g.), mp 145° to 148° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](C=O)=[C:7]([O:13][CH3:14])[CH:6]=1.[OH:15]O>OS(O)(=O)=O.CO.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([OH:15])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1cc(OCCO)ccc1C=O
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COc1cc(OCCO)ccc1O

Procedure:
A solution of 4-(2-hydroxyethoxy)-2-methoxybenzaldehyde (465.6 mg, 2.373 mmol) and 30 wt % hydrogen peroxide (0.313 mL, 3.04 mmol) in conc. H2SO4 (0.0475 mL) and MeOH (4.75 mL) was stirred overnight at 25° C. under N2. After this time the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 55% EtOAc in hexanes over 2394 mL, gradient to 100% EtOAc over 999 mL) to afford 4-(2-hydroxyethoxy)-2-methoxyphenol, as a colorless oil. Rf=0.30 (50% EtOAc/hexanes). LCMS calc.=207.1; found=206.9 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 6.77 (d, J=8.6 Hz, 1 H); 6.47 (d, J=2.8 Hz, 1 H); 6.34 (dd, J=8.7, 2.8 Hz, 1 H); 5.82 (s, 1 H); 3.98 (t, J=4.6 Hz, 2 H); 3.90 (t, J=4.5 Hz, 2 H); 3.76 (s, 3 H); 2.96 (s, 1 H).
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][CH2:11][C:10]([OH:15])([C:13]#[N:14])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[H][H].C([O-])(O)=O.[Na+]>CO>[C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][CH2:11][C:10]([CH2:13][NH2:14])([OH:15])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC2(CC1)CC(O)(C#N)CO2
Reactant: [H][H]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C1CCC2(CC1)CC(O)(CN)CO2
Yield: 82.9 %

Procedure:
8-t-Butyl-3-hydroxy-3-cyano-1-oxaspiro(4,5)decane (2.37 g, 10 mmol) in methanol (25 ml), containing conc. hydrochloric acid (1 ml), was hydrogenated on platinum oxide (0.1 g, 40° C./5 bar hydrogen pressure) until the uptake of hydrogen ceased. Saturated NaHCO3 (3 ml) was added and the solvent was evaporated in vacuo. To the residue was added methanol (30 ml) and MgSO4. The mixture was filtrated and the filtrate was evaporated in vacuo to yield a pale greenish solid (2.0 g). The fairly polar compound was not further purified. It was characterised via its N-cyclohexyl derivative.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23].O.Cl.CCOCC>C(OCC)(=O)C.CO>[ClH:1].[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:4]1[CH:3]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: NCCO
Reactant: Clc1cc(N2CCc3ccccc3C2)nc2ccccc12
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCCNc1cc(N2CCc3ccccc3C2)nc2ccccc12
Temperature: 155 °C
Yield: 26.4 %

Procedure:
4-Chloro-2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline (0.5 g, 1.7 mmol) and ethanolamine (0.61 ml, 10.2 mmol) were mixed and heated at 150-160° C. for 16 hours. The reaction mixture was cooled to room temperature and water (20 ml) was added. After decantation of water, the gummy residue was dissolved in ethyl acetate, dried over Na2SO4 and the solvent was evaporated. The residue was chromatographed over silica gel (CH2Cl2—MeOH, 9:1 then 4:1) to provide a white foam which was dissolved in MeOH (5 ml). HCl-Et2O was added to provide 2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-4-ylamino]-ethanol hydrochloride (0.16 g, 27%) as a white solid, m.p. 130-140° C. and MS: m/e=320.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N(C)C(c2ccccc2)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-Bromo-3-methyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (0.2 g, 0.6 mmol) in DMF (10 mL) is cooled to 0° C., then NaH (16.7 mg, 0.7 mmol) is added. After the addition the mixture is stirred at 0° C. for 0.5 h. Then CH3I (107 mg, 0.76 mmol) is added and the mixture is stirred at r.t. for 2 h. Then H2O is added and is extracted with EtOAc, dried over Na2SO4 and concentrated to give product. This is used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH:20]=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH2:20][N:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:27]=[CH:26][C:25]([C:24]([NH:23][CH3:22])=[O:37])=[CH:30][CH:29]=3)[CH2:32][CH2:33]2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1Oc2c(Cc3ccccc3)cc(C=O)cc2NC1=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cc(Cc4ccccc4)c4c(c3)NC(=O)C(C)O4)CC2)cc1

Procedure:
Using 353A and N-methyl-4-(piperazin-1-yl)benzamide 282 in the general procedure for reductive aminations, the title compound was obtained as a light grey solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (d, J=6.82 Hz, 3H) 2.42-2.49 (m, 4H) 2.74 (d, J=4.29 Hz, 3H) 3.16-3.28 (m, 4H) 3.38 (s, 2 H) 3.89 (s, 2H) 4.54-4.60 (m, 1H) 6.73-6.82 (m, 2H) 6.92 (m, 2H) 7.14-7.19 (m, 1H) 7.19-7.23 (m, 2H) 7.24-7.30 (m, 2H) 7.70 (m, 2H) 8.14 (q, J=4.29 Hz, 1H) 10.60 (s, 1H). ESI-MS: m/z 485.4 (M+H)+. mp=227.0-230.9° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:22])[C@H:12]2[C@@H:15](OS(C)(=O)=O)[CH3:16])[C:9]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:22])/[C:12]/2=[CH:15]/[CH3:16])[C:9]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C=C1/C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(C)=O)C[C@H]12

Procedure:
p-Nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e11) (67 mg) was stirred with K2CO3 (70 mg) in dimethylformamide (2 ml) at room temperature for 1 hour. Work-up as in Example 2 gave a residue which was triturated with ethyl acetate/ether to afford a solid which was collected by filtration. The solid (10 mg) was identified as p-nitrobenzyl (5R,6E)-3-(2-acetamidoethylthio)-6-ethylidene-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e12); δ(DMF-d7) ca. 1.85 (3H, d, CH3CH), 1.87 (3H, s, CH3CO) ca. 2.7-3.5 (6H, m, NCH2CH2S and 4-CH2), 4.85 (1H, br t, J 9 Hz, 5-CH), 5.29 and 5.53 (each 1H, d, J 14 Hz, CH2Ar), 6.38 (1H, br q, J 7 Hz, CH3CH), 7.76 and 8.20 (each 2H, d, J 9 Hz, ArCH2), and ca. 8.0 (1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][O:16][C:15](=O)[CH:14]2[CH3:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]2[CH:20]=[S:22])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1cc(N2CCOC(=O)C2C)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(N2CCOCC2C=S)cc(OC)c1OC

Procedure:
28.1 g (0.1 mole) of 4-(3',4',5'-trimethoxyphenyl)-oxo-methylmorpholine, 100 ml of pyridine and 22.3 g (0.1 mole) of phosphorus pentasulfide are reacted at the boiling point of the reaction mixture for 5 hours. Then the solvent is distilled off and the product is precipitated with water.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=2[O:24]C)=[C:8]([CH3:30])[N:7]=1.[CH3:31]O.Cl>C(Cl)Cl.O1CCOCC1>[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([O:29][CH3:31])=[O:28])[CH:21]=[CH:22][C:23]=2[OH:24])=[C:8]([CH3:30])[N:7]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Reactant: CO
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of boron tribromide (2.51 ml, 1M in DCM) was added portionwise over 30 min to a stirred suspension of the product from example 83 step (iv) (300 mg) in DCM (5 mL) at 0° C. The suspension was allowed to warm to rt and stirred for 3 h. A further portion of boron tribromide (1.674 ml, 1M in DCM) was added and the mixture stirred at rt for a further 2 h. MeOH (2 mL) and 4M HCl in dioxane (2 mL) were added and the mixture stirred for 1 h. The solvent was evaporated under reduced pressure and the residue purified by RPHPLC, to give the title compound as a white solid, 27 mg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>O1CCOCC1>[C:14]([NH:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ncc(Cl)cc1N
Solvent: C1COCCO1
Product: CCOC(=O)c1ncc(Cl)cc1NC(C)=O
Temperature: 50 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of ethyl 3-amino-5-chloropicolinate (107) (2.0 g, 10 mmol) in 10 mL of 1,4-dioxane was added 4 mL of acetic anhydride. The resulting solution was allowed to stir at 50° C. for 24 hr. Solvent was evaporated and water (10 mL) was added to the residue. The mixture was neutralized by saturated sodium bicarbonate solution to pH=7. A pale yellow solid was collected by filtration and dried in vacuo, giving 2.0 g (83%) of the product. mp 98°-100° C. 1H NMR (CDCl3): δ1.476 (t, J=7.2 Hz, 3H), 4.45 (q, J=7.2 Hz, 3H), 8.352 (d, J=2.1 Hz, 1H), 9.218 (d, J=2.1 Hz, 1H), 11.087 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C:8](=O)[C:9]=2[CH:10]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:8]1[CH2:7][CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][C:4]2[NH:3][C:2]([CH3:1])=[CH:10][C:9]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NN
Reactant: Cc1cc2c([nH]1)CC(c1ccccc1)CC2=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc2c([nH]1)CC(c1ccccc1)CC2=NNC(=N)N
Yield: 81.5 %

Procedure:
A mixture of 2-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), aminoguanidine hydrochloride (0.41 g), concentrated hydrochloric acid (0.18 ml), water (0.18 ml) and ethanol (50 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was suspended in ethyl acetate, and the suspension was washed with water. Under reduced pressure, the solvent was evaporated. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid. The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-2-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 4) (0.92 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ccsc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2ccsc12

Procedure:
7 g of 7-methylbenzo[b]thiophene, 8,5 g of N-bromosuccinimide and a spatula tip of α,α'-azoisobutyronitrile are refluxed together for 6 hours in 50 ml of carbon tetrachloride. The resulting mixture is cooled, filtered and concentrated by evaporation. The resulting raw title compound can be directly employed in the next step. M.p. when isolated=57° (isopropanol)