Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:8]=[C:9]2[N:15]([CH:16]=1)[CH2:14][C:13]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:12]=1[NH:11][C:10]2=O>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]2[N:15]([CH:16]=1)[CH2:14][C:13]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:12]=1[N:11]=[C:10]2[Cl:3]
Reactant: O=C1Nc2ccc(Cl)cc2Cn2cc(Cl)cc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClC1=Nc2ccc(Cl)cc2Cn2cc(Cl)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Add phosphoryl chloride (5 equiv; 4.36 mL, 7.19 g, 46.89 mmoles) to 2,7-dichloro-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (1 equiv; 2.505 g, 9.38 mmoles) in chloroform (80 mL) and heat and stir at 50° C. overnight. Decant the reaction solution and evaporate in vacuo to an oil. Dissolve the oil in DCM, wash with saturated aqueous sodium hydrogen carbonate solution. Dry the DCM solution over Na2SO4, filter and concentrate to dryness to give 2,7,11-trichloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine as a cream colored solid. In parallel desalt methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate hydrochloride (0.837 g, 3.54 mmoles) by dissolving in methanol, add the methanolic solution to an SCX-2 column (10 g) wash with methanol and then elute with 2.5M ammonia in methanol solution, evaporate the methanol ammonia fraction to give methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate (0.665 g) as an oil. Mix this oil with 2,7,11-trichloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.505 g 1.77 mmoles), potassium carbonate (0.733 g, 5.31 mmoles) and acetonitrile (20 mL) and heat at reflux overnight. Cool the reaction mixture to room temperature and filter, washing the sinter with EtOAc, then evaporate the filtrate in vacuo to a solid. Chromatograph on silica eluting with methanol/DCM (gradient elution 2:98 to 8:92). Evaporate the fractions containing product to give methyl 3-[4-(2,7-dichloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (0.69 g). MS (m/z): 449.13/451.07 (M+1).
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[O:1]=[C:2]([CH3:6])[CH2:3][CH2:4][O:5][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CCO
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To 400 ml of tetrahydrofuran in a reactor, 15.0 g (0.17 mol) of 3-oxo-1-butanol and 26.3 g (0.19 mol) of benzoyl chloride were dissolved, followed by drop-wise adding 20.6 g (0.20 mol) of triethylamine under ice-cooling. After the end of drop-wise addition, the reaction liquid was stirred at room temperature for 3 hours. Hydrochloric acid salt of triethylamine was filtered, followed by adding water to the filtrate and extracting with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium carbonate, water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5 to 1:3) to obtain 31.5 g (yield: 96%) of 3-oxobutylbenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.BrC1C=CC=C(C=1)OC1C=CC=CC=1C#N.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Oc1ccccc1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: N#Cc1ccccc1Oc1cccc(Br)c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1

Procedure:
The title compound was prepared in a quantitative yield from 5-bromo-2-fluoro-nitrobenzene and phenol in a manner similar to that described for the preparation of 5-bromo-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 8.31 9d, 1H), 7.86(dd, 1H), 7.45(t, 2H), 7.25(t, 1H), 7.13(d, 1H), 7.08(d, 2H); RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 12.70 min.
Reaction SMILES: [H-].[Na+].CN1C(=O)N(C)CCC1.C1(C)C=CC(S(O[CH2:22][CH2:23][CH2:24][CH:25]([CH3:34])[CH2:26][CH:27]([OH:33])[CH:28]=[CH:29][C:30]([CH3:32])=[CH2:31])(=O)=O)=CC=1>C(COC)OC>[CH3:34][CH:25]1[CH2:24][CH2:23][CH2:22][O:33][CH:27](/[CH:28]=[CH:29]/[C:30]([CH3:32])=[CH2:31])[CH2:26]1
Reactant: C=C(C)C=CC(O)CC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN1CCCN(C)C1=O
Product: C=C(C)/C=C/C1CC(C)CCCO1

Procedure:
The procedure described in Example 1 h) was carried on with 2.68 g of NaH (111 mmole) in 130 ml of monoglyme, 3.80 ml of DMPU (31.6 mmole) and 8.52 g (24 mmole) of the above-mentioned p-toluenesulfonate in monoglyme (130 ml). After purification of 5.1 g of crude product, 3.0 g of a more than 98% pure mixture, containing two diastereoisomeric forms (ca. 1:1) of (E)-4-methyl-2-(3-methyl-1,3-butadienyl)oxepane were obtained. P.b. 111°-112°/14.67×102Pa; yield: 69%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21].O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21]
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2cc(Cl)ccc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Cl)ccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 42.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2d (200 mg, 0.587 mmol), 6-mercaptopurine monohydrate (110 mg, 0.646 mmol), K2CO3 (90 mg, 0.651 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 113 mg of a yellow crystalline solid (42%), mp 237.1-238.2° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.55 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 8.11 (s, 1H); 7.94 (d, J=8.3 Hz, 1H); 7.78 (d, J=8.1 Hz, 2H); 7.66 (d, J=6.7 Hz, 1H); 7.48-7.56 (m, 2H); 4.48 (s, 2H). 13C NMR (DMSO-d6) ppm: 159.8, 156.8, 153.5, 151.5, 149.6, 145.8, 143.6, 135.7, 134.0, 132.2, 132.1, 131.7, 131.5, 130.5, 130.2, 129.8, 128.8, 125.8, 121.9, 32.0. MS (ES): m/z 455.0 (M+). Anal. calcd. for C20H12Cl2N6OS.0.1C2H6O.0.6H2O(0.15KCl: C, 50.34; H, 2.89; Cl, 15.82; N, 17.44; S, 6.65. Found: C, 50.02; H, 2.63; Cl, 15.51; N, 17.39; S, 6.81.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[OH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=O>>[OH:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: Cc1ccc(C(=O)O)cc1O
Product: Cc1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1O

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-hydroxy-4-methylbenzoic acid: MS (APCI): m/z 399 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([NH2:23])=O)[NH:6]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:33])[NH2:23])[NH:6]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=O)cc12
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.78 g), Lawesson's reagent (2.26 g) and tetrahydrofuran (120 mL) was stirred at 60° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from dichloromethane-toluene to give the title compound (1.56 g, yield 84%) as pale-yellow crystals. MS:366 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[C:11]1([CH3:14])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:14][CH:11]1[CH2:13][CH2:12]1
Reactant: Oc1cc(F)ccc1Br
Reactant: CC1(Br)CC1
Product: Fc1ccc(Br)c(OCC2CC2)c1

Procedure:
Starting from commercially available 2-bromo-5-fluoro-phenol and commercially available bromo-methyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×103 mbar.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].[K+].C(O[C:15]([S-:17])=[S:16])C.Cl>CN(C=O)C>[SH:17][C:15]1[S:16][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=S)[S-]
Reactant: N#Cc1ccc(Cl)c(N)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(S)nc2c1
Temperature: 115 °C
Yield: 49.4 %

Procedure:
To a solution of 3-amino-4-chloro-benzonitrile (Example 251, 9.0 g, 59 mmol) in 90 mL of DMF was added O-ethylxanthic acid potassium salt (Aldrich, 21.23 g, 133 mmol). The mixture was heated to 115° C. for 4 h. After cooled to room temperature, the mixture was diluted with ice/water and was acidified to pH 2 with 2N HCl. Filtration followed by washing with water gave a crude product, which was recrystallized from EtOH/water to give 5.6 g (49%) of product. 1H NMR (400 MHz, DMSO-d6) δ 14.10 (br s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.69 (dd, J=8.3, 1.1 Hz, 1H), 7.60 (s, 1H). MS (EI): m/z 191 (M−H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl.O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
A suspension of glycine ethylester, monohydrochloride (13.96 g, 100 mmol) and benzophenone imine (18.1 g, 100 mmol) in distilled dichloromethane (600 mL) was stirred at room temperature (RT) for 24 hours (h.). The mixture was diluted with water (250 mL) and the dichloromethane extract was separated, dried (MgSO4), filtered and concentrated under reduced pressure and in vacuo to obtain ethyl-N-(diphenylmethylene)-glycinate as a white solid (25.3 g, 95%). Ref.: M. J. O'Donnell, R. L. Polt J. Org, Chem. 47, 2663, 1982.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH:21]3[CH2:24][N:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:22]3)[N:17]=2)[CH2:11][C:12]([O:14]C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O.Cl>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH:21]3[CH2:22][N:23]([S:25]([CH3:28])(=[O:26])=[O:27])[CH2:24]3)[N:17]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CN(S(C)(=O)=O)C2)no1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CC(c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 88.7 %

Procedure:
A solution of methyl (3R)-6-cyclohexyl-3-{3-[1-(methylsulfonyl)-3-azetidinyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 38) (780 mg, 1.05 mmol) in dioxan (20 ml) and H2O (10 ml) was treated with LiOH.H2O (218 mg, 5.2 mmol) and stirred at room temperature for 2.25 hours. The reaction mixture was acidified with 2M HCl (20 ml) and extracted with EtOAc. The organic extract was washed with H2O and the solvent was removed under reduced pressure. The oil was purified on a silica column eluting with a solvent gradient of DCM:MeOH:AcOH (100:0:0) gradually changing to (90:10:1) to afford a colourless oil which solidified on standing. The solid was triturated with pentane, filtered off and dried under reduced pressure to afford the title compound as a white solid (372 mg, 78%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3(O)[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][C:3]=2[O:2]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a solution of ethyl(1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2Cl2 (3 ml) at 0° C. under an argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml, 2.4 mmol). The reaction mixture was stirred for 10 min, at which time was added ice-cold 1M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was placed on a small pad of silica gel, eluting with CH2Cl2 to provide the title compound (257 mg, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[O-]S(C(F)(F)[F:20])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F.C(=O)([O-])O.[Na+]>O1CCCC1>[F:20][C:9]1[C:10]([CH:13]=[O:14])=[CH:11][NH:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1c[nH]c(-c2ccccc2F)c1F
Reaction time: 2 h
Yield: 12.7 %

Procedure:
To a solution (60 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (3.1 g) in tetrahydrofuran was added 2,6-dichloro-N-fluoropyridinium triflate (5.6 g) at 0° C., and the mixture was stirred at the same temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=2:1) to give the title compound as white crystals (yield 0.43 g, 13%).
Reaction SMILES: C1COCC1.[NH:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:7]([C:17]([OH:19])=O)[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:37][O:38][C:39]([C@@H:41]([NH2:51])[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:40].Cl>CN(C=O)C>[NH:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:7]([C:17]([NH:51][C@H:41]([C:39]([O:38][CH3:37])=[O:40])[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:19])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](N)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 875.5 %

Procedure:
THF (700 ml) and BOC-Ser(Bzl)-OH (23.6 g, 0.8 M) and HOBT (108 g, 0.8 M) were added to H-Ser(Bzl)-Ome.HCl (196.57 g, 0.8 M); and DMF (200 ml) was added to prepare a solution. WSCI (146 ml, 0.8 M) was added dropwise thereto at 0° C. and the mixture was stirred at 0° C. for one hour and at room temperature overnight. The reaction mixture was concentrated in vacuo, and ethyl acetate (1 l.) was added to the residue, which was then washed with 5% sodium bicarbonate solution, 1 N HCl and water, each three times, in that order. Hexane was added to the oily product, which was then crystallized by adding crystalline seed. The material was then recrystallized from ether-hexane to obtain the substance [28] (340.4 g, yield: 87.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.[Si]([C:14]#[N:15])(C)(C)C.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:14]#[N:15])[CH:4]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
To a stirring mixture of 1.2 g (9.67 mmol) of 4-methoxypyridine-N-oxide in 18 mL of CH2Cl2 at r.t. was added 1.6 mL (12.0 mmol) of TMSCN. After 5 min. 0.9 mL (9.8 mmol) of dimethylcarbamoyl chloride. The solution was stirred at r.t. for 13 h and CHCl3 and 20 mL of 10% K2CO3 was added. The aqueous layer was extracted with CHCl3 3 times, and the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (38-44% EtOAc/hexanes) provided 949 mg of 4-methoxypicolinonitrile as a colorless solid in 73% yield.
Reaction SMILES: [OH-:1].[K+].C1(C)C=CC=CC=1.[CH3:10][C:11]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:12]=1[O:13][CH2:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[C:17]([C:21]#[N:22])=[N:18][O:19][CH3:20].Cl>O>[CH3:10][C:11]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:12]=1[O:13][CH2:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[C:17](=[N:18][O:19][CH3:20])[C:21]([NH2:22])=[O:1]
Reactant: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CON=C(C(N)=O)c1ccccc1COc1cc(C)ccc1C
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
85% Potassium hydroxide (0.40 g, 6.0 mmol) and toluene (5 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminobenzyl cyanide (E/Z=15/85)(1.47 g, 5.0 mmol). The mixture was stirred at 95° C. for 2 hours. After completion of the reaction, water was added. The mixture was neutralized with conc. hydrochloric acid, extracted with toluene (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (1.30 g, Yield: 83.2%, E/Z=15/85).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][N:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]1=[O:18].O.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]1=[O:18]
Reactant: COC(=O)C1CN(Cc2ccccn2)C(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)N(Cc2ccccn2)CC1C(=O)O
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
A suspension of sodium hydride (240 mg, 6 mmol, 60% dispersion in oil) in N-methyl-2-pyrrolidinone (6 ml) was stirred at 0° C. under argon. A solution of methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (474 mg, 3 mmol) (prepared as described in step (ii) of Example 8) in N-methyl-2-pyrrolidinone (3 ml) was added dropwise over 10 minutes. The reaction was stirred at 0° C. for 15 minutes and 2-(bromomethyl)pyridine hydrobromide (835 mg, 3.3 mmol) was added portionwise over 5 minutes. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 20 hours. The reaction was treated with ice water and extracted with dichloromethane. The mixture was applied to a SCX ion exchange cartridge and washed with methanol and then 2M ammonia in methanol. The basic fractions were combined and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give methyl 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylate (190 mg), LC/MS [M+H]+=250. (ii) A stirred solution of methyl 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylate (190 mg, 0.76 mmol) in tetrahydrofuran (1.5 ml)/water (1 ml) at 0° C. was treated with lithium hydroxide (55 mg, 2.28 mmol) and the reaction mixture was stirred at 0-5° C. for 3 hours. The reaction was acidified to pH 2 with 2N hydrochloric acid and the solvent was evaporated. The residue was dried to give 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylic acid which was used crude in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]1[C:4](=[O:9])[N:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH3:26])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: COc1ccc[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccn(-c2ccc([N+](=O)[O-])cc2C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
28.5 g (228 mol) of 3-methoxypyridin-2(1H)-one are dissolved in 850 ml of dimethyl sulphoxide, and 31 g (273 mmol) of potassium tert-butoxide are added at RT. The suspension is stirred at RT for 30 min, and 35 g (228 mmol) of 1-fluoro-2-methyl-4-nitrobenzene are then added, and the reaction solution is heated at 80° C. for 20 h. The solution is then carefully diluted with 1 l of water and adjusted to pH 1-2 using 1N hydrochloric acid. The solution is extracted repeatedly with dichloromethane. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated under reduced pressure. The solid obtained is washed with a little tert-butyl methyl ether, filtered off and dried under reduced pressure. This gives 42.8 g (72% of theory) of the desired compound.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[H][H]>CCO.Cl.[Rh]>[CH:1]1([C:11]([OH:13])=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: CCO
Product: O=C(O)C1NCCC2CCCCC21
Yield: 56.8 %

Procedure:
A solution of 1-isoquinolinecarboxylic acid (50 g, 0.288 mol) in EtOH (150 mL) and 60 mL of 5N HCl was reduced over 5% Rh/Al2O3 (14 g) at 52 bar (750 psi) of hydrogen in a high pressure apparatus at 50° C. for 17 hours. The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated in vacuo. The solid was triturated with water, filtered and dried to give DL-perhydro-1-isoquinolinecarboxylic acid (DL-1-Piq-OH) (30 g, 48%) FD-MS 184 (MH+).