Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl.C1COCC1.O>[CH3:14][O:13][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:9]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(C)CC2)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
3-Nitro-5-methoxybenzoic acid (1 g; 5.07 mmol; 1 eq; commercially available IMPAMEX) is dissolved in a mixture of DCM (40 mL) and THF (10 mL) at room temperature. It is then cooled down at 0° C. and thionyl dichloride (1.1 mL; 15.22 mmol; 3 eq) is added slowly. After 30 min, triethylamine (2.11 mL; 15.22 mmol; 3 eq) and 1-methylpiperazine (1.64 mL; 15.22 mmol; 3 eq) are added at 0° C. and the reaction mixture is gently warmed up to rt and stirred for 48 h. Water is added and the solvents are evaporated. The product is extracted with EtOAc and the organic phase is washed with aqueous Na2CO3 and dried over MgSO4. The solvent is concentrated under reduced pressure to afford 900 mg (63.5%) of the title compound. The next step is carried out directly on the crude material. LC/MS: (ES+): 280.3; (ES−): 278.5
Reaction SMILES: Cl.Cl.COC(=O)[C@@H](NC([C@@H]1CC2C=C3OC[C@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)OC3=CC=2CN1)=O)CC1C=CC(C2C=CN=C(C)C=2C)=CC=1.C[O:57][C:58](=[O:117])[C@@H:59]([NH:75][C:76]([C@@H:78]1[CH2:87][C:86]2[CH:85]=[C:84]3[O:88][CH2:89][C@H:90]([C:92]4[CH:97]=[CH:96][C:95]([O:98][CH2:99][C:100]5[CH:105]=[CH:104][C:103]([Cl:106])=[C:102]([Cl:107])[CH:101]=5)=[CH:94][CH:93]=4)[O:91][C:83]3=[CH:82][C:81]=2[CH2:80][N:79]1[C:108]([C:110]1[N:111]=[C:112]([CH3:116])[O:113][C:114]=1[CH3:115])=[O:109])=[O:77])[CH2:60][C:61]1[CH:66]=[CH:65][C:64]([C:67]2[CH:72]=[CH:71][N:70]=[C:69]([CH3:73])[C:68]=2[CH3:74])=[CH:63][CH:62]=1>>[Cl:107][C:102]1[CH:101]=[C:100]([CH:105]=[CH:104][C:103]=1[Cl:106])[CH2:99][O:98][C:95]1[CH:96]=[CH:97][C:92]([C@H:90]2[CH2:89][O:88][C:84]3=[CH:85][C:86]4[CH2:87][C@@H:78]([C:76]([NH:75][C@@H:59]([CH2:60][C:61]5[CH:66]=[CH:65][C:64]([C:67]6[CH:72]=[CH:71][N:70]=[C:69]([CH3:73])[C:68]=6[CH3:74])=[CH:63][CH:62]=5)[C:58]([OH:117])=[O:57])=[O:77])[N:79]([C:108]([C:110]5[N:111]=[C:112]([CH3:116])[O:113][C:114]=5[CH3:115])=[O:109])[CH2:80][C:81]=4[CH:82]=[C:83]3[O:91]2)=[CH:93][CH:94]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)c(C)o1

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was converted to (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester according to General Procedure F. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 862.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[CH:7]=1)[CH3:2].[CH:14](=O)[CH2:15][CH3:16]>>[CH2:1]([C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[C:7]=1[CH2:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(CC)cc1C
Reactant: CCC=O
Product: CCCc1c(CC)[nH]c(C(=O)OCC)c1C

Procedure:
The crude product, obtained as in Example 74 but using 2-ethyl-4-methyl-5-carbethoxypyrrole and propionaldehyde, was sublimed (80° C. 1 × 10-4 mm), m.p. 86°-87° C. (50%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([CH3:28])[CH:20]=4)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:29]C(N(C)C)=O.N1CCCC1>CN(C=O)C>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:20]=[C:21]5[C:22](=[CH:23][CH:24]=4)[NH:25][CH:29]=[CH:28]5)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc3[nH]ccc3c2)C1
Temperature: 130 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a stirred solution of 1-cyclobutyl-4-{[3-(3-methyl-4-nitrophenoxy)azetidin-1-yl]carbonyl}-1,4-diazepane (40 mg, 0.16 mmol) in DMF (2 ml) was added DMF.DMA (100 μl, 0.75 mmol) and pyrrolidine (100 μl, 0.75 mmol) at 130° C. in one portion. The suspension was stirred for 2 h at 130° C. then cooled to room temperature and concentrated at reduced pressure. The residue was dissolved in 1:1 THF/MeOH (4 ml) and Raney Nickel (0.7 ml, 50% w/v in H2O) and hydrazine (0.7 ml, 1M solution in THF) were added. The reaction was stirred at room temperature for 3 hours then filtered over celite and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 95:5:1) to give the title compound (43 mg, 37%) as light brown oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([OH:14])=[O:13])=[O:6])[CH:2]=[CH2:3].[C:15](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([O:14][CH3:15])=[O:13])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CCC[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of (2S)-1-allyloxycarbonyl-2-carboxypyrrolidine (72.4 g) in N,N-dimethylformamide (250 ml) were added potassium carbonate (57.6 g) and methyl iodide (43.2 ml) at ° C. with stirring. The resulting mixture was allowed to warm to ambient temperature and stirring was continued for additional 1 hour. The reaction mixture was taken up into a mixture of ethyl acetate (1.2 l) and water (0.6 l). The organic layer was separated, washed in turn with water (1l×3), brine (1l), dried over magnesium sulfate, and evaporated to give (2S)-1-allyloxycarbonyl-2-methoxycarbonylpyrrolidine (66.21 g).
Reaction SMILES: [CH2:1]=[C:2]([C:7]#[N:8])[C:3]([C:5]#[N:6])=[CH2:4].C(C#N)CC=[CH:12][CH2:13][CH:14]([C:18]#[N:19])[CH2:15][CH2:16][CH3:17]>C(Cl)Cl>[CH2:3]([C:5]#[N:6])[CH2:2][CH2:1][CH2:1][C:2]([C:7]#[N:8])=[C:3]([C:5]#[N:6])[CH2:4][CH2:12][CH2:13][CH:14]([C:18]#[N:19])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC(C#N)CC=CCCC#N
Reactant: C=C(C#N)C(=C)C#N
Solvent: ClCCl
Product: CCCC(C#N)CCCC(C#N)=C(C#N)CCCCC#N

Procedure:
A further preparation employed 1,3-butadiene-2,3-dicarbonitrile in a condensation reaction with 9-oxatricyclo[4.2.12,5.0]non-3-ene-1,6-dicarbonitrile utilizing methylene chloride as diluent under room temperature conditions and a contacting time of about 5 days. By this method, a conversion of about 50 percent was obtained based on the 9-oxatricyclo[4.2.12,5.0]non-3-ene-1,6-dicarbonitrile, resulting in nearly 100 percent ultimate yields of 13-oxatetracyclo[8.2.12,9.0.03,8 ]tridec-5-ene-1,5,6,10-tetracarbonitrile.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Si:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:22][CH:23]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)cc2)cc1

Procedure:
The title compound was prepared by reacting 4-bromobenzaldehyde (730 mg, 3.97 mmol) with 4-tert-butyl-dimethylsilyoxyphenylboronic acid (1.3 g, 5.16 mmol) according to Method B to yield 600 mg (48%) of white crystal: 1H NMR (DMSO-d6): δ 0.24 (6H, s), 1.01 (9H, s), 6.94 (2H, d, J=8.54 Hz), 7.53 (2H, d, J=8.56 Hz), 7.72 (2H, d, J=8.19 Hz), 7.93 (2H, d, 8.20 Hz), 10.04 (1H, s).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][CH2:17][CH3:18])[C:11](=[O:19])[CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH2:15]([N:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]1=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCn1ccc(OCc2ccccc2)cc1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCn1ccc(O)cc1=O
Yield: 99.3 %

Procedure:
A mixture of intermediate D4 (2.01 g, 7.83 mmol) and a catalytic amount of 10% palladium on activated carbon in ethanol (300 ml) was stirred under a hydrogen atmosphere for two hours. The mixture was filtered through diatomaceous earth and the solvent was evaporated in vacuo to yield intermediate D5 (1.3 g, 100%) that was used without further purification.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][C:10](=O)[N:9]([CH3:13])[C:8]2[C:14]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:15][C:16]([CH3:18])=[CH:17][C:7]1=2)[CH2:4][CH3:5])[CH3:2].CSC.B>C1COCC1>[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([CH3:13])[C:8]2[C:14]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:15][C:16]([CH3:18])=[CH:17][C:7]1=2)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CC(=O)N(C)c2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCC(CC)N1CCN(C)c2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of 1-(1-Ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one (21 mg, 0.055 mmol) and 2 M borane dimethylsulfide complex (BH3•DMS) (0.07 ml, 0.14 mmol) in 2 ml of dry THF was heated at reflux for 3 hours. The mixture was cooled to 0° C. and quenched with 0.2 ml of meoh and 0.2 ml of concentrated hydrochloric acid (HCl). The resulting mixture was stirred at room temperature for 2 hours and concentrated to dryness. The residue was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give 19 mg of a clear oil that was purified through silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give 11 mg of the title compound as white crystals, mp 78-80° C.; 1H NMR (CDCl3) δ 6.85(s,2H), 6.28(s,1H), 3.73(m,1H), 3.12 (m,4H), 2.85(s,3H), 2.29(s,3H), 2.,13(s,3H), 2.11 (s,6H), 1.61(m,4H), 0.90(t,6H) ppm.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:21](S([O-])=O)([O-:24])(=[O:23])=[O:22].[Na+].[Na+].[OH-].[Na+].C1C(C(OOC(C)(C)C)=O)=CC=CC=1>O.C(O)(C)C>[S:21]([CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19])([OH:24])(=[O:23])=[O:22]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCC(CCCCCCCCC(=O)O)S(=O)(=O)O
Temperature: 82 °C

Procedure:
Deionized water (150 ml), isopropyl alcohol (200 ml) and oleic acid (43.78 g, 0.155 mol) were placed in a 1.0 liter flask equipped with stirrer, additional funnel, reflux condenser, thermometer and a gas inlet tube. To the additional funnel was added a premix which contained 15.2 g (0.08 mol) of sodium metabisulfite (Na2S2O5) and 1.28 g of NaOH in 55 g of water. The whole device was bubbled gently with nitrogen. After heating to reflux (82° C.), a small portion of t-butyl perbenzoate (out of total amount of 0.5 g, 2.5 mmol) was added to the flask. Then the Na2S2O5/NaOH premix was added through the addition funnel continuously over the course of five hours. The remaining t-butyl perbenzoate was also added in portions during this time.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](O)=[O:4].S(Cl)([Cl:14])=O>>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([Cl:14])=[O:4]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
A solution of α-bromophenylacetic acid (19.3 g, 89.7 mmol) in thionylchloride (100 mL) was refluxed (2 hours), cooled (25° C.), and stirred (25° C., 14 hours). The resulting solution was concentrated in vacuo, diluted with ether, and concentrated again to yield 21.0 g (100%) of α-bromophenylacetylchloride as a slightly yellow oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH:26]([C:27]([O:29]CC)=[O:28])[CH2:25][CH:24]=[CH:23][CH2:22]2)[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:11]([CH2:20][CH:21]2[CH:26]([C:27]([OH:29])=[O:28])[CH2:25][CH:24]=[CH:23][CH2:22]2)[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CC=CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CC=CCC2C(=O)O)OC1(C)C
Yield: 74.9 %

Procedure:
A solution of 4-benzyl-5-(6-ethoxycarbonyl-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (4.72 g) in ethanol (80 ml) was treated with a solution of sodium hydroxide (0.82 g) in water (15 ml) and the resulting solution refluxed for 18 hours. The ethanol was then evaporated and the residue partitioned between water and ethyl acetate. The organic solution was washed with saturated sodium chloride solution, dried (anhydrous magnesium sulfate) and evaporated. The residue was subjected to flash chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 4-benzyl-5-(6-carboxy-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.32 g, 75%) Mass spectrum 430 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[C:17]3[C:24]([C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:10]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:17]3[C:24]([C:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:32])=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)c1
Temperature: 50 °C

Procedure:
To a mixture of tert-butyl(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)benzyl)carbamate (30 mg, 0.068 mmol) in dioxane (0.5 mL) was added 0.5 mL of 4 M HCl in dioxane. The mixture was heated at 50° C. for 1 hour. The solvent was removed under reduced pressure. The residue was washed with DCM and dried on high vacuum to give an off-white solid. M.p.=210-212° C.; 400 MHz 1HNMR (DMSO-d6) δ 13.19 (s, 1H), 11.44 (s, 1H), 8.48 (s, 1H), 8.11 (d, J=8.4 Hz, 2H), 7.98 (s, 1H), 7.87-7.84 (m, 3H), 7.69 (t, J=6.4 Hz, 2H), 7.56 (t, J=7.6 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 5.44 (s, 2H), 4.06 (d, J=6.4 Hz, 2H); LCMS [M+H] 344.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])[CH:3]=1.C(O)(=O)C.C(O)=O.O>C(N(CC)CC)C.[Pd]>[OH:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][NH:18][C:4]1[CH:3]=[CH:2][CH:7]=[C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1c(NCCOCCO)cc(Cl)cc1NCCOCCO
Agent: [Pd]
Solvent: O=CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(NCCOCCO)cccc1NCCOCCO

Procedure:
300 mg of palladium at a concentration of 10% on calcium carbonate are added to 0.015 mole (5.45 g) of 4-chloro-2-(β-hydroxyethoxyethyl)amino-6-(β-hydroxyethoxyethyl)aminonitrobenzene in 11 ml of triethylamine. 1.1 ml of acetic acid and 2.05 ml of formic acid are then run in dropwise. When the additions have been completed the reaction mixture is heated under reflux for 30 minutes. 10 ml of water are added. The reaction mixture diluted in this manner is filtered hot to remove the catalyst. The filtrate is evaporated to dryness under vacuum in the presence of absolute ethanol and the residue is taken up with ethyl acetate. Insoluble organic salts are removed by filtration. The ethyl acetate is evaporated off to dryness. Acetonitrile and then water are added to the residue. The expected product precipitates. Recrystallized from ethyl acetate, it melts at 82° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:27]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:37]3[CH2:38][CH2:39][N:34]([C:28]4[N:27]=[C:26]([CH3:25])[CH:33]=[CH:32][C:29]=4[C:30]#[N:31])[CH2:35][CH2:36]3)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C#N)c(N2CCNCC2)n1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: Cc1ccc(C#N)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)n1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 6-methyl-2-piperazin-1-yl-nicotinonitrile (CAS 622405-21-4) to give the title compound as an off-white solid. MS: 537.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]=[CH:6]2.[Li:14]CCCC>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]([Li:14])[CH:7]=[CH:8]2
Reactant: COc1cc2c(cc1OC)CC=C2
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: [Li]C1C=Cc2cc(OC)c(OC)cc21
Reaction time: 4 h
Yield: 98 %

Procedure:
5,6-Dimethoxy-indene (4.82 g, 27.35 mmol) was dissolved in a mixture of 20 mL of toluene and 180 mL of hexane and 16.25 mL of 1.6 M n-BuLi were added dropwise via a syringe over a 5 min period forming a white precipitate. The reaction mixture was stirred for 4 h then filtered. The solids were washed with 60 mL of hexane and allowed to dry under reduced pressure to afford the desired anion as a light pink solid (4.62 g, 98 percent yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@H:5]([CH2:14][SH:15])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[H-].[Na+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C)C=O>[CH:21]1([CH2:20][S:15][CH2:14][CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CSCC1CC1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
14.7 g (59 mmol) of N-Boc-L-cysteine ethyl ester dissolved in 300 ml of dimethylformamide are added dropwise at 0° to a suspension of 2.49 g (64.8 mmol) of sodium hydride (60% in oil) in 200 ml of dimethylformamide and the mixture is stirred at 0° for 30 minutes. Subsequently, 8.37 g (62 mmol) of bromomethylcyclopropane in 30 ml of dimethylformamide are added dropwise thereto. The solution is stirred at room temperature overnight. The dimethylformamide is evaporated under reduced pressure, the residue is partitioned between ether and water and the aqueous phase is extracted 4 times with ether. The combined organic phases are washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue is chromatographed on silica gel using a 1:19 mixture of ethyl acetate and hexane as the eluent. There are obtained 8.4 g of tert-butyl rac-[2-[(cyclopropylmethyl)thio]-1-(ethoxycarbonyl)ethyl]carbamate as a colourless oil, MS: 304 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([CH3:23])[CH:19]=[CH:18]2)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Se](=O)=[O:25]>O1CCOCC1.O>[Si:1]([O:8][CH2:9][C@H:10]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([CH:23]=[O:25])[CH:19]=[CH:18]2)[CH3:11])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc2cccc(O[C@H](C)CO[Si](C)(C)C(C)(C)C)c2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cccc2ccc(C=O)nc12
Yield: 83.9 %

Procedure:
To a solution of (R)-8-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-methylquinoline (0.33 g, 1.0 mmol) in dioxane (40 mL) and water (0.4 mL) was added selenium dioxide (0.13 g, 1.2 mmol) and the resultant mixture heated at reflux for 1 hour. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10% ethyl acetate/hexanes) providing the title compound (0.29 g, 84%).
Reaction SMILES: [H-].[K+].[CH2:3]([O:5][C:6](=[O:15])[CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:28]#[N:29]>CCCCCC.O1CCCC1>[CH2:3]([O:5][C:6](=[O:15])[C:7]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:28]#[N:29])([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(C(=O)OCC)c1c(C#N)cnc2ccc(I)cc12
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
Potassium hydride (35% oil dispersion, 220 mg, 1.91 mmol) was washed with newly opened hexane for two times under Argon. Then anhydrous tetrahydrofuran (55 mL) was added, followed by addition of 2-ethyl-malonic acid diethyl ester (480 mg, 2.54 mmol). The reaction mixture was stirred at about room temperature for 10 min. Then 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c, 200 mg, 0.64 mmol) in anhydrous tetrahydrofuran (3 mL) was added to the above reaction mixture, and then reaction continued at room temperature for another 30 min. The reaction was quenched with ice water, and then extracted with ethyl acetate. The organic layers were collected, washed with brain, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 20% ethyl acetate in hexane in 25 min) afforded 2-(3-cyano-6-iodo-quinolin-4-yl)-2-ethyl-malonic acid diethyl ester (250 mg, 85%) as colorless viscous oil. LC-MS m/e 467 (MH+).