Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>ClCCl.C(N(CC)CC)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(Cl)cc2)cc1N1CCN(C)CC1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
4-Chlorobenzoic acid (350 mg, 2.23 mmol) was heated at reflux with thionyl chloride (3 ml) and toluene (40 ml) for 2 h, and then evaporated to dryness under reduced pressure. 4-Methoxy-3-(4-methyl-1-piperazinyl)phenylamine (494 mg, 2.23 mmol) in dry dichloromethane (40 ml) was added with triethylamine (2 ml) and the mixture stirred for 1 h. The solution was partitioned between dichloromethane (40 ml) and saturated aqueous potassium carbonate (40 ml), the organic solution dried (sodium sulphate) and evaporated to dryness under reduced pressure to afford an oil, which was purified by column chromatography (silica, chloroform,/methanol 5%) to afford the title compound (774 mg, 97%) which was crystallised from methanol/diethyl ether as the oxalate salt.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11](C)C(=O)C>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N>[C:10]([C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1)#[N:11]
Reactant: CC(=O)N(C)C
Reactant: Cc1nc(Br)ccc1N
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1nc(C#N)ccc1N
Temperature: 20 °C
Reaction time: 22 h

Procedure:
A mixture of 3.5 g (18.6 mmol) of 6-bromo-2-methyl-3-aminopyridine, 352 mg (0.37 mmol) of tris(benzylideneacetone)dipalladium(0), 532 mg (0.92 mmol) of 1,1′-bis(diphenylphosphino)ferrocene, 146 mg (2.2 mmol) of zinc powder and 1.4 g (12 mmol) of zinc cyanide in 70 ml of N,N-dimethylacetamide is prepared and the reaction mixture is then stirred at 20° C. for 22 hours. It is diluted with 200 ml of ethyl acetate and washed with 2 N ammonium chloride solution. (Decantation is obtained only after filtration of the mixture on a filter aid of the Celite type.) The organic phase obtained is washed with sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a dichloromethane/ethyl acetate mixture (9/1; v/v) as the eluent to give 1.6 g of the expected compound in the form of a yellow powder (yield=65%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:37][C:38](=[O:40])[CH3:39])[CH2:7][NH:8][C:9](=[O:36])[C:10]1[C:15]([I:16])=[C:14]([N:17]=[C:18]=[O:19])[C:13]([I:20])=[C:12]([C:21](=[O:34])[NH:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:11]=1[I:35])(=[O:3])[CH3:2].[OH:41][CH2:42][C:43]([CH2:47][OH:48])([CH2:45][OH:46])[CH3:44]>ClCCl>[C:31]([O:30][CH:24]([CH2:23][NH:22][C:21](=[O:34])[C:12]1[C:11]([I:35])=[C:10]([C:9](=[O:36])[NH:8][CH2:7][CH:6]([O:37][C:38](=[O:40])[CH3:39])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:15]([I:16])=[C:14]([NH:17][C:18]([O:41][CH2:42][C:43]([CH2:47][O:48][C:18](=[O:19])[NH:17][C:14]2[C:13]([I:20])=[C:12]([C:21](=[O:34])[NH:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:11]([I:35])=[C:10]([C:9](=[O:36])[NH:8][CH2:7][CH:6]([O:37][C:38](=[O:40])[CH3:39])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:15]=2[I:16])([CH3:44])[CH2:45][OH:46])=[O:19])[C:13]=1[I:20])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:33])[CH3:32]
Reactant: CC(CO)(CO)CO
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)OCC(C)(CO)COC(=O)Nc2c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reaction time: 18 h

Procedure:
To a solution of acetic acid 1-acetoxymethyl-2-[3-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-5-isocyanato-benzoylamino]-ethyl ester in dichloromethane was added 1,1,1-tris(hydroxymethyl)ethane (0.3 equivalent). The reaction mixture was stirred for 18 hours and then purified by column chromatography to give acetic acid 2-acetoxy-3-[3-{2-[3,5-bis-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-phenylcarbamoyloxymethyl]-3-hydroxy-2-methyl-propoxycarbonylamino}-5-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-benzoylamino]propyl ester. This was dissolved in methanol and treated with aquesous ammonia. The material was purified by preparatie HPLC to give 1,3-bis-[N,N′-Bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-5-carbamido-isophthalamide]-2-methyl-2-hydroxymethylpropane as a white powder after freeze drying.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OCC)(=O)C>C1COCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)OCC
Yield: 92.8 %

Procedure:
Diethyl malonate (31.15 g, 194.48 mmoles) was first transferred at 0° C. to a stirring suspension of sodium hydride (4.67 g, 194.58 mmoles) in dry THF (200 mL). To this resulting mixture, was added dropwise (at 0° C.) a solution of t-butyl bromoacetate (23.00 g, 117.91 mmoles). Formation of a white precipitate was instantly observed. The mixture was then stirred at room temperature until complete consumption of the starting material (1.5 hours as confirmed by TLC: 20% ethyl acetate: 80% hexanes). The solvent was then evaporated and the residue was taken-up in 500 mL diethyl ether. This organic phase was washed with water (3×300 mL) and washed once with brine (200 mL) before being dried (anhydrous MgSO4) and evaporated. The obtained residue was first purified by distillation to remove excess malonate and then by flash chromatography (SiO2, 15% ethyl acetate: 85% hexanes) to afford 30.00 g (92.8% yield) of the desired compound as an oil: IR (film) 2982, 1733, 1258, 1152, 1037 cm−1; 13C NMR (CDCl3, 100 MHz) 169.5, 168.1, 80.8, 61.2, 47.7, 33.9, 27.6.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:39])[C:35](=[O:38])[CH2:36][CH3:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:39])[C:35](=[O:38])[CH2:36][CH3:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)CC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)C(=O)CC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-propanoyl-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[C:8]([CH:15]2[O:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)CCC.Br[C:30]1[N:34]([CH3:35])[CH:33]=[N:32][CH:31]=1>>[O:20]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:8]1[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=[C:6]([C:30]2[N:34]([CH3:35])[CH:33]=[N:32][CH:31]=2)[CH:7]=1
Reactant: Cn1cncc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C2OCCCO2)c2occc2c1
Product: Cn1cncc1-c1cc(C2OCCCO2)c2occc2c1

Procedure:
From tributyl-(7-[1,3]Dioxan-2-yl-benzofuran-5-yl)-stannane (0.40 g) and 5-bromo-1-methyl-1H-imidazole (0.13 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:20])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8]>>[F:20][C:6]([F:5])([O:12][C:13]1[CH:14]=[C:15]([F:19])[C:16]([N+:1]([O-:4])=[O:2])=[CH:17][CH:18]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8]
Reactant: CN(C)C(=O)C(F)(F)Oc1cccc(F)c1
Reactant: O=[N+]([O-])O
Product: CN(C)C(=O)C(F)(F)Oc1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Nitric acid (100%, 200 mL, 4.8 mol) was cooled to −5° C. 2,2-Difluoro-2-(3-fluoro-phenoxy)-N,N-dimethyl-acetamide (19.0 g, 81.5 mmol) was added at rate to keep the temperature below −2° C. Upon complete addition stirring was continued for 30 min. The reaction mixture was then poured on 450 mg ice-water. The aqueous phase was extracted with TBME (3×100 mL); the combined organic phases were washed with water (100 mL) and brine (100 mL) and dried over MgSO4. Evaporation of the solvent gave the crude product that was purified by preparative HPLC. The product (6.5 g, >98% by HPLC, 28% yield) was obtained as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25][C@@H:26]2[O:63][C@H:62]([CH2:64][O:65]C(=O)C)[C@H:37]([O:38][C@H:39]3[O:56][C@H:55]([CH2:57][O:58]C(=O)C)[C@H:50]([O:51]C(=O)C)[C@H:45]([O:46]C(=O)C)[C@H:40]3[O:41]C(=O)C)[C@H:32]([O:33]C(=O)C)[C@H:27]2[O:28]C(=O)C)[C@@H:18]([CH2:69][O:70]C(=O)C)[O:17][C@H:6]1[O:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([NH:4][C@@H:5]1[C@@H:20]([OH:21])[C@H:19]([O:25][C@@H:26]2[O:63][C@H:62]([CH2:64][OH:65])[C@H:37]([O:38][C@H:39]3[O:56][C@H:55]([CH2:57][OH:58])[C@H:50]([OH:51])[C@H:45]([OH:46])[C@H:40]3[OH:41])[C@H:32]([OH:33])[C@H:27]2[OH:28])[C@@H:18]([CH2:69][OH:70])[O:17][C@H:6]1[O:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:3])[CH3:2]
Reactant: COC(=O)CCSCCO[C@@H]1O[C@H](COC(C)=O)[C@@H](O[C@@H]2O[C@H](COC(C)=O)[C@H](O[C@H]3O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCSCCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
Compound 81 (350 mg, 0.3 mmol) was dissolved in methanol (10 ml) by warming and then rapidly cooled. Methanolic sodium methoxide (0.2M, 0.2 ml) was added and the mixture was stirred at room temperature for 18 h, neutralized (Duolite C-26 (H+) resin), filtered and concentrated. The residue was dissolved in methanol (7 ml) and methanolic hydrazine hydrate (0.1M, 3 ml) was added. The mixture was refluxed for 33 h while two additional portions (2×3 ml) were added (after 24 and 30 h). The reaction was monitored by TLC (SiO2,chloroform methanol:water 65:35:10, lower phase). The solvent was removed and the residue was treated with a mixture of acetic anhydride (2.5 ml), ethanol (12 ml), and water (4 ml) at room temperature for 1 h. The ethanol was removed and the residue was partitioned between water (20 ml) and dichloromethane (5 ml). The aqueous phase was washed with dichloromethane (3×5 ml) and concentrated. The residue was chromatographed {Sephadex G-10 column. 3×57 cm, water) to give 82 (157 mg, 75%) with [α]D22 +34° (c 0.7, water). 1H-NMR [(CD3)2SO+D2O, 50°, Me4Si]δ inter alia 4.80 (d, 1H, J=3.5 Hz, H1"), 4.40 (d, 1H, J=8 Hz, H1 or H1'), 4.28 (d, 1H, J=7 Hz, H1or H1'), 4.08 (dt, 1H, J=6 and 1 Hz), 3.61 (s, CH3O), 2.75-2.70 and 2.61-2.54 (m, each 2H, SCH2CH2CO), 2.64 (t, 2H, J=7 Hz, OCH2CH2S), 1.80 (s, 3H, MeCON). 13C-NMR (D2O, TSP) δ 178.0, 177.3, 106.1, 103.8, 103.1, 81.6, 80.1, 78.2, 77.7, 75.3, 75.0, 73.7, 73.6, 72.1 (CH2), 72.0, 71.8, 71.4, 63.3 (CH2), 63.2 (CH2), 62.9 (CH2), 58.0 (C2), 55.2 (CH3O), 37.1 (CH 2), 33.8 (CH2), 29.4 (CH2), 23.2.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:43])[C@@H:10]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[C:34]=1[CH3:42])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC(OC)=CC=3)=[CH:18][CH:17]=2)=[N:14][N:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH3:43])[C@@H:10]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[C:34]=1[CH3:42])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][N:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2ccc(-c3nnc([C@H](Nc4ccc(C#N)c(Cl)c4C)[C@H](C)O[Si](C)(C)C(C)(C)C)o3)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 36 h
Yield: 93.8 %

Procedure:
A 250 mL round bottomed flask was charged with 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-(4-methoxybenzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (1.76 g, 2.84 mmol), methylene chloride-H2O (20:1, 80 mL) and 2,3-Dichloro-5,6-Dicyanobenzoquinone (3.87 g, 17.05 mmol). The reaction mixture was stirred at room temperature for 36 h and a saturated aqueous solution of sodium hydrogen carbonate (30 mL) was added followed by methylene chloride (70 mL). The phases were partitioned and the aqueous phase extracted with methylene chloride (60 mL) (×3). The combined organic extracts were dried (Na2SO4) and concentrated to furnish a white solid (1.33 g, 91%). 1H NMR (500 MHz, acetone d6, δ in ppm) δ 9.17 (br s, 1H), 7.85 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 1H), 6.99 (d, J=9 Hz, 2H), 6.84 (d, J=9 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 5.52 (d, J=9 Hz), 5.18 (dd, J=2 and 9 Hz, 1H), 4.74-4.68 (m, 1H), 2.41 (s, 3H), 1.46 (d, J=6 Hz, 3H), 0.86 (s, 9H), 0.1 (s, 3 H) and −0.35 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([NH2:19])=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=[O:27])[C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](=[O:18])[NH2:19])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccccc2C(N)=O)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1

Procedure:
prepared by reaction of 2-(4-tert-butyl-benzenesulfonylamino)-benzamide with tert-butyl bromoacetate
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:11](N)=[CH:10][N:9]=[C:8]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:7]=1)[CH3:2].N([O-])=O.[Na+].[Na+].[Cl-:26]>Cl.O.CCOC(C)=O.[Cu]Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:11]([Cl:26])=[CH:10][N:9]=[C:8]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)ncc1N
Reactant: [Cl-]
Agent: Cl[Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1cc(N2CCN(C)CC2)ncc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
[5-Amino-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid ethyl ester (680 mg, 2.44 mmol) is dissolved under an atmosphere of argon in 18% aqueous hydrochloric acid (12 ml). After cooling the solution to 0° C., a solution of sodium nitrite (244 mg, 3.54 mmol) in water (6 ml) is added over 15 minutes, taking care that the internal temperature did not rise above 5° C. After 20 minutes at 0° C., the reaction mixture is added to a −10° C. solution of copper(I) chloride (freshly prepared, 725 mg, 7.33 mmol) in water (1.8 ml). After 15 minutes at −10° C., TLC analysis indicated complete conversion. The reaction mixture is diluted with EtOAc and poured in a saturated aqueous NaCl solution. The organic layer is separated, dried over Na2SO4, and concentrated. The residue is purified by FCC (CH2Cl2/MeOH, gradient from 98:2 to 90:10) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.27 (t, J=7 Hz, 3H), 2.34 (s, 3H), 2.50 (m, 4H), 3.52 (m, 4H), 3.66 (s, 2H), 4.19 (q, J=7 Hz, 2H), 6.59 (s, 1H), 8.11 (s, 1H). ES+−MS: 298.2, 300.1 (Cl) [M+H]+, ES−−MS: 296.2, 298.2 (Cl) [M−H]−.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:29]=[CH:28][C:14]([CH2:15][N:16]3[C:20]([C:21]([O:23]CC)=O)=[C:19]([CH:26]=O)[N:18]=[CH:17]3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.S(=O)(=O)(O)O>C(O)C.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[C:20]4[C:21](=[O:23])[N:2]([CH3:1])[N:3]=[CH:26][C:19]=4[N:18]=[CH:17]3)=[CH:28][CH:29]=2)=[O:10])=[CH:30][CH:31]=1
Reactant: CNN
Reactant: CCOC(=O)c1c(C=O)ncn1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cn1ncc2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Temperature: 25 °C
Yield: 6.7 %

Procedure:
A solution of methylhydrazine (209 mg) and ethyl 1-[4-(4-chlorobenzoyl)benzyl]-4-formylimidazole-5-carboxylate (6.01 g) in ethanol (10 ml) was refluxed for 2.5 hours. After cooling to room temperature, concentrated sulfuric acid (0.1 ml) was added and the mixture was further refluxed for 15 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=2:1) to provide the title compound as white powder (115 mg, yield 20%). H-NMR (CDCl3) δ: 3.88(3H,s), 5.81(2H,s), 7.46(4H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.77(2H,d,J=8.6Hz), 7.97(1H,s), 8.33(1H,s).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH:12]C(=O)OC(C)(C)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH2:12]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@H]1Cc2ccccc2[C@H]1N
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To tert-butyl [(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]carbamate (253 mg, 0.961 mmol) was added a 4.00 M solution of HCl in 1,4-dioxane (5.00 mL) and the mixture was stirred for 10 min, after which a white solid crashed out. The suspension was concentrated in vacuo and co-evaporated with toluene to afford a white solid, which was dissolved in H2O. The solution was adjusted to pH 10. via addition of Na2CO3. The mixture was then extracted with Et2O (3×30 mL) and the organic extracts were concentrated in vacuo to afford the title compound (150. mg, 99%). LC/MS: Rt=0.85 min, ES+ 164 (AA standard).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1Br
Reactant: Br[Mg]CCCc1ccccc1
Product: OC(CCCc1ccccc1)c1ccccc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 2-bromo-benzaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: C1(OC)C=CC=CC=1.COC1C=CC(C[O:16][N:17]([CH2:21][C:22]2[CH:58]=[CH:57][C:25]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34](=[O:56])[C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]([O:46]CC5C=CC(OC)=CC=5)[C:43]([NH2:45])=[O:44])=[CH:37][CH:36]=4)[CH:29]=3)=[O:27])=[CH:24][CH:23]=2)[C:18]([NH2:20])=[O:19])=CC=1>FC(F)(F)C(O)=O>[OH:46][N:42]([CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:26](=[O:27])[C:25]3[CH:57]=[CH:58][C:22]([CH2:21][N:17]([OH:16])[C:18]([NH2:20])=[O:19])=[CH:23][CH:24]=3)[CH:29]=2)=[O:56])=[CH:36][CH:37]=1)[C:43]([NH2:45])=[O:44]
Reactant: COc1ccc(CON(Cc2ccc(C(=O)c3cccc(C(=O)c4ccc(CN(OCc5ccc(OC)cc5)C(N)=O)cc4)c3)cc2)C(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NC(=O)N(O)Cc1ccc(C(=O)c2cccc(C(=O)c3ccc(CN(O)C(N)=O)cc3)c2)cc1
Reaction time: 6 h
Yield: 81.7 %

Procedure:
With ice-cooling, 10 ml of anisole and 40 ml of trifluoroacetic acid were added to 1.47 g of 1,3-bis[4-[[1-(4-methoxybenzyloxy)ureido]methyl]benzoyl]benzene. The reaction mixture was stirred with ice-cooling for 30 minutes and then at room temperature for 6 hours. The solvent was evaporated under a reduced pressure and the resulting residue was mixed with diethyl ether. The thus formed crystals were collected by filtration and dried to obtain 0.79 g of 1,3-bis[4-[(1-hydroxyureido)methyl]benzoyl]benzene.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:21][CH3:22]>>[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:21]([C:13](=[O:15])[CH2:12][N:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH3:11])[CH3:22]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Product: COC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CN(C)S(=O)(=O)c1ccc(C)cc1

Procedure:
N-(Toluene-4-sulfonyl)sarcosine was coupled to N-methyl-L-phenylalanine methyl ester using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-N-methylphenylalanine methyl ester. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water. Proton and carbon NMR analysis indicated a mixture of amide bond rotomers in about a 65:35 ratio.
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])=[N:5]1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=3)[C:52](O)=[O:53])=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[C:51]([C:52]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:53])[CH:55]=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (108 mg; compound B82) is reacted with 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (88 mg; compound C8) and HBTU (183 mg) in DCM/DMF (10 ml/1 ml) in the presence of DIPEA (227 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] as a solid.