Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Sn](Cl)(Cl)(Cl)Cl>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:8]=2[C:9]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc([N+](=O)[O-])ccc2o1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OC)cc1

Procedure:
reaction of 2-butyl-5-nitrobenzofuran with anisoyl chloride in the presence of tin tetrachloride according to the conditions of the Friedel-Crafts reaction and hydrolysis to form 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran,
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][N:36]([CH3:40])[C:37]([NH2:39])=[O:38].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(Cl)Cl>[CH3:35][N:36]([CH3:40])[C:37](=[O:38])[NH:39][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(N)=O
Reactant: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccnc(Br)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)Nc1cc(CNc2ccccc2C(=O)Nc2cc3ccccc3cn2)ccn1
Yield: 23.7 %

Procedure:
100 mg (0.23 mmol) of 2-[(2-bromopyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide is heated in 2 ml of dioxane with 89 mg (0.28 mmol) of cesium carbonate, 61 mg (0.69 mmol) of N,N-dimethylurea, 4.7 mg (0.0046 mmol) of dipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphos under a cover gas and in a moisture-free environment for 9 hours to a bath temperature of 100° C. It is then mixed with 20 ml of methylene chloride, suctioned off and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate as an eluant. 24 mg (24% of theory) of 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-isoquinolinyl)-benzamide is obtained.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH2:19]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2)[CH3:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH2:19]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)[CH3:20]
Reactant: CCOc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 67.7 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 163 mg of 4-(ethoxy)indoline and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 260 mg of 2-[2-(4-ethoxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([NH2:24])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)CCC>[CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([NH:24][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc2c1oc1ccccc12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1Nc1cccc2c1oc1ccccc12

Procedure:
2-chloro-3-nitropyridine (4.39 g, 27.7 mmol), dibenzo[b,d]furan-4-amine (5.58 g, 30.5 mmol), triethylamine (4.3 mL, 30.9 mmol), and butanol (90 mL) were mixed in a 250 mL round bottom flask. The reaction mixture was refluxed overnight under nitrogen. The solvent was evaporated, leaving an orange solid which was dried under vacuum. The solid was taken up in ethyl acetate, water was added and the layers were separated. The organic layer with washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified on by column chromatography eluting with 10% ethyl acetate/hexanes followed by ethyl acetate (4.6 g, 54%).
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(NCc4ccccc4)cc23)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)C1
Yield: 16.4 %

Procedure:
A mixture of 5-benzylamino-3-(N-methylpyrrolidin-3-yl)-1H-indole (7.80 g, 25.5 mmol), ammonium formate (16.10 g, 255 mmol, 10 eq), and 10% Pd on carbon (0.78 g) in absolute ethanol (250 mL) was heated at reflux under nitrogen for 1 hour. Reaction filtered, and filtrate evaporated under reduced pressure. The residual oil was column chromatographed using silica gel (approximately 200 g) and elution with 0.3% triethylamine in methanol to afford the title compound (0.90 g, 16%) as a pale yellow oil: 1H NMR (CD3OD) δ 7.13 (d, J=8.5 Hz, 1H), 6.94 (br s, 2H), 6.65 (dd, J=2.0 and 8.5 Hz, 1H), 4.91 (s, 2-NH), 3.66-3.50 (m, 1H), 3.17-3.08 (br t, 1H), 2.96-2.85 (m, 1H); 2.67-2.50 (m, 2H), 2.40 (s, 3H), 2.37-2.24 (m, 1H), 2.08-1.93 (m, 1H); FAB LRMS (m/z, relative intensity) 216 (MH+, 100).
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:20])=O)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:20]
Reactant: COC(=O)CC(=O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC(=O)N1C(=O)[C@@H](N)[C@@H]1C
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 155 %

Procedure:
(3S-trans)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-4-methyl-β,2-dioxo-1-azetidinepropionic acid, methyl ester (0.3 g) was dissolved in 10 ml of dichloromethane/trifluoroacetic acid (7:3) and stirred for 15 minutes at -10° C. After evaporation and treatment with ether, 0.31 g of the title compound was obtained as a crystalline material, melting point 75° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)=[O:28]>O1CCCC1>[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:15][CH2:14]2)=[O:35])=[CH:32][CH:31]=1)=[O:28]
Reactant: O=C(CCl)Nc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
2.34 g of 1-[2-(4-chlorophenyl)ethyl]piperazine and 1.57 g of Hunig base (=N-ethyldiisopropylamine) are introduced into 40 ml of tetrahydrofuran. 2.36 g of 4-chloroacetylaminobenzoic acid chloride [see J. Med. Chem. 28 (1985) 910] are added thereto in small portions. After 30 minutes at 40°, the solution is concentrated by evaporation. The residue is chromatographed over silica gel, and recrystallisation is carried out from acetone, yielding 1-(4-chloroacetylaminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 146°-147°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.I[CH2:26][C:27]#[N:28].[C:29]([C:31]1[C@@H:36]([C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)[N:35]2[N:45]=[C:46]([NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:47]=[C:34]2[N:33]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[C:32]=1[CH3:69])#[N:30]>CN(C=O)C>[C:29]([C:31]1[C@@H:36]([C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)[N:35]2[N:45]=[C:46]([N:48]([CH2:26][C:27]#[N:28])[C:49](=[O:58])[O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:47]=[C:34]2[N:33]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[C:32]=1[CH3:69])#[N:30]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Reactant: N#CCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC#N)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (15.7 mg, 113 μmol, 2.1 eq.), 18-crown-6 (30 mg, 113 μmol, 2.1 eq.) and iodoacetonitrile (19 mg, 113 μmol, 2.1 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 μmol) in DMF (2 ml). The reaction mixture was stirred at RT for 12 h and then concentrated under reduced pressure. The residue was acidified with acetic acid and then purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (25 mg, 78% of theory).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:29][C:30]([NH2:32])=[O:31].CO>O>[CH:23]([N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:5][N:2]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:3]5)[CH:27]=[CH:26][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1)([CH3:25])[CH3:24]
Reactant: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: NC(=O)CBr
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CN(CC(N)=O)C3)cc1OCC2

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with bromo acetamide, the crude product was subjected to reverse phase HPLC (Gemini C18 column gradient 10 to 90% MeOH in water+0.1% HCO2H) to give 181 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.33 (s, 1H); 8.21-8.14 (m, 2H); 8.04 (s, 1H); 7.21 (dd, J=8.42, 1.92 Hz, 2H); 7.12-7.02 (m, 2H); 5.44-5.36 (m, 1H); 4.32 (t, J=5.05 Hz, 2H); 3.80-3.61 (m, 3H); 3.30 (t, J=7.44 Hz, 2H); 3.16-3.09 (m, 4H); 1.52 (d, J=6.59 Hz, 6H). LCMS: RT=6.49 min, M+H+=408
Reaction SMILES: N1C2C(=CC=CC=2)C(C2[O:14]C(C)N(C(OC)=O)C=2)=C1.[C:20]([NH:23][CH:24]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])(=[O:22])[CH3:21].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCCC1>[C:20]([NH:23][CH:24]([C:29]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:14])[C:25]([O:27][CH3:28])=[O:26])(=[O:22])[CH3:21]
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)NC(C)=O
Reactant: COC(=O)N1C=C(c2c[nH]c3ccccc23)OC1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(NC(C)=O)C(=O)c1c[nH]c2ccccc12
Yield: 84 %

Procedure:
Oikawa et al. (J. Org. Chem., vol. 42, pp. 1213-1216, 1977) describes preparation of methyl 5-(3-indolyl)-2-methyloxazole-3-carboxylate in 33% yield by oxidation of methyl 2-acetamido-3-(3-indolyl)propionate with DDQ in tetrahydrofuran. Use of aqueous tetrahydrofuran gave methyl 2-acetamido-3-(3-indolyl)-3-oxopropionate in 84% yield. Preparation of the corresponding thiazole or imidazole is not described.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[C:30](=[O:32])=[O:31].Cl>O1CCCC1.O>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C=O
Reactant: CCCCCOc1ccc(-c2ncc(-c3ccc(Br)cc3)s2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCOc1ccc(-c2ncc(-c3ccc(C(=O)O)cc3)s2)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution of 2-(4-pentyloxyphenyl)-5-(4-bromophenyl)thiazole (2.3 g) in dry tetrahydrofuran (60 ml) was cooled to −60° C., and a solution of n-butyllithium (1.66M in n-hexane, 4.46 ml) was added slowly to maintain the reaction temperature at −60° C. After stirring for 1 hour, a solution of n-butyllithium (1.66M in n-hexane, 1.0 ml) was additionally added. The reaction mixture was allowed to warm to −40° C. After stirring for 30 minutes, dry-ice (5 g) was added. The reaction mixture was allowed to warm to room temperature over 30 minutes. To the reaction mixture was added water (25 ml) and 0.5N-hydrochloric acid (100 ml), then extracted with dichloromethane (500 ml). The organic layer was washed with brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in acetonitrile, and collected by filtration to give 4-[2-(4-pentyloxyphenyl)thiazol-5-yl]benzoic acid (1.70 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([N:9]=[C:10]=[O:11])=[O:8])([O-:3])=[O:2].[C:15]([CH:17]1[CH2:19][NH:18]1)#[N:16]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([NH:9][C:10]([N:18]1[CH2:19][CH:17]1[C:15]#[N:16])=[O:11])=[O:8])([O-:3])=[O:2]
Reactant: O=C=NC(=O)c1cccc([N+](=O)[O-])c1
Reactant: N#CC1CN1
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 5.8 g. m-nitrobenzoyl isocyanate in 100 ml. toluene is added dropwise, while stirring, in the course of about 10 minutes to 2.04 g. 2-cyanoaziridine in 50 ml. anhydrous toluene. The reaction mixture is stirred for 30 minutes at ambient temperature and the precipitated solid product is filtered off with suction, washed with toluene and triturated with diethyl ether. There are thus obtained 4.8 g. white 1-(N-3-nitrobenzoyl-carbamoyl)-2-cyanoaziridine; m.p. 156°-158° C. (after drying for 1.5 hours in a vacuum at 70° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[N:13][C:14]([O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:15][CH:16]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ncc(Br)cn1
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of ethyl 2-hydroxyacetate (0.081 g, 0.775 mmol) in toluene (1.0 mL) was added NaH (60% in mineral oil, 0.037 g, 0.931 mmol) at room temperature. The mixture was stirred for 30 min and a solution of 5-bromo-2-chloropyrimidine (0.100 g, 0.517 mmol) in toluene (0.5 mL) was added. The reaction mixture was stirred at 60° C. for 16 h. The mixture was diluted with EtOAc and slowly quenched with water. The organic layer was separated, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (82 mg, 61% yield) as a clear colorless oil. LCMS, [M+H]+=260.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])[N:17]=1)[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])[CH3:2].[CH2:25]([NH:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:16]1[CH:21]=[C:20]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH3:31])[N:19]=[C:18]([CH3:23])[N:17]=1)[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])[CH3:2]
Reactant: CCOC(=O)CN(c1cc(Cl)nc(C)n1)c1c(C)cc(C)cc1C
Reactant: CCCCNCC
Solvent: CS(C)=O
Product: CCCCN(CC)c1cc(N(CC(=O)OCC)c2c(C)cc(C)cc2C)nc(C)n1
Temperature: 135 °C
Yield: 122.2 %

Procedure:
A mixture of [(6-chloro-2-methyl-pyrimidin-4-yl)(2,4,6-trimethylphenyl)-amino]-acetic acid ethyl ester (85 mg, 0.244 mmol) and N-butyl-ethylamine (0.17 ml, 1.1 mmol) in 4 ml DMSO was heated at 135° C. for 15 hours. An additional 1 ml of N-butylethylamine was added and the reaction was heated at that temperature for an additional 15 hours (tlc showed no starting material). The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 123 mg of a light amber oil. The oil was purified through silica gel chromatotron using 5% ethyl acetate in hexane as eluent to give 92 mg (91%) of the title compound as a white glass. 1H NMR (CDCl3) δ 6.94 (s, 2H), 4.69 (s, 1H), 4.23 5,<; (s, 2H), 4.22 (q, 2H), 3.35 (q, 2H), 3.15 (t, 2H), 2.36 (s, 3H), 2.31 (s, 3H), 2.21 (s, 6H). 1.3-1.5 (m, 2H), 1.34 (tL 3H), 1.1-1.3 (m, 2H), 1.01 (t. 3H), 0.80 (t, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([CH2:32][CH2:33]O)=[C:29]([CH3:31])[N:30]=2)=[CH:22][CH:21]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:33][CH2:32][C:28]2[S:27][C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[N:30][C:29]=2[CH3:31])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OCCc2sc(-c3ccc(Cl)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-ethanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][C:17](O)=O)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:26]1CCCC1>>[CH2:1]([C:3]1([CH:16]([OH:26])[CH3:17])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:2]
Reactant: CCC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC1(C(C)O)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
To solution of (1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.52 g, 2.0 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.114 g, 3.0 mmol) in several small portions. The mixture was stirred at room temperature for 6 hours. It was quenched with ethyl acetate carefully and washed with water. The organic layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.389 g (79%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3) δ 7.82 (br, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 7.18 (td, 1H), 7.13 (td, 1H), 4.07 (m, 1H), 4.01 (m, 1H), 3.70 (m, 1H), 3.64 (m, 1H), 2.89 (m, 1H), 2.77 (dt, 1H), 2.71 (br, 1H), 2.20 (m, 1H), 2.05 (m, 1H), 2.00 (m, 1H), 1.90 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=246 (MH+), ESI (−) MS m/e=244 (MH−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O>C(O)CCCC>[CH2:9]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH2:14][CH2:13][CH2:12][CH2:17][CH3:16])=[O:6])[CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCCCCO
Product: CCCCCNc1cc(C(=O)OCCCCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (6 g), n-pentanol (60 ml), and conc. sulphuric acid (0.5 ml) was refluxed for 24 hours. After cooling, the precipitated n-pentyl 3-n-pentylamino-4-phenoxy-5-sulphamyl-benzoate was isolated by filtration and recrystallized from n-pentanol. After drying in vacuo, the compound was obtained with a melting point of 138°-139°C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Li+].[Cl-].[I:11]I>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[I:11]
Reactant: Clc1ccc(Cl)nn1
Reactant: II
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cc(I)c(Cl)nn1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
3,6-Dichloropyridazine (3) (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 30 min according to TP 2. I2 (381 mg, 1.5 mmol) dissolved in dry THF (2 mL) was then dropwise added and the resulting mixture was stirred for 0.5 h. The reaction mixture was quenched with a sat. aq. Na2S2O3 solution (10 mL) and with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:2) furnished compound 5a (231 mg, 84%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][CH2:18][CH:19]2[CH2:23][O:22]C(C)(C)[O:20]2)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=O.Cl.[NH2:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]([CH2:18][CH:19]([OH:20])[CH2:23][OH:22])[C:29](=[O:30])[CH2:28][N:27]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]=2[CH:16]=1
Reactant: NCC(=O)Cl
Reactant: CC1(C)OCC(CNc2ccc(Cl)cc2C(=O)c2ccccc2F)O1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of 5-chloro-2-{[(2,2-dimethyl-1,3-dioxolan-4-yl)-methyl]-amino}-2'-fluorobenzophenone are dissolved in 25 ml of absolute carbon tetrachloride, treated with 1.5 g of glycyl chloride hydrochloride and stirred for 1 hour at 25°C. Then the solvent is completely distilled off on a rotary evaporator and the residue is stirred with 25 ml of 3 N hydrochloric acid for 30 minutes. Subsequently the aqueous acidic solution is extracted with ether, made alkaline with 3 N sodium hydroxide or ammonia and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried over magnesium sulfate, filtered and evaporated. By chromatography on silica gel with ethyl acetate/methanol (9:1) there is isolated from the residue pure 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 116°-117°C. The compounds resulting as intermediates in the reaction 2-amino-4'-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methyl]-2' -(2-fluorobenzoyl)-acetanilide and 2-amino-4'-chloro-N-(2,3-dihydroxypropyl)-2'-(2-fluorobenzoyl)-acetanilide are not isolated.