Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([O:28][CH3:27])=[C:34]([CH3:35])[CH:33]=5)[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)cc1C
Temperature: 80 °C
Yield: 59.4 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (70 mg, 0.18 mmol), 2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (69 mg, 0.27 mmol) and tetrakis(triphenylphosphine)palladium (0) (21 mg, 0.018 mmol) in 1,2-dimethoxyethane (2.0 mL), 2 M Na2CO3 (276 μL, 0.55 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 20 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (50 mg, 58%). ESI-MS m/z calc. 467.4. found 468.7 (M+1)+. Retention time 1.96 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(#N)C>[C:11]([NH:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(Cl)cc1N
Solvent: CC#N
Product: CC(=O)Nc1cc(Cl)ccc1C#N

Procedure:
To 100 ml of acetonitrile were added 30 g of 2-amino-4-chlorobenzonitrile obtained in Step (2) and then 30 ml of acetic anhydride, and the mixture was refluxed by heating. After the completion of the reaction, the solvent was distilled off, then to the residue was added 500 ml of water, and the crystals thus-deposited were collected by filtration, washed with water and dried. Yield: 29 g (75.6%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.C(S)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8][CH2:10][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: SCCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Nc1nc(SCCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine, phenethylmercaptan and DBU in THF. ES-MS m/e (%): 378 (M{81Br}+H+, 100), 376 (M {79Br}+H+, 99).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O.[Cu]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([S:22][C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: Clc1ncccn1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3ncccn3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
3.12 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole is dissolved in 50 ml of absolute dimethylformamide and combined with 0.3 g of sodium hydride (80% strength in white oil). The mixture is stirred for 30 minutes and then 1.26 g of 2-chloropyrimidine in 25 ml of dimethylformamide is added dropwise thereto. The reaction mixture is combined with a pinch of powdered copper and stirred for one week under argon at room temperature. The solution is then poured into 300 ml of ice water, the product is extracted with ethyl acetate, the organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from glacial acetic acid/ether, thus obtaining 2.87 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyrimidylthio)imidazole, mp 86°.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.O.[OH-].[K+].[CH:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(O)C>[CH:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:7]3[N:8]=[CH:9][NH:10][C:6]=3[CH2:5][CH2:4][NH:3]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: NCCc1c[nH]cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(C2NCCc3[nH]cnc32)cc1
Yield: 94.9 %

Procedure:
A mixture of histamine dihydrochloride (1.85 g, 10.0 mmol), water (10 mL), potassium hydroxide (1.72 g, 30.0 mmol), ethanol (25 mL) and 4-isopropylbenzaldehyde (1.62 g, 10.91 mmol) was heated to reflux for 1.5 h. Ethanol was evaporated and the residue was diluted with water (40 mL). Extraction (5×25 mL DCM), washing of the combined extracts (2×50 mL brine) and drying (MgSO4) yielded 2.29 g (87%) of crude 4-(4-isopropylphenyl)-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine, which was used for the next synthetic step without further purification. This amine (0.48 g, 1.99 mmol) was dissolved in DCM (5 mL) and added to a 30 min old mixture of 3-(4-fluorophenyl)propionic acid (0.31 g, 1.84 mmol), HOBt (0.27 g, 1.20 mmol) and EDC (0.42 g, 12.19 mmol) in DCM (10 mL). After 18 h the mixture was washed with water (50 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution with DCM/methanol). 0.24 g (33%) of the title amide was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[O:10]C=CC=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>CC(C)=O.O>[NH2:1][C:2]1[C:3]([C:9]([OH:10])=[O:15])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1-c1ccco1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1ccc(Cl)nc1C(=O)O
Temperature: 0 °C
Yield: 67.7 %

Procedure:
3-Amino-6-chloro-2-(2-furanyl)pyridine (1.06 g) was dissolved in acetone (25 mL) and cooled in an ice bath to 0° C. A solution prepared of potassium permanganate (2.57 g) in water (40 mL) was added drop wise to this solution. After complete addition, the reaction mixture was allowed to warm to room temperature and stirred for hours. The mixture was cooled again to 0° C. and a second portion of potassium permanganate (858 mg) in water (15 mL) was added and the cool bath removed. After stirring for 2 hours, the reaction mixture was filtered through a pad of celite, the filter cake was washed carefully with water, methanol and ethyl acetate and concentrated to approx. 20 mL on a rotary evaporator. 2N Sodium hydroxide solution was added to adjust the pH-value to −12 and the aqueous layer was washed 2× with MTB-ether. The aqueous layer was adjusted to pH ˜2 by addition of 6N hydrochloric acid and extracted 3× with MTB-ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 636 mg of the title compound of the formula
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:28][C:20](=[O:22])[C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6.65 g. of Nα -benzyloxycarbonyl-D-phenylalanine (0.022 mol) and 4.38 g. (0.022 mol) of L-leucine methyl ester hydrochloride in 60 ml. of spectrograde dimethylformamide is chilled in ice and treated with 3.0 ml. of triethylamine (2.24 g.). 1-Hydroxybenztriazole, 3.3 g., and dicyclohexylcarbodiimide, 5 g., are added and the reaction stirred to room temperature overnight and for 24 hours at room temperature. The mixture is filtered and the solvent evaporated under reduced pressure. The residue is dissolved in 200 ml. of ethyl acetate and washed with 0.1N hydrochloric acid, saturated salt solution, 5% sodium bicarbonate solution, saturated salt solution and water. The ethyl acetate solution is dried over magnesium sulfate, filtered and evaporated to a crystalline residue. The product is recrystallized twice from ethyl acetate and petroleum ether; 7.3 g.; m.p. 125°-126° C.; [α]D23 -20.3° (c 1.02, methanol).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=[O:8])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(Br)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2cccc(Cl)c2)c(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
41.0 mg (0.12 mmol) of the compound from Example 14A are provided in 3 ml of tetrahydrofuran, and 28.4 mg (1.19 mmol) of lithium hydroxide and 0.8 ml of water are added at room temperature. The mixture is stirred at room temperature overnight, a 1N aqueous HCl solution is subsequently added until an acidic pH is obtained, the mixture is extracted three times with dichloromethane and the extracts are dried over sodium sulfate, filtered and concentrated. 35.0 mg (83% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1F)[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:23][S:24]([CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:26])=[O:25].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][S:24]([CH3:23])(=[O:25])=[O:26])[CH2:34][CH2:33]1)[CH3:2]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(F)c(CC)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 69.6 %

Procedure:
1-Ethyl-2-fluoro-4-(ethyloxy)-5-nitrobenzene (Example 208, step A) (0.50 g, 2.3 mmol) was dissolved in DMSO (15 mL). K2CO3 (0.97 g, 7.0 mmol) and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, step B) (1.0 g, 4.7 mmol) were added and the reaction mixture was heated to 80° C. and allowed to stir over the weekend. The mixture was then heated to 120° C. for 4 h. The mixture was cooled to rt then poured into H2O and extracted with DCM. The combined organics were dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified on a 40 g ISCO column (EtOAc to 10% MeOH in EtOAc). The desired fractions were combined and the solvent removed in vacuo to give the title compound of Step A (0.63 g, 1.6 mmol, 66%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 6.56 (s, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.23-3.12 (m, 2H), 3.03 (s, 3H), 3.00-2.91 (m, 6H), 2.72-2.62 (m, 4H), 2.57 (q, J=7.5 Hz, 2H), 2.22 (s, 3H), 1.44 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H). MS (M+H, ES+) 386.
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[Cl-].[CH3:14][C:15](=[CH2:22])[C:16]([O:18]CC[NH3+])=[O:17]>O1CCCC1>[N:8]1([C:6]([NH:3][CH2:2][CH2:1][O:18][C:16](=[O:17])[C:15]([CH3:22])=[CH2:14])=[O:7])[CH:9]=[CH:10][N:11]=[CH:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=C(C)C(=O)OCC[NH3+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCNC(=O)n1ccnc1
Temperature: 17 °C
Reaction time: 3 h

Procedure:
25.4 g (0.17 mole, >97% FLUKA) CDI were suspended in about 150 ml THF (tetrahydro furane) at room temperature. Upon partial dissolution the suspension was cooled down to about 17° C. After about 30 min stirring 25.9 g (0.16 mole) 2-(2-Methyl-acryloyloxy)-ethyl-ammonium chloride were added to the mixture under cooling on ice in several portion during about 1 h keeping the reaction mixture at about 23° C. A yellow suspension was obtained. After about 3 h of stirring at about 23° C. the suspension was filtrated. The filter cake was washed with THF. To the clear yellow filtrate about 300 mg phenothiazine were added. Solvent was evaporated. A clear orange viscous resin was obtained (containing traces of residual solvent). Yield was quantitative, 1H NMR indicates the desired product.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C1[O:19][C:8]([CH3:18])([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)OC1>CCOCC>[C:1]([O:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8](=[O:19])[CH3:18])=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC1(Cc2ccc(CO)cc2)OCCO1
Solvent: CCOCC
Product: CC(=O)Cc1ccc(COC(C)=O)cc1

Procedure:
Acetyl chloride (5.0 ml) in dry ether (20 ml) was added dropwise to a stirred solution of 1-(4-hydroxymethylphenyl)propane-2-one ethylene ketal (3.0 g) (as prepared in description 1) in dry ether (50 ml). The mixture was refluxed for 1 h, evaporated and deketalised as described in description 1, to give the title compound as a colourless oil which was bulb distilled, bath temperature 120°-130°/o. 1 mm Hg.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:23]2.O[CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:35][CH:30]([CH2:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[CH:28][CH:27]=2)[C:31]([O:33][CH3:34])=[O:32]
Reactant: OCCCNc1ccccn1
Reactant: COC(=O)C(C)Cc1cc2cc(O)ccc2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C(C)Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.1 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.13 g, 0.57 mmol) was added to the solution of methyl 3-(5-hydroxyindolyl)-2-methylpropanoate (0.062 g, 0.27 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.06 g, 0.40 mmol), as prepared in step b of Example 1, and tri-n-butylphosphine (0.11 g, 0.53 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated and the residue was purified by flash chromatography on silica gel (10%–50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.015 g, 15%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (m, 1H), 7.40 (m, 1H), 7.21 (d, J=8.9 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H), 6.88 (dd, J=8.9, 2.4 Hz, 1H), 6.54 (m, 1H), 6.41 (m, 1H), 4.89 (br s, 1H), 4.45 (dd, J=14.2, 7.3 Hz, 1H), 4.10 (m, 4H), 3.63 (s, 3H), 5.52 (q, J=6.5 Hz, 2H), 2.13 (m, 2H), 1.66 (m, 1H), 1.52 (m, 1H), 1.16 (d, J=7.1 Hz, 3H), 0.93 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)=[CH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH2:13])=[CH:3]1
Reactant: Cn1cc(CCNC(=O)OC(C)(C)C)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(CCN)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of tert-butyl (2-(1-methyl-1H-indol-3-yl)ethyl)carbamate (1.29 g, 4.71 mmol) in DCM (15 mL) was added TFA (7 mL) at ˜0° C. to 5° C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the crude product which was diluted with DCM and washed with sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried and concentrated to give the desired product (700 mg, 4.02 mmol, 85% yield) as yellow oil. MS (ESI) m/z 175.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]([CH3:29])[NH:24][CH2:23][CH2:22]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[CH:27][CH:28]=[C:19]([C:15]5[O:14][CH:18]=[CH:17][CH:16]=5)[CH:20]=4)[CH:25]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3ccco3)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(-c3ccco3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:26]1[S:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:29][N:30]=1)[NH:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:16])=[CH:10][CH:9]=1.CN(C=O)C.CCN=C=NCCCN(C)C.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:53][S:54]([NH:57][C:33](=[O:35])[CH2:32][CH2:31][C:28]1[S:27][C:26]([CH:4]([NH:5][C:6](=[O:25])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[O:16])=[CH:12][CH:13]=2)[CH2:3][CH:2]([CH3:36])[CH3:1])=[N:30][CH:29]=1)(=[O:56])=[O:55]
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)O)s2)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)NS(C)(=O)=O)s2)cc1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A mixture of 3-[2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid (Example 13) (91 mg, 0.2 mmol), DMF (5 ml), EDCI (48 mg, 0.2 mmol) and DMAP (26 mg, 0.2 mmol) was stirred at room temperature. After 10 min. methane sulfonamide (51 mg, 0.5 mmol) was added. After stirring 16 h the solution was diluted with EtOAc and washed with 1N HCl (2×). The organic layer was dried over Na2SO4; filtered; and concentrated under reduced pressure. The resulting solid was purified by Flash 12 chromatography eluting with 10% AcOH in EtOAc to give 30 mg of the title compound as a white amorphous solid. MS [M−1]+584.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
3-Methyl-2-nitrobenzoic acid 67 (30.0 g, 166 mmol, 1.0 equiv.) was suspended in CH2Cl2 (150 ml) and the suspension was cooled to 0° C. using an ice bath. Oxalyl chloride (2.0 M in CH2Cl2, 166 ml, 332 mmol, 2.0 equiv.) was added to the stirred reaction mixture through a pressure equalizing dropping funnel over 30 min. DMF (10 drops) was added dropwise. The reaction mixture was allowed to warm up to room temperature. After 30 min., the reaction was concentrated to dryness on a rotary evaporator. The solid material was re-dissolved in CH2Cl2 (200 ml) and was concentrated to dryness on a rotary evaporator to give 3-methyl-2-nitro-benzoylchloride 68 (32.9 g, 99%) as an off white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1cccc(C(F)(F)F)c1
Yield: 88.6 %

Procedure:
A suspension of 0.492 g (2.6 mmol) of ethyl 1H-indole-2-carboxylate, of 0.683 g (2.86 mmol) of 3-trifluoromethylbenzyl bromide and of 0.898 g (6.5 mmol) of potassium carbonate in 50 ml of dimethylformamide is stirred at 60° C. for 24 hours. The reaction mixture is cooled and is poured into a mixture of ice-cold water and of ethyl acetate. After settling, the organic phase is separated and is then washed with two times 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The solution is dried over magnesium sulfate and filtered, and then the filtrate is concentrated under reduced pressure. 0.8 g of an oil is obtained, which oil is used as is in the following stage.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH:9](O)=[O:10]>>[CH:9]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:10]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=CO
Product: CC(C)[C@H](NC=O)C(=O)O
Reaction time: 17 h

Procedure:
To valine (11.7 g, 0.10 mol) in 88% formic acid (40 ml) is added acetic formylanhydride (26.3 g, 0.30 mol) over 0.5 hr at 5°. The reaction mixture is warmed to 24° and stirred for 17 hours. The reaction is worked up by distilling off (bath temp. 45°-50°) the solvent, excess anhydride and acetic acid, to give, as a white solid, N-formylvaline, recrystallized from hot ethanol, m.p. 143°-145°.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:42]2[C:41](=[C:43](O)[CH2:44][CH3:45])[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.[CH2:51]([O:53][CH:54]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([OH:67])=[CH:63][CH:62]=1)[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH3:52]>C1COCC1.O>[CH:32]1[C:42]2[C:41](=[CH:43][CH2:44][CH2:45][O:67][C:64]3[CH:63]=[CH:62][C:61]([CH2:60][CH:54]([O:53][CH2:51][CH3:52])[C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:66][CH:65]=3)[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: CCC(O)=C1c2ccccc2COc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCC=C2c3ccccc3COc3ccccc32)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethyl azodicarboxylate (0.235 ml, 1.49 mmol) was added at 0° C. to a stirred solution of triphenylphosphine (0.392 g, 1.49 mmol) and 3-(6H-dibenzo[b,e]oxepin-11-ylidene1-propanol (0.252 g, 1.0 mmol) in dry THF (5 ml) and the mixture stirred for 5 min. A solution of ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.356 g, 1.49 mmol) in dry THF (5 ml) was then added, the mixture allowed to warm to room temperature, and stirring continued for 18 h. The resulting mixture was treated with water (50 ml), and the products extracted into dichloromethane (4×50 ml). The extracts were combined, washed with brine, dried (Na2SO4) and evaporated to an orange gum. This was then purified by column chromatography on silica gel (20% Et2O in petroleum eluent) to give the title compound as an inseparable 4:1 mixture of E and Z double-bond isomers, as a pale yellow gum; 0.252 g (53%).