Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)=O)[C:3]([O:5][CH3:6])=[O:4].[C:17]([NH:20][C:21]([NH2:23])=[S:22])(=[O:19])[CH3:18]>O1CCCC1>[C:17]([NH:20][C:21]1[S:22][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[N:23]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)C(Br)C(=O)c1cccc(C#N)c1
Reactant: CC(=O)NC(N)=S
Solvent: C1CCOC1
Product: COC(=O)c1sc(NC(C)=O)nc1-c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a solution of methyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (1.25 g, 4.4 mmol) in 20 mL of tetrahydrofuran was added 1-acetylthiourea (0.52 g, 4.4 mmol). The resulting mixture was stirred at 65° C. for 3 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with 10% aq HCl, saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with hexanes/ethyl acetate left the title compound as a white solid (0.4 g, 30%). MS (ESI) 302.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[CH2:18]([O:17][C:15]([CH:9]1[CH2:10][C:11]([F:14])([F:13])[CH2:12][NH:8]1)=[O:16])[CH:19]=[CH2:20]
Reactant: C=CCOC(=O)C1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)C1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 2-allyl ester 1-tert-butyl ester (Example 14c, 5.85 g, 20.09 mmol) was dissolved in a 5% solution of trifluoroacetic acid in dichloromethane and stirred at 25° C. for 16 h. The solvent was removed in vacuo and the crude 4,4-difluoro-pyrrolidine-2-carboxylic acid allyl ester (6.14 g, 20.09 mmol, 100% yield) was obtained as the trifluoroacetic acid salt, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 2.75-2.86 (1H, m), 2.90-3.02 (1H, m), 3.76-3.93 (2H, m), 4.68-4.78 (3H, m), 5.33-5.39 (2H, m), 5.84-5.94 (1H, m).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Li].O>CCOCC>[OH:1][CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH2:2]1
Reactant: [Li]c1ccccn1
Reactant: c1ccc2c(c1)CC1OC1C2
Solvent: CCOCC
Solvent: O
Product: OC1Cc2ccccc2C(c2ccccn2)C1
Temperature: -20 °C

Procedure:
A solution of 25 g of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene in 250 ml ether is added to a solution of 2-pyridyl lithium (prepared from 2-bromopyridine and butyllithium) cooled to -20° C. After addition, the mixture is allowed to come to room temperature over several hours, then cooled again and treated with water. The separated, dried organics are taken to dryness, and the product purified by chromatography in neutral alumina.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19]4[CH2:25][CH2:26][NH:27][CH2:28][C:18]=4[C:17]=3[CH:16]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:34](C)=O.[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19]4[CH2:25][CH2:26][N:27]([CH3:34])[CH2:28][C:18]=4[C:17]=3[CH:16]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc31)CNCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCc2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc3n2C)C1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in CH3OH (3 mL) was added formaldehyde (30 L, 0.29 mmol) and NaBH(OAc)3 (110 mg, 0.52 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. Then the mixture was concentrated and the residue was dissolved in CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-one (102 mg, 98%) as a yellow solid. The free base was converted to the HCl salt to give the title compound (100 mg, 90%) as a yellow solid: mp 264-268° C. (decompose); 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.56-7.36 (m, 8H), 7.10 (dd, J=8.5, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 3.0 Hz, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.58 (m, 1H), 4.27 (m, 1H), 3.78 (m, 1H), 3.72 (s, 3H), 3.50 (m, 1H), 3.18 (m, 2H), 2.97 (s, 3H); ESI MS m/z 400 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.9 min.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OCc1c(Br)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Temperature: 150 °C
Yield: 27.9 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (150 mg, 0.789 mmol), Acetic acid 2,6-dibromo-benzyl ester (487 mg, 1.58 mmol), cuprous iodide (30 mg, 0.16 mmol) and potassium carbonate (109 mg, 0.789 mmol) were deposited in a sealed vessel. 3 mL DMSO was added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (30 mg, 0.l6 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (93 mg, 0.22 mmol). MS (ESI) 417.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:52]>>[NH2:52][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCCNC(=O)CCCCCn1c(COCC)nc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCNC(=O)CCCCCn1c(COCC)nc2c(N)nc3ccccc3c21

Procedure:
6-[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-N-propylhexanamide (4.1 g, 11 mmol) was treated with mCPBA (5.74 g, 33.3 mmol) followed by ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (2.85 g, 14.9 mmol) according to the method described in Part D of Example 8. The crude product was purified by column chromatography on silica gel (eluting with 97:3 dichloromethane:methanol) followed by recrystallization from methanol:water to provide 0.548 g of 6-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-N-propylhexanamide as beige needles, mp 161-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].Cl.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:32]1([C:35](O)=[O:36])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:35]([C:32]2([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]3[CH3:25])[CH2:34][CH2:33]2)=[O:36])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: CC1CCCCN1C1(C(=O)O)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: CC1CCCCN1C1(C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Yield: 33 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(2-methylpiperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16L carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(2-methylpiperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a yellow solid (33%). MS ISP (m/e): 519.3 (100) [(M+H)]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][NH:10]1.F[C:21](F)(F)S(OC)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]1[CH3:21]
Reactant: CCOC(=O)c1c[nH]n(-c2c(Cl)cccc2Cl)c1=O
Reactant: COS(=O)(=O)C(F)(F)F
Product: CCOC(=O)c1cn(C)n(-c2c(Cl)cccc2Cl)c1=O
Yield: 87 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 2-(2,6-dichlorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.7 g, 12 mmol) and methyl trifluoromethanesulfonate (3 mL) as starting materials, the title compound (3.4 g, 87%) was obtained as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:9][C:5]2=[N:6][C:7]=1[CH3:8].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:9][C:5]2=[N+:6]([O-:24])[C:7]=1[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2nc(C)c(Br)cc2[nH]1
Solvent: ClCCl
Product: CCCCc1nc2c(cc(Br)c(C)[n+]2[O-])[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.7 %

Procedure:
7.8 g (29.1 mmole) of the compound obtained in step 4 was dissolved in 50 ml of methylene chloride and to the resulting solution was added 8.8 g (43.6 mmole) of 85% m-chloroperbenzoic acid. The resultant was stirred for 16 hours at room temperature and filtered to get a solid, which was washed with ethyl ether (12 ml×3) to obtain 8.0 g of the title compound (yield 97%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16]Br)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-:19].[K+].[K+]>CS(C)=O.O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][OH:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1nc(=O)c2cc(CBr)ccc2[nH]1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
To a suspension of 2.0 g of impure 2-butyl-6-(bromomethyl)-4(1H)-quinazolinone in 35 ml of dimethylsulfoxide and 20 ml of water is added 1.0 g of potassium carbonate. The reaction mixture is heated at reflux for 6 hours, resulting in a complete solution. Upon cooling slowly to room temperature a white precipitate forms and is collected by filtration. The filter cake is purified by flash chromatography on silica gel, eluting with 9:1 chloroform-methanol to give 0.67 g of the desired product as a white solid. CI MASS SPEC 233(M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](C(S)C(O)=O)=[S:10])=[CH:4][CH:3]=1.[NH:16]([C:18]([O:20][CH3:21])=[O:19])[NH2:17]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:17][NH:16][C:18]([O:20][CH3:21])=[O:19])=[S:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC(=S)C(S)C(=O)O)cc1
Reactant: COC(=O)NN
Solvent: ClCCl
Product: COC(=O)NNC(=S)Cc1ccc(C)cc1
Yield: 81.8 %

Procedure:
A mixture of 37.0 g of 2-[2-(4-methylphenyl)-1thioxoethyl]thioglycolic acid, 18.2 g of methyl hydrazinocarboxylate and 250 ml of dichloromethane was heated at reflux for one hour and then evaporated in vacuo. The residue was concentrated at high vacuum and 45° C. for one hour. The oily residue was chromatographed on a 75×800 mm dry column of silica gel, eluting with dichloromethane. The desired fractions were pooled and the solid crystallized from toluene-hexane, giving 30 g of the desired compound as off-white needles, mp 104.5-105° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 2.38 (s, CH3); 3.79 (s, 3H, OCH3); 4.07 (s, 2H, CH2CS); 7.23 (s, 4H, C6H4); 8.68 (bs, 1H, NH); 9.52 (bs, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:10](=[O:20])[C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:25](I)[CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([O:20][C:10]1[C:9]([C:21]#[N:22])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=1)[CH:26]=[CH2:25]
Reactant: COc1ccc2[nH]c(=O)c(C#N)c(-c3cccc(F)c3)c2c1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1nc2ccc(OC)cc2c(-c2cccc(F)c2)c1C#N
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.00 g, 3.40 mmol) in 20 mL of N,N-dimethylformamide at 0° C. was added sodium hydride (163 mg of 60% dispersion in mineral oil, 4.08 mmol). After 30 minutes, allyl iodide was added (0.342 mL, 3.74 mmol), and the reaction was stirred for 2 hours. The reaction was quenched with water and partitioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was subjected to flash chomatography through SiO2 (5-60% EtOAc/hexane) to provide the second eluting product as the titled compound. 1H NMR, difference nOe, and HMQC NMR spectral data for the product were consistent with the titled compound. ESI+ MS: 335.1 [M+H]+.
Reaction SMILES: O(CC)[C:2]([S-])=[S:3].[K+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([NH2:16])[CH:10]=1>C(O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][C:2]([SH:3])=[N:16][C:11]=2[CH:10]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: Sc1nc2cc(Cl)ccc2o1
Yield: 99.1 %

Procedure:
A mixture of potassium ethyl xanthate (13.4 g, 84.0 mmol) and 4-chloro-2-aminophenol (10 g, 69.6 mmol) was dissolved in absolute ethanol (200 mL). The mixture was stirred under reflux overnight. After cooling, the solvent was evaporated under reduced pressure, the residue was dissolved in water (200 mL) and treated with HOAc to adjust pH to 5. A solid formed, which was filtered and dried to afford 5-chloro-2-mercaptobenzoxazole (12.8 g, yield 99.1%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10](I)=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:27]=1)[C:21](N(OC)C)=[O:22]>>[Br:15][C:16]1[CH:27]=[C:20]([C:21]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=2)=[O:22])[CH:19]=[N:18][CH:17]=1
Reactant: CC(C)n1cc(I)c2cnc(Cl)nc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Product: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2cnc(Cl)nc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 2-chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 120) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a yellow solid in 41% yield, 1.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:38])[CH2:34][CH2:35][CH2:36][CH3:37]>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:33](=[O:38])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: CCCCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.024 ml pentanoyl chloride (0.2 mmol). After 1.5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 84 mg product as a light yellow solid (98%). MS (ISP) 535.3 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][CH:27]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH3:28]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:35]([C:32]4[CH:33]=[CH:34][C:29]([CH:27]([CH3:28])[CH3:26])=[CH:30][CH:31]=4)(=[O:37])=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C(C)C)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-(propan-2-yl)benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26]([OH:28])=O)[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.Cl.Cl.[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][CH2:42][NH2:43]>C(N(CC)CC)C>[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][CH2:42][NH:43][C:26](=[O:28])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH3:29]
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: NCCc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1nc2ccccc2[nH]1

Procedure:
Following the procedure of Example 70, the title compound was prepared from 0.50 g (1.26 mmol) of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan and 0.33 g (1.41 mmol) of 1H-benzimidazole-2-ethanamine dihydrochloride with 0.5 mL of added triethylamine. The purified product after chromatography was obtained as a white foam, 0.38 g (56%); 1H NMR (CDCl3) δ1.46-1.91 (17H, m), 3.01-3.16 (2H, m), 3.27 (1H, d, J 15 Hz), 3.43 (1H, d, J 15 Hz), 3.58 (2H, m), 4.80 (1H, br s), 5.23 (1H, s), 6.67 (1H, m), 6.89-7.72 (10H, m), 8.28 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH2:7]O.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:7][C:6]1[CH:5]=[C:4]([Cl:9])[S:3][C:2]=1[Cl:1]
Reactant: OCc1cc(Cl)sc1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Clc1cc(CBr)c(Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a solution of (2,5-dichlorothiophen-3-yl)methanol (280 mg, 1.5 mmol) in anhydrous dichloromethane (15 mL) was added dropwise phosphorus tribromide (285 μL, 3.0 mmol). The mixture was stirred at room temperature for 3 hours. Dichloromethane was evaporated. The residue was treated with a saturated sodium bicarbonate solution until no more gas evolved. The resultant mixture was extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 3-(bromomethyl)-2,5-dichlorothiophene (125 mg, 34% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].[OH-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:17]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(=O)O
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCC(=O)O
Yield: 70 %

Procedure:
Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, (20 g) and beta-alanine (9 g) dissolved in 3:2 v/v water/ethanol (500 ml) containing NaOH (10 g) to provide a solution with a pH of at least 13. The solution is refluxed for 15 minutes whereupon it turns from a light orange to an intense red colour. The solution is acidified to pH 7.0 and the ethanol is removed by rotary evaporation. The resulting aqueous solution is washed twice with ethylacetate (100 ml). This solution is then subjected to rotary evaporation until the volume is reduced to 100 ml and this reduced volume of solution is acidified to pH 3.0 to give a white precipitate, which is filtered off to give 3-benzyloxy-1-(2'-carboxyethyl)-2-methylpyrid-4-one in 70% yield, m.p. 156°-157° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10]1>>[O:9]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:10]1
Reactant: OCC1CCOC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OCC2CCOC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and tetrahydrofuran-3-methanol by the method of Example 10 (b).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH2:6][C@H:7]1[CH2:11][N:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:9]([C:16]([NH:18][CH2:19][C@@H:20]([OH:48])[C@@H:21]([NH:29][C:30](=[O:47])[C@H:31]([CH2:43][C:44](=[O:46])[NH2:45])[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[CH2:8]1.C(=O)(O)[O-].[Na+]>O.CN(C)C=O>[C:1]([NH:6][C@H:7]1[CH2:11][N:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[C@H:9]([C:16]([NH:18][CH2:19][C@@H:20]([OH:48])[C@@H:21]([NH:29][C:30](=[O:47])[C@H:31]([CH2:43][C:44](=[O:46])[NH2:45])[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)N1C[C@H](N)C[C@H]1C(=O)NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H]1C[C@@H](C(=O)NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)N(C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
15 mg of freshly distilled acetyl chloride were added to a solution, which was cooled to 0° C. and stirred, of 12 mg of 4(R)-amino-N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide hydrochloride and 21 mg of sodium bicarbonate in 0.5 ml of water and 0.25 ml of dimethylformamide. The mixture was stirred vigorously at 0° C. for 5 hours and then left to stand at room temperature overnight. The mixture was diluted with waterand extracted with dichloromethane. The combined dichloromethane extracts were evaporated to give a gum which was purified by flash chromatography on silica gel using 20% methanol in dichloromethane for the elution. Therewere obtained 2 mg of 4(R)-acetylamino-N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a semi-solid; MS: m/e 639 [M+H]+.