Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH3:37])[CH:32]([NH:38][C:39](=[O:78])[C:40](=[N:66][O:67][C:68]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])([CH3:70])[CH3:69])[C:41]1[N:42]=[C:43]([NH:46][C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[S:44][CH:45]=1)[C:31]2=[O:79])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C.O>CN(C)C=O>[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH:37]=[CH:6][N:7]([CH3:9])[CH3:8])[CH:32]([NH:38][C:39](=[O:78])[C:40](=[N:66][O:67][C:68]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])([CH3:70])[CH3:69])[C:41]1[N:42]=[C:43]([NH:46][C:47]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[S:44][CH:45]=1)[C:31]2=[O:79])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2SC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2SC1
Reaction time: 0.25 h

Procedure:
t-Butoxy-bis dimethylaminomethane (1.9 cc) is added, whilst stirring, to a solution, at 80° C., under nitrogen, of the syn isomer of 2-benzhydryloxycarbonyl-7-{2-[(2-t-butoxycarbonylprop-2-yl)-oxyimino]-2-(2-tritylaminothiazol-4-yl)-acetamido}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (6 g.) in dimethylformamide (64 cc), and the reaction is continued for 15 minutes. The mixture is then poured into a mixture of ethyl acetate (200 cc) and water (200 cc). The organic phase is decanted, washed with water (3×100 cc) and a saturated aqueous solution of sodium chloride (100 cc), dried over sodium sulphate and filtered and the filtrate is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). This yields crude E form of the syn isomer of 2-benzhydryloxycarbonyl-3-(2-dimethylaminovinyl)-7-{2-(2-t-butoxycarbonylprop-2-yl-oxyimino)-2-(2-tritylaminothiazol-4-yl)-acetamido}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene (6.5 g) in the form of a hard brown foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH3:15])[CH3:14])[N:11]=[CH:10][C:9]=2[C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH3:15])[CH3:14])[N:11]=[CH:10][C:9]=2[C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22]([NH:32][CH2:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:23])[N:20]=2)=[CH:4][CH:3]=1
Reactant: NCC1CCOCC1
Reactant: CC(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using the compound obtained in step 4 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27]>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH:10][C:26](=[O:27])[C:25]3[C:24]([Cl:23])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:33])[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COc1ccc(N)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyaniline (1 g) and triethylamine (0.69 mL) in dry dichloromethane (20 mL) at 0° C. is treated dropwise with 2,6-dichlorobenzoyl chloride (1.17 g). After stirring at this temperature for 30 minutes, the mixture is warmed to room temperature and stirred for a further 3 hours. The organic layer is washed with water (100 mL), dried and concentrated. The residue is recrystallized from a mixture of isopropanol and hexane, to give N-(3-cyclopentyloxy-4-methoxyphenyl)-2,6-dichlorobenzamide (0.6 g), m.p. 184-185° C. [Elemental analysis: C,60.2,H,5.0; N,3.6; Cl,18.9%; calculated: C,60.0; H,5.0; N,3.7; Cl,18.65%].
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[Cl:13].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:2][N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(CBr)c(Cl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCN(C)CC2)c(Cl)c1
Yield: 95.5 %

Procedure:
Methyl 4-(bromomethyl)-3-chlorobenzoate (400 mg, 1.5 mmol), 1-methylpiperazine (100 mg, 1.0 mmol), and potassium carbonate (276 mg, 2.0 mmol) in N,N-dimethylformamide (2.5 mL) were stirred at room temperature overnight. The mixture was concentrated and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and concentrated to give product (270 mg, 58%). LCMS (ESI): RT (min)=0.934, M+H+=282.8, method=B.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9]C=2OC)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].N[C:19]1N(C2CCCC2)N=C(C)C=1C#N>>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:15]([NH2:17])=[O:16]
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Reactant: Cc1nn(C2CCCC2)c(N)c1C#N
Product: Cc1nn(C2CCCC2)c(N)c1C(N)=O

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-1-cyclopentyl-3-methyl-1H-pyrazole-4-carbonitrile provided the title compound. 1H NMR (300 MHz, CDCl3): δ 5.39 (br, 2H), 5.32 (br, 2H), 4.26 (m, 1H), 2.38 (s, 3H), 2.04 (m, 4H), 1.9 (m, 2H), 1.66 (m, 2H).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25].CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([NH:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=4)=[O:18])=[CH:20][CH:21]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCCl
Product: CS(=O)(=O)c1cccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 25 °C
Yield: 816.3 %

Procedure:
To a solution of (4-adamantan-1-yl-phenoxy)-acetic acid (50 mg, 0.17 mmol), 3-methanesulfonyl-phenylamine hydrochloride (54.39 mg, 0.26 mmol) and DIPEA (33.85 mg, 0.26 mmol) in DMF (2 mL) was added EDC (50.2 mg, 0.26 mmol) and HOBt (35.39 mg, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature until completion and then poured into water (100 mL). The resulting solid was extracted with ethyl acetate, washed with brine, aqueous sodium bicarbonate and water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (Ethyl acetate:hexanes=2:8 to 4:6) to afford 2-(4-adamantan-1-yl-phenoxy)-N-(3-methanesulfonyl-phenyl)-acetamide as a colorless solid (0.61 g, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH2:22])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1.[N:31]1[CH:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[N:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH:22][C:37]([C:35]5[CH:36]=[N:31][CH:32]=[N:33][CH:34]=5)=[O:38])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(N)CC2)n1
Reactant: O=C(O)c1cncnc1
Product: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(NC(=O)c3cncnc3)CC2)n1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]thiophen-3-yl}-amide (example 61) has been coupled with pyrimidine-5-carboxylic acid to yield the title compound as light yellow amorphous solid. MS: 551.1 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20]([O:22]C)=[O:21]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1F
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1

Procedure:
The title compound was synthesized using the procedure stated in Example 1, Step 2 except that the product from Step 1 was used and THF was not used to yield product as an off white solid. MS (ES+) m/e 318 [M+H]+
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[CH:5]=1.[OH-].[Na+].Cl.[CH3:16][C@H:17]1[CH2:21][O:20][C:19](=[O:22])[CH2:18]1>>[CH3:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([CH3:11])[CH:7]=1)[C:3]([C@H:18]1[CH:17]([CH3:16])[CH2:21][O:20][C:19]1=[O:22])=[O:12]
Reactant: C[C@H]1COC(=O)C1
Reactant: COC(=O)c1cc(C)cc(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)cc(C(=O)[C@@H]2C(=O)OCC2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of (R)-4-methyldihydrofuran-2-one (1.68 g in 40 mL dioxane) were added 5.51 g 3,5-dimethylbenzoic acid methyl ester followed by 1.82 g sodium hydroxide and the mixture heated to reflux on an oil bath. After 3 hours, the mixture was cooled to room temperature and the pH neutralized by the addition of 0.5N hydrochloric acid. The mixture was then extracted with ethyl acetate and the organic portion washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 9:1) gave the title compound (2.42 g).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccc(OC2CCN(Cc3ccccc3)C2)cc1Cl
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.5 h
Yield: 4.4 %

Procedure:
To a stirred solution of 275 ml of 2 molar phosgene (0.55 mole) in benzene under nitrogen gas was added dropwise a solution of 0.5 mole of 1-benzyl-3-(3,4-dichlorophenoxy)pyrrolidine in 200 ml of dry benzene. The reaction mixture was stirred an additional 0.5 hr, then was filtered to remove 10 g of the starting pyrrolidine compound as the hydrochloric acid salt. The filtrate was concentrated under reduced pressure to give an oil. The oil was triturated four times in succession with 200 ml each of 30/60 petroleum ether which removed most of the benzyl chloride by-product. The combined petroleum ether when cooled gave 6.5 g of white crystal product which was separated by filtration. The oil residue, after removing excess petroleum ether under vacuum, crystallized. The crystals were separated by filtration and washed with petroleum ether to give 93 g of tan-colored material. Further work-up of the last petroleum ether filtrate gave 17 g additional crude product. Combined yield of crude tan product was 116.5 g (70%), m.p. 79°-84° C. A portion of the crude was recrystallized from 30/60 petroleum ether to give white crystalline product, m.p. 79°-84° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:21][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:21])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reaction time: 4 h
Yield: 91 %

Procedure:
To a solution of 5-bromo-3,4-difluoro-2-(2-fluorophenylamino)benzoic acid (3.0 g, 8.67 mmol) in a mixture of THF (15 ml) and MeOH (5 ml) was added (trimethylsilyl)diazomethane (5.63 ml, 2 M in Hexanes, 11.3 ml). After stirring for 4 h, the reaction was quenched with AcOH and diluted with EtOAc (100 ml). The organic solution was washed with H2O (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated to dryness to give 2.83 g (91%) of methyl 5-bromo-3,4-difluoro-2-(2-fluorophenylamino)benzoate as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[NH:6][C:7](=[O:10])[CH2:8][NH2:9])[CH3:2].Br.[C:21]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)(=[O:23])[CH3:22].C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[NH:6][C:7](=[O:10])[CH2:8][NH:9][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([O:24][C:21](=[O:23])[CH3:22])=[CH:33][CH:32]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CNC(=O)c1ccc(OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
17.4 g (0.05 mol) of glycyl-L-tyrosine ethyl ester·HBr, 9 g (0.05 mol) of p-acetoxybenzoic acid and 5.1 g (0.05 mol) of triethylamine were dissolved in 250 ml of dichloromethane, and after the solution was cooled to 0° C., 9.6 g (0.05 mol) of 1-ethyl-3(3-dimethylaminopropyl)carbodiimide·HCl was added to the solution, and the solution was stirred overnight. The reaction mixture was washed with a 0.1% aqueous solution of Na2CO3 and with a 0.1 N HCl solution, and was dried over anhydrous sodium sulfate. Dichloromethane was removed from the mixture under reduced pressure to obtain p-acetoxybenzoylglycyl-L-tyrosine ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18](=[O:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:19].[Na].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:21]([O:20][C:18]([NH:19][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(C2(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (320.0 mg, 0.001077 mol, example 258, step 1), t-butyl carbamate (180.0 mg, 0.001536 mol), sodium benzylate (175.01 mg, 0.0015075 mol), tris(dibenzylideneacetone)dipalladium(0) (16.5 mg, 0.0000180 mol) and tri-tert-butylphosphine (18.8 mg, 0.0000929 mol) in toluene (3.0 mL, 0.028 mol) was deaerated and then charged with nitrogen. The resulting mixture was heated at 100° C. overnight. After cooling, the mixture was filtered through a pad of celite and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by Combiflash with ethyl acetate/hexane to give the desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:25]1([NH:28][C:29](=[O:46])[C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH:25]1([NH:28][C:29](=[O:46])[C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][N:15]5[C:18]([C:21]([F:22])([F:24])[F:23])=[N:19][N:20]=[C:14]5[CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:31]=2)[CH2:26][CH2:27]1
Reactant: FC(F)(F)c1nnc2n1CCN(c1nncc3cc(Cl)ccc13)C2
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCn4c(nnc4C(F)(F)F)C3)nncc2c1

Procedure:
The title compound was prepared according to the method described in Example 8 (Method A) using 6-chloro-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)phthalazine (350 mg, 987 μmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (594 mg, 1973 μmol), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (32 mg, 89 μmol), Pd2(dba)3 (27 mg, 30 μmol, Strem), and potassium carbonate (409 mg, 2960 μmol) in dioxane:H2O=4:1 (5 mL). Found MS (ES+) m/z: 494 (M+1).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH2:11][C@H:12]([NH:16][C:17]([C:19]2[CH:38]=[CH:37][C:22]3[N:23]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:24]([C:26]4[CH:30]=[CH:29][O:28][CH:27]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])=[N+:2]=[N-:3].Br[CH2:40][C:41]([O:43]C)=[O:42].C([O-])([O-])=O.[Cs+].[Cs+].CO>CC(C)=O.C1COCC1>[N:1]([C:4]1[CH:5]=[C:6]([CH2:11][C@H:12]([NH:16][C:17]([C:19]2[CH:38]=[CH:37][C:22]3[N:23]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:24]([C:26]4[CH:30]=[CH:29][O:28][CH:27]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[O:10][CH2:40][C:41]([OH:43])=[O:42])=[N+:2]=[N-:3]
Reactant: COC(=O)CBr
Reactant: [N-]=[N+]=Nc1cc(C[C@H](NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1cc(C[C@H](NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)ccc1OCC(=O)O

Procedure:
(S)-3-(3-Azido-4-hydroxy-phenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionic acid (Example 146, 0.230 g, 0.44 mmol) and methyl bromoacetate (0.136 g, 0.89 mmol) were stirred in acetone (4 mL) in the presence of Cs2CO3 (0.058 g, 0.18 mmol) for 20 h at room temperature. The reaction mixture was concentrated to dryness and dissolved in water, acidify to pH 4 and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO4 and concentrated to give a brown oil. This oil was stirred in THF:MeOH (6 mL, 2:1 ratio) in the presence of LiOH monohydrate (0.18 mmol) for 3 h at room temperature. The reaction mixture was concentrated to remove most of the THF and MeOH, acidified with AcOH and purified by reversed phase C18 preparative HPLC to obtain the title compound of example 147.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)C.[CH3:12][CH:13]([CH3:22])[C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15]>O>[CH:13]([C:14]1([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:1][O:15]1)([CH3:22])[CH3:12]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C(=O)c1ccncc1
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(C)C1(c2ccncc2)CO1
Temperature: 0 °C
Yield: 91.3 %

Procedure:
Potassium tert-butoxide (0.098 g, 0.80 mmol) and trimethylsulfonium iodide (0.164 g, 0.8 mmol) were mixed at RT and stirred at 0° C. To this was added 2-methyl-1-(pyridin-4-yl)propan-1-one (0.100 g, 0.671 mmol) slowly. The reaction mixture was stirred at 0° C. for 15 min. and then warmed to and stirred at 70° C. for 1 h. The reaction mixture diluted with water and extracted with EtOAc (3 10 mL), organic layer dried on sodium sulfate and concentrated under vacuum to obtain 4-(2-isopropyloxiran-2-yl)pyridine (0.1 g). 1H NMR (CDCl3, freebase) δ (ppm): 8.6 (d, 2H) 7.26 (d, 2H), 3.05 (d, 1H), 2.29 (septet, 1H), 2.26 (d, 1H), 1.65 (d, 6H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.C(Cl)(=O)C(C)(C)C.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])=[CH:36][C:35]=1[CH3:45]>C(Cl)Cl>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([C:41]#[N:42])([CH3:43])[CH3:44])=[CH:36][C:35]=3[CH3:45])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: Cc1cc(C(C)(C)C#N)ccc1CN
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C#N)ccc1CNC(=O)Cn1cnc2cccc(C#N)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
(7-cyano-1H-benzimidazol-1-yl)acetic acid (86 mg, 0.43 mmol) prepared according to scheme 3 is dissolved in DCM (3 mL). DIPEA (0.1 mL) is added, followed by pivaloyl chloride (53 μL, 0.43 mmol). After 1 hour, 2-[4-(aminomethyl)-3-methylphenyl]-2-methylpropanenitrile (80 mg, 0.43 mmol) prepared according to scheme 19 is added. The mixture is stirred overnight at room temperature, concentrated under vacuo and purified on HPLCMS: Waters prep LCMS, 27 ml/min, X-Bridge Prep C18 OBD, 30×50 mm, 5 μm particle size, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, Gradient used 30% to 50% B in A, in 10 min. The fractions are combined and freeze dried to give the desired product (47 mg, 0.13 mmol, 30%). MS (ESI) (M+1) 372.3. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.65 (s, 6H) 2.31 (s, 3H) 4.29 (d, J=5.08 Hz, 2H) 5.26 (s, 2H) 7.25-7.29 (m, 1H) 7.30-7.40 (m, 3H) 7.73 (dd, J=7.62, 0.98 Hz, 1H) 8.03 (dd, J=8.20, 0.78 Hz, 1H) 8.38 (s, 1H) 8.74 (t, J=5.27 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Br:20]CC1C=CC=C2C=1CCC2=O.P(OCC)(OCC)(OCC)=O>C1(C)C(C)=CC=CC=1>[Br:20][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])[C:2]1=[O:1]
Reactant: CCOP(=O)(Cc1cccc2c1CCC2=O)OCC
Reactant: O=C1CCc2c(CBr)cccc21
Solvent: CCOP(=O)(OCC)OCC
Solvent: Cc1ccccc1C
Product: CCOP(=O)(Cc1cccc2c1CC(Br)C2=O)OCC

Procedure:
The diethyl 1-oxoindan-4-ylmethylphosphonate can be prepared in the following manner: a mixture of 0.5 g of 4-(bromomethyl)indan-1-one, 0.9 g of triethyl phosphate and 5 ml of xylene is heated at reflux for 5 hours. The reaction medium is concentrated in a rotary evaporator and then the residue is purified by chromatography on silica, eluting with an ethyl acetate-petroleum ether (85-15 by volume) mixture. 0.4 g of diethyl (2-bromo-1-oxoindan-4-yl)methylphosphonate is obtained in the form of a colourless oil [1H NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz): 1.20 (6H, t, J=6 Hz, 2 CH3), 2.70 (2H, m, CH2CO), 3.20 (2H, m, CH2), 3.38 (2H, d, J=22 Hz, PCH2), 4.00 (2H, q, J=6 Hz, OCH2), 7.45 (1H, t, J=7 Hz, arom. CH), 7.60 (2H, m, 2 arom. CH)].