Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6](C#N)=[C:7]2[N:11]([N:12]=1)[C:10]([C:13]1[C:18]([CH3:19])=[C:17]([CH3:20])[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:15]([CH3:31])[C:14]=1[CH3:32])=[N:9][NH:8]2)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.O>CO>[C:1]([C:5]1[CH:6]=[C:7]2[N:11]([N:12]=1)[C:10]([C:13]1[C:14]([CH3:32])=[C:15]([CH3:31])[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:17]([CH3:20])[C:18]=1[CH3:19])=[N:9][NH:8]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCCCCCCc1c(C)c(C)c(-c2n[nH]c3c(C#N)c(C(C)(C)C)nn23)c(C)c1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CCCCCCCCCCc1c(C)c(C)c(-c2n[nH]c3cc(C(C)(C)C)nn23)c(C)c1C
Temperature: 0 °C
Yield: 85 %

Procedure:
The nitrile from part (b) (20 g) was added in one portion to 75% sulfuric acid (from concentrated H2SO4 [270 g]) and ice (90 g) with stirring at 140°-150° C. 15-20 minutes later, ice (1000 g) was added. After decantation, the sticky solid was dissolved in methanol (200 ml) and hot water (5 ml) added. On cooling, the precipitate was collected, washed with 90% methanol (2×50 ml) and dried to give the product (85-90%), m.p. 194°-195° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]1=[S:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=S)C1
Yield: 132.6 %

Procedure:
A mixture of 1-benzyl-4-(tert-butyloxycarbonyl)piperazin-2-one (1.0 mg, 3.4 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's Reagent) (837 mg, 2.1 mmol) were heated at 90° C. in toluene (10 mL), under nitrogen for 45 min. The mixture was cooled then partitioned between EtOAc (3×50 mL) and water (50 mL). The combined organic layers were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :EtOAc (100:0→95:5→90:10) to afford the title compound (853 mg, 82%) as a colourless solid. mp. 126-129° C. 1H NMR (250 MHz, CDCl3) δ 1.47 (9H, s), 3.40-3.44 (2H, m), 3.60-3.65 (2H, m), 4.67 (2H, s), 5.31 (2H, s), 7.31-7.39 (5H, m). MS (ES+) (307, M+1).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16](F)(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.[Si:22]([O:29][C:30]1[CH:31]=[C:32](Br)[CH:33]=[CH:34][CH:35]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Si:22]([O:29][C:30]1[CH:31]=[C:32]([S:16]([C:14]2[CH:13]=[CH:12][C:9]3[CH2:10][CH2:11][NH:5][CH2:6][CH2:7][C:8]=3[CH:15]=2)(=[O:17])=[O:18])[CH:33]=[CH:34][CH:35]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)F)cc2CC1)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)Oc1cccc(S(=O)(=O)c2ccc3c(c2)CCNCC3)c1
Yield: 80 %

Procedure:
Prepared from 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride and 3-t-butyldimethylsilyloxybromobenzene using the method of Example 1, yield 80%.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]([NH2:15])=[C:8]([O:16][CH3:17])[C:7]=1[O:18][CH3:19].[O-:20][C:21]#[N:22].[K+].[OH-].[Na+]>O>[Cl:5][C:6]1[CH:14]=[C:10]2[C:9](=[C:8]([O:16][CH3:17])[C:7]=1[O:18][CH3:19])[NH:15][C:21](=[O:20])[NH:22][C:11]2=[O:13]
Reactant: COc1c(Cl)cc(C(=O)O)c(N)c1OC
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Cl)cc2c(=O)[nH]c(=O)[nH]c2c1OC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Acetic acid (10.5 g., 0.175 mole) was added to a vigorously stirred suspension of 5-chloro-3,4-dimethoxyanthranilic acid (28.9 g., 0.125 mole) in 600 ml. water. Then 506 ml. 5% potassium cyanate (0.312 mole) solution was gradually added and stirred 1 hour at 40° C. After cooling the reaction mixture to 20° C., 175 g. (4.37 moles) of sodium hydroxide pellets were added while maintaining the temperature below 40° C. The reaction mixture was heated to 90° C. for 45 minutes. Upon cooling in an ice bath, the sodium salt of the product precipitated, was filtered, resuspended in 125 ml. water, acidified with concentrated hydrochloric acid, cooled and filtered to yield 25.8 g. (80%) of colorless, pure product, M.P. 272°-3° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br)[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.O.[F-:31].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][F:31])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: [F-]
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCOCCBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCOCCF)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of N-cyclopropyl-1-{2-[2-(2-bromoethoxy)ethoxy]-4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (0.23 g) obtained in Example 308a) in acetonitrile (10 ml) was added tetrabutylammonium fluoride monohydrate (0.39 g), and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, and the solvent, was evaporated under reduced pressure. The residue was purified by preparative HPLC (acetonitrile-water) and recrystallized from acetonitrile-water to give the title compound as a white powder (0.04 g, 21%).
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O-2].[Zn+2:39].[Zn].[C:41](=[S:43])=[S:42]>>[CH2:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:41](=[S:42])[S-:43])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[Zn+2:39].[CH2:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:41](=[S:42])[S-:43])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: S=C=S
Agent: [O-2]
Agent: [Zn+2]
Agent: [Zn]
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=S)[S-]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL round bottomed flask was placed 60 g of dioctadecylamine (a fatty amine derived from a natural oil) and 2.40 g of zinc oxide. Carbon disulfide, 9.0 g, was then added dropwise, and the mixture was stirred for 30 minutes. The flask was then stirred and heated for 2 hours at 70° C., and then stirred for an addition 2 hours at 90° C. A vacuum was then applied to remove water of reaction and the temperature was increased to 130° C., and the reaction was maintained in this state for 3 hours. The pale yellow material was then filtered through Celite at 120° C., to give, upon standing at ambient temperature a waxy solid with a Zn content of 4.2%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[CH3:30][C:31]1[C:35]([CH2:36][C:37](Cl)=[O:38])=[C:34]([CH3:40])[O:33][N:32]=1>>[CH3:30][C:31]1[C:35]([CH2:36][C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=[C:11]3[CH3:28])=[CH:6][CH:7]=2)=[O:38])=[C:34]([CH3:40])[O:33][N:32]=1
Reactant: Cc1noc(C)c1CC(=O)Cl
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)Cc2c(C)noc2C)cc1

Procedure:
Synthesis in analogy to Example 17 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and (3,5-dimethyl-isoxazol-4-yl)-acetyl chloride to yield 2-(3,5-dimethyl-isoxazol-4-yl)-N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-acetamide. LC/MS at 254 nm; [M+H] 521; Rt 3,083 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NC2CC2)cn1
Yield: 28 %

Procedure:
As described for example 2b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using cyclopropylamine instead of aminomethylcyclopropane, to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 32 mg, 28%) which was obtained as a white solid. MS: m/e=351.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: OB(O)c1cncnc1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncnc4)nc(N4CCOCC4)c3o2)CC1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (Example 153) was reacted with pyrimidine-5-boronic acid via General Procedure E to give, after purification by reverse HPLC, 30 mg of 6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholino-2-(pyrimidin-5-yl)furo[3,2-d]pyrimidine. MS (Q1) 460 (M+).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]1[CH3:23])(=[O:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]([Cl:1])=[O:4])[CH2:19][C@@H:18]1[CH3:23])(=[O:15])=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H]1CNCCN1S(C)(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)Cl)CCN1S(C)(=O)=O
Temperature: 25 °C
Yield: 154.7 %

Procedure:
Second step: To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (560 mg, 1.88 mmol) in CH2Cl2 (10 mL) at −78° C., was added a solution of (S)-1-methanesulfonyl-2-methyl-piperazine (838 mg, 4.70 mmol) and pyridine (0.74 mL, 9.4 mmol) in CH2Cl2 (10 mL) over 1 hour. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo and flash chromatography (SiO2) EtOAc/H, 1:1) yielded 0.70 g (62%) of (S)-4-methanesulfonyl-3-methyl-piperazine-1-carbonyl chloride as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:15]N1C(=O)CCC1=O>CN(C)C=O>[Br:15][C:11]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[N:14][NH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(-c2ccn[nH]2)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2n[nH]cc2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of 5-(4-nitrophenyl)-1H-pyrazole (595 mmol) in N,N-dimethylformamide (1000 mL) was treated with N-bromosuccinimide (654 mmol). The reaction stirred for 30 min at room temperature and was poured into ice-water (1000 mL). Product precipitated out of solution, was filtered, washed with water (4×500 mL) and dried to provide the title product as an off-white powder (90%). ESMS [M+H]+: 269.2
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(F)c(F)cc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3ncc4cc(F)c(F)cc43)nc12
Reaction time: 15 h
Yield: 16.2 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5,6-difluoro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 240 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0 to 4% of a solution of methanol containing 10% ammonium hydroxide)/dichloromethane gave 2-(5,6-difluoro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (14.4 mg, 16%). MS: (M+H)+=371; 1H NMR (DMSO-d6) δ: 9.02 (s, 1H), 8.53-8.60 (m, 2H), 8.44 (s, 1H), 8.06 (dd, J=10.0, 7.8 Hz, 1H), 7.56 (s, 1H), 1.50 (s, 9H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=1[OH:22])[CH2:2]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH:32]1[CH2:34][CH2:33]1>C(C(C)=O)C(C)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=1[O:22][CH2:31][CH:32]1[CH2:34][CH2:33]1)[CH2:2]2
Reactant: BrCC1CC1
Reactant: CC(=O)Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(=O)Nc1cc(OCC2CC2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Yield: 84.2 %

Procedure:
A suspension of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-hydroxy-4-acetamido-5-chlorobenzamide (6.75 g; 0.02 moles) (m.p. of hydrochloride 315°-317° C. (d)), potassium carbonate (2.76 g; 0.02 moles), 91.5% bromomethylcyclopropane (3.54 g; 0.024 moles) and methyl isobutyl ketone (40 ml) was boiled under reflux for 48 hours. After cooling, the reaction mixture was washed with water, 1N sodium hydroxide aqueous solution and again with water. The organic solution was dried (Na2SO4), decolorized with charcoal and the solvent removed in vacuo to give crude N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide (6.6 g) as an oil, which was crystallized from acetonitrile, m.p. 211°-213° C. (d).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([CH3:21])[CH:12]=[C:13]([F:20])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[F:20][C:13]1[CH:14]=[C:15]2[C:10](=[C:11]([CH3:21])[CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:22][C:23]3([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]3)[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: Cc1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)cc2c1NC(c1cccc(NC3(C(=O)O)CC3)c1)CC2(C)C
Temperature: 25 °C
Yield: 28.4 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-fluoro-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline (348.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-fluoro-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (104.8 mg, 30.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 369.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:16][NH:17][C:18]([CH3:31])([CH3:30])[CH2:19][C:20]2[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH2:40][OH:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:42]1([CH2:49][NH2:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:16][NH:17][C:18]([CH3:31])([CH3:30])[CH2:19][C:20]2[CH:21]=[C:22]([CH2:26][C:27]([NH:50][CH2:49][CH:42]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:28])[CH:23]=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH2:40][OH:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCCCCC1
Reactant: CC(C)(Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c(CO)c1
Product: CC(C)(Cc1cccc(CC(=O)NCC2CCCCCC2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c(CO)c1
Yield: 97 %

Procedure:
The title compound was prepared from (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methyl propyl}phenyl)acetic acid (preparation 148) and cycloheptane methylamine, using a similar method to that of preparation 38, as a white solid in 97% yield. 1H NMR (400 MHz, CD3OD) δ: 7.72 (1H, dd), 7.44 (1H, d), 7.42 (2H, m), 7.38-7.21 (5H, m), 7.19 (1H, d), 7.07 (1H, d), 7.02 (1H, m), 5.08 (2H, d), 5.03 (1H, m), 4.71 (2H, d), 3.51 (2H, d), 3.03-2.96 (4H, m), 1.77-1.34 (13H, m), 1.28 (6H, m), 1.07 (2H, m), 0.93 (9H, s), 0.07 (3H, s), −0.92 (3H, s) ppm; LRMS ESI m/z 688 [M+H]+
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.OC[C:8]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[C:21]1[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])=[N:25][CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:5][CH2:1][C:8]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]=1[C:21]1[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])=[N:25][CH:26]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CO)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CBr)cn1
Temperature: 25 °C

Procedure:
Neat CBr4 (57 mg, 0.17 mmol) was added to a DCM solution (5 mL) of ethyl 3-(5-(2-(hydroxymethyl)-3-isopropyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (75 mg, 0.17 mmol) and PPh3 (45 mg, 0.17 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33]C)=[O:32])=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.C(=O)(O)[O-:37].[Na+].C(O)(=O)C>O>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([OH:33])=[O:32])=[CH:21][CH:20]=2)[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:9]([OH:37])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(-c3ccccc3C(=O)OC)cc2)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1nc(O)c(CC(=O)O)c(Cc2ccc(-c3ccccc3C(=O)O)cc2)n1
Reaction time: 0.5 h

Procedure:
50 mg of the product of Example 7 were introduced into 1 ml of 6N hydrochloric acid and the mixture was heated to gentle reflux. The mixture was stirred for 2 hours 30 minutes and after cooling, the mixture was diluted with 2 ml of water. The pH was adjusted to 7-8 by the addition of sodium bicarbonate, then returned to pH 5-4 by the addition of acetic acid. The mixture was stirred for approximately 30 minutes, followed by separating, and rinsing with water to obtain 30 mg of the expected product melting approx. 220° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:8]=1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH3:41][NH:42][C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1>ClCCl>[CH3:41][N:42]([C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1)[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:8]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)co2)CC1
Reactant: CN[C@@H]1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(C(=O)c1coc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
A mixture of 1-(1,1-dimethylethyl) 4-(4-carboxy-2-oxazolyl)-1-piperidinecarboxylate (600 mg, 2.02 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (425.57 mg, 2.22 mmol) and N-methylmorpholine (224.55 mg, 2.22 mmol) in 4 mL dichloromethane was stirred for 15 minutes at room temperature. To the reaction mixture was added 424 mg (2.63 mmol) of (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine was added and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using 25-75% of ethyl acetate in hexanes as eluant to give 360 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:9]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of 1H-Imidazole-4-carboxylic acid methyl ester (1.0 g, 7.93 mmol) in N,N-dimethylformamide at 25° C. was treated with triethylamine (2.2 mL, 15.86 mmol) and triphenylmethylchloride (2.43 g, 8.72 mmol). The reaction was stirred at 25° C. for 8 h and then concentrated in vacuo. The residue was diluted with ethyl acetate and then washed with water, a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50:50 ethyl acetate/petroleum ether) afforded 1-trityl-1H-imidazole-4-carboxylic acid methyl ester (2.88 g, 98.6%) as a white foam: 1H NMR (DMSO-d6, 300 MHz) δ7.56 (s, 1H), 7.47 (m, 10H), 7.09 (m, 6H), 3.69 (s, 3H).