Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:24])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([S:19](Cl)(=[O:21])=[O:20])=[C:14]([Cl:23])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.C(OCC)(=O)C.[OH-].[NH4+:33]>>[CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:24])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([S:19](=[O:21])(=[O:20])[NH2:33])=[C:14]([Cl:23])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cc2cc(S(=O)(=O)Cl)c(Cl)cc2[nH]c1=O
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1cc2cc(S(N)(=O)=O)c(Cl)cc2[nH]c1=O
Reaction time: 0.5 h

Procedure:
A suspension of the compound obtained in Step E (1.26 g, 3.0 mmol) in 18 ml of 28 % ammonium hydroxide is stirred. After a few minutes, dissolution is observed. Stirring is continued for 30 minutes and the reaction mixture is acidified with 4N HCl. A few ml of ethyl acetate are added, with stirring, and precipitation is produced. The precipitate is filtered off and dried in vacuo to yield the title product in the form of cream-coloured powder.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.Cl[C:50]([O:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:51]>C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:28]2[N:24]([CH2:23][CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:50]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[O:51])[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=3)[C:25](=[O:41])[S:26][C:27]=2[CH:32]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)Oc1ccccc1
Reaction time: 8 h

Procedure:
1.5 g of the compound obtained in Step A of Example 12 are dissolved in 20 ml of ethyl acetate; 1.06 ml of triethylamine are then added and the temperature is lowered to 0° C. 0.637 ml of phenyl chloroformate is then added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH3:33]>>[CH2:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][NH:25][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:33]
Reactant: CCN1CCCC1CN
Reactant: COc1cc(C(=O)O)cc(OC/C=C(\C)CCC=C(C)C)c1OC
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OC)c(OC/C=C(\C)CCC=C(C)C)c1
Yield: 58.3 %

Procedure:
In a manner identical to Example 15, 3,4-dimethoxy-5-geranyloxy benzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.31 g), thereby yielding 0.62 g(58%) of the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.[C:18](OCC)(=O)CC>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17][CH3:18])[N:3]=1
Reactant: CCOC(=O)CC
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Product: CCc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl

Procedure:
This compound was prepared in an analogous manner to the compound of Example 15 from ethyl propionate, mp. 228°-230° C.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH:18]1([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>O>[CH:18]1([C:24]2[S:25][C:26]([C:30]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:15])[F:16])=[O:31])=[C:27]([CH3:29])[N:28]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cc1nc(C2CCCCC2)sc1C(=O)O
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1sc(C2CCCCC2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To 7 ml of N,N-dimethylformamide were dissolved 0.50 g (2.5 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.56 g (2.5 mmol) of 2-cyclohexyl-4-methylthiazole-5-carboxylic acid, followed by the addition of 0.42 g (5.0 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 0.64 g (yield: 78%) of 4,4-difluoro-3-methyl-3-butenyl 2-cyclohexyl-4-methylthiazole-5-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30])=[C:23]([C:31](O)=[O:32])[N:22]=[N:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30])=[C:23]([C:31]([NH:37][CH:34]2[CH2:36][CH2:35]2)=[O:32])[N:22]=[N:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCCCF)c(OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCCCF)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 1-{2-(benzyloxy)-4-[(ethylamino)carbonyl]phenyl}-5-(5-fluoropentyl)-1H-1,2,3-triazole-4-carboxylic acid (0.49 g) obtained in Example 137b) in acetonitrile (5 ml) were successively added cyclopropylamine (0.09 ml), triethylamine (0.18 ml), HOBt (0.20 g) and WSC (0.25 g), and the reaction mixture was stirred at room temperature for 3.5 hr, and then at 60° C. for 1 hr. After allowing the reaction mixture to cool, the solvent was evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a colorless amorphous substance (0.31 g, 59%).
Reaction SMILES: [C:1]([N:4]1[CH:8](Cl)[CH:7](Cl)[N:6]([C:11](=[O:13])[CH3:12])[C:5]1=[O:14])(=[O:3])[CH3:2].CN(C)C=O.O>C(OCC)C.[Zn]>[C:11]([N:6]1[CH:7]=[CH:8][N:4]([C:1](=[O:3])[CH3:2])[C:5]1=[O:14])(=[O:13])[CH3:12]
Reactant: CC(=O)N1C(=O)N(C(C)=O)C(Cl)C1Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)n1ccn(C(C)=O)c1=O
Yield: 95.2 %

Procedure:
Activated zinc (from 63.5 g (1.0 mol) of zinc), prepared in accordance with J. Org. Chem. 29, 2049 (1964), are added in portions to a boiling solution of 119.5 g (0.5 mol) of recrystallised 1,3-diacetyl-4,5-dichloro-imidazolidin-2-one and 8 ml of dimethylformamide in 400 ml of dry diethyl ether and the mixture is heated under reflux until conversion is complete (16 hours). After the reaction solution has cooled, 200 ml of water are added to it, and the mixture is filtered. The filter cake is washed with 3×100 ml of benzene and the organic phases are combined and washed until they give a neutral reaction. Drying over sodium sulphate and evaporation gives 80.0 g (about 95%) of 1,3-diacetyl-4-imidazolin-2-one of melting point 106° C., identical with a sample prepared independently in accordance with J. Amer. Chem. Soc. 54, 3413 (1932).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:31])[CH2:10][O:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:31])[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccc(I)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CO)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
To a solution of 1-iodo-4-{[1-(trityloxy)propan-2-yl]oxy}benzene (350 mg, 0.67 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified by combiflash (petroleum ether:ethyl acetate=10:1 to 4:1) to give the title compound (100 mg, 55%) as a white solid, which was used into next step directly. 1H NMR (400 MHz, CDCl3) ppm 7.55 (d, 2H), 6.72 (d, 2H), 4.45 (m, 1H), 3.70 (m, 2H), 1.96 (t, 1H), 1.25 (d, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.Cl.O[N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[N:29]1([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: On1ccnc1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(COn2ccnc2)cc1)c1ccccc1
Yield: 87 %

Procedure:
The title compound was prepared as its TFA salt in 87% yield as a solid using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 1-hydroxyimidazole, hydrochloride. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.21 (s, 2H), 6.95 (s, 1H), 7.16–7.45 (m, 10H) 8.28 (br s, 1H); HPLC-MS: m/z=324.1 (M+1); Rt=1.92 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:16](/[C:15]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=2)\[C:17]#[N:18])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(F)c(F)c1
Product: COc1ccc(/C(C#N)=C/c2ccc(F)c(F)c2)cc1OC
Yield: 86.4 %

Procedure:
3,4-Difluorobenzaldehyde (426 mg) and 3,4-dimethoxybenzyl cyanide (532 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (780 mg, yield: 86%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:34][C:35](=[O:57])[NH:36][C@@H:37]([CH2:45][CH2:46][CH2:47][CH2:48][NH:49]C(OC(C)(C)C)=O)[C:38]([O:40]C(C)(C)C)=[O:39])[C:24](=[O:33])[NH:25][C@H:26]([C:30](=[O:32])[NH2:31])[CH:27]([CH3:29])[CH3:28])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:49][CH2:48][CH2:47][CH2:46][CH2:45][C@H:37]([NH:36][C:35]([NH:34][C@@H:23]([C:24](=[O:33])[NH:25][C@H:26]([C:30](=[O:32])[NH2:31])[CH:27]([CH3:28])[CH3:29])[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]([O:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:17])=[O:57])[C:38]([OH:40])=[O:39]
Reactant: CC(C)[C@H](NC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1)NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1)NC(=O)N[C@@H](CCCCN)C(=O)O)C(N)=O
Yield: 70.2 %

Procedure:
tert-Butyl(S)-2-{3-[(R)-5-benzyloxycarbonylamino-1-((S)-1-carbamoyl-2-methyl-propylcarbamoyl)-pentyl]-ureido}-6-tert-butoxycarbonylaminohexanoate trifluoroacetate (37 mg, 0.045 mmol) was dissolved in 5 ml of CH2Cl2 and 1 ml of TFA and stirred at RT for 14 h. Preparative HPLC afforded 21 mg (70%) of (S)-6-amino-2-{3-[(R)-5-benzyloxycarbonylamino-1-((S)-1-carbamoyl-2-methyl-propylcarbamoyl)-pentyl]-ureido}-hexanoic acid trifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH2:16][CH2:17][O:18][CH2:19][C:20](O)=[O:21])[CH:13]1[CH2:15][CH2:14]1)(=[O:11])=[O:10].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[N:58]1([CH2:62][C:63]2[S:71][C:70]3[CH2:69][CH2:68][NH:67][CH2:66][C:65]=3[CH:64]=2)[CH2:61][CH2:60][CH2:59]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[N:58]1([CH2:62][C:63]2[S:71][C:70]3[CH2:69][CH2:68][N:67]([C:20](=[O:21])[CH2:19][O:18][CH2:17][CH2:16][N:12]([CH:13]4[CH2:14][CH2:15]4)[S:9]([C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:11])=[O:10])[CH2:66][C:65]=3[CH:64]=2)[CH2:61][CH2:60][CH2:59]1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Reactant: c1c(CN2CCC2)sc2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)N1CCc2sc(CN3CCC3)cc2C1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2-(2-Chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)acetic acid (AC27) (100 mg, 0.288 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate (92 mg, 0.288 mmol) and 1-hydroxybenzotriazole hydrate (40 mg, 0.288 mmol) were dissolved in tetrahydrofuran (3.5 ml) and the mixture was stirred at room temperature for 30 min. A solution of 2-(azetidin-1-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine dihydrochloride (TP13) (97 mg, 0.346 mmol) and N-ethyl-diisopropylamine (146 μl, 0.864 mmol) in tetrahydrofuran (3.5 ml) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and saturated sodium hydrogen carbonate solution and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic layers were washed with saturated sodium chloride solution (1×), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica) with ethyl acetate/methanol 5/1. Yield: 100 mg (64%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH:30]([N:33](C(C)C)CC)(C)C.N#CBr>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:30]#[N:33])[CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCNCC1
Agent: N#CBr
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCN(C#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]quinazoline (Example 3, 104 mg, 0.25 mmol) was dissolved in DCM (10 ml), and diisopropylethylamine (4 μl, 0.28 mmol) was added. Cyanogen bromide solution (3M in DCM, 92 μl, 0.28 mmol) was added, and the solution stirred for 16 hours at ambient temperature. The solvent was evaporated, and the residue purified by chromatography, eluting with 0 to 2% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, and the residue triturated with diethyl ether to give the product as a white solid (75 mg, 68%); 1H NMR: 1.34-1.50 (m, 2H), 1.80-1.90 (m, 2H), 2.02 (m, 1H), 3.10 (m, 2H), 3.37-3.46 (m, 2H), 3.93 (s, 3H), 3.99 (d, 2H), 7.19 (s, 1H), 7.26 (dd, 1H), 7.46 (dd, 1H), 7.46 (dd, 1H), 7.50 (dd, 1H), 7.77 (s, 1H), 8.36 (s, 1H), 9.57 (s, 1H); Mass Spectrum: 442.4, 444.4.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[O:22]=[C:23]([NH:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[CH2:24][C:25](O)=[O:26].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:25](=[O:26])[CH2:24][C:23]([NH:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:32])([F:34])[F:33])=[O:22])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Reactant: O=C(O)CC(=O)NCC(F)(F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21)NCC(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 90.3 %

Procedure:
0.11 g (0.38 mmol) (S)-7-Amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one and 0.09 g (0.38 mmol) 3-oxo-3-(2,2,3,3,3-pentafluoro-propylamino)-propanoic acid in 10 ml tetrahydrofuran were reacted with 0.06 g (0.38 mmol) 1-hydroxybenzotriazole hydrate, 0.13 ul (0.76 mmol) diisopropylethylamine and 0.7 g (0.38 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochlorid at 0° C. for 4 hours. After stirring at room temperature over night the solvent was removed by distillation and the residue purified by chromatography on silicagel with heptane/ethylacetate (gradient 100–0/0-100) to yield 0.17 g (89%) N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
Reaction SMILES: [BH4-].[Na+].C(O)(=O)C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=O)=[CH:16][N:15]=2)=[CH:10][CH:9]=1>O1CCOCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[CH:16][C:17]([CH2:18][NH2:20])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(-c2ccc(F)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NCc1ccc(-c2ccc(F)cc2)nc1
Yield: 8.7 %

Procedure:
To an ice-bath cooled solution of sodium borohydride (5.47 g, 144.5 mmol) in anhydrous 1,4-dioxane (100 ml) was added slowly a solution of glacial acetic acid (8.27 ml, 144.5 mmol) in 1,4-dioxane (50 ml). To this mixture was added 6-(4-fluorophenyl)nicotinamide (Description 24; 6.25 g, 28.9 mmol) and the resulting mixture heated at reflux for 4 hours. The cooled reaction mixture was evaporated and water (60 ml) added slowly. This mixture was extracted with dichloromethane, and the solid which appeared between the layers was removed by filtration. This solid was triturated with a mixture of dichloromethane and iso-hexanes, filtered and dried to give the title compound (510 mg, 8%) as a pale green solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:16]3[N:20]=[N:19][CH:18]=[N:17]3)[CH:13]=2)[NH:8][CH:7]=1)[CH3:3].[C:21]([O-:26])(=[O:25])[C:22]([O-:24])=[O:23]>>[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH3:1][N:2]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:16]3[N:20]=[N:19][CH:18]=[N:17]3)[CH:13]=2)[NH:8][CH:7]=1)[CH3:3]
Reactant: O=C([O-])C(=O)[O-]
Agent: CN(C)CCc1c[nH]c2ccc(Cn3ncnn3)cc12
Product: O=C(O)C(=O)O

Procedure:
N,N-Dimethyl-2-[5-(1,2,3,4-tetrazol-2-ylmethyl)-1H-indol-3-yl]ethylamine.Oxalate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[H-].[Na+].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>O1CCOCC1>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][CH3:6])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC[C@H](N)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@H](N)COc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.01 g (51.3 mmol) (S)-2-amino-1-butanol are dissolved in 30 mL 1,4-dioxane, combined with 2.10 g (52.5 mmol) sodium hydride and stirred for 30 min at ambient temperature. To this reaction mixture are added 5.00 g (36.7 mmol) 2-amino-6-fluorobenzonitrile and the mixture is stirred for 24 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier material used is silica gel and the eluant is dichloromethane to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=[O:14])[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])(C)C.Cl.C([O-])(O)=O.[Na+:27].ClC(OC[C:33]1[CH:38]=[CH:37]C=[CH:35][CH:34]=1)=O>O1CCOCC1>[Na+:27].[CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([O-:15])=[O:14])[C@@H:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])[C:4]1[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)[C@@H]1c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C([O-])[C@@H]1CCN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
trans-2-Phenyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester obtained from preparatory example 8 (10.1 g, 34.8 mmol) was stirred in 1,4-dioxane (145 mL) at 0° C. 6 M HCl (29 mL, 174 mmol) was added and the mixture was slowly warmed to rt and stirred for 16 h. The mixture was then cooled to 0° C. and solid NaHCO3 was carefully added until the aqueous layer was saturated. Benzyl chloroformate was added and the mixture was stirred vigorously at 0° C. for 1 hr, and at rt for 20 h. The suspension was then filtered and the solids were dried under vacuum to give 6.54 g (55%) of the title compound. MS APCI: [M+H]+=326.1
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)=[O:8])[CH3:5]>>[CH2:4]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:2]([CH3:3])[CH3:1])[N:10]=1)=[O:8])[CH3:5]
Reactant: CNC
Reactant: CCNC(=O)c1cccc(Br)n1
Product: CCNC(=O)c1cccc(N(C)C)n1

Procedure:
prepared by reaction of dimethyl-amine with 6-bromo-pyridine-2-carboxylic acid ethylamide
Reaction SMILES: [CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([O:30]C)=[O:29])[CH:22]=4)[NH:17]3)[CH:12]=[CH:13][C:14]=2[F:15])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([OH:30])=[O:29])[CH:22]=4)[NH:17]3)[CH:12]=[CH:13][C:14]=2[F:15])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C3CCCC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NC(=O)C2CCCC2)c1
Yield: 70 %

Procedure:
A mixture of methyl 2-(3-(cyclopentanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.26 mmol, 1.0 eq.) and 4.5 mL sodium hydroxide (1 mol/L) in 3 mL methanol was stirred at reflux for 1-2 h. LC-MS indicated that the starting material was consumed completely. The methanol was removed by reduced pressure. The residue was acidified pH to 5-6 with 1 M hydrochloric acid. A lot of precipitates were formed and collected by filtration to afford 2-(3-(cyclopentanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid; Yield: 70%; MS (ESI+APCI) M+1=411.