Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH2:37][CH2:36]2.C[Si](Cl)(C)C>C(O)CCC>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:4]2[C:5]3[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:32][C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[NH:39][C:38](=[O:43])[CH2:37][CH2:36]4)[N:3]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: COc1ccc(Nc2nc(Cl)nc3c2c(C#N)cn3S(=O)(=O)c2ccc(C)cc2)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)CCC(=O)N4)nc3[nH]cc(C#N)c23)cc1
Temperature: 135 °C
Reaction time: 20 h
Yield: 7.8 %

Procedure:
A mixture of 2-chloro-4-(4-methoxyphenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (68 mg, 0.15 mmol), 6-amino-3,4-dihydroquinolin-2(1H)-one (40 mg, 0.24 mmol) and trimethylsilyl chloride (0.100 mL, 0.790 mmol) in nBuOH (2 mL) was stirred at 135° C. for 20 h. More 6-amino-3,4-dihydroquinolin-2(1H)-one (24 mg, 0.15 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) were added. It was stirred at 135° C. for another 20 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give the titled compound (5 mg). MS 426.4 (M+H); UV 203.5, 290.3 nm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[N:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][C:8]2=[O:20])[CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:38][N:34]1[C:33]2[C:39]([CH3:41])=[CH:40][C:30]([C:28]([C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:11]6[CH:12]=[N:13][C:14]7[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=7[C:10]=6[NH:9][C:8]5=[O:20])[CH2:5][CH2:6]4)[CH:23]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: O=c1[nH]c2c3ccccc3ncc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5c6ccccc6ncc54)CC3)ncn2)cc2oc(=O)n(C)c12

Procedure:
0.11 g (0.40 mmol) 3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one, 0.12 g (0.40 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.14 mL (0.80 mmol) DIPEA were stirred overnight in 3 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with 4M aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:10][C:5]1[CH:6]=[C:7]([F:9])[CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(F)cc(Cl)c1N
Temperature: 25 °C

Procedure:
1,2-Diamino-3-chloro-5-fluorobenzene was prepared using an adaptation of the method of Bellamy, et al., (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 2-chloro-4-fluoro-6-nitroaniline (424 mg, 2.22 mmol) and SnCl2 2H2O (2.50 g, 11.1 mmol) dissolved in 7 mL ethyl acetate and 3 mL absolute ethanol under N2 was heated at 70° C. for 2.5 h. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient solid NaHCO3 was added (foaming ) to bring the pH to 6. The thick yellow white emulsion was then extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown oil which crystallized on standing to yield 290 mg (82%). 1H NMR (CDCl3) δ3.59 (br s, 4H, 2(NH2)); 6.37 (dd, 1H, H5, J4-5 =2.7, JH-F =9.3); 6.55 (dd, 1H, H4, J4-5 =2.7, JHF =8.4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:11]3[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1>CS(C)=O>[CH3:25][O:26][C:27](=[O:37])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:15]2[C:10]3[C:9]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)[O:17][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:31]=1
Reactant: Fc1ccc(-c2c(-c3ccc(Br)cc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(=O)COc1cccc(N)c1
Solvent: CS(C)=O
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(Br)cc4)c(-c4ccc(F)cc4)c23)c1
Yield: 44.5 %

Procedure:
Heat 400 mg (0.991 mmol) of 6-(4-bromophenyl)-4-chloro-5-(4-fluorophenyl)furo[2,3-d]pyrimidine (for preparation see WO 03/018589) and 215.5 mg (1.19 mmol) of 3-aminophenoxyacetic acid methyl ester to 150° C. in an oil bath for 1.5 h. After cooling, take up the residue in DMSO and filter through silica gel (eluent: dichloromethane/ethyl acetate 10:1). 242 mg of a mixture are isolated, which is purified by preparative HPLC. 120 mg (15% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[CH3:22]N(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1
Reactant: CN(C)C=O
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCCC2)CC1(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reaction time: 3 h

Procedure:
To a mixture of 10.5 g (0.0332 mole) of 2-chloro-9-cyclohexyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-246), 25 mL of dimethylformamide and 16.2 g (0.0498 mole) of cesium carbonate was added 28.3 g (0.1992 mole) of iodomethane. The mixture was stirred for 3 hours, then 80 mL of water was added and the solid collected by suction filtration to give 10.0 g of 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246).
Reaction SMILES: Cl[C:2]1[N:25]=[CH:24][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[O:23][CH2:22][CH2:21][O:20]4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([C:2]1[N:25]=[CH:24][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[O:23][CH2:22][CH2:21][O:20]4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1)[CH3:28]
Reactant: Clc1cc2c(Nc3ccc(OCC4OCCO4)cc3)ncnc2cn1
Reactant: CNC
Product: CN(C)c1cc2c(Nc3ccc(OCC4OCCO4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure C from 6-chloro-4-[4-(1,3-dioxolan-2-yl)methoxyanilino]pyrido[3,4-d]pyrimidin and dimethylamine (33% aqueous solution); δH (CDCl3) 9.71 (1H,s), 8.87 (1H,s), 8.38 (1H,s), 7.78 (2H,d), 7.35 (1H,s) 7.09 (2H,d), 5.30 (1H,t), 4.00 (6H,m), 3.25 (6H,s); m/z (M+1)+368.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:13]([NH:15][C@H:16]([C:31](O)=[O:32])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH2:28][CH2:29][Cl:30])[CH2:25][CH2:26][Cl:27])[CH:19]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:57]([O:59][C:60](=[O:67])[C@H:61]([CH2:63][CH2:64][S:65][CH3:66])[NH2:62])[CH3:58]>CN(C)C=O>[CH2:57]([O:59][C:60](=[O:67])[C@H:61]([CH2:63][CH2:64][S:65][CH3:66])[NH:62][C:31](=[O:32])[C@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH2:28][CH2:29][Cl:30])[CH2:25][CH2:26][Cl:27])[CH:19]=1)[NH:15][C:13](=[O:14])[C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[NH:3][CH:1]=[O:2])[CH3:58]
Reactant: O=CN[C@@H](Cc1ccc(F)cc1)C(=O)N[C@@H](Cc1cccc(N(CCCl)CCCl)c1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CCSC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1cccc(N(CCCl)CCCl)c1)NC(=O)[C@H](Cc1ccc(F)cc1)NC=O
Temperature: 15 °C

Procedure:
554 g of N-formyl-p-fluoro-L-phenylalanyl-m-di-(2-chloroethyl)amino-L-phenylalanine are dissolved in 4.5 liters of dimethyl formamide (DMF). The solution is heated slowly for the dissolution step and then cooled to 15° C. While stirring add: 172 g of N-hydroxysuccinimide+225 g of dicyclohexylcarbodiimide+1,235 g-moles of L-methionine ethyl-ester dissolved in DMF. After 16 hours of stirring at room temperature, the precipitated dicylcohexylurea is removed and to the stirred filtrate 18 liters of a mixture of water and ice are added. The white precipitate is filtered, washed with water and completely dried under vacuum. Yield: 710 g (97.2%); m.p.=180°-182° C.; [α]D20 =-7.0°±1° (c=2, DMF).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH:9]=2)=[O:5])[CH3:2].[C:31]1([Mg]Cl)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:30])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1(O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
6-(2-Morpholine-4-ylethoxy)-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (1.5 g, 3.68 mmol) obtained in Step 1 was dissolved in THF, and phenylmagnesium chloride (3.865 mL, 5.89 mmol) was added thereto, followed by stirring for 2 hrs at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 788 mg of the titled compound (yield: 44%).
Reaction SMILES: [CH2:1]([N:4]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:3].[H-].[Na+].[CH2:48](I)[CH2:49][CH3:50]>CN(C=O)C>[CH2:50]([N:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:12]/[CH:11]=[CH:10]/[CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:49]=[CH2:48]
Reactant: CCCI
Reactant: C=CCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CCCN(C/C=C/CN(CCCN(CCC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 0.7 g (1.092 mmol) of (E)-1-allyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene (see Example 2a) in 9.4 ml of DMF there are added, with stirring, 0.087 g (2.175 mmol) of sodium hydride dispersion (approx. 60%) and, after 5 min., 0.212 ml (2.176 mmol) of propyl iodide. The reaction mixture is stirred for 15 h at room temperature; a further 0.043 g (1.075 mmol) of sodium hydride dispersion (approx. 60%) and 0.106 ml (1.088 mmol) of propyl iodide are added, and the mixture is stirred for a further 96 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a) yields the oily title compound, Rf value=0.46 (silica gel/ethyl acetate:hexane (2:3)).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[N+:15]([CH:2]([CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])[CH3:1])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CCCCCC(=O)Nc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(CCCC(=O)Nc1ccccc1)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-nitro-4-n-butylaniline intermediate compound 150 g of a 4-n-butyl-aniline were treated with 300 ml of acetic anhydride at 70° C. for 1 hour and then cooled to 10° C. After filtering the solid product on a Buchner funnel and drying at 60° C. under vacuum, 183 g of 4-n-butyl-acetanilide were obtained. 183 g of 4-n-butylacetanilide were dissolved in 300 ml of acetic acid and this solution, cooled at 5°-10° C., was added to a wellstirred mixture obtained by mixing 123 ml of nitric acid at a density of 1.4 and 325 ml of nitric acid at a density of 1.52. The temperature was kept below 5° C. during the whole addition and at the end the stirring was continued for 4 hours. The reaction mixture was then poured into 4 liters of ice and water under stirring, thus obtaining a yellow solid product that was filtered on a Buchner funnel and purified by recrystallization from ethanol. 217.4 g of 2-nitro-4-n-butyl-acetanilide were obtained and treated with 1,500 ml of toluolated ethanol and 600 ml of concentrated hydrochloric acid. The solution obtained was heated to reflux for two hours and the solvents removed under vacuum using a rotary evaporator. The oil residue, the analysis of which is reported hereinbelow, was used for the preparation of compound 1 without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:8]
Reactant: Cc1cc(F)c(C(=O)O)cc1Cl
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1Cl
Yield: 115.8 %

Procedure:
A solution of 5-chloro-2-fluoro-4-methylbenzoic acid (1 g, 5.2 mmol), methanesulfonamide (760 mg, 8.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 g, 8.0 mmol) and 4-dimethylaminopyridine (1.5 g, 8.0 mmol) in DCM (20 mL) was stirred at room temperature for 16 hrs. The reaction was quenched by water (5 mL), adjusted pH to 1 with HCl (1 M) and the resulting mixture was extracted with DCM (100 mL×3). The combined organic layers were concentrated in vacuo and the residue was recrystallized with petroleum ether and ethyl acetate to give desired product (1.6 g crude). LCMS (ESI) m/z: 263.9 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][C:5]1=[O:16])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[CH:40][N+:41]([O-:43])=[O:42])=[CH:35][C:34]=1[O:44][CH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:9]([CH:8]1[CH2:7][O:6][C:5](=[O:16])[N:4]1[C:1](=[O:3])[CH2:2][CH:39]([C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:34]([O:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:35]=1)[CH2:40][N+:41]([O-:43])=[O:42])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)N1C(=O)OCC1Cc1ccccc1
Reactant: O=[N+]([O-])C=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(CC(C[N+](=O)[O-])c1ccc(OCc2ccccc2)c(OC2CCCC2)c1)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
A mixture of 3-acetyl-4-benzyl-oxazolidin-2-one (2.1 g, 9.4 mmol) in THF (40 mL) was stirred under N2 at −78° C. Lithium diisopropyl amine (5.2 mL, 10.3 mmol, 2.0 M in heptane/THF/ethylbenzene) was then added dropwise. The mixture was stired for 20 min. 1-Benzyloxy-2-cyclopentyloxy-4-(2-nitrovinyl)benzene (3.2 g, 9.4 mmol) dissolved in 20 mL THF was cannulated over and the mixture was stirred for 2 h at −78° C. After quenching the reaction sat. NH4Cl, the mixture was warmed to r.t., extracted with CH3Cl, washed with water and brine, dried and concentrated. Filtration of the solids with 1:1 hexane/EtOAc, afforded 4 g of white solids. Yield: 75%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:8]
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: NCc1ccccn1
Product: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
contacting said 2,5-bis(2,2,2trifluoroethoxy)benzoic acid chloride with 2-aminomethylpyridine to provide 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10])[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>C1COCC1.O>[C:23]([O:22][C:20]([NH:2][CH:3]([CH2:7][CH2:8][C:9]([F:10])([F:11])[F:12])[C:4]([OH:6])=[O:5])=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NC(CCC(F)(F)F)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCC(F)(F)F)C(=O)O
Reaction time: 0.17 h
Yield: 122.4 %

Procedure:
To a stirred solution of 2-amino-5,5,5-trifluoropentanoic acid hydrochloride (400 mg, 1.503 mmol) in THF (8 mL) and water (8 mL) was added K2CO3 (831 mg, 6.01 mmol) at rt and the solution was stirred for 10 min. To this mixture was added BOC2O (656 mg, 3.01 mmol). The reaction mixture was stirred for 8 h at rt. The reaction mixture was concentrated under reduced pressure. The aq. layer was washed with ethyl acetate (3×5 mL). The aqueous layer was acidified with saturated citric acid solution (5 mL) and then extracted with ethyl acetate (3×8 mL). The combined organic layers were washed with water (3×5 mL) followed by brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2-((tert-butoxycarbonyl)amino)-5,5,5-trifluoropentanoic acid (500 mg, 1.84 mmol) quantitatively as a colorless oil. The crude material was taken as such to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 5.04 (s, 1H), 4.38 (s, 1H), 2.15-2.28 (m, 2H), 1.91-1.95 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([NH2:20])([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:7]2[CH2:6]1)=[O:4].Cl[CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[CH3:21][N:2]([CH3:1])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([NH:20][CH2:23][C:24]([N:26]3[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]3[C:32]#[N:33])=[O:25])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(N)(Cc3ccccc3)CC2C1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)CC2C1

Procedure:
5-Amino-5-benzyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14f (0.1 g, 0.35 mmol) was dissolved in 4 mL of the solvent mixture of dichloromethane/N,N-dimethylformamide (V/V=1/1) followed by addition of (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile 13g (66.5 mg, 0.35 mmol) and potassium carbonate (49 mg, 0.35 mmol). The reaction mixture was reacted at 40° C. for 12 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-benzyl-5-[(2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14g (87 mg, yield 56%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:30])=[C:8]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:38])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:30])=[C:8]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:9]2=[C:10]([Br:38])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 103(a) from 3-cyano-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 480 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19]CC3C=CC(OC)=CC=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1.Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1
Reactant: FC(F)(F)c1cccc(CCl)n1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(OC)cc3)c(Cl)c2=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C(F)(F)F)n3)c(Cl)c2=O)c1
Temperature: 45 °C
Yield: 29 %

Procedure:
To a solution of Intermediate 3 (250 mg, 0.81 mmol) in N,N-dimethylformamide (3 mL) was added 2-(chloromethyl)-6-(trifluoromethyl)pyridine (158 mg, 0.81 mmol), potassium carbonate (224 mg, 1.62 mmol) and 18-crown-6 (40 mg). The slurry was heated at 45° C. for eighteen hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a colorless oil. (110 mg, 29% yield). MS (M+H): 468
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(OCC)(=O)C.CO>[NH2:19][C:18]1[CH:17]=[CH:16][C:4]([O:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[CH3:1]
Reactant: COC(=O)c1ccccc1Oc1ccc([N+](=O)[O-])c(C)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccccc1Oc1ccc(N)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
Under a hydrogen atmosphere at atmospheric pressure, a solution of methyl 2-(3-methyl-4-nitrophenoxy)-benzoate (1.85 g, 6.44 mmol) in a mixture of ethyl acetate (15 ml) and methanol (8 ml) was stirred at room temperature for 5 hours. The solution was filtered and the filtrate was concentrated to obtain methyl 2-(4-amino-3-methylphenoxy)-benzoate (1.52 g, 92%).