Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:12]([N:17]([CH3:25])[C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH:26]1[C:38]2[CH:37]([CH2:39][O:40][C:41]([N:43]([CH3:50])[C:44]([CH3:49])([C:46](O)=[O:47])[CH3:45])=[O:42])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.ClCCl>[CH:35]1[C:36]2[CH:37]([CH2:39][O:40][C:41]([N:43]([CH3:50])[C:44]([CH3:45])([C:46]([NH:20][C@H:19]([C:18]([N:17]([C@@H:12]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:25])=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:47])[CH3:49])=[O:42])[C:38]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.2 %

Procedure:
To a round bottom flask containing #6 (4.7 g, 7.9 mmol, 1.0 eq.) and N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N,2-dimethylalanine (3.2 g, 9.4 mmol, 1.2 eq.) and a stir bar under nitrogen, 50 mL of dichloromethane was added followed by HATU (3.6 g, 9.4 mmol, 1.2 eq.) and Hunig's base (5.5 mL, 32 mmol, 4.0 eq.). The reaction was allowed to stir at room temperature for ˜12 hours. Reaction was reduced to a smaller volume, taken up in ethyl acetate, before being washed with 1 N HCl, and brine. Organics where then dried over sodium sulfate, filtered and then reduced down onto silica. Residue was purified by Silica Chromatography (Gradient: 0%-30% acetone in heptane) producing #127 (4.2 g, 78%) as a white solid. LC-MS (Protocol Q): m/z 680.2 [M+H+] retention time=2.52 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6](O)=[O:7].CC[N:18]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([NH2:18])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(Oc1ccc(Cl)cc1Cl)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Oc1ccc(Cl)cc1Cl)C(N)=O
Reaction time: 18 h
Yield: 62 %

Procedure:
A mixture of 3-((3-endo-amino-8-azabicyclo[3.2.1]octan-8-yl)methyl)benzonitrile dihydrochloride (470 mg, 1.49 mmol), commercially available 2-(2,4-dichlorophenoxy)-2-methylpropanoic acid (4) (447 mg, 1.79 mmol), EDCI (430 mg, 2.24 mmol), HOBT (304 mg, 2.24 mmol) and triethylamine (1.3 mL, 9.32 mmol) in CH2Cl2 (5 mL) was stirred 18 h. The resulting mixture was washed with satd. aq. NaHCO3 solution (5 mL), brine (5 mL) successively, dried over MgSO4, filtered and evaporated to give a residue which was purified by column chromatography (ethyl acetate: CH2Cl2=1:1) to give N-(8-(3-cyanobenzyl)-8-azabicyclo[3.2.1]octan-3-endo-yl)-2-(2,4-dichlorophenoxy)-2-methylpropanamide (526 mg, 1.11 mmol, 74% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 1.55 (s, 6H), 1.65 (d, 2H), 1.85 (m, 2H), 2.08 (m, 2H), 2.25 (m, 2H), 3.15 (br s, 2H), 3.55 (ABq, 2H), 4.17 (m, 1H), 7.04 (d, 1H), 7.20 (dd, 1H), 7.44 (m, 2H), 7.48 (m, 1H), 7.54 (m, 1H), 7.62 (d, 1H), 7.70 (br s, 1H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=1)[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:14](=[O:16])[NH:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:20]2[CH:30]=[CH:31][CH:32]=[C:18]([F:17])[CH:19]=2)=[CH:28][CH:27]=1)[CH2:10][CH2:11][S:12][CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
Condensation of (S)-BOC-methionine and 4-(3-fluorobenzyloxy)-phenylamine [Example 3b)] by HBTU yields the (S)-{1-[4-(3-fluoro-benzyloxy)-phenylcarbamoyl]-3-methylsulfanyl-propyl}-carbamic acid tert-butyl ester as a light yellow solid; MS: m/e=449 (M+H)+. The following methylation and cyclisation yields the (S)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester as a white solid; MS: m/e=401 (M+H)+. The cleavage of the BOC-group yields the (S)-3-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride as a white solid; MS: m/e=301 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][OH:23].N1C=CC=CC=1>C(Cl)Cl.C(OCC)C.O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([O:23][CH3:22])=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)Cl)c1ccc2c(c1)CCc1ccccc1C2=O
Reactant: CO
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)C(C)c1ccc2c(c1)CCc1ccccc1C2=O

Procedure:
A solution of 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride (10 g.) in methylene chloride (100 cc.) is added at 20°C. and over the course of 10 minutes to a mixture of methanol (100 cc.) and anhydrous pyridine (10 cc.). On concentrating the reaction mixture to dryness, a paste-like residue (weighing 14 g.) is obtained and the latter is taken up in diethyl ether (500 c.) and water (100 cc.). The ether phase is decanted, washed twice with water (total 100 cc.) and dried over potassium carbonate. On concentrating to dryness, methyl 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionate (8.6 g.) is obtained.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl.O>[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH:12][C:22](=[O:23])[CH2:21][Cl:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 993.1 %

Procedure:
To a suspension of glycine benzylester hydrochloride (25.2 g, 12.5 mmol, Aldrich) in CH2Cl2 (200 ml) was added a solution of K2CO3 (77 g, 55.8 mmol) in H2O (200 ml). The mixture was cooled to 0° C. and chloroacetylchloride (21.0 g, 18.6 mol, Aldrich) was added dropwise in 15 min. The mixture was warmed to room temperature and stirred for 2 h. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (100 ml). The organic layers were combined and washed with H2O (100 ml), brine (100 ml), dried (MgSO4). Evaporation of solvent afforded a light yellowish glassy solid. This was triturated with 250 ml of hexane. The colorless solid was collected and dried to give 30.0 g of the material 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[C:10](OC)(=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: COC(=O)CC(=O)OC
Product: COC(=O)CC(=O)Nc1cc(F)cc(F)c1

Procedure:
Prepared according to Procedure A using 3,5-difluoroaniline (5.00 g, 38.7 mmol) and dimethyl malonate to give methyl 3-(3,5-difluorophenylamino)-3-oxopropanoate. Mass Spectrum (ESI) m/e=230.1 (M+1).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:14])[CH:11]=2)[CH2:6]1)=[O:4]>CC(O)=O>[Br:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:13]2
Reactant: COC(=O)C1Cc2ccc(Br)cc2C1
Solvent: CC(=O)O
Product: O=C(O)C1Cc2ccc(Br)cc2C1

Procedure:
Use of 5-bromo-indan-1-one (Intermediate NINETEEN-1) in a reaction with NaH and dimethylcarbonate (refer to procedures in Method EIGHTEEN) produced 5-bromo-1-oxo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-2). A solution of 5-bromo-1-oxo-indan-2-carboxylic acid methyl ester (4.75 g, 17.7 mmol) in TFA (80 mL) at 0° C. was treated with triethylsilane (TES) (17.0 mL, 6.0 eq) and stirred for 18 h. After evaporation of the solvent, the residue was diluted with Et2O and washed with H2O (5×100 mL), sat. NaHCO3 (3×50 mL), brine (1×75 mL) and dried over MgSO4 to give crude 5-bromo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-3). A solution of 5-bromo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-3) in AcOH containing 20% HCl was stirred overnight. After evaporation of the solvent, the residue was dissolved in 1N NaOH. The resulting mixture was washed with Et2O (3×75 mL) after which it was acidified with HCl (aq). The solution was extracted with CH2Cl2 (3×150 mL) and the combined organic extracts was washed with H2O (3×100 mL), brine (1×75 mL), dried over MgSO4 and concentrated to give crude 5-bromo-indan-2-carboxylic acid. Use of 5-bromo-indan-2-carboxylic acid in Method EIGHTEEN produced 4-(5-bromo-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 148).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]([O:15][CH2:16][CH3:17])[CH2:13][CH:12]([OH:18])[C:11]2=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](O)(=[O:22])[CH3:21]>>[C:1]1([S:7]([N:10]2[CH:14]([O:15][CH2:16][CH3:17])[CH2:13][CH:12]([O:18][C:20](=[O:22])[CH3:21])[C:11]2=[O:19])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC1CC(O)C(=O)N1S(=O)(=O)c1ccccc1
Reactant: CC(=O)O
Product: CCOC1CC(OC(C)=O)C(=O)N1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.50 g of 1-benzenesulfonyl-2-oxo-3-hydroxy-5-ethoxypyrrolidine (trans isomer) in 10 cm3 anhydrous acetic acid is heated to boiling for 1 hour. It is allowed to cool to room temperature and the acetic anhydride is evaporated. It is dissolved in toluene and the azeotrope is evaporated under reduced pressure. The residue is chromatographed on silica by elution with a mixture of ethylacetate-hexane (1-1); 0.48 g of the expected product is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([NH:8][C:9]([O:11]CC2C=CC=CC=2)=O)[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3]1.C(N(CC)CC)C.Br[CH2:32][C:33]1[C:42]([N+:43]([O-:45])=[O:44])=[CH:41][CH:40]=[CH:39][C:34]=1C(OC)=O>C(O)(=O)C.CN(C)C=O.[Pd]>[N+:43]([C:42]1[CH:41]=[CH:40][CH:39]=[C:34]2[C:33]=1[CH2:32][N:8]([CH:7]1[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3][C:2]1=[O:1])[C:9]2=[O:11])([O-:45])=[O:44]
Reactant: CC(=O)OC1CC(NC(=O)OCc2ccccc2)C(=O)NC1=O
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC1CC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)NC1=O

Procedure:
A solution of 2,6-dioxo-3-benzyloxycarbonylamino-5-acetoxypiperidine (9 g, 28.2 mmol) and Pd/C (10%, 0.9 g) in acetic acid (90 mL) is shaken under hydrogen (50–60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with acetic acid and the solvent is then removed in vacuo. The residue, triethyl-amine (2.9 g, 28 mmol), and methyl 2-bromomethyl-3-nitrobenzoate (7.7 g. 28.2 mmol) in dimethylformamide (100 mL) is heated at 80° C. for 18 hours. The solvent is removed in vacuo to give 3-(4-nitro-1-oxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which can be further purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:11]([OH:13])=O)=[O:7])([CH3:4])[CH3:3].C1C=CC2N(O)N=NC=2C=1.[NH2:35][C@H:36]([C:49]([NH:51][C@H:52]([C:55]([NH:57][C@H:58]([C:64]([NH:66][C@H:67]([C:71]([N:73]1[CH2:114][CH2:113][CH2:112][C@H:74]1[C:75]([NH:77][C@H:78]([C:83]([NH:85][C@H:86]([C:90]([NH:92][C@H:93]([C:97]([NH:99][C@H:100]([C:105]([O:107][C:108]([CH3:111])([CH3:110])[CH3:109])=[O:106])[CH2:101][CH:102]([CH3:104])[CH3:103])=[O:98])[C@@H:94]([CH3:96])[OH:95])=[O:91])[CH:87]([CH3:89])[CH3:88])=[O:84])[CH2:79][CH:80]([CH3:82])[CH3:81])=[O:76])=[O:72])[C@@H:68]([CH3:70])[OH:69])=[O:65])[CH2:59][CH2:60][C:61](=[O:63])[NH2:62])=[O:56])[CH2:53][OH:54])=[O:50])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:14]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:10]([C:11]([NH:35][C@H:36]([C:49]([NH:51][C@H:52]([C:55]([NH:57][C@H:58]([C:64]([NH:66][C@H:67]([C:71]([N:73]1[CH2:114][CH2:113][CH2:112][C@H:74]1[C:75]([NH:77][C@H:78]([C:83]([NH:85][C@H:86]([C:90]([NH:92][C@H:93]([C:97]([NH:99][C@H:100]([C:105]([O:107][C:108]([CH3:109])([CH3:110])[CH3:111])=[O:106])[CH2:101][CH:102]([CH3:103])[CH3:104])=[O:98])[C@@H:94]([CH3:96])[OH:95])=[O:91])[CH:87]([CH3:89])[CH3:88])=[O:84])[CH2:79][CH:80]([CH3:81])[CH3:82])=[O:76])=[O:72])[C@@H:68]([CH3:70])[OH:69])=[O:65])[CH2:59][CH2:60][C:61](=[O:63])[NH2:62])=[O:56])[CH2:53][OH:54])=[O:50])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[O:13])[CH2:9][CH2:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)[C@@H](C)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)[C@@H](C)O)C(C)C
Temperature: -22 °C

Procedure:
843 mg Z-Glu(OtBU)-OH and 676 mg HOBt are dissolved in 10 ml DMF. After cooling to -22° C., 2.82 g H-Lys(Boc)-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-OtBu (Example VII.2) and 517 mg DCCI, dissolved in 2 ml DMF, are added to the solution. After stirring at -22° C. for some time, the DCHU is filtered out and the filtrate is evaporated to dryness.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:9]([CH:14]([CH3:20])[C:15](OCC)=[O:16])[C:10]([CH3:13])=[CH:11][CH:12]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH3:7][C:8]1[N:9]([CH:14]([CH3:20])[CH2:15][OH:16])[C:10]([CH3:13])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(C)n1c(C)ccc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Cc1ccc(C)n1C(C)CO
Yield: 96 %

Procedure:
Lithium aluminum hydride (3.1 g; 80.5 mmoles) was added to 100 ml of dry ether, and an ether solution (50 ml) of 17.9 g (91.8 mmoles) of ethyl 2-(2,5-dimethylpyrrol-1-yl)propionate was gradually added dropwise to the mixture. After the addition, the mixture was heated under reflux for 2 hours, and worked up with a saturated aqueous solution of sodium sulfate. The ethereal layer was concentrated under reduced pressure to afford 13.5 g of crude 2-(2,5-dimethylpyrrol-1-yl)-1-propanol. Acetic anhydride (50 ml) and 50 ml of pyridine were added to the product, and the mixture was allowed to stand at room temperature for 20 hours. It was then concentrated under reduced pressure and then distilled under reduced pressure to afford 2-(2,5-dimethylpyrrol-1-yl)propyl acetate (13.0 g, 66.8 mmoles, 75.7%) having a boiling point of 116°-118° C./6 mmHg.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=O.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:2]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Reactant: NCC(F)(F)F
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NCC(F)(F)F
Yield: 32 %

Procedure:
As described for example 100f, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (38 mg, 32%) which was obtained as a white solid. MS: m/e=443.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[C:10](=[O:15])[CH:11]([CH3:14])[CH2:12][CH3:13])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH:24]=[C:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[N:35][C:30]=2[CH2:29][O:28][C:27]2[CH:36]=[CH:37][C:38]([C:40]([OH:43])([CH3:42])[CH3:41])=[CH:39][C:26]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:16]2[CH2:20][CH2:19][N:18]([CH2:22][CH2:23][CH:24]=[C:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[N:35][C:30]=4[CH2:29][O:28][C:27]4[CH:36]=[CH:37][C:38]([C:40]([OH:43])([CH3:42])[CH3:41])=[CH:39][C:26]3=4)[CH2:17]2)[C:10](=[O:15])[CH:11]([CH3:14])[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCC(C)C(=O)C(Cc1ccc(Cl)cc1)N1CCNC1
Solvent: CC(C)O
Product: CCC(C)C(=O)C(Cc1ccc(Cl)cc1)N1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 77 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a heated (77° C.) stirring solution of 1-(4-chloro-phenyl)-2-imidazolidin-1-yl-4-methyl-hexan-3-one (110 mg, 0.374 mmol), 2,6-lutidiene (130_L, 11.229 mmol) and 5 mL isopropanol was added 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (70 mg, 0.187 mmol) portion-wise over a 30 minute period. The resulting solution was monitored using thin layer chromatography and allowed to stir at 77° C. for 16 hours. The solution was concentrated in vacuo at 35° C. The residue was dissolved in ethyl acetate and subjected to column chromatography (SiO2, Biotage 12M column, gradient elution 100% ethyl acetate→92% ethyl acetate/8% methanol with 1% triethyl amine) to afford 54 mg of 1-(4-chloro-phenyl)-2-(3-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-imidazolidin-1-yl)-4-methyl-hexan-3-one as a tan foam. LC/MS: tUV=1.68 min, M/Z=588 amu.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:20][C:21]1[N:22]=[CH:23][C:24]2[CH2:25][C:26](=[O:40])[NH:27][C:28]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:29]=3[C:30]=2[N:31]=1>O1CCOCC1>[NH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[C:4]([NH:20][C:21]2[N:22]=[CH:23][C:24]3[CH2:25][C:26](=[O:40])[NH:27][C:28]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:29]=4[C:30]=3[N:31]=2)[C:3]([CH3:2])=[N:8][CH:7]=1
Reactant: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ncc(CCCN)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.7 %

Procedure:
To a 4M solution of HCl in dioxane (20 mL) was added tert-butyl [3-(6-methyl-5-{[6-oxo-9-(trifluoromethyl)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl]amino}pyridin-3-yl)propyl]carbamate (1.10 g, 2.04 mmol). The reaction mixture was allowed to stir at rt overnight and then concentrated to give 2-{[5-(3-aminopropyl)-2-methylpyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (1.35 g, 2.30 mmol, >99%) as a brown solid. LCMS (FA): Rt=0.55 min, m/z=443.0 (M+H).
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C([Li])CCC.CN(C)CCN(C)C.Br[CH2:26][CH:27]=[CH:28][CH2:29][CH3:30]>O1CCCC1.O>[CH2:26]([C:2]1[CH2:4][C:3]=1[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:27]=[CH:28][CH2:29][CH3:30]
Reactant: CCCCCC1(Br)CC1(Br)Br
Reactant: CCC=CCBr
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC=CCC1=C(CCCCC)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
A solution of 1.00 g (0.00287 mol) of 1,1,2-tribromo-2-pentyl-cyclopropane in 4 ml of tetrahydrofuran was placed under an inert atmosphere of nitrogen via a Firestone valve. To this mixture, cooling in an ice water bath, was added via syringe 3.58 ml (0.00861 mol) of 1.6M n-butyllithium in hexanes. After 30 minutes, 0.432 ml (0.00287 mol) of tetramethylethylene diamine and 0.339 ml (0.00287 mol) of 1-bromo-2-pentene were added by syringe. The reaction stirred for one hour while warming to room temperature, then for three hours at room temperature. To the resulting mixture was added 2 ml of water. This residue was extracted with diethyl ether. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 0.200 g (39.1% of theory) of 1-pent-2-enyl-2-pentyl-cyclopropene as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]5[N:35]=[C:36]([CH:39]6[CH2:45][C:42]7([CH2:44][CH2:43]7)[CH2:41][N:40]6[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])[NH:37][CH:38]=5)[CH:30]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[CH3:67][O:68][C:69]([NH:71][CH:72]([CH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1)[C:73]([OH:75])=O)=[O:70].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.CN(C=O)C>[CH3:55][O:54][C:52](=[O:53])[NH:51][CH:47]([C:46]([N:40]1[CH:39]([C:36]2[NH:37][CH:38]=[C:34]([C:29]3[CH:28]=[CH:27][C:26]4[C:31](=[CH:32][CH:33]=[C:24]([C:21]5[CH:22]=[CH:23][C:18]([C:15]6[NH:14][C:13]([CH:9]7[N:8]([C:73](=[O:75])[CH:72]([NH:71][C:69]([O:68][CH3:67])=[O:70])[CH:76]8[CH2:81][CH2:80][O:79][CH2:78][CH2:77]8)[CH2:12][CH2:11][S:10]7)=[N:17][CH:16]=6)=[CH:19][CH:20]=5)[CH:25]=4)[CH:30]=3)[N:35]=2)[CH2:45][C:42]2([CH2:44][CH2:43]2)[CH2:41]1)=[O:56])[CH:48]([CH3:50])[CH3:49]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1nc(-c2ccc3cc(-c4ccc(-c5cnc(C6SCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1nc(-c2ccc3cc(-c4ccc(-c5cnc(C6SCCN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 11.1 %

Procedure:
2-{5-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-thiazolidine-3-carboxylic acid tert-butyl ester (49.9 mg, 0.064 mmol) was dissolved in DCM (0.33 mL) and HCl in dioxane (4M, 0.33 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.5 mL) and DIEA (24.6 mg, 0.191 mmol) was added. A solution of 2-(L) methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (13.8 mg, 0.064 mmol), HATU (24.1 mg, 0.064 mmol) and DIEA (8.2 mg, 0.064 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 18 hrs all volatiles were removed in vacuo. The crude material, which was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA) to yield the product (6.2 mg) as a TFA salt.