Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]=[C:16]([F:18])[F:17])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>O1CCCC1>[F:17][C:16]([F:18])=[CH:15][CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:10][OH:11]
Reactant: COC(=O)[C@H](CC=C(F)F)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC=C(F)F
Temperature: 5 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
An ambient temperature solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-5,5-difluoropent-4-enoate (1.91 g, 7.20 mmol) in tetrahydrofuran (25 mL) was treated with lithium borohydride (0.31 g, 14 mmol) and stirred for 1 h. The resulting solution was cooled to 5° C., quenched with 0.1 N aqueous hydrochloric acid (50 mL), and extracted with ethyl acetate (3×25 mL). The pooled organic extracts were washed with brine (1×20 mL), dried over MgSO4, and concentrated under reduced pressure. The crude material was purified over SiO2 (20-100% ethyl acetate/hexanes gradient elution) to afford (S)-tert-butyl (5,5-difluoro-1-hydroxypent-4-en-2-yl)carbamate (1.4 g, 5.90 mmol, 82% yield) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.75 (d, J=6.0 Hz, 1H), 4.35-4.05 (m, 1H), 3.82-3.51 (m, 3H), 2.46-2.16 (m, 3H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:3]1[C:2]([Cl:1])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccnc(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccnc(Cl)c1CBr
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of ethyl 2-chloro-3-methylisonicotinate (4.0 g, 20.0 mmol), N-bromosuccinimide (3.7 g, 21.0 mmol), and dibenzoyl peroxide (0.49 g, 2.0 mmol) in carbon tetrachloride (50 mL) is heated at reflux temperature for 2 hours. After cooling to rt, the reaction mixture (suspension) is filtered through a pad of Celite™ (Celite Corporation), and washed with carbon tetrachloride. The filtrate is concentrated to give clear yellow oil. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1) to give 4.1 g (73% yield) of the title compound as a clear yellow liquid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:22][CH2:23][CH2:24][CH2:25]Br.CCOC(C)=O>CN(C=O)C.O>[CH2:7]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:25][CH2:24][CH2:23][Br:22])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(Cl)cc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(OCCCBr)c(Cc2ccccc2)c1
Temperature: 80 °C
Yield: 72.1 %

Procedure:
Powdered K2CO3 (2.07 g, 15.0 mmol) is added to a stirred solution of 2-benzyl-4-chlorophenol (2.19 g, 10.0 mmol) and 1,3-dibromopropane (3.05 mL, 30.0 mmol) in anhydrous DMF (20 mL) at ambient temperature under nitrogen; The mixture is heated at 80° C. for 1 hour. At ambient temperature, EtOAc (100 mL) and water (150 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 0-2% EtOAc in hexane) to give 2.45 g (7.21 mmol, 72% yield) of the title compound as a white solid. EIMS: m/z 338 (M+, 35Cl, 79Br), 340 (M+, 37Cl, 37Br or 35Cl, 81Br), 342 (M+, 37Cl, 81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:14])[NH:12][CH:13]=1.Cl[CH:16]([F:18])[F:17]>O1CCCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:14])[N:12]([CH:16]([F:18])[F:17])[CH:13]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c[nH]1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)cc2Cl)cn1C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.7 g (7.5 mmol) of 4-(2,4-dichlorophenyl)-2-methyl-1H-imidazole stirring in a mixture of 75 ml of tetrahydrofuran and 8 ml of 50% aqueous sodium hydroxide at room temperature, 8 ml of condensed chlorodifluoromethane was added dropwise from a gas addition funnel. The reaction mixture was stirred at ambient temperature overnight. After partitioning between an excess of ethyl acetate and water, the organic layer was separated, washed with water (3×) and brine, dried over magnesium sulfate, and evaporated in vacuo. The resulting dark red oil was flash chromatographed on silica gel (10:1-5:1-3:1-1:1 hexane/ethyl acetate) to give 940 mg of slightly impure 4-(2,4-dichlorophenyl)-1-difluoromethyl-2-methylimidazole, obtained as an oily solid residue and taken directly to the next step.
Reaction SMILES: [C:1]1([C:7]([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)[CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[C:30]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8][CH2:9][N:11]2[CH2:16][CH2:15][C:14]([OH:23])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCC(O)(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
Following the procedures set out in Example 1, 1 part of 3,3,3-triphenylpropionyl chloride and 2 parts of 4-hydroxy-4-phenylpiperidine are reacted to provide 1-(3,3,3-triphenylpropionyl)-4-hydroxy-4-phenylpiperidine. 0.23 Parts of this amide is reacted with 0.05 parts of lithium aluminum hydride in 3.0 parts by volume of ethyl ether to provide 1-(3,3,3-triphenylpropyl)-4-hydroxy-4-phenylpiperidine. This compound has the following structural formula ##STR31##
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[C:18]([O:26][CH2:27][CH:28]1[CH:33]=[CH:32][NH:31][CH2:30][CH2:29]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:18]([O:26][CH2:27][C:28]1[CH2:33][CH2:32][N:31]([CH2:2][C:3]2[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=2)[CH2:30][CH:29]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: O=C(OCC1C=CNCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CC=C(COC(=O)c3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
A suspension of 0.195 g (0.0010 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 5 ml of dimethylformamide was treated with 0.42 ml (0.0030 mol) of triethylamine and 0.365 g (0.0010 mol) of 1,2,3,4-tetrahydro-pyridin-4-ylmethyl benzoate and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed over silica gel with ethyl acetate as the eluent. 0.17 g (74%) of 1-(4-amino-2-methyl-pyrimidin-5-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-ylmethyl benzoate was obtained as a yellow oil. MS (ISP): me/e=339 (C19 H23N4O2+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[CH:5][C:3]=1[NH2:4].[CH3:23][O:24][C:25]1[N:30]=[C:29](S(C)(=O)=O)[N:28]=[C:27]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:26]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[N:12]([CH3:21])[C:11]2=[O:22])=[CH:5][C:3]=1[NH:4][C:29]1[N:28]=[C:27]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:26]=[C:25]([O:24][CH3:23])[N:30]=1
Reactant: COC(=O)COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(OC)nc(Nc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 15.5 %

Procedure:
To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 360 mg of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylsulfonylpyrimidine and 2 ml of N,N-dimethylformamide, 196 mg of potassium carbonate was added, and the mixture was stirred for 5 hours at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 98 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenylamino}-6-methoxy-4-(methoxycarbonyl)methoxypyrimidine [present compound 1-67].
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:13]=[C:14](/[CH:27]=[CH:28]/[CH3:29])[C:15]([O:18][C:19]2[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=2)=[N:16][CH:17]=1)([O:8]COC)[C:4]([F:7])([F:6])[F:5].[CH3:32][CH:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2([CH3:49])[NH:46][C:45](=[O:47])[NH:44][C:43]2=[O:48])=[CH:38][CH:37]=1)[CH3:34]>>[F:31][C:2]([F:1])([F:30])[C:3]([C:12]1[CH:13]=[C:14](/[CH:27]=[CH:28]/[CH3:29])[C:15]([O:18][C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][N:44]2[C:43](=[O:48])[C:42]([C:39]3[CH:38]=[CH:37][C:36]([O:35][CH:33]([CH3:32])[CH3:34])=[CH:41][CH:40]=3)([CH3:49])[NH:46][C:45]2=[O:47])=[N:16][CH:17]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: C/C=C/c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(CO)c1
Product: C/C=C/c1cc(C(O)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(CN2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)c1

Procedure:
After reacting and treating (E)-(3-(5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-3-(prop-1-enyl)pyridin-2-yloxy)phenyl)methanol in a similar manner to Preparation example 3 b), 5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione was used in place of 5-(benzo[d][1,3]dioxol-5-yl)-5-methylimidazolidine-2,4-dione in Example 1 for a similar reaction and treatment, and the title compound was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1CNCC(C)=CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@@H]1CC(O)=O)=O)(C)(C)C.COC1C=C(C=C(OC)C=1OC)C(O)=O.CN(CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=Cc1ccccc1)CNC[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: COc1cc(C(=O)O)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1

Procedure:
Experimental condition analogous to Example 22 were used with 2-(R)-[(2-methyl-3-phenyl-allylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared according to the scheme 13) were used with 2-(R)-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester) 0.5 g (1.51 mmol), 3,4,5-trimethoxy benzoic acid 0.38 g (1.8 mmol), triethylamine 0.1 ml, 1-(dimethylaminopropyl)-3-ethylcarbodiimide 0.43 g (2.2 mmol), and 1-hydroxybenzotriazole 0.2 g (1.5 mmol) in 10 ml DCM. The reaction yielded 0.46 g of 2-(R){[2-methyl-3-phenyl-allyl)-3,4,5-trimethoxy-benzoyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. After BOC deprotection analogous to the Example 13, the compound was transformed to the HCl salt, 0.35 g of a white solid was obtained. Yield: 50%
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:41])[C@@H:35]([NH2:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:40][C@@H:35]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:34]([OH:33])=[O:41])=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@H](C(=O)O)C(C)(C)C)nc(CC4CCCC4)c3c2)cc1
Yield: 87.6 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-3,3-dimethyl-butyric acid methyl ester HCl (24.5 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed by sonication at rt for 3 h and then usual work up as described in general procedure C afforded 54.3 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[C:14]([CH2:28][CH2:29][CH2:30][CH2:31]I)=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36]C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31][N:34]4[CH2:36][CH2:37][CH2:38][CH2:39]4)=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: c1ccncc1
Reactant: COc1cc2c(cc1CCCCI)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Agent: Cl
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1[nH]c3cc(CCCCN4CCCC4)c(O)cc3c21
Yield: 72 %

Procedure:
Demethylation of (173) prepared as described in example 312 with pyridine hydrochloride using the procedure described in example 81 gave (177) (72%). 1H NMR δ [(CD3)2SO] 11.70 (s, 1H), 10.98 (br s, 1H), 9.30 (br, 1H), 8.31 (s, 1H), 7.57 (dd, J=8.0, 2.2 Hz, 1H), 7.49 (s, 1H), 7.49–7.40 (m, 3H), 7.32 (s, 1H), 2.73 (t, J=7.5 Hz, 2H), 2.44–2.36 (m, 6H), 1.69–1.61 (m, 6H), 1.51 (m, 2H). The hydrochloride salt had a mp of 173–178° C. (dec). Found: C, 62.27; H, 5.22; N, 7.74. C28H26ClN3O3.HCl.H2O requires C, 62.00; H, 5.39; N, 7.75.
Reaction SMILES: [CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:32])[F:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:41])C(=O)C1>>[Br:41][C:15]1[C:14]2[CH:13]=[C:12]([O:11][CH2:10][C:9]3[CH:28]=[CH:29][C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:7]([C:30]([F:33])([F:31])[F:32])[CH:8]=3)[CH:20]=[CH:19][C:18]=2[N:17]2[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Product: O=C(O)CC1CCn2c1c(Br)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12

Procedure:
From 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid and NBS, in a similar manner to the one described in Example 1.4, the title compound was obtained as a light yellow solid. LCMS m/z=536.6 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.71 (m, 4H), 1.80-1.89 (m, 2H), 1.95-2.04 (m, 2H), 2.25-2.36 (m, 1H), 2.51-2.57 (m, 1H), 2.78-2.88 (m, 1H), 2.98 (dd, J=16.42, 3.66 Hz, 1H), 3.22-3.28 (m, 1H), 3.58-3.67 (m, 1H), 3.98-4.06 (m, 1H), 4.13-4.20 (m, 1H), 5.18 (s, 2H), 6.88 (dd, J=8.84, 2.40 Hz, 1H), 6.91 (d, J=2.15 Hz, 1H), 7.29 (d, J=8.72 Hz, 1H), 7.63 (d, J=8.21 Hz, 1H), 7.70-7.76 (m, 2H), 12.33 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][C:31]=4[F:32])[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].C1COCC1.Cl>CO.O>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][C:31]=4[F:32])[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4cc5cccnc5cc4F)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4cc5cccnc5cc4F)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
To a solution of Example 135 (0.240 g, 0.605 mmol) in methanol (3 ml), lithium hydroxide (0.237 g, 5.64 mmol) in water (3 ml), THF (6 ml) were added and stirred at RT. After 12 h, pH was adjusted to ca 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.110 g, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[Li+].[CH3:11]C([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.CI>C1COCC1>[CH2:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=1)[CH3:11]
Reactant: COc1ccc(C)nc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCc1ccc(OC)cn1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
5-Methoxy-2-methyl-pyridine (9.5 g, 77 mmol) was added to a cooled −78° C. solution of LDA prepared from n-BuLi (37 mL, 93 mmol, 2.5 M in hexanes) and diisopropylamine (13 mL, 93 mmol) dissolved in THF (100 mL). The deep red reaction mixture was stirred for 30 mins and then treated with methyl iodide (5.4 mL, 85 mmol). After 2 hours the mixture was quenched with conc NH4OH (15 mL). The mixture was poured into H2O and extracted with EtOAc. The organic extracts were washed with brine, drived over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 40% EtOAc in hexanes) gave the product as a clear oil (2.5 g, 24%) and unreacted starting material (3.8 g, 40%). 1H NMR (400 MHz, CDCl3): δ 1.28 (t, J=7.3 Hz, 3 H), 2.76 (q, J=7.3 Hz, 2 H), 3.84 (s, 3 H), 7.08 (d, J=8.3 Hz, 1 H), 7.14 (d, J=8.3 Hz, 1 H), 8.23 (s, 1 H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:15](=[S:16])[C:14]4[CH:17]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=[CH:20][C:13]=4[O:12][C:11]3=[O:25])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(Cl)(Cl)(Cl)Cl.C(N(C(C)C)CC)(C)C.[PH:40](=[O:57])([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C.CN(C)C1C=CN=CC=1>[P:40]([O:21][C:19]1[C:18]([CH:22]([CH3:23])[CH3:24])=[CH:17][C:14]2[C:15](=[S:16])[N:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[CH2:1][CH2:2][CH2:3]4)[C:11](=[O:25])[O:12][C:13]=2[CH:20]=1)([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:57]
Reactant: O=[PH](OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)c1cc2c(=S)n(-c3ccc4c(c3)CCC4)c(=O)oc2cc1O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc2c(=S)n(-c3ccc4c(c3)CCC4)c(=O)oc2cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 100.9 %

Procedure:
To a stirred solution of 0.30 g (0.84 mmols) of 5 in 10 mL of anhydrous acetonitrile at 5° C., was added 0.4 mL (4.24 mmols) of CCl4, 0.31 mL (1.78 mmols) of diisopropylethylamine and 10 mg (85□mols) of 4-dimethylaminopyridine in that order. After stirring the mixture for 5 min. at 5° C., 0.34 mL (1.27 mmols) of dibenzyl phosphonate 6 was added drop wise and the mixture stirred for 1 h at 5° C. The reaction was quenched with water, extracted the product with ethyl acetate and organic layers were washed with water and brine. Filtration of the product through a plug of silica gel afforded 0.52 g of the product 7 as brown liquid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[CH3:9][Si:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][O:13][C:14](Cl)=[O:15]>CCOCC>[CH3:9][Si:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][O:13][C:14]([NH:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)=[O:15]
Reactant: NCCc1c[nH]cn1
Reactant: C[Si](C)(C)CCOC(=O)Cl
Solvent: CCOCC
Product: C[Si](C)(C)CCOC(=O)NCCc1c[nH]cn1

Procedure:
1.84 g (10 mmol) of histamine dihydrochloride is slurried in 50 ml of methylene chloride, and 6.2 ml (44 mmol) of triethylamine is added. The thus resultant mixture is added portionwise to 2-trimethylsilylethylchloroformate in toluene (prepared as described above) at 10°-15° C. The reaction mixture is stirred at room temperature overnight. Undissolved material is filtered off and identified by NMR as being triethylamine hydrochloride. The toluene solution is evaporated, the residue then being slurried in 30 ml of ethyl acetate. 1.0 g of undissolved triethylamine hydrochloride is removed by filtration. The ethyl acetate solution is evaporated, and the residue is slurried twice in petroleum ether. The petroleum ether solutions are evaporated and 1.0 g of a semicrystalline product is obtained; by NMR analysis this product is identified as being histamine in which both the amino group and ring nitrogen have been acylated with 2-trimethylsilylethylchloroformate. The acyl group on the ring nitrogen is removed by treatment of the product for 2 hours with 100 μl of triethylamine in 50 ml of methanol. The solution is evaporated to leave an oil which is transformed into white crystals by treatment with 30 ml of ether. More precipitate is obtained upon addition of 75 ml petroleum ether. 560 mg of I is obtained upon filtration. The structure of the product is established with the aid of its NMR spectrum. 1H NMR spectrum (CDCl3) expressed as values: 2H 7.60 s, 5H 6.82 s, --NH-- 5.20, --CH2CH2 --O-- 4.15 t, --OCONHCH2 -- 3.50 m, 4-CH2 -imidazole 2.82 t, SiCH2CH2 1.00 t, (CH3)3Si 0.03 s.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH:9]1([C@H:12]([NH:20][C:21]([C:23]2[C:32]3[C:27](=[C:28]([F:33])[CH:29]=[CH:30][CH:31]=3)[C:26](=[O:34])[N:25]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[C:24]=2[CH2:41]Br)=[O:22])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH2:11][CH2:10]1.Cl>O1CCCC1>[CH:9]1([C@H:12]([NH:20][C:21]([C:23]2[C:32]3[C:27](=[C:28]([F:33])[CH:29]=[CH:30][CH:31]=3)[C:26](=[O:34])[N:25]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[C:24]=2[CH2:41][N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])=[O:22])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH2:11][CH2:10]1
Reactant: O=C(N[C@H](c1cccc(F)c1)C1CC1)c1c(CBr)n(-c2cccnc2)c(=O)c2c(F)cccc12
Reactant: O=C1CCCN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@H](c1cccc(F)c1)C1CC1)c1c(CN2CCCC2=O)n(-c2cccnc2)c(=O)c2c(F)cccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 72 mg, 1.8 mmol) was added to 2-pyrrolidinone (380 mg, 4.5 mmol) in tetrahydrofuran (2.0 mL) under an atmosphere of Argon. The reaction mixture was stirred for 30 minutes at room temperature. To this mixture, 3-bromomethyl-8-fluoro-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (118 mg, 0.23 mmol) in tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into 25 mL 0.2N HCl (aq). The mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The title compound was isolated by preparative TLC on silica gel (eluent: ethyl acetate).