Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)N([Br:7])C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([O:32][CH3:33])[CH:26]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC1C=CC=CC=1>[Br:24][C:25]1[CH:26]=[C:27]([O:32][CH3:33])[CH:28]=[C:29]([CH2:31][Br:7])[CH:30]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COc1cc(C)cc(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COc1cc(Br)cc(CBr)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
5,5-Dimethyl-1,3-dibromohydantoin (13.1 g, 46 mmol) and azobisisobutyronitrile (1.50 g, 9.1 mmol) were simultaneously added at 80° C. to a solution of 1-bromo-3-methoxy-5-methylbenzene (17.0 g, 91 mmol) synthesized by a method of the document (J. Med. Chem. 2001, 44, 1866) in monochlorobenzene (500 mL), and the reaction mixture was stirred at 80° C. for 30 minutes. The reaction solution was cooled to room temperature and then poured into a 10% aqueous sodium thiosulfate solution (100 mL), and the mixture was stirred for 30 minutes. The mixture was separated into aqueous and organic layers. The aqueous layer was subjected to extraction with toluene (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure to obtain 1-bromo-3-(bromomethyl)-5-methoxybenzene. Without further purification, this compound was dissolved in triethyl phosphite (14.3 mL, 97 mmol) and toluene (50 mL), and the reaction mixture was heated under reflux for 7 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to obtain the title compound (1-2-1) (20.8 g, 64%).
Reaction SMILES: C([C:6]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])(OCC)=O.S(=O)(=O)(O)O.C(O)(=O)C>O>[C:7]1(=[O:12])[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)C1(CCCCCCC(=O)[O-])CCCCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCCCCC1CCCCC1=O

Procedure:
A stirred mixture of 380 g. of mixed methyl and ethyl esters of 7-(2-carbethoxycyclohexan-1-on-2-yl)heptanoate (Example 10), 202 ml. of concentrated sulfuric acid, 970 ml. of glacial acetic acid, and 970 ml. of water is refluxed for 22.5 hours. The cooled reaction mixture is treated with 380 g. of sodium carbonate and 2 liters of water and is extracted with ether. Acidic material is partitioned from the ether extract with 1.0M sodium carbonate. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated to give an oil.
Reaction SMILES: [Cl:1][C:2]1[C:12](I)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: OB(O)c1ccccc1
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(I)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(-c2ccccc2)c1Cl
Temperature: 90 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
To a solution of the compound of Example 239 (0.191 g, 0.5 mmol) and palladium tetrakistriphenylphosphine (23 mg, 0.02 mmol) in toluene (10 mL) was added 2 M sodium carbonate (0.5 mL) and phenyl boronic acid (73 mg, 0.6 mmol). The mixture was heated at 90° C. for 30 h, additional portions of catalyst (20 mg) and 2 M sodium carbonate (0.5 mL) were added and heating was continued for 24 h. The cool reaction was diluted with CH2Cl2 and washed with 2 M sodium carbonate (50 mL with 5 mL conc NH4OH). The organic layer was dried (MgSO4) and concentrated. The crude product was purified by RC (ethyl acetate/hexanes) and recrystallization from hexanes to afford the title compound as white needles (98 mg, 59%). m.p. 134-135° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.O=S(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:9]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[F:16])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: Nc1ccccc1F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Nc1ccc(Br)nc1C(=O)Nc1ccccc1F
Temperature: 130 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A mixture of 3-amino-6-bromopicolinic acid (250 mg, 1.152 mmol) and SOCl2 (5 mL) in toluene (10 mL) was stirred at 130° C. for 2 h, then evaporated and dissolved in tetrahydrofuran (20 mL). 2-fluoro-phenylamine (256 mg, 2.3 mmol) was added dropwise maintaining the temperature at 5° C. The reaction mixture was heated to 90° C. for 15 h. The mixture was cooled to room temperature and quenched with saturated aqueous K2CO3 (10 mL) and extracted with ethyl acetate (10 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with column chromatograph (PE:EtOAc=3:1) to give 3-amino-6-bromo-N-(2-fluorophenyl)picolinamide (160 mg, yield: 45%). MS (M+H)+: 311/313.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:40]=[CH:39][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])(C(O)=O)[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:41]3[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=3)[S:7][C:6]=2[CH:48]=1>CS(C)=O.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:40]=[CH:39][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:41]3[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=3)[S:7][C:6]=2[CH:48]=1
Reactant: O=C(c1ccc(OCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)O)C(=O)O)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(OCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
2-[5-[4-[(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]-phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonic acid (1.1 g, 1.58 mmol) was dissolved in dimethyl sulfoxide (10 ml) and stirred for 3 hours at 120° C. The reaction mixture was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to give 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-6,6,7,7,7-pentafluoroheptanoic acid (732 mg, Yield 71%) as a yellow solid.
Reaction SMILES: [C:1]([O-])(C)(C)[CH3:2].[K+].[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=O)[C:17]([O:19][CH3:20])=[O:18].O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH:1][CH3:2])[C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(C)(C)[O-]
Reactant: COCc1ccccc1C(=O)C(=O)OC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC=C(C(=O)OC)c1ccccc1COC
Temperature: 5 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
At 5° C. 11.2 g (0.1 mol) of potassium tert-butanolate was added to a A mixture of 37.1 g (100 mmol) of ethyltriphenylphosphonium bromide was added under a nitrogen blanket to 300 ml of absolute tetrahydrofuran. At 5° C., 11.2 g (0.1 mol) of potassium tert-butanolate was added. After the mixture had been stirred for 1 hour at 5° C., 20.8 g (100 mmol) of methyl 2-methoxymethylphenylglyoxylate in 100 ml of tetrahydrofuran was dripped in. The mixture wa stirred for 1 hour at 5° C. and for 1 hour at 25° C., 200 ml of water was added and extraction carried out with methylene chloride. After the combined organic phases had been washed with water and dried, the solvent was removed under reduced pressure. The residue was purified chromatographically in a silica gel column (methyl tert-butyl ether/n-hexane=1/2). There was obtained 17.2 g (78%) of the above-mentioned ester as an oil (Z/E isomer=1/9) (compound no. 25).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:9]([NH:16][C:17](=[O:19])[CH3:18])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Br[CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22](=[O:27])[CH2:21][N:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:9]([NH:16][C:17](=[O:19])[CH3:18])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(=O)N[C@H]1CCC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CCC2(CCN(CC(=O)C(C)(C)C)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A suspension of the piperidine (B5) (24 mg, 0.09 mmol), 1-bromo -3,3-dimethylbutan-2-one (13.5 mg, 0.08 mmol) and sodium carbonate (32 mg, 0.3 mmol) in DMF (1 ml) was stirred at 50° C. in a sealed vial for 16 hours. The mixture was cooled and carefully neutralized with TFA and purified by reverse phase HPLC to give the title compound no. 19 as a TFA salt. LC-MS: m/e=357.30 (M+H). Rt=1.61 min. 1H-NMR (500 MHz, DMSO-d6): 9.60 (br. s, 1H), 8.21 (d, 1H), 7.44 (d, 1H), 7.32 (t, 1H), 7.20 (t, 1H), 7.16 (d, 1H), 4.92 (q, 1H), 4.60 (d, 2H), 3.26 (m, 4H), 2.35 (m, 2H), 2.04 (dd, 1H), 1.87 (s, 3H), 1.80 (m, 3H), 1.71 (d, 1H), 1.63 (m, 1H), 1.16 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[Cl:14][C:15]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Cl:14][C:15]1[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: FC(F)(F)c1cccc(CBr)c1Cl
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: N#Cc1ccnc(-c2cn(Cc3cccc(C(F)(F)F)c3Cl)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 4) and 2-chloro-3-(trifluoromethyl)benzyl bromide according to the procedure for the preparation of Example 43, part A using room temp. [M+H] Calc'd for C17H10ClF3N4, 363. Found, 363.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][NH:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1.Br[C:35]1[S:36][CH:37]=[CH:38][N:39]=1.[F-].[K+]>C(O)C>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][N:15]([C:35]4[S:36][CH:37]=[CH:38][N:39]=4)[CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: Brc1nccs1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CNC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(c3nccs3)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A mixture of Example 1 (HCl salt, 32 mg, 0.0554 mmol), 2-bromothiazole (13.62 mg, 0.0831 mmol), TEA (0.0385 mL, 0.277 mmol) and potassium fluoride (1.61 mg, 0.0277 mmol) in ethanol (1 mL) in a sealed tube was heated at 90° C. for 6 days. After aqueous work up, the residue was purified by CombiFlash (eluent: 5% methanol in DCM) to give the product. 1H-NMR (400 MHz, CDCl3): δ 1.50-1.93 (m, 5H), 2.12-2.47 (m, 2H), 2.65-2.80 (m, 2H), 3.03-4.19 (m, 17H), 4.64-5.01 (m, 2H), 6.55 (d, J=3.5 Hz, 1H), 7.20 (d, J=3.5 Hz, 1H), 7.69 (br. s., 1H), 8.71 (d, J=5.1 Hz, 1H); LC/MS: C26H32F3N5O3S: m/z 552.2 (M+H).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]4)[C:14]3=O)=[CH:10][CH:9]=2)[CH2:3]1.[CH3:26][C:27]([S:30]([NH2:32])=[O:31])([CH3:29])[CH3:28].O>C(OCC)(=O)C.C(O[Ti](OCC)(OCC)OCC)C>[F:25][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11](=[CH:10][CH:9]=2)[CH2:12][C:13]2([CH2:18][CH2:19][CH:20]([O:23][CH3:24])[CH2:21][CH2:22]2)[C:14]3=[N:32][S:30]([C:27]([CH3:29])([CH3:28])[CH3:26])=[O:31])[CH2:3]1
Reactant: COC1CCC2(CC1)Cc1ccc(OCC3CC(F)(F)C3)cc1C2=O
Reactant: CC(C)(C)S(N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC1CCC2(CC1)Cc1ccc(OCC3CC(F)(F)C3)cc1C2=NS(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
6′-((3,3-Difluorocyclobutyl)methoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 14, 1.85 g, 5.28 mmol) and 2-methylpropane-2-sulfinamide (1.15 g, 9.50 mmol) were dissolved in 2-Me THF (40 mL). Tetraethoxytitanium (2.21 mL, 10.6 mmol) was added and the resulting mixture was heated to 80° C. over a weekend. The reaction mixture was cooled to r.t., and diluted with ethyl acetate (85 mL). Water (3 mL) was added under vigorous stirring and then the mixture was allowed to stand for 1 h. The mixture was filtered, the solvent was evaporated and the residue was purified by column chromatography on silica using a gradient of 0-70% ethyl acetate in heptanes. The product was recrystallized twice from EtOH. to give 0.750 g of the title compound (31% yield). MS (ES+) m/z 454 [M+H]+.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:9]([C:10](O)=[O:11])[CH:8]=1)=[O:2].[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>O1CCCC1.CN(C)C=O>[CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:9]([C:10]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:11])[CH:8]=1)=[O:2]
Reactant: O=COCCOc1cc(C(=O)O)nc2ccccc12
Reactant: Nc1nnn[nH]1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=COCCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12

Procedure:
N,N' -Carbonyldiimidazole (1.55 g) was added to 4(2-formyloxyethoxy)quinaldic acid (2.5 g) in hot tetrahydrofuran (200 ml) and the solution was heated under reflux for 1.5 hours. 5-Aminotetrazole (0.85 g) in dimethylformamide (4 ml) was added and the mixture was heated under reflux for 2.5 hours. 4(2-Formyloxyethoxy)-N(1H-tetrazol-5-yl)quinaldamide was filtered off and dried, m.p. 263°.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2=[C:18]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27]C)=[O:26])=[CH:23][C:24]=3[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]>CO.C1COCC1.[OH-].[Na+]>[CH3:3][C:2]([CH3:35])([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2=[C:18]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][C:24]=3[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)OC(C)(C)C)c1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc21
Temperature: 50 °C
Yield: 96.5 %

Procedure:
A solution of methyl 5-[(1,1-dimethylethoxy)carbonyl]-13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-carboxylate (1.08 g, 2.28 mmol) in MeOH (40 mL), THF (30 mL) and 5N aqueous NaOH (2 mL) was heated at 50° C. overnight. Additional 10N aqueous NaOH (6 mL) was added and the reaction mixture was again heated at 50° C. for 5 h. The reaction was cooled, concentrated under vacuum and partitioned between EtOAc (60 mL) and ½ saturated aqueous NH4Cl (30 mL). The organic layer was washed with brine (10 mL) and the combined aqueous layers were extracted with EtOAc (40 mL). The combined organic layers were dried (MgSO4), filtered, concentrated to yield 5-[(1,1-dimethylethoxy)carbonyl]-13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-carboxylic acid (1.01 g, 2.20 mmol, 96%) as a yellow solid. 1HNMR (500 MHz, Acetone-d6) δ 8.23 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.60–7.51 (m, 3H), 7.48–7.41 (m, 1H), 4.81 (br s, 1H), 4.66 (br s, 1H), 3.86 (br s, 1H), 3.59 (br s, 1H), 3.12–2.97 (m, 1H), 2.15–1.67 (m, 6H), 1.52–1.20 (m, 4H), 1.18 (s, 9H). LCMS: m/e 461 (M+H)+, ret time 2.26 min, column C, 2 minute gradient, start at 0% B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Li+].CC([N-]C(C)C)C.B(OC)(OC)[O:18]C>C1COCC1.CCCCCCC.C1COCC1>[OH:18][C:7]1[C:2]([F:1])=[N:3][C:4]([F:8])=[CH:5][CH:6]=1
Reactant: COB(OC)OC
Reactant: Fc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Oc1ccc(F)nc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of 2, 6-difluoropyridine (6.7 mL, 73.8 mmole) in THF (100 mL, cooled to -78° C.) was added a 2M solution of LDA in heptane/THF/ethylbenene (38 mL, 76 mmol). The mixture was stirred at -78° C. for 1 hour, and trimethyl borate (6.8 mL, 89.7 mmol) was added. The mixture was stirred for 1 hour and allowed to warm to 20° C., then the reaction was quenched with HOAc (10 mL). The solution was made basic with 20% aq NaOH (20 mL), H2O2 (50%, 200 mL) was added, and the mixture stirred for 16 hours. The mixture was neutralized by addition of HCl (2M, aq) and extracted with EtOAc. The combined EtOAc extracts were dried (MgSO4). The solvent was evaporated under vacuum, and the crude product was chromatographed (silica gel; hexane/EtOAc 9:1 to 6:4) to yield 2.7g (28%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ: 6.75 (dd, J=3.0, 5.5 Hz, 1H), 7.48 (m, 1H). MS (DCI/NH3) m/e 149 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:22]([C:25]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][NH:31][CH2:32]2)=[CH:27][CH:26]=1)([O-:24])=[O:23].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:10][C:11]([N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[CH2:32]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccccc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1)Cc1ccccc1F

Procedure:
(3R)-3-[(tert-Butoxycarbonyl)amino]4-(2-fluorophenyl)butanoic acid (0.69 g; 2.34 mmol) and 7-nitro-1,2,3,4 tetrahydroisoquinoline (0.50 g; 2.34 mmol) were treated with EDC (0.54 g, 2.8 mmol), HOBt (0.38 g, 2.8 mmol) and N,N-diisopropylethylamine (0.60 g, 4.67 mmol) essentially following the procedure outlined in Example 1, Step A. Purification by flash chromatography (silica gel; 35% ethyl acetate/hexanes as eluant) afforded the title compound. LC/MS: 358.1 (M+1-BOC)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:20]([O:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[CH2:38][O:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33]Br)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]1([C:20]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=2[CH2:38][O:39][C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:47])[CH2:33][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=3)[CH:7]=2)=[O:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(-c2cc(O)ccc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(-c2cc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)ccc2C)cc1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 3.07 g (12 mmol) of ethyl 5′-hydroxy-2′-methylbiphenyl-4-carboxylate with 6.7 g (15 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 2 mg (14 mmol) of potassium carbonate, the desired product is obtained in the form of a colourless oil (m=5.7 g; Y=77%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[OH-].[K+]>O1CCOCC1.O>[F:1][C:2]([F:16])([F:17])[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)(c1ccc(C(=O)O)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (6.0 g, 24.2 mmol) and KOH (2.72 g, 48.4 mmol) in 1,4-dioxane (100 mL) and H2O (50 mL) was refluxed for 2 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to remove the 1,4-dioxane. The aqueous residue was acidified with 2N HCl and extracted with CH2Cl2. The extracts were washed with brine and dried. Flash chromatography of the residue, using 3:7 EtOAc-Hexane, gave 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid: 1H NMR (CDCl3) δ 11.0 (br, 1H), 7.95 (d, J=6.8 Hz, 2H), 7.71 (d, J=6.8 Hz, 2H), 6.73 (s, 1H), 1.71 (s, 3H); m/z 235.0 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][N:21]([C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(C)COC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC(C)C)CC3)cc1

Procedure:
Compound eu was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea with isobutyl chloroformate. LC-MS: m/z=+497 (M+H)+.
Reaction SMILES: [OH2:1].O.O.[ClH:4].Cl.Cl.[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1O)[CH:14]([CH2:19][CH2:20][CH:21]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]1[C:49]3[C:44](=[CH:45][C:46]([OH:51])=[C:47]([OH:50])[CH:48]=3)[CH2:43][CH2:42][NH:41]1)[CH2:22][CH2:23][CH:24]1[C:33]3[C:28](=[CH:29][C:30]([OH:35])=[C:31](O)[CH:32]=3)[CH2:27][CH2:26][NH:25]1)[NH:13][CH2:12][CH2:11]2>C(O)(=O)C>[OH2:7].[OH2:1].[OH2:7].[ClH:4].[ClH:4].[ClH:4].[C:47]([OH:50])(=[O:1])[CH3:48].[C:47]([OH:50])(=[O:1])[CH3:48].[C:47]([OH:50])(=[O:1])[CH3:48].[OH:35][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[CH:24]([CH2:23][CH2:22][CH:21]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]1[C:49]3[C:44](=[CH:45][C:46]([OH:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]1)[CH2:20][CH2:19][CH:14]1[C:15]3[C:10](=[CH:9][C:8]([OH:7])=[CH:17][CH:16]=3)[CH2:11][CH2:12][NH:13]1)[NH:25][CH2:26][CH2:27]2
Reactant: Oc1cc2c(cc1O)C(CCCCC(CCC1NCCc3cc(O)c(O)cc31)CCC1NCCc3cc(O)c(O)cc31)NCC2
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CCNC2CCCCC(CCC1NCCc2cc(O)ccc21)CCC1NCCc2cc(O)ccc21

Procedure:
Similarly, when 800 mg. of (10.6) is suspended in 20 ml. glacial acetic acid containing 2 g. of acetyl chloride, and dry hydrogen chloride is bubbled through the mixture, on workup