Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CCNCCN1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with [1,4]-diazepan-5-one (Oakwood Products) to give the title compound. HR-MS (ES, m/z) calculated for C33H39N6O3Cl2 [(M+H)+] 637.2455, observed 637.2452.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.C(#N)C.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([S:35]([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:30]([Sn](C)(C)C)=[CH:29]2>C(Cl)(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([S:35]([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:30]([F:21])=[CH:29]2
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: Cc1ccc(S(=O)(=O)n2c([Sn](C)(C)C)cc3cc(Cl)ccc32)cc1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2c(F)cc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.7 %

Procedure:
N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (2.33 g) was added to an acetonitrile solution (88 ml) containing 5-chloro-1-tosyl-2-(trimethylstannyl)-1H-indole (2.05 g) obtained in the 2nd step in a nitrogen atmosphere, followed by stirring at room temperature for 16 hours. Chloroform was added to the reaction solution, an insoluble precipitate was removed, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:100), and a light yellow solid of 5-chloro-2-fluoro-1-tosyl-1H-indole (520 mg) was thus obtained.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH:13]=[CH:14][CH3:15].B(OC)(OC)[O:26]C.OO>O.C1COCC1>[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:26])=[C:19]([F:23])[C:18]=1[F:24])[CH:13]=[CH:14][CH3:15]
Reactant: CC=CCOc1cccc(F)c1F
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC=CCOc1ccc(O)c(F)c1F
Temperature: -50 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
225 mL of 2.67 M butyllithium hexane solution was added dropwise to THF (500 mL) solution containing 96.0 g of 1-(2-butenoxy)-2,3-difluorobenzene under vigorous stirring at −50° C. or lower, while keeping the internal temperature, and then the stirring was continued for 1 hour at −50° C. While keeping the internal temperature, THF (60 mL) solution containing 63.3 g of trimethyl borate was added dropwise. The stirring was continued for 30 minutes while keeping the temperature, and then the temperature was increased to 0° C. While keeping the internal temperature, 120 mL of water was added dropwise, and then 160 mL of 15% hydrogen peroxide solution was further added dropwise. The stirring was continued for 1 hour at 0° C. The solution was heated to room temperature, and the stirring was further continued for 2 hours. Then, saturated saline was added to separate the organic phase, and extraction was performed from the water phase with toluene (twice). The organic phase was collected, then washed with 10% sodium thiosulfate aqueous solution, 3M hydrochloric acid, water, saturated aqueous solution of sodium hydrogencarbonate, and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated. The obtained residue was purified by column chromatography, and was subjected to recrystallization, to thereby obtain 42.7 g of 4-(2-butenoxy)-2,3-difluorophenol in the form of pale yellow needle-like crystals (E/Z ratio=99/1, according to 1H-NMR analysis).
Reaction SMILES: Br[CH2:2][C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([CH3:14])([CH3:13])[C:3](=[O:15])[CH2:2][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:7][CH:8]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C(=O)CBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(Cc1ccc(Cl)cc1)C(=O)Cn1cncn1
Yield: 356.2 %

Procedure:
37 g (0.13 mol) of 4-bromo-1-(4-chlorophenyl)-2,2-dimethyl-3-butanone, 13.3 g (0.019 mol) of 1,2,4-triazole and 53.8 g (0.39 mol) of potassium carbonate are heated under reflux in 300 ml of acetone for 8 hours. The mixture is allowed to cool, the inorganic residue is filtered off with suction and the filtrate is concentrated. The residue is taken up in chloroform and the mixture is washed with water, dried over sodium sulphate and concentrated. The residue is stirred with diethyl ether, filtered off with suction and dried at 50° C. in vacuo. 18.8 g (52% of theory) of 1-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-3-butanone of melting point 127° C. are obtained. ##STR18##
Reaction SMILES: N[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:3]=1[C:29]#[N:30].[ClH:31].N([O-])=O.[Na+]>O>[Cl:31][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:3]=1[C:29]#[N:30]
Reactant: CNC(=O)c1cc(COc2nc(N)c(C#N)c(-c3ccc(F)cc3)c2C#N)ccn1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)c1cc(COc2nc(Cl)c(C#N)c(-c3ccc(F)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (1.24 mmol) of 4-({[6-amino-3,5-dicyano-4-(4-fluorophenyl)pyridin-2-yl]oxy}methyl)-N-methylpyridine-2-carboxamide (Example 21) were suspended in ice-cooled conc. hydrochloric acid. 257 mg (3.73 mmol) of sodium nitrite were added in portions, and the reaction mixture was then warmed to RT and stirred at RT for 1 h. 25 ml of water were added, and the reaction mixture was extracted three times with dichloromethane. The combined organic phases were washed three times with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([OH:21])CO)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]=[O:21])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=c1c2cc(C(O)CO)ccc2ccc2ncc(Cl)cc12
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (60 mg, 0.20 mmol) was dissolved in 1.8 mL of tetrahydrofuran and 0.9 mL water. Sodium periodate (51 mg, 0.24 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was then diluted with water and extracted with ethyl acetate three times. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 10-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.15 (s, 1H); 8.85 (d, 1H); 8.73 (d, 1H); 8.54 (d, 1H); 8.20 (dd, 1H); 7.75 (d, 1H); 7.47 (d, 1H); 7.31 (d, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].[F:38][C:39]([F:51])([F:50])[C:40]1[CH:49]=[CH:48][CH:47]=[CH:46][C:41]=1[C:42](=[O:45])[CH2:43]Br>ClCCCl.C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:42]([C:41]2[CH:46]=[CH:47][CH:48]=[CH:49][C:40]=2[C:39]([F:38])([F:50])[F:51])([OH:45])[CH2:43][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1(O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (0.30 g, 0.57 mmol) and 2-(trifluoromethyl)phenacyl bromide (0.22 g, 0.85 mmol) in DCE (30 mL) was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (2×50 mL), washed with brine solution (1×25 mL), and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate concentrated, and the residue purified by flash chromatography (0-100% ethyl acetate/hexanes) to provide (Z)-3-(2-isopropylphenyl)-2-((E)-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazono)-4-(2-(trifluoromethyl)-phenyl)thiazolidin-4-ol as a yellow solid (0.15 g, 38% yield): mp 115-117.5° C.; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 7.86-7.77 (m, 5H), 7.73 (d, J=7.2 Hz, 1H), 7.62 (dt, J=21.6, 7.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.37-7.28 (m, 3H), 7.24-7.17 (m, 1H), 4.34 (s, 2H), 3.20 (dt, J=13.7, 6.8 Hz, 2H), 1.25 (d, J=6.9 Hz, 6H); 19F NMR (376 MHz, CDCl3) δ −57.99, −58.02; ESIMS m/z 711 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27]CC)=[O:26])=[CH:5]2.[OH-].[Li+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=1)[O:8][CH:7]([C:21]([F:24])([F:22])[F:23])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(CC)cc3)cc2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 4.43 g (10.4 mmole) of the product of step 1 in 70 mLs of THF and 20 mL of methanol was added a solution of 1.0 g of lithium hydroxide monohydate in 10 mL of water. The mixture was heated to reflux for 30 min and allowed to cool to rt. After stirring overnight, the mixture was treated with 75 mL of 1N HCl and extracted three times with diethyl ether. The combined extracts were washed with brine, dried and concd in vacuo to afford 4.02 g (97%) of a yellow solid: mp 195.5-196.5° C.; 1H NMR (d6-acetone/400 MHz) 1.22 (t, 3H, J=7.5 Hz), 2.66 (q, 2H, J=7.6 Hz), 5.78 (q, 1H, J=7.1 Hz), 6.45 (s, 1H), 7.04 (d, 2H, J=8.4 Hz), 7.31 (d, 2H, J=8.3 Hz), 7.66 (s, 1 H), 7.87 (s, 1H); 19F NMR (d6-acetone/400 MHz) −79.4 (d, 3F, J=7.7 Hz); 13C NMR (d6-acetone/100 MHz) 15.4, 28.1, 70.9 (q, J=32.7 Hz), 105.6, 115.3, 116.0, 117.5, 119.9, 123.9 (q, J=286.8 Hz), 129.8, 131.1, 135.7, 141.5, 153.1, 153.3, 157.3, 164.3; MS (ES−) 397 (M−1, 100); HRMS (ES−) m/z calcd for (C19H13ClF3O4) 397.0449, found 397.0484.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]=2Br)=[CH:8][CH:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC#N>[CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(C2=C(Br)CCc3ccccc32)cc1
Reactant: OB(O)c1ccccc1
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1
Yield: 50 %

Procedure:
Prepared from the coupling of 2k and benzene boronic acid, (R6—Ph)B(OH)2 where R6=H, by the general method described for example 2d. Yield 50%; APcI m/z: 408 (M+H+CH3CN+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH:10]([C:11]2[O:12][C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH2:9][CH2:8][C:7]1=[O:28].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:37]([O:36][C:34]([CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH:10]([C:11]2[O:12][C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH2:9][CH2:8][C:7]1=[O:28])=[O:35])[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc(CN2C(=O)CCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 101.7 %

Procedure:
A solution of 1-(3-hydroxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.13 g), ethyl bromoacetate (0.21 g), potassium carbonate (99 mg) and potassium iodide (catalytic amount) in acetonitrile (10 ml) was refluxed for 9 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-(3-ethoxycarbonylmethoxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.16 g). MS (m/z): 497 (M+ +1) NMR (CDCl3, δ): 1.28 (3H, t, J=7.1 Hz), 2.20-2.96 (4H, m), 4.23 (2H, q, J=7.1 Hz), 4.38 (1H, d, J=14.7 Hz), 4.43 (2H, s), 4.70 (1H, d, J=14.7 Hz), 4.76 (1H, m), 6.70-6.87 (3H, m), 7.15 (1H, t, J=7.8 Hz), 7.33-7.56 (6H, m), 7.57-7.61 (4H, m)
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:10]=2[CH2:17][OH:18])O1>Cl>[OH:16][CH2:15][C:13]1[CH:12]=[CH:11][C:10]2[CH2:17][O:18][B:4]([OH:5])[C:9]=2[CH:14]=1
Reactant: CC1(C)OB(c2cc(CO)ccc2CO)OC1(C)C
Agent: Cl
Product: OCc1ccc2c(c1)B(O)OC2
Reaction time: 8 h
Yield: 50.7 %

Procedure:
(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-phenylene)dimethanol (CVII) (2.0 g, 7.57 mmol) was dissolved in 6 M aqueous HCl (100 ml) at 60° C. and stirred overnight. The reaction mixture was concentrated under vacuum and the oily residue was triturated with Et2O to give a light-brown solid. The solid was removed by filtration and washed with Et2O. The filtrate (which according to LC/MS contained the product) was concentrated under vacuum to give 6-(hydroxymethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CVIII) (0.63 g, 3.84 mmol, 35% purity). ESIMS found for C8H9BO3 m/z 163.0 (M−H). The crude product was used without further purification for Step 5.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(-c3cccc(NCc4ccc(CC(=O)O)cc4)c3)c(C(=O)c3ccccc3)cnc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc2c(-c3cccc(NCc4ccc(C(Cc5ccccc5)C(=O)O)cc4)c3)c(C(=O)c3ccccc3)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (4-{[3-(3-benzoyl-8-methyl-quinolin-4-yl)-phenylamino]-methyl}-phenyl)-acetic acid (0.04 g, 0.08 mmol), benzyl bromide (0.12 g, 0.8 mmol), and cesium carbonate (0.33 g, 1 mmol) in 5 mL of DMF was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organics were washed with water, dried over magnesium sulfate and concentrated. The crude ester was treated with LiOH followed by semi-preparative HPLC purification to give the title compound. MS (ESI) m/z 577.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1)=[O:5].[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[O:34]1[CH2:35][CH2:36][N:31]([C:37]([O:1][C:2]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][C:3]=2[C:4]([NH:6][C:7]2[CH:8]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=2)=[O:5])=[O:38])[CH2:32][CH2:33]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccccc2)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccccc2)ccc1OC(=O)N1CCOCC1
Yield: 91.4 %

Procedure:
Using 2-hydroxy-5-phenyl-N-[3,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>>[CH2:24]([O:23][P:22]([CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8])([O:26][CH2:27][CH3:28])=[O:29])[CH3:25]
Reactant: CCOP(OCC)OCC
Reactant: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1CCl
Product: CCOP(=O)(Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C)OCC
Temperature: 160 °C
Reaction time: 15 h
Yield: 57.9 %

Procedure:
A mixture of tert-butyl 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperazine-1-carboxylate (2.91 g) and triethyl phosphite (3.20 g) was stirred at 160° C. for 15 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2-4:1, v/v) to give tert-butyl 4-{4-[(diethoxyphosphoryl)methyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate as a yellow oil (2.20 g, yield 58%).
Reaction SMILES: [CH2:1](C(CO)(CO)CC)[OH:2].C[CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=O)[CH3:12]>>[CH2:20]([CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:11][CH3:12])[CH2:1][OH:2])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCC(CO)(CO)CO
Reactant: CC(C)CCCCCCCCCCCCC(=O)O
Product: CCCCCCCCC(CO)CCCCCC

Procedure:
The ester oil of claim 1 being the triisopalmitic acid ester of trimethylolpropane, said isopalmitic acid being obtained by the oxidation of 2-hexyldecanol formed from n-octanol by the Guerbet synthesis.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([CH3:24])([CH3:23])[C:14]([N:16]3[CH:20]4[CH2:21][CH2:22][CH:17]3[CH2:18][CH2:19]4)=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1.[CH3:33][C:34]([CH3:45])=[CH:35][CH:36]1[O:38][CH:37]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]12[N:16]([C:14](=[O:15])[C:13]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[NH:6][C:5]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=3)=[C:4]4[CH2:3][CH2:2][NH:1][C:34]([CH3:45])([CH3:33])[CH:35]=[CH:36][CH:37]([OH:38])[C:39]3[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=3)([CH3:24])[CH3:23])[CH:20]([CH2:19][CH2:18]1)[CH2:21][CH2:22]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN)c1
Reactant: CC(C)=CC1OC1c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(C)(C)C=CC(O)c2ccncc2)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-azabicyclo[2.2. 1 ]hept-7-yl)-2-methylpropan-1-one (prepared essentially as described in EXAMPLE 2, 70 mg in 6 mL dry tetrahydrofuran) was added 2 mL of a solution of 86 mg 4-[3-(2-methylpropenyl)oxiranyl]pyridine in tetrahydrofuran followed by 24 mg tetrakis(triphenylphosphine)palladium and the mixture heated to 65 ° C. on an oil bath. After 2 hours, the mixture was cooled to room temperature, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (methylene chloride:methanol, 92:8; then 88:12) to give the title compound (91 mg).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][OH:29])=[CH:23][C:22]=3[F:30])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[C:31]([O:35][C:36]([NH:38][CH2:39][C:40](O)=[O:41])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(Cl)CCl.[C+](=O)C1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][O:29][C:40](=[O:41])[CH2:39][NH:38][C:36]([O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:37])=[CH:23][C:22]=3[F:30])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CO)cc3F)CC2)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=[C+]c1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(COC(=O)CNC(=O)OC(C)(C)C)cc3F)CC2)CC1
Reaction time: 20 h

Procedure:
Compound 10-1 (40 mg, 0.094 mmol), tert-butoxycarbonylamino-acetic acid (17 mg, 0.097 mmol), DMAP (3 mg, 0.024 mmol), EDC(22 mg, 0.11 mmol) and DCM (1 mL) were combined in that order and the reaction mixture was stirred for 20 h. The mixture was then washed with aqueous NaHCO3 (1 mL), concentrated under a stream of nitrogen and purified by Jones flash LC(eluent: 10-40% ethyl acetate+0.1% triethylamine in hexanes) to afford 12-1: LC-MS 408.2 (benzylium fragment).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8](OCC)=[O:9])=[C:5]([CH3:7])[N:6]=1.[BH4-].[Na+]>CCO.O>[Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(Br)sc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate (7 g, 28 mmol) in EtOH (120 mL) and H2O (20 mL) was added portion-wise NaBH4 (3.2 g, 84 mmol). After the addition, the mixture was stirred at room temperature overnight. TLC (petroleum ether/EtOAc=5:1) showed the reaction was complete. The reaction mixture was carefully concentrated in vacuum. The residue was separated between EtOAc (50 mL) and H2O (50 mL). The inorganic layer was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuum to give the title compound as a colorless oil (3.8 g, 65%).