Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:25][CH:26]=1)=[O:20].O>O1CCCC1>[C:1]1([CH2:7][C:8]([O:10][CH2:18][C:19](=[O:20])[C:21]2[CH:26]=[N:25][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:23][CH:22]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C(CBr)c1cnc(-c2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)OCC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 40 °C
Yield: 57.7 %

Procedure:
To a solution consisting of phenylacetic acid (27 mg, 0.20 mmol) and cesium carbonate (117 mg, 0.360 mmol) in tetrahydrofuran (1.5 mL) at room temperature was added 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone (Step B, 50 mg, 0.18 mmol). The reaction mixture was heated at 40° C. for one hour and cooled to room temperature. To the mixture was added water (10 mL) with vigorous stirring and the precipitate was filtered, washed with water, and dried on the suction filter to provide 2-oxo-2-(2-phenylpyrimidin-5-yl)ethyl 2-phenylacetate as a tan solid (34.5 mg, 57% yield) as an isolated intermediate. The tan solid was dissolved in toluene (4 mL) and freshly prepared ammonium acetate under toluene (300 mg wet with toluene) was added and the mixture was stirred vigorously and heated in a capped vial at 112° C. overnight. The brown reaction mixture was poured into aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to dryness. The brown solid was dissolved in dichloromethane and chromatographed on a 4 g silica column eluted with 1:4:5 to 1:6:3 dichloromethane-ethyl acetate-hexane to afford the title compound as a tan solid; Rf 0.08 with 6:4 v/v hexanes-ethyl acetate and Rf 0.61 with 3:7 v/v hexanes-ethyl acetate; melting point 235° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.21 (s, 2H), 8.3-8.5 (m, 2H), 7.82 (d, 1H), 7.5-7.6 (m, 3H), 7.2-7.4 (m, 5H), 4.08 (s, 2H); MS (ESI+) m/z 313 (M+1); H-PGDS FPBA IC50: 0.625 μM; H-PGDS inhibitor EIA IC50: 0.059 μM.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[C:8]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[OH-].[Na+]>O1CCCC1>[N:1]1([C:8]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CCNc1nc(Cl)nc2ccccc12
Reactant: C1CCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)CCNc1nc(N2CCCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
A solution of 6.4 g of pyrrolidine in 50 ml of tetrahydrofuran was added to 10 g of 2-chloro-4-(2-diethylaminoethylamino)quinazoline hydrochloride in 100 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for about one hour and then was heated for 5 hours. The reaction mixture was poured into ice-water, made alkaline by the addition of dilute aqueous sodium hydroxide solution, and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue, a gummy solid, was triturated with about 5 ml of hexane, and the resulting mixture was chilled overnight in a refrigerator. The mixture then was filtered and the solid obtained was recrystallized from aqueous ethanol to give 2 g of 2-pyrrolidinyl-4-(2-diethylaminoethylamino)quinazoline; m.p. 87°-90°. The following analytical data were obtained:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].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.[CH3:64][N:65]([CH3:69])[CH2:66][CH2:67][NH2:68]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:68][CH2:67][CH2:66][N:65]([CH3:69])[CH3:64])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccccc2)C[C@@H]1C
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: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cc3)cc2[C@H](Nc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Yield: 20 %

Procedure:
4-((2S,4R)-1-Acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 35) (90 mg, 0.225 mmol) was dissolved in anhydrous DMF (3 ml and HATU (103 mg, 0.270 mmol) added. DIPEA (0.118 ml, 0.674 mmol) was added to the mixture and after a further 5 min of stirring at r.t. N1,N1-dimethylethane-1,2-diamine (0.030 ml, 0.449 mmol). The reaction mixture was stirred at r.t. overnight, concentrated and partitioned between EtOAc and water. The Organic phase was separated, dried (Na2SO4) and concentrated. The yellow residue was purified by chromatography a silica cartridge (10 g), eluting with MeOH/DCM (1-6% over 120 mls, followed by 6-20% over 120 mls) to give 4-((2S,4R)-1-acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2(dimethylamino)ethyl)benzamide (24 mg, 0.05 mmol, 20% yield) as a light brown solid. LCMS (Formic, 2 min), Rt=0.79 min, MH+=471.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:60]C(OC(C)(C)C)=O)[C:16]([O:18][C@H:19]1[C@@H:23]([OH:24])[C@H:22]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[O:21][C@H:20]1[CH2:35][O:36][P:37]([O:40][C@H:41]1[CH2:45][C@H:44]([N:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[N:48][C:47]2=[O:53])[O:43][C@@H:42]1[CH2:54][O:55][P:56]([OH:59])([OH:58])=[O:57])([OH:39])=[O:38])=[O:17])=[N+:9]=[N-:10]>ClCCl>[NH2:60][C@H:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:8]=[N+:9]=[N-:10])[C:16]([O:18][C@H:19]1[C@@H:23]([OH:24])[C@H:22]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[O:21][C@H:20]1[CH2:35][O:36][P:37]([O:40][C@H:41]1[CH2:45][C@H:44]([N:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[N:48][C:47]2=[O:53])[O:43][C@@H:42]1[CH2:54][O:55][P:56]([OH:59])([OH:58])=[O:57])([OH:39])=[O:38])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCN=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCCCC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-azido-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk50) (30.2 mg, 0.034 mmol) in dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 30 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-azidohexanoate (Lys(N3)-pdCpA) (Compound tk51) (19.4 mg, 72%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([O-:32])=[O:31]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:21])[CH:10]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)[CH2:37][C:36]1[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(CC(=O)OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (4-tert-Butyl-phenyl)-acetic acid benzyl ester (92 g, 7.1 mmol) in tetrahydrofuran (50 ml) was added lithium diisopropylamide (8.5 mmol) at −78° C. After 30 min, 4-nitrobenzyl bromide (1.6 g, 7.5 mmol) was added. The cold bath was removed and the reaction mixture was allowed to warm to ambient temperature in 1 h. The reaction mixture was concentrated, partitioned between ethyl acetate and 1N ammonium chloride, washed with water, and dried over magnesium sulfate. Chromatography of the residue (5% ethyl acetate in hexane) afforded 2-(4-tert-Butyl-phenyl)-3-(4-nitro-phenyl)-propionic acid benzyl ester as a yellow oil (2.46, 83%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]1([C:12]2[CH2:16][C:15](=O)[N:14]([CH3:18])[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-]>>[Cl:3][C:15]1[N:14]([CH3:18])[N:13]=[C:12]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1N=C(C2CCCCC2)CC1=O
Agent: [OH-]
Product: Cn1nc(C2CCCCC2)cc1Cl
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (15.3 g, 0.1 mole) is added to 3-cyclohexyl-1-methyl-2-pyrazolin-5-one and the mixture stirred and heated at 120° to 135° C. for 8 hours. The cooled reaction mixture is then poured into ice-water, made alkaline with 1% aqueous hydroxide and extracted with methylene chloride. Removal of solvent under reduced pressure, then in vacuo at 70° C. affords an oil, 8 g, (93.8%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4](Cl)[CH:3]=1.[CH3:24][O-:25].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4]([O:25][CH3:24])[CH:3]=1
Reactant: C[O-]
Reactant: Cc1c(Cn2cnc3c(Cl)cc(Cl)nc32)cccc1C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc2c1ncn2Cc1cccc(C(F)(F)F)c1C

Procedure:
5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (200 mg, 0.555 mmol) was suspended in Methanol (1.5 mL), sodium methoxide (0.150 mL, 0.656 mmol) was added and the mixture was irradiated in a microwave oven for 90 min at 110° C. Conversion to desired product was observed by LC/MS (5,7-dimethoxy product, 5-methoxy isomer and 7-OH-5-Cl derivative observed by mass as well). The mixture was diluted with water and the precipitate formed was collected by filtration, washed with water and dried. The solid was purified on silica gel (ISCO 0-60% EtOAc in hexanes) to give 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (125 mg, 0.351 mmol, 63.3% yield) as a white powder. Additional material was prepared from 120 mg of 5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine, irradiated in a microwave for 30 min at 110° C. in the presence of NaOMe. After work-up, 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (109 mg, 0.306 mmol, 55.2% yield) was obtained and carried on without further purification to the next step. MS (ES+) m/e 356 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[C:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]3)[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40](NC1N=C(C2C=CC=C(C)N=2)C=C(C2C=NC=C(Br)C=2)C=1)C1C=CC=CC=1>>[CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:40])[N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[C:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]3)[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N1CCN(CC#Cc2cncc(-c3cc(NCc4ccccc4)nc(-c4ccccn4)c3)c2)CC1
Reactant: Cc1cccc(-c2cc(-c3cncc(Br)c3)cc(NCc3ccccc3)n2)n1
Product: Cc1cccc(-c2cc(-c3cncc(C#CCN4CCN(C(C)(C)C)CC4)c3)cc(NCc3ccccc3)n2)n1

Procedure:
This compound is prepared analogously to Benzyl-{5″-[3-(4-tert-butyl-piperazin-1-yl)-prop-1-ynyl]-[2,2′;4′,3″]terpyridin-6′-yl}-amine (Example 2.138) by replacing Benzyl-(5″-bromo-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 1.25) with Benzyl-(5″-bromo-6-methyl-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 2.40, step1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:23]=[CH:22][C:13]2[N:14]([CH2:18][C:19]([NH2:21])=[O:20])[C:15](=[O:17])[O:16][C:12]=2[C:11]=1[F:24]>S(=O)(=O)(O)O>[Cl:1][C:22]1[C:13]2[N:14]([CH2:18][C:19]([NH2:21])=[O:20])[C:15](=[O:17])[O:16][C:12]=2[C:11]([F:24])=[C:10]([F:9])[CH:23]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)Cn1c(=O)oc2c(F)c(F)ccc21
Agent: O=S(=O)(O)O
Product: NC(=O)Cn1c(=O)oc2c(F)c(F)cc(Cl)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, N-chlorosuccinimide (0.29 g; 2.19 mmol) is added to a suspension of 2-(6,7-difluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide 18 (0.5 g, 2.19 mmol) and sulfuric acid (90% w/w, 20 ml) at 0° C. The reaction mixture is stirred at room temperature for two days and another portion of N-chlorosuccinimide (0.29 g, 2.19 mmol) is added. After 14 days at room temperature, the reaction mixture is poured carefully into ice. The precipitate is collected by filtration, washed with water and recrystallized EtOH/water (20/80 (v/v)) to afford 0.42 g of a powder which is further purified by column chromatography on reverse phase to give 2-(4-chloro-6,7-difluoro-2-oxo-benzooxazol-3-yl)-acetamide 24 after recrystallization in ethanol.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])=[N:5][CH:4]=[C:3]1[C:17]#[N:18].P(Cl)(Cl)([Cl:21])=O>C(#N)C>[Cl:21][C:2]1[C:3]([C:17]#[N:18])=[CH:4][N:5]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@H](Nc1ncc(C#N)c(=O)[nH]1)c1ccccc1
Solvent: CC#N
Product: C[C@H](Nc1ncc(C#N)c(Cl)n1)c1ccccc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
1.69 g of the 6-oxo-2-{[(1S)-1-phenylethyl]amino}-1,6-dihydro-5-pyrimidinecarbonitrile [54-1] was dissolved in 100 mL of acetonitrile, then 5 mL of phosphorus oxychloride was added, and stirred at 85° C. for 2 hours. After concentrating the reaction mixture under reduced pressure, the obtained residue was placed in an ice bath, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine in the subsequent order. After drying over anhydrous magnesium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 1.54 g of 4-chloro-2-{[(1S)-1-phenylethyl]amino}-5-pyrimidinecarbonitrile [54-2] was obtained as an oily product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C([O-])(O)=O.[Na+]>ClCCl>[CH3:15][S:16]([O:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:18])=[O:17]
Reactant: OCC1CCOC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a stirring solution of (3-oxolanyl)methan-1-ol (25 g, 245 mmol) and triethylamine (34.37 mL, 245 mmol) in dry dichloromethane (250 mL) at 0° C. under N2 atmosphere was added dropwise methanesulfonyl chloride (18.94 mL, 245 mmol). The reaction mixture was stirred overnight after warming to room temperature, then a saturated solution of NaHCO3 (100 mL) was added and the mixture stirred for another 30 min. The biphasic mixture was separated and the organic layer was discarded. The aqueous layer was extracted with dichloromethane (3×25 mL) and the combined dichloromethane extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give 42.16 g of (3-oxolanyl)methyl methanesulfonate (99%) as a light brown liquid.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][NH:8][C:9](=O)[O:10]CC)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[C:9]1(=[O:10])[C:4]2[C:3]3[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=3[S:1][C:5]=2[CH2:6][CH2:7][NH:8]1
Reactant: CCOC(=O)NCCc1cc2ccccc2s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: O=C1NCCc2sc3ccccc3c21
Yield: 15.1 %

Procedure:
A mixture of ethyl [2-(benzo[b]thiophen-2-yl)ethyl]carbamate (285 mg), polyphosphoric acid (4 g) and phosphorus pentoxide (250 mg) was heated at 100°-110° for 6h. The cooled mixture was treated with water (25 ml) and the suspension was extracted with ethyl acetate (3×25 ml) The combined, dried organic extracts were purified by SPCC eluting with System B (1:1) to give the title compound (35 mg) as a solid, m.p. 143°-144°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O>[CH2:41]([NH:48][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccsc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccsc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
To a stirred mixture of 3-methyl-2-thiophenecarboxylic acid (5.00 g, 35.17 mmol), 1-hydroxybenzotriazole (7.13 g, 52.73 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.11 g, 52.74 mmol) in anhydrous N,N-dimethylformamide (50 mL) was added N,N-diisopropylethylamine (18.4 mL, 105.6 mmol), followed by benzylamine (3.84 mL, 35.19 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h, and partitioned between ethyl acetate (200 mL) and 10% aqueous hydrochloric acid (100 mL). The organic layer was washed with 10% aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (2×100 mL) and water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with 5% ethyl acetate in hexanes to afford the title compound as a colorless solid (6.63 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 6H), 6.90 (d, J=4.9 Hz, 1H), 6.08 (br s, 1H), 4.62 (d, J=5.6 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 232.3 (M+1).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[C:30]([F:33])([F:32])[F:31])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:34](O)(C(F)(F)F)=O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:34][CH2:24][CH:25]([C:27]([OH:29])=[O:28])[CH2:26]2)[CH:16]=[C:15]3[C:30]([F:33])([F:32])[F:31])[CH2:7][CH2:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CCC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid (Example 168) using the appropriate amine. ESI-MS (M+H+): 479.2; 1H NMR (400 MHz, METHANOL-d4) Shift 8.17 (d, J=9.29 Hz, 1H), 7.85 (s, 1H), 7.58 (dd, J=2.38, 9.41 Hz, 1H), 7.39 (br. s., 1H), 4.85 (br. s., 2H), 4.32-4.44 (m, 1H), 3.39-3.53 (m, 1H), 2.51 (br. s., 1H), 2.41 (br. s., 1H), 2.27 (d, J=10.79 Hz, 2H), 1.86-1.99 (m, 2H), 1.34-1.55 (m, 2H), 1.19-1.34 (m, 2H), 1.03-1.19 (m, 1H), 0.91 (s, 9H). 1.3 TFA per molecule.
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]=[C:32]=[O:33]>C1COCC1>[CH2:1]([C@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[CH2:12][CH2:11][N:10]([C:32]([NH:31][CH3:30])=[O:33])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2Cc2ccccc2)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CNC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61 %

Procedure:
To a solution of the compound (0.39 g) obtained in Example 404 in THF (10 ml), methyl isocyanate (0.12 ml) was added, and the reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated under reduced pressure, and then the obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound as colorless crystals (0.27 g, 61%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.O>CN(C)C=O.[Al]>[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:12][C:11]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cc2ccncc2)cc1
Agent: [Al]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Cc2ccncc2)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
A solution of N-bromosuccinimide (1.4 gm) in 10 mL dimethylformamide was added in a dropwise manner to a solution of 4-(4-aminobenzyl)pyridine (1.5 gm) in 10 mL of dimethylformamide. The reaction flask was wrapped in aluminum foil to prevent exposure of the reagents to light. The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by thin-layer chromatography. When the reaction was completed, the reaction mixture was combined with 100 mL of H2O with stirring. A reddish brown precipitate was formed, filtered out of solution, washed with H2O, and air dried. The solid was dissolved in ethyl acetate, back washed with saturated NaCl, dried over MgSO4 and triturated with ethyl ether. The solid was filtered from the solution and air dried yielding 1.6 gm of 4-(4-amino-3-bromobenzyl)pyridine as reddish/tan crystals.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24][NH2:25]>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][NH:25][CH2:24][C:23]3[C:22]([F:21])=[CH:29][CH:28]=[CH:27][C:26]=3[F:30])=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Reactant: NCc1c(F)cccc1F
Solvent: CCO
Product: O[C@H](CNCc1c(F)cccc1F)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 2,6-difluorobenzylamine and ethanol essentially as described above in Example 94. Purity by LC/MS=99%, [M+H]+=426.