Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH3:37][N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([CH2:47][NH2:48])=[CH:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:48][CH2:47][C:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:38]([CH3:37])[CH:39]=1)=[O:24]
Reactant: Cn1cc(CN)c2ccccc21
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2cn(C)c3ccccc23)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-(1-methyl-1H-indol-3-yl)-methylamine.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([NH2:21])=[N:18][C:17]=2[CH3:22])=[O:15])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([NH:21][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[N:18][C:17]=2[CH3:22])=[O:15])=[CH:23][CH:24]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccc(Cl)cc1
Product: Cc1nc(NC(=O)C2CC2)sc1C(=O)NCc1ccc(Cl)cc1
Yield: 55 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use cyclopropanecarbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid 4-chlorobenzylamide, the title compound was obtained as a white solid in 55% yield; 1H NMR (DMSO-d6, 300 MHz) δ 8.51 (t, J=6.0 Hz, 1H), 7.36-7.25 (m, 4H), 4.32 (d, J=6.0 Hz, 2H), 2.50 (s, 3H), 1.94-1.84 (m, 1H), 0.93-0.87 (m, 4H); MS (ES+) m/z 350.1 (M+1).
Reaction SMILES: C([O:3][C:4]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]2[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:14]1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[C:4]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]2[C:21]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:14]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C[C@H]1CCCC[C@H]1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C[C@H]1CCCC[C@H]1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
A mixture of cis-3-[2-(2-ethoxycarbonylmethyl-cyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (89.7 mg), 1N aqueous sodium hydroxide (1 ml), and dioxane (4 ml) was stirred at room temperature for 5 hours and at 70° C. for 4 hours. Dioxane was removed in vacuo. The remaining aqueous solution was diluted with water and extracted with ethyl acetate (10 ml). The aqueous layer was acidified with 1N hydrochloric acid and extracted with dichloromethane (10 ml×2). The combined extracts were washed with brine (10 ml), dried over anhydrous magnesium sulfate, and evaporated in vacuo to give colorless crystals of cis-3-[2-(2-carboxymethylcyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (71.4 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[CH2:13]([CH2:15][NH2:16])[OH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:14][CH2:13][CH2:15][NH:16][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: NCCO
Reactant: N#Cc1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(CCCNCCO)cc1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
4-(3-Bromopropyl)benzonitrile (20 g, 0.089 mol) in acetonitrile was added to a vigorously stirred mixture of ethanolamine (27.2 g, 0.447 mol) and potassium carbonate (18.5 g, 0.133 mol) in 300 mL of dry acetonitrile. Stirring was then continued at room temperature overnight under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The crude product thereby obtained was purified by column chromatography (using methanol in chloroform) to yield 15 g of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCCC3O
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCC=C3
Temperature: -20 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-11-chloro-8-hydroxy-4H-azocino[3,2,1-hi]indole-2-carboxylate (0.70 g, 2.27 mmol), triethylamine (0.61 g, 6.00 mmol) and tetrahydrofuran (30 ml) was cooled to -20° C. with stirring, and methanesulfonyl chloride (0.31 g, 2.73 mmol) was added dropwise. After completion of the dropwise addition, the reaction temperature was raised to room temperature and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed with an aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain 0.63 g of ethyl 5,6-dihydro-11-chloro-4H-azocino[3,2,1-hi]indole-2-carboxylate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([CH3:10])[CH:4]=1>C(O)C.O=[Mn]=O>[CH3:10][C:5]1[CH:4]=[C:3]([CH:2]=[O:1])[CH:8]=[C:7]([CH3:9])[N:6]=1
Reactant: Cc1cc(CO)cc(C)n1
Agent: O=[Mn]=O
Solvent: CCO
Product: Cc1cc(C=O)cc(C)n1

Procedure:
4-Hydroxymethyl-2,6-dimethylpyridine (1.00 g, 7.28 mmol) was dissolved in ethanol (20 mL), and activated MnO2 (2.24 g, 21.8 mmol) was added; the reaction mixture was refluxed for 17 hours. The mixture was cooled and concentrated, purified by column chromatography (silica gel 230-400 mesh; 20% ethyl acetate in hexanes as eluent) to give 2,6-dimethyl-4-pyridinecarboxaldehyde as a yellow oil. Yield: 0.14 g (14%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:15](OC(=O)C)=[O:16].CO>CCOCC>[CH:15]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:16]
Reactant: CC(=O)OC=O
Reactant: Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: CO
Product: O=CNc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 90.4 %

Procedure:
(4-Aminophenylsulphonyl)nitromethane (0.96 g, 4.44 mmol) was suspended in ether (50 ml). Acetic formic anhydride (1.0 g, 11.36 mmol) was added dropwise and the reaction mixture was stirred for 16 hours. The white precipitate was collected by filtration and triturated with ether (50 ml). There was thus obtained (4-formamidophenylsulphonyl)nitromethane (0.98 g, 90% yield), m.p. 192°-193° C. (after recrystallisation from aqueous methanol); microanalysis, found: C, 39.3; H, 3.1; N, 11.4%; C8H8N2O5S requires: C, 39.3; H, 3.3; N, 11.5%.
Reaction SMILES: [CH3:1][Mg]I.[CH3:4][N:5]1[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]=2[N:9]=[CH:8][C:7]2=[CH:16][CH:17]=[CH:18][N:6]12>O1CCCC1>[CH3:4][N:5]1[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]=2[NH:9][CH:8]([CH3:1])[C:7]2=[CH:16][CH:17]=[CH:18][N:6]12
Reactant: C[Mg]I
Reactant: CN1c2ccncc2N=Cc2cccn21
Solvent: C1CCOC1
Product: CC1Nc2cnccc2N(C)n2cccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To 8.4 ml of a solution of methyl magnesium iodide (3.2M in diethyl ether, diluted with 10 ml tetrahydrofuran) was added a solution of 4.1 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 70 ml of tetrahydrofuran. After stirring at ambient temperature for 20 hours, the reaction mixture was quenched into 200 ml of an iced ammonium chloride solution and extracted with ethyl acetate (2×). The combined organics were washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The crude product was preadsorbed on silica (230-400 mesh) and flash chromatographed (elution with diethyl ether) to afford a solid, recrystallization of which from toluene yielded 2.1 g (48%) of 10,11-dihydro-5,10-dimethyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp 157°-160° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=[O:19])[CH:17]=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClCCCl>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:17](=[O:18])[CH:16]([OH:19])[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O

Procedure:
A mixture of 21.2 g (0.10 mol) of 2,4-di-tert-butylphenol (97%), 16.3 g (0.11 mol) of 50% aqueous glyoxylic acid and 0.05 g (0.26 mmol) of p-toluenesulfonic acid monohydrate in 30 ml of 1,2-dichloroethane is refluxed under nitrogen for 3.5 hours on a water separator. Afterwards the reaction mixture is concentrated on a vacuum rotary evaporator. The residue is taken up in 80 ml of hexane and washed three times with water. The aqueous phases are separated in the separating funnel and further extracted with 30 ml of hexane. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. The residue yields 26.23 g (~100%) of analytically pure 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one in the form of a thick yellowish resin (compound (101 ), Table 1).
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH:5]=[CH:4][C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([O:3][C@@H:2]2[CH:4]=[CH:5][C@H:6]3[CH2:8][O:9][C@@H:1]2[O:7]3)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1C=C[C@H]2CO[C@@H]1O2)c1ccc(Cl)cc1
Yield: 84.4 %

Procedure:
1.28 g (10.0 mmol) of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose, 5.25 g (20.0 mmol) of triphenyl phosphine, and 3.13 g (20.0 mmol) of 4-chlorobenzoic acid were added to 16 ml of dry THF, and a solution obtained by dissolving 3.13 g (20.0 mmol) of diethylazodicarboxylate in 16 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 22 hours. The solvent was distilled from the reaction solution at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column chromatograph (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:chloroform=4:1) to obtain 2.25 g (yield: 84.3%) of 1,6-anhydro-2-O-(4-chlorobenzoyl)-3,4-dideoxy-β-D-erythro-hex-3-enopyranose.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]1([CH:7]2[CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:29])[F:27])=[CH:16][CH:15]=3)[CH2:10][CH2:11][N:12]2[C:30](=[O:32])[CH3:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 mg of 3-phenyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equiv. of acetylchloride and 2 equiv. of N,N-diisoproylethylamine were added. The reaction was shaken at room temperature overnight. The solvent was removed in vacuo, the residue was dissolved in DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentration in vacuo afforded 27 mg of the title compound as hydrochloride salt. Yield 40% ES MS m/z 439
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1.[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:41][C:38]2[CH:39]=[CH:40][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:26](=[O:28])(=[O:27])[NH:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:36][CH:37]=2)[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)[nH]1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 92 %

Procedure:
The alkylation of 2-(2-bromo-5-nitrophenyl)-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) with [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 7) was carried out according to the procedure of Example 8, Step A, to give a 92% yield of the title compound as a yellow solid, mp 126°-128° C.; homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 642, 644 (M+1)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:28]([F:29])=[C:27]([NH2:30])[C:9]2[C:10](=[O:26])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[C:16]([F:25])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:31])(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[C:28]([F:29])=[C:27]([NH2:30])[C:9]2[C:10](=[O:26])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:32]=[N+:33]=[N-:34])=[C:16]([F:25])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCl)c(F)c3)oc2c1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CN=[N+]=[N-])c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 7-(acetoxymethyl)-5-amino-2-[4-(chloroacetamido)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (1.00 g, 2.20 mmol) in dimethylformamide (50 mL) was added sodium azide (715 mg, 11 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added thereto, and the crystals precipitated were collected by filtration to afford 7-(acetoxymethyl)-5-amino-2-[4-(azidoacetamido)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (1.01 g, 100%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:25]=[C:26]2[N:45]([CH3:46])[CH:44]=[CH:43][C:27]2=[N:28][C:29]=1[C@@H:30]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:31]>>[CH2:35]([O:34][C:33]([NH:32][C@H:30]([C:29]1[N:28]=[C:27]2[CH:43]=[CH:44][N:45]([CH3:46])[C:26]2=[CH:25][C:24]=1[C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=1)[CH3:31])=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccn(C)c2cc1Br
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccn(C)c2cc1C1=CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared similar to STEP A in PREPARATION 17 using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and benzyl (S)-(1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate as starting materials.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccncc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
To a suspension of 3.05 g of 60% sodium hydride (76.0 mmol) in toluene (50 mL) in a 250 mL RB flask was added 12.2 g of diethyl malonate (76.0 mmol) dropwise. The reaction mixture was stirred for 30 min under nitrogen, and a solution of 10.8 g of 4-chloro-3-nitropyridine (prepared according to the procedure of Houston et al. J. Med. Chem. 1985, 28, 467) in toluene (50 mL) was added dropwise and the resulting mixture refluxed for 4 hours. The reaction mixture was concentrate, and the residue was partitioned between 100 mL each of dilute hydrochloric acid and diethyl ether. The aqueous phase was extracted twice with 100 mL of ether, and the combined ether phases were dried over magnesium sulfate and concentrated to give a dark oil. This was chromatographed on silica gel eluting with a hexane-30% hexane/EtOAc gradient to give 3.5 g of the title compound as a colorless oil which crystallized on standing. 1H NMR (DMSO-d6): δ1.15 (t, J=7.1 Hz, 6H), 4.16 (q, J=7.1 Hz, 4H), 5.55 (s, 1H), 7.59 (d, J=5.1 Hz, 1H), 8.89 (d, J=5.1 Hz, 1H), 9.24 (s, 1H); C12H14N2O6: APES−MS m/z 281 (M−H).
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([CH:20]2[CH2:22][CH2:21]2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)[CH3:3].[C:23]([O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][C:32]=1[CH3:38])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:23]([O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH:2]([C:4]2[C:5]([CH:20]3[CH2:22][CH2:21]3)=[N:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:8][CH:9]=2)[CH3:3])=[CH:33][C:32]=1[CH3:38])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc(S)ccc1OCC(=O)OC(C)(C)C
Reactant: CC(Cl)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(SC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 180 mg (0.551 mmol) [rac]-5-(1-chloro-ethyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 28H]) and 140 mg (0.551 mmol) (4-mercapto-2-methyl-phenoxy)-acetic acid tert-butyl ester in 3 ml DMF was added 315 mg (0.66 mmol) cesium carbonate. The reaction mixture was stirred for 3 h at RT and then partitioned between ether, 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/Heptan 1:9 to give 150 mg of pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:3]=1[NH2:4].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[OH:14][CH2:13][CH2:15][NH:16][C:6]1[CH:5]=[C:3]([NH2:4])[C:2]([Br:1])=[CH:8][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: NCCO
Reactant: Nc1cc(Br)c([N+](=O)[O-])cc1Br
Solvent: CCO
Product: Nc1cc(NCCO)c([N+](=O)[O-])cc1Br

Procedure:
0.02 mole (5.92 g) of 2,5-dibromo-4-nitroaniline (compound B) is added to 15 ml of 96° ethanol to which 12 ml of ethanolamine have been added. The mixture is heated in refluxing alcohol for 6 h 30 min. After cooling and dilution of the reaction mixture with 100 ml of iced water, the expected product precipitates.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5](=[O:27])[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH3:26].[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CC(=O)OCC>[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5](=[O:27])[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH3:26])=[O:33]
Reactant: O=C(Cl)c1ccccc1O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N(C)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N(C)CCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
To a solution of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-aminoethyl)-N-methyldocosa-4,7,10,13,16,19-hexaenamide (104 mg, 0.27 mmol), 2-hydroxybenzoyl chloride (37 mg, 0.27 mmol) and imidazole (19 mg, 0.27 mmol) in EA (4 mL) at 0° C. was added dropwise a solution of DCC (0.57 g, 0.27 mmol) in EA (4 mL). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel, eluting with EA-PE (1:3) to afford 2-hydroxy-N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)benzamide (100 mg, 73%) as a colorless oil. Mass calculated for C32H44N2O3=504.70. found: [M+H]+=505.5.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.[CH:11]([OH:14])([CH3:13])[CH3:12]>>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:14][CH:11]([CH3:13])[CH3:12])[CH:5]=1
Reactant: CC(C)O
Reactant: Clc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To isopropanol (12 ml) under Ar was added 55% sodium hydride in oil (343 mg, 7.86 mmol) in two portions. After 30 min stirring at rt was added 4-bromo-2-chloropyridine (Aldrich, Buchs, Switzerland, 1.01 g, 5.24 mmol) and the reaction mixture was heated with microwave irradiation to 150° C. for 30 min. The reaction mixture was concentrated, quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by MPLC (heptane/EtOAc 0% to 20%) to give the title compound as an oil. (HPLC: tR 3.58 min (Method A); M+H=216, 218 MS-ES)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[C:14]([O:17][CH2:18][CH:19]1[CH:24]=[CH:23][C@H:22]([NH2:25])[CH2:21][O:20]1)(=[O:16])[CH3:15].C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:14]([O:17][CH2:18][CH:19]1[CH:24]=[CH:23][C@H:22]([NH:25][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:21][O:20]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OCC1C=C[C@H](N)CO1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC1C=C[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CO1
Temperature: 90 °C
Yield: 82.7 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (156 mg, 0.727 mmol), [(5S)-5-amino-5,6-dihydro-2H-pyran-2-yl]methyl acetate (129 mg, 0.754 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) in isopropyl alcohol (1.7 mL) was heated at 90° C. for 2 h. The reaction mixture was concentrated and purified with flash chromatography to give the desired product (0.21 g 83%). LCMS calculated for C15H16N3O5S (M+H)+: m/z=350.1. Found: 350.0.