Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=S)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][C:18](=[O:44])[NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]1[CH:29]=[C:28]([C:30]([N:32]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH:27]=[CH:26][C:25]=1[NH2:43])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[CH3:41][CH:40]([CH3:42])[CH2:39][CH2:38][N:32]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:30]([C:28]1[CH:27]=[CH:26][C:25]2[N:43]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:18](=[O:44])[O:17][C:13]([CH3:16])([CH3:14])[CH3:15])[C:24]=2[CH:29]=1)=[O:31]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc2nc(Nc3ccc([N+](=O)[O-])cc3)n(CCCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 88 %

Procedure:
4-nitrophenyl isothiocyanate (305 mg, 1.5 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; charge 1.9 mmol/g; 1.75 g, 3 eq) are successively added to a solution of tert-butyl-3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamate prepared according to Example A1 (500 mg, 1 eq) in tetrahydrofuran (30 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 7:3 to 2:8) produces the expected compound in the form of a yellow solid (584 mg; 88% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH:9]=O)[C:5]([CH2:11][OH:12])=[CH:4][N:3]=1.Cl.[C:14]([NH:18][S:19]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([F:35])[CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][S:19]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][CH2:9][C:6]3[C:5]([CH2:11][OH:12])=[CH:4][N:3]=[C:2]([CH3:1])[C:7]=3[OH:8])=[C:30]([F:35])[CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Reactant: Cc1ncc(CO)c(C=O)c1O
Agent: Cl
Product: Cc1ncc(CO)c(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2F)c1O

Procedure:
The reductive amination of pyridoxal hydrochloride (436.4 mg, 2.143 mmol) and 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (760 mg, 2.357 mmol), following the procedure described in Example 7, gave 3′-fluoro-4′-[(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (9).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:15]3=[N:14][C:13]=2[CH3:29])=[O:11])=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1.[Cl-].[NH4+].C(OCC)(=O)C>CN1CCCC1=O>[CH:23]1([CH2:22][O:21][C:20]2[C:15]3[N:16]([C:12]([C:10]([NH:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([N:30]5[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]5)=[N:7][CH:6]=4)=[O:11])=[C:13]([CH3:29])[N:14]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NCc1ccc(Cl)nc1
Reactant: CCOC(=O)C1CCCNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCCN(c2ccc(CNC(=O)c3c(C)nc4c(OCC5CCCCC5)cccn34)cn2)C1

Procedure:
To a solution of 70 mg of N-[(6-chloropyridin-3-yl)methyl]-8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide in 1 mL of N-methyl-2-pyrrolidone was added 0.12 mL of ethyl piperidine-3-carboxylate to carry out a reaction at 240° C. for 50 minutes under microwave irradiation. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 43 mg of ethyl 1-{5-[({[8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]pyridin-2-yl}piperidine-3-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[N:15]=[CH:14][C:13]4[N:19]([CH3:30])[C:20](=[O:29])[N:21]([C:22]5[C:23]([CH3:28])=[N:24][N:25]([CH3:27])[CH:26]=5)[C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl>[CH3:27][N:25]1[CH:26]=[C:22]([N:21]2[C:12]3[C:11]4[CH:10]=[C:9]([C:5]5[CH:4]=[C:3]([CH2:2][NH:1][C:40](=[O:42])[CH3:41])[CH:8]=[N:7][CH:6]=5)[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:19]([CH3:30])[C:20]2=[O:29])[C:23]([CH3:28])=[N:24]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(CN)c4)cc3c21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1
Reaction time: 0.75 h

Procedure:
To a mixture of 8-(5-aminomethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 230, 0.053 mmol) and Hünig's base (0.014 ml) in dichloromethane (1 ml) was added acetyl chloride (Aldrich, Buchs, Switzerland, 0.058 mmol). The RM was stirred for 45 min at it then evaporated to dryness. The residue was taken in MeOH and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: tR 1.95 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.56-8.53 (m, 1H), 8.48-8.46 (m, 1H), 8.40 (t, 1H), 8.16-8.12 (m, 2H), 7.94-7.90 (m, 1H), 7.78-7.75 (m, 1H), 7.58-7.56 (m, 1H), 4.38-4.27 (m, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 1.95 (s, 3H), 1.89 (s, 3H))
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]([NH2:12])=[NH:11])[N:3]=1.CS[C:15](=[NH:17])[NH2:16]>CO>[NH2:8][C:6]1[N:5]=[C:4]([NH:9][C:10]([NH2:12])=[NH:11])[N:3]=[C:2]([NH:1][C:15]([NH2:17])=[NH:16])[CH:7]=1
Reactant: CSC(=N)N
Reactant: N=C(N)Nc1nc(N)cc(N)n1
Solvent: CO
Product: N=C(N)Nc1cc(N)nc(NC(=N)N)n1

Procedure:
A mixture of 1.7 g (0.01 m) of 4,6-diamino-2-guanidinopyrimidine prepared as in Example 2, 0.9 g (0.01 m) of S-methylisothiourea and 150 ml of methanol is heated at reflux overnight. Evaporation of the volatiles gives 6-amino-2,4-diguanidinopyrimidine.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][C:22]#[C:23][C:24]([O:27]C2CCCCO2)([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:42]C2CCCCO2)[CH2:9]1.C(=O)([O-])O.[Na+].[H][H]>C(O)C.[Ni]>[OH:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([OH:42])[CH2:9]1
Reactant: [H][H]
Reactant: C[C@H](CC#CC(C)(C)OC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A solution of 0.2 g (0.3 mmol) of 1α,3β,25-tris[(tetrahydro-2H-pyran-2-yl)oxyl]-cholest-5-en-23-yne in 10 ml of ethanol was treated with 0.05 g of sodium hydrogen carbonate and 0.4 ml of concentrated ethanolic Raney-nickel suspension, and the mixture was shaken in a hydrogen atmosphere at normal pressure for 24 hours. The catalyst was filtered off, and the filtrate was evaporated. The residue, containing 1α,3β,25-tris[(tetrahydro-2H-pyran-2-yl)oxy]-cholest-5-ene, was dissolved in 5 ml of methanol. 10 mg of p-toluenesulphonic acid monohydrate were added. The solution was left at room temperature for 3 hours. While stirring there were added dropwise 5 ml of water, the suspension was suction filtered, and the residue was dried. There was obtained 0.11 g (89%) of 1α,3β,25-trihydroxy-cholest-5-ene which melts at 174°-176° C. after recrystallization from acetone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.F[B-](F)(F)F.[CH3:18][O+](C)C.[OH-].[Na+]>ClCCl>[CH3:18][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=1
Reactant: C[O+](C)C
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2cc(Br)ccc2n1

Procedure:
A mixture of 6-bromo-2-[1H]-quinolone (2.90 g) and trimethyloxoniumtetrafluoroborate (2.10 g) was stirred in dichloromethane (50 cm3) for 48 hours under nitrogen. Aqueous 10% sodium hydroxide (20 cm3) was added and the aqueous phase was extracted with dichloromethane (2×40 cm3). The dried (MgSO4) extracts were evaporated and the residue was crystallised from petroleum ether (b.p. 60°-80°) to yield 2-methoxy-6-bromoquinoline, m.p. 90°-94°, (2.16 g).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])(=[O:8])[O:5]CC)C.[CH3:14][Si:15](I)([CH3:17])[CH3:16]>C(Cl)(Cl)(Cl)Cl>[CH3:14][Si:15]([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])(=[O:8])[O:5][Si:15]([CH3:17])([CH3:16])[CH3:14])([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)I
Reactant: CCOP(=O)(CCCC#N)OCC
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)OP(=O)(CCCC#N)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
In an experiment to demonstrate this method, 4.0 g of diethyl-3-cyanopropylphosphonate in 12 ml of carbon tetrachloride, was treated with 5.6 ml of trimethylsilyl iodide. This was cooled to 0° C. and stirred for ten minutes, and allowed to warm to room temperature, forming bis(trimethylsilyl)-3-cyanopropylphosphonate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:20]([O:19][CH3:18])[CH:21]=[CH:22][C:23]=3[O:26][CH3:27])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14]
Reactant: CCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(OC)c(B(O)O)c1
Product: CCNC(=O)c1nnc2c(-c3cc(OC)ccc3OC)cccc2c1N
Yield: 53.9 %

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-ethyl-cinnoline-3-carboxamide (100.0 mg, 0.339 mmol) and 2,5-dimethoxyphenyl boronic acid (123.3 mg, 0.678 mmol) according to Method A. The solid obtained after chromatography was washed with diethyl ether and dried overnight at 40° C. to afford the title compound as a fluffy white solid (64.4 mg, 54% yield). 1H NMR (300.132 MHz, CDCl3) δ 8.51 (bt, J=5.2 Hz, 1H), 7.86 (dd, J=7.5, 2.1 Hz, 1H), 7.76-7.68 (m, 2H), 6.97-6.91 (m, 3H), 3.79 (s, 3H), 3.64 (s, 3H), 3.52 (dq, J=5.7, 7.3 Hz, 2H), 1.26 (t, J=7.3 Hz, 3H). MS APCI, m/z=353 (M+H). HPLC 2.41 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=O)[CH2:10][CH2:9][CH2:8]2.[CH3:14][O:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][O:21][CH3:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:18]([CH2:19][CH2:20][O:21][CH3:22])[CH2:17][CH2:16][O:15][CH3:14])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(=O)CCC2
Reactant: COCCNCCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C1CCc2cccc(OC)c2C1
Reaction time: 48 h
Yield: 78.4 %

Procedure:
A solution of 1.76 g (10 mmol) 8-methoxy tetralone, 2.66 g (20 mmol) N,N-bis(-2methoxyethyl)amine, and 25 mg p-toluenesulfonic acid in toluene was heated to reflux under a N2 atmosphere. The flask was equipped with a Dean-Stark trap to collect H2O. TLC analysis was used to monitor the reaction. After 48 hours, the solvent was removed in vacuo. The crude ene-amine was hydrogenated using 450 mg 10% pd/C in 50 mL MeOH at 50 psi H2 for 24 hours. The reaction mixture was filtered over celite and the filtrate purified by liquid chromatography on 400 g of silica gel-60 (230-400 mesh), eluting with hexane/ethyl acetate/isopropanol (10:5:1). Fractions homogeneous by TLC were combined and concentrated in vacuo to give pure title compound as a yellow oil (2.3 g, 80%).
Reaction SMILES: [O:1]=[C:2]1[C:11](/[CH:12]=[CH:13]/[C:14](Cl)=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:17]([OH:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20].C(N(CC)CC)C>O1CCCC1>[C:17]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:14](=[O:15])/[CH:13]=[CH:12]/[C:11]1[C:2](=[O:1])[O:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([OH:26])=[O:25]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)/C=C/c1cc2ccccc2oc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/c1cc2ccccc2oc1=O)Nc1ccccc1C(=O)O

Procedure:
Prepared analogously to Example 31 from trans-3-(2-oxo-2H-chromen-3-yl)-acrylic acid chloride and anthranilic acid in tetrahydrofuran with the addition of triethylamine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])[C:11]2=[O:31])[CH:6]=[CH:5][N:4]=1)#[N:2].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:37]([O:36][C:34](=[O:35])[CH2:33][N:15]([C@H:12]1[CH2:13][CH2:14][N:10]([CH2:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=2)[C:11]1=[O:31])[S:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=2)[CH:20]=1)(=[O:18])=[O:17])([CH3:40])([CH3:39])[CH3:38]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1
Reactant: CC(C)(C)OC(=O)CBr
Product: COc1ccc2ccc(S(=O)(=O)N(CC(=O)OC(C)(C)C)[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared from 7-methoxynaphthalene-2-sulfonic acid-[1-(2-cyano-pyridin-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using tert-butyl bromoacetate in place of benzyl bromide. The crude product is purified by column chromatography eluting with gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1.C([Li])(CC)C.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(OCC)(=O)C>O1CCCC1>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: CC(c1ccc(Br)cc1)C1SCCCS1
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1ccc(CCCCBr)cc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene (27.2 g, 94 mmol) in tetrahydrofuran (200 ml) was charged with sec-butyllithium (99 ml, 1.3M in cyclohexane, 0.13 mole) dropwise at -78° C. under nitrogen. The mixture was stirred at ambient temperature for 1.5 hours, and then quenched with 1,4-dibromobutane (42 g, 0.2 mole). After being stirred for 3 hours, the mixture was poured into ethyl acetate, and then washed with water and brine. The organic solution was then dried (Na2SO4) and concentrated to an oil. The crude product was purified by flash chromatography over a silica gel column. The 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)-ethylbenzene thus purified was a light oil, 22.3 g.
Reaction SMILES: [CH:1]([C:3]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:2].[OH-].[Na+].Cl>C(O)C.O>[CH:1]([C:3]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])=[O:2]
Reactant: COC(=O)c1cccc(COc2cccc(O)c2C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=Cc1c(O)cccc1OCc1cccc(C(=O)O)c1

Procedure:
Methyl 3-(2-formyl-3-hydroxyphenoxy)methylbenzoate (Example 18) (500 mg, 0.00175 M) was dissolved in ethanol (5 ml) and 1 N sodium hydroxide solution (5 ml) and stirred at room temperature (21/2 hr). The solution was diluted with water and acidified with concentrated hydrochloric acid with cooling and the solid produced filtered off and washed with water to give 3-(2-formyl-3-hydroxyphenoxy)methylbenzoic acid, m.p. 209°-211° C. from ethanol/water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11](=O)[CH2:12][CH2:13][CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCC=O
Reactant: Fc1ccc2[nH]ccc2c1
Product: CCCC(c1c[nH]c2ccc(F)cc12)c1c[nH]c2ccc(F)cc12
Yield: 45 %

Procedure:
This was prepared in the same way as described in example 2/2 starting from 5-fluoroindole and butyraldehyde. The reaction, however, was heated under reflux for 24 hours. The end product was isolated and purified by chromatography on an SiO2 column using a hexane:ethyl ether gradient ranging from 7:3 to 4:6 as the eluent. Yield 45%.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[N:8]=[C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]2[CH:18]=1.[C:19](=O)([O-])[OH:20].[Na+]>CN(C)C=O>[CH:19]([C:18]1[N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]2=[N:8][C:7]=1[CH3:6])=[O:20]
Reactant: O=C([O-])O
Reactant: Cc1cn2cccc([N+](=O)[O-])c2n1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc2c([N+](=O)[O-])cccn2c1C=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
20 ml phosphoroxychloride is added dropwise within 5 minutes to a solution of 7.6 g 2-methyl-8-nitro-imidazo[1,2-a]pyridine in 100 ml dimethylformamide at 0° C. After stirring for 1 hour at 0° C. and for 2 hours at 70° C. the mixture is cooled again to 0° C. 10 ml phosphoroxychloride is added dropwise and the same procedure is carried out as before. When the reaction is finished the mixture is poured over 200 ml icewater, neutralized with saturated sodium hydrogen carbonate solution and extracted 3×with 50 ml ethyl acetate each time. The solvent is stripped off in vacuo and the residue is washed with ether and recrystallized from acetronitrile, giving the title compound of m.p. 188°-189° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]>[Pd]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC=Cc1cccs1
Agent: [Pd]
Product: O=C(O)CCCCCCCCc1cccs1
Yield: 87.4 %

Procedure:
This compound was synthesized from 9-(2-thienyl)-8-nonenoic acid (1.19 g, 5 mmol) by a hydrogenation reaction using Pd/C (120 mg). Crystallization afforded the product (1.05 g, 88%) as white crystals (mp 32-33° C.); IR: 3400-2500, 1715, 705 cm-1 ; 1H-NMR: 1.35 (m, 12 H), 2.35 (t, 2 H), 2.85 (t, 2 H), 6.95 (m, 3 H), 10.35 (bs, 1 H). Anal. Calcd. for C13H20SO2 : C, 64.96, H, 8.39%; Found: C, 64.81, H, 8.43%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[S:23]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1OCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1cc([N+](=O)[O-])ccc1N
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a stirred suspension of 2 (42 g) and triethylamine (30.4 g) in dichloromethan (400 ml) in an ice bath was added dropwise a solution of methanesulfonyl chloride (25.2 g) in dichloromethane (100 ml). The mixture was stirred for 30 min. and the precipitate was collected by filtration and recrystallized from ethyl acetate to give 33.77 g (58%) of 3: mp 132°-135° C.; MS m/e 276 (M+).
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[CH3:7][C:8](=[O:11])[C:9]#[CH:10]>C(O)C>[SH:1][C:2]1(/[CH:10]=[CH:9]/[C:8](=[O:11])[CH3:7])[N:6]=[CH:5][CH2:4][S:3]1
Reactant: C#CC(C)=O
Reactant: SC1=NCCS1
Solvent: CCO
Product: CC(=O)/C=C/C1(S)N=CCS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-mercaptothiazoline (3.7 g., 0.03 mole) in aqueous ethanol (35 ml) at 35° C., a solution of 3-butyn-2-one (2.0 g., 0.03 mole) in ethanol (10 ml) was added dropwise over 10 minutes. The resulting solution was refluxed for 2 hours and stirred at ambient temperature for 18 hours. The volatiles were removed in vacuo and the residue was extracted into ethyl acetate and washed thoroughly with water. After drying (MgSO4), the solution was concentrated to an amber oil consisting of the cis and trans isomers. Purification and isolation of the isomers was accomplished via column chromatography on silica gel using hexanes/ethyl acetate (4:1), yielding 2.7 g cis-isomer as a white solid, mp 69°-72° C. IR.(nujol) uc=o 1660 cm-1. The trans-isomer was recovered as an amber oil, 0.2 g IR (neat) uc=o 1660 cm-1.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[Cl:29][C:30]1[CH:46]=[CH:45][C:33]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([Cl:29])=[CH:46][CH:45]=3)=[CH:41][CH:40]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: OB(O)c1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(Cl)cc3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 59.6 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0473 g, 0.104 mmol), (4-((4-chlorobenzyl)oxy)phenyl)boronic acid (0.041 g, 0.156 mmol) and 2M Na2CO3 (0.130 ml, 0.260 mmol) in DMF 92 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.012 g, 10.39 μmol) was added, degassed for 5 min and placed in a oil bath pre-heated to 110 C. After 2 h, cooled and purified by pre-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(5-(4-((4-chlorobenzyl)oxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.0368 g, 0.062 mmol, 59.7% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.38-7.44 (m, 4H), 7.16-7.19 (m, 1H), 7.02-7.09 (m, 3H), 6.01 (br. s., 1H), 5.09-5.16 (m, 2H), 4.24-4.31 (m, 1H), 4.19 (qd, J=7.1, 10.8 Hz, 1H), 3.04-3.27 (m, 1H), 2.83 (br. s., 1H), 2.67 (br. s., 3H), 2.28 (br. s., 4H), 1.94-2.13 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.20 (s, 9H), 0.88 (m, 3H), 0.68 (br. s., 3H). 4H of piperidine were not resolved. LCMS (M+H)=593.3.