Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH:6]2[C:21](=[O:22])[N:8]3[C:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.[O:29]1CCCC1>O>[C:4]([C:3]1[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=1[C:1]([NH:5][CH:6]1[C:21](=[O:22])[N:8]2[C:9]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:28])([OH:29])=[O:23]
Reactant: C1CCOC1
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Solvent: O
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3C(=O)O)[C@H]2SC1

Procedure:
A solution of 800 mg. (2 mmol.) of t-butyl 7-phthalimido-3-methyl-3-cephem-4-carboxylate in 25 ml. of tetrahydrofuran and 8 ml. of water was cooled in an ice bath. To the solution 660 mg. of Na2S.9H2O were added, and the mixture was stirred and cooled for 10 min. At the end of this period 10 ml. of water were added, and the mixture was extracted with 40 ml. of ethyl acetate. The extract was discarded. The aqueous portion was acidified to pH 4.3 with 1N H2SO4 and then extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated, giving 700 mg. of the title compound. The product was recrystallized from chloroform/cyclohexane; m.p. 178°-179°; ir (nujol) 1770, 1735, and 1680 cm-1 ; nmr (CDCl3 + DMSOd6) δ 1.5 (s, 9, t-BU), 2.1 (s, 3, CH3), 3.2 and 3.5 (ABq, 2, J = 18 Hz), 5.02 (d, 1, J = 4.5 Hz), 5.82 (dd, 1, J = 4.5 and 9Hz), and 7.4-8 (m, H, ArH).
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[S:9])[NH:2]1.[OH-].[Na+].I[CH3:15]>C(O)C.O>[CH3:15][S:9][C:3]1[C:4]2=[CH:8][S:7][CH:6]=[C:5]2[S:1](=[O:10])(=[O:11])[N:2]=1
Reactant: O=S1(=O)NC(=S)c2cscc21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC1=NS(=O)(=O)c2cscc21
Yield: 36.3 %

Procedure:
To a mixture of 0.9 g (0.0044 mole) of thieno[3,4-d]isothiazol-3(2H)-thione 1,1-dioxide in 4 ml of ethanol is added a solution of 0.35 g (0.0044 mole) of 50% sodium hydroxide in 3 ml of water. To this thick mixture is added 0.62 g (0.0044 mole) of iodomethane. The mixture is heated under reflux for 5 minutes, and then filtered to give 0.35 g of product. On cooling, a second crop of 0.1 g of material is obtained. A small amount of the first crop is recrystallized from ethanol to afford an analytical sample, m.p. 184°-6° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][C:9]=1[NH:10][S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][C:15]=1[CH3:22])(=[O:13])=[O:12])=[O:4].[I:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][C:9]=1[N:10]([S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][C:15]=1[CH3:22])(=[O:13])=[O:12])[CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([I:29])[CH:31]=1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NS(=O)(=O)c1cc(C)c(Cl)cc1C
Reactant: BrCc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(Cc1cccc(I)c1)S(=O)(=O)c1cc(C)c(Cl)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
To a solution of 3-(4-Chloro-2,5-dimethyl-benzenesulfonylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (100 mg, 0.229 mmol) in anhydrous DMF (6 mL), 3-iodobenzyl bromide (82 mg, 0.276 mmol) and cesium carbonate (88 mg, 0.276 mmol) were added and the reaction mixture was stirred at room temperature under a N2 atmosphere for 12 h. The reaction mixture was partitioned, between water and ether. The ether layer was separated, dried (Na2SO4), concentrated. The residue, was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 3-[(4-Chloro-2,5-dimethyl-benzenesulfonyl)-(3-iodo-benzyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (130 mg, 87%) as a syrup.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][C:24]([OH:26])=O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:52]([O:59][NH2:60])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>O1CCCC1>[C:53]1([CH2:52][O:59][NH:60][C:24](=[O:26])[CH2:23][NH:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:12][CH2:11]3)=[CH:18][CH:17]=2)(=[O:20])=[O:21])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C(O)CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: NOCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)NOCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In a separate flask containing a cool (5° C.), stirred solution of [4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetic acid (0.2307 g, 0.0006161 mol) and 1-hydroxy-benzo-1,2,3-triazole (0.0842 g, 0.000623 mol) in anhydrous tetrahydrofuran (10 mL) was added in one portion 1,3-dicyclohexyl-carbodiimide (0.1449 g, 0.000702 mol). The mixture was stirred for 30 minutes at 5° C. then allowed to warm to room temperature. After 3 hours at room temperature, the mixture was added in one portion to the filtrate containing O-benzylhydroxylamine. The mixture was stirred at room temperature for 16 hours, then refluxed (74° C.) for 1 hour. The volatiles were rotary evaporated off, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 0.1 M NaOH, water, 0.1 M HCl, water, and saturated sodium chloride. The organic layer was dried (MgSO4) and rotary evaporated. The residue was dissolved in chloroform, and chromatographed on silica gel (34 g, 230-400 mesh) eluting with dichloromethane-acetone (9:1, 10×30 mL). Fractions containing product were rotary evaporated to give a white solid. The solid was dried in vacuo; yield 0.1448 g (49%), mp=163-165° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([N:14]([CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[C:4]([O:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][N:14]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:15])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: CN(Cc1ccccc1)CC(C)(C)CO
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OCC(C)(C)CN(C)Cc1ccccc1
Reaction time: 1.5 h

Procedure:
One gram of diketen was added dropwise to a stirred solution of 3-(N-benzyl-N-methylamino)-2,2-dimethyl propanol in 1 ml of benzene at 70° C. Sturing was continued for 1.5 hours at 70° C. after the addition. The solvent was distilled off to leave an oily residue. The residue was chromatographed over silica gel to afford 2.8 g of desired 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate (oily substance).
Reaction SMILES: [Cl:1][CH:2]=[C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[O:4][Si](C(C)C)(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(#N)C>[Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:4]
Reactant: CC(C)[Si](OC(=CCl)c1ccccn1)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(CCl)c1ccccn1
Yield: 84.6 %

Procedure:
Crude 2-{2-chloro-1-[(triisopropylsilyl)oxy]ethenyl}pyridine (117.3 g, 0.376 mol) is placed in a 4 L plastic bottle and is dissolved in acetonitrile (0.4 L). To the stirring solution is added 48% aqueous HF (170 mL, 0.45 mL/mmol) and the progress of the reaction is monitored by reverse phase analytical HPLC. After. Ca. 2 hours the reaction is judged to be complete, and the pH of the solution is carefully adjusted to ca. 8 with saturated aq. NaHCO3. The mixture is poured into a separatory funnel containing CH2Cl2 (1.5 L). The organic phase is removed and the aq. layer is extracted with CH2Cl2 (2×1.0 L). The combined organic layers are dried (Na2SO4), and concentration in vacuo affords the title compound (49.5 g, 85%) as a tan solid (after cooling). The crude material is judged to be quite pure by 1H-NMR and HPLC and is used as is in the Noyori asymmetric reduction.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:9][CH2:10][CH2:11][CH:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[OH:13].[O-]CC.[Na+]>C(O)C>[C:3]([CH2:2][S:1][CH2:9][CH2:10][CH2:11][CH:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[OH:13])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: OC(CCCCl)c1ccco1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCCCC(O)c1ccco1

Procedure:
To a stirred, refluxing mixture of ethyl mercaptoacetate, and 4-chloro-1-(2-furyl)-1-butanol (Example 160), and sodium ethoxide in ethanol. The resulting mixture is stirred at reflux for 3 hours, cooled, and concentrated to remove most of the ethanol. The residue is partitioned with ether and water. The ether phase is washed with brine and dried over potassium carbonate. The solution is concentrated, diluted with xylene, and again conentrated to give an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][N:14]=[CH:15][C:8]=2[NH:7][C:6]1=[O:16].[I-].[CH3:19][N:20]1[C:28]2[C:23](=[C:24]([CH3:29])[CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:30][N+](C)(C)C)=[CH:21]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][N:14]=[CH:15][C:8]=2[N:7]([CH2:30][C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[N:20]([CH3:19])[CH:21]=2)[C:6]1=[O:16]
Reactant: COC(=O)Cn1c(=O)[nH]c2cnccc2c1=O
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)c2ccncc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a solution of 62 mg of (2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl)-acetic acid methyl ester in N,N-dimethylformamide (2.5 mL) is added 109 mg of (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide and 44 mg of potassium carbonate at room temperature. The solution is heated to 60° C. for 2.5 h. Then the reaction is cooled to room temperature and stirred for another 16 hrs. Then 50 mL of water is added and a pale yellow solid is formed. The solid is collected and rinsed with water. Purification of this solid by flash chromatography on silica gel gives 98 mg (95%) of [1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl]-acetic acid methyl ester.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Cl:7][C:8]1[C:13]([CH2:14]Cl)=[CH:12][N:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C(#N)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:16]([F:19])([F:17])[F:18])[N:11]=[CH:12][C:13]=1[CH2:14][C:5]#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: FC(F)(F)c1cc(Cl)c(CCl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CCc1cnc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
Trimethylsilylcyanid (TMSCN) (69.3 g, 0.7 mol) was added to a solution of 4-chloro-5-(chloromethyl)-2-(trifluoromethyl)pyridine (Int-13) (80 g, 0.348 mol) and Tetra-n-butylammoniumfluoride (129.5 g, 0.7 mol) in acetonitrile (1.5 L) slowly. Then the mixture was stirred at 20-30° C. for 2 hours. Thin layer chromatography (petroleum ether: EtOAc=3:1) showed all of starting material was consumed. The mixture was concentrated and the residue was purified by silica gel chromatography eluted with petroleum ether: EtOAc=20:1˜3:1 to yield [4-chloro-6-(trifluoromethyl)pyridin-3-yl]acetonitrile (Int-14) (50 g, 60% from NMR, 39% of yield) as yellow syrup.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][O:23][CH3:24])[CH:12]=[CH:11][C:10]=1[N:25]1[S:29](=[O:31])(=[O:30])[NH:28][C:27](=[O:32])[CH2:26]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][O:23][CH3:24])[CH:12]=[CH:11][C:10]=1[N:25]1[S:29](=[O:31])(=[O:30])[NH:28][C:27](=[O:32])[CH2:26]1
Reactant: COCc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: COCc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
A solution of 5-[2-benzyloxy-4-(2-methoxymethylbenzyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (270 mg) in ethanol (5 mL) is hydrogenated over 5% Pd/C at 1 atm for 2 h. The catalyst is removed by filtration through Celite and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC to give the title compound. (M−1)−=361. HPLC retention time=1.01 min (Method A).
Reaction SMILES: [C:1]1([CH3:40])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:39])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[O:25])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:41][S:42](O)(=[O:44])=[O:43]>ClCCl>[C:35]1([CH3:38])[CH:36]=[CH:37][C:32]([S:29]([CH2:28][CH2:27][O:26][C:24](=[O:25])[CH2:23][O:22][C:17]2[CH:18]=[CH:19][C:20]([S:42]([Cl:41])(=[O:44])=[O:43])=[CH:21][C:16]=2[O:15][CH2:14][C:13]([O:12][CH2:11][CH2:10][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:40])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[O:39])(=[O:30])=[O:31])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccccc2OCC(=O)OCCS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccc(S(=O)(=O)Cl)cc2OCC(=O)OCCS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
{2-[2-(Toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-phenoxy}-acetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 37) (13 g, 22 mmole) was added to dichloromethane (30 mL), and cooled in an ice bath. Chlorosulfonic acid (10 mL) was slowly added, and the mixture was stirred at 0° C. for 2 hr., then at room temperature for 1 hr. Thereafter it was poured into crushed ice (200 g) with stirring. The precipitates were extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated, the residue was dried in vacuo to yield 17.3 g of {4-chlorosulfonyl-2-[2-(toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-phenoxy}-acetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 38).
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][C:9]2[C:10]([CH3:20])=[C:11]([OH:19])[C:12]([C:15](OC)=[O:16])=[N:13][CH:14]=2)=[CH:6][CH:5]=1>O1CCCC1>[F:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][C:9]2[C:10]([CH3:20])=[C:11]([OH:19])[C:12]([C:15]([NH:1][OH:2])=[O:16])=[N:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: NO
Reactant: COC(=O)c1ncc(Cc2ccc(F)cc2)c(C)c1O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(F)cc2)cnc(C(=O)NO)c1O

Procedure:
5.0 mL of hydroxylamine solution (50 wt. % in water) was added to a solution of 0.169 g of methyl 5-(4-fluorobenzyl)-3-hydroxy-4-methylpicolinate 7c (0.615 mmol, 1 eq) in 5.0 mL of tetrahydrofuran. The reaction mixture was stirred at reflux overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:16]([O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:33]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2/[CH:33]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc(OCc4ccccc4)cc23)cc(OC)c1OC
Yield: 2.4 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 5-benzyloxyindole-3-carboxaldehyde (2.51 g) except that the obtained crude crystals were recrystallized twice from acetone, to give Compound 28 (107 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C([O:17][C:18](=[O:55])[CH2:19][CH:20]([NH:24][C:25](=[O:54])[CH:26]([S:34]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21](O)=[O:22])(C)(C)C>>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][C:21](=[O:22])[CH:20]([NH:24][C:25](=[O:54])[CH:26]([SH:34])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:19][C:18]([OH:55])=[O:17])=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C(Cc1ccccc1)SC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Product: O=C(O)CC(NC(=O)C(S)Cc1ccccc1)C(=O)NCCc1c[nH]c2ccccc12
Yield: 39 %

Procedure:
This compound was prepared by condensing tryptamine with 2-(3-phenyl-2-tritylsulfanyl-propionylamino)-succinic acid 4-tert-butyl ester using the same coupling conditions as previously described. Deprotection and purification then provided the title compound (39%): (Pos FAB) 440 (MH+).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[CH:6]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[CH:29]([CH3:43])[C:28]1=[O:44])[CH2:7][CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCO>[C:23]([Si:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:40])[F:42])[CH:34]=2)[CH:29]([CH3:43])[C:28]1=[O:44])[CH2:5][OH:4])([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1CCN(c2cccc(C(F)(F)F)c2)C(C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1C(=O)N(C(CO)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCN1c1cccc(C(F)(F)F)c1
Yield: 49.1 %

Procedure:
Sodium borohydride (59 mg, 1.6 mmol) was added at RT to a solution of 4-(tert-butyl-diphenyl-silanyloxy)-2-[3-methyl-2-oxo-4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid methyl ester (480 mg, 0.78 mmol) in EtOH (7 mL), then after 20 h the reaction mixture was partitioned between 10% aq. KHSO4 solution and CH2Cl2. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 4:1) afforded the title compound (224 mg, 49%). Light yellow oil, MS: 585.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:47]=[CH:46][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[N:39]=3)[CH:36]=2)=[C:28]([F:48])[CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:46]=[CH:47][C:26]([NH:25][C:16]([C:5]5[C:6](=[O:15])[N:7]([C:8]6[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=6)[C:2]([CH3:1])=[CH:3][CH:4]=5)=[O:18])=[CH:27][C:28]=4[F:48])=[CH:36][N:35]3[CH:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1cccc(-n2c(C)ccc(C(=O)O)c2=O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc(-n2c(C)ccc(C(=O)Nc3ccc(Oc4ccc5nc(NC(=O)C6CC6)cn5c4)c(F)c3)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution (3 mL) of 6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (120 mg, 0.50 mmol) in tetrahydrofuran were added oxalyl dichloride (130 mg, 1.0 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure, and the solvent was evaporated. N,N-Dimethylformamide (3.0 mL) and a solution (2.0 mL) of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (130 mg, 0.40 mmol) in N,N-dimethylformamide were successively added, and the mixture was stirred at room temperature for 5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (150 mg, 69%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]O[CH2:24][CH2:23]1>ClCCl.CCN(C(C)C)C(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:13][CH2:14][CH3:15])[CH:16]3[CH2:17][CH2:18][N:19]([C:28]([N:22]4[CH2:27][CH2:26][CH2:24][CH2:23]4)=[O:29])[CH2:20][CH2:21]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCN(C1CCNCC1)C1CCc2ccc(Br)cc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C1CCN(C(=O)N2CCCC2)CC1)C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (200 μL of 0.25 M in dichloromethane, 50 μmol) was added 220 μL of 0.25 M solution of morpholine 4-carbonyl chloride in dichloromethane and 30 μL of DIEA. The reaction was stirred at 25° C. for 24 h. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford {4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-pyrrolidin-1-yl-methanone 34 (4.6 mg), [M+H]+=562.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].C([Li])CCC.C1C[O:20][CH2:19]C1>>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:1][CH2:2][C:3]#[C:4][CH2:19][OH:20]
Reactant: C1CCOC1
Reactant: C#CCCOC1CCCCO1
Agent: [Li]CCCC
Product: OCC#CCCOC1CCCCO1
Temperature: -23 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 8.0 mL (51 mmol) of 2-(3-butynyloxy)tetrahydro-2H-pyran in 150 mL of THF under nitrogen atmosphere at −23° C. was added dropwise a solution of 33 mL (53 mmol) of 1.6M butyllithium in hexanes, maintaining the temperature at −23° C. The resulting solution was stirred at 0° C. for 2 h, recooled to −23° C. and 2.4 g (76.5 mmol) of parafomaldehyde was added in several portions. The mixture was stirred at −23° C. for 1h and let warm to room temperature and stirred for 18 h. The reaction mixture was poured into a large excess of ice water and extracted with ether. The organics were washed with brine until neutral, dried over MgSO4, filtered and concentrated in vacuo. The residue was kugelrohr distilled to provide 7.26 g (77%) of 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol as a colorless liquid. EI Mass Spec: 185.1 (M+H)+