Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.O.CO>CCOC(C)=O.[OH-].[Na+]>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]#[C:21][C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[N:9]=1
Reactant: C[Si](C)(C)CCOCn1nc(C#Cc2ccccn2)c2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(C#Cc2ccccn2)c2ccc(N)cc21
Reaction time: 0.5 h

Procedure:
A mixture of 6-Nitro-3-pyridin-2-ylethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (2 mmol), SnCl2 (1.37 g, 6.0 mmol), water (0.5 mL), and MeOH (10 mL), were stirred in a 60 deg C oil bath for 30 min at which time HPLC indicated complete reduction. The resulting mixture was stripped of methanol, suspended in EtOAc (50 mL) and diluted with 1M NaOH (18 mL). The resulting emulsion was gently extracted EtOAc (10×25 ml). The combined organics were extracted with 1M Na2CO3, brine, dried over MgSO4, concentrated and filtered through a pad of silica eluted with EtOAc. The yield of crude product for two steps was 701 mg, 96% mass recovery. ESIMS (M+H+): 365.1.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].F[P-](F)(F)(F)(F)F.S1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=C1.C(N(CC)CC)C.[Br:43][C:44]1[C:45]([CH3:63])=[C:46]([CH:60]=[CH:61][CH:62]=1)[C:47]([NH:49][CH2:50][C:51]1[CH:59]=[CH:58][C:54]([C:55]([O-])=[O:56])=[CH:53][CH:52]=1)=[O:48]>CN(C=O)C>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:55](=[O:56])[C:54]1[CH:58]=[CH:59][C:51]([CH2:50][NH:49][C:47](=[O:48])[C:46]2[CH:60]=[CH:61][CH:62]=[C:44]([Br:43])[C:45]=2[CH3:63])=[CH:52][CH:53]=1
Reactant: Nc1ccccc1N
Reactant: Cc1c(Br)cccc1C(=O)NCc1ccc(C(=O)[O-])cc1
Agent: CN(C)[P+](O[SH]1C=Nc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Br)cccc1C(=O)NCc1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
Phenylenediamine (217 mg, 2.01 mmol), 1H-benzothiazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (BOP; 667 mg, 1.51 mmol) and triethyl amine (203 mg, 2.01 mmol) were dissolved in 3 mL of DMF. 350 mg of the 4-((3-bromo-2-methylbenzamido)methyl)benzoate obtained in step 2 (1.01 mmol) was added thereto and stirred at room temperature overnight. The resulting mixture was subjected to thin layer chromatography to monitor the amount of 4-((3-bromo-2-methylbenzamido)methyl)benzoate consumed, and DMF was removed under a reduced pressure. 50 mL of saturated sodium bicarbonate was added to the resulting mixture, extracted with methylene chloride (3×75 mL) and the separated organic layer was dried over anhydrous magnesium sulfate. The residue was dissolved in methylene chloride and n-pentane was added thereto. The resulting solid thus obtained was filtered and washed with ethanol to obtain the title compound (231 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[OH:12]
Reactant: Cc1cc(F)c(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(O)c(F)c1
Reaction time: 18 h
Yield: 33.6 %

Procedure:
2-Fluoro-4-methyl-6-nitrophenol (D115, 3.276 g, 19.14 mmol) was dissolved in ethanol (100 mL). 10% Pd/C (0.323 g, 0.304 mmol) was added and the reaction mixture hydrogenated for ˜18 hr. Catalyst was filtered off and the filtrate evaporated to dryness. TLC showed only a small amount of material had been reduced. Solid was redissolved in 350 mL ethanol, 150 mL of this solution was passed down the H-cube at 1 mL/min with full hydrogen. After ˜2 hr the cartridge had been exhausted. A new cartridge was used and the reaction mixture was left recycling through the instrument for ˜4 hr.-30% of nitro compound was still remaining. The reaction mixture was evaporated to dryness. Redissolved in EtOH and passed through the H-cube with a new cartridge to give fully reduced material 2-fluoro-4-methyl-6-aminophenol (907 mg, 6.43 mmol, 33.6% yield) as a brown solid. The remaining nitro compound was passed down the H-cube at 1 mL/min with full hydrogen—still only 58% conversion. Redissolved in EtOH and passed through the H-cube with a new cartridge. Evaporated to dryness redissolved in MeOH and loaded onto an SCX-2 cartridge (50 g) washed with MeOH and eluted with 1M NH3/MeOH, evaporated to dryness to give a brown solid batch 2 (1.319 g, 9.35 mmol, 48.8% yield).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C([O-])(=O)C.[Na+].[C:10]([C:13]1[C:14]([CH2:20][S:21][C:22]2[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][N:23]=2)=[C:15]([CH3:19])[S:16][C:17]=1[CH3:18])(=O)[CH3:11].O>C(O)C>[CH3:27][C:25]1([CH3:28])[O:24][N:23]=[C:22]([S:21][CH2:20][C:14]2[C:13]([C:10](=[N:4][O:3][CH3:2])[CH3:11])=[C:17]([CH3:18])[S:16][C:15]=2[CH3:19])[CH2:26]1
Reactant: CC(=O)c1c(C)sc(C)c1CSC1=NOC(C)(C)C1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=C(C)c1c(C)sc(C)c1CSC1=NOC(C)(C)C1
Reaction time: 5 h
Yield: 36 %

Procedure:
0.57 g (6.8 mmoles) of O-methylhydroxylamine hydrochloride and 0.56 g (6.8 mmoles) of sodium acetate were added to a solution of 1.0 g (3.4 mmoles) of 3-(4-acetyl-2,5-dimethylthiophen-3-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 50 ml of ethanol. The mixture was stirred for 5 hours under refluxing, to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g (36.4%) of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylthio]-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[CH:9]([O:11][CH3:12])=[CH2:10]>>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:9]([O:11][CH3:12])[CH3:10])=[CH:1][CH:2]=1
Reactant: C=COC
Reactant: Oc1ccc(Br)cc1
Product: COC(C)Oc1ccc(Br)cc1
Yield: 90 %

Procedure:
Using p-bromophenol (17.3 g, 0.1 mole) and methyl vinyl ether (14.0 g, 0.2 mole), the reaction was carried out in the same manner as described in Synthesis Example 1, (1), and the crude oil (24 g) was purified by distillation under reduced pressure to afford 20.8 g of p-bromo-(1-methoxyethoxy)benzene as a pale yellow oil having a boiling point 89-90° C./2 mmHg.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:3]1.[H][H]>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C@@H:4]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:3]1
Reactant: CC(=O)NCC1CC(=O)c2ccccc2O1
Reactant: [H][H]
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CC(=O)c2ccccc2O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
35.1 g of N-(4-oxochroman-2-ylmethyl)acetamide are suspended in 90 ml of toluene, and 1.6 ml of a 10 millimolar solution consisting of [Rh((S)-ToIBINAP)(COD)Cl] in toluene, are added under inert conditions. This suspension is hydrogenated in an autoclave at 100 bar of hydrogen and 100° C. After 12 hours, enantiomerically pure (>99% ee) (R)-N-(4-oxochroman-2-ylmethyl)acetamide is crystallised by cooling to room temperature. Drying gives 31.04 g of (R)-N-(4-oxochroman-2-ylmethyl)acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Br)cc(OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
To a solution of 3-bromo-5-nitro-phenol (770 g, 3.53 mol) in acetone (10 L) was added pulverized K2CO3 (2.45 kg, 17.75 mol) in one portion at rt followed by addition of benzyl bromide (632 mL, 5.32 mol) over a period of 30 min. The resulting reaction mixture was stirred for 15 min then heated at reflux for 3 h. After reaction completion (by TLC), the reaction mixture was filtered through celite and the acetone distilled off. The crude residue thus obtained was purified over silica gel (60-120 M) using EtOAc:hexane (5:95) to obtain the desired product (551 g, 51%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N1CCCCC1)=O>CCOC(C)=O>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1cccc(Cl)c1C#N
Reactant: C1CCNCC1
Agent: O=CN1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCCCC2)c1C#N
Temperature: 150 °C
Reaction time: 96 h

Procedure:
2-Methyl-6-piperidin-1-ylbenzonitrile (1 b) was prepared according to the method described by Grell, W. J. Med. Chem. 1998, 41, 5219. A mixture of 2-chloro-6-methylbenzonitrile (1a, 8.5 g), piperidine (16.6 mL, 3 eq) and N-formyl piperidine (12.5 mL) was heated in an oil bath at 150° C. under N2. After a period of 4 days, HPLC indicated complete conversion of starting materials to product. The reaction mixture was cooled to RT, dissolved in 100 mL of EtOAc, washed with water, 10% HCl, and NaHCO3 (sat), dried over anhydrous MgSO4 and treated with charcoal. The product was concentrated under vacuum to give the crude product (1 b) as pale yellow oil (12.01 g); C18 reversed phase HPLC indicated 88% homogeneity at 220 nm. This crude product was purified by flash column chromatography (hex-EtOAc, 1:0 to 20:1 to 10:1) to afford 2-methyl-6-piperidin-1-ylbenzonitrile (1 b) as colorless oil which solidifies upon standing (˜80% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][CH2:37][CH2:36][S:35]3(=[O:40])=[O:39])=[CH:30][CH:29]=2)O1>>[Cl:19][C:12]1[C:13]([F:18])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:38][CH2:37][CH2:36][S:35]3(=[O:40])=[O:39])=[CH:32][CH:33]=2)[CH:3]=1
Reactant: CC1(C)OB(c2ccc(N3CCCS3(=O)=O)cc2)OC1(C)C
Reactant: Nc1ncc(Br)cc1OCc1c(F)ccc(F)c1Cl
Product: Nc1ncc(-c2ccc(N3CCCS3(=O)=O)cc2)cc1OCc1c(F)ccc(F)c1Cl

Procedure:
3-(2-Chloro-3,6-difluoro-benzyloxy)-5-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine was prepared following procedure 3 from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]isothiazolidine 1,1-dioxide.
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[CH:17]=[O:18].[CH:19](O)(C)C>>[CH2:1]([N:8]([CH2:19][CH:17]([OH:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC/C=C/C=O
Reactant: ONCc1ccccc1
Reactant: CC(C)O
Product: CCCCCCC(O)CN(O)Cc1ccccc1
Yield: 38 %

Procedure:
The procedure of Example 1 is repeated using 5.0 g of N-benzylhydroxylamine and 5.26 g octene-1-oxide in 20 ml of isopropanol. Purification by liquid chromatography affords the title compound in a 38% yield as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[O:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2I)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[C:22]1([P:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CCOCC>[C:1]([C:5]1[O:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[P:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C1=N[C@H](c2ccccc2I)CO1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C1=N[C@H](c2ccccc2P(c2ccccc2)c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 4a (94 mg, 0.286 mmol) in 4 mL ether was added t-BuLi (1.7 M solution, 0.34 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 min before diphenylchlorophosphine (2.43 g, 11.0 mmol) was added slowly. The solution was allowed to warm to rt and was stirred overnight. Water was added. The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated. The residue was purified by flash column chromatography to give 5a as a colorless oil (40%). [α]20D=−50.9 (c=2.0, CHCl3); 1H NMR (CD2Cl2, 360 MHz) δ 7.40-7.26 (m, 12H), 7.19 (dt, J=1.5 Hz, J=7.5 Hz, 1H), 6.93-6.89 (m, 1H), 5.82-5.75 (m, 1H), 4.24 (dd, J=is 8.4 Hz, J=10.2 Hz, 1H), 3.64 (dt, J=0.5 Hz, J=8.4 Hz, 1H), 1.28 (s, 9H); 13C NMR (CD2Cl2, 90 MHz) δ 175.8, 148.4 (d, J=24.0 Hz), 136.9 (d, J=10.2 Hz), 135.4-134.2 (m), 130.0-129.3 (m), 127.9 (br s), 126.8 (br s), 75.4 (d, J=4.4 Hz), 67.5 (m), 33.9, 28.3; 31P NMR (CD2Cl2, 145 MHz) δ-14.97; HRMS (M++1) m/z calculated for C25H27NOP 388.18248, found 388.17930.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]3[N:18]=[C:17]([N:19](CC)[CH2:20][C:21]4C=CC(OC)=CC=4)[C:16]4=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:15]4[N:14]=3)[CH:10]=2)[N:5]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)[CH:4]=1)#[N:2].[C:49]1([O:55]C)[CH:54]=CC=C[CH:50]=1.C(O)(C(F)(F)F)=O>ClCCCl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH2:20][CH3:21])[C:16]4=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:15]4[N:14]=3)[CH:10]=2)[N:5]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:50][C@@H:49]([OH:55])[CH3:54])[CH2:38][CH2:37]2)[CH:4]=1)#[N:2]
Reactant: COc1ccccc1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2ccc3c(c2)c(C#N)cn3C2CCN(C(=O)OC(C)(C)C)CC2)nn2c(C#N)cnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCNc1nc(Nc2ccc3c(c2)c(C#N)cn3C2CCN(C[C@H](C)O)CC2)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 4-(3-cyano-5-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-1H-indol-1-yl)piperidine-1-carboxylate (500 mg, 0.503 mmol) was mixed with anisole (0.5 mL, 4.58 mmol) and DCE (5 mL). TFA (1 mL, 12.98 mmol) was added. The mixture was stirred at 25° C. for 24 hrs. LC/MS showed product formation. The mixture was concentrated to dryness, diluted with MeOH and applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol. Removal of the solvents left 2-((3-cyano-1-(piperidin-4-yl)-1H-indol-5-yl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg) as solid.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2([C:22](=[O:25])C=C)CC2)C=CC=CC=1.COC1(OC)CC[N:30](CCC(=O)C2(C3C=CC=CC=3)CC2)[C@H:29]1C/C=C\CCCC(OC)=O.COC1(OC)CCN[C@H]1C/C=C\CCCC(OC)=O>CCOC(C)=O.CCCCCC>[CH3:22][O:25][N:30]([CH3:29])[C:10]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:8]1)=[O:12]
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: COC(=O)CCC/C=C\C[C@@H]1N(CCC(=O)C2(c3ccccc3)CC2)CCC1(OC)OC
Reactant: C=CC(=O)C1(c2ccccc2)CC1
Agent: COC(=O)CCC/C=C\C[C@@H]1NCCC1(OC)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CON(C)C(=O)C1(c2ccccc2)CC1

Procedure:
The title compound was prepared according to the procedure described for intermediate 16.1 from 1-phenyl-1cyclopropane carboxylic acid. Rf 0.30 (EtOAc/hexanes 3/7). Intermediate 18.2: 1-(1-phenylcyclopropyl)prop-2-en-1-one. The title compound was prepared according to the procedure described for intermediate 16.2 using intermediate 16.1. Rf 0.90 (EtOAc/hexanes 3/7). Intermediate 18.3: methyl(5Z)-7-{(2S)-3,3-dimethoxy-1-[3-oxo-3-(1-phenylcyclo-propyl)propyl]pyrrolidin-2-yl}hept-5-enoate. The title compound was prepared according to the procedure described for intermediate 13.1 from methyl(5Z)-7-[(2S)-3,3-dimethoxypyrrolidin-2-yl]hept-5-enoate (intermediate 5.3) and intermediate 18.2. Rf 0.30 (EtOAc/hexanes 1/1); MS (m/z) 444 (M+1). Intermediate 18.4: methyl(5Z)-7-{1-β-hydroxy-3-(1-phenylcyclopropyl)propyl]-3,3-dimethoxypyrrolidin-2-yl}hept-5 enoate. The title compound was prepared according to the procedure described for intermediate 13.2 from intermediate 18.3. (mixture of diastereoisomers) Rf 0.50 & 0.45 (EtOAc/hexanes 1/1); MS (m/z) 446 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[C:26]([O:33][CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12].[Li+].[OH-].O>CO.C(OCC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([O:33][CH2:34][CH2:35][O:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1OCCOc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1OCCOc1ccccc1
Yield: 73.2 %

Procedure:
The title compound 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(2-phenoxyethoxy)picolinic acid (27) was prepared by the following procedure: A mixture of methyl 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(2-phenoxyethoxy)picolinate (27D) (114 mg, 0.20 mmol) and LiOH (18 mg, 0.75 mmol) was stirred in MeOH (3 mL) and water (1 mL) for 20 hours. The mixture was diluted with diethyl ether (2 mL) and the aqueous layer was separated and acidified with 1M HCl. The precipitate was filtered, washed with EtOAc, and dried to provide 83 mg (75%) of the desired product 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(2-phenoxyethoxy)picolinic acid (27): 1H NMR (300 MHz, DMSO-d6) δ 7.98 (1H, d), 7.77 (2H, d), 7.65 (1H, m), 7.38-7.18 (6H, m), 6.99-6.91 (4H, m), 4.46 (2H, m), 4.31 (2H, m), 3.93 (2H, m), 2.79 (2H, m), 1.90 (2H, m). LC/MS (APCI): m/z 567.2 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH3:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>>[Cl-:1].[CH3:8][N+:9]1[CH:13]=[CH:12][N:11]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[CH:10]=1
Reactant: C=CCCCCCl
Reactant: Cn1ccnc1
Product: C=CCCCCn1cc[n+](C)c1
Product: [Cl-]
Reaction time: 4 h

Procedure:
The procedure of Example 1 was repeated with minor changes. 51.0 g of 6-chloro-1-hexene (Aldrich) and 35.3 g of 1-methylimidazole (Aldrich) were added into a 2000 ml three-neck round-bottom flask. The reaction temperature was set from 75 to 80° C. After four hours the milk-like solution transferred into a homogenous solution. The reaction was continued for three days. Then, the product was washed with ethyl acetate five times. After that, it was dried under vacuum for three days.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[ClH:28].[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(NCc3cccc(Cl)c3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Clc1cccc(CNc2ccnc(N3CCNCC3)n2)c1

Procedure:
The title compound (4-A) was prepared from 4-[4-(3-chloro-benzylamino)-pyrimidin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (I-4a) and TFA according to a procedure analogous to that described in Example 3.
Reaction SMILES: OO.Cl[C:4]1C(C(SC2C=NC(Cl)=CC=2)C2C=CN=CC=2)=NC(Cl)=CC=1.C(OCC)(=O)C.[Si:32]([O:39][CH2:40][CH2:41][CH:42](C)[CH:43]([C:54]1[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:55]=1[F:61])[S:44]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)(=[O:46])=[O:45])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CO.CCCCCC>[Si:32]([O:39][CH:40]([CH3:4])[CH2:41][CH2:42][CH:43]([C:54]1[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:55]=1[F:61])[S:44]([C:47]1[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=1)(=[O:46])=[O:45])([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34]
Reactant: Clc1ccc(SC(c2ccncc2)c2nc(Cl)ccc2Cl)cn1
Reactant: CC(CCO[Si](C)(C)C(C)(C)C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: OO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
A 31% aqueous hydrogen peroxide solution (2 ml) and hexaammonium heptamolybdate tetrahydrate (30 mg) were added to a solution of 3,6-dichloro-2-[(6-chloropyridin-3-ylthio) (pyridin-4-yl)methyl]pyridine (82 mg, 0.24 mmol) in methanol (4 ml). The resulting mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture. After washing with a saturated aqueous solution of sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column. A fraction obtained from the elution portion with hexane:ethyl acetate=3:2 was concentrated under reduced pressure, whereby the title compound A (41 mg, 0.098 mmol, 46%) was obtained. A fraction obtained from the elution portion with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, whereby the title compound B (isomer A) (low polarity) (8 mg, 0.020 mmol, 9%) and the title compound B (isomer B) (high polarity) (8 mg, 0.020 mmol, 9%) were obtained, respectively each as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2].[CH3:20][C:21]([O:24][C:25]([NH:27][C@H:28]([CH2:32][CH3:33])[C:29](O)=[O:30])=[O:26])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:29]([C@H:28]([NH:27][C:25](=[O:26])[O:24][C:21]([CH3:23])([CH3:22])[CH3:20])[CH2:32][CH3:33])=[O:30])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCc1noc2cccc(Oc3ccc(N)cn3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1noc2cccc(Oc3ccc(NC(=O)[C@@H](CC)NC(=O)OC(C)(C)C)cn3)c12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6-[(3-ethyl-1,2-benzisoxazol-4-yl)oxy]-3-pyridinamine (Intermediate 33) was dissolved in DMF (0.5 mL) and added to a mixture of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (7.7 mg, 0.038 mmol), DIPEA (0.008 mL, 0.047 mmol) and HATU (14.4 mg, 0.038 mmol) in 1 ml of DMF. The reaction mixture was then stirred at 50° C. for 2 hours. After the removal of DMF, water was added and the mixture was extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated. The residue was then charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/EtOAc (from all 10/0 to 7/3, then 7/3) to afford the title compound (4.4 mg).