Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[CH2:3]([Sn+:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].[C:16]([O:20]CCO)(=[O:19])[CH:17]=[CH2:18]>>[CH2:1]([O:2][C:17](=[CH2:18])[C:16]([O-:20])=[O:19])[CH3:3].[CH2:12]([Sn+:7]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][CH3:15]
Reactant: C=CC(=O)OCCO
Reactant: C[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Product: C=C(OCC)C(=O)[O-]

Procedure:
Tributyltin methoxide (5 g; 0.0155M) and 2-hydroxyethyl acrylate (1.8 g; 0.0155M) were mixed together in a round bottom flask which was then put on a rotary evaporator for 0.5 hr to strip off the methanol produced. 6.5 g (100% of theory) of the title compound was obtained. The product was subjected to infrared and NMR spectral analysis and the results are summarised in Table S1 below. In the NMR spectrum a small peak at δ=3.8 was observed which was assigned to residual unreacted tributyltin methoxide.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C@@H:7]([C:22](=[O:32])[NH:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:6]1)=[O:4].O.[OH-].[Li+]>CO.O>[CH2:25]([O:24][NH:23][C:22]([C@H:7]1[CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][N:8]1[S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)(=[O:13])=[O:12])=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CC[C@@H](C(=O)O)C[C@@H]2C(=O)NOCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred cold (0° C.) solution of (2R,4R)-2-benzyloxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (4.0 g, 8.6 mmol) in 10 mL of 9:1 methanol/water was added lithium hydroxide monohydrate (1.8 g, 43 mmol). The mixture was stirred for 2 hours before Amberlite IR-120 resin (96 g) was added. After 15 minutes, the mixture was filtered and the filtrate was concentrated to give (2R,4R)-2-benzyloxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid, which was used in the subsequent reaction without purification.
Reaction SMILES: [O:1]1C(C)(C)[CH:2]1[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1.Cl(O)(=O)(=O)=O.[Cl-].[Na+].I([O-])(=O)(=O)=O.[Na+]>O.O1CCCC1>[O:1]=[CH:2][CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: CC(=CCOc1ccc2c(c1)OCC2)CCC1OC1(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CC(=CCOc1ccc2c(c1)OCC2)CCC=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.64 g. of 6-[(6,7-epoxy-3,7-dimethyl-2,6-nonadienyl)-oxy]-2,3-dihydrobenzofuran (see Example 3) are dissolved in 14 ml. of tetrahydrofuran, diluted with 7.5 ml. of water and treated with a mixture of 0.1 ml. of 70% by weight perchloric acid in 1 ml. of water. The mixture is stirred at room temperature for 4 hours, 10 ml. of saturated aqueous sodium chloride solution are added thereto and the resulting mixture is extracted three times with diethyl ether methylene chloride (9:1 parts by volume). The extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The thus-obtained crude diol is dissolved in 30 ml. of tetrahydrofuran and treated, with ice cooling and under a nitrogen atmosphere, with a solution of 3.2 g. of sodium metaperiodate in 35 ml. of water following which the mixture is stirred overnight at room temperature. For working up, 100 ml. of water are added to the mixture which is then extracted three times with diethyl ether. The extracts are washed with 10% by weight aqueous potassium bicarbonate solution and with semi-saturated and saturated sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (19:1 parts by volume) there is obtained pure 6-[(6-oxo-3-methyl-2-hexenyl)-oxy]-2,3-dihydrobenzofuran which is distilled in a bulb-tube at 100° C./0.02 mmHg.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:42]=[CH:41][C:31]([O:32][C:33]([CH3:40])([CH3:39])[C:34](OCC)=[O:35])=[CH:30][CH:29]=3)[C:24]([CH2:43][CH3:44])=[N:23][C:22]=2[CH2:45][CH2:46][CH3:47])=[CH:16][CH:15]=1)#[N:7]>C(O)C.O1CCCC1.C(OCC)(=O)C.Cl>[CH2:43]([C:24]1[N:25]([C:28]2[CH:29]=[CH:30][C:31]([O:32][C:33]([CH3:40])([CH3:39])[CH2:34][OH:35])=[CH:41][CH:42]=2)[C:26](=[O:27])[C:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[C:8]([C:6]#[N:7])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:19][CH:18]=2)=[C:22]([CH2:45][CH2:46][CH3:47])[N:23]=1)[CH3:44]
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C(=O)OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
To a solution of sodium borohydride (0.84 g) in ethanol (20 mL)-tetrahydrofuran (20 mL) was added calcium chloride (1.2 g) under ice-cooling, and the mixture was stirred for 15 min. A solution of ethyl 2-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate (1.6 g) in tetrahydrofuran (20 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added in the reaction mixture, and the mixture was stirred for 15 min, and diluted with ethyl acetate and 1 M hydrochloric acid. The organic layer was separated, washed with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a colorless solid (1.0 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([OH:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=3)[N:10](C(OC(C)(C)C)=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:24])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(C(O)c3ccccc3)ccc21
Agent: Cl
Product: O=C(c1ccccc1)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Yield: 17.6 %

Procedure:
A total of 30 mg of tert-butyl 3-(3-fluorophenyl)-5-[hydroxy(phenyl)methyl]-1H-1-indazolecarboxylate as a starting material was oxidized by the procedure of Production Example I-4-c, was treated with 5 N hydrochloric acid by the procedure of Production Example I-25-b, to give 4 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:34][CH2:33]1>C(Cl)Cl>[OH:19][C:20]1[C:21](=[O:22])[C:13]2[CH:8]3[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]3)[CH2:6][CH:5]([O:4][C:2](=[O:3])[CH3:1])[C:14]=2[C:15]2([CH3:30])[C:16]=1[C:17](=[CH:18][N:44]1[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][N:35]3[CH2:34][CH2:33][O:32][CH2:37][CH2:36]3)[CH2:46][CH2:45]1)[C:23](=[O:24])[O:25][CH:26]2[CH2:27][O:28][CH3:29]
Reactant: C(CN1CCNCC1)CN1CCOCC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCN(CCCN3CCOCC3)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 1-(3-morpholinopropyl)piperazine (99 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 645 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:24][CH3:25])[C:11]=1[CH:12]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:13]([O:15]CC)=[O:14])[N:8]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:7]=[C:6]([C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][C:36]=1[CH3:46])=[O:32])[C:5]2=[O:47].[Li+].[OH-].Cl>O1CCOCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:24][CH3:25])[C:11]=1[CH:12]([CH:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1)[C:13]([OH:15])=[O:14])[N:8]([CH2:26][C:27]([F:30])([F:28])[F:29])[CH:7]=[C:6]([C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:43])([F:44])[F:45])=[CH:37][C:36]=1[CH3:46])=[O:32])[C:5]2=[O:47]
Reactant: CCOC(=O)C(c1c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c2c1OC)C1CCNCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C(C(=O)O)C2CCNCC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Yield: 98.9 %

Procedure:
60 mg (0.089 mmol) of the compound of Example 5 are stirred in 2.2 ml of dioxane and 444 μl of LiOH 1M (5 eq.) in water at RT overnight. The mixture is acidified with 1N HCl and diluted with ethyl acetate. It is extracted by shaking twice with water and once with a saturated NaCl solution. The organic phase is dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue is dried under HV. 57 mg of the title compound (94% of theory) are obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:20]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][OH:11])=[C:8]([Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccccc1Cl
Temperature: 45 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (Example 3(i) Method A) (10.2 g. 0.0368 mol) in tetrahydrofuran (100 ml) was treated portionwise with N-chlorosuccinimide (NCS) (4.92 g, 0.0368 mol) and stirred at 45° C. for a total of 3 hours after the addition of the NCS. The tetrahydrofuran was evaporated and the residue was partitioned between water and ethyl acetate. The organic extracts were washed with water, dried and concentrated to the residual product that crystallized when stirred with ether to yield 5.1 g (44%) of 2-n-butyl 4-chloro 1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp 134°-135° C. (from acetonitrile).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CS(O[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)(=O)=O>C(O)C.C(OCC)(=O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2
Reactant: NCCO
Reactant: CS(=O)(=O)OCCc1cccc2cc[nH]c12
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCNCCc1cccc2cc[nH]c12
Yield: 84.6 %

Procedure:
Add ethanolamine (5 mL, 82 mmol) to a solution of 7-(2-(methanesulfonyloxy)eth-1-yl)indole (0.79 g, 3.3 mmol) in ethanol (50 mL) and stir the reaction mixture at reflux overnight. Dilute with ethyl acetate (150 mL), wash sequentially with water (3×50 mL) and saturated aqueous sodium chloride (2×50 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure to provide 7-(2-(N-[2-hydroxyeth-1-yl]amino)eth-1-yl)indole as a light-brown solid (0.57 g, 85%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30]Cl)=[CH:27][C:21]=3[CH2:20][S:19](=[O:34])(=[O:33])[C:18]=2[CH:35]=1)=[O:13]>CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30][N:4]4[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:33])(=[O:34])[C:18]=2[CH:35]=1)=[O:13]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: OCCN1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCN(CCO)CC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 6 h

Procedure:
2-Piperazin-1-yl-ethanol (0.227 g, 1.74 mmol) was added with stirring to a solution of Example 56k (0.5 g, 1.16 mmol) in DMF (10 mL) in an atmosphere of nitrogen. The reaction mixture was stirred at 110° C. for 6 h, concentrated, treated with chilled water and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as an off-white solid. Yield: 0.521 g, (85.69%); 1H NMR (DMSO-d6): δ 2.50 (s, 3H, CH3), 3.10 (t, 4H, 2CH2), 3.70 (t, 10H, 5CH2), 3.90 (s, 3H, OCH3), 4.40 (s, 2H, CH2), 5.20 (s, 2H, CH2), 6.10 (s, 1H, Ar), 6.80-6.85 (m, 2H, Ar), 8.10 (m, 2H, Ar); MS: m/e (ES+) 551 (M+).
Reaction SMILES: [CH3:1]O.CO.C[O-].[Na+].[OH:8][C@H:9]([C@H:24]1[CH2:28][O:27]C(=O)[O:25]1)[C@H:10]1[C@H:15]2[N:16]=[C:17]([CH3:19])[O:18][C@@H:14]2[CH:13]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[O:11]1>C1(C)C=CC=CC=1>[OH:25][C@H:24]([CH2:28][OH:27])[C@H:9]([C@H:10]1[C@H:15]2[N:16]=[C:17]([CH3:19])[O:18][C@@H:14]2[CH:13]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[O:11]1)[O:8][CH3:1]
Reactant: COC(=O)C1=C[C@H]2OC(C)=N[C@@H]2[C@H]([C@H](O)[C@H]2COC(=O)O2)O1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1=C[C@H]2OC(C)=N[C@@H]2[C@H]([C@H](OC)[C@H](O)CO)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanol (460 ml) and a 25.4% sodium methoxide methanol solution (14.36 g) were added to a toluene solution (approximately 675 ml) of a compound, which was obtained by subjecting methyl(3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate (46.00 g) to Step A-5 of Example 1, at room temperature, and the mixture was stirred for 30 minutes at the same temperature. The solvent of the reaction solution was distilled off under reduced pressure until the amount of solution became approximately 138 ml, methanol (460 ml) was added, and the reaction solution was stirred for 30 minutes at room temperature. After acetic acid (4.41 g) was added to the reaction solution and the solvent was distilled off under reduced pressure until the amount of solution became approximately 138 ml, toluene (230 ml) was added to the reaction solution and then the solvent was distilled off again under reduced pressure until the amount of solution became 138 ml to give a toluene suspension of the title compound.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C(Cl)Cl>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([S:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:4][OH:3])[CH2:11][CH2:10]2)(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of the above ester (1.29 g, 4.79 mmol) in CH2Cl2 (20 mL) at 0° C. was added a solution of LiAlH4 in THF (1.0 M, 13.9 mL, 13.87 mmol) and the mixture was heated to reflux. After 1 h, the mixture was cooled back down to 0° C. and quenched with H2O (0.51 mL), 15% NaOH (0.51 mL), and H2O (1.53 mL). After stirring for 30 min, the reaction mixture was dried (MgSO4), filtered, and concentrated to afford [1-(toluene-4-sulfonyl)-piperidin-4-yl]-methanol as a clear oil (1.24 g, 100%). 1H NMR (CDCl3) δ 1.31-1.43 (m, 4H), 1.79 (d, 2H, J=12.0 Hz), 2.24 (t, 2H, J=12.0 Hz), 2.43 (s, 3H), 3.47 (d, 2H, J=6.0 Hz), 3.81 (d, 2H, J=12.0 Hz), 7.32 (d, 2H, J=6.0 Hz), 7.64 (d, 2H, J=6.0 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1>O1CCCC1>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: COCCOC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: COCCOC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
In a 10 L round-bottomed flask 8-{[2-(methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane D60 (151 g, 700 mmol) was dissolved in tetrahydrofuran (THF) (3000 mL) to give a colourless solution. 3M hydrochloric acid (2333 mL, 7000 mmol) was added. Reaction was allowed to stir at room temperature overnight. The organic solvent was partially evaporated under vacuum and then the aqueous layer was back extracted with DCM (3×500 mL). The organic phase was dried over Na2SO4, filtered and concentrated to obtain 121 g of crude material as yellow oil. The crude product was purified by Biotage® 75 L SiO2 column eluting with c-hex/EtOAc 8/2 to get title material (76 g; 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[C:35](B(O)O)[C:36]2[C:37]([N:42]=1)=[N:38][CH:39]=[CH:40][N:41]=2.C(=O)([O-])O.[Na+]>CN(C=O)C.O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:35]4[C:36]5[C:37](=[N:38][CH:39]=[CH:40][N:41]=5)[N:42]=[C:33]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[F:26])[CH:34]=4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cncc(Br)c3)cn2)CC1
Reactant: OB(O)c1cc(-c2ccccc2F)nc2nccnc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cncc(-c4cc(-c5ccccc5F)nc5nccnc45)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A suspension of 296 mg (0.73 mmol) 4-[4-(5-bromo-pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl-ester, 215 mg (0.80 mmol) [6-(2-fluorophenyl)pyrido[2,3-b]pyrazin-8-yl]-boronic acid and 10 mg (0.015 mmol) bis-(triphenylphosphine)-palladium(II)-chloride in 1.5 ml DMF water was heated to 80° C. under nitrogen. Then a solution of 73 mg (0.87 mmol) sodium hydrogen carbonate in 0.75 ml water was added. The reaction mixture was stirred for 20 hours at 80° C. The reaction mixture was cooled to room temperature. Water was added, the resulting precipitate was filtered off, washed with water and dried under vacuum. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 4-(4-{5-[6-(2-fluoro-phenyl)-pyrido[2,3-b]pyrazin-8-yl]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as off-white solid crystals; HPLC-MS (A): 2.37 min, [M+H] 552.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:22])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.1 %

Procedure:
3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid (0.20 g, 0.64 mmol) as dissolved in N,N-dimethylformamide (3 ml), and glycine tert-butyl ester (0.11 g, 0.67 mmol), WSC (0.25 g, 1.3 mmol) and HOBt (0.18 g, 1.3 mmol) were added successively thereto. The reaction mixture was stirred at room temperature for 17 hrs, concentrated under reduced pressure and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (15 g) column chromatography. The fractions eluted with hexane-ethylacetate (1:1, v/v) were collected and concentrated to give the titled compound (0.27 g, 99%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH2:32][CH2:33][CH:34]([F:36])[F:35])([CH2:27][CH2:28][CH:29]([F:31])[F:30])[C:24]([OH:26])=O)[CH:8]=2)[N:3]=1.[CH2:37]([NH2:39])[CH3:38]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH2:27][CH2:28][CH:29]([F:31])[F:30])([CH2:32][CH2:33][CH:34]([F:35])[F:36])[C:24]([NH:39][CH2:37][CH3:38])=[O:26])[CH:8]=2)[N:3]=1
Reactant: CCN
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C(CCC(F)F)(CCC(F)F)C(=O)O)ccc2n1
Product: CCNC(=O)C(CCC(F)F)(CCC(F)F)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1

Procedure:
(Preparation by reaction of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoic acid [“A66”] with ethylamine);
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.C(N(CC)CC)C.[CH2:20]([NH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:21]>C(O)C>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH3:26])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCCCNCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCN(CC)c1nc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
Part A. A solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (prepared using the methods of Albert, et al., J. Chem. Soc. 1954, p. 3832) (2.77 g, 13.3 mmol) in absolute ethanol (25 mL) was cooled to 0° C., and treated with triethylamine (2.00 mL, 14.3 mmol). Then, a solution of ethylbutylamine (1.80 mL, 13.2 mmol) in ethanol (3 mL) was added dropwise with stirring. The mixture was allowed to stir and warm to ambient temperature overnight, then was partitioned between water and ethyl acetate (100 mL each). The organic phase was seperated, washed with satd. aq. brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, dichloromethane) to afford 4-chloro-6-(ethylbutylamino)-2-methyl-5-nitropyrimidine as an oil (3.34 g, 12.2 mmol, 92%). Spectral data: TLC RF 0. 59 (dichloromethane). 1H NMR (300 MHz, CDCl3): δ 3.45 (2H, q, J=7.0 Hz), 3.38 (2H, t, J=7.7 Hz), 2.50 (3H, s), 1.62-1.52 (2H, m), 1.38-1.26 (2H, m), 1.20 (3H, t, J=7.0 Hz), 0.94 (3H, t, J=7.3 Hz). MS (NH3—CI): m/e 276 (4), 275 (40), 274 (16), 273 (100).