Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[OH:16].[OH-].[K+]>O>[C:1]([C:5]1[S:9][C:8]2[NH:10][C:14](=[O:16])[O:13][C:11](=[O:12])[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C(C)(C)C)sc1N
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc2c(=O)oc(=O)[nH]c2s1
Temperature: 80 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To a vial containing methyl 5-tert-butyl-2-aminothiophene-3-carboxylate (0.643 g) in 1:1 methanol: H2O (6 mL) was added KOH (0.5069 g). The vial was capped and the mixture was stirred at 80° C. for 6 h. The solvent was removed under vacuum and the crude product was dissolved in water (50 mL) and transferred to a 100 mL round bottom flask. To the vigorously stirred aqueous solution was added at room temperature drop wise phosgene (2M toluene, 6 mL) over a 15 minute period. The resulting mixture was stirred at room temperature overnight. The crude reaction mixture was filtered; the precipitate was washed with water, dried and dissolved in ethyl acetate (10 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum to give 654.9 mg (96%) of the expected 6-tert-butyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.Cl.[F:37][C:38]1([F:43])[CH2:42][CH2:41][NH:40][CH2:39]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:37][C:38]1([F:43])[CH2:42][CH2:41][N:40]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH2:39]1
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: FC1(F)CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CCC(F)(F)C3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
A suspension of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (204 mg, 0.4 mmol), 3,3-difluoropyrrolidine hydrochloride (71.8 mg, 0.5 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), Xantphos (23.1 mg, 0.04 mmol), and NaOtBu (96.1 mg, 1.0 mmol) in 1,4-dioxane (2 mL) was stirred for 3 h at 90° C. under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography followed by purification by preparative HPLC. Recrystallization from MeOH/H2O gave the title compound (21.0 mg, 11% yield) as a yellow solid: mp 195-197° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.46-2.60 (2H, m), 3.52 (2H, t, J=7.2 Hz), 3.66 (2H, t, J=12.8 Hz), 3.89 (3H, s), 6.09 (1H, dd, J=2.6, 9.0 Hz), 6.23 (1H, dd, J=2.6, 13.9 Hz), 6.33 (1H, t, J=9.0 Hz), 7.25 (1H, J=1.9 Hz), 7.33-7.44 (5H, m), 7.71 (1H, d, J=2.3 Hz), 7.77 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 468 [M+H]+. Anal. Calcd for C24H20F3N5O2: C, 61.67; H, 4.31; N, 14.98. Found: C, 61.51; H, 4.38; N, 14.89.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][CH:13]([C:17]#[C:18][CH3:19])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]([OH:42])([CH3:41])[C:37]([F:40])([F:39])[F:38])=[CH:32][N:31]=1>CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:30]3[N:31]=[CH:32][C:33]([C:36]([OH:42])([CH3:41])[C:37]([F:38])([F:39])[F:40])=[CH:34][N:35]=3)[CH:13]([C:17]#[C:18][CH3:19])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1
Reactant: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 140 °C
Yield: 48.1 %

Procedure:
To a 20 mL vial was added 1-((6-chloro-3-pyridinyl)sulfonyl)-3-(1-propyn-1-yl)piperazine (1.70 g, 7.47 mmol, Example 240, Step 4), diisopropylethylamine (4.20 mL, 24.2 mmol), and NMP (8.0 mL), and 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (1.4 g, 6.37 mmol, Intermediate E). The vial was sealed and heated at 140° C. for 9 h. The reaction mixture was cooled to rt and partitioned between EtOAc (200 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (2×75 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (120 g of silica, 10 to 50% EtOAc in hexanes) to afford 2-(2-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (1.5 g) as a light yellow solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:12]([O:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=2)(=[O:24])=[O:23])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:41](N(CCCC)CCCC)[CH2:42]CC.C(O)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[CH2:41]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([S:22]([O:21][C:12]2[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][C:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:23])=[O:24])=[CH:26][C:27]=1[OH:34])[CH3:42]
Reactant: CCCCN(CCCC)CCCC
Reactant: O=C(c1ccccc1)c1cc(-c2ccccc2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2ccccc2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S(=O)(=O)Oc2c(-c3ccccc3)cc(C(=O)c3ccccc3)cc2-c2ccccc2)cc1O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A stirred solution containing 4-(5'-benzoyl-[1,1';3',1"]terphenyl-2'-yloxysulfonyl)-2-hydroxy-benzoic acid (0.106 g, 0.192 mmol), tributylamine (0.110 mL, 0.462 mmol), ethanol (0.0677 mL, 1.15 mmol) and 2-chloro-1-methyl pyridinium iodide (0.0607 g, 0.231 mmol) in CH2Cl2 (2 mL) was refluxed for 18 h. The reaction was cooled to ambient temperature, quenched with 1N HCl (20 mL) and extracted with EtOAc. The organic extracts were successively washed with 1N HCl (3×), with brine (3×), dried (MgSO4) and concentrated. Purification on Biotage KP-Sil eluting with 20% acetone/hexane gave 0.039g (35%) of the title compound as a white solid, mp 75-85° C. 1H NMR (DMSO-d6) δ 1.36 (t, 3H), 4.38 (q, 2H), 6.67 (d, 1H), 6.73 (dd, 1H), 7.30-7.36 (m, 6H), 7.45-7.52 (m, 5H), 7.57-7.61 (m, 2H), 7.68-7.71 (m, 3H), 7.84 (d, 2H), 10.60 (s, 1H). mass spectrum (El) m/z 578 (M+). Anal. Calcd. for C34H26O7S 0.5H2O: C,69.49; H,4.63; N,0.00. Found: C,69.38; H,4.76; N,0.10.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH2:24][OH:25])=[C:11]([I:26])[C:10]1=2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:25][CH2:24][C:12]1[C:13]([CH:21]([CH3:23])[CH3:22])=[N:14][C:15]2[CH2:16][C:17]([CH3:19])([CH3:20])[CH2:18][C@H:9]([OH:8])[C:10]=2[C:11]=1[I:26]
Reactant: CC(C)c1nc2c(c(I)c1CO)C(O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(I)c1CO)[C@@H](O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.67 g (S)-(5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-ylmethanol in 50 ml tetrahydrofurane are added 6.8 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofurane. The solution is stirred for 2 hours at room temperature, then the solvent is evaporated in vacuo and the residue is redissolved in dichloromethane. After washing successively with water, saturated aqueous sodium bicarbonate and brine the organic phase is dried with sodium sulphate. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 3:1).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[N:12]=[C:13]([CH3:15])[CH:14]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]1([NH:7][C:8]([C:10]2[N:11]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH:23]4[CH2:24][CH2:25][N:26]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH2:27][CH2:28]4)=[CH:20][CH:21]=3)[N:12]=[C:13]([CH3:15])[CH:14]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCC1
Reactant: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(OC3CCNCC3)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)n1
Reaction time: 1 h
Yield: 3.4 %

Procedure:
To a solution of 5-methyl-2-[4-(piperidin-4-yloxy)phenyl]-2H-pyrazole-3-carboxylic acid cyclohexylamide (60 mg, 0.157 mmol) in methylene chloride (9 mL) was added cyclopentanone (21 μL, 0.24 mmol) and acetic acid (150 μL). After 1 hour at room temperature, sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and the reaction was allowed to stir for an additional 4 hours. The reaction was quenched with 10% NaOH and extracted with methylene chloride. The methylene chloride solution was dried (MgSO4) and concentrated. The residue was purified by semi-prep LC-MS to give 2.4 mg of the desired product. LC-MS (C27H38N4O2 calculated 450) m/z 451 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.34-7.31 (m, 2H), 7.01-6.98 (m, 2H), 6.78 (d, J=8.4 Hz, 1H), 6.70 (s, 1H), 4.42 (m, 1H), 3.95-3.93 (m, 1H), 2.87-2.83 (m, 2H), 2.68-2.54 (m, 3H), 2.23 (s, 3H), 2.15-1.14 (m, 22H).
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]([C:21]([F:24])([F:23])[F:22])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>O1CCOCC1.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=[O:29])[CH:16]([C:21]([F:24])([F:22])[F:23])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(C(F)(F)F)C1
Reactant: O=Cc1ccccc1F
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C(C(F)(F)F)C1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
tBuOK (136 mg; 1.21 mmol; 1.5 eq.) was added to a solution of 4-hydroxy-3-trifluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (239 mg; 0.89 mmol; 1.1 eq.) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 50° C. for 15 minutes. After cooling down to room temperature, 2-fluoro-benzaldehyde (100 mg; 0.81 mmol; 1 eq.) was added and the reaction was stirred at 50° C. for 30 minutes. The solution was diluted with water and extracted with EA (3×). The combined organics were dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (10% to 30% EA in heptane) afforded the title compound (181 mg, 60%) as colourless oil. HPLC (max plot) 99.9%, Rt 5.02 min. UPLC/MS: (MS+) 274.2 ([M-(Boc)+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:28])=[C:11]([C:13]3[C:14](=[O:27])/[C:15](=[CH:20]/[CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)/[CH2:16][C:17]=3[O:18]C)[N:12]=2)=[CH:4][CH:3]=1.Cl>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:28])=[C:11]([CH:13]3[C:14](=[O:27])/[C:15](=[CH:20]/[CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)/[CH2:16][C:17]3=[O:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)/C(=C/C2CCOCC2)C1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C/C(=C\C2CCOCC2)C1=O
Temperature: 120 °C
Yield: 92.9 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-3-methoxy-5-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopent-2-enone (190 mg, 0.45 mmol) in acetone (2 ml) was added 2N hydrochloric acid (2 ml) and the reaction heated to 120° C. for 30 minutes by microwave irradiation. The crude reaction was diluted with ethyl acetate (25 ml) and washed with saturated aqueous ammonium chloride solution (25 ml), brine (25 ml) and the organic later separated, dried over magnesium sulphate and the solvent removed under reduced pressure to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (168 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([B:8]([OH:10])[OH:9])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=2)[N:3]=1.[CH2:26]([CH:34]([CH2:37]O)[CH2:35]O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[C:7]([B:8]2[O:9][CH2:35][CH:34]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:37][O:10]2)=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=2)[N:3]=1
Reactant: CCCCCCCCC(CO)CO
Reactant: CCCCCCCCOc1ccc(-c2ccc(B(O)O)c(F)n2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(B3OCC(CCCCCCCC)CO3)c(F)n2)cc1
Yield: 83.1 %

Procedure:
1.00 g (3.00 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyridine-3-boronic acid (prepared as described in Example 10), 0.56 g (3.00 mmol) of 2-octylpropane-1,3-diol and 1.50 g of sodium sulfate in 30 ml of tetrahydrofuran are stirred at room temperature for 48 hours. Sodium sulfate is then filtered off, the filtrate is concentrated, and the residue is recrystallized from hexane, giving 1.24 g of 2-fluoro-3-(5-octyl-1,3-dioxaborinan-2-yl)-6-(4-octyloxyphenyl)pyridine. ##STR61##
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:12](O)[CH2:13][OH:14].CCCCCC>C1COCC1>[B:9]([O:11][CH2:12][CH2:13][OH:14])([OH:10])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: OCCO
Reactant: N#Cc1cccc(B(O)O)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(B(O)OCCO)c1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
3-Cyanophenyl boronic acid (1 g, 6.8 mmol) was dissolved in dry THF (10 mL) under nitrogen. Ethylene glycol (379 μL, 422 mg, 6.8 mmol) was added and the reaction was heated to reflux for 4 hours then cooled to room temperature. THF was removed by rotary evaporator to give a white solid. Cold hexane was added and the product was collected by filtration giving a white solid (1.18 g, quant. yield). 1H-NMR (300.058 MHz, DMSO-d6) δ ppm 7.92-8.01 (3H, m), 7.50-7.64 (1H, m), 4.35 (4H, s)
Reaction SMILES: [Cl:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=1.[OH-].[Na+].[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29]Br)([CH3:24])([CH3:23])[CH3:22]>C(#N)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:21]([O:25][C:26]([NH:27][CH2:28][CH2:29][N:6]1[C:2]([Cl:1])=[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5]1)=[O:31])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1c[nH]c(Cl)c1-c1cccc(C#N)c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cn(CCNC(=O)OC(C)(C)C)c(Cl)c1-c1cccc(C#N)c1
Yield: 92.9 %

Procedure:
To a solution of 9.38 g (36.0 mmol) of methyl 5-chloro-4-(3-cyano-phenyl)-1H-pyrrole-3-carboxylate in 60 ml of acetonitrile are added 2.88 g (72.0 mmol) of powdered sodium hydroxide and 0.49 g (1.4 mmol) of tetrabutylammonium hydrogen sulfate, and the mixture is stirred vigorously for a few minutes, followed by adding 9.68 g (43.2 mmol) of tert-butyl(2-bromoethyl)carbamate (CAS 39684-80-5), and the mixture is then stirred for 6 hours at reflux. After cooling, the mixture is taken up in 250 ml of water and the product is extracted with ethyl acetate. The organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give an orange-coloured oil, which is purified by chromatography on a column of 150 g of silica gel, eluting with a mixture of 2% methanol in dichloromethane, to give 13.5 g of methyl 1-(2-tert-butyloxycarbonylaminoethyl)-5-chloro-4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in the form of a yellow oil.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[C:8]([CH:13]([NH:30][C:31]([CH:33]2[CH2:36][CH2:35][CH2:34]2)=O)[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][N:12]=1>>[Cl:6][C:7]1[C:8]2[N:9]([CH:31]([CH:33]3[CH2:36][CH2:35][CH2:34]3)[NH:30][C:13]=2[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: ClC1=NC=CN2C1=C(c1ccc3ccc(-c4ccccc4)nc3c1)NC2C1CCC1
Temperature: 70 °C

Procedure:
A mixture of POCl3 (5 mL, 8 g, 55 mmol) and cyclobutanecarboxylic acid [(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)methyl]-amide [275 mg, 0.583 mmol] is heated to 70° C. for 21.5 h. POCl3 is evaporated, a cold solution of NH3 in zPrOH (2M, 11 mL, 22 mmol) is added, the suspension is sonicated, the solid is filtered off and washed with iPrOH. The solid is suspended in CHCl3 and filtered, and the filtrate is concentrated to obtain the title compound as yellow solid. 1H NMR (CDCl3, 400 MHz) δ 2.04-2.15 (m, 1H), 2.15-2.28 (m, 1H), 2.50-2.60 (m, 2H), 2.64-2.76 (m, 2H), 3.89 (quint, J=8.4 Hz, 1H), 7.35 (d, J=4.8 Hz, 1H), 7.1447.50 (m, 1H), 7.51-7.57 (m, 3H), 7.89-7.93 (m, 3H), 8.17-8.22 (m, 2H), 8.27 (dd, J=0.8, 8.8 Hz, 1H), 8.53 (d, J=0.8 Hz, 1H). MS (ES+): m/z 410.9/412.9 (100/39) [MH+]. HPLC: tR=3.7 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [I-].C[S+](C)C.[Li][CH2:7]CCC.[C:11]([Si:15]([O:18][CH2:19][C@@H:20]1[C@H:24]2[O:25][C:26]([CH3:29])([CH3:28])[O:27][C@H:23]2[C@@H:22]2[O:30][C@H:21]12)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Si:15]([O:18][CH2:19][C@@H:20]1[C@H:24]2[O:25][C:26]([CH3:29])([CH3:28])[O:27][C@H:23]2[C@H:22]([OH:30])[C:21]1=[CH2:7])([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:17])[CH3:16]
Reactant: CC1(C)O[C@H]2[C@@H]3O[C@@H]3[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2O1
Reactant: [Li]CCCC
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Product: C=C1[C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a −10° C. suspension of trimethylsulfonium iodide (30 g, 149.5 mmol) in THF (150 mL) was added n-BuLi 2.5 M hexane solution (46.0 mL, 83.0 mmol). After 30 min, epoxide (10) (5.0 g, 16.6 mmol) in THF (20 mL) was introduced and the reaction slowly allowed to warm to 0° C. over 1 h; the mixture was then stirred at ambient temperature for 2 hr. The reaction was quenched with water and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residues were purified on silica gel column chromatography (10% EtOAc/Hexane) to give allylic alcohol 11 (4 g, 80%) as an oil. [α]22D −20.35° (c 2.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.31 (s, 1H), 5.11 (s, 1H), 4.52 (d, J=6 Hz, 1H), 4.32-4.31 (m, 1H), 4.13-4.11 (m, 1H), 3.81-3.79 (m, 2H), 3.62-3.60 (m, 1H), 3.91-3.90 (m, 1H,), 2.62 (br, 1H), 1.30 (s, 3H), 1.20 (s, 3H), 0.80 (m, 9H), 0.013-0.006 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 157.9, 115.9, 92.6, 88.8, 84.1, 72.4, 59.0, 32.6, 31.5, 30.4, 24.0, 0.05; HR-MS Calcd. For (C16H30O4Si+H)+ 315.1913, found 315.1892.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]([N:5]([CH2:23][CH:24]1[CH2:28][O:27][C:26](=[O:29])[O:25]1)[C:6]1[C:11](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=[C:8]([O:21][CH3:22])[N:7]=1)=[O:4].[H][H]>C(O)C.[Pd]>[CH3:30][C:2]([CH3:1])([CH3:31])[C:3]([N:5]([CH2:23][CH:24]1[CH2:28][O:27][C:26](=[O:29])[O:25]1)[C:6]1[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=[C:8]([O:21][CH3:22])[N:7]=1)=[O:4]
Reactant: [H][H]
Reactant: CCCCOC(=O)/C=C/c1ccc(OC)nc1N(CC1COC(=O)O1)C(=O)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)CCc1ccc(OC)nc1N(CC1COC(=O)O1)C(=O)C(C)(C)C
Yield: 98 %

Procedure:
A solution of butyl (2E)-3-[2-{(2,2-dimethylpropanoyl)[(2-oxo-1,3-dioxolan-4-yl)methyl]amino}-6-(methyloxy)-3-pyridinyl]-2-propenoate (6.156 g, 14.184 mmol) in ethanol (200 ml) was treated with palladium on carbon (10% paste, 1.23 g) and the mixture was then stirred at rt under 1 atmosphere of hydrogen for 18 h. The reaction mixture was then filtered through a thin pad of Celite, eluting with more ethanol (200 ml). The organic filtrate was then evaporated to give the product as a yellow oil (6.065 g, 98%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][OH:10].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>CO>[C:12]([N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])[CH2:8][CH2:9][OH:10])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: OCCNCCNCCO
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCO)CCN(CCO)C(=O)OC(C)(C)C

Procedure:
The product was prepared by treating N,N′-bis(2-hydroxyethyl)ethylenediamine in methanol with (BOC)2O at room temperature. The reaction mixture was chilled to −15° C. to −20° C. to precipitate the product. After filtration, the precipitate was desiccated to yield the product.
Reaction SMILES: [CH2:1]([C:5]1([CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36])[CH2:2][CH2:3][CH3:4].[ClH:38]>O1CCOCC1>[ClH:38].[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 90 %

Procedure:
A solution of Example 33A (0.349 g, 0.664 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (0.277 g, 90%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.54 (m, 1 H) 0.69 (m, 3 H) 0.86 (m, 1 H) 1.09 (m, 2 H) 1.56 (m, 3 H) 2.13 (m, 2 H) 7.04 (m, 2 H) 7.51 (m, 2 H) 7.76 (m, 2 H) 8.16 (m, 1 H) 13.57 (m, 1 H). MS (ESI−) m/z 424 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][CH2:11][O:13]2)=[CH:4][CH:3]=1
Reactant: OC(CCCCl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Brc1ccc(C2CCCO2)cc1
Reaction time: 2 h
Yield: 105.4 %

Procedure:
To a solution of 1-(4-bromophenyl)-4-chlorobutan-1-ol (1.0 g, 3.8 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (110 mg, 4.56 mmol) at 0° C. After being stirred for 2 hours, the reaction mixture was quenched with water, brought to pH=6 with 1 M HCl aqueous, and extracted with ethyl acetate. The organic was washed with brine, dried over sodium sulfate, filtered and concentrated to give the target compound (910 mg, 100%) as a yellow solid.