Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([F:17])[C:7]=1[C:8]([NH2:10])=O>CN(C=O)C>[F:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([F:17])[C:7]=1[C:8]#[N:10]
Reactant: COc1cc(F)c(C(N)=O)c(F)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(F)c(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of thionyl chloride (139.0 g, 1.17 mol) in dry DMF (150 ml) was added to a stirred solution of compound 26 (20.0 g, 0.11 mol) in dry DMF (250 ml) at room temperature. The mixture was stirred at room temperature overnight and then poured onto ice-water. The product was extracted into ether (twice), and the combined ethereal extracts were washed with water, saturated sodium hydrogen carbonate, water and dried (MgSO4). The solvent was removed in vacuo to give off-white crystals.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:19].C([O-])([O-])=O.[K+].[K+].F[C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][CH3:34])=[O:32])=[CH:29][CH:28]=1>CS(C)=O>[CH3:34][NH:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:27]([N:16]2[CH2:17][CH2:18][CH:13]([O:12][C:10]3[CH:9]=[CH:8][C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:19])[NH:4][C:5]=4[CH:11]=3)[CH2:14][CH2:15]2)=[CH:28][CH:29]=1
Reactant: CNC(=O)c1ccc(F)cc1
Reactant: CC1Oc2ccc(OC3CCNCC3)cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(N2CCC(Oc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 22.8 %

Procedure:
In a 4 mL screw cap vial, 2-methyl-6-(piperidin-4-yloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one 394E (0.054 g, 0.206 mmol), K2CO3 (0.142 g, 1.029 mmol), and 4-fluoro-N-methylbenzamide (0.038 g, 0.247 mmol) were suspended in DMSO (0.412 mL) to give a brown suspension. The reaction was stirred at 120° C. for 72 hr. The crude material was purified by prep HPLC-MS (40-75% MeCN in water). The fractions were collected and concentrated in vacuo affording the product as a tan solid (0.0186 g, 22.85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.47 (m, 3H) 1.59-1.74 (m, 2H) 1.93-2.07 (m, 2H) 2.71-2.82 (m, 3H) 3.09-3.23 (m, 2H) 3.61 (br. s., 2H) 4.38-4.50 (m, 1H) 4.58 (q, J=6.65 Hz, 1H) 4.68 (d, J=6.57 Hz, 1H) 6.50 (d, J=2.78 Hz, 1H) 6.53-6.62 (m, 1H) 6.67 (dd, J=8.72, 2.91 Hz, 1H) 6.88 (d, J=8.84 Hz, 1H) 6.94-7.06 (m, 2H) 7.71 (d, J=8.84 Hz, 2H) 7.81-7.88 (m, 1H) 8.10-8.20 (m, 1H) 10.57 (s, 1H). ESI-MS: m/z 396.3 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O.[CH:34]([C:37]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]([CH3:46])[CH3:45])[C:38]=1[NH2:39])([CH3:36])[CH3:35]>CN(C=O)C>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:39][C:38]1[C:40]([CH:44]([CH3:45])[CH3:46])=[CH:41][CH:42]=[CH:43][C:37]=1[CH:34]([CH3:36])[CH3:35])=[O:33]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CCCCCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
WSC ( 809 mg, 4.6 mmols) and HOBt (621 mg, 4.6 mmols) were added to a DMF (20 ml) solution of the resulting carboxylic acid (1.19 g, 5 mmols) and 2,6-diisopropylaniline (738 mg, 4.2 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer:hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 666 mg (yield: 34%) of 9-bromo-N-(2,6-diisopropylphenyl)nonanamide as colorless needle-like crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl.O>[CH3:23][C@:20]12[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:37])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:5]1([NH:4][CH2:3][CH2:2][NH:1][S:54]([CH3:53])(=[O:56])=[O:55])[CH2:22][CH2:21]2
Reactant: CS(=O)(=O)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCNS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-aminoethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (15 mg, 0.026 mmol) and Hunig's Base (0.013 mL, 0.077 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (3.81 mg, 0.033 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with distilled water (3 mL), extracted with dichloromethane (3×3 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a yellow solid (15 mg, 88%). LCMS: m/e 665.55 (M+H)+, 2.44 min (method 11).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:27]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4].[CH3:28][C:29]1(B(O)O)[CH:33]=[C:32]([CH3:34])[O:31][NH:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Pd].O1CCOCC1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:27]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:33]4[C:29]([CH3:28])=[N:30][O:31][C:32]=4[CH3:34])=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Br)cc3)c(C3CCCCC3)c(=O)n2n1
Reactant: CC1=CC(C)(B(O)O)NO1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc2[nH]c(-c3ccc(-c4c(C)noc4C)cc3)c(C3CCCCC3)c(=O)n2n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of 42 mg (0.1 mmol) of 5-(4-bromo-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester, 21 mg (0.15 mmol) of 3,5-dimethyl-isoxazoleboronic acid, 7.3 mg (0.01 mmol) of Pd catalyst, and 63 mg (0.3 mmol) of potassium phosphate in 1 mL of 1,4-dioxane was shaken at 95° C. in a sandbath overnight. The reaction mixture was then diluted with dichloromethane, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a residue, which was purified via reverse-phase chromatography (Gilson) to afford desired 6-cyclohexyl-5-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by LC-MS—calcd for C25H26N4O4 [M++H]+: 447.19, found: 447.3. This material was then converted to 6-cyclohexyl-5-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (591) via the well known LiOH saponification protocol (37% yield over 2 steps); LC-MS—calcd for C24H24N4O4 [M++H]+: 433.18, found: 433.1.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (3 g, 6.6 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.65 g (59%); off white powder; mp 191° C.; MS: 428 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:15][C:16]([OH:18])=[O:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Product: O=C(O)C=Cc1ccc(C(F)(F)F)c(F)c1

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3h20) between 3-fluoro-4-trifluoromethyl-benzaldehyde (9.000 g; 46.848 mmol) and malonic acid (9.262 g; 89.012 mmol) gave the product 3-(3-fluoro-4-trifluoromethyl-phenyl)-acrylic acid as a colorless solid (9.520 g; 87%). LC-MS: tR=0.90 min; [M+H]+: no ionisation.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:14]1[NH:19][C:18]([NH2:20])=[N:17][CH:16]=[C:15]1[N+:21]([O-:23])=[O:22]>CN(C=O)C>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:16]2[C:15]([N+:21]([O-:23])=[O:22])=[CH:14][N:19]=[C:18]([NH2:20])[N:17]=2)=[CH:4][CH:3]=1
Reactant: Ic1ccc2cn[nH]c2c1
Reactant: NC1=NC=C([N+](=O)[O-])C(Cl)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc([N+](=O)[O-])c(-n2ncc3ccc(I)cc32)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-iodo-1H-indazole (537 mg, 2.20 mmol) in DMF (16 mL) was added NaH (60% oil dispersion) (132 mg, 3.30 mmol) at 0° C. Mixture was stirred at RT for 10 min before addition of a portion of 6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine (60% pure, 500 mg, 1.71 mmol). The mixture was stirred at RT for 20 min. Another portion of NaH (60% oil dispersion) (132 mg, 3.30 mmol) was added at RT. After 10 min, another portion of 6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine (60% pure, 300 mg, 1.03 mmol) was added. Stirring continued for 30 min. The reaction mixture was cooled in an ice bath before quenching with water. The mixture was acidified by addition of 1 M aq HCl then the pH was adjusted to 8-9 by dropwise addition of saturated aq NaHCO3.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[F:47][C:48]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:49]=1[O:50][CH:51]1[CH2:56][CH2:55][N:54]([C:57]2[N:58]=[C:59]3[CH2:70][CH2:69][NH:68][CH2:67][C:60]3=[N:61][C:62]=2[NH:63][CH:64]([CH3:66])[CH3:65])[CH2:53][CH2:52]1>CC(N(C)C)=O>[F:47][C:48]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:49]=1[O:50][CH:51]1[CH2:52][CH2:53][N:54]([C:57]2[N:58]=[C:59]3[CH2:70][CH2:69][N:68]([C:3](=[O:4])[CH:2]([F:6])[F:1])[CH2:67][C:60]3=[N:61][C:62]=2[NH:63][CH:64]([CH3:66])[CH3:65])[CH2:55][CH2:56]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)C(F)F)C2
Temperature: 60 °C

Procedure:
A solution of 2,2-difluoroacetic acid (8.2 μL, 0.13 mmol) in DMA (0.4 mL) was treated with HATU (49.6 mg, 0.130 mmol) and DIPEA (45.6 μL, 0.261 mmol). To this was added a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (45 mg, 0.087 mmol) in DMA (0.47 mL). The reaction mixture was heated at 60° C. for 50 min. The reaction mixture was allowed to cool to room temperature and was purified directly by HPLC Method B, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column was used, using a 55% to 90% ACN gradient to give the title compound, as a TFA salt, as a yellow solid (10.0 mg, 19.3%). 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.28 (m, 6H), 1.96 (m, 2H), 2.12 (m, 2H), 2.79 (t, J=5.9 Hz, 0.7H), 2.85 (t, J=5.8 Hz, 1.3H), 3.05 (m, 2H), 3.42 (m, 2H), 3.92 (dt, J=11.3, 5.8 Hz, 2H), 4.15 (m, 1H), 4.48 (m, 1H), 4.65 (s, 2H), 6.56 (m, 1H), 6.88 (m, 1H), 6.98 (ddd, J=11.3, 8.5, 2.9 Hz, 1H), 7.17 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 482.5.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[C:50]([O:51][CH2:52][CH2:53][NH:54][CH3:55])[C:43]=23)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1.[C:56]([OH:60])(=O)[CH2:57][OH:58].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[C:50]([O:51][CH2:52][CH2:53][N:54]([CH3:55])[C:56](=[O:60])[CH2:57][OH:58])[C:43]=23)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1
Reactant: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)C(=O)CO
Reaction time: 8 h
Yield: 99.8 %

Procedure:
HATU (52 mg) was added to a stirred solution of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-3-[2-(methylamino)ethoxy]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 60/47 mg, 0.10 mmol), glycolic acid (10 mg, 0.13 mmol) and DIPEA (60 μl) in DMF (4 ml) and the solution was stirred overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between water and DCM. Organic extracts were dried and concentrated and the residue triturated with ether to give the title compound as a white solid (50 mg, 94%); Mass Spectrum 500.8 (M+/retention time 2.18 minutes).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:15])=[CH:6][C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=1)[CH3:2].Cl[CH2:17][CH2:18][CH2:19][OH:20].C(O)(C)C>CC(OC)(C)C>[CH2:1]([O:3][C:4]1[C:5]([O:15][CH2:17][CH2:18][CH2:19][OH:20])=[CH:6][C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=1)[CH3:2]
Reactant: OCCCCl
Reactant: CCOc1cc2ccc(=O)oc2cc1O
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: CCOc1cc2ccc(=O)oc2cc1OCCCO
Yield: 69 %

Procedure:
Method K; starting materials: 6-ethoxy-7-hydroxy-2H-1-benzopyran-2-one and 3-chloro-1-propanol; yield 69%; fusion point 96°-98° C. (from isopropanol and TBME).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([NH:30][C@H:31]([C:35]([O:37][CH3:38])=[O:36])[C@@H:32]([CH3:34])[OH:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOCC>[CH2:3]([O:33][C@H:32]([CH3:34])[C@@H:31]([C:35]([O:37][CH3:38])=[O:36])[NH:30][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A 250-mL, round-bottomed flask, under an atmosphere of N2, was charged with sodium hydride (60% oil dispersion, 772 mg, 19.3 mmol). The sodium hydride was washed with 3 portions of hexanes to remove the oil and then 8 mL of anhydrous DMF was added followed by benzyl bromide (3.38 mL, 28.4 mmol). The solution was cooled to 0° C. and then a solution of methyl N-trityl-L-threoninate (4.83 g, 12.9 mmol) dissolved in 12 mL of DMF was added dropwise via cannula over 5 minutes. After stirring for 2 hours, the reaction mixture was treated with saturated aqueous Na2CO3 solution and 200 mL of Et2O and the layers were separated. The organic portion was washed successively with H2O (5×100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5-10% ethyl acetate/hexanes) gave 4.61 g of methyl O-benzyl-N-trityl-L-threoninate as a colorless syrup.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pt]>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH3:7])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Pt]
Solvent: CC(=O)O
Product: Cc1ccc(C(F)(F)F)cc1
Reaction time: 10 h
Yield: 77.7 %

Procedure:
4-Trifluoromethylbenzaldehyde (20.0 g) was dissolved in acetic acid (100 ml) and treated with hydrogen in the presence of platinum (0.5 g) at ambient temperature and pressure for 10 hours. The solution was filtered, poured into water (400 ml), basified by addition of aqueous sodium hydroxide solution (2M), extracted with ether (3×100 ml). The combined extracts were washed with water (2×100 ml), dried over anhydrous magnesium sulphate, evaporated to dryness. The residue was distilled to give 4-trifluoromethyltoluene (14.3 g) b.p. 131°-132° C. as a colourless mobil liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](B(O)O)=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:19]2)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2ccccc21

Procedure:
A solution of 2,4-dichloropyrimidine (2.42 g, 16 mmol), 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid (3.89 g, 13 mmol) and sodium carbonate (5.03 g, 47 mmol) in acetonitrile/water (2:1, 60 mL) was degassed with argon, then tetrakis(triphenylphosphine)palladium (300 mg, 1.6 mol) was added. The resulting mixture was heated to reflux for 2 h while a white suspension formed. The precipitate was cooled and filtered through a CELITE™/Silica gel plug. The filter cake was washed with EtOAc, the organic layer separated, washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was recrystallized from EtOAc/hexanes to give 1-benzenesulfonyl-3-(2-chloro-pyrimidin-4-yl)-1H-indole as a light-pink solid. The solid filtrate from the reaction mixture was dissolved in DCM, dried over Na2SO4, filtered, and combined with the previous batch of product. The collected solids were dissolved in DCM, the solvent was evaporated under reduced pressure and EtOAc was added to form a suspension, the product was filtered and washed with hexanes, to give 1-benzenesulfonyl-3-(2-chloro-pyrimidin-4-yl)-1H-indole (2.0 g, 33% yield) as a light-pink solid. An additional 0.45 g of product was obtained from the mother liquors.
Reaction SMILES: B(O)O.[CH3:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][N:6]=1.N1C=CC=CC=1.CC1N([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH:28]=2)N=C(C(OCC)=O)C=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH:28]=2)[N:6]=1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc3cc(OC)ccc3c2)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C)nn1-c1ccc2cc(OC)ccc2c1
Reaction time: 96 h
Yield: 37 %

Procedure:
To a solution of the above-prepared boronic acid (0.84 g, 3.2 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.49 g, 3.2 mmol) in 20 mL dry DCM were added pyridine (0.77 mL, 9.5 mmol) and anhydrous powder of copper(II) acetate (1.15 g, 6.3 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stirred for 4 days under argon. The mixture was diluted with DCM. It was filtered through celite. The blue filtrate was washed with water (×2), dried, concentrated and purified by flash column to separately afford ethyl 3-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-5-carboxylate [37% yield. Rf 0.80 (1:1 EtOAc:hexane). ES-MS: (M+H)+311] and ethyl 5-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-3-carboxylate [25% yield. Rf 0.69 (1:1 EtOAc:hexane). ES-MS: (M+H)+311]in a 1.5:1 ratio.
Reaction SMILES: [CH:1]([C:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1)=O.C(N)CCC.[N+:19]([CH3:22])([O-:21])=[O:20]>C1(C)C=CC=CC=1>[C:8]1([N:5]2[CH2:6][CH:7]=[C:3]([CH:1]=[CH:22][N+:19]([O-:21])=[O:20])[NH:4]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CC1=NN(c2ccccc2)CC1
Reactant: C[N+](=O)[O-]
Solvent: CCCCN
Solvent: Cc1ccccc1
Product: O=[N+]([O-])C=CC1=CCN(c2ccccc2)N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of 3-formyl-1-phenyl-2-pyrazoline (3.48 g), n-butylamine (0.2 ml) and nitromethane (10 ml) was stirred at 100° C. for 1 hour, then was cooled to room temperature. The resultant dark red crystalline mass was dissolved in toluene and was eluted down a silica column with toluene. The major orange fraction was evaporated to dryness under reduced pressure and the residue was recrystallised from ethanol to give a 59% yield of dark red micro crystals (MP 150° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>C(O)C>[NH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:2]([CH3:13])[CH3:1])=[CH:9][CH:8]=1
Reactant: CN(C)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CN(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.7 %

Procedure:
In ethanol (100 ml) was dissolved dimethyl-4-nitro-benzylamine (20.7 g), and to the mixture was added dried 10% palladium on carbon (1.00 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was separated and purified with column chromatography (ethyl acetate) to give 4-aminobenzyldimethylamine (8.75 g) as pale yellow oil.