Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(O[Si](C)(C)C(C)(C)C)c2ncccc12
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)c2ncccc12
Temperature: 60 °C

Procedure:
A mixture of Example 201C (4.03 g, 10.5 mmol) and Rh(PPh3)3Cl (972 mg, 1.05 mmol) in toluene (40 mL) was degassed and flushed with hydrogen three times. The solution was heated to 60° C. under a hydrogen atmosphere for 16 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5-10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][CH2:47][Cl:48]>CN(C=O)C>[Cl:48][CH2:47][CH2:46][CH2:45][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:5]2
Reactant: Cn1c(=O)c(-c2nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n2)cc2cc(O)ccc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n2)cc2cc(OCCCCl)ccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a mixture of 6-hydroxy-1-methyl-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (600 mg, 1.22 mmol) and potassium carbonate (337 mg, 2.44 mmol), was added DMF (100 ml), and the resultant mixture was stirred. 1-Bromo-3-chloropropane (578 mg, 3.64 mmol) was then added thereto, followed by stirring at a bath temperature of 60° C. for four hours. The reaction mixture was concentrated under reduced pressure, and water was added thereto, followed by extraction with a mixture of chloroform-methanol (10:1). The residue was dried over sodium sulfate anhydrate, and the solvent was removed under reduced pressure, to thereby obtain the title compound (638 mg) in a crude form as yellow oily matter.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])#[N:5].C(=O)(O)[O-].[Na+]>C(O)C>[OH:3][NH:2][C:4](=[NH:5])[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19]
Reactant: NO
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C#N)cccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Temperature: 60 °C
Yield: 71.7 %

Procedure:
Hydroxylamine hydrochloride (24.51 g, 353 mmol) was added to a mixture of 1,1-dimethylethyl 3-(5-cyano-1-isoquinolinyl)propanoate (D35; 24.9 g, 88 mmol) and sodium bicarbonate (44.5 g, 529 mmol) in ethanol (200 ml) and the mixture heated at 60° C. for 5 h. The cooled mixture was filtered and the filtrate concentrated in vacuo. The residue was partitioned between water (100 ml) and ethyl acetate (3×100 ml) and the combined organic extracts washed with brine (100 ml) and dried (MgSO4). The solvent was evaporated to give a pale yellow solid which was triturated under ether (100 ml) and filtered to give the title compound as a colourless solid (19.91 g)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]=[C:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8].C([O:14][C:15](O[Si](C)(C)C)=[CH:16][C:17]([O:21][Si](C)(C)C)=[CH:18][CH2:19][CH3:20])C.C(O)C.[F-].[NH4+]>O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[C:15]([OH:14])=[CH:16][C:17]([OH:21])=[C:18]([CH2:19][CH3:20])[C:5]=1[CH2:4][C:3]([O:2][CH3:1])=[O:11]
Reactant: CCC=C(C=C(OCC)O[Si](C)(C)C)O[Si](C)(C)C
Reactant: COC(=O)C=C=CC(=O)OC
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCc1c(O)cc(O)c(C(=O)OC)c1CC(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
The above-obtained penta-2,3-dienedioic acid dimethyl ester (4.6 g, 30 mmol) and 1-ethoxy-1,3-bis(trimethylsiloxy)hexa-1,3-diene (13 g, 41 mmol) were mixed and stirred at a room temperature for 1.5 hours. The reaction mixture was added with ethanol (100 mL) and ammonium fluoride (5.4 g) and stirred at a room temperature for 2 hours. The reaction mixture was further added with water and extracted with ethyl acetate 3 times. The organic layers were combined, sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was triturated with hexane (50 mL) to obtain Compound 23 (3.2 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:13][C:14](=O)[CH2:15][O:16][C:17](=[O:19])[CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[C:14]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(Br)cn1
Reactant: CC(=O)OCC(=O)CCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
(5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml) and acetic acid 3-chloro-2-oxo-propyl ester (1 eq.) is added and stirred 2 h at 70° C. After cooling to RT the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A5” is obtained as colourless powder in a yield of 82%; mp. 200.9-201.6° C.; HPLC (method C): 1.80 min; LC-MS (method A): 1.800 min, 327.95 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.516 (s, 1H), 8.391 (d, 1H, J=2.4 Hz), 7.892 (dd, 1H, J=8.9 Hz, J=2.4 Hz), 7.020 (d, 1H, J=8.9 Hz), 6.998 (s, 1H), 5.015 (s, 2H), 2.062 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C@@H:22]([OH:23])[CH2:21][CH2:20][C@@:19]2([CH3:24])[CH:3]1[CH2:4][CH2:5][C:6]1[C:7]3[C@:15]([CH3:25])([CH2:16][CH2:17][C:18]=12)[C@@H:10]([C@H:11]([CH3:14])[CH2:12][OH:13])[CH2:9][CH:8]=3.C(=O)(O)[O-].[Na+]>ClCCl>[OH:23][C@H:22]1[CH2:21][CH2:20][C@@:19]2([CH3:24])[CH:3]([CH2:4][CH2:5][C:6]3[C:7]4[C@:15]([CH3:25])([CH2:16][CH2:17][C:18]=32)[C@@H:10]([C@H:11]([CH3:14])[CH:12]=[O:13])[CH2:9][CH:8]=4)[C:2]1([CH3:1])[CH3:26]
Reactant: C[C@H](CO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reaction time: 1 h
Yield: 23.1 %

Procedure:
To a solution of 1 g (20S)-4,4,20-trimethyl-pregna-8,14-dien-3β,21-diol in 10 ml dichloromethane 5.4 ml of a 0.5 M Dess-Martin-Periodinane solution were added at room temperature. The mixture was stirred for one hour, poured into saturated sodium bicarbonate solution, extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 230 mg (20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al as a white solid.
Reaction SMILES: C(N(CCCC)C(C1N=C(C2C=CC(C(O)=O)=CC=2C(N2CCC3C(=CC=CC=3)C2)=O)N(C)C=1)=O)CCC.[CH2:39]([N:43]([CH2:74][CH2:75][CH2:76][CH3:77])[C:44]([C:46]1[N:47]=[CH:48][N:49]([CH3:73])[C:50]=1[C:51]1[CH:60]=[CH:59][C:54]([C:55]([O:57]C)=[O:56])=[CH:53][C:52]=1[C:61]([N:63]1[CH2:72][CH2:71][C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64]1)=[O:62])=[O:45])[CH2:40][CH2:41][CH3:42]>>[CH2:39]([N:43]([CH2:74][CH2:75][CH2:76][CH3:77])[C:44]([C:46]1[N:47]=[CH:48][N:49]([CH3:73])[C:50]=1[C:51]1[CH:60]=[CH:59][C:54]([C:55]([OH:57])=[O:56])=[CH:53][C:52]=1[C:61]([N:63]1[CH2:72][CH2:71][C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64]1)=[O:62])=[O:45])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN(CCCC)C(=O)c1ncn(C)c1-c1ccc(C(=O)OC)cc1C(=O)N1CCc2ccccc2C1
Agent: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Product: CCCCN(CCCC)C(=O)c1ncn(C)c1-c1ccc(C(=O)O)cc1C(=O)N1CCc2ccccc2C1
Yield: 77.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 264L, methyl 4-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (400 mg, 0.75 mmol) was converted to the title compound (300 mg, 77%). MS(ESI+) m/z 517.6 (M+H)+.
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14](=O)[CH2:15][S:16][C:17]#[N:18])[CH:11]=[CH:12][CH:13]=1.O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=2)[N:18]=1
Reactant: COc1cccc(C(=O)CSC#N)c1
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
A 25% hydrogen bromide/acetic acid (65 ml) solution was added to a solution of 2-(3-methoxyphenyl)-2-oxoethyl thiocyanate (6.50 g, 31.4 mmol) in acetic acid (65 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 3.80 g (44.8%) of the desired product as a solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:17]3[CH2:25][OH:26])=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27]O>C(#N)C.Cl>[CH3:27][O:26][CH2:25][C:17]1[N:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: OCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Reactant: CO
Agent: Cl
Solvent: CC#N
Product: COCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Reaction time: 2 h

Procedure:
{1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}methanol (15 mg) was dissolved in a mixture of methanol, acetonitrile, and 1 N HCl. After standing at room temperature for 2 hours, the solution was purified by semi-prep LC-MS to give 1.1 mg of the desired product. LC-MS (C23H28N2O2 calc'd 364) m/z 365 (M+H); 1H NMR (300 MHz, CDCl3) d 7.66-7.61 (m, 1H), 7.33 (d, J=9 Hz, 2H), 7.20-6.75 (m, 5H), 6.66 (s, 1H), 4.40 (s, 2H), 4.10 (t, J=6.3 Hz, 2H), 3.28 (s, 3H), 2.82-2.71 (m, 6H), 2.17-2.08 (m, 2H), 1.87 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:29][CH:28]([CH2:30][NH2:31])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][CH2:30][CH:28]3[CH2:29][O:26][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1COC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(oxetan-3-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (d, 1 H), 7.89-7.87 (t, 1 H), 7.69-7.65 (m, 2 H), 7.50-7.46 (t, 1 H), 7.31 (d, 1 H), 7.24-7.21 (m, 1 H), 6.79-6.76 (t, 1 H), 6.04 (s, 1 H), 5.08 (s, 2 H), 4.74-4.70 (m, 2 H), 4.37 (t, 4 H), 3.61 (t, 4 H), 3.28 (m, 1 H), 2.35 (s, 3 H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc([C@@H]2C[C@H]2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a cooled solution of tert-butyl ((trans)-2-(4-aminophenyl)cyclopropyl)carbamate (1 g, 4.03 mmol) in dichloromethane (5 mL) was added TEA (0.842 mL, 6.04 mmol), acetyl chloride (0.315 mL, 4.43 mmol) and stirred for 2 h at RT. The reaction mixture was diluted with ice cold water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated. The residue was purified using silica gel (100-200 mesh) column chromatography, compound eluted in 2% MeOH in DCM to afford tert-butyl ((trans)-2-(4-acetamidophenyl)cyclopropyl)carbamate (900 mg, 77% yield) as brown solid. LCMS (ES) m/e 289.26 (M−H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:19]2[C:14]([CH:15]=[N:16][C:17]([NH:20][C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)=[N:18]2)=[C:13]([CH3:33])[N:12]=1)(=O)C.C1COCC1.O.[Li+].[OH-].Cl>O.CCOC(C)=O>[CH3:33][C:13]1[N:12]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])[N:19]2[C:14]=1[CH:15]=[N:16][C:17]([NH:20][C:21]1[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=1)=[N:18]2
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4OC(C)=O)n3n2)cc(OC)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4O)n3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl acetate (Example 23 below) (26 mg, 0.058 mmol) in 5:1 THF/H2O (4 mL) was added LiOH (30 mg, 1.25 mmol). The reaction was stirred at room temperature for 3 hours then poured into EtOAc (100 mL) and water (20 mL) with aqueous 1 N HCl (2 mL). The aqueous layer was extracted with EtOAc and the combined organic layers then washed with brine, dried over MgSO4, concentrated and purified by silica gel chromatography, eluting with 1% MeOH/DCM to give 2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}phenol (13 mg, (56%)) as a yellow solid. 1H NMR (CDCl3): δ12.73 (s, 1H), 8.94 (dd J=7.87, 1.46 Hz, 1H), 8.86 (s, 1H), 7.31 (m, 1H), 7.09 (d, J=8.06 Hz, 1H), 6.86-6.96 (m, 4H), 3.90 (s, 6H), 3.88 (s, 3H), 2.61 (s, 3H). MS m/z 407 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4]I.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:30]([O:37][C:38]1[CH:43]=[C:42](I)[CH:41]=[CH:40][C:39]=1[N:45]1[S:49](=[O:51])(=[O:50])[N:48]([CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:47](=[O:58])[CH2:46]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.[Zn].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]>[CH2:30]([O:37][C:38]1[CH:43]=[C:42]([CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])[CH:41]=[CH:40][C:39]=1[N:45]1[S:49](=[O:50])(=[O:51])[N:48]([CH2:52][CH2:53][Si:54]([CH3:56])([CH3:55])[CH3:57])[C:47](=[O:58])[CH2:46]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: FC(F)(F)CCI
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCC(F)(F)F)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1,1,1-trifluoro-3-iodopropane (0.088 mL, 0.75 mmol) in DMF (2 mL) is added Rieke zinc (0.9 mmol) and the mixture is stirred at RT for 5 h then P(o-tolyl)3 (22.8 mg, 15 mol %), Pd2(dba)3 (13.7 mg, 3 mol %) and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (272 mg, 0.5 mmol) is added and the mixture is stirred at RT for 18 h. The mixture is partitioned between EtOAc and 1N HCl and the organic phase is washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 0-15% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([CH3:24])=[C:12]2[CH2:25][C:26]([NH2:28])=[O:27])C.[OH-].[Na+].O.Cl>CO>[NH2:28][C:26](=[O:27])[CH2:25][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])[CH:10]=2)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]=1[CH3:24]
Reactant: CCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)O)ccc21
Yield: 24 %

Procedure:
A mixture of 170 mg (0.42 mmol) of [4-[[3-(2-amino-2-oxoethyl)-1-hexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 1 mL of 5N NaOH in 20 mL of MeOH was heated to maintain reflux for 2.5 hours, cooled, poured into water and made strongly acidic with 5N HCl. The mixture was extracted with ethyl acetate, dried (Na2SO4), concentrated at reduced pressure and the residue crystallized from MeOH. There was obtained 37 mg (24% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-hexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid. mp, 169-170° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([NH2:8])[NH:5][N:4]=1)[CH3:2].[C:9]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21](=O)[CH2:22][C:23](OCC)=[O:24])=[CH:18][CH:19]=2)[CH:14]=[N:13]1)(=[O:11])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:9]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[NH:8][C:6]4[N:5]([N:4]=[C:3]([CH2:1][CH3:2])[N:7]=4)[C:23](=[O:24])[CH:22]=3)=[CH:18][CH:19]=2)[CH:14]=[N:13]1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Reactant: CCc1n[nH]c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1nc2[nH]c(-c3ccc4c(cnn4C(C)=O)c3)cc(=O)n2n1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
To a solution of 3-ethyl-1H-1,2,4-triazol-5-amine (150 mg, 1.34 mmol) in diphenyl ether (2 ml) was added ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate (550 mg, 2.00 mmol) and TsOH (8 mg, 0.04 mmol), and the reaction mixture was stirred for 1 h at 170° C. The solids were collected by filtration and washed with hexane (10 ml) and ethanol (3 ml) to afford 5-(1-acetyl-1H-indazol-5-yl)-2-ethyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a yellow solid (130 mg, crude).
Reaction SMILES: [N:1]1([C:7]2[CH:40]=[CH:39][C:10]([O:11][CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]4[NH:23][C:22]5[CH:24]=[C:25](B6OC(C)(C)C(C)(C)O6)[CH:26]=[CH:27][C:21]=5[C:20](=[O:37])[NH:19][C:18]=4[CH:38]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F-].[Cs+].CO[CH2:45][CH2:46]OC>CO.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>[N:1]1([C:7]2[CH:40]=[CH:39][C:10]([O:11][CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]4[NH:23][C:22]5[CH:24]=[C:25]([C:46]6[C:45]7[C:17](=[CH:18][N:19]=[CH:20][CH:21]=7)[NH:23][CH:22]=6)[CH:26]=[CH:27][C:21]=5[C:20](=[O:37])[NH:19][C:18]=4[CH:38]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC1(C)OB(c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)OC1(C)C
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: O=C1Nc2cc(CCOc3ccc(N4CCOCC4)cc3)ccc2Nc2cc(-c3c[nH]c4cnccc34)ccc21
Temperature: 25 °C

Procedure:
A mixture of Example 695G (53 mg, 0.1 mmol), Example 695K (30 mg, 0.1 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), and CsF (46 mg, 0.3 mmol) in DME (4 mL) and MeOH (2 mL) was heated under reflux overnight. After the reaction mixture cooled to room temperature, it was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified flash column chromatography on silica gel with 100:5:0.5 ethyl acetate/methanol/NH4OH. The desired fractions were collected and concentrated under vacuum, and the residue was further purified by preparative reverse phase HPLC to provide 8 mg of the title compound as a diTFA salt. MS (APCI) m/e 530 (M-H)+, 1H NMR (500 MHz, DMSO-d6): □ 13.30 (s, 1H), 9.78 (s, 1H), 9.26 (s, 1H), 8.71 (d, J=1.87 Hz, 1H), 8.38-8.45 (m, 2H), 7.96 (s, 1H), 7.80 (d, J=8.11 Hz, 1H), 7.47 (d, J=1.56 Hz, 1H), 7.30 (dd, J=8.11, 1.56 Hz, 1H), 6.82-6.96 (m, 7H), 4.05 (t, J=6.86 Hz, 2H), 3.71-3.73 (m, 4H), 2.97-2.99 (m, 4H), 2.87 (t, J=6.55 Hz, 2H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9])(=[O:4])=[O:3].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:7]=1[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1NS(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
Preparation B5, Step 4: To a mixture of methyl 2-(methylsulfonamido)-5-(trifluoromethyl)benzoate (1.0 g, 3.367 mmol) in THF (20 ml) and water (20 ml) was added lithium hydroxide (0.4242 g, 10.10 mmol) and stirred at RT for 6 h. The reaction mixture was acidified with 1.5 N HCl and extracted with ethyl acetate (3×50 ml). The organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The solid was filtered and dried under vaccum to get 2-(methylsulfonamido)-5-(trifluoromethyl)benzoic acid (0.7 g, 73%) as white solid. 1H NMR (400 MHz, CDCl3) δ 3.31 (s, 3H), 7.78 (d, 1H), 7.97 (d, 1H), 8.24 (s, 1H), 11.13 (bs, 1H); 13C NMR (100 MHz, CDCl3) δ 40.74, 116.5, 118.3, 122.8 (m), 128.8, 131.6, 144.3, 169.1. MS found: (M−H)−=282.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([C:15]2[CH2:19][C:18]([CH2:24][C:25]([O:27]C)=[O:26])([C:20]([O:22]C)=[O:21])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([C:15]2[CH2:19][C:18]([CH2:24][C:25]([OH:27])=[O:26])([C:20]([OH:22])=[O:21])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1(C(=O)OC)CC(c2cc(OCc3ccccc3)ccc2C)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(OCc2ccccc2)cc1C1=NOC(CC(=O)O)(C(=O)O)C1
Yield: 99.7 %

Procedure:
A mixture of methyl 3-(5-(benzyloxy)-2-methylphenyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (6.80 g), THF (70 mL), methanol (70 mL), and a 1 M aqueous sodium hydroxide solution (70 mL) was stirred at room temperature for 30 minutes. The reaction mixture was rendered acidic using 6 M hydrochloric acid at 0 C, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (6.30 g).