Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH:14]#[C:15][CH2:16][CH2:17][CH3:18]>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)#[C:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCC
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCCC#Cc1nccs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.2 %

Procedure:
2-Bromo-1,3-thiazole (2.0 g, 12 mmol) and CuI (183 mg, 0.96 mmol) were combined in DME (30 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (8 mL, 60 mmol) and PdCl2(PPh3)2 (337 mg, 0.48 mmol) were added and 1-pentyne (979 mg, 14.4 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 6 h at which time GC/MS analysis indicated that the reaction was not complete. Additional 1-pentyne (3.0 mL, 29 mmol) was added and the reaction was heated to 35° C. under a condenser. After heating for 16 h, GC/MS analysis indicated that the reaction was complete. The mixture was filtered through Celite™, and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane, 99:1, then 97:3 hexane:ethyl acetate to 2-(1-pentynyl)-1,3-thiazole (820 mg, 44% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, J=3.0 Hz, 1H), 7.28 (d, J=3.0 Hz, 1H), 2.47-2.42 (m, 2H), 1.68-1.60 (m, 2H), 1.08-0.99 (m, 3H). MS (ESI) 151.6 (M+).
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:44])[C:38]1C=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:37]([NH:44][S:25]([C:2]([F:1])([F:29])[C:3]([F:23])([F:24])[C:4]([F:21])([F:22])[C:5]([F:20])([F:19])[C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:26])=[O:27])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 g (100.0 mmol) of perfluoroctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 10.12 g (100.0 mmol) of benzylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted three times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:20]#[C:21][C:22]([OH:24])=O)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1.[NH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)(Cl)Cl.O>[CH:37]1[C:38]2[CH:26]([NH:25][C:22](=[O:24])[C:21]#[C:20][C:10]3[CH:11]=[CH:12][C:13]([N:14]4[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]4)=[C:8]([O:7][CH3:6])[CH:9]=3)[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: NC1c2ccccc2-c2ccccc21
Reactant: COc1cc(C#CC(=O)O)ccc1-n1cnc(C)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc(C#CC(=O)NC2c3ccccc3-c3ccccc32)ccc1-n1cnc(C)c1
Yield: 37.1 %

Procedure:
A DMF (2 mL) solution of [3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propiolic acid (74 mg) and 9-aminofluorene (65 mg) and BOP (133 mg) and N,N′-IPEA (77 μL) was agitated at room temperature overnight. Water and chloroform were added to the reaction solution, the organic layer was partitioned and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex NH, elution solvent:heptane-ethyl acetate system), and 45 mg of the title compound was obtained.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C@@H:8]1[CH2:23][C@@:16]2([C:20](=[O:21])[NH:19][C:18](=[O:22])[NH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:24])[CH:14]=2)[O:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:26][CH2:27][CH2:28][Cl:29].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([NH:5][C:6]([C@@H:8]1[CH2:23][C@@:16]2([C:20](=[O:21])[N:19]([CH2:26][CH2:27][CH2:28][Cl:29])[C:18](=[O:22])[NH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:24])[CH:14]=2)[O:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCBr
Reactant: CCCCNC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCCl)C2=O)c2cc(F)ccc2O1
Reaction time: 5 h
Yield: 80.4 %

Procedure:
To a solution of (2S,4S)-N-butyl-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (25.0 g, 74.6 mmol) in N,N-dimethylformamide (125 ml, 1.62 mmol) was added 1-bromo-3-chloropropane (23.5 g, 149 mmol). After adding 60% NaH (3.00 g, 75.0 mmol) over 30 minutes at 15°-22° C., the mixture was stirred for 5 hours at 25°-28° C. The reaction mixture was poured into iced water (500 ml), extracted with AcOEt (1000 ml×3), dried over MgSO4. The solvent was distilled off, the residue was chromatographed on silica gel, eluted with CH2Cl2 -CH2Cl2 /MeOH (9/1), and recrystallized from AcOEt to give the desired compound (24.7 g, 80.5%) as colorless prism crystals.
Reaction SMILES: O=[C:2]1[C:7]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:6][CH:5]=[N:4][NH:3]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccn[nH]c1=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccnnc1Cl
Yield: 89 %

Procedure:
2-[(3-Oxo-2,3-dihydropyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione (1.1 g, 4.27 mmol) was mixed with phosphoryl chloride (10 mL) and heated to reflux for 1 hour. After completion of the reaction, phosphoryl chloride was removed under reduced pressure. The resulting residue was diluted with chloroform and water. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give the desired product (89% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([C:46]2[NH:47][C:48]([CH3:51])=[N:49][N:50]=2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([C:46]5[NH:47][C:48]([CH3:51])=[N:49][N:50]=5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:9][CH2:10]2)[C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nnc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)o1
Reactant: COc1cnc(-c2nnc(C)[nH]2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(-c2nnc(C)[nH]2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4nnc(C)o4)CC3)c12
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)methylene]-piperidine-1-carboxylic acid tert-butyl ester (0.0348 g, 0.098 mmol) in CH2Cl2 (1 mL) was added TFA (0.5 mL) and the reaction mixture was stirred for 30 min. The solvent was then removed in vacuo and the residual material was dissolved in CHCl3 (1 mL). To this solution was then added 4-methoxy-7-(5-methyl-1,3,4-triazol-2-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.0621 g, 0.206 mmol) and iPrNEt2 (0.18 mL, 1.03 mmol), followed by BOP-Cl (0.0670 g, 0.263 mmol). The mixture was stirred at rt for 2 h and then the solvent was removed in vacuo. The residue was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated, and the residue was purified by preparative HPLC (NH4OAc) to give the title compound (0.0093 g, 18%) as a colorless solid:
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([C:31]4([C:58](=O)[CH3:59])[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]5[CH2:44][CH2:43][N:42]([C:45]6[CH:50]=[CH:49][C:48]([C:51]7[N:56]=[CH:55][CH:54]=[CH:53][N:52]=7)=[CH:47][N:46]=6)[CH2:41][CH:40]5[CH3:57])=[O:38])[CH2:32]4)=[O:30])[CH:26]=3)[NH:21][N:20]=2)=[CH:15][CH:14]=1>CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([C:31]4([C:58](=[N:4][O:2][CH3:3])[CH3:59])[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]5[CH2:44][CH2:43][N:42]([C:45]6[CH:50]=[CH:49][C:48]([C:51]7[N:52]=[CH:53][CH:54]=[CH:55][N:56]=7)=[CH:47][N:46]=6)[CH2:41][CH:40]5[CH3:57])=[O:38])[CH2:32]4)=[O:30])[CH:26]=3)[NH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: CON
Reactant: CC(=O)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cn3)CC2C)C1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C(C)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cn3)CC2C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Added methoxylamine hydrochloride (100 mg, 1.197 mmol) and triethylamine (0.2 ml, 1.43 mmol) to a solution of 3-Acetyl-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (11N) (100 mg, 0.15 mmol) in MeOH (5 ml), then stirred for 3 hours at room temperature. The solvent was evaporated and the residue was extracted with MeCl2, washed with water, dried over Na2SO4, filtered and solvent was evaporated yielding a solid which chromatographed on silica gel eluting with 7% v/v MeOH/MeCl2 containing 2% NH4OH yielding 2 isomers:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[O:12]1.[CH2:20](OC(OCC)OCC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:20]=[C:14]2[C:15](=[O:17])[O:16][C:11]([CH3:19])([CH3:10])[O:12][C:13]2=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1cccc(N)c1
Solvent: CCO
Product: COc1cccc(NC=C2C(=O)OC(C)(C)OC2=O)c1
Temperature: 85 °C
Yield: 88.5 %

Procedure:
A mixture of m-anisidine (22 g, 178 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (30.75 g, 214 mmol) and triethylorthoformate (30 mL, 178 mmol) in ethanol (200 mL) was heated at 85° C. for two hours. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration and washed with ethanol to give 43.7 g (89% yield) of product as a pale yellow solid, mp 108° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][C:8]2[CH:26]=[CH:25][C:11]([C:12]([N:14]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:15][C:16]([F:19])([F:18])[F:17])=[O:13])=[CH:10][C:9]=2[N+:27]([O-])=O)=[CH:2]1.O.O.[Sn](Cl)Cl>CN(C=O)C>[NH2:27][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:8]=1[NH:7][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[C:12]([N:14]([CH2:20][C:21]([F:22])([F:23])[F:24])[CH2:15][C:16]([F:18])([F:19])[F:17])=[O:13]
Reactant: O=C(c1ccc(NCc2ccoc2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)N(CC(F)(F)F)CC(F)(F)F)ccc1NCc1ccoc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[(3-Furylmethyl)amino]-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (108 mg, 0.254 mmol) was dissolved in 5 mL of DMF. Tin(II) chloride dihydrate (860 mg, 1.27 mmol) was added and the solution was stirred under nitrogen at RT for 24 h. The solvent was evaporated and the residue was taken up in EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was used directly for the next step. Yield: 80 mg (80%); MS (ESI) 396.11 (MH+).
Reaction SMILES: C(N1CC[C:15]2[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:13][C:12]([C:24]3[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=3)=[N:11][C:10]=2C1)C1C=CC=CC=1.Cl[C:32]1[NH:37][C:36](=[O:38])[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=1.O1[CH2:46][CH2:45]OCC1>>[CH2:12]([N:11]1[CH2:46][CH2:45][C:10]2[N:11]=[C:12]([C:24]3[CH:30]=[CH:29][C:27]([NH:28][C:32]4[NH:37][C:36](=[O:38])[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=4)=[CH:26][CH:25]=3)[N:13]=[C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:15]=2[CH2:10]1)[C:24]1[CH:30]=[CH:29][CH:27]=[CH:26][CH:25]=1
Reactant: C1COCCO1
Reactant: Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(Cc2ccccc2)C3)cc1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Product: Cn1c(=O)cc(Nc2ccc(-c3nc4c(c(N5CCOCC5)n3)CN(Cc3ccccc3)CC4)cc2)[nH]c1=O

Procedure:
4-(7-Benzyl-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (0.0500 g, 0.000124 mol) Palladium(II) acetate (0.0043 g, 0.000019 mol) Cesium Carbonate (0.0921 g, 0.000283 mol) 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0255 g, 0.0000441 mol) and 6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione (0.0321 g, 0.000200 mol) were combined, nitrogen purged three times, added dry 1,4-Dioxane (0.88 mL, 0.011 mol) The reaction was microwaved on 300 watts, 120° C. for 160 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 8.53 (s, 1H), 8.27 (d, J=8.7, 2H), 7.42-7.34 (m, 4H), 7.28 (dd, J=15.1, 7.8, 3H), 5.01 (s, 1H), 3.72 (dd, J=9.7, 5.0, 6H), 3.55 (s, 2H), 3.50 (d, J=4.4, 4H), 3.08 (s, 3H), 2.68 (dd, J=18.0, 4.8, 4H). LC/MS-m/z+528.3 (M+H)+
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=O)=O.[Cl:20]C1C=C2C(=CC=1)NC=C2CC(N)(C)C.[Cl:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][C:40]([CH3:45])=[C:39]2[CH2:46][C:47]([NH2:50])([CH3:49])[CH3:48]>>[ClH:20].[Cl:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][C:40]([CH3:45])=[C:39]2[CH2:46][C:47]([NH:50][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]([CH3:18])[CH3:19])([CH3:48])[CH3:49]
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1[nH]c2ccc(Cl)cc2c1CC(C)(C)N
Reactant: CC(C)COc1ccccc1OCCOS(C)(=O)=O
Product: Cc1[nH]c2ccc(Cl)cc2c1CC(C)(C)NCCOc1ccccc1OCC(C)C
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(2-methylprop-1-yloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(5-chloro-2-methyl-1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(5-chloro-2-methyl-1H-indol-3-yl)-1,1-dimethylethyl]{2-[2-(2-methylprop-1-yloxy)phenoxy]ethyl}amine hydrochloride, m.p. 202°-204° C.
Reaction SMILES: C(C1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][N:4]=1)#N.[CH3:13][Mg]I.C([O:18][CH2:19][CH3:20])C.Cl>C1COCC1>[C:19]([C:20]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:18])[CH3:13]
Reactant: C[Mg]I
Reactant: CCOCC
Reactant: N#Cc1ncccc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ncccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
Dissolve 2-cyano-3-trifluoromethylpyridine (30.0 g, 0.174 moles) in anhydrous THF (200 mL) under N2 atmosphere and cool in an ice bath. Add drop wise 3.0 M MeMgI in diethyl ether (120 ml, 0.348 mol) to the reaction mixture and stir in an ice bath for 30 minutes. Pour the reaction mixture over ice cold water, acidify the mixture with 2.0 N aq. HCl to pH 2 to 3. Extract the reaction mixture with EtOAc (3×300 mL) and dry over anhydrous MgSO4. Filter, concentrate under vacuum to afford crude product. Purify the crude product by vacuum distillation to afford desired 2-acetyl-3-trifluoromethylpyridine as colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1.[C:13]([Si:17]([CH3:24])([CH3:23])[O:18][CH2:19]CC#C)([CH3:16])([CH3:15])[CH3:14].CO>N>[Si:17]([O:18][CH2:19][CH2:11][C:10]#[C:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:24])[CH3:23]
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Reactant: OCCCc1cccc(CO)c1
Agent: N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCC#Cc1cccc(CO)c1

Procedure:
Prepared by the method of Aromatic Intermediate 18, step a using tert-butyldimethyl(but-3-ynyloxy)silane (0.92 g) in place of tert-butyl dimethyl(prop-2-ynyloxy)silane. The preparative HPLC conditions were changed to XBridge™, Gradient: 75-99% methanol in 0.2% aqueous ammonia to avoid cleavage of the silyl protecting group. Yield 0.79 g.
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]([OH:11])[CH3:10].[Br:12][C:13]1[CH:14]=[C:15]([NH2:20])[CH:16]=[CH:17][C:18]=1[CH3:19].O>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[C:15]([NH:20][CH2:10][CH2:9][OH:11])[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(N)cc1Br
Reactant: CC(O)Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(NCCO)cc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Triethylamine (0.28 mL, 2.00 mmol) and bromoethanol (0.14 mL, 1.98 mmol) were added to a solution of 3-bromo-4-methyl-phenylamine (240 mg, 1.29 mmol) in toluene (2 ml). The mixture was stirred at 100° C. overnight and H2O was then added, followed by extraction with AcOEt (×2). The organic layers were combined and sequentially washed with H2O and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/AcOEt) to give 2-(3-bromo-4-methyl-phenylamino)-ethanol (185 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:7])[CH:5]=O.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:7])[CH2:5][NH:22][C:21]1[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=1
Reactant: COC(=O)C(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Nc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(C)(CNc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-methyl-3-oxo-propionic acid methyl ester (2.35 g, 6.71 mmol) in methanol (25 mL) was added 4-fluoroaniline (0.53 mL, 5.59 mmol) and acetic acid (0.16 mL, 2.80 mmol). A solution of sodium cyanoborohydride (188 mg, 2.99 mmol) in methanol (25 mL) was added dropwise and the reaction mixture stirred for 3 hours at room temperature post addition. The solvent was removed in vacuo and the residue dissolved in DCM (50 mL). The organic solution was treated with aqueous sodium carbonate solution (20 mL, 1N), stirred for 20 min, and the aqueous layer removed. Concentration of the organic layer followed by purification of the residue using flash chromatography (SiO2, DCM) afforded the title compound as a yellow oil (970 mg, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14](=O)[CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])[CH3:24])C(C)C.[BH-](OC(C)=O)(OC(C)=O)[O:27][C:28](C)=O.[Na+].CC([O-])=O.[Na+]>ClCCCl.CC(O)=O>[C:1]([O:5][C:6]([N:8]([CH2:13][CH:14]([NH:19][C@@H:23]1[CH2:25][CH2:28][O:27][CH2:24]1)[CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(CN(CC(=O)O)C(=O)OC(C)(C)C)N[C@@H]1CCOC1

Procedure:
To a solution (0.56 M) of (3S)-tetrahydrofuran-3-amine. HCl (prepared as described in Helv. Chim. Acta 2000, 83, 1825-1845) in DCE were added N-(tert-butoxycarbonyl)-N-(2-oxopropyl)glycine (1.3 eq), DIPEA (1 eq), NaBH(OAc)3(2 eq), cat. AcOH and cat. NaOAc. Reaction mixture was irradiated at MW for 20 min at 120° C. DCE was removed under reduced pressure and the residue purified by filtration on silica gel eluting of the desired intermediate with EtOAc. Evaporation of the organic solvent yielded (II1). MS (ES) C14H26N2O5 requires: 302, found: 303 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH2:14][N:15](C)[C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[C:6]([CH:12]=[O:13])[O:7]2.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:17](=[O:19])[CH:16]([N:15]1[CH2:14][C:5]2[CH2:4][C:3]3[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][C:6]=2[C:12]1=[O:13])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Reactant: Nc1ccccn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)CC(C(=O)Nc1ccccn1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 220.1 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (300 mg, 2.1 mmol), commercially available 2-aminopyridine (101 mg, 1.07 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (190 mg, 0.98 mmol), and N-hydroxybenzotriazole (HOBt) (132 mg, 0.982 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, to afford S)-2-(8-Chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid pyridin-2-ylamide (970 mg, 26.4%), as a white solid. 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.34 (d, J=3.9 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.77 (t, J=7.3 Hz, 1H), 7.21-7.42 (m, 2H), 7.02-7.17 (m, 2H), 5.07 (d, J=4.9 Hz, 1H), 4.44 (d, J=18.6 Hz, 1H), 4.07 (d, J=18.6 Hz, 1H), 3.75 (s, 2H), 1.75-1.90 (m, 1H), 1.61-1.74 (m, 1H), 1.46 (br. s., 1H), 1.24 (s, 1H), 0.93 (t, J=5.9 Hz, 6H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][C:22](=[O:24])[CH3:23]>C(Cl)(Cl)Cl>[C:22]([CH:23]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:24])[CH3:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)CCl
Solvent: ClC(Cl)Cl
Product: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
In a dried flask, 131.15 g (0.5 mole) of triphenylphosphine and 47.2 g (0.51 mole) of chloroacetone were dissolved in 300 ml of chloroform and heated under reflux for 20 hrs. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was added to 1L of water and 5N sodium hydroxide was added to the mixture. Solid substance thus formed was extracted with methylene chloride, and dried using anhydrous magnesium sulfate. The residue where the organic solvented was removed, was washed with n-hexane and dried under vacuum to give 143.1 g of the title compound(yield: 90%). Chemical analysis was performed to identify the desired compound by 1H-NMR spectroscopy.