Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([C@@H:25]2[CH2:29][C@@H:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][N:26]2[C:35](=[O:62])[CH2:36][C:37]([C:54]2[CH:59]=[CH:58][C:57]([CH:60]=[CH2:61])=[CH:56][CH:55]=2)([C:46]2[CH:51]=[CH:50][C:49]([CH:52]=[CH2:53])=[CH:48][CH:47]=2)[C:38]2[CH:43]=[CH:42][C:41]([CH:44]=[CH2:45])=[CH:40][CH:39]=2)=[O:24])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd].[H][H]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([C@@H:25]2[CH2:29][C@@H:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][N:26]2[C:35](=[O:62])[CH2:36][C:37]([C:54]2[CH:55]=[CH:56][C:57]([CH2:60][CH3:61])=[CH:58][CH:59]=2)([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=2)[C:46]2[CH:51]=[CH:50][C:49]([CH2:52][CH3:53])=[CH:48][CH:47]=2)=[O:24])=[O:17])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C=Cc1ccc(C(CC(=O)N2C[C@H](OC(C)(C)C)C[C@H]2C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(C(=O)OC(C)(C)C)C2)(c2ccc(C=C)cc2)c2ccc(C=C)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C(CC(=O)N2C[C@H](OC(C)(C)C)C[C@H]2C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(C(=O)OC(C)(C)C)C2)(c2ccc(CC)cc2)c2ccc(CC)cc2)cc1
Reaction time: 4.5 h
Yield: 76.4 %

Procedure:
To a solution of 15.6 mg of (2R)-N-({(3R)-1-(tert-butoxy-carbonyl)-3-piperidyl}methyl)-1-((2S,4R)-4-(tert-butoxy)-1-{3,3,3-tris(4-vinylphenyl)-propanoyl}pyrrolidin-2-yl)carbonylpyrrolidine-2-carboxamide in 0.6 ml of methanol, 5 mg of 10% palladium-carbon catalyst was added at room temperature, followed by 4.5 hours' stirring in hydrogen atmosphere. After filtering the catalyst off, the solvent was distilled off under reduced pressure to provide 12 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[O:13][C:12](=[O:14])[NH:11][C@@H:10]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH:6]=[CH:7][CH:8]=1.BrC1C=C([C@H]2[C@H](C3C=CC=C(OC)C=3)OC(=O)N2)C=CC=1.C1(C#C)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[O:13][C:12](=[O:14])[NH:11][C@H:10]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Agent: COc1cccc([C@@H]2OC(=O)N[C@H]2c2cccc(Br)c2)c1
Solvent: C#Cc1ccccc1
Product: COc1cccc([C@@H]2OC(=O)N[C@H]2c2cccc(C#Cc3ccccc3)c2)c1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with (−)-(4S,5S)-4-(3-bromophenyl)-5-(3-methoxyphenyl)oxazolidin-2-one and phenylacetylene. 1H-NMR (CDCl3, 500 MHz) δ 7.56 (m, 4H), 7.36-7.45 (m, 4H), 7.34 (m, 1H), 7.30 (m, 1H), 6.92-6.98 (m, 1H), 6.85-6.90 (m, 2H), 5.93 (bs, 1H), 5.31 (d, J=7.3, 1H), 4.78 (d, J=7.3, 1H), 3.84 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 160.2, 158.6, 138.92, 138.85, 132.3, 131.8, 130.2, 129.6, 129.4, 128.7, 128.5, 126.4, 124.6, 122.9, 118.1, 115.0, 111.2, 90.6, 88.6, 85.9, 64.6, 55.5. Mass spec.: 370.14 (MH)+.
Reaction SMILES: CO[CH:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:9]1([C:4](=[CH:3][S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: COC=C(C(=O)OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(=CSc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2.0 g (10.4 mmol) of methyl 3-methoxy-2-phenyl-2-propenoate 1.26 g (11.4 mmol) of thiophenol and 10 mg of p-toluenesulfonic acid monohydrate in 28 ml of toluene was stirred at 90° C. for 9 hours. The reaction mixture was cooled to room temperature and then concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 1.75 g of methyl 2-phenyl-3-(phenylthio)-2-propenoate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[CH2:42]([O:45][CH3:46])[C:43]#[CH:44]>C(NCC)C.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.[Cu](I)I>[CH3:46][O:45][CH2:42][C:43]#[C:44][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39]
Reactant: C#CCOC
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: COCC#Cc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 72.2 %

Procedure:
In a similar manner to Step 2 of Example 161, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (400 mg, 0.674 mmol) was dissolved in diethylamine (16 mL), and the solution was treated with bis(triphenylphosphine)dichloropalladium (56.7 mg, 0.012 mmol), copper iodide (46.2 mg, 0.243 mmol) and methyl propargyl ether (0.398 mL, 4.72 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1 to 8/1) to obtain 4-(3-methoxy-1-propinyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (250 mg, yield 72%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[CH:8][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CCO>[F:30][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:21]=1)[C:17]([NH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:7][CH:8]=1)=[O:31]
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Solvent: CCO
Product: O=C(Nc1ccc(OCCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Yield: 64.7 %

Procedure:
A solution of N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide (0.125 g, 0.283 mmol) and morpholine (0.123 g, 1.4 mmol) in EtOH (3 ml) is heated at 180° C. for 30 min by microwave. The mixture is then concentrated under vacuum and the residue purified by column chromatography on silica gel (5% MeOH in EtOAc) to give 3-fluoro-N-[4-(3-morpholin-4-yl-propoxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide as a white powder (90 mg, 64%). Mp: 70-72° C. 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.23 (m, 1H), 7.86 (m, 1H), 7.56 (m, 2H), 7.45 (s, 1H), 7.42 (d, J=8.1, Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 7.01 (d, J=8.1Hz, 1H), 6.93 (s, 1H), 4.23 (t, J=6.3 Hz, 2H), 3.60 (t, J=4.5 Hz, 4H), 3.29 (m, 4H), 2.55 (m, 2H), 2.42 (bs, 4H), 2.04 (q, J=6.6 Hz, 2H), 1.60 (bs, 6H). MS: 492.4 (M+1).
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br-:13].[K+].N([O-])=O.[Na+].C1(C)C=CC=CC=1>S(=O)(=O)(O)O.C(O)(=O)C>[Br:13][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [Br-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)[C@@H](Br)Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of L-phenylalanine (30.0 g., 0.175 mole) and potassium bromide (73.5 g., 0.618 mole) in 2.5N sulfuric acid (365 ml.) was cooled down to 0° (ice-salt bath) and treated portionwise with sodium nitrite (19.3 g., 0.28 mole) over a period of 1.0 hour. Stirring was continued for 1.0 hour at 0° and at room temperature for 1.0 hour after which the reaction mixture was extracted with ether (3×250 ml.). The combined organic extracts were washed with water (100 ml.) and brine (50 ml.), dried (anhydrous magnesium sulfate), filtered, evaporated to dryness and dried in vacuo to give 34.46 g., of product; Rf =0.45 (toluene:acetic acid, 95:5).
Reaction SMILES: C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[CH2:32])[CH3:31])[C:25]=1[O:33][CH3:34].[F:35][C:36]([F:45])([F:44])[C:37](=[O:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1(C)C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[F:23][C:24]1[C:25]([O:33][CH3:34])=[C:26]([C:30](=[CH2:31])[CH2:32][C:37]([OH:43])([C:36]([F:45])([F:44])[F:35])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:27]=[CH:28][CH:29]=1
Reactant: C=C(C)c1cccc(F)c1OC
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: C=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cccc(F)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
1.56 g (5.7 mmol) of 1,1′-bi-2-naphthol are admixed with 5.7 ml (2.85 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred for 2 hours at room temperature. 9.5 g (57.2 mmol) of 2-fluoro-6-(1-methyleneethyl)anisole and 12.5 ml (95 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-5%) to give 8.9 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 8.9 g (26.5 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate are dissolved in 200 ml of methanol and 2 ml of acetic acid, and 890 mg of palladium on carbon (10%) are added. The suspension is shaken for 1.5 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 560 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 8.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanoate. 8.6 g (25.4 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanoate in 350 ml of diethyl ether are cooled to −30° C. and over 15 minutes 1.7 g (44.7 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1.5 hours, in the course of which the temperature climbs to −15° C., followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate has formed. The suspension is filtered through Celite, the filter bed being thoroughly rinsed with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/diisopropyl ether 0-15%) yields 3.1 g of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[C:23]([C:31]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[CH3:32])[CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH:16]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH2:45]>CN(C=O)C.O>[CH3:37][C:31]([C:23]1[CH:24]=[C:25]2[C:30](=[C:21]([C:17]3[CH:16]=[C:15]([C:2]4[C:3]([C:5]5[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][CH:6]=5)=[N:45][C:40]5[C:39](=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:38]=4)[CH:20]=[CH:19][CH:18]=3)[CH:22]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)([S:33]([CH3:36])(=[O:35])=[O:34])[CH3:32]
Reactant: CC(C)(c1cc(-c2cccc(C(Br)C(=O)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: Nc1ccccc1N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(c1cc(-c2cccc(-c3nc4ccccc4nc3-c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 25 °C

Procedure:
A solution of 2-bromo-2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1-[4-(methylsulfonyl)phenyl]ethanone from EXAMPLE 1, step 4 in DMF (0.05M) and 1,2-diaminobenzene (2 eq) was stirred at 130° C. for 18 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexane:EtOAc, 1:1) to afforded the title compound.
Reaction SMILES: CC([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])CO.C(C(CCCCCCCCCC)[CH2:19][OH:20])C>>[CH2:12]([CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5])[CH2:19][OH:20])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCC(C)CO
Reactant: CCCCCCCCCCC(CC)CO
Product: CCCCCCC(CO)CCCC

Procedure:
2-methyl-1-tridecanol; 2-ethyl-1-dodecanol;
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.C(OCC)(=O)C>[C:26]1([NH:25][C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
A solution of 2-chloro-6-trifluoromethyl-nicotinic acid (5 g, 22.2 mmol) in tetrahydrofuran (20 mL) cooled to −78° C. was treated with lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 66.5 mL, 66.5 mmol). This solution was stirred at −78° C. for 2 h. At this time, the reaction was treated with a solution of aniline (19.6 g, 19.2 mL, 210 mmol) in tetrahydrofuran (20 mL). The reaction was allowed to gradually warm to 25° C. and was stirred at 25° C. overnight. At this time, the reaction mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×150 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in ether to afford 2-phenylamino-6-trifluoromethyl-nicotinic acid (6.19 g, 96.9%) as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N-:12]=[N+:13]=[N-:14].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[N:12]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]2[NH:8][CH:9]=[CH:10][C:4]=12)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1c(Br)cnc2[nH]ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1c(Br)cnc2[nH]ccc12
Temperature: 110 °C
Yield: 43.1 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (1.5 g, 6.5 mmol), sodium azide (2.11 g, 32 mmol), and ammonium chloride (1.73 g, 32 mmol) were suspended in anhydrous dimethylformamide (10 mL). The reaction was heated to 110° C. for 19 h. The reaction mixture was diluted with water and the solids were collected. The solids were dissolved in a mixture of acetone and ethylacetate, the solution was filtered and concentrated to afford 4-Azido-5-bromo-1H-pyrrolo[2,3-b]pyridine (670 mg, 2.8 mmol, 43%). MS: m/z 238.0/240.0 (M+H+).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:50]([O:59][C:60]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[C:51]([O:55][CH:56]([F:58])[F:57])[N:52]=[CH:53][CH:54]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:50]([O:59][C:60]=3[C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[C:51]([O:55][CH:56]([F:57])[F:58])[N:52]=[CH:53][CH:54]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(OC(F)F)nccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(OC(F)F)nccc4c3=O)cc2)CCC1
Yield: 46 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-difluoromethoxy-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a pale orange solid (9 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J=5 Hz, 1H), 7.90 (t, J=72 Hz, 1H), 7.80 (d, J=5 Hz, 1H), 7.44-7.35 (m, 7H), 7.16-7.13 (m, 2H), 2.40-2.32 (m, 2H), 2.12-2.04 (m, 2H), 2.04-1.95 (m, 1H), 1.70-1.61 (m, 1H). LCMS (Method E): RT=3.74 min, [M+Na]+=457.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[CH3:16][CH:17]([CH3:28])[C:18](=[O:27])[CH2:19][CH2:20][C:21]1[S:25][CH:24]=[N:23][C:22]=1[CH3:26]>>[CH3:8][O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][C:18]([OH:27])([CH2:19][CH2:20][C:21]1[S:25][CH:24]=[N:23][C:22]=1[CH3:26])[CH:17]([CH3:16])[CH3:28]
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ncsc1CCC(=O)C(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Product: COC(=O)CC(=O)CC(O)(CCc1scnc1C)C(C)C

Procedure:
The title compound was prepared as described in General Method 6 from 1.00 g (8.61 mmol) of methyl acetoacetate, 0.38 g (9.50 mmol) of sodium hydride, 4.5 mL of 2.1 M nBuLi (9.45 mmol), and 1.53 g (7.75 mmol) of 4-methyl-1-(4-methyl-thiazol-5-yl)-pentan-3-one (prepared in Example C-2.) The crude compound was used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][NH:8][C:9]2[S:13][C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=[C:17]4[C:33]3[N:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[C:41](=[O:46])[CH2:40]4)[CH:36]=[N:35][CH:34]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[K+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[S:13][C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][CH:18]=[C:17]4[C:33]3[N:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[C:41](=[O:46])[CH2:40]4)[CH:36]=[N:35][CH:34]=3)=[N:11][N:10]=2)=[CH:47][CH:48]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(N5CCN(C)C(=O)C5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(-c5cncc(N6CCN(C)C(=O)C6)n5)c4c3)s2)cc1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with 4-(6-(5-(5-(4-methoxybenzylamino)-1,3,4-thiadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yl)-1-methylpiperazin-2-one (70 mg, 0.103 mmol) in THF (2 mL) followed by 1 M KOH (500 μL, 0.500 mmol). The mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 1 h, then cooled to RT. The mixture was diluted with H2O, and extracted with DCM. The combined organic layers were dried, filtered and concentrated to give the crude 4-(6-(5-(5-(4-methoxybenzylamino)-1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyrazin-2-yl)-1-methylpiperazin-2-one. MS (ESI, pos. ion) m/z: 527 (M+1). A glass microwave reaction vessel was charged with the above crude compound (54 mg, 0.103 mmol) in TFA (1 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min, then solvent was removed. The residue was purified with RP-HPLC to give 4-(6-(5-(5-amino-1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyrazin-2-yl)-1-methylpiperazin-2-one (10.0 mg, 0.025 mmol, 24%) as a light yellow solid. MS (ESI, pos. ion) m/z: 407 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (1H, br. s.), 8.73 (1H, s), 8.48 (1H, s), 8.28 (1H, d, J=2.5 Hz), 8.05 (1H, s), 7.74 (1H, dd, J=8.5, 1.5 Hz), 7.53 (1H, d, J=8.4 Hz), 7.26 (3H, s), 4.23 (2H, s), 4.06 (2H, t, J=5.4 Hz), 3.60 (2H, t, J=5.5 Hz), 3.28 (1H, s), 2.96 (3H, s)
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:29][O:30]CC=C)[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:28])[CH:6]=[CH:7][CH:8]=1>C(Cl)Cl>[O:27]=[C:11]1[N:10]([CH3:28])[C:9]([CH2:29][OH:30])([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:34])([F:35])[F:1])[CH:4]=2)[C:13](=[O:14])[N:12]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: C=CCOCC1(c2cccc(C(F)(F)F)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Solvent: ClCCl
Product: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 782 mg of 4-[4-(3-Trifluoromethylphenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in DCM (5 mL), 662 μL of trifluoroborane-dimethylsulfide complex are added. The mixture is stirred 6 hours at room temperature, diluted with DCM, washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound.
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]([CH:21]1[CH2:23][O:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C1C=C(C=N[C@H]2[C@H](N=CC3C([O-])=C(C(C)(C)C)C=C(C(C)(C)C)C=3)CCCC2)C([O-])=C(C(C)(C)C)C=1)(C)C.[Co+2].C(O)(=O)C.O>[CH:8]([C@@H:21]1[CH2:23][O:22]1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(C(c2ccccc2)C2CO2)cc1
Agent: [Co+2]
Agent: CC(C)(C)c1cc(C=N[C@@H]2CCCC[C@H]2N=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2[O-])c([O-])c(C(C)(C)C)c1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)[C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A mixture of (R,R)-(−)-N,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane diaminocobalt (II) (0.22 g, 0.37 mmol, 0.8%), toluene (5 ml), and acetic acid (0.044 g, 0.74 mmol) was stirred for 1 h at room temperature. The solvent was removed in vacuo and the residue was dried. 2-Benzhydryl-oxirane (9.6 g, 45.7 mmol) was added in one portion and stirred, the mixture was then cooled by means of an ice-bath. H2O (0.58 g, 32 mmol) was slowly added over a 30-min period. After water addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 72 h. Compounds were separated via flash chromatography on silica gel column to give (2R)-2-benzhydryl-oxirane (23a) 4.5 g ([α]D=(+)9.58, c=1, MeOH) and (2S)-3,3-diphenyl-propane-1,2-diol 24.3.53 g ([α]D=(+)48, c=1, MeOH, ee=97%). The proton and carbon NMR data of (2R)-2-benzhydryl-oxirane was identical to the racemate 2-benzhydryl-oxirane.