Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:28])=[C:15]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)=O)[CH:16]=1.[SiH](CC)(CC)CC.[OH-].[K+]>C(Cl)Cl.CC#N>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:28])=[C:15]([CH2:17][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH:16]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 156.4 %

Procedure:
At −20° C., BF3.Et2O (0.75 mL) was added slowly into a solution of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (2 g) and Et3SiH (2 mL) in dry DCM (5 mL) and CH3CN (10 mL), then the mixture was stirred at room temperature for overnight. 7M KOH was slowly added into the mixture, and then the mixture was extracted with DCM, the organic phases were combined, dried over Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica-gel column chromatography (PE/EA=10/1) to obtain 3 g of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:22](O)=[O:23])=[CH:20][CH:21]=1)=[O:16]>>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:22](=[O:23])[NH:12][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH3:11])=[CH:20][CH:21]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: CC(N)c1ccc([N+](=O)[O-])cc1
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc([N+](=O)[O-])cc2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 1, step 3 from 1-(4-nitro-phenyl)-ethylamine and thiophene-2,5-dicarboxylic acid monomethyl ester.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[CH2:35]2.Cl>CN(C=O)C>[O:49]=[C:43]1[CH:42]([N:36]2[CH2:35][C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:8](=[O:10])[C:7]4[CH:6]=[CH:5][C:4]([S:3][CH2:1][CH3:2])=[CH:12][CH:11]=4)[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: CCSc1ccc(C(=O)O)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of 4-(ethylthio)benzoic acid (0.26 g, 1.4 mmol) and CDI (0.24 g, 1.5 mmol) in DMF (30 ml) was stirred at 40° C. for 4 hours. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) was added and the mixture was stirred at 40° C. for 2 h. 4% Aqueous HCl (30 mL) was added and the resulting precipitate was filtered, washed with water (30 mL) and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-ethylsulfanyl-benzamide as a white solid, (0.39 g, 66% yield); mp 217-219° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 35/65 CH3CN/0.1% H3PO4, 5.75 (99.03%); 1H NMR (DMSO-d6) δ 1.26 (t, 3H, J=7.2 Hz), 1.97-2.01 (m, 1H), 2.03-2.45 (m, 1H), 2.57-2.62 (m, 1H), 2.85-2.97 (m, 1H), 3.05 (q, 2H, J=7.2 Hz), 4.30 (d, 1H, J=17.4 Hz), 4.44 (d, 1H, J=17.4 Hz), 4.58 (d, 1H, J=7.8 Hz), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 7.37 (d, 2H, J=8.4 Hz), 7.46 (d, 1H, J=7.8 Hz), 7.53 (s, 1H), 7.69 (d, 1H, J=7.8 Hz), 7.85 (d, 2H, J=8.7 Hz), 9.12 (t, 1H, J=5.7 Hz), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 13.9, 22.5, 25.2, 31.2, 42.7, 47.1, 51.5, 122.0, 122.9, 126.3, 127.0, 127.8, 130.3, 130.6, 140.9, 142.3, 143.9, 165.7, 167.9, 170.9, 172.8; LCMS: MH=438; Anal. Calcd for C23H23N3O4S: C, 62.37; H, 5.37; N, 9.49. Found: C, 62.30; H, 5.29; N, 9.60.
Reaction SMILES: CC(=C(C)C)C.B.C1COCC1.[N+:13]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH2:23][CH:22]=[CH:21]2)([O-:15])=[O:14].[OH-].[Na+].OO.[C:29]([O:32]C(=O)C)(=[O:31])[CH3:30]>C1COCC1.C1(C)C=CC=CC=1.N1C=CC=CC=1.O>[C:29]([O:32][CH:22]1[CH2:23][C:24]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[N+:13]([O-:15])=[O:14])[CH2:21]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccc2c1CC=C2
Agent: B
Agent: CC(C)=C(C)C
Agent: OO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OC1Cc2cccc([N+](=O)[O-])c2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of 2,3-dimethyl-2-butene (21.5 mg, 0.31 mmol) in THF (2 ml) at 0° C. was added borane-THF (0.307 ml, 0.31 mmol) dropwise. After stirred for 1 hour at 0° C., 7-nitro-1H-indene (45.0 mg, 0.28 mmol) in THF (5 ml) was added dropwise, and the mixture was stirred for 2 hours at ambient temperature. The mixture was cooled to 0° C., and water (0.15 ml), 4N aqueous sodium hydroxide (0.45 ml), and 30% H2O2 (0.45 ml) were added. The mixture was then warmed to room temperature and poured into water, extracted with ethyl acetate and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. To the obtained mixture in toluene (1 ml) was added acetic anhydride (40.8 mg, 0.40 mmol) and pyridine (0.4 ml), and then stirred for 16 hours at room temperature. The mixture was concentrated under reduced pressure, and the obtained residue was purified by preparatory TLC (hexane:ethylacetate 2:1) to obtain 4-nitro-2,3-dihydro-1H-inden-2-yl acetate (16.0 mg).
Reaction SMILES: NC1OC[C@:5]2([N:21]=1)[C:18]1C=C(Br)[CH:15]=[CH:14][C:13]=1OC1C2=CC(O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC1C=CC=CC=1C#N.[NH2:37][C:38]1[O:39][CH2:40][C@:41]2([N:65]=1)[C:54]1[CH:53]=[C:52](Br)[CH:51]=[CH:50][C:49]=1[O:48][C:47]1[C:42]2=[CH:43][C:44]([O:56][C:57]2[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=2[C:59]#[N:60])=[CH:45][CH:46]=1.N1C=CC=C(B(O)O)C=1.C(=O)([O-])[O-].[K+].[K+]>O.CCOC(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.C1COCC1.CN(C=O)C>[NH2:37][C:38]1[O:39][CH2:40][C@:41]2([N:65]=1)[C:54]1[CH:53]=[C:52]([C:18]3[CH:5]=[N:21][CH:15]=[CH:14][CH:13]=3)[CH:51]=[CH:50][C:49]=1[O:48][C:47]1[C:42]2=[CH:43][C:44]([O:56][C:57]2[CH:64]=[CH:63][CH:62]=[CH:61][C:58]=2[C:59]#[N:60])=[CH:45][CH:46]=1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
Reactant: N#Cc1ccccc1Oc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
A vial was charged with (R)-2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (210 mg, 0.605 mmol), cesium carbonate (237 mg, 0.726 mmol), and DMF (4033 μL). The mixture was stirred for 15 min, then 2-fluorobenzonitrile (81 μL, 0.665 mmol) was added. The mixture was heated at 85° C. overnight. The reaction was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 40-g Redi-Sep column, eluting with 0-100% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM. The product isolated this way was impure, so the material was resubjected to chromatography on a 40-g Redi-Sep column, this time eluting with 0-100% EtOAc/Hexane. This gave (R)-2-(2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)benzonitrile as 94% pure by HPLC. It was a yellow solid after evaporation from DCM/hexane. Step 2: A vial was charged with (R)-2-(2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)benzonitrile (75 mg, 0.167 mmol), pyridin-3-ylboronic acid (51.4 mg, 0.418 mmol), tetrakis(triphenylphosphine)palladium(0) (9.67 mg, 8.37 μmol), THF (837 μL), and potassium carbonate (418 μL, 0.837 mmol) (as a 2.0 M aq. solution). The vial was sealed and heated to 100° C. in a shaker overnight. The mixture was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were evaporated, and the residue was chromatographed on a 25-g SNAP column, eluting with 0-80% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-2-(2-amino-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)benzonitrile as a pale-yellow solid.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[C@@H:11]([CH3:15])[O:10]C1(C)C)(OC(C)(C)C)=O.[F:18][C:19]1[C:20](I)=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])/[C:22]/2=[CH:29]\[C:30]1[NH:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36].FC(F)(F)C(O)=O.C(Cl)Cl>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.[Cu]I.CN(C=O)C.CCN(CC)CC.C(Cl)Cl.O>[NH2:8][C@@H:12]([C@H:11]([OH:10])[CH3:15])[C:13]#[C:14][C:20]1[C:19]([F:18])=[CH:27][CH:26]=[C:25]2[C:21]=1/[C:22](=[CH:29]/[C:30]1[NH:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36])/[C:23](=[O:28])[NH:24]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@@H]1[C@@H](C)OC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](N)[C@@H](C)O)c21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Using Method C above, (4R,5R)-N-Boc-2,2,5-trimethyl-4-ethynyl-oxazolidine (0.18 g, 0.65 mmol) (Example 102B) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P)4Pd (30 mg) and CuI (6 mg) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 85° C. for 1 day. To the resulting compound in CH2Cl2 (6 mL) was added a 1:1 mixture of trifluoroacetic acid/CH2Cl2 (6 mL) and 3 drops of water at 0° C. and the mixture was stirred at 0° C. for 1.5 h. The mixture was then quenched with conc. NH4OH (6 mL) and diluted with EtOAc. The organic layer was washed with brine and dried with MgSO4. (Z)-4-[(3R,4R)-3-Amino-4-hydroxy-1-pentynyl]-1,3-dihydro-5-fLuoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was purified via flash column chromatography (10% MeOH in CH2Cl2). (Yield 44 mg, 48%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([N:25]5[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]5)[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[C:32](OC(=O)C)(=[O:34])[CH3:33].CCOCC>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][CH:22]([N:25]5[CH2:29][CH2:28][CH:27]([NH:30][C:32](=[O:34])[CH3:33])[CH2:26]5)[CH2:23][CH2:24]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N5CCC(N)C5)CC4)n3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(C2CCN(c3nc(-c4ccc5c(c4)C(C)(C)CCC5(C)C)cs3)CC2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
150 mg (0.32 mmol) of 1-{1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-yl}pyrrolidin-3-ylamine were dissolved in 1 ml of pyridine, and 90 μl of acetic anhydride were added. The reaction mixture was stirred at RT for 15 h and subsequently evaporated. The residue was taken up in ethyl acetate, washed with sat. NaHCO3 solution, dried over Na2SO4 and evaporated. The oil obtained in this way was stirred with ether, and the precipitate formed was filtered off with suction, washed with ether and dried.
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.C[CH2:13][O:14]CC.[Br:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:37])=[C:22]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=2)=O)[C:23]=1OC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.C(#N)C>[Br:17][C:18]1[C:19]([O:14][CH3:13])=[CH:20][C:21]([Cl:37])=[C:22]([CH2:26][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH3:36])=[CH:32][CH:33]=2)[CH:23]=1
Reactant: CCOc1ccc(C(=O)c2c(Cl)ccc(Br)c2OC)cc1
Reactant: CCOCC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCOc1ccc(Cc2cc(Br)c(OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.5 %

Procedure:
Then, Et3SiH (1.62 mL, 10.1 mmol) and BF3.Et2O (0.772 mL, 6.09 mmol) were added sequentially to a chloroform-acetonitrile (1:1; 16 mL) solution of (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.50 g, 4.06 mmol) at −5° C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After the reaction mixture was added with a saturated sodium carbonate aqueous solution and extracted with chloroform, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain a colorless oily title compound (1.48 g, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:27])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[CH3:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C(Nc1cn2cc(O)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.6 %

Procedure:
To a solution of N-(6-hydroxyimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (200 mg, 0.92 mmol) and 4-fluoro-2-methyl-1-nitrobenzene (171.3 mg, 1.1 mmol) in dimethyl sulfoxide (2 mL) was added cesium carbonate (450 mg, 1.38 mmol), and the mixture was stirred at room temperature for 6 hr. Ethyl acetate and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate and collected by filtration to give the title compound (232 mg, 72%) as a brown solid.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[N:9]2)[CH2:3][OH:4].CC1(C)N([O])C(C)(C)CCC1.[K+].[Br-].Cl[O-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C@@H:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=[O:4]
Reactant: C[C@H](CO)Cc1ccc2nccnc2c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](C=O)Cc1ccc2nccnc2c1
Reaction time: 0.08 h

Procedure:
A solution of crude (S)-2-methyl-3-quinoxalin-6-yl-propan-1-ol (3.68 g, 18.19 mmol) in toluene (37 ml) is treated with TEMPO (28.4 mg, 0.152 mmol) and KBr (216.5 mg, 1.82 mmol) in 0.9 ml water. 37 ml of a 0.5 M sodiumhypochlorite solution of pH 8-9 (prepared by mixing 34 ml 0.75 M sodiumhypochlorite solution with 16 ml water and 0.85 g NaHCO3) is added dropwise over 20 minutes at 5° to 8°. After 5 minutes stifling at 0°, the two phase mixture is filtered over Hyflo, the phases separated, the organic phase washed with a solution of 116 mg KI in 15 ml 1 N HCl, then 15 ml of a 5% Na2S2O3 solution and finally 15 ml brine. Drying over Na2SO4 and evaporation afford crude aldehyde. MPLC purification (silicagel, EtOAc/hexane 2:1) yield pure (S)-2-Methyl-3-quinoxalin-6-yl-propionaldehyde as a slightly yellow clear oil. TLC (silicagel, EtOAc/hexanes 2:1): rf 0.37.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:36])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:36][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])=[CH:34][CH:35]=1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: CN(C)CCCOc1ccc(N)cc1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(OCCCN(C)C)cc4)cc3)c(C)c2)no1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 4-(3-dimethylaminopropoxy) aniline (D29) using a similar procedure to Example 20 (38%), as an off-white solid mp 162°-165° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)=[N:8][C:6]=2[N:7]=1.NN.O>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[N:8][C:6]=2[N:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C

Procedure:
To a solution of 2-((5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methyl)isoindoline-1,3-dione 58 (100 mg, 0.24 mmol) in MeOH (7 mL) was added H2N—NH2.H2O. The reaction was heated at reflux for 1 h. After cooling to room temperature the reaction was quenched with water (10 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo to afford (5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methanamine 59.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:45]([O:49][C:50]([NH:52][C@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][C@H:54]1[C:59](O)=[O:60])=[O:51])([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:45]([O:49][C:50](=[O:51])[NH:52][C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]1[C:59]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)=[O:60])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)O
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.348 g, 1.00 mmol), HOBt (0.135 g, 1.0 mmol), EDCI (0.230 g, 1.2 mmol) and rac-cis-2-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid (0.276 g, 1.1 mmol) were dissolved in 5 ml of dry CH2Cl2. The mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of CHCl3 and washed with 10 ml of H2O. The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 30% to 70% EtOAc in hexane to afford the rac-((1R,2S)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidine-1-carbonyl}-cyclohexyl)-carbamic acid tert-butyl ester (573 mg, 100%). The product (0.120 g, 0.21 mmol) was taken up in 1 ml of EtOAc, and cooled in ice bath. 4N HCl-EtOAc (1.0 ml) was added slowly, and the mixture was stirred at room temperature for 5 hours. The solvent was removed and remaining material was triturated with ethyl ether to give the desired product 4 (colorless amorphous, 90 mg, 84%) as hydrochloride salt. LC: 100%. MS: m/z=473.