Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[N:16]([CH:17]=1)[C:15]([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)=[CH:14][S:13]2)([O-])=O>C(O)C.[Pd]>[N:19]1([CH2:18][C:15]2[N:16]3[CH:17]=[C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH2:1])[N:11]=[C:12]3[S:13][CH:14]=2)[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: O=[N+]([O-])c1ccccc1-c1cn2c(Cn3cncn3)csc2n1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1-c1cn2c(Cn3cncn3)csc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.1 %

Procedure:
6-(2-Nitro-phenyl)-3-[1,2,4]triazol-1-ylmethyl-imidazo[2,1-b]thiazole (54 g, 165 mmol) was dissolved in ethanol (2.0 L). Pd/C (10%, 20 g) was added, and the flask was evacuated and backfilled with H2. The reaction mixture was stirred under H2 at room temperature (2 days). The reaction mixture was then passed through a silica gel pad, and the filtrate was concentrated in vacuo to give a yellow solid. The solid was washed with ethanol to give 2-(3-[1,2,4]triazol-1-ylmethyl-imidazo[2,1-b]thiazol-6-yl)-phenylamine as a yellow solid (46 g, 94% yield).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[C:14](O)(=[O:16])[CH3:15].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:9][C:14](=[O:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a solution of 4-(trifluoromethoxy)benzylamine (3.46 g, 57.6 mmol) in DMF (75 mL) and acetic acid (10.0 g, 52.3 mmol) at −10° C. were added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (20.2 g, 62.8 mmol) and N,N-diisopropylethylamine (20.0 mL, 115 mmol) and the reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added and the organic phase was washed with water (100 mL), 0.25 M NaOH (100 mL), saturated aqueous NaHCO3 (100 mL), water (100 mL), 0.5 M HCl (100 mL), and water (100 mL), dried over MgSO4, and concentrated in vacuo to afford 11.2 g (92%) of a colourless oil.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:24])[NH:8][CH2:9][C:10]2([C:13]3[N:23]=[C:16]4[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][N:15]4[N:14]=3)[CH2:12][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:25]N1C(=O)CCC1=O.B(F)(F)F.[O-]S([O-])(=S)=O.[Na+].[Na+]>C([O-])(O)=O.[Na+]>[CH:1]1([O:6][C:7](=[O:24])[NH:8][CH2:9][C:10]2([C:13]3[N:23]=[C:16]4[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[C:20]([I:25])[N:15]4[N:14]=3)[CH2:11][CH2:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccn2nc(C3(CNC(=O)OC4CCCC4)CC3)nc12
Reactant: O=C1CCC(=O)N1I
Agent: FB(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: COc1ccc(I)n2nc(C3(CNC(=O)OC4CCCC4)CC3)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere [1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-carbamic acid cyclopentyl ester was mixed with N-iodosuccinimide. BF3*2H2O was added at 0° C. The dark suspension was stirred at rt for 3 h after which it was poured onto a 1:1 solution of saturated Na2S2O3 and saturated NaHCO3 (20 mL). The aqueous phase was extracted with DCM (×2) and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica to afford [1-(5-Iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-carbamic acid cyclopentyl ester.
Reaction SMILES: C(OC(N[C@H](C1C=CC=C(NC(OCCC2C=CC(Br)=CC=2C)=O)C=1)CC(OCC)=O)=O)C1C=CC=CC=1.[N:39]([C:42]1[CH:43]=[C:44]([CH:54]=[CH:55][CH:56]=1)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[C:40]=[O:41].[Br:57][C:58]1[CH:63]=[CH:62][C:61]([CH2:64][CH2:65][OH:66])=[C:60]([Cl:67])[CH:59]=1>>[C:49]([O:48][C:47]([NH:46][CH2:45][C:44]1[CH:43]=[C:42]([NH:39][C:40]([O:66][CH2:65][CH2:64][C:61]2[CH:62]=[CH:63][C:58]([Br:57])=[CH:59][C:60]=2[Cl:67])=[O:41])[CH:56]=[CH:55][CH:54]=1)=[O:53])([CH3:51])([CH3:52])[CH3:50]
Reactant: CC(C)(C)OC(=O)NCc1cccc(N=C=O)c1
Reactant: OCCc1ccc(Br)cc1Cl
Agent: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Product: CC(C)(C)OC(=O)NCc1cccc(NC(=O)OCCc2ccc(Br)cc2Cl)c1
Yield: 50 %

Procedure:
Using a procedure analogous to that used to prepare 34D, 61C (1.94 g, 8.73 mmol) was reacted with 61B to give 61D (1.84 g, 50%) as an oil. MS (ESI) m/z 385.1 (M+H)+.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([NH:6][CH3:4])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Methylamine hydrochloride (1057 mg, 15.65 mmol) and triethylamine (3.3 mL, 23.48 mmol) were dissolved in dichloromethane (20 mL) and then 3-bromobenzene-1-sulfonyl chloride (4.0 g, 15.65 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours, diluted with dichloromethane, and washed with brine. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. The resultant target compound (3.5 g, 90% yield) was used in the following reaction without purification.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:13]([NH2:23])=[C:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C1COCC1>[N:1]1([C:10]2[N:15]=[C:14]3[C:13]([NH:23][C:35](=[O:36])[N:16]3[CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(NC2CCOCC2)nc(-n2cnc3ccccc32)nc1-c1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]c2c(-c3ccccc3)nc(-n3cnc4ccccc43)nc2n1C1CCOCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 29.5 %

Procedure:
To 30 mg (0.078 mmol) of crude 2-(1H-benzo[d]imidazol-1-yl)-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-4,5-diamine in 3 mL THF was added CDI (38 mg, 0.233 mmol, 3 equiv.) and the reaction mixture was stirred at 50° C. for 18 h. The solvent was removed in vacuo and the residue purified by preparative TLC (silica gel, 5% methanol in methylene chloride) to afford the desired product (9.5 mg, 30% yield). 1H NMR (300 MHz, CDCl3) δ, ppm: 9.16 (br s, 1H), 8.68 (d, 1H), 8.06 (br m, 2H), 7.90 (d, 1H), 7.71-7.62 (m, 3H), 7.52-7.33 (m, 3H), 4.82-4.68 (m, 1H), 4.31-4.20 (m, 2H), 3.64 (app t, 2H), 3.01-2.82 (m, 2H), 1.89 (br d, 2H); MS (EI) m/z 413.2 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12][C:11]=2[C:19]([O:21]C)=[O:20])[CH:5]=[CH:6][CH:7]=1.C1COCC1.CO.[OH-].[Li+]>O>[Br:1][C:2]1[C:3]([CH3:23])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:17])([CH3:18])[CH3:16])[S:12][C:11]=2[C:19]([OH:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(C(C)(C)C)cc1CNc1cccc(Br)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(Br)cccc1NCc1cc(C(C)(C)C)sc1C(=O)O
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A 50-mL single-necked round-bottomed flask equipped with a magnetic stirrer was charged with 102d (1.30 g, 3.28 mmol), THF (5.0 mL), methanol (5.0 mL) and water (5.0 mL). Lithium hydroxide (1.38 g, 32.8 mmol) was added and the mixture was placed in a 40° C. oil bath. After 16 h the reaction mixture was cooled to room temperature and the volatiles removed under reduced pressure. The resulting aqueous solution was acidified with 2 N hydrochloric acid to pH of 4. The resulting solid was filtered off and dried in a vacuum oven at 40° C. affording a quantitative yield (1.25 g) of 102e as a white solid: mp 150-152° C.; 1H NMR (300 MHz, DMSO-d6) δ 6.85 (t, 1H, J=7.8 Hz), 6.75-6.67 (m, 3H), 4.35 (s, 2H), 2.18 (s, 3H), 1.26 (s, 9H); MS (APCI−) m/z 380.2 (M−H).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[OH:17])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:28]>C(OCC)(=O)C>[NH2:28]/[C:6](/[C:5]1[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=1[N+:1]([O-:3])=[O:2])=[C:8]1\[C:9](=[O:17])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12]\1
Reactant: N
Reactant: O=C(c1ccccc1[N+](=O)[O-])c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1[N+](=O)[O-]
Yield: 21 %

Procedure:
Prepared as in Example 1 from 2-(2-nitrobenzoyl)-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated aqueous ammonia with a yield of 21% of theory. M.p. 185°-186° C. (ethyl acetate).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([NH:40][CH3:41])=[O:39])=[CH:36][C:35]=1[O:44][CH3:45].C(=O)([O-])[O-].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.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]>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]5[N:15]=[C:16]([CH3:18])[O:17][C:13]=5[CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:33][C:34]3[CH:43]=[CH:42][C:37]([C:38]([NH:40][CH3:41])=[O:39])=[CH:36][C:35]=3[O:44][CH3:45])[N:3]=2)[CH2:32][CH2:31]1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CC5)c34)cc2o1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Nc2nc(OC3CC3)c3c(-c4ccc5nc(C)oc5c4)cn(COCC[Si](C)(C)C)c3n2)c(OC)c1
Temperature: 140 °C
Yield: 57.5 %

Procedure:
A mixture of 6-(2-chloro-4-cyclopropoxy-7-((2-(trimethylsilyl)-ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-methoxy-N-methylbenzamide (2 equiv), potassium carbonate (3.5 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.23 equiv), tris(dibenzylideneacetone)dipalladium (0.23 equiv) in 1,4-dioxane (0.085 M) was purged with nitrogen and sealed. The reaction mixture was heated to 140° C. for 1.5 h. After cooling to room temperature the reaction mixture was purified using flash chromatography (0-100% ethyl acetate in hexane then 0-20% MeOH in DCM) eluted with 17% MeOH in DCM to give the title compound (57.5% yield) as brown oil. MS (ESI) m/z 615.4 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[CH:14][C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[C:7]3[CH:8]=[CH:9][S:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[Li]CCCC.[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:29][C:9]1[S:10][C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=3[C:6](=[CH:14][C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cccc(C=C2c3ccc(Cl)cc3CCc3sccc32)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1cccc(C=C2c3ccc(Cl)cc3CCc3sc(Cl)cc32)c1
Yield: 21 %

Procedure:
As in Example 553 (above), using 3-(7-chloro-9,10-dihydro-1-thia-benzo[f]azulen-4-ylidenemethyl)-phenylamine, n-BuLi in hexanes, THF, and hexachloroethane. Purify the crude residue by column chromatography (5% to 20% to 30% EtOAc:hexanes) to give title compound as an oil (21%) along with recovered starting material: 1H NMR (CDCl3, 400 MHz) δ 2.06-3.02 (m, 4 H), 3.53 (br s, 2 H), 6.32 (s, 1 H), 6.38 (d, J=7.2 Hz, 1 H), 6.48 (dd, J=7.2 Hz, 1.6 Hz, 1 H), 6.79 (s, 1 H), 6.93-6.96 (m, 3 H), 7.02 (dd, J=8.2 Hz, 2.2 Hz, 1 H), 7.27 (d, J=8.2 Hz, 1 H). TLC Rf=0.55 (30% EtOAc:hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH:46]([NH2:48])[CH3:47]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:48][CH:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[F:39])[CH3:47])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(N)c1ccccc1F
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4ccccc4F)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 84 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-(2-fluorophenyl)ethylamine: yield 84%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].C(OC(=O)[CH2:32][C:33]#[N:34])(C)(C)C.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.C1(C)C=CC=CC=1.O>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH2:32][C:33]#[N:34])=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CC(C)(C)OC(=O)CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
2-(4-fluoro-3-nitrophenyl)-1,3-benzoxazole (200 mg, 0.77 mmol) was dissolved in DMSO (5 mL) and K2CO3 (267 mg, 1.94 mmol) was added. The resulting yellow mixture was warmed to 65° C. and tert-butylcyanoacetate (137 mg, 0.97 mmol) was added dropwise. The dark red mixture was heated to 65° C. for 30 min, cooled to rt, and poured into H2O. The aqueous layer was acidified to pH 3 (with a 10% aqueous HCl solution) and it was extracted with EtOAc (3×). The organics were combined, washed with brine (2×), dried over Na2SO4, and evaporated to dryness. The yellow residue and p-toluenesulfonic acid (29.5 mg, 0.15 mmol) were dissolved in toluene (15 mL) and the mixture was refluxed for 20 h. After cooling to rt, the mixture was poured in H2O and the two layers were separated. The aqueous was extracted with EtOAc (3×), the organics were combined, dried over Na2SO4, and evaporated to dryness. Purification of the residue by flash chromatography on silica gel eluting with EtOAc:hexanes (3:7 to 2:3 to 1:1) afforded the desired [4-(1,3-benzoxazol-2-yl)-2-nitrophenyl]acetonitrile as an orange solid (M.p. 203° C.). 1H NMR (CDCl3, 300 MHz) δ 8.79 (s, 1H), 8.57 (dd, 1H), 7.97 (d, 1H), 7.86 (m, 2H), 7.54–7.44 (m, 2H), 4.50 (s, 2H). MS (ESI) 280 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[S:11](=[O:44])(=[O:43])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH:20][C:21]2[C:26]([C:27]3[N:35]=[CH:34][N:33]=[C:32]4[C:28]=3[N:29]=[CH:30][N:31]4C3CCCCO3)=[CH:25][CH:24]=[CH:23][N:22]=2)[C:14]=1[F:42])=[O:5]>>[CH3:2][O:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[S:11](=[O:44])(=[O:43])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH:20][C:21]2[C:26]([C:27]3[N:35]=[CH:34][N:33]=[C:32]4[C:28]=3[N:29]=[CH:30][NH:31]4)=[CH:25][CH:24]=[CH:23][N:22]=2)[C:14]=1[F:42])=[O:5]
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Agent: Cl
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F
Reaction time: 2 h
Yield: 87 %

Procedure:
1M aqueous hydrochloric acid solution was added into the methyl-3-(N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (20 mg, 0.032 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 15 mg of the target compound, methyl-3-(N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)sulfamoyl)thiophene-2-carboxylate (percentage yield: 87%), was obtained.
Reaction SMILES: [NH2:1][C@@H:2](/[CH:5]=[C:6](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)\[CH2:7][CH3:8])[CH2:3][OH:4]>CO.[Pd]>[NH2:1][C@@H:2]([CH2:5][CH:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][CH3:8])[CH2:3][OH:4]
Reactant: CC/C(=C\[C@H](N)CO)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC(C[C@H](N)CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (E)-(S)-2-amino-4-phenyl-hex-3-en-1-ol (1.0 g) at r.t. in methanol (50 ml) under an argon atmosphere was added 10% Pd/C (278 mg). The mixture was stirred at r.t. under a hydrogen atmosphere for 30 min. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: dichloromethane/methanol) to give (S)-2-amino-4-phenyl-hexan-1-ol (mainly one epimer) (0.81 g, 80%) as a colourless oil. MS (ISP): 194.4 ([M+H ]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1>[Pd].CO>[CH3:12][C:4]1[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=[CH:2][N:3]=1
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccnc(C)c1
Yield: 52.9 %

Procedure:
A mixture of methyl 2-chloro-6-methyl-pyridine-4-carboxylate (1.8 g, 10 mmol) and 10% palladium-on-charcoal catalyst (200 mg) in methanol (100 ml) was stirred under hydrogen at 5 atmospheres pressure. The catalyst was removed by filtration and the volatiles removed from the filtrate by evaporation. The residue was treated with 10% aqueous sodium hydroxide solution and extracted with ether (3×30 ml). The combined extracts were dried (MgSO4) and the solvent removed by evaporation to give methyl 2-methyl-pyridine-4-carboxylate (800 mg, 53%) as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].O.[CH3:15]S(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:3]([C:7]1[O:11][C:10]([CH:12]=[CH2:15])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc(C=O)o1
Reactant: CS(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: O
Product: C=Cc1ccc(C(C)(C)C)o1
Temperature: 15 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Sodium hydride (7.09 g-50% suspension in oil, 0.148 mol) was washed with petroleum ether, suspended in dry DMSO (100 ml) and heated with stirring at 60°-70° C. for 2 hours. The reaction mixture was then cooled to 15° C. and methyltriphenylphosphonium bromide (52.74 g, 0.136 mol) was added portionwise with rapid stirring over a 1/2 hour period. The reaction mixture was stirred at room temperature for a further 1 hour after the addition and 5-t-butyl-2-furancarboxaldehyde (22.46 g, 0.148 mol) was added dropwise over a period of 1 hour. The resultant reaction mixture was stirred at room temperature for 12 hours, poured into water (300 ml) and extracted with ether (4×150 ml). The ethereal extracts were washed with water (4×100 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow oil which was purified by column chromatography (silica eluted with petroleum ether) to give (5-t-butylfuran-2-yl)-ethylene (11.03 g, 50%). Ethyl diazoacetate (4.45 g, 0.039 mol) in dry dichloromethane (70 ml) was added dropwise to a solution of (5-t-butylfuran-2-yl)-ethylene (5.85 g, 0.039 mol) and anhydrous copper (II) sulphate (0.3 g) in dry dichloromethane (30 ml) at 90° C. by means of a syringe pump over a period of 5 hours. The dichloromethane was distilled over during the addition. After complete addition the remaining dichloromethane was removed in vacuo and the resulting brown oil purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) to give ethyl 2-(5-t-butylfuran-2-yl)-cyclopropanecarboxylate (2.1 g, 23%).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21](S(O)(=O)=O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH2:9][C:8]2[CH2:28][C:18]3[C:23]([C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=CC(c2ccccc2)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: c1ccc(C2=C(CC3=C(c4ccccc4)c4ccccc4C3)Cc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 246.7 %

Procedure:
In a 500 mL flask equipped with magnetic stirring bar were introduced 4.46 g (0.023 moles) of 1-phenyl-indene, 0.35 g (0.0117 moles) of formalin and 0.88 g (0.0046 moles) of para-toluenesulphonic acid in 200 ml of toluene; the mixture was heated to 80° C. and was maintained under stirring for 6 hours at 80° C. Then the reaction was quenched with water/NaHCO3; the organic layer was separated, washed with water and brought to dryness under reduced pressure. The crude product was crystallized upon standing at room temperature, and then was further purified by washing with pentane or MeOH, thus isolating 4.5 g of bis(3-phenyl-2-indenyl)methane (purity of 97.3% by G.C.; yield=95.2%).
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][CH:7]=[C:8]([C:13]2[CH:14]=[N:15][C:16]([N+:19]([O-])=O)=[CH:17][CH:18]=2)[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([NH:4][C:5]1[NH:6][CH:7]=[C:8]([C:13]2[CH:14]=[N:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])nc2)c1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1[nH]cc(-c2ccc(N)nc2)c1C(N)=O
Yield: 81.7 %

Procedure:
0.15 g (0.519 mmol) of 2-acetylamino-4-(6-nitropyridin-3-yl)-1H-pyrrole-3-carboxamide is added at a temperature in the region of 25° C. to a suspension of 0.015 g (0.014 mmol) of 10% palladium on carbon in 20 cm3 of methanol. After hydrogenating for 2 hours in an autoclave under 2 bar of hydrogen, at a temperature in the region of 30° C., the reaction mixture is filtered, the catalyst is rinsed with twice 2 cm3 of ethyl ether. After draining and drying, 0.11 g of 2-acetylamino-4-(6-aminopyridin-3-yl)-1H-pyrrole-3-carboxamide is obtained, in the form of a brown solid. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 2.13 (s, 3H); 6.01 (broad s, 2H); from 5.50 to 8.85 (very broad m, 2H); 6.35 (d, J=2.5 Hz, 1H); 6.49 (d, J=8.5 Hz, 1H); 7.36 (dd, J=2.5 and 8.5 Hz, 1H); 7.87 (d, J=2.5 Hz, 1H); 10.65 (s, 1H); 11.35 (broad s, 1H).
Reaction SMILES: [C:1](Cl)(=O)C.[CH:5]1[C:10]([CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])=[CH:9][C:8]([OH:17])=[C:7]([OH:18])[CH:6]=1>CO>[CH3:1][O:14][C:13]([C@@H:12]([NH2:16])[CH2:11][C:10]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([OH:17])[CH:9]=1)=[O:15]
Reactant: CC(=O)Cl
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Temperature: 15 °C
Yield: 117.3 %

Procedure:
A 3-Liter three-necked round-bottom flask equipped with a cooling bath, a thermometer and a condenser was charged with 1.5 Liters methanol, and acetyl chloride (119 ml, 1.2 mol) was carefully added thereto at 0° C. The cooling bath was replaced with a heating mantle and the mixture was heated to 15° C. 60 grams (0.3 mol) of L-3-(3,4-dihydroxy-phenyl)alanine was then added and the reaction mixture was refluxed for 3 hours and thereafter concentrated under reduced pressure at 60° C. to afford 74.3 grams (100% yield) of Compound 2 (see, Scheme 1). The product structure was confirmed by 1H-NMR.