Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]#[C:12][N:13]3[C:21]4[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[C:15]4[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:14]3=4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:1]1[C:10]2[C:5](=[C:6]([CH:11]=[CH:12][N:13]3[C:21]4[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[C:15]4[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:14]3=4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1ccc2c(c1)c1c(n2C#Cc2cccc3cnccc23)CCN(C)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2C=Cc2cccc3cnccc23)CCN(C)C1
Yield: 22.1 %

Procedure:
To a solution of 5-isoquinolin-5-ylethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (90 mg, 0.256 mmol) in MeOH (6 mL) were added 10% dry Pd—C (25 mg) and ammonium formate (81 mg, 1.282 mmol). The reaction mixture was refluxed for 2 h and filtered through Celite. The filtrate was concentrated under reduced pressure to afford crude product, which was purified by reverse phase HPLC to yield 20 mg of 5-(2-isoquinolin-5-yl-vinyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 9.7 (s, 1H), 8.57 (d, 1H), 8.5 (d, 1H), 8.3 (d, 1H), 7.65 (t, 1H), 7.59 (d, 1H), 7.4 (d, 1H), 7.22 (d, 1H), 7.2 (s, 1H), 6.7 (m, 2H), 4.63 (d, 1H), 4.3 (d, 1H), 3.7 (m, 1H), 3.47 (m, 1H), 3.08 (s, 3H), 2.9-3.0 (m, 2H), 2.31 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[C:10](=[O:21])[CH:9]=1.[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.O.C(OCC)(=O)C>[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH:33][C:14](=[O:16])[C@@H:13]([N:11]2[CH2:12][C:8]([O:7][C:6]3[CH:22]=[CH:23][CH:24]=[C:4]([CH2:3][C:2]([OH:1])([CH3:26])[CH3:25])[CH:5]=3)=[CH:9][C:10]2=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[N:29]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Reactant: Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a solution of (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (0.100 g, 0.28 mmol) in dichloromethane (10 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.040 g, 0.41 mmol), N,N-diisopropylethylamine (0.110 g, 0.85 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.180 g, 0.41 mmol) at 0° C. The mixture was allowed to slowly warm up to room temperature and then stirred for 2 h. The mixture was partioned between ethyl acetate and water. The organic layer was then collected and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 30% to 100% ethyl acetate/hexanes) which afforded (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.075 g, 62%) as a white solid: HR-ES-MS m/z calculated for C24H32N4O4 [M+H]+ 441.2497, observed 441.2497; 1H NMR (300 MHz, CDCl3) δ ppm 0.92-1.01 (m, 6H), 1.24 (s, 6H), 1.40-1.69 (m, 2H), 1.68-1.97 (m, 2H), 2.78 (s, 2H), 3.82 (br. s., 3H), 4.07 (d, J=18.1 Hz, 1H), 4.27 (d, J=17.5 Hz, 1H), 4.79-4.94 (m, 1H), 4.97 (s, 1H), 6.60 (br. s., 1H), 7.07 (br. s., 2H), 7.14 (d, J=7.5 Hz, 1H), 7.30-7.40 (m, 2H), 8.55 (br. s., 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][S:16](=[O:20])(=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:22]([C:24]1[N:25]=[C:26]([C:37](O)=[O:38])[N:27](COCC[Si](C)(C)C)[CH:28]=1)#[N:23].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N>>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:14][NH:15][S:16](=[O:20])(=[O:19])[NH:17][CH2:18]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:37]([C:26]2[NH:27][CH:28]=[C:24]([C:22]#[N:23])[N:25]=2)=[O:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CNS(=O)(=O)NC3)cc2C2=CCCCC2)n1
Yield: 25 %

Procedure:
2-Cyclohex-1-enyl-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenylamine (as prepared in the previous step, 30.7 mg, 0.100 mmol) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d), 33.6 mg, 0.260 mmol) as described in Example 1, step (l) to obtain the title compound (14 mg, 25%) after purification on silica (20-50% EtOAc-hexane): Mass spectrum (ESI, m/z): Calcd. for C26H36N6O4SSi, 557.2 (M+H). found 556.8.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:28]1[C:42]2=[C:43]3[C:35]([C:36]4[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:34][CH:33]=[CH:32][C:31]3=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].N#N.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CCO.O>[CH:28]1[C:42]2=[C:43]3[C:35]([C:36]4[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:34][CH:33]=[CH:32][C:31]3=[C:30]([C:2]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:29]=1
Reactant: CCOC(=O)c1cc(-c2cccc3ccccc23)c(C(=O)OCC)cc1Cl
Reactant: OB(O)c1ccc2c3c(cccc13)-c1ccccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccc3c4c(cccc24)-c2ccccc2-3)c(C(=O)OCC)cc1-c1cccc2ccccc12

Procedure:
15.4 g (40 mmol) of diethyl 2-chloro-5-naphthalen-1-ylterephthalate, 14.0 g (56 mmol) of fluoranthene-3-boronic acid and 17.7 g of Cs2CO3 are initially introduced in 70 ml of dry dioxane and saturated with N2 for 30 min. 0.8 ml of a 1.0 M solution of tri-tert-butylphosphine in toluene, followed by 91 mg (0.4 mmol) of Pd(OAc)2 are then added. The mixture is heated at the boil for 4 h, extended with water and EtOH, the precipitate is filtered off with suction, washed with heptane and dried. The solid is recrystallised from toluene and then has, according to 1H-NMR, a purity of >95%. The yield is 8.5 g (38%) of colourless solid.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:12][C:11](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18](=[CH:23][CH:24]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:10][CH:9]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([C:3]1([C:8]2[S:12][C:11]([CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18](=[CH:23][CH:24]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:10][CH:9]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2]
Reactant: CCC1(c2ccc(/C=C/c3ccc(C(=O)OC)c(C(=O)OC)c3)s2)OCCO1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC1(c2ccc(CCc3ccc(C(=O)OC)c(C(=O)OC)c3)s2)OCCO1
Temperature: 80 °C

Procedure:
9.3 g (23 mmol) of dimethyl 4-{(E)-2-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienyl]vinyl}phthalate are dissolved in 150 mL of dioxane and 1 mL of triethylamine is then added. The mixture is degassed using a stream of nitrogen and 9.3 g of 5% palladium-on-charcoal are then added to the reaction medium. A positive pressure of hydrogen is maintained in the reaction medium for 5 hours, with heating at 80° C. After cooling and then filtration through Celite and evaporation, the desired product is obtained in the form of a yellow oil (m=9.4 g; Y=100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]1[O:17][C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:10][CH2:9]1>CC1C=CC(C)=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][C:11]3([O:17][CH2:8][CH2:9][O:10]3)[CH2:12][CH2:13]2)=[CH:3][CH:4]=1
Reactant: Clc1ccncc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: Cc1ccc(C)cc1
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 90.5 %

Procedure:
A solution of 46 g (0.4 mol) 4-chloropyridine and 123.5 g (0.86 mol) 4-piperidone ethylene ketal is heated for 48 hours to reflux in 400 ml p-xylene. Subsequently the reaction mixture is cooled, the precipitated precipitate is removed by filtration, the mother liquor is concentrated to dryness and the residue is purified by column chromatography on silica gel (ethyl acetate/saturated ammonia-alkaline methanol 9/1). In this way 79.7 g (90%) 8-pyridin-4-yl-1,4-dioxa-8-aza-spiro[4.5]decane is obtained as a white powder. m/e=220; f.p.=65° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10]C)=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].ClC1C2OCOC=2C=CC=1C=O.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:9]2[O:10][CH2:13][O:12][C:8]=2[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(C=O)c(Cl)c1OC
Agent: O=Cc1ccc2c(c1Cl)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1Cl)OCO2

Procedure:
2-Chloro-3,4-dimethoxybenzaldehyde was converted to 4-chloro-1,3-benzodioxole-5-carboxaldehyde by the method of S. T. Ross, R. G. Franz, J. W. Wilson, R. A. Hahn and H. M. Sarau, J. Heterocyclic Chemistry, (1986) 23, 1805. Reduction of the aldehyde was then carried out with sodium borohydride (1 equivalent) in THF at 0° C. to provide 4-chloro-1,3-benzodioxole-5-methanol (Examples 30A, 31 A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NCc1ccccn1
Product: O=C(NCc1ccccn1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-(aminomethyl)pyridine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-2-ylmethyl)terephthalamide. MS (Q1) 477 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[N:32]=[CH:33][C:34]([C:37]([O:39]CC)=[O:38])=[N:35][CH:36]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.CSC.[Br-].[Al+3].[Br-].[Br-]>ClCCl.C(#N)C.CCOC(C)=O.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[N:32]=[CH:33][C:34]([C:37]([OH:39])=[O:38])=[N:35][CH:36]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:42])=[C:16]([F:22])[CH:17]=1
Reactant: CCOC(=O)c1cnc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cn1
Agent: [Al+3]
Agent: [Br-]
Solvent: CSC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cnc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 5 h

Procedure:
To a solution of ethyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)pyrazine-2-carboxylate (27.6 mg, 0.0448 mmol) in dichloromethane (2 ml) were added DIMETHYL SULFIDE (846 mg, 0.0136 mmol) and ALUMINUM BROMIDE (64.5 mg, 0.242 mmol). The mixture was stirred under argon for 5 hrs. The reaction mixture was diluted with acetonitrile (2 ml), EtOAc (10 ml) and water (10 ml) and stirred for several minutes. After more ethyl acetate (50 ml) was added, the organic layer was separated and washed with saturated ammonium chloride (10 ml), water (10 ml) and sat. sodium chloride (10 ml). The organic layers were dried over Na2SO4 and concentrated and purified by silica gel chromatography with methanol and dichloromethane to give chiral 5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazine-2-carboxylic acid as an off-white lyophilized solid (19.7 mg, 74%). MS (ES+) m/z Calcd: [(M+H)+]: 588.13. found: 588.0
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.Cl.CC[O:26]CC>C(Cl)Cl>[I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: CCOCC
Reactant: N#Cc1cc(C(F)(F)F)ccc1I
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-iodo-5-(trifluoromethyl)benzonitrile (EXAMPLE 2, 42 g) in CH2Cl2 (300 mL) at −78° C. was added a solution of DIBAL in CH2Cl2 (175 mL, 1M) over 30 minutes. A precipitate formed. The reaction was warmed to 0° C. An additional 25 mL of the DIBAL solution was added dropwise over 30 minutes. The reaction was poured into 200 mL 2N aqueous HCl, diluted with ether and stirred 1 hour. TLC analysis indicates imine still present and an additional 100 mL 2N aqueous was added and the reaction stirred overnight. Imine was still present by TLC analysis and 200 mL 2N aqueous HCl was added and the mixture stirred 2 hours. The layers were separated and the aqueous layer back extracted with ether. The ether extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The product was purified by silica gel chromatography eluting with 95:5 hexanes/EtOAc to give 2-Iodo-5-(trifluoromethyl)benzaldehyde as a white solid. 1H NMR (500 MHz, CDCl3): δ 10.00 (s, 1H), 8.12 (s, 1H), 8.11 (d, J=8 Hz, 1H), 7.53 (dd, J=2 Hz, 8 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C)=[CH:11][CH:10]=1)[N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.[NH4+].[OH-]>Cl>[CH3:1][CH:2]([CH3:19])[CH:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[N:4]1[CH:8]=[N:7][CH:6]=[N:5]1
Reactant: CC(=O)Nc1ccc(C(C(C)C)n2cncn2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)C(c1ccc(N)cc1)n1cncn1
Temperature: 60 °C
Yield: 75.4 %

Procedure:
A mixture of (±)-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]acetamide (0.095 mol) in HCl (3N) (250 ml) was stirred and heated at 60° C. for 5 hours. The mixture was cooled, poured into ice, basified with concentrated NH4OH and extracted with CH2Cl2. The organic layer was dried, filtered off and evaporated. The residue was crystallized from 2-propanone/(C2H5)2O and filtered off, yielding 15.5g (75%) of (±)-4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-benzenamine (interm. 2; mp. 117.8° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 887.3 %

Procedure:
A mixture of tert-butyl 2-nitrobenzoate (2.1 g.) in methanol (200 ml.) was hydrogenated over palladium-carbon (2 g.) with shaking at atmospheric pressure and room temperature for 3.5 hours. The reaction mixture was filtered to remove the catalyst and then evaporated. To the residue were successively added diethyl ether and an aqueous solution of sodium chloride followed by shaking. The organic layer was separated, dried over magnesium sulfate, treated with activated charcoal and then evaporated to give an oil of the title compound (16.13 g.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)c2ccco2)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 (99 mg, 0.34 mmol) and piperidinomethyl polystyrene resin (100 mg) in 1 mL of dry CH2Cl2 was added 2-furoyl chloride (95%, 56.0 mg, 1.2 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed though an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 20 (80 mg, 61%). LRMS 286 (M-100)+.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)[C:5](N[C@H](C1C=CC=CC=1)CO)=[O:6])[CH3:2].S(=O)(=O)(O)[OH:39].O1CCOCC1>O>[CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=2)=[CH:22][CH:23]=1)[C:5]([OH:6])=[O:39])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Yield: 79 %

Procedure:
(S)-2-Ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide (4.49 g; 8.59 mmole), concentrated sulfuric acid (12.5 ml), dioxan (50 ml) and water (50 ml) were stirred at 80° C. for 6 hours. After cooling, water (100 ml) was added and the product was extracted with dichloromethane (2×100 ml). The organic phases were combined and washed with brine (60 ml), dried (sodium sulfate), filtered and evaporated in vacuo. Purification by chromatography on silica gel using heptan:ethyl acetate:acetic acid (10:10:1) as gradient and azeotropic destination with toluen gave 2.78 g (yield 79%) of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl} ethoxy)phenyl]propanoic acid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17]S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[O:38]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39]1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C=O)C.Cl[Pd-2](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>[O:38]1[CH:42]=[CH:41][C:40]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[NH:4][CH:3]=2)=[CH:39]1
Reactant: OB(O)c1ccoc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Oc1cccc(-c2cnc3[nH]cc(-c4ccoc4)c3c2)c1
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
To toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol, prepared method 6), furan-3-boronic acid (11 mg, 0.1 mmol) and dichlorobis (triphenylphosphino)palladium (ii) (3 mg, 0.0046 mmol) in a Smith process vial was added 0.6 mL of a 1:1 mixture of acetonitrile, and a 2 M solution of sodium carbonate in water. The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. The mixture was diluted with DMF (ca. 5 mL) and filtered with a syringe filter (0.45 micron). The filtrate was concentrated in vacuo and redissolved in DMSO. Purification by reverse phase chromatography using a gradient of H2O and acetonitrile (with 0.1% formic acid as a modifier) afforded 3-(3-furan-3-yl-1H-pyrrolo[2,3-b]pyridine-5-yl)-phenol as an off-white solid (6 mg, 56% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.70 (dd, J=2.5, 8.0 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 7.07 (t, J=2.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.67 (t, J=1.5 Hz, 1H), 7.77 (d, J=2.5 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 9.5 (broad s, 1H), 11.8 (s, 1H). MS: m/z 277 (M+H+).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C:29]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([C:29]5([OH:28])[CH2:32][CH2:31][CH2:30]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C1(O)CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1(O)CCC1

Procedure:
The title compound, off-white solid (68 mg, 64%), MS (ISP) m/z=429.4 [(M+H)+], mp 250° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 1-hydroxy-cyclobutane-carboxylic acid.
Reaction SMILES: ClC(Cl)(Cl)Cl.C(#N)C.[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C@@H:24]1[O:26][C@H:25]1[CH2:27][OH:28].I([O-])(=O)(=O)=[O:30].[Na+]>O.O.O.[Ru](Cl)(Cl)Cl.O>[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C@@H:24]1[O:26][C@H:25]1[C:27]([OH:30])=[O:28]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COCCOCOCCCCCCCC[C@@H]1O[C@H]1CO
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COCCOCOCCCCCCCC[C@@H]1O[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 ml of tetrachloromethane, 2.5 ml of acetonitrile, 3.9 ml of water, 1.5 mmol of the alcohol 5, 4.5 mmol of sodium periodate and 5 mol % of ruthenium(III) chloride trihydrate are combined in this sequence, and the mixture is stirred overnight at room temperature. The batch is evaporated, and the residue is taken up in 10 ml of saturated NaCl solution and 8 ml of CH2Cl2. The phases are separated, the aqueous phase is extracted with CH2Cl2, the combined organic phases are washed with saturated NaCl solution and dried over MgSO4, and the solvent is removed in vacuo. The oxiranecarboxylic acid obtained is employed without further purification.