Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[CH2:12][CH2:11][CH2:10]C1.O1CC(=O)C1>[Cl-].[Na+].O.C(O[Ti](OCC)(OCC)OCC)C>[CH3:1][C:2]([S:5]([N:7]=[C:11]1[CH2:10][O:8][CH2:12]1)=[O:6])([CH3:4])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)S(N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Agent: O=C1COC1
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)S(=O)N=C1COC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a 250 mL round-bottomed flask was added 2-methylpropane-2-sulfinamide (3.36 g, 27.8 mmol) followed by tetraethoxytitanium (11.64 ml, 55.5 mmol) to a tetrahydrofuran (69.4 ml) solution of oxetan-3-one (2 g, 27.8 mmol) at room temperature. The mixture was stirred at 50° C. for 5 hours, cooled and poured into brine. The suspension was filtered through a pad of diatomaceous earth eluting with ethyl acetate. The organics were combined, dried with sodium sulfate, filtered and concentrated under vacuum. The residue was purified by regular phase flash column chromatography to give the title compound.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[N:17]3)[N:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:15][N:16]3[CH:20]=[CH:19][C:18]([NH2:21])=[N:17]3)[CH:12]=[CH:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cccc(Cn3ccc([N+](=O)[O-])n3)n2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2cccc(Cn3ccc(N)n3)n2)OCCO1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a 0.1M solution of 2-(2-methyl-[1,3]dioxolan-2-yl)-6-(3-nitro-pyrazol-1-ylmethyl)-pyridine (270 mg, 0.93 mmol), iron powder (157 mg, 2.79 mmol) and NH4Cl (251 mg, 2.79 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 90 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by 1N NaOH (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a pale yellow oil. TLC: rf (EA)=0.20. LC-MS-conditions 02: tR=0.59 min; [M+H]+=261.40.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[N:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.CS(O[CH2:34][CH:35]1[CH2:38][C:37]([F:40])([F:39])[CH2:36]1)(=O)=O>>[F:39][C:37]1([F:40])[CH2:38][CH:35]([CH2:34][O:1][C:2]2[CH:28]=[CH:27][C:5]3[N:6]=[C:7]([C:9]4[N:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH3:18])=[CH:11][CH:10]=4)[O:8][C:4]=3[CH:3]=2)[CH2:36]1
Reactant: C[C@@H](COc1ccc(-c2nc3ccc(O)cc3o2)nc1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCC1CC(F)(F)C1
Product: C[C@@H](COc1ccc(-c2nc3ccc(OCC4CC(F)(F)C4)cc3o2)nc1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl [(1S)-2-{[6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate and (3,3-difluorocyclobutyl)methyl methanesulfonate, and in the same manner as in Example 2, step E, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12](C(OCC)=O)[N:11]([CH2:19][CH2:20][NH:21][C:22]([O:24]C(C)(C)C)=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl.O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]2[C:22](=[O:24])[NH:21][CH2:20][CH2:19][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1NCCn2nc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Ethyl 3-(benzyloxy)-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1H-pyrazole-5-carboxylate (0.51 g, 1.31 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (6.53 mL). The mixture was stirred at room temperature for 1 hour and then basified with a saturated solution of Na2CO3. The mixture was stirred at room temperature for 1 hour, diluted with water and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.31 g, 99% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH:20]2[CH2:23][CH2:22][CH2:21]2)[CH2:18][CH3:19])[C:11]=1[N+:24]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH:20]2[CH2:21][CH2:22][CH2:23]2)[CH2:18][CH3:19])[C:11]=1[NH2:24]
Reactant: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-])C1CCC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1N)C1CCC1
Yield: 108.4 %

Procedure:
[4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-propyl)-amine (0.33 g, 0.88 mmol) and Na2S2O4 (1.33 g, 7.6 mmol) were treated substantially as described in Part E of Example 9 to give 0.33 g (100%) 4-(2-chloro-4-methoxy-phenyl)-N2-(1-cyclobutyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 345.9 [(M+H)+, 100].
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:11][CH:12]=1>C(O)(=O)C.O>[F:32][C:24]1[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:14]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH:2]=[O:1])=[CH:12][N:11]=3)[S:21][C:20]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 90 °C
Yield: 76.5 %

Procedure:
A suspension of 318 (2.64 g, 5.82 mmol) in 80% aqueous acetic acid (42 mL) was heated at 90° C. for 18 h. The reaction mixture was cooled to r.t. and diluted with water. The resulting precipitate was collected by suction filtration. The solid was transferred to a round-bottomed flask, the remaining water was removed by azeotropic distillation with toluene (4 times), and the solid dried in vacuo yielding 325 (1.76 g, 76%). LRMS (M+H): 396.3
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15](OB(O)O)[CH:16]=[CH:17][CH:18]=1>>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:17]1[CH:18]=[C:13]([OH:12])[CH:14]=[CH:15][CH:16]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: OB(O)Oc1cccc(O)c1
Product: Oc1cccc(-c2ccc3ccccc3c2)c1
Reaction time: 18 h
Yield: 47 %

Procedure:
The compound is prepared by the reaction of 2-bromonaphthalene (303 mg, 1.46 mmol, 1 eq) with 3-hydroxyphenylboric acid (242 mg, 1.76 mmol, 1.2 eq) according to method A within 18 h. Purification by column chromatography with dichloromethane as the eluent yields the desired product in a yield of 47%, 152 mg.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=O)[C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[CH3:21]>O>[OH:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[C:3]=1[CH3:21]
Reactant: COc1ccc(-c2coc3c(C)c(O)ccc3c2=O)cc1
Solvent: O
Product: COc1ccc(C2COc3c(ccc(O)c3C)C2)cc1

Procedure:
As example 26, but using 7-hydroxy-8-methyl-3-(4-methoxyphenyl)-4H-1-benzopyran-4-one (28 mg) instead of 7-hydroxy-8-methyl-3-(4-methylphenyl)-4H-1-benzopyran-4-one. A crystalline precipitate is formed when water is added; it is filtrated off and washed with water. 3,4-Dihydro-7-hydroxy-8-methyl-3-(4-methoxyphenyl)-2H-1-benzopyran is obtained; m.p. 140°-141°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2.[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:1]([O:8][CH2:9][C@@H:10]([C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[CH:32][C:24]=2[CH3:23])[NH:28][CH:27]=1)[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2[nH]ccc12
Reactant: O=CC=CCOCc1ccccc1
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C(O)c1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cccc2[nH]cc([C@@H](CC=O)COCc3ccccc3)c12
Yield: 97.6 %

Procedure:
Prepared according to the general procedure from benzoic acid 4-benzyloxy-but-enal (143 mg, 0.750 mmol), 4-methyl-1H-indole (80.5 mg, 0.500 mmol), 2,4-dinitrobenzoic acid (21.2 mg, 0.100 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −60° C. for 2.5 h to provide, after silica gel chromatography (15:85 EtOAc/hexanes), the title compound as a colorless oil (150 mg, 94% yield, 94% ee) after silica gel chromatography in 15% EtOAc/hexanes. IR (film) 3406, 2947, 2923, 2843, 2738, 1717, 1620, 1604, 1584, 1451, 1411, 1383, 1344, 1315, 1271, 1178, 1114, 1066, 1226, 969 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.82 (dd, J=2.1, 2.1 Hz, 1H, CHO), 8.14 (s, 1H, NH), 8.02 (dt, J=1.5, 7.2 Hz, 2H, ArH), 7.58 (tt, J=1.5, 6.6 Hz, 1H, ArH), 7.45 (tt, J=1.2, 6.9 Hz, 2H, ArH), 7.24-7.08 (m, 3H, ArH, NCH), 6.91 (dt, J=0.9, 7.2 Hz, 1H, ArH), 4.74 (dd, J=4.2, 10.5 Hz, 1H, CH2O), 4.52-4.43 (m, 1H, ArCH), 4.32 (dd, J=8.4, 10.8 Hz, 1H, CH2O), 3.05 (ddd, J=2.1, 6.9, 16.8 Hz, 1H, CH2CO); 2.95 (ddd, J=2.1, 7.8, 16.8 Hz, 1H, CH2CO), 2.82 (s, 3H, ArCH3); 13C NMR (75 MHz, CDCl3) δ 201.3, 166.3,136.5, 133.2, 130.5, 130.0, 129.7, 128.5, 125.1, 122.6, 122.1, 121.7, 115.8, 109.4, 68.9, 47.8, 31.7, 21.0; HRMS (CI) exact mass calcd for (C20H19NO3) requires m/z 321.1365, found m/z 321.1353. [α]D=−26.6 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (10:90 ethanol/hexanes, 1 mL/min); S isomer tr=47.8 min and R isomer tr=42.4 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([Br:26])=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+].Cl>CO.C1COCC1.O>[Br:26][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]2[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)[nH]c2ccc(Br)cc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
5-Bromo-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (65 mg, 0.15 mmol, 1.0 equiv) was dissolved in 10 mL of 1:1 methanol/THF. To this was added a solution of lithium hydroxide hydrate (200 mg, 4.8 mmol, 31 equiv) in 5 mL water. The reaction was heated at 50° C. for 15 min and then stirred at ambient temperature overnight. The reaction was cooled to 0° C. and acidified to pH˜2 with concentrated HCl. The product was extracted with ethyl acetate (2×25 mL). The solution was dried over anhydrous sodium sulfate, filtered, and evaporated to give 55 mg of 5-bromo-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid (55 mg, 91%). This material was used without further manipulation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:20]([C:21](=[O:22])[CH3:23])[C:19]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(OCc2ccccc2)ccc1C=O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1OC)C(C)=O

Procedure:
A solution of 4-(benzyloxy)-2-methoxybenzaldehyde (28.3 g), ethyl acetoacetate (18 ml), acetic acid (1.74 ml) and piperidine (0.56 ml) in toluene (400 ml) was heated under reflux for 48 h. A solution of acetic acid (1.74 ml) and piperidine (0.56 ml) in toluene (10 ml) was added and the solution heated under reflux for a further 48 h. The solvent was evaporated under reduced pressure and the residue partitioned between EtOAc and brine. The organics were separated, washed with aq NaHCO3 soln, 1M HCl, brine, dried and evaporated under reduced pressure to give the subtitle compound, 40 g (used crude in next step).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.Br[CH2:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=O.C(=O)([O-])O.[Na+]>COCCOC.C1COCC1>[CH:13]1([C:11]2[N:8]=[C:3]3[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]3[CH:10]=2)[CH2:15][CH2:14]1
Reactant: O=C(CBr)C1CC1
Reactant: Cc1nccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1nccn2cc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 70 h
Yield: 43 %

Procedure:
[step 1] 3-Methylpyrazin-2-amine (16 g, 147 mmol) was dissolved in 1,2-dimethoxyethane (122 mL) and THF (61 mL), 2-bromo-1-cyclopropylethanone (36 g, 220 mmol) was added, and the mixture was stirred at room temperature for 70 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-85/15 v/v) to give 2-cyclopropyl-8-methylimidazo[1,2-a]pyrazine (11g, 43%).
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:3].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:3][CH:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCC(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(C)NS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
To a solution of 10 g (50 mmol) 2-aminotridecane and 5 g triethylamine in 100 ml methylene chloride is added 6 g methanesulfonyl chloride while cooling and stirring for a period of 10 minutes. After one hour of additional stirring, it was allowed to stand over night. The reaction mixture was subsequently transferred to a separatory funnel, washed three times with water, dried over Na2SO4, evaporated to a white solid and dried in a vacuum oven.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1B(O)O.Cl>CN(C)C(=O)C.C(#N)C.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.O>[ClH:1].[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CC#N
Product: Cc1c(CN2CCN(c3nccnc3-c3cc(F)ccc3F)CC2)cnn1C
Temperature: 115 °C
Yield: 11.9 %

Procedure:
Dissolve 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (153 mg, 0.50 mmol) in N,N-dimethylacetamide (2 mL, nitrogen purged) under nitrogen. Add potassium carbonate (166 mg, 1.20 mmol) then 2,5-difluorobenzeneboronic acid (95 mg, 0.60 mmol) and purge with nitrogen for 10 min. Add deoxygenated water (1 mL) and tetrakis(triphenylphosphine)palladium(0) (0.003 g, 0.003 mmol) then purge with nitrogen for 10 min. Heat at 115° C. for between 24 and 42 hr. Cool to room temperature, add water (5 mL) and extract with DCM (4×5 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®. Concentrate the filtrate and purify by SCX-2® chromatography washing with methanol then eluting with approximately 2 M ammonia in methanol. Purify (silica gel chromatography, eluting with 0:100 to 10:90 methanol:DCM). Further purify by low pH reverse phase HPLC, followed by passage through an SCX-2® ion exchange cartridge (wash with methanol, elute with 7M ammonia in methanol). Concentrate to provide the free base. Dissolve the free base in acetonitrile and add 2M aqueous HCl solution. Add water and lyophilize to give the title compound as a yellow solid (25 mg, 12%). MS (ES): m/z=385 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([N:6]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:5].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]C)=[O:36])=[CH:27][CH:26]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([N:6]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[CH2:7][CH2:8][CH2:9][C:10]([N:31]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:28]1[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=1)=[O:12])=[O:5]
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Reactant: CCC(C)(C)N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C)(C)N(CCCC(=O)N(CCCC(=O)O)c1ccc(OC)cc1)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(2,4-dichlorobenzoyl)-4-[(1,1dimethylpropyl)amino]butyric acid and methyl γ-(p-anisidino)butyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(2,4-dichlorobenzoyl)-4-(1,1-dimethylpropylamino)butyryl]-4-(p-anisidino)butyric acid.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[CH3:20][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)n1nc(O)c2cc(C(=O)OC)ccc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)n1c2ccc(C(=O)OC)cc2c(=O)n1C

Procedure:
1-Ethyl 5-methyl 3-hydroxy-1H-indazole-1,5-dicarboxylate (1.75 g, 6.62 mmol) was suspended in acetone (85 mL). Cesium carbonate (2.27 g, 6.95 mmol) and methyl iodide (1.3 mL, 20 mmol) were added and the reaction was stirred at reflux for 22 hours. The reaction was concentrated to dryness and the residue was partitioned between dichloromethane (60 mL) and water (100 mL). The layers were separated and the aqueous was extracted again with dichloromethane (60 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (7-60% ethyl acetate/heptanes) gave two regioisomeric products.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H][H]>O.C(O)C.[Pd]>[OH:10][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(CO)cc1
Yield: 99.3 %

Procedure:
Terephthalaldehyde (25.0 g) was suspended in water (20 ml) and ethanol (80 ml). Pd/C (220 mg) was added to the suspension and then hydrogen gas (4.3 l ) was introduced. The catalyst was removed by filtration and the filtrate was concentrated to give p-hydroxymethylbenzaldehyde (25.2 g). The product was dissolved in toluene (100 ml) and 48% HBr (50 ml) and the solution was refluxed for 2 hours. The reaction mixture was poured into iced water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline and dried, and then the solvent was removed by evaporation under reduced pressure. The residue was recrystallized from n-hexane to give colorless needles (37.5 g, yield: 82%). mp 97.5°-98.0° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1B(O)O.C([O-])(O)=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.O.CCOC(C)=O.O.[Pd]>[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: OB(O)c1cc2ccccc2o1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(Br)nc1-c1cc2ccccc2o1
Yield: 83.3 %

Procedure:
A solution of 3,5-dibromopyrazin-2-amine (200 mg, 0.7908 mmol), benzofuran-2-ylboronic acid (140.9 mg, 0.8699 mmol), NaHCO3 (199.3 mg, 2.372 mmol) and palladium; triphenylphosphane (91.38 mg, 0.07908 mmol) in dimethoxyethane (2.000 mL) and water (1.000 mL) was heated at 120° C. in the microwave for 10 minutes. The reaction was diluted with EtOAc/Water and the layers separated. The aqueous layer was extracted further with EtOAc (2×), dried (MgSO4) and concentrated in vacuo. The mixture was purified on silica gel by flash column chromatography (0-20% EtOAc/Petrol) to afford the product as a bright yellow solid (191 mg, 83% Yield). MS (ES+) 291.89
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH2:12].N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCOCC.O>[CH2:23]([O:22][C:20](=[O:21])[NH:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[Br:1])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)Nc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 2-bromo-5-trifluoromethylphenylamine (27.06 g, 112.74 mmol) and 200 mL of pyridine. Cool in an ice bath and add ethyl chloroformate (18.35 g, 169.11 mL, 1.5 eq). After addition was complete, allow the reaction to gradually warming to room temperature. After 18 hours, evaporate in vacuo to give a residue. Dissolve the residue in Et2O/water and transfer to a separatory funnel. Separate the layer and extract the aqueous layer with Et2O (2×300 mL), combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give N-(2-bromo-5-trifluoromethylphenyl)carbamic acid ethyl ester which may be used without further purification.
Reaction SMILES: [H][H].[OH:3][C:4]([CH3:33])([CH3:32])[CH:5]([NH:7][C:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([C:21]#[C:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:15][C:14]=3[NH:13][C:12]=2[C:11]([C:29]([NH2:31])=[O:30])=[CH:10][N:9]=1)[CH3:6]>CCO.[Pd]>[OH:3][C:4]([CH3:32])([CH3:33])[CH:5]([NH:7][C:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([CH2:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:15][C:14]=3[NH:13][C:12]=2[C:11]([C:29]([NH2:31])=[O:30])=[CH:10][N:9]=1)[CH3:6]
Reactant: [H][H]
Reactant: CC(Nc1ncc(C(N)=O)c2[nH]c3cc(C#Cc4cccnc4)ccc3c12)C(C)(C)O
Agent: [Pd]
Solvent: CCO
Product: CC(Nc1ncc(C(N)=O)c2[nH]c3cc(CCc4cccnc4)ccc3c12)C(C)(C)O

Procedure:
Hydrogen was bubbled through a solution of 1-[(2-hydroxy-1,2-dimethylpropyl)amino]-7-(pyridin-3-ylethynyl)-5H-pyrido[4,3-b]indole-4-carboxamide (10 mg, 0.024 mmol) and Pd/C (10%, 2.6 mg) in EtOH (1.3 mL). After complete conversion, the mixture was purged with nitrogen, filtered through a pad of Celite, and concentrate to afford the title compound. LRMS (APCI) calc'd for (C24H27N5O2) [M+H]+, 418.2. found 418.2.