Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1[O:3][CH2:4][CH2:5][C:6]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH-].[Na+]>CO>[NH2:7][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH2:5][CH2:4][OH:3]
Reactant: CC1=NC(C)(c2ccccc2)CCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(N)(CCO)c1ccccc1
Temperature: 80 °C
Yield: 92.7 %

Procedure:
The product of Example 457D (0.886 g, 4.68 mmol) in methanol (15 ml) at room temperature was reacted with 6N NaOH (15 ml) and the resulting mixture heated under nitrogen at 80° C. overnight. The methanol was evaporated in vacuo and the aqueous residue isolated by extraction with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give the title compound (0.717 g, 93%) as a pale yellow solid used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[Br:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([CH2:38]O)[CH:37]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:31][C:32]1[CH:37]=[C:36]([CH2:38][N:24]2[C:20](=[O:30])[C:21]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:22]3[C:23]2=[O:25])[CH:35]=[N:34][CH:33]=1
Reactant: OCc1cncc(Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
5-Bromo-3-(phthalimidomethyl)pyridine is produced by adding triphenylphosphine (12.1 g, 46.3 mmol) and phthalimide (6.80 g, 46.3 mmol) in dry THF (70 mL) to a stirred suspension of 3-bromo-5-hydroxymethylpyridine (6.70 g, 35.6 mmol), and then adding a solution of diethyl azodicarboxylate (7.30 mL, 46.3 mmol) in dry THF (30 mL) drop-wise. The reaction mixture was stirred at room temperature overnight. After removal of the solvent by rotary evaporation, the crude material was purified by column chromatography to yield 5-bromo-3-(phthalimidomethyl)pyridine (9.5 g, 85% yield).
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[NH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>O>[F:5][C:6]1[CH:15]=[C:14]([N:17]2[CH2:22][CH2:21][S:20][CH2:19][CH2:18]2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCSCC2)cc1F
Temperature: 80 °C
Yield: 58 %

Procedure:
To a 30 ml dimethyl sulfoxide solution of 3.44 g (20 mmol) of methyl 2,4-difluorobenzoate, 1.9 ml (20 mmol) of thiomorpholine and 2.76 g (20 mmol) of potassium carbonate were added, and the mixture was stirred at 80° C. Then, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 2.96 g (58%) of the captioned compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].S(OOS([O-])(=O)=O)([O-])(=O)=[O:13].[Na+].[Na+]>[OH-].[Na+].O>[NH2:1][C:2]1[C:10]([OH:13])=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(O)ccc(F)c1C(=O)O

Procedure:
2-amino-6-fluorobenzoic acid (5.00 g, 32.2 mmole) was dissolved in 30 ml of 2N sodium hydroxide. To this was added dropwise a solution of sodium persulfate (7.67 g, 32.2 mmole) in 80 ml of water. After stirring over night the resulting black solution was extracted with 2 L of ether and 1 L of ethylacetate. Evaporation of the water gave a black solid that was used with no purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][CH:8]([NH:20][CH2:21][CH:22]([OH:37])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29]CC1C=CC=CC=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.CO>[H][H].[C].[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][CH:8]([NH:20][CH2:21][CH:22]([OH:37])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc(CC(C)NCC(O)c2ccccc2OCc2ccccc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: COc1ccc(CC(C)NCC(O)c2ccccc2O)cc1OC

Procedure:
A mixture of one g of α-[(α-methyl-3,4-dimethoxyphenethylamino)methyl]-2-benzyloxybenzylalcohol oxalate [the diastereoisomer of M.p. 152°-153° C. (decomp.)], 0.2 g of 10% palladium-carbon and 15 ml of 90% aqueous methanol is shaken at room temperature in hydrogen atmosphere under atmospheric pressure. After hydrogen uptake is completed, insoluble materials are removed by filtration, and the filtrate is condensed. The residue thus obtained is recrystallized from ethanol. 0.72 g of α-[(α-methyl-3,4-dimethoxyphenethylamino)methyl]-2-hydroxybenzylalcohol oxalate [the diastereoisomer of M.p. 155°-156° C. (decomp.)] is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1([CH3:18])[CH2:17][CH2:16]1)[CH:9]=[CH:8]2)=[O:4].[OH-].[Na+]>CO>[CH3:18][C:15]1([C:10]2[CH:9]=[CH:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[N:11]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc2nc(C3(C)CC3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(c2ccc3cc(C(=O)O)ccc3n2)CC1
Yield: 83.7 %

Procedure:
A solution of methyl-2-(1-methylcyclopropyl)quinoline-6-carboxylate (225 mg, 0.93 mmol) and 2M sodium hydroxide solution (2 ml, 4 mmol) in methanol (10 ml) was heated at 60° C. for 2 hours. After the solvent was evaporated in vacuo, the residue was dissolved with water. The aqueous solution was neutralized with 2M hydrochloric acid solution (2 ml) and the precipitate white solid was extracted with ethyl acetate (×3). The combined solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give crude white solid, which was recrystallized from ethyl acetate and hexane to furnish the title compound (177 mg, 84%) as a white solid. MS (ESI): m/z 228.15 [M+H]+, 226.13 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCc1ccccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccccc1F)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 250-mL, round-bottomed flask containing a solution of 2-fluorophenethylamine (4.7 mL, 35.9 mmol) and diisopropylethylamine (6.3 mL, 35.9 mmol) in dichloromethane (35 mL) was cooled to 0° C. and treated dropwise with 4-(trifluoromethyl)benzoyl chloride (5.4 mL, 35.9 mmol) over 5 min. The ice-bath was removed after 2 h and the reaction mixture was stirred overnight. The precipitate formed was collected by filtration. The filtrate was diluted with dichloromethane (100 mL) and transferred to a separatory funnel, extracted with water (35 mL), brine (25 mL), and 1N HCl (25 mL). The dichloromethane layer was separated and formation of more precipitate was observed which was collected by filtration. The solids collected were combined and dried under vacuum to yield N-(2-fluorophenethyl)-4-(trifluoromethyl)benzamide as an off-white solid. MS (ESI pos. ion) m/z: 312 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([CH3:19])=[CH2:18]>CC(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:17]([CH3:19])=[CH2:16])=[CH:4][CH:3]=1
Reactant: C=C(C)CBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: C=C(C)COc1ccc(Br)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a solution of 4-bromo phenol (7.0 g, 40.40 mmol) in acetone (165 mL) was added K2CO3 (27.8 g, 202 mmol) followed by 3-bromo-2-methylprop-1-ene (4.9 mL, 44.5 mmol). The mixture was stirred at reflux temperature for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (200 mL), washed with H2O (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (6) (8.0 g, 93%) as a colorless liquid. 1H NMR (CDCl3, 400 MHz) δ 7.37 (d, J=9.2 Hz, 2H), 6.81 (d, J=9.2 Hz, 2H), 5.08 (s, 1H), 5.00 (s, 1H), 4.41 (s, 2H), 1.83 (s, 3H); MS (ESI, M+H+) C10H12BrO, calcd. 227.1. found 227.0, 229.0.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:11][C:10]=1[CH2:30][CH2:31][CH3:32])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:30]([C:10]1[CH:11]=[C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:9]4[CH:29]=[CH:28][CH:12]=[CH:11][CH:10]=4)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH:28]=[CH:29][C:9]=1[OH:8])[CH2:31][CH3:32]
Reactant: [H][H]
Reactant: CCCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1O

Procedure:
A solution of 4-[2-(4-benzyloxy-3-propylphenoxy)ethyl]-5-methyl-2-phenyloxazole (3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[N:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[NH:23][C:24](=[O:28])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1cccc(-c2cnc3ccc(-c4c[nH]nc4-c4ccc(F)cc4)cn23)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.9 %

Procedure:
A mixture of 54 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-(6-methoxy-2-pyridyl)imidazo[1,2-a]pyridine obtained in Example 23, 2 mL of 48% hydrobromic acid and 2 mL acetic acid was stirred at room temperature for 4 hours and then heated for 10 minutes under reflux. The reaction solution was cooled and neutralized with 5 N aqueous sodium hydroxide, and the precipitated solid was collected by filtration, washed with water and air-dried. Then, the solid was triturated with diethyl ether, collected by filtration and dried in vacuo to give 5.4 mg of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH:5]=O.[CH:9]([CH:11]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].CCOCC.CCCCCC>ClCCl>[F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4]/[CH:5]=[CH:11]/[CH:9]=[O:10]
Reactant: O=CCCC(F)(F)F
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C/C=C/CCC(F)(F)F

Procedure:
A solution of 12.6 g (0.1 mol) of 4,4,4-trifluorobutanal [T. Fuchikami and I. Ojima, J. Am. Chem. Soc. 104, 3527 (1982)] and 30.4 g (0.1 mol) of formylmethylenetriphenylphosphorane (see Tripett and D. M. Walker, J. Chem. Soc. 1961, 1266] in 200 ml of dichloromethane is heated under reflux for 24 hours under argon. The red solution is freed of solvent at room temperature in vacuo, and the residue is stirred thoroughly with ether/hexane (1:1). The solid portion is filtered off and subsequently washed three times with ether/hexane (1:1). The filtrate is concentrated by evaporation in vacuo and the residue is chromatographed with dichloromethane on silica gel. The product is eluted in the second fraction (Rf =0.4). 6,6,6-Trifluoro-2-trans-hexenal is obtained in the form of a light-yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:36])[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:22]([O:34][CH3:35])[CH:21]=2)=[CH:11][C:10]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S([O-])(=O)=O.[Ba+2].C1COCC1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.[Pd].C(O)(C)C>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C:17](=[O:36])[CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([O:37][CH3:38])[CH:11]=2)=[CH:21][C:22]=1[O:34][CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(C=CC(=O)C=Cc2ccc(OCc3ccccc3)c(OC)c2)ccc1OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1cc(CCC(=O)CCc2ccc(OCc3ccccc3)c(OC)c2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogenation of 21.5 g (42.6 mmol) of 1,5-bis-(4-benzyloxy-3-methoxy-phenyl)-penta-1,4-dien-3-one prepared in Example D was effected as described in General Method 3 using 1.0 g 5% Pd over BaSO4 and 600 mL of THF under hydrogen atmosphere. The product contained both ketone and alcohol. Therefore, the mixture was dissolved in acetone (approximately 500 mL), treated with 20 mL of 8.0N Jones reagent, and stirred overnight at room temperature. Isopropanol was added, and the mixture was filtered through Celite. The filtrate was concentrated, and the residue was triturated with 1:1 hexane:EtOAc to give the title compound. 1H NMR (DMSO-d6) δ 2.71 (m, 8 H), 3.74 (s, 6 H), 5.02 (s, 4 H), 6.66 (m, 2 H), 6.82 (br s, 2 H), 6.87 (m, 2 H), 7.29-7.43 (m, 10 H).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1.[Si]([Cl:36])(C)(C)C>C(OCC)(=O)C>[ClH:36].[CH3:31][N:2]([CH3:1])[C:3]1([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][CH2:5][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2cccs2)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
N,N-dimethyl-4-(3-(2-(pyridin-4-yl)ethyl)-1H-indol-2-yl)-1-(thiophen-2-yl)cyclohexanamine (more polar diastereoisomer) (43 mg, 0.1 mmol) was dissolved in ethyl acetate (20 ml). Me3SiCl (19 μl, 0.15 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×5 ml) and then dried. Example 304 (40 mg, m.p. 188-191° C., yield 87%) was a white solid.
Reaction SMILES: N[C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:12](O)(=O)[CH3:13].N(OCCCCC)=O.[OH-].[Na+]>CO.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]>[CH2:12]=[CH:13][C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1S(=O)(=O)O
Reactant: CC(=O)O
Agent: [Pd]
Agent: CCCCCON=O
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Product: C=Cc1ccccc1S(=O)(=O)O
Reaction time: 1 h
Yield: 87.5 %

Procedure:
13.0 g of aniline-2-sulphonic acid were suspended in 200 ml of methanol and treated with 20 g of glacial acetic acid. Under a nitrogen atmosphere, 9.5 g of amyl nitrite were added dropwise at a temperature of 0° to 5° C. and the suspension was stirred for 1 hour. A solution of 15 g of NaOH in 100 ml of methanol was then added dropwise at such a rate that the temperature of the mixture did not exceed 20° C. After addition of 0.5 g of bis(dibenzylideneacetone)palladium(0), the mixture was stirred at 20° C. for 3 hours under an ethylene pressure of 20 bar, the solid was then filtered off with suction and the filtrate was evaporated to dryness. 12.1 g (78%) of styrene-2-sulphonic acid, Na salt, were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[C:8]([S:11](Cl)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[C:8]([S:11]([NH:22][C:20]3[N:19]([C:23]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:24]=4[CH:25]=[CH:26][CH:27]=[N:28]5)[N:18]=[C:17]([CH3:16])[CH:21]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CC1(C)Cc2cc(S(=O)(=O)Cl)ccc2O1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc3c(c2)CC(C)(C)O3)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 39 %

Procedure:
A stirring mixture of 2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonyl chloride (0.10 g, 0.41 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.11 g, 0.49 mmol) in pyridine (0.41 mL) was heated at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in hexanes), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.070 g, 0.16 mmol, 40%). 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J=3.2 Hz, 1H), 7.19 (d, J=6.8 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 6.24 (s, 1H), 2.89 (s, 2H), 2.34 (s, 3H), 1.51 (s, 6H); MS: (ES) m/z calculated for C23H23N4O3S [M+H]+ 435.2. found 435.3.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:55]=[CH:54][C:33]2[N:34]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[C:40]([N:47]5[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]5)[CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH:35]=[N:36][C:32]=2[CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:8][CH2:9][C:10]([NH:53][CH:50]1[CH2:49][CH2:48][N:47]([C:40]2[CH:41]=[CH:42][CH:43]=[C:44]3[C:39]=2[N:38]=[C:37]([N:34]2[C:33]4[CH:54]=[CH:55][C:30]([O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:31][C:32]=4[N:36]=[CH:35]2)[CH:46]=[CH:45]3)[CH2:52][CH2:51]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COCCOc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(N)CC3)c2n1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCCOc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(NC(=O)CN)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
N-(tert-butoxycarbonyl)glycine (105 mg, 0.600 mMol) was dissolved in 3 mL of DCM under an atmosphere of dry N2. To this mixture was added 1,1′-carbonyldiimidazole (100 mg, 0.61 mMol) and the reaction mixture was stirred at ambient temperature for 30 minutes. To this solution was then added 4-dimethylaminopyridine (8.0 mg, 0.065 mMol) and 1-{2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine 33 (170 mg, 0.408 mMol). The reaction mixture was subsequently stirred overnight at ambient temperature. The reaction mixture was then partitioned between DCM and saturated aqueous NaHCO3. The organic layer was saved and washed again with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under vacuum to give a yellow foam. The residue was chromatographed on flash silica gel eluting with MeOH/DCM (397) to give 182 mg of a yellow residue. The residue was dissolved in 0.5 ml of TFA and stirred at ambient temperature for 30 minutes under an atmosphere of dry N2. The reaction mixture was subsequently concentrated under vacuum and then partitioned between 0.1 N aqueous NaOH. The organic layer was saved and washed again with 0.1 N aqueous NaOH, dried over Na2SO4, filtered and concentrated under vacuum to give a yellow foam. The foam was chromatographed on flash silica gel eluting with MeOH/DCM (595) to give 75 mg of the title compound as 54 a yellow solid.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.CN(C)C=O.Br[C:17]1[N:25]2[C:20]([CH:21]=[N:22][C:23]([S:26][CH3:27])=[N:24]2)=[CH:19][CH:18]=1>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>[CH3:27][S:26][C:23]1[N:22]=[CH:21][C:20]2=[CH:19][CH:18]=[C:17]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:25]2[N:24]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: C[Sn](C)(C)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ncc2ccc(-c3ccccn3)n2n1
Temperature: 80 °C
Yield: 70 %

Procedure:
2-Trimethylstannanyl-pyridine (0.557 g, 2.30 mmol) in N,N-Dimethylformamide (7.6 mL, 98 mmol) was added 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.250 g, 1.02 mmol) and Tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.058 mmol) in a vial, and the mixture was heated in a block at 80° C. The reaction mixture was then diluted with EtOAc (30 mL) and washed with water (1×, 10 mL), 2.5M KF (2×, 10 mL), and brine (1×, 10 mL), followed by drying with sodium sulfate, filtering, and conc. in vacuo. The crude product was purified by ISCO column chromatography (0-25, 25-100% EtOAc/Hex) to give 2-Methylsulfanyl-7-pyridin-2-yl-pyrrolo[2,1-f][1,2,4]triazine (0.173 g, 70%). 1H-NMR (DMSO-d6): 9.09 (s, 1H), 8.71 (m, 2H), 7.98 (dt, 1H, J=7.80 Hz), 7.63 (d, 1H, J=4.74 Hz), 7.38 (dt, 1H, J=6.40), 7.12 (d, 1H, 4.98 Hz), 2.65 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-])=O)([CH2:13][CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H][H]>[Pd].C(O)C>[NH2:15][C:2]([CH3:1])([CH2:13][CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCC(C)(Cc1c[nH]c2ccccc12)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(N)Cc1c[nH]c2ccccc12
Temperature: 70 °C
Reaction time: 7 h
Yield: 95.3 %

Procedure:
Reduction: A mixture of 90.0 g (388 mM) of the nitro intermediate and 9.0 g of palladium catalyst (5% on carbon) and 1000 ml of absolute ethanol was covered with hydrogen at a pressure of 25 atmospheres gauge in the autoclave whereupon it was heated to 70°C. and agitation was continued at this temperature for 7 hours. Filtration, evaporation in vacuo, recrystallisation from xylene and processing of the mother liquor yielded 74.7 g of 3-(2'-amino-2'-methylbutyl)-indole. (Yield: 95% of the theoretical).