Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:34])[N:4]([C:19]2[CH:20]=[C:21]([NH:26][C:27](=[O:33])OC(C)(C)C)[CH:22]=[CH:23][C:24]=2[F:25])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(N(CC)CC)C.[C:42]([O:45][CH2:46]C(Cl)=O)(=[O:44])[CH3:43].[Cl-].[NH4+]>O1CCCC1>[C:42]([O:45][CH2:46][C:27]([NH:26][C:21]1[CH:22]=[CH:23][C:24]([F:25])=[C:19]([N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Br:1])[C:3]2=[O:34])[CH:20]=1)=[O:33])(=[O:44])[CH3:43]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(NC(=O)OC(C)(C)C)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the compound of Example 722 (0.5 g, 1.05 mmol) in tetrahydrofuran (20 mL) was treated with triethyl amine (0.3 mL, 2.1 mmol) and acetoxy acetylchloride (0.12 mL, 1.15 mmol). After stirring at room temperature for 2 h, the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride. The solids were filtered off and were washed with water and diethyl ether. Title product was isolated as a white solid (0.32 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.65 (m, 3H), 7.32 (t, J=8.4 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.64 (s, 1H), 5.35 (s, 2H), 4.68 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ−111.56 (1F), −115.99 (1F), −129.48 (1F) ppm. LC/MS, tr=5.35 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 540 (M+H). Step 2 Preparation of N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorophenyl}-2-hydroxyacetamide
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>>[CH2:19]([N:22]([CH2:23][CH:24]=[CH2:25])[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:20]=[CH2:21]
Reactant: Cc1csc2c(NC3CCCCC3)nc(Cl)nc12
Reactant: C=CCNCC=C
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCN(CC=C)c1nc(NC2CCCCC2)c2scc(C)c2n1
Yield: 72.5 %

Procedure:
In a sealed tube were heated 338 mg (1.2 mmol) of 2-chloro-4-cyclohexylamino-7-methylthieno[3,2-d]pyrimidine and 1.87 g (19.2 mmol) of diallylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 298 mg (yield: 72.7%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]2[C@H:12]3[CH2:17][CH2:16][CH2:15][C@H:13]3[N:14]=[C:3]12.[H-].[Na+].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH:7]=[N:6][C:5]=2[N:4]2[C@H:12]3[CH2:17][CH2:16][CH2:15][C@H:13]3[N:14]=[C:3]12
Reactant: CN1C(=O)c2[nH]cnc2N2C1=N[C@@H]1CCC[C@@H]12
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2c(ncn2Cc2ccc(Cl)cc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 50 °C

Procedure:
Add a solution of cis-5,6a,7,8,9,9a-hexahydro-5-methylcyclopenta[4,5]imidazo[2,1-b]purin-4-one (0.5 g=2.2 mmol)in DMF drop-wise to a slurry of 60% NaH (0.1 g=2.4 mmol) in DMF at 30° C. When gas evolution ceases, add 4-chlorobenzyl chloride (0.5 g=2.4 mmol) in 2 ml DMF. Heat at 50° C. two hours. Remove DMF and partition between EtOAc and water. Dry, solvent strip, and recrystallize from CH3CN to give the title compound, a white solid. CI MS: M+ =356.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[CH3:10])=[O:7]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2ccc(F)c(F)c2)cc1
Yield: 53.8 %

Procedure:
The title compound (D34) (39 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D14) (50 mg, 0.18 mmol) and 3,4-difluorobenzyl bromide (0.046 ml, 0.36 mmol). (Na2CO3: 2.5 eq; reaction time: 5 hrs; 70° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[N:16]=3)=[C:4]2[CH:3]=1.Br[CH2:35][CH:36]1[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]2[N:12]=[C:13]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:35][CH:36]4[CH2:38][CH2:37]4)=[CH:31][CH:32]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)[N:16]=3)=[C:4]2[CH:3]=1
Reactant: Oc1ccc(-c2nn3c(NC4CC4)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1cc(NC2CC2)n2nc(-c3ccc(OCC4CC4)cc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 4[5-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-7-(cyclopropylamino)pyrazolo[1,5-a]pyridin-2-yl]phenol (110 mg, 0.24 mmol) in acetonitrile was added bromomethyl cyclopropane (96 mg, 0.72 mmol) and cesium carbonate (85 mg, 0.26 mmol). The reaction mixture was heated at reflux for 6 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The organic phase was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (2:5 hexanes/ethyl acetate), gave 5-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine (75 mg, 61%) as a yellow solid. 1H NMR (CDCl3) δ 7.97 (d, 1H), 7.90 (s, 1H), 7.50 (d, 2H), 6.95 (d, 2H), 6.38 (s, 1H), 6.32 (d, 1H), 6.28 (d, 1H), 5.13 (d, 1H), 4.36 (m, 1H), 3.85 (d, 2H), 2.64 (m, 1H), 2.10 (m, 2H), 1.80-1.66 (m, 4H), 1.55 (m, 2H), 1.30 (m, 1H), 0.88 (m, 2H), 0.74 (m, 2H), 0.66 (m, 2H), 0.39 (m, 2H). MS m/z 515 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:22][N:21]=4)[C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:34]=1)=O.CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[OH:2][CH2:3][C:5]1[C:6]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:22][N:21]=4)[CH:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:34]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)(C)O)c(C(F)(F)F)n1)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)C1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(C)(C)O)c(C(F)(F)F)n1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a solution of (R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (109 mg, 0.196 mmol) in DCM (4 mL) was added a solution of DIBAL-H in DCM (0.98 mL of a 1.0 M solution, 0.98 mmol) dropwise at −78° C. The reaction slowly warmed to −10° C. over approximately 1 h, at which point 1 mL of MeOH was added to quench the excess DIBAL-H. Sat. aq. Rochelle salt (potassium sodium tartrate (KNaC4H4O6)) solution (5 mL) and DCM (5 mL) were added and the mixture stirred vigorously for 15 min. The DCM layer was separated and the aqueous layer was extracted with DCM (2×5 mL). The DCM layers were combined, dried using Na2SO4 and evaporated to give the crude product. Purification using ISCO FCC eluting with 70% EtOAc in Hexanes gave 71 mg of 2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol as a racemic mixture (69%). LC-MS MS (ESI) m/z 528.25 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 8.72 (s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 6.01 (d, J=7.6 Hz, 1H), 5.27 (d, J=4.4 and 14.0 Hz, 1H), 5.00-4.86 (m, 2H), 4.26-4.08 (m, 2H), 3.74-3.67 (m, 1H), 3.15 (s, 3H), 3.15-3.10 (m, 1H), 2.47-2.40 (m, 1H), 1.96 (b, 1H), 1.59 (s, 6H), 1.23 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc([N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a solution of 3-nitro-1H-indole (1 g, 6.17 mmol) in dry DMF (10 ml), under nitrogen, sodium hydride (60% w/w dispersion in mineral oil, 0.259 g, 6.48 mmol) was added. The mixture was stirred at room temperature for 15 minutes, and then ethyl 2-bromoacetate (0.723 ml, 6.17 mmol) was added. After stirring at the same temperature for 45 minutes, the mixture was partitioned between aqueous sat. NaHCO3 and Et2O; the aqueous layer was extracted with Et2O and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed and the resulting crude solid was purified by flash chromatography on silica gel (petroleum ether:Et2O from 6:4 to 1:1) to give ethyl 2-(3-nitro-1H-indol-1-yl)acetate (983 mg, 3.96 mmol, 64% yield). MS/ESI+ 249.1 [MH]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.ClCCl>COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[Pd]Cl>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11][CH3:12])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1-c1cccc(Cl)c1
Yield: 92 %

Procedure:
To a flask containing a bi-phasic mixture of 2-bromo-4-nitroanisole (15.0 g, 64.6 mmol) and 3-chlorophenylboronic acid (12.1 g, 77.6 mmol) in ethylene glycol dimethyl ether (187.5 mL) and 2.0 N aqueous cesium carbonate (97 mL) was added 1-1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II), complex with dichloromethane (1:1) (1.5 g). The mixture was heated at reflux for 4 hours under a nitrogen atmosphere. The crude reaction mixture was partitioned between ethyl acetate (350 mL) and brine (250 mL) and then filtered through a Buchner funnel. Layers were separated and the organic layer was washed with brine (250 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to a dark oil. The crude residue was purified by flash chromatography on silica gel using dichloromethane as the eluent to afford 2-(3-chlorophenyl)-4-nitroanisole as a yellow solid (13.9 g, 59.4 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[F:29][C:30]([F:59])([F:58])[C:31]1[C:35](B(O)O)=[CH:34][N:33]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:32]=1>>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:35]5[C:31]([C:30]([F:58])([F:59])[F:29])=[N:32][N:33]([C:39]([C:46]6[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=6)([C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)[C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[CH:34]=5)[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[CH2:13][CH2:14]2)=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1ccc(OC2CCN(c3ccnc4ccc(Br)cc34)CC2)cc1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Product: CS(=O)(=O)c1ccc(OC2CCN(c3ccnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5C(F)(F)F)cc34)CC2)cc1
Yield: 98.9 %

Procedure:
150 mg 6-bromo-4-{4-[4-(methylsulfonyl)phenoxy]piperidino}quinoline (compound in Production Example 89) and 180 mg 3-trifluoromethyl-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 31) were reacted in the same manner as in Example 9, to give 244 mg 4-[4-(4-methylsulfonylphenoxy)piperidin-1-yl]-6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl) quinoline. This product was reacted in the same manner as in Example 67, to give 130 mg of the title compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11](=O)[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.P(Cl)(Cl)([Cl:22])=O.C(Cl)(Cl)Cl>>[Cl:22][C:11]1[N:12]=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:9][N:10]=1
Reactant: O=c1ncc(-c2cccc(F)c2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Fc1cccc(-c2cnc(Cl)nn2)c1
Yield: 21 %

Procedure:
A mixture of 6-(3-fluoro-phenyl)-2H-[1,2,4]triazin-3-one (15.2 g, 79.5 mmol, crude) and 2 ml of DMF in 250 ml of 1:1 phosphorous oxychloride-chloroform was maintained at reflux overnight. The mixture was then concentrated at reduced pressure, diluted with methylene chloride and poured onto ice with stirring. When the ice melted the mixture was neutralized with sodium bicarbonate solution, and the layers were separated, the aqueous layer was extracted with dichloromethane once, the combined organic layer was washed with water, dried and concentrated to a brown oil which was purified by column chromatography (eluting with pure petroleum) to give title compound as a pale yellow solid (3.5 g, 21.0%): 1H NMR (CDCl3): δ 8.88 (s, 1H), 7.87-7.82 (m, 2H), 7.60-7.52 (m, 1H), 7.32-7.27 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[C:5]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24]>C(O)(C(F)(F)F)=O.CCOCC>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)[C:5]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(-c3ccccc3)ccc2C2(CCCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)CNC(=O)C1=C(O)c2cc(-c3ccccc3)ccc2C2(CCCC2)C1=O
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
1,1-Dimethylethyl N-((4′-hydroxy-2′-oxo-6′-phenyl-spiro[cyclopentane-1,1′-naphthalen]-3′-yl)carbonyl)glycinate (115 mg, 257 μmol) was dissolved in TFA (2 mL) at ambient temperature. The reaction was stirred for 30 minutes and was then concentrated to give an oil, dissolved in ether, concentrated again to give an amorphous solid, precipitated with ether, filtered, washed with ether, and dried in a vacuum oven to give the title compound (21 mg) as a white solid. MS (m/z)=392 (M+H)+. Calculated for the C23H21NO5 391.14.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:23][CH2:22][C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.Br[CH2:30][CH2:31][CH2:32][Cl:33]>CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:23][CH2:22][C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]([CH2:30][CH2:31][CH2:32][Cl:33])[C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCCCl)c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (335 mg, 60%) was added to a solution of 3-tert-butyloxycarbonyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.99 g) and DMF (21.0 mL) at 0° C. The solution was stirred at 0° C. for 30 min and then 1-bromo-3-chloropropane (0.74 mL) was added. The solution was stirred at 0° C. for 1 h and 16 h at room temperature. The solution was diluted with EtOAc, which was washed with water (3×20 mL). The combined aqueous layers were extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude material was purified by chromatography (Biotage, silica gel, 4:1-1:1 hexane:EtOAc) to give 1.38 g of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ 7.50, 7.10-7.40, 4.28, 3.55-3.82, 3.52, 2.95-3.10, 2.15-2.30, 1.51; MS (ESI) m/z 363 (M+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][NH:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13])[CH2:6][CH3:7].[Br:18][CH:19]([CH3:23])[C:20](Cl)=[O:21]>>[Br:18][CH:19]([CH3:23])[C:20]([N:9]([CH2:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH2:2][CH3:1])[CH2:10][CH:11]([CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:21]
Reactant: CCCCC(CC)CNCC(CC)CCCC
Reactant: CC(Br)C(=O)Cl
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)C(C)Br
Yield: 98 %

Procedure:
Step A is conducted starting with 2,2′-diethylhexylamine and 2-bromopropionyl chloride and leads to 2-bromo-N,N-bis(2-ethylhexyl)propanamide (Yield: 98%) for which the 1H and 13C NMR characterisations are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:16][N:15](S(C3C=CC(C)=CC=3)(=O)=O)[C:12]2=[N:13][CH:14]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1
Reactant: COc1ccccc1-c1cnc2c(n1)c(-c1ccccc1OC)cn2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1cnc2[nH]cc(-c3ccccc3OC)c2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.5 %

Procedure:
To a solution of 2,7-Bis-(2-methoxy-phenyl)-5-(toluene-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine (200 mg, 0.412 mmol) in MeOH (5 mL) was added a solution of NaOH (66 mg, 1.65 mmol) in water (200 μL). The mixture was stirred at room temperature for 3.5 hours before the solvents were removed. The resulting yellow residue was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 2,7-Bis-(2-methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (43 mg, 32% yield) as a pale yellow solid. 1H-NMR (500 MHz, CD3OD) δ12.21 (s br, 1H), 8.80 (dd, 6.0 Hz, 1.75 Hz, 1H), 8.69 (s, 1H), 7.76 (dd, 6.0 Hz, 1.75 Hz, 1H), 7.43 (dt, 7.5 Hz, 1.75 Hz, 1H), 7.20 (m, 2H), 7.13 (m, 2H), 7.04 (t, 7.3 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H). MS: m/z 332.1 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22]C)[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([NH2:16])=[C:10]2[C:17]#[N:18].C[Si](I)(C)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:25][O:24][C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:21]=1[OH:22])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([NH2:16])=[C:10]2[C:17]#[N:18]
Reactant: COc1cc(Oc2ccc3[nH]c(N)c(C#N)c3c2)cc(OC)c1OC
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Oc2ccc3[nH]c(N)c(C#N)c3c2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
A solution of 5-(3,4,5-trimethoxyphenoxy)-2-amino-1H-indole-3-carbonitrile (Example 11) (50 mg; 0.147 mmol) in CH2Cl2 (1.0 ml) was treated with trimethyl silyl iodide (30 ul; 0.2 mmol) and the mixture was stirred at room temperature overnight. The mixture was treated with aqueous Na2S2O3 (0.5 M), the CH2Cl2 evaporated and the mixture extracted with EtOAc. The organic phase was washed with water, brine and dried over MgSO4. Evaporation gave 5-(3,5-dimethoxy-4-hydroxy-phenoxy)-2-amino-1H-indole-3-carbonitrile (50 mg).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[N:26]4[CH:27]=[CH:28][N:29]=[C:25]4[CH:24]=[CH:23][CH:22]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].C1C(=O)N([Cl:39])C(=O)C1.O>C(O)C>[Cl:39][C:27]1[N:26]2[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:13])([F:12])[F:14])=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=4)[O:20][N:19]=3)=[CH:22][CH:23]=[CH:24][C:25]2=[N:29][CH:28]=1
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4nccn34)no2)cc1C(F)(F)F)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCO
Product: CC(Oc1ccc(-c2nc(-c3cccc4ncc(Cl)n34)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Reaction time: 15 h
Yield: 68.3 %

Procedure:
To a solution of 5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (150 mg) in ethanol was added NCS (67 mg) at room temperature, followed by stirring at 80° C. for 15 hours. To the reaction solution was added water, followed by extraction with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (n-hexane:EtOAc=90:10 to 75:25) to obtain 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (110.4 mg) as a white solid. To a solution of 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (100 mg) in methylene chloride (2 ml) was added dropwise 10 equivalents of 4M HCl/dioxane at room temperature. After stirring at room temperature as it was for 1 hour, it was concentrated under reduced pressure. It was powdered/washed with diisopropyl ether, and then collected by filtration to obtain 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine hydrochloride (102.6 mg) as a white solid.