Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[CH:18][C:17]=1[CH3:34].Cl.[OH-].[Na+]>O1CCCC1>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([CH3:34])[CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccccc4Cl)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccccc4Cl)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 79.8 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylphenyl}-2-(2-chlorophenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[C:35](Cl)(=[O:37])[CH3:36].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([CH:8]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[NH:25][C:35](=[O:37])[CH3:36])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
C-(3-Chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine (250 mg, 0.72 mmol) was dissolved in 4.0 mL of CH2Cl2 and DIPEA (139.8 mg, 1.08 mmol) and DMAP (8.8 mg, 0.07 mmol) were added. The reaction was cooled to 0° C. and acetyl chloride (68 mg, 0.87 mmol) was added to the homogenous reaction mixture. After 3 h the reaction was complete. Water was added and the organic layer was washed with NaHCO3 sat. aq. sol (1×), H2O and Brine. The organic layers where combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified with silica gel column chromatography [Jones Flashmaster, 10 g cartridge, eluting with 2% MeOH: CH2Cl2] to yield a dark oil; 1H NMR (400 MHz, CDCl3) δ 2.08 (s, 3H), 6.80 (d, 1H, J=7.9 Hz), 7.26-7.23 (m, 4H), 7.70-7.92 (m, 4H), 8.09-8.11 (m, 2H), 8.17 (d, 1H, J=8.60 Hz), 8.37 (d, 1H, J=2.40 Hz), 8.57 (d, 1H, J=2.49 Hz); MS (ES+): 430.84 (M+1), 432.83 (M+3), 433.92 (M+4).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]([NH:23][CH:24]1[C:32]2[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1>C(Cl)Cl>[C:11]1([C:9]2[N:10]=[C:6]([CH:5]3[CH2:4][CH2:3][CH2:2][N:23]3[CH:24]3[C:32]4[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[O:7][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc2c1CCC2NC(CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: ClCCl
Product: COc1cccc2c1CCC2N1CCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
To a solution of 1-[[4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.27 g) in CH2Cl2 (5 ml) was added SOCl9 (1 ml) at 0° C. After being stirred for 17 hours at room temperature, the solvent was evaporated in vacuo and the residue was dissolved in DMF (5 ml). To the mixture was added K2CO3 (2.07 g). After being stirred for 1 day at room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-2,3-dihydro-4-methoxy-1H-indene (0.15 g). MS (m/z): 437 (M+ +1) NMR (CDCl31 5) 1.42-3.20 (10H, m), 3.74 (2.5H, s), 3.81 (3.5H, s), 4.02-4.76 (2H, m), 6.58-7.72 (13H, m)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[CH2:16][C:17]2([OH:34])[C:21](=[O:22])[O:20][C@H:19]3[C:23]4[C@@:28]([CH3:31])([CH2:29][CH2:30][C:18]23[OH:33])[CH2:27][CH2:26][CH2:25][C:24]=4[CH3:32])(=O)=O)=CC=1>CN(C)C=O>[N:1]([CH2:16][C:17]1([OH:34])[C:21](=[O:22])[O:20][C@H:19]2[C:23]3[C@@:28]([CH3:31])([CH2:29][CH2:30][C:18]12[OH:33])[CH2:27][CH2:26][CH2:25][C:24]=3[CH3:32])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1=C2[C@@H]3OC(=O)C(O)(COS(=O)(=O)c4ccc(C)cc4)C3(O)CC[C@@]2(C)CCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C2[C@@H]3OC(=O)C(O)(CN=[N+]=[N-])C3(O)CC[C@@]2(C)CCC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Sodium azide (32.5 mg, 0.5 mmol) was added to the solution of compound of example 5 (218 mg, 0.5 mmol) in dimethylformamide (DMF) (2 mL) and stirred at 50° C. under nitrogen atmosphere for 24 hours. The reaction mixture was concentrated, dried and was dissolved in water (25 mL) and was extracted with ethyl acetate (3×50 mL). The ethyl acetate layer was washed with water and brine and was dried over sodium sulfate. Solvent was removed and crude product was washed with petroleum ether, to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@@H:33]([CH3:35])OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>>[CH2:21]([O:20][C:18]([C:13]1[N:14]([C@@H:33]([CH3:35])[CH2:34][NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=2)=[O:19])[CH3:22]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1[C@@H](C)CNC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
The title compound was synthesized in analogy to example 8, intermediate a), from ethyl 5-benzyloxyindole-2-carboxylate (commercially available), (R)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO02/010169) and potassium tert-butoxide, to give the desired compound as a yellow solid (100%).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[F:46]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:42]2[CH:43]=[CH:44][C:45]([F:46])=[C:40]([Cl:39])[CH:41]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(F)c(Cl)c2)c1

Procedure:
5-(tert-Butyl)-3′-chloro-4′-fluoro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 3-chloro-4-fluorophenylboronic acid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][CH:8]([F:18])[C:9]1[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]([CH3:17])[N:10]=1.Br[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]1[C:30](=[C:31]([Cl:33])[Cl:32])[CH:25]2[CH2:24][CH2:23]1.CNCCNC>>[Cl:32][C:31]([Cl:33])=[C:30]1[CH:22]2[C:21]3[C:26]([CH:25]1[CH2:24][CH2:23]2)=[CH:27][CH:28]=[CH:29][C:20]=3[NH:16][C:14]([C:13]1[C:9]([CH:8]([F:7])[F:18])=[N:10][N:11]([CH3:17])[CH:12]=1)=[O:15]
Reactant: ClC(Cl)=C1C2CCC1c1c(Br)cccc12
Reactant: Cn1cc(C(N)=O)c(C(F)F)n1
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1cc(C(=O)Nc2cccc3c2C2CCC3C2=C(Cl)Cl)c(C(F)F)n1
Reaction time: 24 h

Procedure:
A 20 ml screw-cap vial was filled with the following solids: CuO (0.05 mmol, 4.0 mg), anhydrous CuCl2 (0.05 mmol, 6.7 mg), K2CO3 (2.0 mmol, 277 mg), 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid amide (1.1 mmol, 193 mg) and 5-bromo-9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalene (1.0 mmol, 304 mg). A magnetic stir bar was added, and the open vial was gently flushed with N2. Dioxane (2 mL) was added, followed by N,N′-dimethylethylenediamine (0.45 mmol, 48 μl). The vial was sealed and placed into a preheated screening block at 130° C. Conversion was complete after 24 hours. The yield (HPLC-analysis) of the compound of formula I was 70%.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.FC(F)(F)C(O)=O.ICI.[C:16]12([CH2:26][O:27][C:28]3[C:40](/[CH:41]=[CH:42]/C)=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[C:30]([F:44])[CH:29]=3)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.Cl>ClCCl>[C:16]12([CH2:26][O:27][C:28]3[C:40]([C@@H:41]4[CH2:42][C@H:4]4[CH3:5])=[CH:39][C:31]([C:32]([OH:34])=[O:33])=[C:30]([F:44])[CH:29]=3)[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: CC[Zn]CC
Reactant: C/C=C/c1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@H]1c1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
To a mixture of diethylzinc (1.0 M solution in heptane, 6.75 mL, 6.75 mmol) in anhydrous dichloromethane (2 mL) was added a solution of trifluoroacetic acid (0.52 mL, 6.80 mmol) in anhydrous dichloromethane (3 mL) at 0° C. and the reaction mixture was stirred for 10 minutes at 0° C. A solution of diiodomethane (0.54 mL, 6.75 mmol) in dichloromethane (2 mL) was added to the reaction mixture at 0° C. and stirring was continued for 10 minutes at 0° C. To the reaction mixture was then added a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate (0.90 g, 2.25 mmol) in anhydrous dichloromethane (3 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 4 hours. After addition of 1 N hydrochloric acid (10 mL), the mixture was diluted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate gave a residue which was purified by reverse-phase preparative HPLC to afford the title compound as an off-white solid (0.086 g, 11%): MS (ES−) m/z 357.3 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)[C:5]#[N:6].[CH2:19]1[CH2:21][CH2:20]1>>[CH:19]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)[C:5]#[N:6])[CH2:21][CH2:20]1
Reactant: N#Cc1ccc(C2CCCc3cncn32)c(Br)c1
Reactant: C1CC1
Product: N#Cc1ccc(C2CCCc3cncn32)c(C2CC2)c1

Procedure:
3-Bromo-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile, prepared above, is converted to the corresponding cyclopropane by the method outlined in Tet. Lett. 2002, 43, 6987. MS (ESI) m/z 264.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 0.69-0.80 (m, 2H), 0.94-1.06 (m, 2H), 1.69-1.80 (m, 2H), 1.93-2.04 (m, 2H), 2.24-2.34 (m, 1H), 2.76-2.86 (m, 2H), 5.95 (d, J=6.1 Hz, 1H), 6.64-6.72 (m, 2H), 7.15 (s, 1H), 7.35 (s, 1H), 7.39 (d, J=8.1 Hz, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][N:32]=[CH:31]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]ncc4c3)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Yield: 43 %

Procedure:
A mixture of 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (235 mg, 0.62 mmol), (prepared as described for the starting material in Example 7), 5-hydroxyindazole (100 mg, 0.75 mmol) and cesium carbonate (303 mg, 0.93 mmol) in acetone (15 ml) was heated at reflux for 1.25 hours. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The residue was further purified by preparative HPLC to give 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1H-indazol-5-yloxy)-6-methoxyquinazoline (127 mg, 43%) as a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(Cl)Cl.I[C:39]1[N:43]2[C:44]3[C:49]([N:50]=[C:51]([NH:52][CH2:53][CH2:54][CH2:55][OH:56])[C:42]2=[N:41][CH:40]=1)=[CH:48][C:47]([C:57]([F:60])([F:59])[F:58])=[CH:46][CH:45]=3.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[OH:56][CH2:55][CH2:54][CH2:53][NH:52][C:51]1[C:42]2[N:43]([C:39]([C:2]3[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=3)=[CH:40][N:41]=2)[C:44]2[C:49]([N:50]=1)=[CH:48][C:47]([C:57]([F:60])([F:59])[F:58])=[CH:46][CH:45]=2
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(I)cnc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)c1cccc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A suspension of 3-bromobenzenesulfonamide (50 mg, 0.21 mmol), bis(pinacolato)diboron (54 mg, 0.21 mmol), potassium acetate (78 mg, 0.80 mmol) and Pd(dppf)Cl2.DCM (9 mg, 0.0105 mmol) in anhydrous dimethylformamide (1 mL) was degassed under argon for 10 minutes and then stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to room temperature and 3-{[1-iodo-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol (46 mg, 0.105 mmol), an aqueous solution of sodium carbonate 2M (367 μL, 0.735 mmol) and Pd(PPh3)4 (5 mg, 0.0042 mmol) was added. The mixture was stirred under argon at 80° C. overnight and then cooled to room temperature, diluted with cold water and extracted four times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 90/10) to afford 3-{4-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-1-yl}benzenesulfonamide (14 mg, 28%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1.O>[CH:41]1([S:47]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:49])=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)C2CCCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (664 mg) was added dropwise, and the mixture was stirred for 5 min. Cyclohexanesulfonyl chloride (367 mg) was added and the mixture was further stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 420 mg, 89%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:15][CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCCc1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCc2c[nH]cn2)cc1

Procedure:
1.49 g (9 mmol) of ethyl 4-hydroxybenzoate, 251 mg (1.5 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride, 500 g (3.6 mmol) of potassium carbonate and sodium iodide (catalyst) are stirred at 80° C. for 4 days in 5 ml of dimethylformamide. The reaction mixture is cooled and then filtered. The filtrate is evaporated under reduced pressure to give an oily residue. The excess ethyl 4-hydroxybenzoate is extracted with ether at pH=1. The aqueous solution is evaporated under reduced pressure to give the title compound. The latter is purified by preparative high performance chromatography and converted to the oxalate which, after crystallization from an isopropanol/ether mixture, melts at 160°-164° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]([CH:11]=1)[CH2:9][OH:10])([O-])=O.OCC1C=C(C=CC=1OC)N>>[OH:10][CH2:9][C:8]1[CH:11]=[C:4]([CH:5]=[CH:6][C:7]=1[O:12][CH2:13][CH2:14][CH3:15])[NH2:1]
Reactant: CCCOc1ccc([N+](=O)[O-])cc1CO
Agent: COc1ccc(N)cc1CO
Product: CCCOc1ccc(N)cc1CO
Yield: 37 %

Procedure:
This compound was prepared by reduction of 5-nitro-2-propyloxy-benzylalcohol using the method described for the preparation of 3-hydroxymethyl-4-methoxyaniline in 37% yield: 1H NMR (DMSO-d6, 500 MHz) δ6.66 (d, 1H, J=2.5 Hz), 6.60 (d, 1H, J=8.6 Hz), 6.35 (dd, 1H, J=2.7 and 8.5 Hz), 4.79 (t, 1H, J=5.8 Hz), 4.54 (br, 2H), 4.37 (d, 2H, J=6.1 Hz), 3.74 (t, 2H, J=6.4 Hz), 1.65 (m, 2H), 0.94 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[BH4-].[Na+].B(F)(F)F>O1CCCC1>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)Cc1ccc(CO)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCNCCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 98.1 %

Procedure:
To a stirred solution of N-heptyl-2-(4-hydroxymethyl-phenyl)-acetamide (5.6 mmol, 1.48 g) dissolved in tetrahydrofuran (15 mL) under a nitrogen atmosphere at 0° C. was added sodium borohydride (16.9 mmol, 639 mg) followed by the dropwise addition of boron trifluoride diethyletherate (22.5 mmol, 2.85 mL). The mixture was allowed to stir at room temperature for 11 hours. The reaction was quenched by the cautious addition of 2N HCl until gas evolution had ceased. The resulting mixture was refluxed for 45 minutes, cooled to room temperature and concentrated to a white solid. The solid was dissolved in water, then brought to pH 14 with 2N NaOH. The aqueous solution was extracted with diethyl ether (3×). The organic layers were combined, washed with brine (1×), dried over anhydrous sodium sulfate and concentrated to give [4-(2-heptylamino-ethyl)-phenyl]-methanol as a clear oil (1.37 g, 98%).
Reaction SMILES: C([O:4][C:5]1[N:10]=[C:9]([O:11][C@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)[CH:8]=[CH:7][CH:6]=1)C=C.[C:28]1(C)[CH:33]=CC=C[CH:29]=1>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>[CH2:33]([N:10]1[C:5](=[O:4])[CH:6]=[CH:7][CH:8]=[C:9]1[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1)[CH:28]=[CH2:29]
Reactant: Cc1ccccc1
Reactant: C=CCOc1cccc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCn1c(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)cccc1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
An oven-dried 100 mL Kjeldahl Flask under nitrogen was charged with the product of Step 5 (2.82 g, 7.45 mmol) and toluene (15 ml). Degassed 5 minutes with nitrogen. Added tetrakis(triphenylphosphine)palladium(0) (0.431 g, 0.373 mmol). Heated in a 60° C. oil bath for 1 hour. HPLC/MS shows product. HPLC/MS looks good after 2 hours. Cooled. Evaporated. Subjected to flash column chromatography eluting with 99 methylene chloride/1 methanol. Evaporation of fractions containing product gave the title compound as an oil/foam. (1.91 g, 5.05 mmol, 67,7% yield). LCMS (ES+) m/z 379.3 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1nc(C(=O)NCCCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 90.3 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 4-aminobutyric acid (97 mg, 0.94 mmol) (Aldrich) in 0.5 M NaOMe/MeOH (1.25 mL, 0.63 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (60 mL), acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 109 mg (0.28 mmol) in 89% yield. LC-MS ESI−: 390.04 (M−1)−.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([Cl:9])[CH:8]=1>CO.[Pt](=O)=O>[ClH:2].[Cl:9][C:7]1[CH:6]=[C:5]([CH:10]2[CH2:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:18][NH:19]2)[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: COC(=O)c1ccnc(-c2cc(Cl)cc(Cl)c2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2cc(Cl)cc(Cl)c2)C1
Reaction time: 4 h
Yield: 136.9 %

Procedure:
Methyl 2-(3,5-dichlorophenyl)isonicotinate hydrochloride (6.88 g, 21.6 mmol) was dissolved in MeOH (50 mL), added platinum(IV) oxide (0.049 g, 0.22 mmol) and hydrogenated in a Büchi hydrogenator at 5 bar for 4 h. Reaction mixture filtered, washed with MeOH until all product had dissolved and evaporated. Methyl 2-(3,5-dichlorophenyl)piperidine-4-carboxylate hydrochloride (4.8 g, 69%) was isolated as a yellowish solid. MS m/z 288 (M+H)+