Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH2:18]([N:25]([CH3:41])[C:26]1[CH:27]=[C:28]([NH:33][C:34]2[N:39]=[C:38](Cl)[CH:37]=[CH:36][N:35]=2)[CH:29]=[CH:30][C:31]=1[CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CC(O)C>[CH2:18]([N:25]([CH3:41])[C:26]1[CH:27]=[C:28]([NH:33][C:34]2[N:35]=[C:36]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])[C:3]=3[S:14]([NH2:17])(=[O:16])=[O:15])[CH:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[CH3:32])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(OCC(F)(F)F)c1S(N)(=O)=O
Reactant: Cc1ccc(Nc2nccc(Cl)n2)cc1N(C)Cc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc(Nc2nccc(Nc3cccc(OCC(F)(F)F)c3S(N)(=O)=O)n2)cc1N(C)Cc1ccccc1

Procedure:
A solution of 2-amino-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide (54 mg, 0.2 mmol) and N3-benzyl-N1-(4-chloro-pyrimidin-2-yl)-N3,4-dimethyl-benzene-1,3-diamine (according to step a), 55 mg, 0.163 mmol) in 2-propanol (6 mL) and 1M HCl (0.32 mL) is heated under reflux for 1 h. Solvents are evaporated and the residue is adjusted to pH 8 by the addition of aqueous NH3. Partition between EtOAc and water, washing with 10% brine, drying of the organic phase (Na2SO4), evaporation of solvents, and chromatography (silica gel) of the residue gives 2-{2-[3-(benzyl-methyl-amino)-4-methyl-phenylamino]-pyrimidine-4-ylamino}-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide, eluted with EtOAc/hexanes 2:3. 1H-NMR (400 MHz, DMSO-d6): 2.20 (s, CH3C(4″)); 2.43 (s, NCH3); 3.90 (s, NCH2C6H5); 4.90 (q, J=9, OCH2CF3); 6.20 (d, J=5, H—C(5′)); 6.93 and 6.97 (2d, J=9; H—C(5), H—C(5″); 7.14-7.20, 7.20-7.34, and 7.34-7.4 (3m, NCH2C6H5, H—C(2″), H—C(6″), SO2NH2); 7.45 (t, J=8, H—C(4)); 8.05 (d, J=5, H—C(6′)); 8.12 (db, J=9, H—C(3′)); 9.12 (b, NH); 8.9-10.3 (NH).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O.[CH:21]1([C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27])[CH2:23][CH2:22]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:21]1([C:24]([C:25]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[C:3]3[C:4]4[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:26]=2[CH3:27])=[O:29])[CH2:23][CH2:22]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(=O)C3CC3)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 31.5 %

Procedure:
To a stirred solution of 60 mg (0.21 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (the preparation of which is described in example 8) in 2 ml acetic acid was added 35 mg (0.28 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 25 mg (32%) cyclopropyl-[4-(4-methoxy-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-methanone as a light brown oil. ES-MS m/e (%): 378 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)=[O:19]
Reactant: N#CCc1ccc(N)cc1
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#CCc1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A solution of 4-aminobenzyl cyanide (7.5 g, 56.7 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (11.4 g, 4.98 mL, 56.7 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 10.5 g (95%) of the title compound as a pale-orange solid, mp 127°-135° C. (decomp): 1H NMR (DMSO-d6) δ10.45 (s, 1H), 7.59 (d, J=9.2, 2H), 7.31 (d, J=9.2, 2H), 4.03 (s, 2H), 3.98 (s, 2H); 13C NMR (DMSO-d6) δ164.83, 137.98, 128.60, 126.42, 119.61, 119.26, 30.31, 21.81; MS (EI, m/z) 252 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:46](=[O:50])[CH:47]([CH3:49])[CH3:48].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:47]([CH3:49])([CH3:48])[CH:46]2[OH:50])=[O:19])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
To a mixture of 4-(benzylidene-amino)-benzoic acid ethyl ester (5.1 g, 20.0 mmol) and ytterbium(III) triflate hydrate (1.3 g, 2.0 mmol) in dry tetrahydrofuran (20.0 mL) at 25° C. was added isobutyraldehyde (18.2 mL, 200 mmol) and water (0.36 mL, 20.0 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-3,3-dimethyl-2-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (6.6 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C20H23NO3 (M+H)+: 326.40, observed: 308.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=3)[C:19]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)=[O:20])(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:34]([F:37])([F:36])[F:35])=[N:3]1.CN1C(C2SC(S(Cl)(=O)=O)=CC=2)=[CH:42][C:41](C(F)(F)F)=N1>>[CH2:41]([O:27][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:31]=[CH:32][CH:33]=[C:16]([NH:15][S:12]([C:10]3[S:11][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([C:34]([F:35])([F:37])[F:36])[CH:5]=4)=[CH:8][CH:9]=3)(=[O:14])=[O:13])[CH:17]=2)=[CH:23][CH:24]=1)[CH3:42]
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)Nc2cccc(C(=O)Nc3ccc(C(=O)O)cc3)c2)s1
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)Cl)s1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(-c4cc(C(F)(F)F)nn4C)s3)c2)cc1

Procedure:
4-{3-[5-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonlyamino]-benzoylamino}-benzoic acid, MS (ISP): m/e=549.2 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonyl chloride and yielded 4-{3-[5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonylamino]-benzoylamino}-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][N:14]=[N+]=[N-])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][NH2:14])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: [N-]=[N+]=NCCOc1cc(F)cc2ccoc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCOc1cc(F)cc2ccoc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
A solution 2-(5-fluoro-benzofuran-7-yloxy)-ethylazide (0.82 g, 3.7 mmol) and triphenylphosphine (1.17 g, 4.4 mmol) in tetrahydrofuran (50 ml) and water (2 ml) was allowed to stir for 18 hours at room temperature. The solvent was removed under vacuum. Chromatography (30% methanol-methylene chloride plus ammonium hydroxide) afford 0.55 g (73%) of product as a yellow oil: MS ESI 196 m/e (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[O:22])[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>[Pt]=O.CO>[CH2:1]([O:3][C:4]([C:6]1([CH:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[C:11](=[O:22])[CH2:10]2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1(C2=CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Agent: O=[Pt]
Solvent: CO
Product: CCOC(=O)C1(C2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Yield: 99 %

Procedure:
A 13.1 g (43.8 mmol) portion of 4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenylethyl]-3-pyrrolin-2-one was dissolved 300 ml of methanol, mixed with 400 mg of platinum oxide and then stirred in an atmosphere of hydrogen for 18 hours. After completion of the reaction, the reaction solution was filtered and concentrated to yield 13.0 g (99 %) of the titled compound as an oily substance.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[CH3:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Reactant: Cc1ccc(N=C=O)cc1C
Agent: Cl
Product: Cc1ccc(NC(=O)N2CCC(=O)N(CCCN3CCC4(CC4)[C@H](O)C3)C[C@H]2C)cc1C
Yield: 32 %

Procedure:
In analogy to the procedure described in example 58F, (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 58E) and 3,4-dimethylphenyl isocyanate (without addition of 0.1 eq. of 3,4-dimethylphenyl isocyanate) gave 0.035 g (32%) of the title compound as white foam. MS: 443.3 (MH+).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH2:28]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)=[CH:6][CH:5]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc(NCc2ccccc2)cc1

Procedure:
The title compound is prepared from N-(4-aminophenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-acetamide dihydrochloride (Example 181) and benzaldehyde according to the method described in Example 177. Melting Point: 84-106° C. (dec.) (diethylether-ethyl acetate)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]4)=[CH:43][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 67 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(ethyloxy)-4-{4-[2-(methylsulfonyl)-ethyl]-1-piperazinyl}aniline (Example 143, step C) (64 mg, 0.194 mmol), and p-toluenesulfonic acid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (98 mg, 0.13 mmol, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.36 (s, 1H), 8.34 (d, J=13.00 Hz, 2H), 8.21 (d, J=4.94 Hz, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.59 (s, 1H), 7.36-7.48 (m, 3H), 7.19 (t, J=7.97 Hz, 2H), 6.96 (s, 1H), 6.66 (s, 1H), 6.41-6.52 (m, 2H), 4.05 (q, J=6.59 Hz, 2H), 3.30-3.37 (m, 2H), 3.07-3.14 (m, 4H), 3.02 (s, 3H), 2.74 (t, J=6.32 Hz, 2H), 2.54-2.61 (m, 4H), 1.22 (t, J=6.68 Hz, 3H). MS (ESI): 753 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH:19]([CH3:21])[CH3:20]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OC(C)C
Temperature: 65 °C

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde (20.0 g), anhydrous potassium carbonate (26.2 g) and 2-bromopropane (18.3 mL) in dry dimethylformamide (300 mL) is stirred and heated at 5514 65° C. for 24 hours. The cooled mixture is poured into water and extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated in vacuo at 40° C., to give 4-methoxy-3-prop-2-yloxybenzaldehyde, in the form of an oil (24.2 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[N+:2]=[N-:3].[OH-].[K+].O>CO>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CCCCCN=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Ethyl 6-azidohexanoate (8.59 g, 44.8 mmol) and KOH (13.0 g, 0.231 mol) were dissolved into a mixture of 120 ml of water and 180 ml of MeOH. The solution was stirred at 0° C. for 2 hrs then MeOH was removed in vacuo. The aqueous layer was extracted by CHCl3 (2×100 ml), acidified to pH=1 by 2N aqueous HCl and extracted by Et2O (2×100 ml). The organic layers were combined, washed with water (100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 6-azidohexanoic acid (6.56 g, 93%) was obtained as a colorless oil.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)[CH:7]=[CH:6]2>CO>[NH2:16][CH2:15][CH2:14][N:13]([CH2:18][CH2:17][Cl:1])[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Reactant: Cl
Solvent: CO
Product: NCCN(CCCl)c1ccc2cc(Cl)ccc2n1
Reaction time: 1 h
Yield: 84 %

Procedure:
HCl (gas) was transferred into a solution of tert-butyl 4-(6-chloro quinolin-2-yl)piperazine-1-carboxylate (1.6 g, 4.6 mmol) in methanol (40 ml) at room temperature with stirring for 1 hour and then concentrated under vacuum to afford N-(2-aminoethyl)-6-chloro-N-(2-chloroethyl)quinolin-2-amine as a white solid (1.1 g, 84%). (ES, m/z): [M+H]+ 248
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1I.[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH3:19])=[N:16][CH:17]=1)#[CH:11].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[C:11]#[C:10][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH3:19])=[N:16][CH:17]=1
Reactant: Cc1nccc(Cl)c1I
Reactant: C#Cc1ccc(NC)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1ccc(C#Cc2c(Cl)ccnc2C)cn1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 20 mg (0.08 mmol) 4-chloro-3-iodo-2-methyl-pyridine and 11 mg (0.09 mmol) (5-Ethynyl-pyridin-2-yl)-methyl-amine using 1.5 mg (0.01 mmol) CuI, 5.5 mg (0.01 mmol) PdCl2(PPh3)2 and 0.11 mL (0.8 mmol) triethylamine in 1 mL dry DMF. After completion of the reaction the product is purified by RP-HPLC using a ACN/H2O gradient (95:5 to 70:30). Yield: 20 mg (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:15].Br[CH2:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:15][CH2:17][CH2:18][CH2:19][OH:20]
Reactant: Oc1ccc(Oc2ccccc2)cc1Cl
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCCOc1ccc(Oc2ccccc2)cc1Cl
Temperature: 70 °C
Yield: 95.4 %

Procedure:
To a 100 ml DMF solution of 2-chloro-4-phenoxyphenol (10 g, 45 mmol) were added 3-bromopropanol (8.2 ml, 91 mmol) and cesium carbonate (6.2 g, 50 mmol). The resulting suspension was heated to 70° C. for 7 hr. Solvent was removed under reduced pressure. The residue was diluted with AcOEt and water. The organic layer was separated. The aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 30% AcOEt/hexanes gave 3-(2-chloro-4-phenoxyphenoxy)-propanol 11.96 g (95%). This material was dissolved in acetonitrile 200 ml. To it was added triphenylphosphine (18.5 g, 55.8 mmol) and carbon tetrabromide (16.9 g, 64.4 mmol). After stirring at rt for 1 hr, the solvent was removed, and the residue was chromatographed on silica gel. Elution with 5% THF/hexanes gave the title compound as colorless oil 10.9 g (74%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:10][Si:11]([CH3:14])([CH3:13])Cl>BrCCBr.C1COCC1>[CH3:10][Si:11]([CH3:14])([CH3:13])[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cl)c1
Reactant: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1cccc([Si](C)(C)C)c1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A solution of m-chlorotoluene (25.3 g, 0.20 mol), 1,2-dibromoethane (2.18 g, 11.6 mmol) and THF (40 cm3) was added to magnesium turnings (5.35 g, 0.22 mol). The mixture was heated under reflux in an atmosphere of argon for 4 h, after which the heating bath was removed and trimethylchlorosilane (23.9 g, 0.22 mol) was added so that gently reflux was maintained. The mixture was stirred for another 30 min and then separated between 5% NaHCO3 (100 cm3) and dichloromethane (3×100 cm3). The organic extract was washed with brine and dried (MgSO4). The solvent was removed under reduced pressure affording the title compound (29.4 g, 89%) as a pale yellow liquid, which was used without purification in the next reaction. All spectroscopic data were identical to those reported in the literature (Eisenhut et al., ibid).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:29]([OH:32])([CH3:31])[CH3:30])[CH:19]=[N:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH3:28])[CH2:23]1>C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:29]([OH:32])([CH3:31])[CH3:30])[CH:19]=[N:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([C:2]2[NH:3][C:4]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=3[N:6]=2)[C@H:24]([CH3:28])[CH2:23]1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: C[C@@H]1CN(c2ncc(C(C)(C)O)cc2Cl)CCN1
Solvent: CCO
Product: C[C@@H]1CN(c2ncc(C(C)(C)O)cc2Cl)CCN1c1nc2cc(C(F)(F)F)ccc2[nH]1

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-benzoimidazole (58 mg, 0.26 mmol, Example 1c) and 2-[5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl]-propan-2-ol from step (c) above (90 mg, 0.33 mmol) in ethanol (1 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 454 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18](O)=[O:19])[C:6]=2[CH:21]=1.C1C=CC2N(O)N=[N:33][C:31]=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.CN>CN(C=O)C>[Br:1][C:2]1[C:3]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([NH:33][CH3:31])=[O:19])[C:6]=2[CH:21]=1
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3F)c(C(=O)O)c2cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2F)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (440 mg, 0.99 mmol), HOBT (199 mg, 1.48 mmol) and EDCI (283 mg, 1.48 mmol) in dry DMF (10 mL) was stirred at 25° C. After 2 hours, Et3N (299 mg, 2.96 mmol) and MeNH2 (200 mg, 2.96 mmol) was added to the mixture and then stirred overnight. The solvent was removed by vacuum, the mixture was washed with H2O (20 mL) and extract with EtOAc (40 mL*3), dried over Na2SO4, After concentrated, the resulting residue was purified using column chromatography (dichloromethane:EtOAc=2:1) to provide 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (400 mg, yield: 88%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.61 (s, 1H), 8.19 (d, J=3.6 Hz, 1H), 7.97 (s, 1H), 7.80˜7.86 (m, 1H), 7.73 (s, 1H), 7.44˜7.50 (m, 1H), 7.27˜7.31 (m, 1H), 3.02 (s, 3H), 2.75 (d, J=4.8 Hz, 3H). MS (M+H)+: 459/461.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C>[Br:1][C:2]1[O:6][C:5]([CH2:7][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(Br)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Brc1ccc(CN2CCOCC2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a mixture of 5-bromo-2-furaldehyde (1.76 g) and morpholine (1.00 ml) in 40 mL anhydrous THF at room temperature was added acetic acid (0.60 mL) followed by sodium triacetoxyborohydride (3.28 g). The mixture was stirred at room temperature for 3 h and then poured into a saturated solution of sodium bicarbonate (100 mL). After stirring vigorously for 5 min the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. Purification of the residue by flash chromatography afforded 2.09 g (8.49 mmol, 84% yield) of 4-(5-bromo-2-furylmethyl)morpholine.