Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:37])=[C:4]([CH3:36])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([NH:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=O)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:34]=1[CH3:35].Cl>O1CCCC1>[NH2:1][C:2]1[C:3]([CH3:37])=[C:4]([CH3:36])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][NH:20][CH:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:34]=1[CH3:35]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(C(=O)NC(c3ccccc3)c3ccccc3)CC1)O2
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(CNC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 70.4 %

Procedure:
To a solution of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphenylmethyl)-4-piperidinecarboxamide (1.3 g) in tetrahydrofuran (20 mL) was added 17 mL of 1 M borane tetrahydrofuran complex solution in tetrahydrofuran with ice-cooling and the mixture was refluxed under nitrogen gas for 23 hours. After this reaction mixture was cooled with ice, 12 mL of 5N-hydrochloric acid was added dropwise and the mixture was concentrated under reduced pressure. The residue was neutralized with sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethanol=10:1) to give 0.89 g of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphenylmethyl)-4-piperidinemethylamine. Yield 68%. This product was dissolved in methanol and a stoichiometric excess of 10% HCl solution in methanol was added dropwise. The mixture was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:5]1=2)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:5]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C(C)C)ncc1Cl
Yield: 52 %

Procedure:
In an analogous procedure to Example 651, part c, 1-isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was combined with (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield 7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1-isopropyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (50.70 mg, 52% yield) as a beige powder. 1H-NMR (CDCl3) δ 8.15 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.98 (s, 1H), 6.54 (s, 1H), 6.47 (d, J=8.9 Hz, 1H), 4.83 (m, 1H), 3.90 (m, 8H), 3.13 (m, 5H), 2.75 (m, 1H), 2.53 (m, 1H), 2.23 (m, 3H), 1.86 (m, 1H), 1.42 (d, J=6.7 Hz, 3H), 1.05 (d, J=6.9 Hz, 3H). LC/MS (ESI+)=537 (M+H). MP=153-154° C.
Reaction SMILES: C([Li])(CC)C.CC12CO[C:10]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)([O:11]C1)[O:9]C2.C[O:28][B:29](OC)[O:30]C>C1COCC1>[B:29]([C:18]1[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:10]([OH:11])=[O:9])([OH:30])[OH:28]
Reactant: COB(OC)OC
Reactant: CC12COC(COc3ccc(C(F)(F)F)cc3)(OC1)OC2
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(C(F)(F)F)cc1B(O)O
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of sec-butyllithium (66 ml, 1.4M in cyclohexane) was added dropwise over 10 min to a stirred solution of the product from step (iii) (9.44 g) in THF (100 ml) at −78° C. After 3 h the mixture was warmed to −40° C. for 5 min, then cooled to −78° C. Trimethylborate (14.1 ml) was added, then after 10 min the reaction quenched with 2M hydrochloric acid. The mixture was warmed to RT and the organic phase separated. The aqueous layer was extracted with ethylacetate, the organics combined and evaporated under reduced pressure. The residue was dissolved in methanol (500 ml) then bondelut-NH2 resin(180 g) added and the mixture swirled for 0.5 h then filtered. The resin was washed with 10% acetic acid/methanol, the washings then evaporated under reduced pressure and dried under high vacuum. The residue was dissolved in methanol (50 ml), tetrahydrofuran (50 ml) and saturated aqueous sodium hydroxide solution (2 ml), left for 30 min then 2M hydrochloric acid (50 ml) added and the organics evaporated under reduced pressure. The residual aqueous layer was extracted with ethylacetate, the organics separated, dried and evaporated under reduced pressure, yield 5.05 g.
Reaction SMILES: [CH:1]([N:4]1[C:10]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2]>[Pd].CO>[CH:1]([N:4]1[C:10]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCCOc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCCOc2ccc(N)cc21
Yield: 97.5 %

Procedure:
9-Isopropyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (0.128 g, 0.000542 mol), 10% Palladium on Carbon (50% Wet) (0.023 g). and Methanol (0.57 mL) was shaken under an atmosphere of Hydrogen at 40 psi overnight. Filtration and conc. afforded 9-Isopropyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzo-cyclohepten-2-ylamine as a brown oil (109 mg, 98%). LCMS: 206.
Reaction SMILES: CN(C(N=NC([N:10]([CH3:12])C)=O)=O)C.[C:13]12(CS(O)(=O)=O)[C:20](C)(C)[CH:17]([CH2:18][CH2:19]1)[CH2:16][C:14]2=[O:15].O1CCCOO1>C(Cl)Cl.OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Cu+2]>[O:15]1[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:20]=[CH:12][NH:10]1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CN(C)C(=O)N=NC(=O)N(C)C
Agent: [Cu+2]
Agent: C1COOOC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C1=Cc2ccccc2ON1
Yield: 450.6 %

Procedure:
To 6.5 g (27 mmol) of the phenolic diamide in 200 mL of anhydrous CH2Cl2 was added 6.5 g CuSO4, 2.3 g (10 mmol) camphor sulfonic acid, 36 g (400 mmol) trioxane, and 10 drops H2SO4 with rapid stirring. The resulting suspension was heated to reflux under argon atmosphere and refluxed for 72 hr. The reaction mixture as concentrated to 100 mL by simple distillation at which point no starting material was seen by TLC (EtOAc). The reaction mixture was diluted to 400 mL with CH2Cl2, and then filtered through celite. The filtrate was washed with 100 mL of 1 N NaOH, dried over Na2SO4, and concentrated in vacuo yielding 6.0 g crude benzoxazine intermediate. The crude benzoxazine was chromatographed on 200 g of silica gel (EtOAc) yielding 4.0 g (59%) of intermediate with one spot to TLC and the following property: FTIR 3327, 1664, 1641, 1552, 1428, 1329.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH:11]([CH3:14])[CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][CH2:14][CH2:11][CH:12]=[O:13]
Reactant: Cc1cc(Cl)ccc1N
Reactant: CC(Br)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)ccc1NCCC=O
Temperature: 150 °C

Procedure:
2-Methyl-4-chloroaniline (1.0 mole), the diethyl acetal of 2-bromopropionaldehyde (1.0 mole) and sodium carbonate (1.0 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is heated at a temperature of about 150°C for a period of about 24 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then distilled under vacuum to yield the desired product the diethyl acetal of 3-(2-methyl-4-chloroanilino)propionaldehyde as the residue.
Reaction SMILES: [CH2:1]([C:4]1[O:5][C:6]([C:17](OC)=[O:18])=[C:7]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:8]=1)[CH2:2][CH3:3].CC(C[AlH]CC(C)C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH2:1]([C:4]1[O:5][C:6]([CH2:17][OH:18])=[C:7]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(COC2CCCCO2)c(C(=O)OC)o1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CCCc1nc(COC2CCCCO2)c(CO)o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
To a solution of 2-propyl-4-(((2-tetrahydropyranyl)oxy)methyl)oxazole-5-carboxylic acid, methyl ester (1.68 g, 5.94 mmol), from step 53a above, in 60 mL of methylene chloride cooled to -78° C. was added DIBAL (1.0M in hexane, 15 mmol). The reaction mixture was then stirred for 15 minutes at 0° C., and methanol (1.5 mL) was added carefully to quench the reaction. Saturated potassium sodium tartrate (50 mL) was added, and the mixtrue was stirred for 1 hour at room temperature. The layers were separated, and the aqueous layer was extracted with methylene chloride. The organic solutions were combined, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane to 3% methanol in ethyl acetate, to afford 1.27 g of the title compound as an oil. MS m/z: 256 (M+H)+. NMR (CDCl3) δ:4.72-4.51 (m, 5H), 3.85 (m, 1H), 3.55 (m, 1H), 2.97 (t, J=6 Hz, 1H), 2.71 (t, J=7.5 Hz, 2H), 1.90-1.50 (m, 8H), 0.99 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([CH2:18]Cl)=[CH:5]2.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([CH2:18][N:26]1[C:27]3=[CH:28][N:29]=[CH:30][CH:31]=[C:32]3[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]1)=[CH:5]2
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: CS(=O)(=O)CCn1c(CCl)cc2cc(Cl)cc(F)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCn1c(Cn2nc(S(C)(=O)=O)c3ccncc32)cc2cc(Cl)cc(F)c21
Reaction time: 8 h
Yield: 11 %

Procedure:
A mixture of the crude 5-chloro-2-(chloromethyl)-7-fluoro-1-(2-(methylsulfonyl)ethyl)-1H-indole (0.36 mmol), 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (60 mg, 0.30 mmol) and K2CO3 (198 mg, 1.44 mmol) in 3 mL of DMF was stirred overnight and then the precipitate was filtered off. The filtrate was purified by preparative-HPLC to give 1-({5-chloro-7-fluoro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (16 mg, yield: 11%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:21]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N#Cc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)cc1
Yield: 16.6 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 4-Formylbenzonitrile (36.8 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 17.15 mg (17%) of the title compound. (300 MHz, DMSO-d6) 13.55 (s, 1H), 8.29 (d, J=8 Hz, 1H), 8.05-7.99 (m, 3H), 7.78 (s, 1H), 7.36 (m, 1H), 7.25 (s, 1H), 6.43 (m, 1H), 6.38 (m, 1H), 5.18 (t, J=17 Hz, 8.5 Hz, 1H), 2.90 (s, 1H), 2.81 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=405 (M+H), HPLC: 2.42 min. (G Method)
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=1[O:29]CC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].O1CCCC1.C(O)C>[C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[OH:29])(=[O:18])=[O:19])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1O

Procedure:
(S)-3-(2-Benzyloxy-4-nitro-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester (150 mg, 0.28 mmol) was hydrogenated with 10% Pd/C (50 mg) in 1:1 tetrahydrofuran/ethanol (10 mL) at room temperature under 50 psi hydrogen in a Parr shaker for 3 h. The reaction mixture was filtered over a celite pad, the catalyst was washed with ethanol, the organics were combined and the solvent was removed under reduced pressure to give (S)-3-(4-amino-2-hydroxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester, 100 mg, 85%. RP-HPLC (10 to 90% acetonitrile in 0.1 N aqueous ammonium acetate over 10 min at 2 mL/min using a Waters Symmetry C18 150×4.6 mm column) 8.3 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[O:19][C:18]4[C:13](=NC=[CH:16][CH:17]=4)[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.BrC1N2N=C(Cl)C=CC2=[N:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[O:19][C:18]4[CH:17]=[CH:16][N:23]=[CH:22][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: Clc1ccc2ncc(-c3cc4ncccc4o3)n2n1
Product: Clc1ccc2ncc(-c3cc4cnccc4o3)n2n1

Procedure:
6-Chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine was prepared in analogy to 6-chloro-3-(furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine starting from 314 mg (1.35 mmol) of 3-bromo-6-chloroimidazo[1,2-b]pyridazine to yield 62% of a solid material.
Reaction SMILES: [Mg].[CH:2](Cl)([CH3:4])[CH3:3].[OH:6][C:7]([C:16]([F:19])([F:18])[F:17])([C:12]([F:15])([F:14])[F:13])[C:8](OC)=[O:9].[Cl-].[NH4+]>O1CCCC1>[CH3:3][CH:2]([CH3:4])[CH:8]([OH:9])[C:7]([C:12]([F:13])([F:14])[F:15])([OH:6])[C:16]([F:19])([F:18])[F:17]
Reactant: COC(=O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)C(O)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A flask was charged with 9.5 g of magnesium and 300 ml of tetrahydrofuran, to which 35.0 g of isopropyl chloride was added dropwise at 50° C. After the completion of dropwise addition, the contents were stirred for one hour at 60° C., and 22.6 g of methyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate was added dropwise below 50° C. The mixture was stirred for one hour at room temperature, after which an ammonium chloride aqueous solution was added. This was followed by ordinary work-up and vacuum distillation, obtaining 20.2 g of the target compound (yield 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:14]([NH:18][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:3]=1[O:2][CH3:1])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: COc1cccc(C(=O)O)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of 2,3-dimethoxybenzoic acid (4.55 g, 25.0 mmol) in metylene chloride (250 mL) were added butylamine (2.01 g, 27.5 mmol) and DMAP (3.36 g, 27.5 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g, 27.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was washed with 5% HCl (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL) and dried over MgSO4. Concentration in vacuo afforded 5.59 g (94%) of a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=2)=[CH:3][C:2]([C:42]2[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Yield: 100.2 %

Procedure:
Following general procedure F, tert-butyl 4-{5-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]pyridin-2-yl}piperazine-1-carboxylate (65 mg, 0.118 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (51 mg, 0.177 mmol) to afford the crude product (75 mg) as an orange solid: ESI MS m/z 634 [C33H33C12N5O4+H]+.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH2:21]([NH:28][CH2:29][CH2:30][O:31][C:32]1[CH:40]=[C:36]([C:37]([NH2:39])=[O:38])[C:35]([OH:41])=[CH:34][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[CH2:21]([N:28]([CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([OH:41])=[C:36]([C:37](=[O:38])[NH2:39])[CH:40]=1)[CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)c(OCC2CO2)c1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccccc2-c2cc3ccccc3[nH]2)ccc1O

Procedure:
The starting compound is obtained in the following manner: (13a) A solution of 10.5 g of 2-[2-(2,3-epoxypropoxy)-phenyl]-indole and 10.2 g of 5-(2-benzylaminoethoxy)-salicylamide in 300 ml of isopropanol is reacted analogously to Example 4(c) and yields crude 1-[N-benzyl-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]]-3-[2-(indol-2-yl)-phenoxy]-2-propanol in the form of an orange resin that is further processed in that form.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2(O)[CH2:25][CH2:24][CH2:23][N:22]3[CH:26]=[N:27][CH:28]=[C:21]23)=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][N:22]3[CH:26]=[N:27][CH:28]=[C:21]23)=[CH:16][CH:15]=1
Reactant: CSc1ccc(C2(O)CCCn3cncc32)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ccc(C2CCCn3cncc32)cc1
Reaction time: 0.17 h

Procedure:
12.6 mmol of sodium borohydride are suspended in 6 ml of tetrahydrofuran. 19.1 mmol of boron trifluoride ethyl etherate are added dropwise at 0° C. and the reaction mixture is stirred thoroughly for 10 minutes. A suspension of 1.27 mmol of 8-(4-methylsulphanylphenyl) 5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol in 6 ml of tetrahydrofuran is added and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is subsequently poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (3×). The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) as a white solid. Rf=0.63 (dichloromethane/methanol 9:1); Rt=5.73 (Gradient I).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccc(C(F)(F)F)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-(trifluoromethyl)benzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-trifluoromethyl benzoyl chloride in a similar manner as described above to give a tan solid (63% yield). 1H-NMR (CDCl3): δ 8.83 (s, 1H), 7.89 (d, 2H), 7.70 (d, 2H), 7.61 (m, 1H), 7.23 (d, 1H), 7.18 (d, 1H), 6.42 (d, 1H), 5.33 (m, 1H), 2.72 (m, 2H), 2.31 (m, 1H), 1.97 (m, 3H); MS m/z 437 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: ClCCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OCCCCl
Temperature: 50 °C
Reaction time: 30 h

Procedure:
2-Nitrophenol (70 mmol), 1-bromo-3-chloropropane (360 mmol), potassium carbonate (water free, 110 mmol), potassium iodide (2 mmol) and tetrabutyl-ammonium bromide (1 mmol) are suspended in acetone (130 ml) and heated up to 50° C. and the mixture is then stirred at this temperature for 30 hours. After cooling down to RT the solid material is filtered off and the filtrate is evaporated. The excess of 1-bromo-3-chloropropane is distilled of under vacuum (70° C.). A yellow-orange oil with Rf=0.55 (hexane/ethyl acetate=2:1) is obtained, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Br.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH2:9][CH:11]1[CH2:12][O:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCC1CO1
Reactant: CNc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC1CO1)c1ccccc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 5 g of N-methylaniline, 7.65 ml of epibromohydrin, 2.44 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 100 ml of anhydrous dimethylformamide were used, to give 1.67 g of the title compound as a pale yellow oil having an Rf value of 0.33 (on silica gel thin layer chromatography, using a 1:10 by volume mixture of ethyl acetate and hexane as the developing solvent).