Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:19][C:18](=[O:20])[NH:17][C:16]=2[CH:21]=1>CN(C=O)C>[Cl:5][CH2:6][CH2:7][C:8]([C:13]1[C:12]([Cl:11])=[CH:21][C:16]2[NH:17][C:18](=[O:20])[NH:19][C:15]=2[CH:14]=1)=[O:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2[nH]1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(CCCl)c1cc2[nH]c(=O)[nH]c2cc1Cl
Temperature: 0 °C

Procedure:
44.68 g of aluminium chloride (0.335 mol) are initially introduced into a reaction flask. 4.9 ml of DMF are slowly added dropwise with stirring, the temperature rising to approximately 56° C. 6.9 ml of 3-chloropropionyl chloride (0.072 mol) are added to this mixture. 8.07 g of 6-chloro-2,3-dihydrobenzimidazol-2-one (0.048 mol) are then slowly added in portions and the mixture is stirred at 80° C. for one hour. After completion of the reaction the reaction mixture obtained is stirred into 400 g of ice, and the precipitate is filtered off with suction and washed with plenty of water and small amounts of acetone. The reaction leads to a slightly more non-polar product which can be separated by thin-layer chromatography using an eluent consisting of-chloroform and methanol in the mixture ratio 9:1. Yield: 9.72 g of 5-(3-chloro-1-oxopropyl)-6-chloro-2,3-dihydrobenzimidazol-2-one (78.2% of theory); m.p.: 201°-204° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[CH2:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH2:19]>CN(C=O)C>[CH:11]1([CH2:10][O:9][C:4]2[CH:3]=[C:2](/[CH:19]=[CH:18]/[CH2:17][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Fc1cc(Br)cc(OCC2CCCCC2)c1
Reactant: C=CCNC(=O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NC/C=C/c1cc(F)cc(OCC2CCCCC2)c1)C(F)(F)F

Procedure:
Coupling of 1-bromo-3-(cyclohexylmethoxy)-5-fluorobenzene with N-allyl-2,2,2-trifluoroacetamide following the method used in Example 10 except DMF was used as solvent gave (E)-N-(3-(3-(cyclohexylmethoxy)-5-fluorophenyl)allyl)-2,2,2-trifluoroacetamide as a white solid. Yield (0.44 g, 64%): 1H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, CDCl3) δ 9.68 (t, J=4.0 Hz, 1H), 6.79-6.86 (m, 2H), 6.65 (dt, J=10.8, 2.0 Hz, 1H), 6.45 (d, J=15.6 Hz, 1H), 6.31 (dt, J=16.0, 5.6 Hz, 1H), 3.95 (t, J=4.8 Hz, 2H), 3.77 (d, J=5.6 Hz, 2H), 1.58-1.80 (m, 6H), 1.10-1.28 (m, 3H), 0.90-1.06 (m, 2H).
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)=[N:11][CH:12]=1.C(N(C(C)C)C(C)C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:21][CH:22]=2)=[N:11][CH:12]=1
Reactant: C1COCCN1
Reactant: OCc1ccc(CCC#Cc2ccc(Br)cn2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc(C#CCCc2ccc(CN3CCOCC3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
36 μL (0.46 mmol) methanesulphonic acid chloride are added to a solution, cooled to 0° C., of 120 mg (0.38 mmol) {4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol (Example 2.20a) in 5 mL DCM. A solution of 78 μL (0.46 mmol) ethyldiisopropylamine in 1 mL DCM is slowly added dropwise, the mixture is stirred for a further 30 min at 0° C., then 80 μL (0.92 mmol) of morpholine are added, the mixture is allowed to come up to RT and kept at RT for 2 h. The mixture is evaporated down i.vac., the residue is combined with 20 mL EtOAc and 10 mL water, acidified with 1 M HCl and the phases are separated. The aqueous phase is combined with 2 M Na2CO3 solution, extracted with 20 mL EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the product is obtained.
Reaction SMILES: Br[C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1>>[CH:25]1([C:2]2[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[N:6]=2)[CH2:27][CH2:26]1
Reactant: OB(O)C1CC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)OCc2ccccc2)nc1Br
Product: C[Si](C)(C)CCOCn1cc(C(=O)OCc2ccccc2)nc1C1CC1

Procedure:
The title compound was prepared using the procedure described in Example 59(a) starting from benzyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (7.31 mmol, 3 g) and cyclopropylboronic acid (14.63 mmol, 1.25 g). Yield 1.02 g. 1H-NMR (400 MHz; CDCl3): δ −0.02 (s, 9H), 0.91 (t, 2H), 0.99 (bs, 2H), 1.15 (bs, 2H), 1.87-1.94 (m, 1H), 3.52 (t, 2H), 5.32 (s, 2H), 5.34 (s, 2H), 7.29-7.43 (m, 5H), 7.59 (s, 1H). LC-MS: [M+1]=373.31.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:5].[C:24](Cl)(Cl)=[O:25]>C1(C)C=CC=CC=1>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][CH:17]=2)[NH:1][C:24]1=[O:25]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)NCCc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1CCc1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a stirred solution of 2-amino-N-[2-(2,4-dichlorophenyl)ethyl]-4-nitrobenzamide (1.0 g, 2.82 mmol) in toluene (30 mL) was added a 1.9 M solution of phosgene in toluene (4.5 mL, 8.5 mmol). The reaction mixture was heated to 60° C. and stirred for 4 hours. The solvent was removed under reduced pressure and CH2Cl2 was added to the residue. The precipitate was collected via vacuum filtration and washed with CH2Cl2 to give the product (0.92 g, 86% yield) as a white solid. HPLC retention time: 3.28 min; Method A; LRMS (ESI) m/z 378 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[F:18][C:19]([F:32])([F:31])[O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:31])[F:32])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 4-trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC.
Reaction SMILES: [OH:1][C@H:2]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[N:4]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[C:37]1([C@H:2]([C@H:3]2[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH2:21][CH2:22]4)=[O:16])=[CH:11][CH:10]=3)[NH:4]2)[OH:1])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCN(Cc4ccccn4)CC3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)N1CCN(Cc2ccccn2)CC1

Procedure:
A solution of 0.038 g (0.067 mmol) of the title compound from Step A above in 1 mL dichloromethane and 1 mL trifluoroacetic acid was stirred at ambient temperature for 1 h. All volatiles were removed in vacuo and the crude light brown residue was purified directly by reverse-phase HPLC to afford the title compound (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). 1H-NMR (500 MHz, CD4O) δ 8.70 (d, J=4.9 Hz, 1H), 7.99-7.98 (m, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.53-7.34 (m, 10H), 4.76 (d, J=8.8 Hz, 1H), 4.51 (s, 2H), 4.10-3.81 (m, 6H), 3.42-3.39 (m, 4H), 3.33-3.08 (m, 2H), 2.10-2.00 (m, 1H), 1.86-1.75 (m, 3H). LC/MS: m/z (ES) 471.3 (MH)+, 493.3 (MNa)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(C)(C)C.[ClH:34]>O1CCOCC1.C(OCC)C>[ClH:32].[ClH:34].[NH2:7][CH2:8][CH2:9][N:10]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)[C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)c1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCN(Cc1ccc(Cl)cc1)C(=O)c1ccc(-c2ccncc2)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
The {2-[(4-chlorobenzyl)-(4-pyridin-4-yl-benzoyl)-amino]-ethyl}-carbamic acid tert-butyl ester (184 mg, 0.395 mmol) was dissolved in 2.0 mL of 1,4-dioxane and treated with 2.0 mL of 4M HCl in 1,4-dioxane. The reaction was allowed to stir for one hour to completion and diluted with diethyl ether. The product was isolated by vacuum filtration to afford the N-(2-amino-ethyl)-N-(4-chlorobenzyl)-4-pyridin-4-yl-benzamide bis-hydrochloride salt as a fine pale-yellow powder (166 mg, 96%). 1H NMR (DMSO-d6, 400 MHz) δ 8.91 (d, J=6.0 Hz, 2H), 8.26 (d, J=6.0 Hz, 2H), 8.13 (brs, 3H), 8.05 (d, J=8.0 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.45 (brs, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.26 (d, J=7.6 Hz, 2H), 4.57 (brs, 2H), 3.61 (m, 2H), 3.08 (m, 2H). LCMS (APCI+) m/z 366 [M+H]+; Rt=2.13 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])=[N:10]1.Cl.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH:33]1[CH2:38][C:39]([OH:41])=[O:40]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])[NH:12][C:13]([CH2:20][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH:33]2[CH2:38][C:39]([OH:41])=[O:40])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)CC1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Yield: 42.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(2,4,6-trifluorophenyl)-1,4-dihydropyrimidine-5-carboxylate (1.21 g, 2.2 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.4 g, 2.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.58 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1.CO.[OH-].[Na+]>O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(OCCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(OCCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
4-Hydroxyphenylacetic acid (100 g, 0.6 mol) and cesium carbonate (250 g) were suspended in 300 mL of anhydrous acetonitrile followed by addition of 1,2-dibromoethane (300 mL). The suspension was brought to reflux for 24 hours in a 2L 3 neck round bottom flask fitted with a mechanical stirrer and reflux condenser then cooled to room temperature. The mixture was diluted to a volume of 2L by addition of ethyl ether and the suspension was filtered. Concentration of the filtrate in vacuo afforded a colorless oil which was purified by vacuum distillation (0.2 mm Hg, 140-145° C.) to give methyl 4-(2-bromoethoxy)-phenylacetate (93.14 g, 60% yield) as a colorless oil. The methyl 4-(2-bromoethoxy)-phenylacetate was taken into methanol (250 mL) and the resulting solution was cooled to 0° C. Sodium hydroxide (29 g) in a minimum of water was added to the methanol solution in portions and the mixture was stirred at 0° C. for an additional 30 minutes. The solution was warmed to room temperature then concentrated to a white solid. The residue was taken into water and the solution washed once with ethyl ether. The aqueous solution was then acidified to pH 1 by addition of concentrated aqueous hydrochloric acid to give a thick suspension. Filtration and drying afforded 4-(2-bromoethoxy)-phenylacetic acid (86 g, 97% yield) as a colorless solid. The 4-(2-bromoethoxy)-phenylacetic acid (50 g) was taken into thionyl chloride (70 mL) and brought to reflux under an atmosphere of nitrogen for 2 hours. Fractional vacuum distillation (0.2 mm Hg, 139-140° C.) afforded 4-(2-bromoethoxy)phenylacetyl chloride (46.0 g, 86% yield) as a colorless oil that quickly crystallized on cooling. 1H NMR (CDCl3) 6.95, 6.76, 6.60 (m, 11H, Ar—H), 4.68 (m, 1H), 4.24 (m, 2H), 3.80 (m, 1H), 3.41-3.63 (m, 3H), 3.07 (m, 1H), 2.87 (m, 2H), 2.61 (m, 1H); ES−MS (m/z) 458 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1C(O)=O.S(Cl)(Cl)=O.[N-:16]=[N+]=[N-].[Na+]>O>[CH3:1][C:2]1[C:3]([NH2:16])=[C:7]([CH3:11])[CH:8]=[CH:9][N:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccnc(C)c1C(=O)O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1ccnc(C)c1N
Temperature: 60 °C
Yield: 73.7 %

Procedure:
A mixture of 1a (0.98 g, 6.5 mmol) and thionyl chloride (5 ml) was heated to 60° C. for 1 hour. The mixture was concentrated to dryness. The mixture was then dissolved in acetone (10 ml) prior to the addition of NaN3 (0.65 g, 10 mmol) and water (5 ml). The solution was heated to 70° C. for 1 hour. Acetone was evaporated from the reaction mixture which was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield 1b (0.585 g, 4.79 mmol, 74%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl.Cl.[NH2:16][NH2:17].O.C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:17][N:16]=1
Reactant: CCOC(=O)C(=O)CC(=O)COC
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(COC)n[nH]1

Procedure:
Ethyl 5-methoxy-2,4-dioxopentanoate (2.168 g, 11.52 mmol) was dissolved in ethanol (100 ml) and hydrazine dihydrochloride (4.84 g, 46.1 mmol) was added. The resulting mixture was refluxed for 2 h. 200 ml of water was added and the pH of the mixture was neutralized with NaHCO3. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried with Na2SO4, filtered and evaporated. The product was used in the next step without further purification. 1H-NMR (400 MHz; DMSO-d6): δ 1.29 (t, 3H), 3.26 (s, 3H), 4.27 (q, 2H), 4.42 (s, 2H), 6.72 (s, 1H), 13.62 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[F:11])=[O:3].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].C[O-].[Na+]>CCOCC.CO>[F:11][C:5]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=1[C:2](=[O:3])[CH2:1][C:14]([C:13]([F:20])([F:19])[F:12])=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1cc(F)ccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C(CC(=O)C(F)(F)F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
28.5 g of 2,5-difluoroacetophenone and 26 g of ethyl trifluoroacetate were stirred in 400 ml of anhydrous ether and cooled in an ice bath. 42 ml of 25 wt % sodium methoxide in methanol was then added over 5 minutes. After stirring 1 hour at room temperature, the reaction mixture was extracted with water, the water acidified and extracted with methylene chloride to give 42 g of 1-(2,5-difluorophenyl)-3-(trifluoromethyl)propane-1,3-dione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][OH:6].[N+]([O-])(O)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6]
Reactant: OCc1ccc(F)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.1 %

Procedure:
10.2 g (0.05 mol) of 3-bromo-4-fluoro-benzyl alcohol were added to a mixture of 10 g of nitric acid (density: 1.4) and 5 ml of water at 30°-35° C. and the mixture was then stirred at room temperature for 5 hours. After adding 30 g of ice, sodium hydroxide solution was added to the mixture until the pH value reached 13, and the mixture was then extracted by shaking with 200 ml of toluene. The organic phase was washed three times with 50 ml of water each time, dried over sodium sulphate and then evaporated. The residue was distilled. 6.1 g (60% of theory) of 3-bromo-4-fluoro-benzaldehyde were thus obtained in the form of an oil which slowly solidified and had a melting point of 29°-31° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH:11]([CH2:13][C:14](O)=[O:15])[CH3:12].C(N(CC)CC)C>CS(C)=O>[CH3:12][N:11]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:14](=[O:15])[CH2:13]1
Reactant: CNCC(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccccc21

Procedure:
5.2 g of o-fluoro-nitrobenzene, 3.2 g of sarcosine and 5.2 ml triethylamine was stirred in 25 ml DMSO at 70° C. for 4 days. The mixture was then evaporated in vacuo and the residue was partitioned between water and methylene chloride. The organic phase was evaporated in vacuo. The residue was dissolved in 100 ml 96% ethanol and was hydrogenated at normal pressure using 0.5 g Pd/C. After completion of hydrogen uptake, the mixture was filtered and evaporated in vacuo. The residue was washed with water with disodium carbonate, ether and water. Yield of title compound: 1.3 g M.p. 132° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH2:29][CH:28]([CH2:33][N:34]([CH3:36])[CH3:35])[CH2:27][CH2:26]3)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:1]([NH:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH2:29][CH:28]([CH2:33][N:34]([CH3:35])[CH3:36])[CH2:27][CH2:26]3)=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)CC1CCc2cc(OCc3ccc(NC(=O)c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzoyl chloride (0.14 ml) was added dropwise to pyridine solution (6 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (300 mg) under ice-cooling, which was stirred at room temperature for 30 minutes. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent; ethyl acetate), and recrystallized (THF-IPE) to give the titled compound (240 mg).
Reaction SMILES: [N+:1]([C:4]1[C:14]2[C:13](=[O:15])[NH:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:14]2[C:13](=[O:15])[NH:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NCCNc2cccc([N+](=O)[O-])c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1C(=O)NCCN2

Procedure:
To a solution of 6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (0.2 g, 0.0011 mols) in methanol (8 mL) in a Parr bottle was added 10% palladium on carbon and the mixture subjected to hydrogen at 50 psi for 4 h. The reaction mixture was filtered through celite and washed with DMF and methanol. The filtrate was concentrated in vacuo to give 6-amino-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and carried on without purification. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 6.87 (d, 1H, J=7.6 Hz), 6.75-6.88 (m, 2H), 3.59 (t, 2H, J=6 Hz), 2.46 (t, 2H, J=6 Hz); MS (m/e) 178 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[C:32]([F:33])=[CH:31][C:30](B(O)O)=[C:29]([O:37][CH3:38])[CH:28]=1>CN(C=O)C>[F:26][C:27]1[C:32]([F:33])=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:29]([O:37][CH3:38])[CH:28]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1cc(F)c(F)cc1B(O)O
Solvent: CN(C)C=O
Product: COc1cc(F)c(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 4,5-difluoro-2-methoxy phenylboronic acid (CAS RN 870777-32-5) and using DMF as reaction solvent. Off-white solid (27%). MS (ESI): m/z=491.4 [M+H]+.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C@H:3]1[CH2:15][NH:14][CH2:13][CH2:12][C@H:4]13.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl.CCN(CC)CC>[CH:16]1([C:19]([N:14]2[CH2:13][CH2:12][C@H:4]3[N:5]4[CH2:11][CH2:10][C:7]5[CH:8]=[CH:9][CH:1]=[C:2]([C:6]4=5)[C@H:3]3[CH2:15]2)=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CC1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H]2[C@H](C1)c1cccc3c1N2CC3
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-cis-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole from Example 3 (0.050 g, 0.25 mmol) was dissolved in CH2Cl2 (5 mL) with Et3N (0.75 mL) and cooled to 0° C. The cyclopropanecarbonyl chloride (0.026 g, 0.26 mmol) was then added dropwise. The solution was stirred at 0° C. for 1 h and then warmed to room temperature and stirred for 1 h. The reaction mixture was partitioned between water and CHCl3 (3×15 mL) and the layers separated. The aqueous layer was extracted with CHCl3. The combined organics were washed with brine, H2O and dried (Na2SO4) and evaporated affording a light yellow liquid which was further purified by preparatory silica gel TLC (5% MeOH/CH2Cl2). The title compound was isolated as a clear colorless liquid (0.042 g, 65%). 1H NMR (CD3OD, 300 MHz) δ 7.22-7.58 (m, 3H), 4.62-4.75 (m, 1H), 3.85-4.30 (m, 5H), 3.55-3.62 (m, 2H), 1.9-2.18 (m, 3H), 0.75-0.9 (m, 4H) ppm.