Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=1[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:18]=3[CH3:27])[C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Cc1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cn2c(C)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 164.7 %

Procedure:
A mixture of 4-bromo-2-methyl-6-nitro-1H-benzo[d]imidazole (22 g, 78 mmol), prepared as described in example 1, step b, 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (22 g, 86 mmol) and cesium carbonate (38 g, 117 mmol) in DMF (400 mL) was stirred at 80° C. for 3 h. After cooled to room temperature, the mixture was poured into 300 mL of water and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over sodium sulphate and combined with a separate batch prepared similarly and then evaporated to give the crude product (55 g, 62%) as a yellow solid; LC/MS: MS (ES+) m/e 428 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.54 (s, 3H), 2.55 (s, 3H), 5.78 (s, 2H), 6.35 (d, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.31 (d, J=1.5 Hz, 1H), 8.63 (d, J=1.5 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16].N1C=CN=C1.[OH:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39]>O1CCCC1>[OH:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:15](=[O:16])[NH:6][C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:3][CH3:2])=[O:14]
Reactant: CC(C)CCNCCO
Reactant: CNC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)N(CCO)CCC(C)C
Yield: 93 %

Procedure:
In anhydrous tetrahydrofuran (7 ml) are suspended N-methyl-L-phenylalanine amide hydrochloride (Reference compound No. 8-2, 429 mg), 1,1′-carbonyldiimidazole (422 mg) and imidazole (136 mg) under a nitrogen atmosphere, and the suspension is stirred at room temperature for 20 minutes. A solution of N-(2-hydroxyethyl)isoamylamine (Reference compound No. 13-2, 525 mg) in anhydrous tetrahydrofuran (3 ml) is added to the reaction mixture, and the mixture is refluxed for 0.5 hour. The reaction mixture is concentrated under reduced pressure, a 10% aqueous citric acid solution is added to the concentrate, and the whole is extracted with ethyl acetate. The organic layer is washed with a 10% aqueous citric acid solution, water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 626 mg (93%) of the titled compound (Compound No. 20-1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=2)=[CH:5][CH:4]=1>C(O)C.[Pd]>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([CH2:15][NH2:16])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Agent: [Pd]
Solvent: CCO
Product: NCc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Yield: 95.6 %

Procedure:
To a solution of solution of 6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carbonitrile (1.34 g, 5.37 mmol) in ethanol (40 mL) was added 10% Pd/C (700 mg) and the reaction mixture was placed under a H2 atmosphere (55 psi) for 3 hours. The reaction mixture was filtered through a pad of celite and concentrated to provide the desired product (1.3 g, 97%). 1H NMR (400 MHz, CDCl3) δ 9.23 (d, J=1.2, 1H), 8.23 (d, J=8.1, 2H), 7.83 (s, 1H), 7.77 (d, J=8.2, 2H), 4.08 (s, 2H), 1.59 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N(Br)C(=O)C1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl.CCO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: Cc1ccc(I)cc1F
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Fc1cc(I)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 2-fluoro-4-iodotoluene (23.60 g, 0.10 mol) in CHCl3 (1000 mL) was added BPO (0.55 g, 2.27 mmol) and NBS (24.92 g, 0.14 mol) under N2. The reaction mixture was refluxed for 6 h, then cooled and filtered. The filtrate was concentrated in vacuo. The residue was added to a solution of morpholine (43.56 g, 0.50 mol) in EtOH (1000 mL) under N2. The resulting mixture was stirred at rt overnight, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a white solid (4.82 g, 15%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([O:28][C:26](=[O:27])[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([C:9]3[N:13]=[CH:12][N:11]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=4)[N:10]=3)=[CH:5][CH:4]=2)=[CH:30][CH:31]=1)([O-:37])=[O:36]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 60.7 %

Procedure:
A suspension of 4-[1-(4-trifluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine (1.2 g, 3.7 mmol) in EtOH (4 mL) was treated with 1H-benzotriazole (0.48 g, 4.0 mmol) and formaldehyde (0.5 mL of 37% aqueous, 6 mmol), and the solution was heated to 40° C. for 10 min. Upon cooling, a solid formed, which was collected by filtration. There was obtained 1.33 g of the triazole adduct as a light yellow solid, mp 185-187° C. This material (1.2 g, 2.66 mmol) was dissolved in THF (20 mL) and treated with NaBH4 (0.11 g, 2.9 mmol). The solution was stirred at ambient temperature for 30 min, then heated to reflux for 1 h. After cooling, the solution was poured onto water (30 mL) and extracted with ether. Drying and concentration, followed by silica gel chromatography (75:25 Hexanes:EtOAc) furnished methyl-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-amine (0.76 g, 86%) as a white solid, mp 121-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.78 (d, J=9.1 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 6.68 (d, J=8.8 Hz, 2H), 3.96 (s, 1H), 2.91 (s, 3H); ELMS m/z 499 (M+). A portion of this amine (0.11 g, 0.33 mmol) was dissolved in dry THF (2 mL) and treated with 4-nitrophenyl chloroformate (0.069 g, 0.34 mmol). The solid which formed over 10 min was collected by filtration and air-dried to give an off-white solid (0.10 g): mp 145-147° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.28 (d, J=8 Hz, 4H), 7.8 (d, J=8 Hz, 2H), 7.50-7.3 (m, 6H) 3.55 (s, 3H); EIMS m/z 499 (M+).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:24][C:23]4[C:18](=[C:19]([F:26])[CH:20]=[C:21]([CH3:25])[CH:22]=4)[C:17]3(F)[F:27])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CC([O-])(C)C.[K+]>O1CCCC1>[F:27][C:17]1[C:18]2[C:23](=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[F:26])[CH2:24][C:16]=1[CH:13]1[CH2:12][CH2:11][CH:10]([CH:7]2[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)[CH2:15][CH2:14]1
Reactant: CCCC1CCC(C2CCC(C3Cc4cc(C)cc(F)c4C3(F)F)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(C3=C(F)c4c(F)cc(C)cc4C3)CC2)CC1

Procedure:
10.0 g (0.025 mol) of 4-propyl-4′-(1,1,7-trifluoro-5-methylindan-2-yl)-bicyclohexyl are stirred together with 5.6 g of potassium tert-butylate in 200 ml of tetrahydrofuran at 60° C. for 6 hours. The mixture is then subjected to conventional work-up.
Reaction SMILES: Cl.Cl[CH:3]1[C:12]2[NH:11][C:10](=[O:13])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(C)C>[NH:14]([CH:3]1[C:12]2[NH:11][C:10](=[O:13])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: O=c1ccc2c([nH]1)C(Cl)CCC2
Agent: Cl
Solvent: CC(C)O
Product: O=c1ccc2c([nH]1)C(Nc1ccccc1)CCC2

Procedure:
110 g (0.5 mol) of 8-chloro-5,6,7,8-tetrahydro-2-quinolone hydrochloride are suspended in 800 ml of isopropanol and at 80° C. 186 g (2.0 mols) of aniline are added dropwise. A clear solution gradually forms which is refluxed for 10 minutes. The colorless crystalline 8-aniline-5,6,7,8-tetrahydro-2-quinolone separating on cooling is filtered off with suction and washed with acetonitrile. It is obtained in a yield of 94 g, corresponding to 78.3% of the theory and melts at 225° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12](O)=O.O=P(Cl)(Cl)[Cl:22]>>[Cl:19][C:16]1[CH:17]=[CH:18][C:10]2[N:9]=[C:3]3[C:2]([CH3:8])([CH3:1])[CH2:6][CH2:5][C:4]3=[C:12]([Cl:22])[C:11]=2[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)CCCC1=O
Reactant: Nc1ccc(Cl)cc1C(=O)O
Product: CC1(C)CCc2c1nc1ccc(Cl)cc1c2Cl
Temperature: 100 °C

Procedure:
2,2-Dimethylcyclopentanone (1.12 g, 10 mmol) and 2-amino-5-chlorobenzoic acid (1.72 g, 10 mmol) were stirred at rt for 10 minutes followed by the addition of POCl3 (10 mL). The resulting mixture was heated to 100° C. for 5 h and overnight at rt. After this time the reaction mixture was poured into ice water and extracted with EtOAc. The solvent was evaporated in vacuo and flash column chromatography on silica (using a gradient of EtOAc/hexane, 0-100% eluent) gave 7,9-dichloro-3,3-dimethyl-2,3-dihydro-1H-cyclopenta[b]quinoline. Mass Spectrum (ESI) m/e=267 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)C=O)#[N:10].[C:19](OC(=O)C)(=O)C>>[CH3:8][C:4]1[N:3]=[C:2]([CH:1]=[CH:19][C:12]2[CH:13]=[CH:16][CH:17]=[CH:18][C:11]=2[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)n1
Product: Cc1cccc(C=Cc2ccccc2C#N)n1

Procedure:
A solution of 2,6-dimethyl pyridine (4.2 ml, 36.28 mMol), 3-cyanobenzaldehyde (4.95 g, 37.74 mMol) in acetic anhydride (6.85 ml) is heated under reflux for 16 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 400 g). The column is first eluted with toluene (400 ml) and then with toluene/ethyl acetate 95:5. The fractions containing the desired compound are combined, and evaporated in vacuo. The solid residue is recrystallized from methylene chloride/hexane and 3.18 g of white crystals are isolated. (melting point: 91-92°).
Reaction SMILES: [CH:1]1([CH:6]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CCCCCC.C(O)C.C(O)C.O1CCCC1>[CH:1]1([CH:6]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
Ethyl 3-{[(4-{[cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (4.18 g) obtained in Example A67(5) was dissolved in hexane-ethanol (1:1, volume ratio), subjected to HPLC using CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), and eluted with hexane-ethanol (1:1, volume ratio) as a mobile phase at 30° C. and at a flow rate 60 mL/min. The resulting fraction containing an optically active form having a longer retention time was concentrated to give an amorphous form (2.04 g, 99.9% ee). The obtained amorphous form (2.04 g) was dissolved in ethanol (9 mL) and tetrahydrofuran (9 mL), 1N aqueous sodium hydroxide solution (8.5 mL) was added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (15 mL) was added, and the mixture was neutralized with 1N hydrochloric acid (8.5 mL) under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration, and dried to give the title compound (1.88 g, 98%, 99.9% ee) as a colorless amorphous form.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]>CO>[Cl:19][C:18]1[C:13]([C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([CH2:5][O:2][CH3:1])[CH:7]=2)=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COCc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
7.0 g of a 30% by weight solution of sodium methoxide in methanol were added to a solution of 5.0 g of 2-(3-bromomethyl-4-chlorophenyl)-3-chloro-5-trifluoromethylpyridine in 100 ml of anhydrous methanol. The mixture was refluxed for 8 hours and then concentrated. The residue was taken up in 100 ml of 10% strength hydrochloric acid, after which three extractions with 50 ml of ether each time were carried out. The ether phases were dried over sodium sulfate and concentrated. The oily residue was induced to crystallize with a little cold cyclohexane. Yield: 2.9 g (67%) of colorless crystals; melting point: 52°-54° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:35][CH3:36])[C:19]([Cl:37])=[CH:18][N:17]=1>>[Cl:37][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:35][CH3:36])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCCOc2c(N)cccc21
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 179. Product was isolated as a tan solid (78 mg, 80%). LCMS (m/e) 510 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.06 (s, 1H), 7.82 (m, 2H), 7.46 (dm, 1H, J=9 Hz), 6.84 (d, 1H, J=8 Hz), 6.75 (t, 1H, J=8 Hz), 6.68 (s, 1H), 6.52 (d, 1H, J=9 Hz), 3.91 (m, 2H), 3.77 (d, 7H), 3.16 (m, 4H), 1.96 (m, 2H), 1.60 (m, 2H), 1.30 (s, 6H).
Reaction SMILES: [I:1][CH:2]1[CH:6]2[O:7][C:8](=[O:14])[CH:9]3[CH:10]([C:11]([OH:13])=O)[CH:3]1[CH2:4][CH:5]23.Cl.[NH2:16][CH2:17][C:18]#[N:19].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.C(N(CC)CC)C>CN(C)C=O>[C:17]([CH2:18][NH:19][C:11]([CH:10]1[CH:3]2[CH2:4][CH:5]3[CH:6]([CH:2]2[I:1])[O:7][C:8](=[O:14])[CH:9]13)=[O:13])#[N:16]
Reactant: O=C(O)C1C2CC3C(OC(=O)C31)C2I
Reactant: N#CCN
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1C2CC3C(OC(=O)C31)C2I
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
To (3R/S,3aR/S,5S/R,6S/R,6aS/R,7S/R)-6-iodo-2-oxohexahydro-2H-3,5-methano-cyclopenta[b]furan-7-carboxylic acid (1.51 g, 4.90 mmol) was added aminoacetonitrile hydrochloride (502 mg, 5.43 mmol) and) benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.56 g, 4.91 mmol. After adding dimethylformamide (10 mL), the reaction mixture was cooled to 0° C. and triethylamine (1.7 mL, 12 mmol) was added. After stirring the reaction mixture at ambient temperature for 4.5 h, the product was extracted into ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Chromatography of the residue on silica gel with 1:1 ethyl acetate:hexanes eluent gave (3R/S,3aR/S,5S/R,6S/R,6aS/R,7S/R)-N-(cyanomethyl)-6-iodo-2-oxohexahydro-2H-3,5-methanocyclopenta[b]furan-7-carboxamide as a colorless syrup.
Reaction SMILES: [CH:1]([CH2:3][NH:4][C:5]([C:9]1[O:10][CH:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=12)=[CH:6][C:7]#[N:8])=O.FC(F)(F)C(O)=O>O>[O:10]1[C:11]2[CH:12]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:13]=[C:9]1[C:5]1[NH:4][CH:3]=[CH:1][C:6]=1[C:7]#[N:8]
Reactant: N#CC=C(NCC=O)c1occ2ccccc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc[nH]c1-c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
β-[(Formylmethyl)amino]-2-benzofuranacrylonitrile (1.00 g, 3.33 mmol) is added dropwise to trifluoroacetic acid (5 mL). The reaction mixture is stirred at room temperature for one hour, diluted with water and extracted with ethyl acetate. The organic extract is washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, decolorized with charcoal and concentrated in vacuo to obtain an orange solid. Dry column chromatography of the solid using silica gel and methylene chloride gives the title product as a brown-white solid (0.32 g 46% mp 157°-160.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23])[CH:8]=2)([O-])=O>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:23])[F:24])[CH:8]=2
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3C(F)(F)F)ccc2c1
Agent: O=[Pt]
Solvent: CCO
Product: Nc1cnc2cc(OCc3ccccc3C(F)(F)F)ccc2c1
Reaction time: 3 h

Procedure:
In ethanol (30 mL) was suspended 3-nitro-7-(2-trifluoromethylbenzyloxy)quinoline (600 mg, 1.72 mmol.), and to the suspension was added platinum oxide (72 mg). Then, catalytic reduction was performed for 3 hours. After the completion of reaction was confirmed, the reaction mixture was filtered over Celite®, and the filtrate was placed under reduced pressure to leave the desired compound as brown oil in the quantitative yield.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:23])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24].N1C=CC=CC=1.ClCCl.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:23])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(N)c4)cc3CC[C@@H]12
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(NC(=O)C(C)(C)C)c4)cc3CC[C@@H]12
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-(3-aminophenyl)-10b-methyl 1,2,3,4,4a,5,6,10b octahydrobenzo[f]quinolin-3-one (31 mg, 0.097 mmol), N,N-dimethylaminopyridine (3 mg, 0.024 mmol), 1 mL of pyridine and 0.5 mL of dichloromethane. The solution was cooled to 0°, and excess pivaloyl chloride (0.086 mL, 0.69 mmol) was added. The stirred mixture was allowed to warm to room temperature over 2 h. The mixture was diluted with chloroform, and washed with 5% aqueous hydrochloric acid solution, water, 5% queous sodium hydroxide solution, water, and the combined organic extracts were dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give 25 mg (64%) of the title compound as a yellow solid. mp 95°-98°. FDMS m/e=404. α[D]589 =+62.50 (c=0.16, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[O:4][C:5]1[C:6]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][CH:8]=[N:9][C:10]=1[O:11][CH2:12][CH2:13][OH:14].[CH3:33][S:34][C:35]1[CH:36]=[N:37][C:38](Cl)=[N:39][CH:40]=1>>[CH3:33][S:34][C:35]1[CH:36]=[N:37][C:38]([O:14][CH2:13][CH2:12][O:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[O:4][C:3]2[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:2]=2[Cl:1])=[N:39][CH:40]=1
Reactant: CSc1cnc(Cl)nc1
Reactant: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)NCc3ccccc3)ncnc2OCCO)c1
Product: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)NCc3ccccc3)ncnc2OCCOc2ncc(SC)cn2)c1
Yield: 45.7 %

Procedure:
Benzylsulfamic acid [6-[2-(5-methylsulfanyl-pyrimidin-2-yloxy)-ethoxy]-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-amide (138 mg) (Example 213) was prepared from benzylsulfamic acid [5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide (240 mg) (Example 211) and 5-methylsulfanyl-2-chloropyrimidine (180 mg) according to the procedure described in Example 14. LC-MS: tR=5.22; [M+H]+=606.75.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[NH:9][C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[Cl:32][C:33]1[S:37][C:36]([C:38]2[O:42][N:41]=[C:40]([CH2:43]OS(C)(=O)=O)[CH:39]=2)=[CH:35][CH:34]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]=[C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:15][CH2:16][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:18][CH2:19]3)[N:11]([CH2:43][C:40]3[CH:39]=[C:38]([C:36]4[S:37][C:33]([Cl:32])=[CH:34][CH:35]=4)[O:42][N:41]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C4CC4)CC3)nc2c1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(Cl)s2)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(C(=O)NC3CCN(C4CC4)CC3)n(Cc3cc(-c4ccc(Cl)s4)on3)c2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
17.3 g (50.52 mmol) 2-(1-Cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester were dissolved in 800 mL DMF. Subsequently 10.47 g (75.8 mmol) K2CO3 and 14.84 g (50.52 mmol) methanesulfonic acid 5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl ester were added and the resulting mixture was stirred for 2 h at 80° C. The mixture was concentrated under reduced pressure. The residue was suspended in 800 mL ethyl acetate. The next day the resulting precipitate was filtered off and washed with 100 mL ethyl acetate to give 3-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid methyl ester. The filtrate was concentrated to a volume of approx. 100 mL. Again the formed precipitate was filtered off. That procedure was repeated once again. The remaining filtrate was concentrated under reduced pressure and finally purified by flash-chromatography on silica gel using ethyl acetate as eluent. The product containing fractions were concentrated under vacuo to give pure (>98%) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester as a light brown crystalline solid.