Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:31]>CC(=O)CC>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33]2)=[O:31])[CH2:12][CH2:11]1
Reactant: O=C(CCCCBr)N1CCc2ccccc21
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Solvent: CCC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCN1CCN(c2cccc(Cl)c2Cl)CC1)N1CCc2ccccc21
Temperature: 45 °C

Procedure:
A mixture of 1-(2,3-dichlorophenyl)piperazine hydrochloride (8.0 g) and diisopropylethylamine (15 mL) in butanone (50 mL) was heated to 45° C. followed by the addition of 5-bromo-1-(2,3-dihydro-1H-indol-1-yl)pentan-1-one (5.4 g). The resulting mixture was boiled under reflux for 40 h and filtered hot. The remaining organic phase was left to crystallise, and a white crystalline material was collected by filtration and washed with acetone (3.8 g). Mp 121–123° C. 1H NMR (DMSO-d6): 1.50–1.70 (m, 4H); 2.30–2.65 (m, 8H); 3.00 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, 1H); 7.10–7–15 (m, 2H); 7.20 (d, 1H); 7.25–7.35 (m, 2H); 8.10 (d, 1H). MS m/z: 432 (MH+), 315, 202.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>CCOC(C)=O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: NCc1ccccc1Cl
Reactant: COC(=O)C(OC)OC
Solvent: CCOC(C)=O
Product: COC(OC)C(=O)NCc1ccccc1Cl
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl dimethoxyacetate (1.41 g, 10.4 mmol) and 2-chlorobenzylamine (1.45 g, 9.73 mmol) in a microwave vial was sealed and heated in the microwave reactor to 130° C. for 30 min and then to 140° C. for 40 min. The reaction solution was dissolved in EtOAc (≈60 mL) and washed with dil. HCl, water, sat. Na2CO3 solution, and brine, and dried over MgSO4. The EtOAc extract was filtered, concentrated, and dried in vacuo overnight, giving the title compound as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ=7.41-7.35 & 7.27-7.22 (AA′BB′, 4H), 6.98 (brs, 1H), 4.74 (s, 1H), 4.58 (d, J=6.0 Hz, 2H), 3.40 (s, 6H). MS(ES+): m/z=266.05/268.01 (41/13) [MNa′], 244.07/246.02 (86/58) [MH+], 212.03/214.02 (56/21) [MH+-MeOH], 180.07/182.05 (63/26) [MH+-2 MeOH]. HPLC: tR=2.87 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)=NNc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of 2,4-dichlorophenylhydrazine (16.00 g, 0.075 mol), ethyl pyruvate (14.47 g, 10.3 mL, 0.12 mol), glacial acetic acid (0.9 mL), absolute ethanol (105 mL) was refluxed for 2 hours. After cooling at room temperature, the solid which formed was filtered and recrystallized from ethanol to give 17.0 g (83%) of the title compound, mp 118-120° C. (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:15](=[O:16])[C@@H:14]3[C@H:17]([OH:20])[CH2:18][CH2:19][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:22]N1C(=O)N(C)CCC1.[Li+].CC([N-]C(C)C)C.IC>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:15](=[O:16])[C@:14]3([CH3:22])[C@H:17]([OH:20])[CH2:18][CH2:19][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN1CCCN(C)C1=O
Reactant: Cc1c(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@@]3(C)C2=O)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of compound 23G (600 mg, 1.96 mmol) in anhydrous THF (10 mL) at rt was added DMPU (4 mL). The resulting clear solution was cooled to −78° C., then a 2.0 M solution of LDA in THF (1.96 mL, 3.92 mmol) was added slowly so that the reaction temperature was maintained below −72° C. The resulting dark brown solution was stirred at −78° C. for 30 min, then iodomethane (0.36 mL, 3.92 mmol) was added dropwise. After addition, the reaction was stirred at −78° C. for 30 min, then at 0° C. for 3 h. The reaction was quenched with 5% aqueous KHSO4 and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica gel), eluting with 1% MeOH in EtOAc/CH2Cl2 (1:9) to give a mixture of compound 25 and compound 26 (150 mg), which was further purified using preparative HPLC to afford the title compound (20 mg). HPLC: 99% at 4.40, 5.20 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=7.9 min (99%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in hexane for 30 min at 1 mL/min, MS (ES) m/z 320 [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.[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C>[CH3:26][O:27][C:28]1[C:33]([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)=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: COc1ncccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: COc1ncccc1-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 2-methoxy-3-pyridinyl boronic acid (CAS RN 163105-90-6) and using DMF as reaction solvent. Colorless solid (23%). MS (ESI): m/z=455.8 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([N:15]=[C:16]=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CCCCCC>[CH2:7]([NH:15][C:16]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCN=C=O
Reactant: CCCCCN
Solvent: CCCCCC
Product: CCCCCCCCNC(=O)NCCCCC
Reaction time: 8 h
Yield: 97 %

Procedure:
To 0.262 g (3.00 mmol) of pentylamine in 20 mL of hexane is added 0.53 mL (0.47 g, 3.0 mmol) of octylisocyanate with stirring to eventually produce a white crystalline solid. After standing overnight the mixture is cooled, the solid product collected, and washed with cold hexane. On air drying there is obtained 0.705 g (2.91 mmol, 97%) of 1-octyl-3-pentylurea as very fine white needles, mp 65.0-65.5° C. The material displays a 13C-NMR and a mass spectrum consistent with the assigned structure. 13C-NMR (CDCl3): δ 159.0 (C═O), 40.47 and 40.45 (C-1 and C-1′), 31.8 (C-6 and C-3′), 30.4 (C-2), 30.1 (C-2′), 29.3 (C-4), 29.2 (C-5), 27.0 (C-3), 22.5 (C-7), 22.4 (C-4′), 13.9 (C-8 and C-5′); important infrared absorption bands (KBr disc) are present at 3334 (s, N—H), 1617 (vs, C═O), and 1579 (vs, amide II) cm−1.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H]([C@H](CO)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.C([C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1)#N>>[OH:2][CH2:1][C@@H:33]1[CH2:32][CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@@H:34]1[C@H:35]1[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]1
Reactant: C[C@]12CCCCC1C[C@@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1C[C@@H](CO)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
7α-Hydroxymethylandrostane-3,17-dione (II-bx) was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-7α-hydroxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.30 (t, 1H), 3.48 (m, 2H), 2.46-0.95 (m, 21H), 1.00 (s, 3H), 0.78 (s, 3H)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[Cl:24])[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:17][C:16]=1[Cl:24])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOc1ccc(B(O)O)cc1Cl
Reactant: O=Cc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCCOc1ccc(-c2cccc(C=O)n2)cc1Cl
Temperature: 80 °C
Yield: 82 %

Procedure:
To a solution of 6-bromopicolinaldehyde (4.07 g, 21.88 mmol) in dioxane (40 mL) at ambient temperature was added 4-butoxy-3-chlorophenylboronic acid (5.00 g, 21.9 mmol), 2M cesium carbonate (22.0 mL, 43.8 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.357 g, 0.438 mmol). The mixture was degassed (3× vacuum/purge N2) then heated at 80° C. overnight. The mixture was cooled to room temperature then partioned between water and CH2Cl2. The organic phase was concentrated and purified by chromatography (silica gel, 10% ethyl acetate:hexanes) to provide 5.20 g (82%) of the title compound. MS (DCI+) m/z 290 (M+H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][N:8]=1)(=O)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([O:18][C:10]1[CH:11]=[C:12]([CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:7]([C:30]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=2[F:28])=[N:8][CH:9]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)Cc1cc(OCc2ccccc2)cnc1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ncc(OCc3ccccc3)cc2CC(C)(C)C)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
Under an argon atmosphere, to a solution of 5-(benzyloxy)-3-neopentylpyridin-2-yl trifluoromethanesulfonate (3.35 g) in toluene (25 mL) were added (2-fluoro-5-methoxyphenyl)boronic acid (2.12 g), tetrakis(triphenylphosphine)palladium (0) (961 mg) and 2.0 M aqueous sodium carbonate solution (12.5 mL), and the mixture was stirred at 90° C. for 3 hr. Water was added at room temperature, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.95 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[C:26]([F:29])[C:27]=1[F:28])[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1>>[CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH:24][C:21]3[N:22]=[CH:23][N:19]([CH2:18][C:17]4[CH:25]=[C:26]([F:29])[C:27]([F:28])=[C:15]([F:14])[CH:16]=4)[N:20]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1
Reactant: Nc1ncn(Cc2cc(F)c(F)c(F)c2)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4cc(F)c(F)c(F)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3,4,5-trifluoro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[S:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([C:35]3([OH:38])[CH2:36][CH2:37][S:32][CH2:33][CH2:34]3)=[N:10][CH:9]=2)[CH:5]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=2)[CH:3]=1
Reactant: O=C1CCSCC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCSCC3)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 4, 1.50 g, 4.46 mmol) in THF (10 mL) was added dropwise to a solution of lithium diisopropylamide (7.43 ml, 13.38 mmol) in THF (15 mL) at −78° C. and the resulting mixture was stirred at −78° C. for 30 minutes. Tetrahydrothiopyran-4-one (0.57 g, 4.91 mmol) in THF (5 mL) was then added, the dry ice bath was removed and the reaction was allowed to warm to room temperature. The reaction was quenched with aqueous saturated NH4Cl solution, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (SiO2, gradient elution 0 to 30% EtOAc in toluene) afforded 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]tetrahydro-2H-thiopyran-4-ol (1.21 g, 2.67 mmol, 60% yield) as a yellow foam. MS ESI: [M+H]+ m/z 453.0.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:21]([O-])=O.C(O)(=O)C>[Fe].C(O)C>[NH2:21][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[Cl:1])[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Yield: 99.7 %

Procedure:
A mixture comprising 1.00 g (2.86 mmol) of 4-(4-chloro-3-nitrobenzyl)amino-6-chloroquinazoline, 0.85 g of powdered iron, 10 ml of acetic acid and 50 ml of ethanol was heated under reflux for several hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 0.91 g of the title compound as a pale-yellow crystal.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]O)=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CCOCC>[CH2:5]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Br:2])=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCCCCCCCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
PBr3 (0.23 ml) was added drop wise to a stirred solution of the product of Step A (0.082 g; 0.37 mmol) in Et2O (2 ml) at −15° C. The mixture was allowed to warm up to room temperature and the stirring was continued for 4 h. This was poured onto ice (5 g) and the product was extracted with fresh Et2O (2×10 ml). The combined extracts were washed with 5% NaHCO3, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane) to give the title compound (0.04 g; 40%) as a colourless solid. 1H-NMR (CDCl3) 7.28 (d, 2H, J=8 Hz); 7.13 (d, 2H, J=8 Hz); 4.48 (s, 2H); 2.57 (t, 2H, J=7.9 Hz); 1.57 (m, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:16])[C:9](=[O:22])[CH2:8][CH2:7]2)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH:15]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[CH3:16])[C:9](=[O:22])[CH2:8][CH2:7]2
Reactant: CC(CN1C(=O)CCc2cc([N+](=O)[O-])ccc21)N1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(CN1C(=O)CCc2cc(N)ccc21)N1CCCC1

Procedure:
A suspension of 6-nitro-1-(2-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (585 mg, 1.93 mmol) and palladium on activated carbon (10%, 103 mg, 0.096 mmol) in 15 mL ethanol was stirred under a balloon of hydrogen overnight. The suspension was filtered through a pad of silica gel. The filter pad was rinsed with 20 mL of 2M NH3 in methanol and the filtrate was concentrated to give a viscous oil. The crude product was used without further purification. (490 mg, 92.9%). 1H-NMR (CDCl3) δ: 7.20 (d, J=8.7 Hz, 1H), 6.63 (dd, J=2.4, 8.7 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 3.58 (brs, 2H), 2.82-2.77 (m, 2H), 2.63-2.58 (m, 2H), 2.1 (br s, 4H), 1.80-1.62 (br s, 5H), 1.30 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(O[C:27](=[O:29])[CH3:28])(=O)C>>[C:17]([N:1]([C:27](=[O:29])[CH3:28])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[CH2:22])[N:10]([C:16](=[O:21])[CH3:15])[N:9]=2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Product: C=C1Cc2cc3c(cc2C(c2ccc(N(C(C)=O)C(C)=O)cc2)=NN1C(C)=O)OCO3
Yield: 34.4 %

Procedure:
2.93 g (0.01 mol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were refluxed with 20 ml of acetic anhydride for 6 hours. The solution was evaporated at reduced pressure, the residue was taken up in 2×20 ml of anhydrous ethanol, the solution was repeatedly evaporated and the resulting residue of 4.55 g was submitted to column chromatography (adsorbent: Kieselgel 60, eluant: ethyl acetate--benzene 4:1). The raw produce was triturated with 20 ml of hot isopropanol to yield 1.44 g (34.4%) of the aimed product, m.p. 240°-245° C. (slight decomp.).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=O)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:14][OH:15]>C(O)C.N1C=CC=CC=1>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[N:14][OH:15])[CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCCOc2ccccc21
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CCCOc2ccccc21
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A solution of 10.0 g (62 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one (J. Chem. Soc., Perkin Trans. 1 (1991), 2763) and 4.63 g (68 mmol) of hydroxylamine hydrochloride in 45 ml of ethanol and 45 ml of pyridine was heated under reflux for 5 h. After distilling off the solvents on a rotary evaporator, the residue was treated with water, adjusted to pH 2 with dil hydrochloric acid and stirred for 3 h. After filtering off the precipitated product with suction and drying it, 10.2 g of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime were obtained, m.p. 96-98° C. b) A solution of 2.0 g (11.3 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime in 15 ml of 1,2-dimethoxyethane (DME) was added dropwise at 0° C. under argon to a mixture of 4.5 g (23.7 mmol) of titanium tetrachloride and 1.79 g (47.4 mmol) of sodium borohydride in 50 ml of DME over the course of 20 min. After stirring at RT for 2 days, 100 ml of water were added dropwise and the mixture was rendered alkaline using conc. ammonia solution. After filtering off the precipitate with suction, the filtrate was extracted three times with EA. After washing with sodium chloride solution, drying over magnesium sulfate and concentrating, 2.1 g of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine were obtained. c) 0.86 g (6.7 mmol) of ethanesulfonyl chloride was added dropwise with ice cooling to a solution of 1.0 g (6.1 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 2.5 g (24 mmol) of triethylamine in 20 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the deposited product was filtered off with suction. 1.1 g of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-berzoxepine were obtained, m.p. 109-111° C. d) A solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF were added dropwise under nitrogen to a suspension of 0.16 g (5.4 mmol) of 80 percent sodium hydride in 10 ml of THF. After stirring at RT for 3 h, 1.6 g (11 mmol) of methyl iodide were added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 1.0 g of 5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 122-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A carboxylic acid, e.g., 6-Chloronicotinic acid (3.151 g, 20 mmol) was dissolved in dry DCM. The mixture was cooled down to 0° C. Oxalyl chloride (2.58 mL, 30 mmol) followed by DMF (77 μL) were added. The mixture was stirred at 0° C. for 1 h 30, then at RT overnight. The solvents were evaporated. The crude product was dissolved in toluene and the solvents were evaporated again to give the corresponding acid chloride (XVIII*), e.g., 6-chloronicotinoyl chloride (2.886 g, 82% yield). It was dissolved in benzene (50 mL) and AlCl3 (5.248 g, 39.4 mmol) was added. The mixture was stirred overnight at 80° C. After cooling down to RT, water was added. The two phases were separated and the aqueous layer was extracted with two portions of ethyl acetate. Combined organic layers were washed with brine and dried over MgSO4, filtrated and concentrated to give the desired product (XIX*), e.g., (6-chloropyridin-3-yl)(phenyl)methanone as a yellowish oil (3.884 g, 67% yield). It was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1.CS([C:19]1[N:24]=[CH:23][C:22]2=[CH:25][CH:26]=[C:27]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)[N:21]2[N:20]=1)=O>>[CH3:33][N:31]1[CH:32]=[C:28]([C:27]2[N:21]3[C:22]([CH:23]=[N:24][C:19]([NH:15][C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])[CH:10]=4)=[N:20]3)=[CH:25][CH:26]=2)[CH:29]=[N:30]1
Reactant: CN1CCCC1COc1cccc(N)c1
Reactant: Cn1cc(-c2ccc3cnc(S(C)=O)nn23)cn1
Product: CN1CCCC1COc1cccc(Nc2ncc3ccc(-c4cnn(C)c4)n3n2)c1

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(1-Methyl-pyrrolidin-2-ylmethoxy)-phenylamine and 2-Methanesulfinyl-7-(1-methyl-1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazine. 1H-NMR (DMSO) δ 9.7 (brs, 1H), 9.4 (s, 1H), 8.9 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7 (d, J=4.6 Hz, 1H), 6.9 (d, J=4.6 Hz, 1H), 6.6 (d, J=7.2 Hz, 1H), 4.3 (m, 1H), 4.2 (m, 1H), 3.9 (s, 3H), 3.8 (m, 1H), 3.6 (m, 1H), 3.1 (m, 1H), 2.9 (s, 3H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H), 1.8 (m, 1H); LC/MS (ESI+): 401 (M+H).