Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].S(=O)(=O)(O)O.[F:10][C:11]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:14][C:12]=1[NH2:13].O.O.[Sn](Cl)Cl.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[F:10][C:11]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19][CH2:20][C:21]([F:22])([F:24])[F:23])=[CH:14][C:12]=1[NH:13][NH2:1]
Reactant: O=N[O-]
Reactant: Cc1cc(F)c(N)cc1SCC(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Temperature: 20 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
53 g of sodium nitrite was added to 300 ml of concentrated sulfuric acid at 50° C. or lower, and 300 ml of acetic acid was added dropwise at 50° C. or lower. To this mixed solution, 100 ml of an acetic acid solution of 182 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)aniline was added dropwise over a period of 2 hours at 20° C. or lower, followed by stirring at 20° C. for 3 hours. The reaction mixture was added dropwise at 5° C. or lower to a mixed solution of 390 g of tin(II)chloride dihydrate and 1,000 ml of 6N hydrochloric acid, followed by stirring for 30 minutes. Toluene was added to this reaction mixture, and the reaction mixture was neutralized with a 10% aqueous sodium hydroxide solution. The insolubles were filtered off, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 177 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine.
Reaction SMILES: B.[Na].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]2=[O:13]>C(O)C>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:8]2[OH:13]
Reactant: CC(C)CC1Cc2c(Br)cccc2C1=O
Agent: B
Agent: [Na]
Solvent: CCO
Product: CC(C)CC1Cc2c(Br)cccc2C1O
Reaction time: 16 h
Yield: 96.4 %

Procedure:
A 300-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 2.51 g (66.3 mmol) of sodium boron hydride and 85 ml of ethanol. To the mixture was added dropwise a solution containing 37.0 g (132.6 mmol) of the above-obtained 4-bromo-2-i-butyl-1-indanone dissolved in 55 ml of ethanol at room temperature under a nitrogen atmosphere. After the addition was completed, the mixture was further stirred for 16 hours. Then, the reaction mixture was concentrated under reduced pressure, which was then extracted with 150 ml of water and 150 ml of ether. The organic phase was separated, and the aqueous phase was further extracted with 100 ml of ether. The combined organic phase was washed with 100 ml of a saturated NaCl aq. two times, followed by dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain 34.4 g of the desired product (mixture of two isomers) as a pale yellow solid (yield: 96%). This alcohol was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([CH:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([O:23]C)=[O:22])=[CH:18][CH:19]=2)[NH:14][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[K+].C>C(O)C.O>[CH2:1]([CH:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)[NH:14][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC1CNc2cc(C(=O)OC)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCC1CNc2cc(C(=O)O)ccc21
Yield: 100.2 %

Procedure:
(RS)-Methyl 3-(n-undecyl)indoline-6-carboxylate (12.4 g) in ethanol (350 ml), containing potassium hydroxide (3.33 g) and water (45 ml), was stirred and refluxed for 24 hours. The solvent was removed in vacuo to give an off-white solid. The solid was dissolved in water, and the solution was treated with charcoal and filtered through diatomaceous earth. Glacial acetic acid (50 ml) was slowly added to the stirred solution and an off-white solid was collected and recrystallised from ethyl acetate to give (RS)-3-(n-undecyl)indoline-6-carboxylic acid (11.9 g), in the form of a white solid, m.p. 107°-111° C.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[CH:60]=[C:59]([F:61])[C:58]([Br:62])=[CH:57][C:52]=1[C:53]([NH:55][CH3:56])=[O:54]>>[Br:62][C:58]1[C:59]([F:61])=[CH:60][C:51]([NH:50][C:26]2[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:48][CH3:49])[N:25]=2)=[C:52]([C:53](=[O:54])[NH:55][CH3:56])[CH:57]=1
Reactant: CNC(=O)c1cc(Br)c(F)cc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cc(F)c(Br)cc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 2-amino-5-bromo-4-fluoro-N-methylbenzamide (Compound 7D, 0.327 g, 1.32 mmol) to afford the title compound as 642 mg of a white solid (88% yield). 1H NMR (DMSO-d6, 400 MHz): δ 11.94 (br. s., 1H), 9.15 (br. s., 1H), 8.88 (d, J=4.6 Hz, 1H), 8.53 (br. s., 1H), 8.42 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.02 (s, 1H), 6.82-6.90 (m, 1H), 3.93-4.02 (m, 4H), 3.77 (s, 3H), 3.18-3.27 (m, 2H), 2.77 (d, J=4.3 Hz, 3H), 1.19 (t, J=7.1 Hz, 6H). MS (ESI): m/z 664.09 [M+H]+. UPLC: tR=1.60 min (UPLC-TOF: polar—3 min).
Reaction SMILES: C([NH:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10](O)[CH3:11])=[S:7])(C)(C)C.Cl>O>[CH2:13]([C@H:9]1[C@H:10]([CH3:11])[S:7][C:6]([NH2:5])=[N:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)[C@H](Cc1ccccc1)NC(=S)NC(C)(C)C
Agent: Cl
Solvent: O
Product: C[C@@H]1SC(N)=N[C@H]1Cc1ccccc1
Temperature: 100 °C

Procedure:
The process is performed as in Example 3, starting with 3.9 g of diastereoisomer A of the N-(tert-butyl)-N′-((1S)-1-benzyl-2-hydroxypropyl)thiourea in 46 cm3 of aqueous 6N hydrochloric acid. After heating for 5 hours at a temperature in the region of 100° C., the reaction mass is concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. The oil obtained is dissolved in 50 cm3 of water; the solution is washed with twice 50 cm3 of dichloromethane. The aqueous phase is made alkaline by addition of 3 cm3 of 30% caustic soda and then extracted with 3 times 50 cm3 of dichloromethane. The organic extracts are combined and dried over sodium sulfate. After filtration and concentration under reduced pressure (5 kPa) at a temperature in the region of 40° C., 2.5 g of (−)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine are obtained in the form of a white solid melting at 89° C. (transisomer). (αD20=−87.3±1.3 at a concentration of 0.5% in methanol).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25]>C1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]32[O:25][CH2:24][CH2:23][O:11]3)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=C1CCc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)C1(CC2)OCCO1

Procedure:
A mixture of Example 3 (13.0 g, 61.8 mmol), p-toluenesulfonic acid (23 mg, 0.12 mmol) and ethylene glycol (27.6 mL, 494.6 mmol) in benzene (140 mL) was heated to reflux for about 24 hours, using a Dean-Stark trap to separate the forming water. The mixture was cooled, poured into excess 5% aqueous sodium bicarbonate and was extracted with toluene. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using dichloromethane as the mobile phase to provide the desired product. MS (DCI-NH3): m/z 254, 256 (M)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[O:13]1[CH2:17][CH2:16][C@H:15]([O:18][CH2:19][C:20]2[N:25]=[C:24]([CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=2)[CH2:14]1.C(N(CC)CC)C>CC(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([NH:9][CH:10]=[O:11])=[C:6]([NH:27][CH2:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][O:18][C@H:15]3[CH2:16][CH2:17][O:13][CH2:14]3)[N:25]=2)[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: NCc1cccc(CO[C@H]2CCOC2)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Nc1nc(Cl)c(NC=O)c(NCc2cccc(CO[C@H]3CCOC3)n2)n1
Yield: 72.5 %

Procedure:
A mixture of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (17.24 g, 82.46 mmol), 6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethylamine (18.89 g, 90.70 mmol) and triethylamine (12.64 mL, 90.70 mmol) in propan-2-ol (165 mL) was heated at reflux for 2 h, cooled and the resulting precipitate was filtered, washed with cold propan-2-ol and dried to give the title compound (22.66 g, 73%) as a pink solid; LC-MS retention time 1.46 min, (M+H)+ 379.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[CH:37][N:36]=4)[C:31](=[O:49])[N:30]([CH3:50])[N:29]=3)[C:18]=1[CH2:19][O:20]C(=O)C)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[CH:37][N:36]=4)[C:31](=[O:49])[N:30]([CH3:50])[N:29]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(CN4CCN(C)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN1CCN(Cc2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzyl ester (4.5 g, 6.61 mmol, Eq: 1.00) and potassium carbonate (1.37 g, 9.92 mmol, Eq: 1.50) were dissolved in methanol and heated at 40° C. for 1 hour. The reaction was cooled to room temperature and water was added dropwise. The reaction was stirred at room temperature overnight. The solid that formed was filtered, washed with water, and dried in a vacuum oven over the weekend to give 3.64 g (86.2%) of an off-white crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.39 (s, 1H) 8.53 (s, 1H) 8.50 (d, J=2.3 Hz, 1H) 8.15 (d, J=1.9 Hz, 1H) 7.86 (d, J=1.5 Hz, 1H) 7.74 (dd, J=13.4, 1.7 Hz, 1H) 7.57-7.62 (m, 1H) 7.50-7.57 (m, 2H) 7.43-7.49 (m, 2H) 4.52-4.61 (m, 1H) 4.40 (br. s., 2H) 3.77 (s, 3H) 3.36 (s, 2H) 2.30 (br. s., 8H) 2.11 (s, 3H) 1.37 (s, 9H). MS: (M+H)+=639.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[CH2:18]([OH:21])[C:19]#[CH:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:21][CH2:18][C:19]#[C:20][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: C#CCO
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1C#CCO
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 0.37 g (0.5 mmole) of dichlorobis(triphenylphosphine)palladium II, 70 mg (0.35 mmole) of cuprous iodide, 36.1 g (0.1 mole) of 5-chloro-2'-fluoro-2-iodobenzophenone and 12 ml (0.2 mole) of propargyl alcohol in 200 ml of diethylamine was stirred at room temperature for 4 days. The mixture was concentrated at reduced pressure and the residue was partitioned between ether and water. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give the product as an amber oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3([NH:22]C(=O)OC(C)(C)C)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1.Cl>O1CCOCC1>[F:31][C:2]([F:1])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3([NH2:22])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1(Cc2nc(-c3ccc(OC(F)(F)F)cc3)c[nH]2)CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(Cc2nc(-c3ccc(OC(F)(F)F)cc3)c[nH]2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To tert-butyl [4-({4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)tetrahydro-2H-pyran-4-yl]carbamate (Preparation 4, 0.166 g, 0.376 mmol) was added 4M hydrogen chloride in 1,4-dioxane (3 mL) and the reaction left to stir at room temperature for 18 hours before concentrating in vacuo. The residue was purified by preparative HPLC conditions (A-HPLC) to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][N:13]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[CH3:12][N:13]([CH:21]1[CH2:22][CH2:23][N:24]([C:2]2[C:3]3[C:10]([CH3:11])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:25][CH2:26]1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1c[nH]c2ncnc(N3CCC(N(C)C(=O)OC(C)(C)C)CC3)c12
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine D4 (1 g), 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (1.918 g, 8.95 mmol, commercially available from e.g. Fluorochem, Apollo or Butt Park) and N,N-diisopropylethylamine (2.61 mL, 14.92 mmol) was heated at 150° C. for 20 minutes. LC/MS showed incomplete reaction. Further NMP (2 mL) and DIPEA (1.3 mL) was added. The mixture was heated at 150° C. for 20 minutes. The mixture was partitioned between ethyl acetate (70 mL) and water (60 mL) and the organic phase washed with water (2×60 mL) and brine (50 mL). It was dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by silica chromatography, eluting 50-100% EtOAc in isohexane. The desired fractions collected and the solvent has been evaporated to give the desired product D22 in 0.793 g as a white solid. LCMS [M+H]+345.87@0.88 min (2 min run)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16](O)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2.S(Cl)(C)(=O)=O.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:40][CH2:39]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:26][O:25][C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:9]([C:14](=[O:19])[C:15]=1[C:16]([NH:48][CH2:47][CH2:46][CH2:45][CH2:44][N:41]1[CH2:42][CH2:43][N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:39][CH2:40]1)=[O:17])=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Reactant: NCCCCN1CCN(c2ccccn2)CC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)NCCCCN2CCN(c3ccccn3)CC2)cc(OC)c1OC

Procedure:
Under the conditions described in Example 1 (a) 3.6 g 3',4',5'-trimethoxyflavone-3-carboxylic acid were converted with 2.1 g 4-dimethylaminopyridine and 0.72 ml mesyl chloride in 100 ml absolute dichloromethane into the mixed anhydride, and this was then reacted under the conditions described in Example 4 (d) with 2.2 g of 4-[4-(2-pyridyl)-piperazin-1-yl]-butylamine. The reaction mixture was then worked up analogously to Example 4 (d). 3.4 g of 3',4',5'-trimethoxy-3-{4-[4-(2-pyridyl)-piperazin-1-yl]-butylaminocarbonyl}-flavone were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][N:13]2[C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Fc1cc(C2NCCc3ccccc32)ccc1C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(3-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-isoquinoline (0.0845 g, 0.286 mmol, Example 71 Step 3) in 3 mL of DCM, 4-fluorophenyl isocyanate (0.0358 mL, 0.315 mmol) was added. The solution was stirred for 1 h. Solvent was evaporated and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to yield the title compound as a white solid. MS (ESI pos. ion) m/z: 433.1 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.51 (t, J=7.75 Hz, 1H) 7.22-7.39 (m, 6H) 7.06-7.19 (m, 2H) 6.96-7.05 (m, 2H) 6.63 (s, 1H) 6.45 (s, 1H) 3.59-3.81 (m, 2H) 2.76-3.08 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH2:20]Br)[CH:17]=[CH:18][CH:19]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([CH2:20][O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(COC2CCC3(CC2)OCCO3)c1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 9, using 4.7 grams (0.030 mole) of 1,4-dioxaspiro[4.5]decan-8-ol (prepared as in Step B of Example 8), 7.2 grams (0.030 mole) of 3-trifluoromethylphenylmethyl bromide, and 1.3 grams (0.033 mole) of sodium hydride (60% in mineral oil) in 60 mL of toluene, yielding 8-(3-trifluoromethyl phenyl methoxy)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:24]=[CH:23][C:10]([O:11][CH:12]3[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:14]1[CH2:13][CH:12]([O:11][C:10]2[CH:23]=[CH:24][C:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:8][CH:9]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CCCC3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(OC2CNC2)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.1 %

Procedure:
A solution of 1A (5.2 g, 15.5 mmol) in DCM (50 mL) was treated with TFA (10 g, 88 mmol) and stirred at RT for 17 h. The reaction mixture was concentrated and then co-evaporated using DCM. The residue was dissolved in water and the pH adjusted to pH 10 by adding NaOH. The solution was extracted several times with DCM and the organic solutions were filtered through a phase separator. The solvent was removed by evaporation. There was obtained 3.1 g (85%) of 1B as an oil. 1H NMR (500 MHz, CDCl3): δ 1.69-1.83 (m, 4H), 2.43-2.57 (m, 4H), 3.53 (s, 2H), 3.73-3.81 (m, 2H), 3.87-3.92 (m, 2H), 4.93-5.01 (m, 1H), 6.68 (d, 2H), 7.20 (d, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[O:24][CH3:25])[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:28][O:29][CH2:30][CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][N:32]1[CH3:37].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:15]([NH:14][C:11]1[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]4[CH2:34][CH2:33][N:32]([CH3:37])[CH:31]([CH2:30][O:29][CH3:28])[CH2:36]4)[CH:27]=[CH:26][C:9]=3[N:10]=1)[CH2:16][CH2:17]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Reactant: COCC1CNCCN1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCC1CN(CC(=O)Nc2ccc3c(c2)COC(NC2CCc4cccc(OC)c42)=N3)CCN1C
Yield: 33 %

Procedure:
Prepared from rac-2-chloro-N-[2-(7-methoxy-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 55, step A) (328 mg, 0.85 mmol), commercially available rac-2-methoxymethyl-1-methyl-piperazine (CAS no. 734507-92-7) (123 mg, 0.85 mmol) and diisopropylethyl amine (723 ul, 4.25 mmol) in acetonitrile (2 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (137 mg, 33%), MS (ISP) m/e=494.3 [(M+H)+].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](/[C:9](=[CH:16]\[CH3:17])/[CH:10]([CH3:15])[CH2:11][N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)C.[ClH:31]>C1(C)C=CC=CC=1.CC(C)=O.C(O)C.O>[ClH:31].[CH3:14][N:12]([CH3:13])[CH2:11][CH:10](/[C:9](/[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)=[CH:16]/[CH3:17])[CH3:15]
Reactant: C/C=C(\c1cccc(OC)c1)C(C)CN(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: C/C=C(\c1cccc(O)c1)C(C)CN(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
182 g (Z)-(RS)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethylamine, dissolved in 360 ml toluene, were added drop-wise at room temperature to 1.6 l of a 20 weight % solution of diisobutylaluminium hydride in toluene. The mixture was then heated for 11 hours under reflux. After cooling to 0° C., 450 ml ethanol were added drop-wise with cooling. The mixture was then stirred for 15 minutes and diluted with 1 l toluene. Thereafter, 450 ml of an ethanol/water mixture (1:1) were added drop-wise with cooling. After stirring for one hour at room temperature, the precipitated aluminium hydroxide was filtered off under suction and the solvent was removed from the organic phase by distillation. 167 g (97.6% theoretical) of crude base were obtained, which were dissolved in 1.67 l acetone and treated with 65 ml of concentrated hydrochloric acid. 152 g (76% theoretical) of hydrochloride (3) crystallised out, and had a melting point of 161°-162° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17](C1C=CC=CC=1)[C:18](=O)[O-:19])[CH2:6][CH2:5]2.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([N:31]1[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]1)=[O:19])[CH2:6][CH2:5]2
Reactant: CN1CCNCC1
Reactant: O=C([O-])N(c1ccccc1)c1ccccc1N1CCc2cc(Br)ccc21
Solvent: CCOCC
Product: CN1CCN(C(=O)Nc2ccccc2N2CCc3cc(Br)ccc32)CC1
Yield: 90 %

Procedure:
A solution of N-[2-(5-bromo-1-indolinyl)phenyl]phenylcarbamate (11.5 g, 28.5 mmoles), N-methylpiperazine (15 ml) and ether (50 ml) was stirred at room temperature for 2 hours. The ether was evaporated. The mixture was filtered through a silica gel column (150 g), packed with dichloromethaane, and the column was washed with 2% methanol-dichloromethane solution (2 l). The solvent was evaporated. The residue was purified by flash chromatography on a silica gel column (150 g, 230-400 mesh), eluted with 1% methanol/dichloromethane (4 l), 1.5% methanol/dichloromethane (2 l), and 2% methanol/dichloromethane. The fractions containing the desired material were collected and evaporated to give 10.9 g (90%) of product. Crystallization from chloroform and hexane afforded the analytical sample, mp 108°-110° C.