Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][OH:9].C(N(CC)CC)C.[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:20]([O:9][CH2:8][CH:7]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: C=C1CC(=O)O1
Reactant: OCC=Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCC=Cc1cccs1

Procedure:
1.50 g (10.7 mmol) of 3-(thiophene-2-yl)-2-propene-1-ol, 0.5 ml (3.59 mmol) of triethylamine and 1.0 ml (13.0 mmol) of diketene were heated to 70° C. under stirring in 30 ml of toluene for 1.5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture at room temperature. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13].[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[Cl:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:18][CH2:19]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Fc1ccc(OCCCCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCOc2ccc(F)cc2Cl)CC1

Procedure:
A mixture of 3.3 g of 2-(3-chloropropoxy)-5-fluorochlorobenzene, 3.3 g of 1-(4-piperidinyl)-2-oxobenzimidazoline, 0.9 g of sodium carbonate and 80 ml of dimethylformamide was heated at 80° - 90° C for 15 hours. After cooling, the reaction mixture was poured into water and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was triturated with ether, cooled and filtered to give 1-{3-(2-chloro-4-fluorophenoxy)propyl}-4-(2-oxo-1-benzimidazolinyl)piperidine, m.p. 130° - 132° C; recrystallized from benzenecyclohexane, m.p. 149° - 149.5° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH:4]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][CH3:21])[N:16]=[C:15](S(C)(=O)=O)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:6])[CH3:5]>CS(C)=O>[CH:4]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][CH3:21])[N:16]=[C:15]([C:1]#[N:2])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: CCCc1cc(-c2cccc(C(C)C)c2)nc(S(C)(=O)=O)n1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCc1cc(-c2cccc(C(C)C)c2)nc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Sodium cyanide (65 mg, 1.32 mmol) was added at room temperature to 4-(3-isopropyl-phenyl)-2-methanesulfonyl-6-propyl-pyrimidine (211 mg) in DMSO (2 mL). The mixture was stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: Cyclohexane/Ethyl acetate 7/3) to afford a pink oil which crystallised in pentane. After filtration, 4-(3-isopropyl-phenyl)-2-cyano-6-propyl-pyrimidine (164 mg) was obtained as an off white solid (mp=64° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:25]=[CH:24][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].Cl[C:38]1C=C(NC2C=CC(F)=CC=2F)C=C[C:39]=1C(C1C=C(C2N=NN(CC(O)=O)C=2)C=CC=1C)=O.N1CCCC1>>[Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:25]=[CH:24][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]([N:21]3[CH2:39][CH2:38][CH2:23][CH2:22]3)=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: CCNC(=O)Cn1cc(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Reactant: Cc1ccc(-c2cn(CC(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: C1CCNC1
Product: Cc1ccc(-c2cn(CC(=O)N3CCCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 112, using compound 111 (0.12 mmol) and pyrolidine (0.12 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/EtOAc 0:100 to 5:95 as the eluent to afford the title compound as almost yellow syrup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:24])[CH2:9][C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=1)[CH2:11][C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH3:24])[CH2:9][C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@@H](CC(=O)O)c1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of 102 (632 mg, 1.756 mmol) in 4:1 THF/H2O (5 mL) was added 3M aq. LiOH (5.855 mL, 17.56 mmol). The reaction mixture was stirred at RT for 4 h. The aqueous solution was acidified with 2N HCl to ca. pH 2-3 and then twice extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated to afford 598 mg (98.46%) of (S)-4-(tert-butoxycarbonyl(methyl)amino)-3-(4-chloro-3-fluorophenyl)butanoic acid (104).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][N:9]([CH2:27][CH2:28][NH:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:10]([NH:19]C(OC(C)(C)C)=O)=[N:11]C(OC(C)(C)C)=O.[C:49]1([C:55](Cl)([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:7][N:6]1[C:2]([NH:1][C:55]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:3]([CH2:8][N:9]([CH2:27][CH2:28][NH:29][C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]([NH2:19])=[NH:11])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(CN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cn1ncc(CN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=N)N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution of N-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-N′,N″-bis(tert-butoxycarbonyl)-N-[2-(tritylamino)ethyl]guanidine (1.84 g) in pyridine (10 ml) was added triphenylmethyl chloride (0.94 g), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added chloroform (50 ml). The mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give N′,N″-bis(tert-butoxycarbonyl{-N-([1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]methyl}-N-[2-(tritylamino)ethyl]guanidine (1.60 g) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C@:12]2([CH3:23])[O:16][C:15]3=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]3[CH2:13]2)[CH2:7][CH2:6]1)=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:2][C:3]([N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C@:12]3([CH3:23])[O:16][C:15]4=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]4[CH2:13]3)[CH2:7][CH2:6]2)=[O:4])=[CH:27][CH:26]=1
Reactant: C[C@]1(CN2CCN(C(=O)CCl)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CCN(C(=O)COc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
A mixture of (S)-2-chloro-1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazin-1-yl]ethanone prepared in Example 420 (300 mg, 0.87 mmol), 4-chlorophenol (170 mg, 1.32 mmol), potassium carbonate (180 mg, 1.3 mmol) and DMF (5 ml) was stirred at 60° C. for 3 hours. The reaction mixture was allowed to return to room temperature, then diluted with water. The solution was extracted with ethyl acetate twice. The organic phases were combined, washed with a sodium hydroxide solution, water and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to afford (S)-2-(4-chlorophenoxy)-1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]ethanone (260 mg, yield 68%) as a light brown powder.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:22][N:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:32](=[O:48])[C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[CH:25][C:24]1=[O:49].C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([NH:31][CH2:30][CH2:29][C:26]4[CH:27]=[CH:28][N:23]([CH3:22])[C:24](=[O:49])[CH:25]=4)=[O:48])=[CH:34][CH:35]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: Cn1ccc(CCNC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1=O
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: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccc(C(=O)NCCc4ccn(C)c(=O)c4)cc3)nc3scnc23)cc1OC
Yield: 11.8 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (150 mg, 0.47 mmol), N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (220 mg, crude), Pd(PPh3)4 (40 mg, 0.035 mmol) and Na2CO3 (100 mg, 0.94 mmol) in 3 mL of water was added in 30 mL of 1,4-dioxane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with DCM/MeOH (20/1, v/v) to give 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (30 mg, 12%) as a yellow sold. 1H NMR (300 MHz, CD3OD): δ 9.13 (s, 1H), 8.52-8.50 (m, 2H), 7.89-7.80 (m, 3H), 7.58 (d, 1H, J=6.9 Hz), 7.40 (dd, 1H, J1=8.4 Hz, J2=2.4 Hz), 7.03 (d, 1H, J=8.7 Hz), 6.46 (s, 1H), 6.38 (dd, 1H, J1=6.6 Hz, J2=1.8 Hz), 3.94 (s, 3H), 3.88 (s, 3H), 3.66 (t, 2H, J=7.0 Hz), 3.54 (s, 3H), 2.84 (t, 2H, J=7.0 Hz). LC-MS: 543 [M+H]+, 541 [M−H]−, tR=1.37 min. HPLC: 100% at 214 nm, 100% at 254 nm, tR=5.36 min.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[C:10]2[N:11]=[CH:12][N:13]=[CH:14][C:9]=2[S:8][CH:7]=1)CCC.[NH2:23][C:24]1[N:25]=[CH:26][C:27]([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]3)[CH:38]=2)=[C:28]2[CH:32]=[C:31](Cl)[O:30][C:29]=12.[F-].[Cs+]>CN(C=O)C.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>[NH2:23][C:24]1[N:25]=[CH:26][C:27]([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]3)[CH:38]=2)=[C:28]2[CH:32]=[C:31]([C:6]3[C:10]4[N:11]=[CH:12][N:13]=[CH:14][C:9]=4[S:8][CH:7]=3)[O:30][C:29]=12
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc2cncnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5csc6cncnc56)cc34)cn2)CC1
Temperature: 130 °C
Yield: 27.8 %

Procedure:
A portion of 7-(tributylstannanyl)thieno[3,2-d]pyrimidine (0.030 g, 0.071 mmol) was dissolved in DMF (0.8 mL), and the solution was degassed with nitrogen for 10 min. To this mixture was added 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (0.017 g, 0.047 mmol), Pd(PPh3)4 (0.0066 g, 0.0057 mmol) and cesium fluoride (0.0241 g, 0.159 mmol). The mixture was heated in a microwave reactor for 30 min at 130° C. Purification by MDP and then ISCO chromatography (0 to 20% methanol:DCM) afforded 0.006 g (30%) of the title compound an off-white solid. 1H NMR (400 MHz, CD3OD): δ 9.53 (s, 1 H), 9.36 (s, 1 H), 8.94 (s, 1 H), 8.15 (s, 1 H), 8.03 (s, 1 H), 7.93 (s, 1 H), 7.91 (br. s., 1 H), 4.72 (d, J=13.1 Hz, 1 H), 4.65-4.54 (m, 2 H), 4.14 (d, J=9.6 Hz, 1 H), 2.90 (dt, J=2.8, 13.0 Hz, 1 H), 2.33-2.22 (m, 2 H), 2.20 (s, 3 H), 2.19-2.11 (m, 1 H), 2.10-1.97 (m, 1 H); MS (ESI): 460.36 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH2:12]O)[CH:4]=1.C([O-])(O)=O.[Na+].O=S(Cl)[Cl:21]>>[Cl:21][CH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1
Reactant: COc1cc(CO)cc2c1OCO2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(CCl)cc2c1OCO2
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of SOCl2 (150 mL) was added (7-methoxybenzo[d][1,3]dioxol-5-yl)methanol (9.0 g, 54 mmol) in portions at 0° C. The mixture was stirred for 0.5 h. The excess SOCl2 was evaporated under reduced pressure to give the crude product, which was basified with sat. aq. NaHCO3 to pH ˜7. The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10 g 94%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 6.58 (s, 1H), 6.57 (s, 1H), 5.98 (s, 2H), 4.51 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12](Cl)[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cu](C#N)[C:22]#[N:23].CN1CCCC1=O.O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([C:22]#[N:23])[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1ccc2c(c1)CCc1c(Cl)cccc1S2
Reactant: N#C[Cu]C#N
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc2c1CCc1cc(C(F)(F)F)ccc1S2
Reaction time: 18.5 h
Yield: 14.7 %

Procedure:
The mixture of 450mg of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin, 0.4g of copper cyanide, 0.05g of anhydrous copper sulfate and 10ml of N-methylpyrrolidone was stirred at 180° to 210° C for 18.5 hrs. while preventing the moisture. A ter cooling, to the mixture was added 2.5ml of conc. ammonia water and 35ml of water and the resulting mixture was filtered with the use of celite. The thus obtained solution was extracted with benzene and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 0.3g of a brown oily substance, which was chromatographed on a silica gel, eluted with n-hexane, and there was obtained 64mg of the desired product. This was recrystallized from n-hexane to afford 2-trifluoromethyl-9-cyano-10,11-dihydrodibenzo-[b,f]thiepin having a melting point of 113° to 114.5° C as colorless crystals.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:42][CH2:43][CH:44](CO)[OH:45]>>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:44]([OH:45])[CH2:43][OH:42])=[O:26])=[CH:29][CH:30]=1)([O:3][CH3:4])=[O:2]
Reactant: OCC(O)CO
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-(15-carbomethoxypentadecylamino)benzoate, 280 mg. of glycerol, and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 4 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 2,3-dihydroxypropyl 4-(15-carbomethoxypentadecylamino)benzoate.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2ccc(N)cc21
Reaction time: 2 h
Yield: 98.6 %

Procedure:
1-Acetyl-6-nitroindoline (3.8 g, 18.3 mmol) is suspended in EtOAc (200 mL). Pd/C (650 mg, 10%) is added, and the mixture is hydrogenated at 40-55 p.si.i. for 2 hours. The mixture is then filtered through celite. The filtrate is concentrated, and the residue is triturated with ether to yield 1-acetyl-6-aminoindoline (3.18 g, 99%) as an orange solid.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:8]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([C:20]2[N:24]4[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:28][C:23]4=[N:22][CH:21]=2)[CH:16]=[CH:15]3)[CH2:7][N:6]([C:34]([O:36][CH2:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[O:35])[CH2:5]1.I[CH3:49]>CN(C=O)C>[CH3:49][O:3][C@H:4]1[C@H:8]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([C:20]2[N:24]4[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:28][C:23]4=[N:22][CH:21]=2)[CH:16]=[CH:15]3)[CH2:7][N:6]([C:34]([O:36][CH2:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[O:35])[CH2:5]1
Reactant: CI
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5O)c4n3)cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5OC)c4n3)cnc2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
Sodium hydride (0.017 g, 0.43 mmol) was added to a solution of (trans)-naphthalen-2-ylmethyl 3-hydroxy-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-1-carboxylate (0.117 g, 0.194 mmol) in DMF (1 mL). The reaction was cooled to 0° C. and stirred for 20 minutes. Iodomethane (0.012 ml, 0.194 mmol) was added, and the ice bath was removed. The reaction was stirred for 1 hour. Water was added, and the reaction mixture was extracted with CHCl3. The combined organic layers were washed with brine, dried and condensed. The residue was purified by silica gel chromatography to provide 54 mg of the desired product. MS APCI (+) m/z 619.1 (M+1) detected.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=4[CH:27]=3)[CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:36][C:32]1([CH3:37])[CH2:31][CH2:30][C:29]([CH3:38])([CH3:39])[C:28]2[CH:27]=[C:26]([C:23]3[CH:22]=[C:21]([N:18]4[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]4)[O:25][N:24]=3)[CH:35]=[CH:34][C:33]1=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)no2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(N4CCNCC4)on3)ccc21

Procedure:
The protecting group was cleaved off as already described using TFA in DCM starting from 27 mg (0.06 mmol) of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)isoxazol-5-yl]piperazine-1-carboxylic acid tert-butyl ester from step d. The product is in the form of the TFA salt.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C=O)C.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=C1NC(=O)c2cc(O)ccc21
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0° C. was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture was allowed to return to room temp. and was stirred for 1 h, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70° C. overnight, then cooled to room temp. and diluted slowly with water (150 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) Rf 0.28; 1H NMR (DMSO-d6) δ 7.32 (d, J=12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285 ((M+H)+, 100%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O=[C:13]1[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]1.[C-]#N.[Na+]>O.CO>[NH2:22][CH2:21][CH2:20][C@H:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:14][CH2:15]1)[CH3:23]
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: Nc1ccc2c(c1)OCCO2
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](CCN)N1CCC(Nc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Using general procedure A with 1,4-benzodioxan-6-amine (170 mg, 1.1 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (206 mg, 1.2 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL) and stirred at room temperature for 20 minutes. Work-up and purification afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine as a white solid (245 mg, 71% over 2 steps).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:17]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27][Br:28])[CH:24]=[C:23]([CH2:29]Br)[CH:22]=1)[CH3:18]>>[Br:28][CH2:27][C:25]1[CH:24]=[C:23]([CH2:29][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:22]=[C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:31])[CH:26]=1
Reactant: COCCOc1cc(O)cc(C(=O)OC)c1
Reactant: CCOC(=O)c1cc(CBr)cc(CBr)c1
Product: CCOC(=O)c1cc(CBr)cc(COc2cc(OCCOC)cc(C(=O)OC)c2)c1

Procedure:
The subtitle compound was prepared from the product of step (iii) (1.5 g) and 3,5-bis(bromomethyl)benzoic acid ethyl ester (4.9g) by the method of example 11 step (i). Purification was by chromatography eluting with 30% ethyl acetate in isohexane. Yield 1.6 g. Used directly in the next step