Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc([N+](=O)[O-])cn2)C[C@H](C)N3C(C)=O)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(N)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a flask charged with methyl 4-((2S,4R)-1-acetyl-2-methyl-4-((5-nitropyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 20)(2.43 g, 5.28 mmol), ammonium formate (3.33 g, 52.8 mmol) and palladium on carbon (0.562 g, 5.28 mmol) was added MeOH (50 mL) and the resulting mixture was refluxed for 30 min. The reaction was cooled to room temperature, filtered through Celite™ and the residue washed with MeOH then DMF. The methanolic filtrate and washings were combined and concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with a MeOH/DCM gradient to give methyl 4-((2S,4R)-1-acetyl-4-((5-aminopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (2.0 g, 4.65 mmol, 88% yield) as a dark pink foam. LCMS (HpH, 2 min), Rt=0.94 min, MH+=431.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:3]=1[CH:4]=[O:5].C[C:15](=[O:19])[O:16]CC>>[F:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:3]=1[CH:4]([OH:5])[C:15]([OH:19])=[O:16]
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(C)=O
Product: O=C(O)C(O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
The 2,3,4,5,6-pentafluorobenzaldehyde (49.4 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 52.3 g. (86.0). EA, MS(FD).
Reaction SMILES: [NH:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[NH:20]([C:36]([CH3:38])=[O:37])[C@H:21]([C:33](O)=[O:34])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CC(=O)OCC>[NH:20]([C:36]([CH3:38])=[O:37])[C@H:21]([C:33]([N:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4])=[O:34])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27]
Reactant: CC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(CNC(=O)[C@@H]1CCCN1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
6.4 g of H-Pro-Gly-OBzl, 4.6 g of Ac-Orn(Boc)-OH, 3.0 ml of NEM and 3.1 g of HOBt are dissolved in 30 ml of EA and then 4.8 g of DCC in 10 ml of EA are added. After the mixture has been stirred at room temperature for 24 hours, it is filtered and the filtrate is evaporated. Chromatography of the residue on silica gel (system 1) results in 4.7 g (yield: 41%) of the desired compound being isolated as a colorless powder. Rf (system 1)=0.3; MS (FAB): 519 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20](I)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1Cl
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#C[Si](C)(C)C)c3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 114.5 %

Procedure:
A mixture of 5-(4-chloro-3-methyl-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (5.85 g, 12.4 mmol), trimethylsilylacetylene (3.33 mL, 24.1 mmol) and triethylamine (3.71 mL, 26.7 mmol) in N,N-dimethylformamide (20 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (94 mg, 1 mol %), PPh3 (35 mg, 1 mol %) and CuI (8 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water (2×50 mL) and brine (70 mL), dried (MgSO4) and evaporated to give 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (5.79 g, 106%) as an orange solid, which was dissolved in THF (70 mL) and MeOH (70 mL), while stirring at 0° C. potassium carbonate (196 mg, 1.42 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (250 mL) and extracted with TBME (3×250 mL). The combined organic layers were washed with brine (300 mL), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/EtOAc 9:1) followed by trituration with heptane to give 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (3.22 g, 68%) as an orange solid. MS (EI) 335.0 [(M+H)+]; mp 166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH:5]=O.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH2:5][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: COc1cc(OC2CCCCO2)cc(C)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(OC2CCCCO2)cc(C)c1CN1CCCCC1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
To a pre-stirred solution of 2-methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzaldehyde (2.14 g, 8.6 mmol) and piperidine (0.93 mL, 9.4 mmol) in DCM (35 mL) at 0° C. was added sodium triacetoxyborohydride (2.72 g, 12.8 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and then partitioned between water (30 mL) and ethyl acetate (75 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (2.78 g, quantitative yield) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 6.51 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 5.40 (t, J=3.3 Hz, 1H), 3.98-3.88 (m, 1H), 3.76 (s, 3H), 3.64-3.55 (m, 1H), 3.39 (s, 2H), 2.42-2.27 (m, 7H), 2.07-1.93 (m, 1H), 1.90-1.77 (m, 2H), 1.75-1.52 (m, 3H), 1.54-1.44 (m, 4H), 1.43-1.34 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH:15]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:16]1([CH:15]2[CH:13]3[CH2:12][CH2:11][CH:10]2[CH2:9][NH:8][CH2:14]3)[CH:20]=[N:19][N:18]=[N:17]1
Reactant: c1ccc(CN2CC3CCC(C2)C3n2cnnn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1nnnn1C1C2CCC1CNC2
Yield: 91.4 %

Procedure:
To a nitrogen flushed solution of the title compound from Step D (790 mg, 2.93 mmol) in methanol (10 ml) was added 10% Palladium on carbon (75 mg) and the resulting mixture stirred under a balloon of hydrogen for 2 h. The mixture was filtered through Celite® and the filtrate evaporated to give the title compound 480 mg (91%) as a clear oil. 1H NMR (CDCl3): 1.80 (m, 4H), 2.82 (m, 2H), 2.95 (dd, J 13.1 and 2.7 Hz, 2H), 3.03 (d, J 12.7 Hz, 2H), 4.55 (s, 1H), 8.62 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](O)=[O:16])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH3:27][N:28]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N+:38]([O-:40])=[O:39])(=[O:31])=[O:30]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:44]2[CH2:43][CH2:42][CH:41]([N:28]([CH3:27])[S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N+:38]([O-:40])=[O:39])(=[O:31])=[O:30])[CH2:46][CH2:45]2)=[O:16])=[CH:20][CH:21]=1
Reactant: CN(C1CCNCC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: Cl
Product: CN(C1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
Prepared according to EXAMPLE 231 from 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)-propionic acid (EXAMPLE 230) and N-methyl-2-nitro-N-piperidin-4-yl-benzenesulfonamide hydrochloride (Preparation 75). m/z (ES+)=643.36 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][NH:34][CH2:35]5)=[CH:30][CH:29]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][N:34]([CH2:39][CH2:40][OH:41])[CH2:35]4)=[CH:30][CH:29]=3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Nc1ncnn2c(Cc3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(Cc3ccc4c(c3)CN(CCO)CC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
5-(2-Benzyl-2H-indazol-6-yl)-7-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (200 mg, 0.41 mmol) was dissolved in DMF (4 mL) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (0.15 g, 0.62 mmol) was added followed by triethylamine (0.17 mL, 1.26 mmol) and sodium iodide (0.006 g, 0.004 mmol). The resulting mixture was stirred at 50° C. overnight. The mixture was concentrated, dried using a vacuum pump for 2 hours. The residue was dissolved in 2 mL dichloromethane and TFA (0.30 mL) was added and the resulting solution was stirred overnight, concentrated and purified by preparative HPLC to afford 32 mg (15%) of the title compound. 1H-NMR (CD3OD-d4) 8.36-8.33 (m, 1 H), 7.81 (s, 1 H), 7.76 (dd, 1H), 7.63-7.61 (m, 1 H), 7.38-7.29 (m, 5 H), 7.19 (dd, 1 H), 7.11-6.98 (m, 3 H), 6.46 (s, 1 H), 5.65 (s, 2 H), 4.24 (s, 2 H), 3.76 (t, 2 H), 3.67 (s, 2 H), 2.93-2.79 (m, 4 H), 2.69 (t, 2 H); LC-MS [M+H]+=530.3, RT=2.36 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[C:11]([F:17])[CH:10]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](Cl)=[O:39])[C:33]2=[O:41])=[CH:28][CH:27]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:38]([C:34]2[C:33](=[O:41])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[CH:37]=[CH:36][CH:35]=2)=[O:39])=[C:11]([F:17])[CH:10]=1
Reactant: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1cc(F)c(Oc2ccncc2Br)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)c(Oc2ccncc2Br)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of Example A2 (0.100 g, 0.332 mmol) in THF (1 mL) was treated with triethylamine (0.069 ml, 0.498 mmol) and a suspension of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (0.125 g, 0.498 mmol) in THF (2 mL). The mixture was blanketed with argon and stirred overnight at room temperature. The solids were removed via filtration, rinsed with THF and the filtrate was concentrated to dryness. The crude material was purified by silica gel chromatography (10-100% EtOAc/Hex) to afford N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (122 mg, 71% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H); 8.74 (s, 1H); 8.58 (m, 2H); 8.38 (d, J=5.6 Hz, 1H); 8.15 (dd, J=6.6, 2.2 Hz, 1H); 7.67 (dd, J=11.0, 7.3 Hz, 1H); 7.60 (dd, J=8.8, 4.9 Hz, 2H); 7.41 (t, J=8.7 Hz, 2H); 6.89 (d, J=5.6 Hz, 1H); 6.74 (t, J=7.0 Hz, 1H); MS (ESI) m/z: 516.0, 518.0 (M+H+).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][CH2:14][OH:15]>CS(C)=O.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1
Reactant: OCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OCCCOc1ccc(Br)cc1
Reaction time: 2.5 h

Procedure:
Powdered sodium hydroxide (2.2 g) was added to a solution of 4-bromophenol (3.46 g) and 3-bromopropanol (2.36 ml) in DMSO (18 ml). The mixture was stirred vigorously at 20° for 2.5 h then diluted with ethyl acetate (100 ml) and washed successively with 2N hydrochloric acid (100 ml), water (100 ml×2) and brine. Concentration of the dried organic phase yielded the title compound (5.02 g) as a pale orange oil. T.l.c. (diethyl ether) Rf 0.32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:16][CH2:15][C:14](=[CH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)C=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 72.2 %

Procedure:
The product of Example 94 (150 mg, 0.32 mmol) in tetrahydrofuran (20 mL) at −40° C. was treated dropwise with L-Selectride™ (1M solution in tetrahydrofuran, 0.5 mL, 0.5 mmol). The reaction was stirred at −40° C. for 90 minutes, then quenched by the addition of ethanol (4 drops) then water (10 mL). The mixture was extracted into ethyl acetate (2×50 mL) and the combined organics washed with brine (50 mL), dried (MgSO4) and evaporated to leave a residue which was purified by flash column chromatography on silica eluting with diethyl ether:dichloromethane:iso-hexane 1:2:1, to afford the desired product (107 mg).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH3:46][C:38]1([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:10]([C:7]4[N:8]=[N:9][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:29]=3)[C:33]2=[O:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CCSc1ccc(C(=O)O)nn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A stirred mixture of 6-ethylsulfanyl-pyridazine-3-carboxylic acid (0.37 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-Aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 3 h, the product was isolated by filtration, washed with water (10 mL) and dried in vacuo to give 6-ethylsulfanyl-pyridazine-3-carboxylic acid [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]amide as a white solid (0.76 g, 81% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 5.24 min (95.32%); mp: 160-162° C.; 1H NMR (DMSO-d6) δ 1.38 (t, J=7.3 Hz, 3H, CH3), 1.88 (s, 3H, CH3), 1.95-2.14 (m, 1H, CHH), 2.52-2.61 (m, 2H, CHH, CHH), 2.61-2.79 (m, 1H, CHH), 3.24-3.43 (m, 2H, CH2), 4.66 (d, J=6.2 Hz, 2H, CH2), 7.74-7.87 (m, 4H, Ar), 7.96 (d, J=8.9 Hz, 1H, Ar), 9.97 (t, J=6.2 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 12.67, 19.51, 22.51, 27.07, 27.60, 40.92, 57.25, 120.31, 121.67, 123.40, 125.41, 128.17, 129.87, 132.06, 145.52, 148.23, 161.45, 163.51, 166.22, 166.37, 170.65, 170.71; LCMS: MH=468; Anal Calcd for C22H21N5O5S+0.2H2O: C, 56.09; H, 4.58; N, 14.87. Found: C, 55.86; H, 4.59; N, 14.72.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.Br[CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].O>CN(C=O)C>[Si:33]([O:32][CH2:31][CH2:30][NH:2][C@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4N)s2)cc1C#N
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NCCO[Si](C)(C)C(C)(C)C)s2)cc1C#N
Temperature: 95 °C
Reaction time: 12 h
Yield: 15.6 %

Procedure:
Prepared using General Procedure 9. To a suspension of (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 5 (50 mg, 0.12 mmol) in anhydrous DMF (5 mL) was added TEA (36.7 mg, 0.36 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (34.6 mg, 0.14 mmol). The solution was stirred at 95° C. After 16 h more (2-bromoethoxy)(tert-butyl)dimethylsilane (34.6 mg, 0.14 mmol) was added and heating continued for 12 h. Water (5 mL) was added and the reaction mixture was extracted with EA (2×5 mL). The organic layers were washed with brine, dried, and purified by column chromatography (EA/hexanes) to afford 10 mg (15%) of (R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile. LCMS-ESI (m/z) calculated for: C29H38N4O2SSi: 534.3; found 535.3 [M+H]+, tR=3.08 min.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1.O1CCOCC1>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cn1cnc2ccccc21
Yield: 94.7 %

Procedure:
A solution of potassium tert-butoxide (0.6 mmol) in THF (0.6 mL) was added to a solution of 1H-benzoimidazole (71 mg, 0.6 mmol) in dioxane (15 mL) under stirring. tert-Butyl bromoacetate (97 mg, 0.5 mmol) was added to the white suspension and the mixture was stirred overnight at ambient temperature. The solvents were removed in vacuum and the product was purified on a silica gel column using a gradient of ethyl acetate in heptane) to afford benzimidazol-1-yl-acetic acid tert-butyl ester (110 mg, 95%). Mass spectrum (ESI) m/z: 233.0. 1H NMR (400 MHz, MeOD) δ ppm 1.5 (s, 9 H), 5.0 (s, 2 H), 7.3 (m, 2H), 7.4 (d, J=7.1 Hz, 1H), 7.7 (d, J=6.6 Hz, 1H), 8.1 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH2:20]1>CS(C)=O>[CH2:34]1[O:33][C:30]2[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][N:21]3[CH2:22][CH2:23][CH2:24][C@H:20]3[CH2:19][N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)=[CH:28][C:29]=2[O:35]1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: Cl[C@@H]1CCCN(CCc2ccc3c(c2)OCO3)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)COc1ccccc1N2C[C@@H]1CCCN1CCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
Sixty-percent sodium hydride (0.11 g, 2.8 mmols) was washed with petroleum ether, and then suspended in 10 ml of dimethyl sulfoxide. To the suspension were added 450 mg (2.3 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 0.56 g (2.1 mmols) of (R)-(−)-3-chloro-1-(3,4-methylenedioxyphenethyl) piperidine[[α]D25=−11.9° (c=1.0, ethanol)] in 5 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 12 hours and at 40° C. for 4 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:5. This mixed solvent was distilled off under reduced pressure. Further, the thus-obtained residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform and methanol at a ratio of 200:1. This mixed solvent was then distilled off under reduced pressure to give 0.46 g of (S)-(−)-5,11-dihydro-5-[1-(3,4-methylenedioxyphenethyl)-2-pyrrolidinyl-methyl]dibenzo [b,e][1,4]oxazepine as a pale yellow oil in a yield of 51%.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH:2]=[CH2:3].C(NC1C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1)(=O)C.N12CCCN=C1CCCCC2.[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:4][C:5](=[O:15])[C:6](=[N+:29]=[N-:30])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Cc1ccc(F)c(F)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOC(=O)C(=[N+]=[N-])c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
(3,4-Difluoro-phenyl)acetic acid allyl ester (64 g) was dissolved in acetonitrile (400 mL) and 4-acetamidobenzenesulfonyl azide (p-ABSA, 87 g, 0.36 mol) was added and the mixture stirred at room temperature for 15 min. The mixture was then cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 58.6 mL) was added dropwise at 0° C. during 30 min. The mixture was allowed to warm up to rt (room temperature) and stirred at rt for 4-20 h (until TLC showed completion of reaction). Saturated ammonium chloride (500 mL) was added and the organic phase was separated from the water phase. The water phase was extracted with diethylether (3×200 mL) and the four combined organic phases were dried (Magnesium sulphate) and evaporated in vacuo. The resulting solid was extracted with a 50:50 mixture of diethylether/pentane (3×200 mL). The combined ether phases were evaporated in vacuo (keep temperature below 40°) and purified by flash column chromatography (silicagel, eluent: 10:90 mixture of diethylether/pentane). The yellow fractions were combined and evaporated in vacuo (keep temperature below 40°) to give 70 g diazo-(3,4-Difluoro-phenyl)acetic acid allyl ester.