Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[NH2:22].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:22]/[C:15]1[C:14]([Cl:13])=[CH:19][C:18]([F:20])=[CH:17][C:16]=1[Cl:21])=[N+:2]=[N-:3]
Reactant: Nc1c(Cl)cc(F)cc1Cl
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 4-azido-5-fluoro-pyridine-3-carbaldehyde (2.44 g, 14.7 mmol), 2,6-dichloro-4-fluorophenylamine (2.65 g, 14.7 mmol) and triethylamine (6.1 mL, 44 mmol) in DCM (50 mL) was added titanium tetrachloride (1M in DCM, 8.8 mL, 8.8 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour, warmed to room temperature, and stirred for a further 4 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in toluene and filtered through Celite®. The filtrate was concentrated under to dryness under reduced pressure to afford the title compound that was used without further purification.
Reaction SMILES: [I-].C[S+](C)C.[CH3:6]C(C)([O-])C.[K+].[C:12]([O:16][C:17]([CH:19]=[C:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(OCC)(=O)C>CS(C)=O>[CH2:33]([O:32][C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:23]2[CH2:24][CH2:25][C:20]3([CH:19]([C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:18])[CH2:6]3)[CH2:21][CH2:22]2)=[CH:36][CH:35]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)c1ccc(C2CCC(=CC(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C2CCC3(CC2)CC3C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 7.6 %

Procedure:
5.11 g of trimethylsulfonium iodide (23.23 mmol, 4 eq.) are dissolved with stirring in 20 mL of DMSO in a 250 mL three-necked flask under a nitrogen atmosphere. 2.61 g of potassium tert-butoxide (23.23 mmol, 4 eq.) are added and the reaction medium is stirred for 3 hours. 2 g of ethyl 4-(4-tert-butoxycarbonylmethylenecyclohexyl)benzoate dissolved in 5 mL of DMSO are added and stirring is continued for 2 days. 2.56 g of trimethylsulfonium iodide (11.61 mmol, 2 eq.) are dissolved in 20 mL of DMSO in a 25 mL three-necked flask under a nitrogen atmosphere, and 1.0 g of potassium tert-butoxide (11.61 mmol, 2 eq.) is added with stirring. After 3 hours, this reaction medium is added to the 250 mL three-necked flask and stirring is continued for 18 hours. Ethyl acetate is added. The organic phase is washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate and filtered. The residue is chromatographed on silica gel with a gradient of ethyl acetate in heptane ranging from 10% to 50%. 0.159 g of tert-butyl 6-(4-ethoxycarbonylphenyl)spiro[2.5]octane-1-carboxylate is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]#N)=[CH:16][CH:15]=1.C([O:28][C:29](=O)[C@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:31])(=O)C>>[OH:31][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([N:11]([C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:21][CH2:20][C:17]1[CH:18]=[N:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=1)=[O:28]
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Reactant: Nc1cnc2ccccc2c1
Product: O=C([C@@H](O)c1ccccc1)N(CCc1ccc(C(F)(F)F)nc1)c1cnc2ccccc2c1

Procedure:
In analogy to example 47 (step 2) and example 48 (steps 3 & 4), Quinolin-3-ylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled and hydrolysed to give the target compound. MS(m/e): 452.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=5)[CH2:29][CH2:30]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-pyridin-2-yl-piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=449.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][NH:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1>>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:17]1[CH2:18][CH2:19][C@H:15]([NH:14][CH3:13])[CH2:16]1
Reactant: CN[C@H]1CCNC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Product: CN[C@H]1CCN(c2ccc([N+](=O)[O-])cc2OC)C1
Temperature: 130 °C

Procedure:
A mixture of 1-chloro-2-methoxy-4-nitrobenzene (200 mg, 1.066 mmol) and (S)—N-methylpyrrolidin-3-amine (153 mg, 1.528 mmol) was heated at 130° C. in a sealed tube for 5 h. After cooling down to room temperature, the obtained black solid product (Example 41A) was used for next step without further purification. LCMS (ES): m/z 252.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH:22]=1)[CH:20]=[O:21]>CS(C)=O.O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[C:19]([CH:22]=1)[CH:20]=[O:21]
Reactant: CC1CCCCN1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1CCCCN1c1ccc(Br)cc1C=O
Temperature: 120 °C
Yield: 88.9 %

Procedure:
2-Methylpiperidine (15.4 mL, 130.0 mmol) and anhydrous sodium carbonate (13.8 g, 130.0 mmol) were added into a solution of 5-bromo-2-fluorobenzaldehyde (13.2 g, 65.0 mmol) in DMSO (160 mL) and water (40 mL). The resulting mixture was heated at 120° C. for 16 hours. The reaction mixture was diluted with water (1 L) and extracted with Et2O (2×750 mL). The organic layers were washed with brine (500 mL, pH 5-6 adjusted with a 5N aqueous solution of HCl), combined and dried (MgSO4). The solvents were removed under reduced pressure to give the title compound as a brown yellow oil (16.3 g, 89%) used without further purification in the next step. HPLC (Method A), Rt 2.20 min (purity: 93.7%). HPLC/MS, M+(ESI): 282.1, 284.1. 1H NMR (CDCl3, 300 MHz) δ 10.40 (s, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.62 (dd, J=8.6, 2.5 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 3.17 (m, 1H), 3.06 (m, 1H), 2.81 (ddd, J=11.7, 7.6, 3.9 Hz, 1H), 1.89 (m, 1H), 1.83-1.65 (m, 3H), 1.58-1.42 (m, 2H), 0.91 (d, J=6.3 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].[CH:10]1[CH:11]=[CH:12][C:13]2N(O)N=N[C:14]=2[CH:15]=1.C(N(CC)CC)C.[C:27]([O:31][C:32](=[O:36])[C@H:33]([CH3:35])[NH2:34])([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[CH2:27]([O:31][C:32]([NH:1][C@H:2]([C:7]([NH:34][C@H:33]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:36])[CH3:35])=[O:9])[CH2:3][CH2:4][S:5][CH3:6])=[O:36])[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:15]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 109.3 %

Procedure:
Z-Protected L-methionine (10 g) was dissolved in DMF (200 ml) and 1-[3-(dimethylamino)propyol]-3-ethylcarbodiimide hydrochloride (8.13 g) was added followed by HOBT (5.72 g) and triethylamine (19.7 ml). The mixture was stirred for 1 h then L-alanine tert-butyl ester (7.7 g) was added and stirring continued for 18 h. The mixture was concentrated under reduced pressure and partitioned between diethyl ether and water. The separated organic phase was washed with hydrochloric acid (1M), saturated sodium bicarbonate solution and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (11.9 g) as an orange oil which crystallised on standing.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[N:13]1[N:17]=[C:16]([C:18](O)=[O:19])[C:15]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:14]1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].ON1C2C=CC=CC=2N=N1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:37]=[CH:38][CH:39]=[C:30]([NH:29][C:18]([C:16]2[C:15]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:14][N:13]([C:7]3[C:6]([Cl:5])=[CH:11][CH:10]=[CH:9][C:8]=3[Cl:12])[N:17]=2)=[O:19])[CH:31]=1
Reactant: O=C(O)c1nn(-c2c(Cl)cccc2Cl)nc1COc1ccccc1
Reactant: COC(=O)c1cccc(N)c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(NC(=O)c2nn(-c3c(Cl)cccc3Cl)nc2COc2ccccc2)c1
Reaction time: 72 h
Yield: 62.3 %

Procedure:
EDC (869 mg, 4.53 mmol) was added to a stirred solution of the product from step c (1.10 g, 3.02 mmol), methyl 3-aminobenzoate (685 mg, 4.53 mmol), N-hydoxybenzotriazole (612 mg, 4.53 mmol) and 4-DMAP (cat) in DMF (10 ml). The solution was stirred for 72 h and then diluted with ethyl acetate (40 mL). The solution was washed sequentially with water (40 mL) and twice with brine (40 mL). The organic phase was dried (MgSO4) and the filtrate was evaporated at reduced pressure. The residue was purified by flash column chromatography (100% DCM) to yield the title compound (935 mg, 62%). 1H NMR (CDCl3) 8.71 (1H, br s), 8.21-8.20 (1H, t, J=1.8 Hz), 8.05-8.02 (1H, m), 7.86-7.83 (1H, m), 7.54-7.43 (4H, m), 7.31-7.26 (2H, m), 7.11-7.07 (2H, m), 7.00-6.97 (1H, m), 5.65 (2H, s), 3.92 (3H, s).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6]1([SH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH:13][CH2:14][CH2:15][O:16][C:17]1[CH:28]=[CH:27][C:20]([CH:21]=[C:22]([C:25]#[N:26])[C:23]#[N:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[NH2:4][C:3]1[C:2]([C:1]#[N:5])=[C:21]([C:20]2[CH:27]=[CH:28][C:17]([O:16][CH2:15][CH2:14][OH:13])=[CH:18][CH:19]=2)[C:22]([C:25]#[N:26])=[C:23]([S:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:24]=1
Reactant: Sc1ccccc1
Reactant: N#CCC#N
Reactant: N#CC(C#N)=Cc1ccc(OCCO)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(OCCO)cc1

Procedure:
0.765 g (11.6 mmol) of malononitrile, 1.28 g (11.6 mmol) of thiophenol and 2.48 g (11.6 mmol) of 2-[4-(2-hydroxyethoxy)benzylidene]malononitrile [preparation according to WO 03/053441, Example 6/Method 2, Step 1] are dissolved in 15 ml of ethanol, and 0.03 ml of triethylamine is added. The mixture is stirred under reflux for 2 h. After cooling, the reaction mixture is filtered and the residue is washed with ethanol and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][N:4]=1.[CH3:11][N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CCOC(C)=O>[NH3:4].[CH3:15][CH2:14][O:17][C:3]([CH3:7])=[O:2].[CH3:1][O:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]([C@H:14]2[CH2:15][CH2:16][N:12]([CH3:11])[CH2:13]2)[N:4]=1
Reactant: CN1CC[C@@H](O)C1
Reactant: COc1n[nH]cc1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nn([C@H]2CCN(C)C2)cc1[N+](=O)[O-]
Product: N
Reaction time: 18 h
Yield: 150.9 %

Procedure:
To a suspension of 3-methoxy-4-nitro-1H-pyrazole (2.00 g, 14.0 mmol, 1.00 eq), (R)-1-methyl-pyrrolidin-3-ol (1.56 g, 15.4 mmol, 1.10 eq), and polystyrene bound triphenylphosphine (6.53 g, 19.6 mmol, 1.40 eq, 3 mmol/gram) in THF (140 mL) was added a solution of di-tert-butyl azodicarboxylate (4.51 g, 19.6 mmol, 1.40 eq) in THF (25 mL) in a drop-wise manner over 5 min. The reaction mixture was allowed to stir for 18 hr. The reaction mixture was then diluted with EtOAc (100 mL), filtered and the filtrate concentrated. The crude reaction mixture was purified via flash chromatography on silica gel eluting with a gradient of 50-100% EtOAc in heptane then to 10% 7 N methanolic ammonia/EtOAc to give the title compound (2.39 g, 80% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (s, 1H), 4.84-4.72 (m, 1H), 3.94 (s, 3H), 2.86-2.75 (m, 2H), 2.72 (dd, J=7.0, 10.0 Hz, 1H), 2.40 (dt, J=6.2, 8.4 Hz, 1H), 2.36-2.29 (m, 1H), 2.28 (s, 3H), 2.16-2.06 (m, 1H). m/z (APCI+) for C9H15N4O3 227.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:44])[NH:13][CH2:14][C:15]([N:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]([C:28](=[O:36])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH:18]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:16])[CH:8]=[CH:9][CH:10]=1)=[O:4].O.CO>[OH-].[K+]>[C:40]([O:39][C:37]([CH:18]1[CH2:19][CH:20]([C:28](=[O:36])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]1[C:15](=[O:16])[CH2:14][NH:13][C:12](=[O:44])[NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([OH:4])=[O:2])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)Nc3ccccc3)C2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CC(C(=O)Nc2ccccc2)C(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 14.1 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 4 g of tert-butyl (2RS,4SR,5SR)-1-{2-[3-(3-(methoxycarbonyl)phenyl)ureido]acetyl}-5-phenyl-4-(phenylcarbamoyl)pyrrolidine-2-carboxylate in a mixture of 6.7 cm3 of a normal aqueous potassium hydroxide solution, 30 cm3 of distilled water and 120 cm3 of methanol. After treatment, there is obtained 0.55 g of (2RS,4SR,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-4-phenylcarbamoyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 160° C.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=[O:7].N.C(COC)OC>>[F:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[C:9]([NH2:1])=[O:10]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: N
Solvent: COCCOC
Product: NC(=O)c1c(F)cccc1C(=O)O
Reaction time: 0.67 h

Procedure:
A first solution of 3.32 parts of 3-fluorophthalic anhydride in 43 parts of dimethoxyethane was prepared. Separately, 86 parts of dimethoxyethane was added to a reaction vessel and ammonia was bubbled in to form a saturated solution of ammonia in dimethoxyethane. The ammonia addition was continued to maintain an excess while the 3-fluorophthalic anhydride solution was added to the ammonia/dimethoxyethane solution, slower with stirring over a 40 minute period. When all of the 3-fluorophthalic anhydride had been added, the ammonia addition was stopped and the reaction mixture was stirred for an additional five minute period to assure completion of the reaction. The dimethoxyethane was removed under reduced pressure. The remaining crude product was analyzed by C13 nuclear magnetic resonance 3-fluorophthalamic acid. A portion of the salt was dissolved in water, acidified, with concentrated hydrochloric acid to a pH of about 2.0, then cooled to form a white crystalline 3-fluorophthalamic acid having a melting point of 129°-132° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=2)[C:5](=[O:20])[CH2:4][CH2:3]1.[CH3:22][Si:23](C#C)([CH3:25])[CH3:24].[CH2:28](N(CC)CC)[CH3:29]>O1CCCC1.C(OCC)C.[Cu]I.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>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:10]=2)[C:5](=[O:20])[CH:4]([C:28]#[CH:29])[CH2:3]1
Reactant: CCN(CC)CC
Reactant: CC1(C)CCC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC1CC(C)(C)c2cc([Si](C)(C)C)ccc2C1=O
Temperature: 70 °C
Yield: 72 %

Procedure:
A solution of 4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 11, 0.46 g, 1.43 mmol) in triethyl amine (3 mL) and anhydrous tetrahydrofuran (8 mL) was treated with copper(I)iodide (0.1 g, 0.53 mmol) and sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.85 mL, 6 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (0.25 g, 0.36 mmol). The resulting reaction mixture was heated at 70° C. for 17 h. It was then cooled to ambient temperature, diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound (0.28 g, 72%).
Reaction SMILES: [CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[C:5]([C:11]([O:13][CH2:14][C@H:15]3[C@@H:17]([CH2:18][O:19][CH3:20])[C@@:16]3([CH3:33])[C:21]3[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[C:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:34].[CH2:35](OCC1[C@H](CO)C1(C)C1C=C(C(C)C)C=C(C(C)C)C=1)C.[CH2:57](I)C.CCOC(C)=O>CCCCCC>[CH3:1][C:2]12[C:8]([CH3:9])([CH3:10])[C:5]([C:11]([O:13][CH2:14][C@H:15]3[C@H:17]([CH2:18][O:19][CH2:20][CH3:35])[C@@:16]3([CH3:33])[C:21]3[CH:26]=[C:25]([CH:27]([CH3:28])[CH3:29])[CH:24]=[C:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:34].[CH3:1][C:2]12[C:8]([CH3:9])([CH3:10])[C:5]([C:11]([O:13][CH2:14][C@@H:15]3[C@@H:17]([CH2:18][O:19][CH2:20][CH3:57])[C@:16]3([CH3:33])[C:21]3[CH:26]=[C:25]([CH:27]([CH3:28])[CH3:29])[CH:24]=[C:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:34]
Reactant: CCI
Reactant: COC[C@@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Reactant: CCOCC1[C@H](CO)C1(C)c1cc(C(C)C)cc(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC[C@@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOC[C@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 43 %
Yield: 41 %

Procedure:
Following a procedure similar to that for the preparation of Intermediates 41 and 42 but using Intermediate 40b as the starting material, ethyl iodide as the alkylating reagent and using 10% EtOAc in hexane as normal phase HPLC eluent afforded Intermediate 43b (59 mg, 43% yield) and Intermediate 44b (56 mg, 41% yield) as colorless oils:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][NH:8][CH:9]=1)=[O:4].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CCOCC>[O:15]=[C:13]1[C:7]2[NH:8][CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=2[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1c[nH]cc1CCCC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1c[nH]c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
4-[4-(methoxycarbonyl)-1H-pyrrol-3-yl]butanoic acid (500 mg, 2.36 mmol) was dissolved in TFA (3 mL). TFAA (0.329 mL, 2.36 mmol) was added and the reaction was stirred at room temperature for 1 h. Organic solvent was evaportated to dryness and the residue suspended in Et2O (15 mL) and filrated to give 320 mg (yield: 64%) of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[S:22][C:21]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=4[CH:19]=3)[CH2:13][C:12]2=[O:28])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:29]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[S:22][C:21]5[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=5[CH:19]=4)[CH2:13][C:12]3=[O:28])=[CH:7][CH:6]=2)[NH:1][N:29]=1
Reactant: N#Cc1ccc(CN2CCN(Cc3cc4ccc(Cl)cc4s3)CC2=O)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2cc(CN3CCN(Cc4cc5ccc(Cl)cc5s4)CC3=O)ccc12
Yield: 38.2 %

Procedure:
To a cooled solution (0° C.) of 2-Amino-4-[4-(6-chloro-benzo[b]thiophen-2-ylmethyl)-2-oxo-piperazin-1-ylmethyl]-benzonitrile (0.365 g, 0.89 mmol) in concentrated HCl (2.1 ml) is added dropwise a solution of sodium nitrite (0.068 g, 0.98 mmol) in H2O (0.2 ml). The reaction mixture is added to a cooled solution (0° C.) of tin (II) chloride dihydrate (1.61 g, 7.12 mmol) in concentrated HCl (0.62 ml) and H2O (3 ml). The precipitate is collected by vacuum filtration and dried under high vacuum. The crude solid is purified by column chromatography eluting with 10% 7M NH3 in CH3OH/CH2Cl2 to yield the title compound (0.144 g, 0.34 mmol) as a yellow solid. 1H NMR (DMSO, 300 MHz) δ11.35 (bs, 1H), 8.05 (d, 1H), 7.78 (d, 1H), 7.64 (d, 1H), 7.37 (m, 2H), 7.08 (s, 1H), 6.78 (d, 1H), 5.75 (s, 1H), 5.40 (bs, 1H), 4.58 (s, 2H), 3.88 (s, 2H), 3.20 (m, 4H), 2.70 (bt, 2H). MS (ion spray): m/z 426 (M+H)+. Anal. cald. for C21H20N5OSCl;(H2O)0.25: C, 58.6; H, 4.8; N, 16.3. Found C, 58.6; H, 4.7; N, 15.9. M.P.=246-248° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]3[N:32]([CH3:33])[C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[N:29]=3)[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])=O)(C)(C)C>C(Cl)Cl.CCOCC>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[O:14])[CH2:16][CH2:17]2)=[CH:22][C:23]=1[C:28]1[N:32]([CH3:33])[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]=1
Reactant: Cn1c(-c2cc(N3CCN(C(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)ccc2F)nc2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(-c2cc(N3CCN(C(=O)[C@@H]4CCCN4)CC3)ccc2F)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of (S)-2-{-4-[4-fluoro-3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.05 g, 0.10 mmol) in DCM (0.5 mL) 2M HCl in Et2O (2.0 mL) was added and the resulting suspension was stirred at room temperature overnight. The reaction was concentrated under reduced pressure then water (4.0 mL) was added and the mixture was concentrated again to afford 0.04 g of the title compound as chlorhydrate salt (86%).