Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:11].[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]>C1COCC1.[Zn]>[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24]([C:2]3[C:10]4[C:5](=[CH:6][N:7]=[CH:8][CH:9]=4)[S:4][C:3]=3[CH3:11])=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: Cc1sc2cnccc2c1Br
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4cnccc34)c(C)nc12
Temperature: 100 °C
Yield: 15.4 %

Procedure:
190 mg of 3-Bromo-2-methyl-thieno[2,3-c]pyridine (0.83 mmol) is placed into the vial with 1.78 ml of Reiki Zn, suspension in THF (1.25 mmol) and capped and heated at 100° C. for 2 h. The excess Zinc is allowed to settle down and the solution is transferred to the vial containing 172 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.5 mmol) and 24 mg of PdCl2(pddf) (0.03 mmol) in 3 ml of dry THF. The vial is capped with a Teflon cap and heated at 80° C. overnight. The reaction mixture is quenched with sat. NH4Cl, extracted with CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:5:1) to give 28 mg of the title compound. Yield 15%. mass spectrum (m/e): 365 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([F:23])[C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:27][C@@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.C(O)C>[F:23][C:13]1[C:12]([CH3:24])=[C:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:26][CH:25]=2)[CH:20]=[C:15]2[C:14]=1[CH2:21][N:27]([C@@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]1)[C:16]2=[O:17]
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1F)CN([C@H]1COCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.2 %

Procedure:
A mixture of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-formyl-4-methylbenzoate (7.97 g), (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (2.65 g), anhydrous magnesium sulfate (5.23 g) and THF (160 mL) was stirred at room temperature for 5 hr under nitrogen atmosphere. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was dissolved in a mixed solvent of methanol (120 mL)-THF (150 mL), sodium triacetoxyborohydride (9.59 g) was added thereto, and the mixture was stirred at room temperature for 15 hr. Sodium triacetoxyborohydride (9.59 g) was again added thereto, and the mixture was stirred for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMSO-toluene, and the solution was purified by NH silica gel column chromatography (ethyl acetate/hexane). The obtained crude product was dissolved in THF, the solution was washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was washed with a mixed solvent of diisopropyl ether-ethyl acetate to give a crude product. The crude product (5.28 g) was dissolved in hot ethanol (60 mL), and recrystallized over 4 hr under ice-cooling to give the title compound (4.88 g).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].[CH3:31][N:32]([CH3:37])[C:33](=[O:36])[CH2:34]Cl>C(Cl)Cl.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[C:17]4[CH:20]=[CH:21][C:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH2:34][C:33]([N:32]([CH3:37])[CH3:31])=[O:36])[CH2:26][CH2:25]5)=[CH:23][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: CN(C)C(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(CC(=O)N(C)C)CC4)cc2OCC3)n(C(C)C)n1
Yield: 37.5 %

Procedure:
A suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (310 mg, 0.72 mmol) in DCM (6 mL) and TEA (0.3 mL, 2.16 mmol) was sonicated and stirred before adding N,N-dimethyl-2-chloroacetamide (98 mg, 0.8 mmol) and TBAI (28 mg, 0.072 mmol) and the reaction mixture stirred for 72 h at RT before being concentrated in vacuo. The resultant residue was partitioned between water and DCM and the aqueous extracted five times with DCM, the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) then triturated in diethyl ether to give 329 as a white solid (129 mg, 38%). LCMS: RT=2.71 min, [M+H]+=478. 1H NMR 400 MHz (CDCl3) δ: 8.44 (1H, d, J=8.30 Hz), 7.61 (1H, s), 7.04 (1H, d, J=8.43 Hz), 6.91 (1H, s), 5.91 (1H, t, J=6.63 Hz), 4.45 (4H, d, J=14.92 Hz), 3.39 (2H, m), 3.11 (2H, m), 3.10 (3H, s), 2.99 (1H, m), 2.98 (3H, s), 2.54 (2H, m), 2.41 (3H, s), 1.90 (4H, s), 1.57 (6H, d, J=6.65 Hz)
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([O:4][C:5]1[C:6]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1N(C)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)Oc1ccc(N)cc1N(C)C(C)C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A suspension of 2-isopropoxy-N-isopropyl-N-methyl-5-nitrobenzenamine 3 (300 mg, 1.19 mmol, 1 equiv) in ethanol (3 mL) was charged with 10% Pd/C (50% water, 253 mg, 0.119 mmol, 0.10 equiv) and air was evacuated with vacuum. The vacuum was replaced with a balloon filled with hydrogen gas, and the reaction was allowed to stir for 2 hours. The catalyst was filtered off using a pad of celite and rinsed with ethanol. The filtrate was concentrated to give 6-isopropoxy-N1-isopropyl-N1-methylbenzene-1,3-diamine 5 (264 mg, 100%) as a solid which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:6](O)([CH3:12])[CH2:7][CH2:8][CH2:9][C:10]#[N:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.C1(C(C)CCCC#N)CCCC=1>C(O)(=O)C.CC(OC)(C)C>[C:1]1(=[C:6]([CH3:12])[CH2:7][CH2:8][CH2:9][C:10]#[N:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)(CCCC#N)C1CCCC1
Agent: CC(CCCC#N)C1=CCCC1
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: CC(CCCC#N)=C1CCCC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
Crude 5-cyclopentyl-5-hydroxyhexanenitrile (18 g; 0.1 mol) from example 13(a) was added into a solution of sulphuric acid (15 ml) in acetic acid (150 ml). The reaction mixture was stirred at 5° C. for 1 hour, then poured into ice (100 g), diluted with MTBE (100 ml), washed with saturated sodium bicarbonate solution (5×300 ml) and brine (2×300 ml), dried (MgSO4), concentrated in vacuo, and bulb-to-bulb distilled to give 2.1 g (13% yield) of 5-cyclopentylidene-hexanenitrile and 5-(cyclopent-1-enyl)-hexanenitrile mixture (GC: 43+57%).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11][C:10]=1[C:29]([O:31][CH3:32])=[O:30])C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11][C:10]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-(benzyloxy)-7-(4-methoxybenzylamino)isoquinoline-3-carboxylate (200.0 mg, 0.47 mmol) in EtOAc (21 mL) was added a suspension of Pd/C (171.3 mg, 0.16 mmol, 10% by weight) in EtOH (21 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The resulting suspension was filtered through a pad of celite. The filtrate was concentrated in vacuo and then purified by flash chromatography (0-30% EtOAc/CH2Cl2) to give the title compound in 120.0 mg. 1H NMR (CDCl3, 200 MHz): δ=11.63 (s, 1H), 8.51 (s, 1H), 8.13 (d, 1H, J=9.0 Hz), 7.30 (d, 2H, J=6.6 Hz), 7.06 (d, 1H, J=9.0 Hz), 6.94-6.82 (m, 3H), 4.39 (s, 2H), 4.04 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH:13]1[CH2:15][CH2:14]1)[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19].[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>N1C=CC=C(C)C=1>[CH:13]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([Cl:1])=[C:11]([N:26]4[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH2:20][CH3:21])[CH2:25]4)[CH:10]=3)[C:5](=[O:19])[C:6]([C:16]([OH:18])=[O:17])=[CH:7]2)[CH2:15][CH2:14]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(Cl)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: Cc1cccnc1
Product: CCNCC1CCN(c2cc3c(cc2Cl)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A solution of 0.30 g (1.0 mmole) of 6,7-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.26 g (2.0 mol) of N-ethyl-3-pyrrolidinemethanamine and 10 ml of 3-picoline was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature and the solid filtered off and washed with acetonitrile to give 0.33 g of the title compound, mp >310° C.
Reaction SMILES: CN1CCN=C1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Br:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.[CH3:35][N:36]([N:38]=C1C=CC(N)=CC1)[CH3:37].C(Cl)CCl>CN(C=O)C.O>[CH3:35][N:36]([N:38]=[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Br:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH2:8]1)[CH3:37]
Reactant: CN(C)N=C1C=CC(N)=CC1
Reactant: CN1CCN=C1c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2Br)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2Br)=CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of 2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 77, 60 mg, 0.16 mmol) and 4-(dimethylaminoimino)phenylamine (51 mg, 0.31 mmol) in DMF (4 mL) and H2O (1 mL), EDC (120 mg, 0.62 mmol) was added. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (40 mg). MS 528.2 and 530.2 (M+H, Cl+Br pattern).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH:19]4[CH2:21][CH2:20]4)[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:28]([O:32][C:33](=[O:52])[N:34]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[C:45]([F:51])[N:44]=1)[C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)([CH3:31])([CH3:30])[CH3:29].O>O1CCCC1>[C:28]([O:32][C:33](=[O:52])[N:34]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([C:12]2[C:13]3[C:18]([CH:19]4[CH2:21][CH2:20]4)=[N:17][CH:16]=[N:15][C:14]=3[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:50])=[C:45]([F:51])[N:44]=1)[C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(C3CC3)ncnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: -5 °C
Yield: 90 %

Procedure:
To a solution of 7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (32, 0.760 g, 1.79 mmol) in 5.43 mL of tetrahydrofuran at −40° C. under nitrogen, isopropylmagnesium chloride (0.892 mL, 2.0 M in tetrahydrofuran, 1.78 mmol) is added slowly. The reaction is allowed to warm to −5° C. over 75 minutes, then cooled to −45° C. and (6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-yl)-carbamic acid tert-butyl ester (57, 0.38 g, 1.1 mmol) in 2.0 mL of tetrahydrofuran is added. The reaction is allowed to warm to room temperature over 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (75, 0.64 g). MS (ESI) [M+H+]+=647.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:13]([CH3:23])[N:12]=[C:11]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH2:10]2)=[CH:5][CH:4]=1.CS(C)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[C:13]([CH3:23])[N:12]=[C:11]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=C(C)N=C(N3CCN(c4ccccc4)CC3)CC2c2ccc(OC)cc2)cc1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(N3CCN(c4ccccc4)CC3)nc(C)c2-c2ccc(OC)cc2)cc1
Yield: 69 %

Procedure:
7 g (15 millimol) of 4,5-bis-(4-methoxyphenyl)-6-methyl-2-(4-phenylpiperazino)-3,4-dihydropyridine were suspended in 150 ml of analytically pure dimethylsulphoxide, whilst stirring, and 1.7 g (15 millimol) of potassium tert.-butylate were added to the suspension. The mixture was stirred in a closed vessel until a clear, orange-red coloration had formed. The reaction solution was then stirred in an open reaction flask for 1 hour. After the reaction solution had been neutralised with glacial acetic acid, the colourless precipitate which had separated out was filtered off under suction, washed with methanol and dried in vacuo to obtain 4,5-bis-(4-methoxyphenyl)-6-methyl-2-(4-phenylpiperazino)-pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH:14]=O)[N:10]=2)=[CH:5][CH:4]=1)#[N:2].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1>N1C=CC=CC=1>[C:18](/[CH:17]=[CH:14]/[C:11]1[N:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[O:13][N:12]=1)([OH:20])=[O:19]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1ccc(-c2nc(C=O)no2)cc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2nc(/C=C/C(=O)O)no2)cc1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A mixture of 5-(4-cyanophenyl)-3-formyl-1,2,4-oxadiazole (2.0 g), malonic acid (4.18 g) and piperidine (0.50 ml) in pyridine (20 ml) was refluxed for 1 hour. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate, acidified to pH 2.0 with 4N hydrochloric acid washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ethanol to give 3-{(E)-2-carboxyvinyl}-5-(4-cyanophenyl)-1,2,4-oxadiazole (1.2 g).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:32][N:14]3[CH2:15][CH2:16][N:17]([C:19](=[O:31])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3]>O1CCCC1.[Pd]>[CH:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:32][N:14]3[CH2:15][CH2:16][N:17]([C:19](=[O:31])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=4)[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(C(=O)Cc4cccc(C(F)(F)F)c4)CCN3C2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)c1cnc(O[C@@H]2C[C@H]3CN(C(=O)Cc4cccc(C(F)(F)F)c4)CCN3C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of the product from Example 152D (42 mg, 0.094 mmol) in tetrahydrofuran (4 mL) was added to 5% Pd/C (8.40 mg, 0.079 mmol) in a 50 mL pressure reactor, and the mixture was stirred for 30 minutes under hydrogen (30 psi) at ambient temperature. The mixture was filtered through a 0.45 micron filter, and the solvents were evaporated in vacuo to afford the title compound (41 mg, 97%). 1H NMR (300 MHz, CDCl3) 8 ppm 8.12 (s, 1H), 7.91 (d, J=1.3 Hz, 1H), 7.59-7.40 (m, 4H), 5.43-5.29 (m, 1H), 4.71 (dd, J=40.2, 12.7 Hz, 1H), 3.97-3.61 (m, 4H), 3.34-2.68 (m, 3H), 2.54-1.76 (m, 6H), 1.26 (dd, J=14.5, 8.8 Hz, 6H); MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:28])([CH3:27])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:35](Br)[CH:36]=[CH2:37].CC(N(C)C)=O>CCOCC>[C:1]([C:5]1[C:14]2[CH:13]=[C:12]([N:15]([CH2:37][CH:36]=[CH2:35])[C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:27])([CH3:28])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: C=CCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C
Temperature: 75 °C

Procedure:
A mixture of ethyl 4-(8-t-butyl-5,5-dimethyl-5,6-dihydronaphthalen-2-ylamino)-benzoate (Compound 84, 170 mg, 0.45 mmol), K2CO3 (900 mg), allyl bromide (1 mL) and dimethylacetamide (5 mL) was heated to 75° C. in a sealed tube for 7 days. The mixture was diluted with ether (70 mL), washed with brine, dried and the solvent was removed. Silica gel flash chromatography gave the title compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][C:20]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=2)([OH:24])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: COc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To a suspension of magnesium (7.8 g, 325 mmol) in THF (120 mL) at room temperature under a nitrogen atmosphere was added a solution of 3-bromoanisole (37.5 mL, 296 mmol) in THF (60 mL) over 10 min. The resulting mixture was stirred at 50° C. for 4 hours and was cooled to room temperature. To the mixture was added a solution an N-benzyl-3-piperidinone (30.0 g, 159 mmol) in THF (50 mL). The reaction was stirred at room for 10 hours. The mixture was poured slowly over ice-water (100 mL) and the aqueous layer was washed with EtOAc (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography with hexanes/EtOAc (3:1) to afford 38.4 g of 1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-ol 1HNMR (400 MHz, CDCl3) δ 7.31-7.20 (comp, 6H), 7.09 (s, 1H), 7.01 (d, 1H), 6.79 (d, 1H), 4.01-3.96 (br, 1H), 3.79 (s, 3H), 3.58 (s, 2H), 2.91 (d, 1H), 2.74 (d, 1H), 2.32 (d, 1H), 2.09-1.82 (comp, 2H), 1.81-1.61 (comp, 3H); MS (M+1) 298.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]12CC(C=C1)C=[CH:14]2.[O-]Cl.[Na+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH:14]=[CH:13][O:10][N:9]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C1=CC2C=CC1C2
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccon2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
4-Nitrobenzaldehyde oxime (Intermediate 3, 20 g, 120.5 mmol) and bicyclo[2.2.1]hepta-2,5-diene (32.45 ml, 3015.25 mmol) were added to THF (200 ml) followed by dropwise addition of bleach (6.15% NaOCl, 861.5 ml). The reaction was allowed to stir overnight and then the THF and H2O layers were separated, the THF layer was dried over Na2SO4 and then concentrated under vacuum. The dried material was added to dioxane and heated to 100° C. for 7 days. The crude material was purified by column chromatography using 5–50% EtOAc in hexanes to yield the final product (10 g).
Reaction SMILES: [N:1]1([C:7]([C:9]2[NH:13][N:12]=[C:11]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[S:20](=[O:23])(=[O:22])[CH2:21][C:10]=23)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(#N)C>[CH2:30]([N:12]1[C:11]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[S:20](=[O:22])(=[O:23])[CH2:21][C:10]=2[C:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])=[N:13]1)[CH3:31]
Reactant: O=C(c1[nH]nc2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1nc(C(=O)N2CCOCC2)c2c1-c1ccccc1S(=O)(=O)C2
Temperature: 60 °C

Procedure:
To a solution of 3-(morpholin-4-ylcarbonyl)-2,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (0.400 g, 1.2 mmol) in acetonitrile (10 mL) is added potassium carbonate (0.49 g, 3.6 mmol) followed by ethyl iodide (0.56 g, 3.6 mmol). The reaction mixture is heated at 60° C. overnight. The crude reaction mixture is filtered through a celite pad and the filtrate concentrated under reduced pressure. The residue is purified by preparative HPLC to afford the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.02 (d, J=7.72 Hz, 1H), 7.94 (d, J=7.84 Hz, 1H), 7.89 (t, J=7.52 Hz, 1H), 7.72 (t, J=7.64 Hz, 1H), 4.79 (s, 2H), 4.57 (q, J=7.12 Hz, 2H), 3.94 (brs, 2H), 3.66-3.63 (m, 6H), 1.46 (t, J=7.16 Hz, 3H). MS (ESI+): 362.0. HPLC (max plot) 95.0%; Rt 2.99 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([NH2:25])=[O:24]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[C:23]([NH2:25])=[O:24])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: NC(=O)[C@@H]1CCCN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 40 mg, 171 μmol) and (2S)-2-pyrrolidinecarboxamide (CAN 7531-52-4; 21.5 mg, 189 μmol) as starting materials and isolated (49 mg, 87%) as white solid; LC-MS (UV peak area, ESI) 100%, 330.1818 [MH+].
Reaction SMILES: B(OC)(OC)OC.COS(O)(=O)=O.C[C:15]([O:17][CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O>>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][O:17][CH3:15])[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -5 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
15.80 g of trimethyl borate were added to 17.9 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2). The mixture was cooled to -5° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at -5° C. for 5 hours. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2 to give 2.04 g (yield 83%) of the desired compound in a highly pure form.