Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](OC)=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:6][CH:5]=1.O=P(Cl)(Cl)[Cl:25]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([Cl:25])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:6][CH:5]=1
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)cn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1-c1cc(Cl)c(C(=O)OC)cn1
Temperature: 80 °C

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-methoxy-nicotinic acid methyl ester (4.0 g, 13.4 mmol), DMF (10 mL) and POCl3 (10 mL) is heated at 80° C. overnight. The volatile material is removed in vacuo. Ice water, NaHCO3 and hexane (50 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with hexane (2×30 mL). The combined organic layer is washed with water, dried, and concentrated. The crude product is purified by silica gel chromatography (1% MeOH in CH2Cl2) to give 4-chloro-6-(2,6-diethyl-phenyl)-nicotinic acid methyl ester. 1H NMR (CDCl3) 9.12 (s, 1H), 7.40 (s, 1H), 7.30 (d, 1H), 7.15 (d, 2H), 4.00 (s, 3H), 2.30 (q, 4H), 1.05 (t, 6H).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:27][NH:26][CH2:25]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>>[CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:18])([F:19])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:25][N:26]([CH:40]3[CH2:41][CH2:42][CH:37]([C:34]4[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)[CH2:38][CH2:39]3)[CH2:27]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: COc1ccc(C2CCC(=O)CC2)cn1
Product: COc1ccc(C2CCC(N3CC(NC(=O)CNc4nn(C(=O)NC(C)C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid isopropylamide (as prepared in Example 90, Step A) and 4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[C:12]([NH:23][C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:11]=1>FC(F)(F)C(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:23][C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1NC(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2cc3ccccc3o2)ccc1C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-(benzofuran-2-yl)-2-(4-fluorobenzamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 52 mg of 4-(benzofuran-2-yl)-2-(4-fluorobenzamido)benzoic acid as while solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:28][C:29]1[N:34]=[C:33](Cl)[N:32]=[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]=1>C1COCC1>[Cl:28][C:29]1[N:30]=[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:32]=[C:33]([N:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:17]=3[C:18]3[C:10]2=[CH:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=3)[N:34]=1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Reactant: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc(-c2ccccc2)nc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
29.9 g (93.6 mmol) of 3,6-diphenyl-9H-carbazole are dissolved in 660 ml of THF under a protective-gas atmosphere, and 7.49 g of 60% NaH in mineral oil (187 mmol) are added. After 1 h at room temperature, a solution of 2,4-dichloro-6-phenyl-1,3,5-triazine (63.1 g, 279.3 mmol) in 300 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene and recrystallised from dichloromethane/isopropanol. The yield is 28.4 g (56 mmol, 60%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([C@@H:17]4[C@@H:22]5[CH2:23][C@@H:19]([CH2:20][CH2:21]5)[N:18]4C(OC(C)(C)C)=O)[NH:14][C:13]=3[CH:31]=2)[O:3]1.Cl.O1CCOCC1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([CH:49]([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CO>[CH3:50][CH:49]([CH3:51])[C@H:45]([NH:44][C:42](=[O:43])[O:41][CH3:40])[C:46](=[O:47])[N:18]1[C@H:17]([C:15]2[NH:14][C:13]3[CH:31]=[C:9]([B:4]4[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:32])([CH3:1])[O:3]4)[CH:10]=[CH:11][C:12]=3[N:16]=2)[C@@H:22]2[CH2:23][C@H:19]1[CH2:20][CH2:21]2
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1)C(C)C
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of (1R,3S,4S)-tert-butyl 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 2.3 mmol), methanol (10 mL), and 4M HCl in dioxane (11 mL, 44 mmol) was stirred at room temperature. The reaction was thoroughly concentrated after one hour. The resulting residue was dissolved in dimethylformamide (11.4 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (419 mg, 2.4 mmol) and HATU (909 mg, 2.4 mmol). Diisopropylethylamine (1.4 mL, 8.1 mmol) was added and the reaction was stirred at room temperature. After thirty minutes, the reaction was diluted with ethyl acetate. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield methyl (S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate (1.08 g, 95%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:4][CH2:3]1>C(O)C.[Pt]>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: COc1cc(N2CCCN(C)CC2)ccc1N
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 1-methyl-4-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (1.77 g, 6.67 mmol) in 15 mL of ethanol (with 1 mL DMF added to aid solubility) was added 5% platinum on carbon (200 mg) and subjected to a H2 balloon for 16 h. At this time the reaction mixture was filtered through celite and washed with methanol. Solvents were evaporated under reduced pressure to afford 4-(4-methylhexahydro-1H-1,4-diazepin-1-yl)-2-(methyloxy)aniline (1.46 g, 6.2 mmol, contains residual DMF). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (ddd, J=11.55, 6.05, 5.87 Hz, 2 H) 2.24 (s, 3 H) 2.39-2.47 (m, 2 H) 2.54-2.60 (m, 2 H) 3.28-3.36 (m, 2 H) 3.36-3.42 (m, 2H) 3.73 (s, 3 H) 3.93 (s, 2 H) 6.07 (dd, J=8.43, 2.66 Hz, 1 H) 6.23 (d, J=2.57 Hz, 1 H) 6.49 (d, J=8.43 Hz, 1 H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH:18][NH2:19]>C(Cl)Cl>[CH3:17][NH:18][NH:19][C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:16]
Reactant: CNN
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Solvent: ClCCl
Product: CNNC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Added a solution of N,N-dicyclohexylcarbodiimide (I M in CH2Cl2, 5 ml, 5 mmol) to a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (1 g, 4.36 mmol) and N-methyl hydrazine (0.3 g, 6.51 mmol) in CH2Cl2 (20 ml) then stirred for 1 hour. The precipitated solid was filtered, mother liquors were concentrated and residue purified by chromatography on silica gel eluting with 3% v/v MeOH/CH2Cl2 to yield (R)-tert-butyl 3-(2-methylhydrazinecarbonyl)piperidine-1-carboxylate as a white solid (0.85 g).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[CH:31][CH:30]=4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:42])[N:16]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].[NH4+].[Cl-]>CO.O.[Fe]>[NH2:1][CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[CH:33][CH:34]=4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:42])[N:16]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN1CCN(c2ccc(Nc3ncc4c(n3)-c3c(c(C(=O)N[C@H](CN=[N+]=[N-])c5ccccc5)nn3C)CC4)cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CN1CCN(c2ccc(Nc3ncc4c(n3)-c3c(c(C(=O)N[C@H](CN)c5ccccc5)nn3C)CC4)cc2)CC1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a solution of 129 mg (0.228 mmol) of N-[(1S)-2-azido-1-phenylethyl]-1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide in 16 mL of methanol, 65 mg (1.2 mmol) of NH4Cl dissolved in 3.2 mL of water and 39 mg of iron (0.7 mmol) were added and the mixture refluxed overnight. The suspension was cooled to room temperature and filtered. After removal of methanol, solid Na2CO3 was added portionwise to the aqueous phase up to pH 10 and the product was then extracted with dichloromethane. Flash chromatography of the crude (eluant dichloromethane/methanol 95/5) yielded 94 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH2:18]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:41]([O:40][C:38]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH:17]([CH2:16][O:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])[CH2:18]1)=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(OCC2CNc3ccccc3C2)c(NC(=O)OC(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OCC2Cc3ccccc3N(C(=O)OCc3ccccc3)C2)c(NC(=O)OC(C)(C)C)c1
Reaction time: 24 h

Procedure:
To a stirred solution of [5-Methyl-2-(1,2,3,4-tetrahydro-quinolin-3-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester. To a stirred solution of 2-N-Boc-amino-4-methylphenol (129 mg, 0.35 mmol) in CH2Cl2 (1.5 mL) at 0° C. under nitrogen was added DIEA (61 μL, 0.35 mmol) followed by benzyl chloroformate (50 μL, 0.35 mmol) and DMAP (4 mg, 0.035 mmol). After 24 hours, the reaction was diluted to 30 mL with CH2Cl2 and washed (2×30 mL) with 2N HCl and (2×30 mL) with saturated NaHCO3. The organics were dried (MgSO4), filtered and concentrated to a brown oil, which appeared to be a mixture of product and starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1)#[N:19].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:27][NH:26][C:24](=[O:25])[C:23]2[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:29][CH:28]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a pre-cooled (−30° C.) solution of (2R,3R)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoic acid (1.06 g, 4.16 mmol) and 4-cyanobenzohydrazide (671 mg, 4.16 mmol) in anhydrous THF (60 mL) was added 1-Hydroxybenzotriazole monohydrate (637 mg, 4.16 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (1.60 g, 8.32 mmol) at −30° C. followed by triethylamine (1.16 mL, 8.32 mmol). The reaction mixture warmed to room temperature and stirred for 16 h, then quenched with 5% aq. citric acid (150 mL). The solution was extracted with EtOAc (150 mL). The organic extract was washed with 5% aq. citric acid (2×75 nit), sat, aq, NaHCO3 (3×80 mL), H2O (2×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as an off white solid (1.65 g, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.11 (dm, 18.8 Hz, 2H), 7.94 (dm, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz, 1H), 6.96 (d, J=2.3 Hz, 1H), 6.85 (dd, 2.3, 8.8 Hz, 1H), 6.44 (d, 7.4 Hz, 1H), 4.21-4.11 (m, 2H), 1.35 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH:13]4[CH2:17][NH:16][CH2:15][CH:14]4[CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>CN1CCCC1=O>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH:13]4[CH2:17][N:16]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:15][CH:14]4[CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CNCC4C3)cc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CN(S(C)(=O)=O)CC4C3)cc12
Reaction time: 3 h

Procedure:
To a solution of Example 282A in 1-methyl-2-pyrrolidinone (2 mL) was added triethylamine (0.177 mL, 1.267 mmol) and methanesulfonyl chloride (0.033 mL, 0.422 mmol) and the mixture was stirred for 3 hours. The mixture was treated with water and stirred for 10 minutes and the precipitate was filtered, washed with water, and vacuum oven-dried. The solid was suspended in 1 mL methanol and treated with 1 mL 2M hydrogen chloride in ether. The suspension was diluted with 4 mL ether, stirred for 10 minutes, filtered, washed with ether, and vacuum oven-dried to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, Methanol-d4) δ 2.63-2.76 (m, 1H), 2.85 (s, 3H), 3.00-3.13 (m, 1H), 3.11-3.24 (m, 2H), 3.37-3.54 (m, 3H), 3.68-3.77 (m, 1H), 3.80 (s, 3H), 6.39-6.48 (m, 2H), 7.20-7.29 (m, 2H), 7.28-7.37 (m, 1H), 8.43 (d, J=3.9 Hz, 1H). MS (ESI+) m/z 446.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:17][NH:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH:22]=[CH:23][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O[K])(C)(C)C>CC(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:14]1([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([N:18]([CH3:17])[C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=4)[CH:22]=[CH:23][CH:24]=2)[N:7]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CNc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Reactant: O=C(Nc1nc2ccc(Br)nc2s1)C1CC1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: CN(c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 130 °C
Reaction time: 2.5 h
Yield: 15.9 %

Procedure:
To a suspension of N-(5-bromo[1,3]thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (298 mg, 1.00 mmol) in 2-methylpropan-2-ol (10 mL) were added N-[3-(methylamino)phenyl]-3-(trifluoromethyl)benzamide (306 mg, 1.04 mmol), tris(dibenzylideneacetone)dipalladium(0)(55.2 mg, 60.3 μmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-phos) (63.1 mg, 132 μmol) and t-butoxy potassium (283 mg, 2.52 mmol), and the mixture was stirred at 130° C. for 2.5 hr under microwave irradiation in a sealed tube. After the reaction solution was allowed to cool to room temperature, the insoluble material was filtered off, and washed with ethyl acetate, tetrahydrofuran and methanol. The filtrate and the washing solution were combined and diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride solution (100 mL×2), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→50/50), and further purified by reverse phase silica gel column chromatography (containing 0.1% TFA, water/acetonitrile=5/95→95/5), fractions containing the object product was concentrated, and the residue was dissolved in saturated aqueous sodium hydrogen carbonate solution. The aqueous solution was extracted with ethyl acetate (100 mL×2), the combined organic layer was dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was recrystallized from ethyl acetate and diisopropyl ether to give the title compound (81.2 mg, 16%) as colorless crystals.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:24]>O1CCOCC1>[ClH:24].[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH:3]=2)=[C:16]([CH3:23])[CH:17]=1
Reactant: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C2=CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
A solution of tert-butyl 4-hydroxy-4-(4-methoxy-2-methylphenyl)piperidine-1-carboxylate (2.3 g, 7.2 mmol) in 1,4-dioxane (20 mL) was chilled to 0° C. and treated with a solution of HCl in dioxane (4.0 M, 1.8 mL, 7.2 mmol). The reaction mixture was stirred at rt for 12 h, and then the solvents were evaporated to provide a crude compound which was triturated with diethyl ether to provide the desired product as a solid (1.2 g, 82%). LC/MS (Method P) RT=0.63 min. (M+H)+=204.0; 1H NMR (300 MHz, DMSO-d6) δ 9.51-9.09 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 6.79-6.71 (m, 2H), 5.52 (t, J=1.5 Hz, 1H), 3.73 (s, 3H), 3.67 (br. s., 2H), 3.26 (d, J=4.5 Hz, 2H), 2.45 (d, J=1.9 Hz, 2H), 2.25 (s, 3H)
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[C:28](O)(=[O:32])[CH2:29][CH2:30][CH3:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[C:28]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([CH2:14][O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=2[C:7]#[N:8])[CH2:16]1)(=[O:32])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC(=O)O
Reactant: N#Cc1c(OC[C@H]2CCCNC2)cccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of (S)-2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride (Example 1d, 9.8 g, 32.92 mmol) in CH2Cl2 (550 mL) and DMF (50 mL) was added triethylamine (9.2 mL, 65.84 mmol). After being stirred at room temperature for 5 min., a solution of butyric acid (3.33 mL, 36.21 mmol), EDCI (6.94 g, 36.21 mmol) and HOBt (4.89 g, 36.21 mmol) in DCM (50 mL) was added, and the reaction mixture was then stirred at room temperature overnight. The resulting mixture was diluted with CH2Cl2, washed with 0.5 N HCl, water, NaHCO3 and brine, dried over MgSO4, filtered and evaporated to give the crude product as a light brown gel, used as this in the next step. MS 332 (MH+).
Reaction SMILES: C(NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:46]=[C:47]3[C:51](=[CH:52][CH:53]=2)[C:50](=[O:54])[N:49]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([O:58]C)=[O:57])[CH2:48]3)=[CH:41][CH:40]=1)=[O:37]>>[F:33][C:34]1[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:35]=1[C:36]([NH:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:46]=[C:47]3[C:51](=[CH:52][CH:53]=2)[C:50](=[O:54])[N:49]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([OH:58])=[O:57])[CH2:48]3)=[CH:43][CH:44]=1)=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(F)cc4F)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)c4ccccc4)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)c4ccc(F)cc4F)cc3)ccc2C1=O
Yield: 87 %

Procedure:
The compound of example 317 was prepared analogous to compound of example 305 by hydrolysis of compound of example 316.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:17][C:16](=[O:18])[N:15]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Br:21])[CH:23]=3)[CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cccc(Br)c1)C(=O)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
Sodium hydride (246 mg, 60% dispersion in mineral oil, weight percent) was suspended under a nitrogen atmosphere in DMF (15 mL). Compound A3 (1.5 g, 5.85 mmol) was added thereto and the reaction mixture was stirred for 10 min at RT. 3-Bromobenzyl bromide (1.48 g, 5.91 mmol) was added thereto. The reaction mixture was stirred for 18 h at RT, combined with water and extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was dissolved in a mixture of ether and heptane. After removal of the ether, the desired product 3-(3-bromobenzyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A6) (2.33 g, 93% of theoretical) was obtained as a white solid by filtration.