Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]1>>[CH:7]([N:6]1[C:2]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15][CH2:14]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=[N:5]1)([CH3:9])[CH3:8]
Reactant: CC(C)n1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Product: CC(C)n1ncc([N+](=O)[O-])c1N1CCC(CNC(=O)OC(C)(C)C)CC1
Yield: 92 %

Procedure:
Reaction of 5-chloro-1-isopropyl-4-nitro-1H-pyrazole and tert-butyl piperidin-4-ylmethylcarbamate gave tert-butyl (1-(1-isopropyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a pale yellow solid (0.45 g, 92%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 4.78 (hep, J=6.7 Hz, 1H), 4.64 (s, 1H), 3.42-3.29 (m, 2H), 3.11 (t, J=6.6 Hz, 2H), 2.95-2.87 (m, 2H), 2.05 (s, 1H), 1.81 (d, J=12.8 Hz, 2H), 1.46 (s, 9H), 1.43 (d, J=6.7 Hz, 6H), 1.37 (dd, J=12.1, 4.3 Hz, 2H)
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:5]=1.[NH2:27][C:28]1[C:29]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=2)=[O:35])=[N:30][CH:31]=[CH:32][CH:33]=1>>[CH3:1][S:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:27][C:28]2[C:29]([C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=3)=[O:35])=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:10])=[C:6]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:5]=1
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: CSCc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Product: CSCc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 43 %

Procedure:
Using a procedure analogous to Example 1-G, 3-[4-(methylthiomethyl)-2-(1-t-butoxycarbonylpiperidin-4-yloxy)-benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a white solid (751 mg, 43%).
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:10]([C:20](=[O:38])[N:21]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH3:22])=[CH:9][N:8]=1)=O>C(OCC)C.C1(C)C=CC=CC=1>[F:32][C:30]([F:31])([F:33])[C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=1)[CH2:23][N:21]([CH3:22])[C:20](=[O:38])[C:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:12][C:7]([CH2:5][OH:4])=[N:8][CH:9]=1
Reactant: COC(=O)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(CO)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 73.4 %

Procedure:
To a solution of 9 mg (4 mmol) lithium borohydride in 0.5 ml diethyl ether was added a solution of 346 mg (0.678 mmol) 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridine-2-carboxylic acid methyl ester in 0.6 ml toluene. The mixture was gradually heated to 100° C., whereby diethyl ether was distilled off. After heating for 2 h at 100° C. the resulting suspension was concentrated. The residue was treated with 5 ml of a 1 M aqueous solution of hydrochloric acid for 5 min. Basification with potassium carbonate was followed by extraction with tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate and concentrated. Flash chromatography afforded 240 mg (73.4%) of the title compound as a light brown oil.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][NH:20][CH:21]1[CH2:23][CH2:22]1.C(N(CC)CC)C>O1CCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][N:20]([CH:21]1[CH2:22][CH2:23]1)[C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[F:1])=[O:10]
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: Clc1cc(-c2ccccc2)ccc1CNC1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(F)c1C(=O)N(Cc1ccc(-c2ccccc2)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
At ambient temperature, a solution of 226 mg (1.28 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 300 mg (1.164 mmol) of N-[(3-chlorobiphenyl-4-yl)methyl]cyclopropanamine and 0.18 ml of triethylamine in 5 ml tetrahydrofurane. The reaction mixture is stirred for 15 hrs at room temperature. The solvent is removed under vacuum and 10 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×50 ml) and the combined organic layers are successively washed by a 1M solution of HCl, a saturated solution of potassium carbonate and brine and filtered over a ChemElut cartridge to yield after concentration 350 mg (72% yield) of N-[(3-chlorobiphenyl-4-yl)methyl]-N-cyclopropyl-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide as a yellow oil (M+H=398).
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][S:8][CH2:7][CH2:6]1.C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:34][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[N:16]=[CH:15][C:14]([C:13]([N:5]4[CH2:10][CH2:9][S:8][CH2:7][CH2:6]4)=[O:12])=[CH:19][CH:18]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: C1CSCCN1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of thiomorpholine (124 mg, 120 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 4 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:3) afforded the title compound (124 mg, 100%) which was obtained as a light yellow gum. MS: m/e=414.4 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C@H:12]([OH:21])[CH2:13]/[CH:14]=[CH:15]\[CH2:16][Si](C)(C)C.C([O:26]O)(C)(C)C.COP(OC)OC>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C@H:12]([OH:21])[CH2:13][C@H:14]([OH:26])[CH:15]=[CH2:16]
Reactant: C[Si](C)(C)C/C=C\C[C@@H](O)CC#CCOC1CCCCO1
Reactant: CC(C)(C)OO
Agent: COP(OC)OC
Solvent: Cc1ccccc1
Product: C=C[C@@H](O)C[C@@H](O)CC#CCOC1CCCCO1
Reaction time: 1.5 h

Procedure:
17.83 g (57.4 mmol) of (Z)-(5R)-9-(tetrahydro-pyran-2-yloxy)-1-trimethylsilanyl-non-2-en-7-yn-5-ol was dissolved in 210 ml of abs. toluene. At -15°, 30.6 ml t-butyl-hydroperoxide (3 M, toluene) was added, followed by 761 mg (5 mol %) of vanadium-oxyacetylacetonate. The temperature was then rised within 16 h to 22°. TLC indicated the disappearance of starting olefin. While cooling in an ice bath, 13.5 ml (115 mmol) of trimethylphosphite was added in order to destroy the excess of hydroperoxide. 90 minutes later, a solution of 39.8 g of dry TBAF in 125 ml of THF was added and the reaction mixture kept for 90 minutes at RT. The homogeneous solution was then poured onto crushed ice, extracted with AcOEt, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=6/4) yielded 10.40 g of (3S,5S)-9-(tetrahydro-pyran-2-yloxy)-non-1-en-7-yne-3,5-diol as slightly yellow oil (1:1 epimeric mixture).
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([F:13])[CH:8]=2)[N:3]=1.[CH3:17][C:18]([CH3:21])([O-:20])[CH3:19].[K+].C1(C)C=CC=CC=1.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C>[C:18]([O:20][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9](=[CH:8][C:7]([F:13])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=2)[N:10]=1)([CH3:21])([CH3:19])[CH3:17]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cc2nc(Cl)c(Cl)nc2cc1F
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1nc2cc(F)c([N+](=O)[O-])cc2nc1Cl
Yield: 69.9 %

Procedure:
To a solution of 2,3-dichloro-6-fluoro-7-nitroquinoxaline 5.24 g in tetrahydrofran (50 mL), was added dropwise a solution of potassium tert-butoxide 2.51 g in tert-butanol 60 mL at −10 to −8° C. for about 1 hr. After the addition, the mixture was stirred at 0° C. for 1 hr, to which toluene 100 mL and a solution of 0.1M sodium dihydrogen phosphate 20 mL were added, then which was poured into a separatory funnel. The organic layer was washed with water and saturated saline, dried over MgSO4, and evaporated under reduced pressure. The residue was purified with silica gel column (120 g, toluene:hexane=1:1), to give the title compound (pale yellow crystal) 4.19 g.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:38])=[C:17]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[C:32]5[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=5[O:30][N:29]=4)[CH2:24][CH2:23]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[C:50]([N:57](Br)[CH2:58][CH3:59])([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CC(C)=O>[Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:38])=[C:17]([CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[C:32]5[CH:33]=[CH:34][C:35]([O:37][CH2:59][CH2:58][NH:57][C:50](=[O:51])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[CH:36][C:31]=5[O:30][N:29]=4)[CH2:26][CH2:27]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(Br)C(=O)OC(C)(C)C
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(O)ccc34)CC1)CCCC2O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(OCCNC(=O)OC(C)(C)C)ccc34)CC1)CCCC2O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 9-((tert-butyldimethylsilyl)oxy)-3-(2-(4-(6-hydroxybenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in the previous step, (50 mg, 0.093 mmol) in acetone (0.5 mL) and DMF (0.5 mL) was treated with potassium carbonate (33.3 mg, 0.24 mmol) and N-Boc-2-bromoaminoethane (27 mg, 0.12 mmol), and the reaction mixture was stirred for 17 h at 60° C. under argon. The reaction mixture was evaporated at 40° C. under reduced pressure and dissolved in water (10 mL) and extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over Na2SO4, filtered, and the solvent was evaporated yield the crude title compound. (ESI-MS (M+1) 682)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]1[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH:16]=1.[K+].[C:24]([C:26]1[N:27]=[C:28]([C:39]([O-])=[O:40])[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=1)#[N:25]>>[CH3:21][C:18]1([CH3:22])[CH2:19][CH2:20][C:15]([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:39]([C:28]2[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[C:26]([C:24]#[N:25])[N:27]=2)=[O:40])=[CH:16][CH2:17]1
Reactant: CC1(C)CC=C(c2cc(C3CCC(=O)CC3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: CC1(C)CC=C(c2cc(C3CCC(=O)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-cyclohexanone (as prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) according to the procedure in Example 1, step (f). Mass spectrum (APCI, m/z): Calcd. for C31H42N4O3Si, 547.3 (M+H), found 547.0.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2].[CH3:11][N:12]([CH3:16])[C:13](=[S:15])[S-:14].C[NH2+]C>C(=S)=S>[CH3:11][N:12]([CH3:16])[C:13](=[S:14])[S:15][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1cccs1
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1cccs1

Procedure:
As in Example 17, reaction of 2-(2-nitrovinyl)thiophene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave α-(nitromethyl)-2-thenyl dimethyldithiocarbamate melting at 88° C.-90° C. when recrystallized without heating from acetone-ethanol solution.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([N:16]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:18][C:17]1=[NH:25])[CH2:13][C:14]#[CH:15].[F:26][C:27]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(N(CC)CC)C>C(Cl)Cl>[C:21]([C:19]1[S:18]/[C:17](=[N:25]\[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:27]=2[F:26])/[N:16]([CH2:12][CH2:13][C:14]#[CH:15])[CH:20]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: C#CCCn1cc(C(C)(C)C)sc1=N
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.9 %

Procedure:
A mixture of 3-(but-3-ynyl)-5-tert-butylthiazol-2(3H)-imine p-toluenesulfonate (prepared as described in US20080242654) (2.6 g, 6.83 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl chloride (1.55 g, 6.83 mmol) in anhydrous CH2Cl2 (30 mL) was treated dropwise at 0° C. with triethylamine (1.91 mL, 1.38 mmol). The mixture was allowed to warm to room temperature and stirred for 14 hours. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with hexane-EtOAc (2:1) to afford 2.5 g of the title compound. MS (DCI/NH3) m/z 399 (M+H)+.
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:9])[CH2:8][CH2:7]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[C:17]([N:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[OH:35])[CH2:28][CH2:27]3)[C:20]2=[O:36])[C:16]([CH3:37])=[C:15]([F:38])[CH:14]=1.Cl>C1COCC1.O>[CH:6]1([NH:9][C:12](=[O:11])[C:13]2[CH:18]=[C:17]([N:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[OH:35])[CH2:28][CH2:27]4)[C:20]3=[O:36])[C:16]([CH3:37])=[C:15]([F:38])[CH:14]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc(F)c(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (30.1 ml of a 2M solution in THF) was added over 20 min to a solution of cyclopropylamine (10.61 mL) and 3-fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid methyl ester (Example 259b, 6.16 g) in tetrahydrofuran (200 mL) and the reaction stirred at room temperature under nitrogen for 1 h. Water (100 mL) and 2M HCl (200 mL) were cautiously added and the aqueous layer extracted with dichloromethane (3×200 mL) and the combined organic extracts dried (MgSO4) and the solvent removed to give the subtitle compound (5.00 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[C:9]1=[O:37])(=O)=O.[NH4+:38].[OH-]>CC(O)C.O>[NH2:38][CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[N:10]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:27][CH:28]=2)[C:9]1=[O:37]
Reactant: CS(=O)(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: NCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 80 °C
Yield: 96 %

Procedure:
2-(3-(4-(4-Chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)ethyl methanesulfonate (85.0 mg, 0.153 mmol) is dissolved in a mixture solvent of iPrOH (0.5 mL) and concentrated ammonia aqueous solution (0.5 mL). The reaction mixture is heated at 80° C. for 2 h, cooled down to room temperature, taken in H2O (10 mL), and extracted with EtOAc (3×5 mL). The combined organic layer is dried over MgSO4 and evaporated in vacuo to provide the crude title compound (69.7 mg, 96% yield) as a colorless oil-like product; HPLC-MS calculated for C24H21ClF3N3O2 (M+H+) 476.1, found 476.1.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[C:22](I)=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=1.ClC1C=C([I:35])C(C(F)(F)F)=CN=1>C1COCC1.II>[Cl:16][C:17]1[N:18]=[C:19]([I:35])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Reactant: FC(F)(F)c1cnc(Cl)c(I)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Cl)nc1I
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (4.277 g, 5.110 mL, 30.28 mmol) in THF (18.00 mL) cooled to −78° C. was added nBuLi in hexanes (11.72 mL of 2.5 M, 29.30 mmol). The solution was allowed to warm up to 0° C. and was stirred for 15 minutes at that temperature before cooling it again to −78° C. Iodine (12.40 mg, 2.515 μL, 0.04884 mmol) was added followed by a dropwise addition of a solution containing a mixture of 2-chloro-3-iodo-5-(trifluoromethyl)pyridine (2 g, 6.505 mmol) and 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (4.000 g, 13.01 mmol) in THF (18.00 mL). The solution was stirred at −78° C. for 2 hours. The reaction mixture was partitioned between a 1M solution of HCl and ether. The organic extract was washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a pale yellow oil (1.92 g, 32% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[N:23]OCC)[CH:20]=4)[NH:15][N:14]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:27][NH:28][C:29](=O)[CH2:30][N:31]([CH3:33])[CH3:32].C[O-].[Na+]>CO>[CH3:32][N:31]([CH2:30][C:29]1[N:23]=[C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[CH:12]=[CH:11][CH:10]=2)[NH:27][N:28]=1)[CH3:33]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4CC4)c3)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5CC5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using N-cyclopropyl(3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)carboxamide.2HCl (377 mg, 0.89 mmol), N-amino-2-(dimethylamino)acetamide (315 mg, 2.69 mmol) and sodium methoxide (515 μL of a 25% w/w in methanol) in anhydrous methanol (5.0 mL) with a reaction time of 24 h. Purification of the residue by flash chromatography on silica gel with 50% methanol in ethyl acetate gave the desired product as a light orange solid. Further purification by preparatory TLC using 50% methanol in ethyl acetate afforded the title compound (145 mg, 40% yield) as an off-white powder. 1H NMR (DMSO-d6) δ 8.8 (br d, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 8.14–8.05 (m, 2H), 7.84 (d, 1H), 7.7–7.6 (m, 2H), 3.55 (s, 2H), 2.92–2.85 (m, 1H), 2.2 (s, 6H); ES-MS (m/z) 402 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][NH2:16])=[O:14].C(N(CC)CC)C.C1C=CC(O[C:35](OC2C=CC=CC=2)=[N:36][C:37]#[N:38])=CC=1>CC(O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]1[O:14][C:35]([NH:36][C:37]#[N:38])=[N:16][N:15]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NN)c1Cl
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2nnc(NC#N)o2)c1Cl
Yield: 21.7 %

Procedure:
To a suspension of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzoic acid hydrazide (394.1 mg, 1.27 mmoles) in 20 ml of 2-propanol is added triethylamine (200 μl, 1.43 mmoles) followed by diphenyl cyanocarbonimidate (371.9 mg, 1.56 mmoles). After 1.5 hours the resultant yellow solution is concentrated in vacuo. The residue is dissolved in 10 ml of ethyl acetate and partitioned between water and a 1:1 mixture of ether and hexane. The aqueous layer is acidified with 1N hydrochloric acid, and the resultant white solid is collected by filtration to provide 99.3 mg (22%) of 5-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-1,3,4-oxadiazol-2-yl-cyanamide, mp above 215° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([Br:11])=[C:8]([CH3:10])[CH:9]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:22].[Na+].OO>O1CCCC1>[Br:11][C:7]1[C:6]([CH3:12])=[CH:5][C:4]([CH2:1][CH2:2][CH2:3][OH:22])=[CH:9][C:8]=1[CH3:10]
Reactant: [OH-]
Reactant: C=CCc1cc(C)c(Br)c(C)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(CCCO)cc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-allyl-2-bromo-1,3-dimethylbenzene (1.0 g) is cooled to 0° C., 9-borabicyclo[3.3.1]nonane (9-BBN, 26 mL of a 0.5 M solution in tetrahydrofurane) is added dropwise and the mixture is stirred for 2 hours at room temperature. After cooling to 0° C. NaOH (6.7 mL, 4 M) and H2O2 (6.7 mL, 35%) are added dropwise. The mixture is stirred for 12 hours while warming to room temperature. Then the mixture is partitioned between brine and diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 95:5→70:30) to give the title compound. Yield: 750 mg; LC (method 8): tR=0.28 min; Mass spectrum (ESI+): m/z=260 [M+NH4]+.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[C:18]([CH:2]2[C:7](=[O:8])[NH:6][C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[O:3]2)[CH:19]=1
Reactant: O=C1Nc2ccccc2OC1Br
Reactant: COc1ccc(Br)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Br)cc1C1Oc2ccccc2NC1=O

Procedure:
To 2-bromo-2H-1,4-benzoxazin-3(4H)-one (I10) (1.40 g, 6.14 mmoles) in methylene chloride (20 mL) was added 4-bromoanisole and then tin (IV) chloride. Addition of tin (IV) chloride caused a brown solution to form. The solution was refluxed for 5 hours, diluted with methylene chloride (100 mL) and washed with water (2×50 mL). After drying over Magnesium sulphate the mixture was concentrated until the product (I11) precipitated (0.58 g). Concentration of the mother liquors and chromatography on silica gel afforded an additional amount of product (I11) (0.55 g).