Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[CH3:2][C:3]1[C:11]([C:12]2[S:14][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:30])([F:31])[F:32])[N:13]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1C(F)(F)F
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1C(F)(F)F
Yield: 83.2 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (100 mg, 0.44 mmol) produced in Example 11-B(v), ethyl 2-chloro-3-oxo-3-[2-(trifluoromethyl)phenyl]propanoate (250 mg, 0.85 mmol) produced in the above and 2-propanol (25 mL) as starting materials and in the same manner as in Example 11-B(vi), the title compound (158 mg, 84%) was obtained as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:10]=[C:11](/[CH:15]=[CH:16]/[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]1([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:15]3[O:34][CH:16]3[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cccc(NCC2CCCCC2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1OC1c1cccc(NCC2CCCCC2)c1
Temperature: 25 °C

Procedure:
To a solution of (E)-tert-butyl 3-(3-(cyclohexylmethylamino)phenyl)allylcarbamate in CH2Cl2 is added MCPBA (77%) followed by Na2CO3. The reaction mixture is stirred at room temperature until no starting material is seen by TLC. Aqueous NaHCO3 (10%) is added and the product is extracted with CH2Cl2 three times. Combined organic layers are washed with brine-NaHCO3, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (10% to 50% EtOAc—hexanes gradient) gives tert-butyl (3-(3-(cyclohexylmethylamino)phenyl)oxiran-2-yl)methylcarbamate which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:38])([F:37])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34](O)=[O:35])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:34]([C:29]3[N:30]=[C:31]([CH3:33])[O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:37])([F:19])[F:38])[CH:23]=3)=[O:35])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-trifluoromethoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: C([O-])=O.[NH4+].[F:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[NH:11][N:10]=1>CO.C1COCC1.CO.[Pd]>[F:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[NH:11][N:10]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Cc3ccccc3F)c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2[nH]nc(Cc3ccccc3F)c2c1
Yield: 90.1 %

Procedure:
Ammonium formate (50 mg, 0.792 mmol) and 10% Pd/C (5 mg) were added to a solution of 3-(2-fluoro-benzyl)-5-nitro-1H-indazole (50 mg, 0.184 mmol) in MeOH/THF (3 ml, 1/1) then refluxed for 3 hours. The reaction was diluted with MeOH (20 ml) and filtered through a celite pad. The solvent was evaporated, residue dissolved in MeCl2, dried over Na2SO4, filtered and solvent evaporated yielding title compound as white solid (40 mg, 88%) ESMS (MH, 242).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[CH:10][CH:9]=1.[CH3:19][Mg]Br.[Cl-].[NH4+]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:17])[CH3:19])=[CH:10][CH:9]=1
Reactant: C[Mg]Br
Reactant: O=C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)CCc1ccc(-c2ccccc2Cl)cc1
Temperature: -70 °C

Procedure:
A solution of β-(2'-chloro-4-biphenylyl)propionyl chloride (28 g.) in anhydrous ether 1 l. is cooled to -70°C. To it is added dropwise a solution of 3M methylmagnesium bromide in ether (34 ml.). The reaction is stirred vigorously throughout. When addition of the grignard is complete (approx. 1 hr), the mixture is allowed to come to room temperature and is decomposed by adding carefully a saturated ammonium chloride solution (approx. 500 ml). The ether phase is washed with brine, dried over sodium sulfate, evaporated in vacuo and the residue distilled to yield 4-(2'-chloro-4-biphenylyl)butan-2-one.
Reaction SMILES: C(O[C:4]([C:6]1[N:18]=[C:17]([C:19]#[N:20])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]=2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[C:19]([C:17]1[C:16]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8]=2[C:7]([OH:27])=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:18]=1)#[N:20]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c3ccccc3n(-c3ccccc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c1c1ccccc1n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 1(e) from 1-cyano-4-hydroxy-5-phenyl-5H-pyrido[4,3-b]indole-3-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 385 (M−1)−.
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH3:11][C:12]1([CH3:25])[CH2:24][C:15]2[C:16]3[CH2:21][CH2:20][NH:19][C:18](=[O:22])[C:17]=3[S:23][C:14]=2[CH2:13]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]([N:19]2[CH2:20][CH2:21][C:16]3[C:15]4[CH2:24][C:12]([CH3:11])([CH3:25])[CH2:13][C:14]=4[S:23][C:17]=3[C:18]2=[O:22])[C:3]=1[CH:4]=[O:5]
Reactant: CC1(C)Cc2sc3c(c2C1)CCNC3=O
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Temperature: 90 °C
Yield: 9.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 2-bromo-4-chloronicotinaldehyde 103a (660 mg, 3.0 mmol), 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-9-one 106h (665 mg, 3.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (270 mg, 0.3 mmol), XantPhos (340 mg, 0.6 mmol), Cs2CO3 (2.0 g, 6.0 mmol), and 1,4-dioxane (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane to afford 109a as yellow solid (105 mg, 14%). MS: [M+H]+ 361.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:15])=[C:7]([C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[OH:16][CH2:17][C@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1.CCN(C(C)C)C(C)C>C1COCC1>[C:8]([C:7]1[C:6]([CH3:15])=[C:5]([C:3](=[O:4])[CH2:2][N:23]2[CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:19][C@H:18]2[CH2:17][OH:16])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14])#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: COc1ccc(C(=O)CBr)c(C)c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)c(C)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the 3-(bromoacetyl)-6-methoxy-2-methylbenzonitrile (2.25 g, 8.40 mmol) in THF was added tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.18 g, 10.8 mmol) and Hunig's Base (2.93 mL, 16.8 mmol). The reaction was allowed to stir at RT for 16 hours. TLC showed good reaction at that point. The crude reaction was adsorbed onto silica gel, and purified by silica gel flash chromatography to afford the title compound.
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC4CCOCC4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OC3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
Ethyl 3-[{[4-({cyclohexyl[3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.6 g) synthesized in the above-mentioned (6) was dissolved in ethanol (20 mL), 1N aqueous sodium hydroxide solution (3 mL) was added at room temperature, and the mixture was stirred at room temperature for 12 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (3 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetone to give the title object compound (0.5 g, 77%) as colorless crystals.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH2:45][C:46]5[CH2:51][CH2:50][C:49]([CH3:53])([CH3:52])[CH2:48][C:47]=5[C:54]5[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=5)[CH2:41][CH2:40]4)[CH:36]=[CH:35][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:61][C:62]([CH3:64])=O.C([BH3-])#N>O1CCCC1.C(O)(=O)C>[Cl:60][C:57]1[CH:56]=[CH:55][C:54]([C:47]2[CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][CH2:51][C:46]=2[CH2:45][N:42]2[CH2:41][CH2:40][N:39]([C:37]3[CH:36]=[CH:35][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH:26]5[CH2:31][CH2:30][N:29]([CH:62]([CH3:64])[CH3:61])[CH2:28][CH2:27]5)=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:38]=3)[CH2:44][CH2:43]2)=[CH:59][CH:58]=1
Reactant: CC(C)=O
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCC(Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cnc4[nH]ccc4c3)cc2[N+](=O)[O-])CC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 226B (79 mg) in tetrahydrofuran (3 mL) and acetic acid (1 mL) was added acetone (54 mg) and MP-cyanoborohydride (150 mg, 2.25 mmol/g). The mixture was stirred overnight. The mixture was filtered. The filtrate was concentrated and the residue was loaded on a silica gel cartridge and eluted with 5 to 10% 7N NH3 in methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12.09 (s, 1H), 8.34 (m, 1H), 7.93 (m, 2H), 7.66 (m, 4H), 7.35 (d, 2H), 7.06 (d, 2H), 6.89 (m, 1H), 6.74 (dd, 1H), 6.59 (dd, 1H), 6.50 (d, 1H), 3.11 (m, 6H), 2.73 (m, 4H), 2.26 (m, 9H), 1.97 (s, 3H), 1.40 (t, 2H), 1.23 (s, 8H), 0.94 (s, 6H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=3)=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:37][C:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)=[O:23])=[CH:26][CH:27]=1)([CH3:36])[C:32]([O:34][CH3:35])=[O:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(C)C(=O)OC)cc3)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(C)(Br)C(=O)OC)cc3)cc2)cc1
Yield: 45 %

Procedure:
A mixture of MOPPP (see Example 20d; 1.1 mmole) in dry CCl4 (10 ml) with N-bromosuccinimide (1.8 mmole) and a catalytic quantity of azo-isobutyronitril (5 mg) was heated for 24 hours. After cooling, the reaction mixture was purified directly by column chromatography (silica gel eluted with hexane/chloroform). MBOPP was recrystallised from hexane as fine needles (yield 45%; mp 104°-5° C.). The results of IR, 1H-NMR and mass spectroscopy and elemental analysis were consistent with the assigned structure.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C>C1(C)C=CC=CC=1.[Cu].O>[N+:8]([C:4]1[CH:3]=[C:2]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cccc(-n2ccnc2)c1
Temperature: 200 °C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
An intimate mixture of 1-iodo-3-nitrobenzene (24.9 g, 0.1 mol), copper bronze (320 mg, 5 mmol), potassium carbonate (15.2 g, 0.11 mol) and imidazole (15.0 g, 0.22 mol) was heated under a stream of nitrogen at 200° C. for 90 minutes. The reaction was cooled to 100° C., carefully treated with water (750 ml) and the resulting suspension stirred to ambient temperature over 16 hours. Filtration gave a grey-coloured solid which was dissolved in hot toluene (125 ml) and treated with decolourising charcoal (2 g). Filtration and cooling afforded 1-(3-nitrophenyl)-1H-imidazole as pale green needles (13.5 g, 71%). δH (360 MHz, CDCl3) 7.29 (1H, br s), 7.38 (1H, br s), 7.68-7.78 (2H, m), 7.97 (1H, br s), 8.23-8.29 (2H, m).
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=3)=[CH:3][C:2]2=1>CC(=O)CC>[CH:1]([N:12]1[CH:9]2[CH2:10][CH2:11][CH:1]1[C:2]1[CH:3]=[C:4]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=3)[CH:5]=[CH:6][C:7]=1[CH2:8]2)([CH2:2][CH3:7])[CH3:11]
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Solvent: CCC(C)=O
Product: CCC(C)N1C2CCC1c1cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc1C2
Yield: 189.5 %

Procedure:
Following a procedure analogous to 80a, N-{(1R,2R)-2-[2-(12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (90 mg, 0.19 mmol) and 2-butanone were converted to the title compound as an off-white solid (96 mg, 95%): 1:1 mixture of diastereomers. 1HNMR (400 MHz, MeOD) 7.9 (s, 1H), 7.5 (m, 2H), 7.1 (d, 1H, J=8.3 Hz), 4.6 (m, 1H), 4.2 (m, 1H), 4.0 (m, 1H), 3.3 (m, 1H), 2.9 (d, 3H, J=4.0 Hz), 2.8 (m, 1H), 2.7 (d, 1H, J=7.4 Hz), 2.4-2.3 (m, 2H), 2.2-2.0 (m, 3H), 1.9-1.8 (m, 3H), 1.6-1.2 (m, 10H), 1.0-0.9 (m, 3H); MS (m/e) 533 (M+1); mp 162-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1ccccc1
Agent: N
Product: Clc1cncc(-c2cc(-c3ccccc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-benzene (Aldrich, 31 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.52-7.66 (m, 3H), 7.78 (s, 1H), 7.85-7.98 (m, 2H), 8.45 (t, J=2.1 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 9.09 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 257 (M+H)+, 259 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[S:16][CH:17]=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21])=[O:8])[CH2:2][CH3:3]
Reactant: NC(=O)c1ccsc1N
Reactant: CCCOc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccccc1C(=O)Nc1sccc1C(N)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 2-propoxybenzoyl chloride (0.99 g) in acetonitrile (7.5 ml) was added dropwise over 5 minutes to a cooled (0° C.), stirred mixture of 2-aminothiophene-3-carboxamide (0.71 g) and triethylamine (0.51 g) in acetonitrile (7.5 ml). The reaction mixture was stirred for one hour while being allowed to warm to ambient temperature and was then allowed to stand overnight. Acetonitrile was removed under reduced pressure and the residue was washed with water and recrystallised from ethanol-water to afford 2-(2-propoxybenzamido)thiophene-3-carboxamide, 0.91 g, m.p. 176.5-178.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:31])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[O:24][C:25]([C:28](O)=[O:29])=[CH:26][CH:27]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:43]=[CH:44][CH:45]=[N:46]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:31])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[O:24][C:25]([C:28](=[O:29])[NH:46][CH:45]3[CH2:43][CH2:44]3)=[CH:26][CH:27]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)o1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)o1

Procedure:
In a similar procedure as described for the synthesis of Compound 5352 (Example 352), treatment of (S)-2-[4-(5-Carboxy-furan-2-yl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester with HATU (0.23 g, 0.6 mmol), DIEA (0.2 mL, 1.53 mmol), and cyclopropylamine (0.1 1 mL) furnished the desired product. 1HNMR (DMSO-d6) δ(ppm) 12.59-12.57 (d, 1H), 8.42-8.39 (m, 1H), 7.64-7.62 (d, 1H), 7.36-7.30 (m, 2H), 7.14-7.10 (m, 3H), 6.73-6.70 (m, 1H), 5.10-4.87 (m, 2H), 4.51-4.43 (m, 2H), 3.52-3.36 (m, 2H), 2.80-2.77, (m, 2H), 2.27-2.24 (m, 1H), 1.94-1.83 (m, 3H), 0.73-0.58 (m, 4H); MS: 481.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[CH:3]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O.[F:62][C:63]1[CH:64]=[C:65]([C@@H:69]2[NH:73][CH2:72][C@@H:71]([C:74]#[N:75])[CH2:70]2)[CH:66]=[CH:67][CH:68]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(O)(C)C>[C:74]([C@@H:71]1[CH2:72][N:73]([C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[CH:3]=2)[C@@H:69]([C:65]2[CH:66]=[CH:67][CH:68]=[C:63]([F:62])[CH:64]=2)[CH2:70]1)#[N:75]
Reactant: N#C[C@@H]1CN[C@@H](c2cccc(F)c2)C1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cnn2ccc(N3C[C@@H](C#N)C[C@@H]3c3cccc(F)c3)cc12
Temperature: 120 °C

Procedure:
A N2 purged flask was charged with ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (30 mg, 0.11 mmol), palladium acetate (1.0 mg, 5 μmol), RuPhos (5 mg, 10 μmol), cesium carbonate (65 mg, 0.20 mmol), tBuOH (0.5 mL) and (3S,5R)-5-(3-fluorophenyl)pyrrolidine-3-carbonitrile 2,2,2-trifluoroacetate (I-31) (30 mg, 0.10 mmol). The contents were heated to 120° C. overnight in an oil bath. Upon cooling to room temperature the reaction was filtered through celite and concentrated. The crude product was purified by column chromatography on silica gel with an EtOAc/hexane gradient as eluant to yield ethyl 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-19). 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1 H), 8.22 (d, J=7.6 Hz, 1 H), 7.40-7.32 (m, 1 H), 7.07-6.96 (m, 3 H), 6.88 (d, J=9.4 Hz, 1 H), 6.24 (dd, J=2.7, 7.6 Hz, 1 H), 5.10 (dd, J=2.5, 8.0 Hz, 1 H), 4.39-4.29 (m, 2 H), 4.23-4.14 (m, 1 H), 3.95-3.78 (m, 1 H), 3.42-3.29 (m, 1 H), 2.92-2.78 (m, 1 H), 2.50-2.39 (m, 1 H), 1.36 (t, J=7.1 Hz, 3 H). MS m/z 379.1 (M+1)+. Further elution with MeOH/DCM gradient afforded ethyl 5-((2R,4S)-4-carbamoyl-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-20). MS m/z 397.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:20]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([Cl:20])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc2ccc(Br)cc2[nH]1
Solvent: CN(C)C=O
Product: Clc1cnc2ccc(Br)cc2n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a suspension of 7-bromoquinoxalin-2(1H)-one (224 g, 1 mol, 1.0 eq.) in POCl3 (1000 mL) was added DMF (3.65 g, 0.05 mol, 0.05 eq.). The resulting mixture was stirred at 120° C. for 2 h, then cooled to rt and slowly poured into ice-water with vigorous stirring. The precipitate was collected by filtration and dried to afford 7-bromo-2-chloroquinoxaline as brown solid (180 g, 75%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:12]1([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(C2CC2)cc1[N+](=O)[O-]
Yield: 143.8 %

Procedure:
4-Bromo-2-nitroaniline (2.17 g, 10 mmol), cyclopropylboronic acid (1.12 g, 1.30 mmol), potassium phosphate (7.42 g, 35 mmol), palladium (II) acetate (120 mg, 0.5 mmol), and cyclohexylphosphine (280 mg, 1 mmol) were combined in toluene (40 mL) and water (2 mL) and heated on an oil bath at 100° C. for 16 hours. The mixture was cooled, and the mixture was triturated with dichloromethane and water. The resulting mixture was filtered through a pad of celite. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate. Concentration gave an oil that was chromatographed over silica gel (30% v/v diethyl ether in hexanes). The faster moving compound was collected and the solvent was concentrated to give an orange oil. The oil was dissolved in hot hexanes/ethyl acetate and cooling gave 4-cyclopropyl-2-nitroaniline as orange needles (333 mg, 1.87 mmol, 19% ).