Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12]C=O)([CH3:11])[CH3:10])=[C:4]([CH3:15])[CH:3]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:12])([CH3:10])[CH3:11])=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(F)ccc1CC(C)(C)NC=O
Agent: Cl
Product: Cc1cc(F)ccc1CC(C)(C)N

Procedure:
In order to prepare the amine, 27.0 g (130 mmol) of N-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethyl]formamide is reacted as described in the method for Example 10(c). White solid. Yield: 15.5 g (55%, hydrochloride); melting point: 277° C.–280° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[N:16]([O-:18])=[O:17].[Na+].O>C(O)(C(F)(F)F)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C[C@H](C)N2C(C)=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)[C@@H](C)C2
Yield: 90.5 %

Procedure:
A 0° C. orange solution of (2S)-1-acetyl-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indole (5.19 g, 25.3 mmol) in TFA (30 mL) was treated with NaNO2 (1.745 g, 25.3 mmol) portion wise. After 2 h more NaNO2 (800 mg, 11.6 mmol) was added. After 1 h the resulting mixture was poured into water (450 mL). The resulting slurry was filtered and the solids were washed with water. The solids were dissolved in CH2Cl2. The layers were separated, the organic layer was dried (Na2SO4) and concentrated to afford (2S)-1-acetyl-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole as a green solid (5.73 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.23 Hz, 3H), 2.22 (s, 3H), 2.76 (d, J=17.21 Hz, 1H), 3.45 (dd, J=17.03, 8.97 Hz, 1H), 3.89 (s, 3H), 4.58-4.78 (m, 1H), 7.35 (s, 1H), 8.41 (s, 1H); ESIMS (M+H)+=251.02.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:23]=1>C1(C)C=CC=CC=1>[CH3:15][C:4]1[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=[C:2]([CH:22]=[CH2:23])[CH:3]=1)[C:7]#[N:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(Br)cc(C#N)c1-n1cncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=Cc1cc(C)c(-n2cncn2)c(C#N)c1
Temperature: 25 °C
Yield: 1043.1 %

Procedure:
A mixture of 5-bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.6 g, 2.3 mmol), potassium carbonate (0.95 g, 6.87 mmol), vinyl boronic anhydride (0.82 g, 3.43 mmol) and triphenylphosphine (0.13 g, 0.114 mmol) in toluene (20.0 mL) were stirred and degassed with argon for 30 min. The reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to RT, diluted with water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound that was purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford the title compound as a pink solid (0.25 g, 52%): 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (d, J=17.6, 1H), 5.52 (d, J=10.8 Hz, 1H), 2.21 (s, 3H), ESIMS m/z 211.35 ([M+H]+); IR (thin film) 2236, 1511 cm−1.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:11]=[C:10]([O:25][CH3:26])[N:9]=1)=[O:7])(=O)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[CH3:26][O:25][C:10]1[N:11]=[C:12]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:13]=[C:8]([C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)[N:9]=1
Reactant: COc1ccc(CCNc2cc(C(=O)NNC(C)=O)nc(OC)n2)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCNc2cc(-c3nnc(C)o3)nc(OC)n2)cc1
Yield: 61.3 %

Procedure:
To a solution of 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid [100 mg, 0.33 mmol, Intermediate (56)] in dimethylformamide (1 mL) is added N,N-diisopropylethylamine (145 μL, 0.83 mmol) followed by TBTU (128 mg, 0.4 mmol). Stirred the reaction mixture for 5 minutes before adding acetic hydrazide (37 mg, 0.5 mmol) and continued stirring the reaction mixture overnight at ambient temperature. The reaction mixture is poured into water (25 mL) and subsequently extracted three times with 25 mL ethyl acetate. The combined organic extracts are washed three times with 25 mL water, with 25 mL brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The material obtained is subjected to flash column chromatography on silica (10 g) eluting with 0 to 5% MeOH in DCM gradient to afford 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid N′-acetyl-hydrazide (42 mg). A mixture of 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid N′-acetyl-hydrazide (42 mg, 0.12 mmol), p-toluenesulfonylchloride (34 mg, 0.18 mmol) and PS-BEMP (218 mg, 0.48 mmol) in THF (1.5 mL) is irradiated in a microwave to 140° C. for 6 minutes. The material is filtered and absorbed onto silica gel and subjected to flash column chromatography on silica gel eluting with 10 to 50% EtOAc in heptane gradient to afford [2-methoxy-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [25.1 mg, 63%, Example 44]. LCMS: RT=2.64 minutes, MS: 342 (M+H). IC50=55 nM
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:38])[C:6]([C:9]([NH:11][C:12]2[N:17]=[C:16]([C@:18]3([CH3:36])[CH2:23][C@@H:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20]([NH:28]C(=O)OC(C)(C)C)=[N:19]3)[C:15]([F:37])=[CH:14][CH:13]=2)=[O:10])=[N:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[NH2:28][C:20]1[O:21][C@H:22]([C:24]([F:25])([F:27])[F:26])[CH2:23][C@:18]([C:16]2[N:17]=[C:12]([NH:11][C:9](=[O:10])[C:6]3[C:5]([CH3:38])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:13]=[CH:14][C:15]=2[F:37])([CH3:36])[N:19]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(NC(=O)OC(C)(C)C)=N2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(N)=N2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl ((4S,6S)-4-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (9a, 0.052 g, 0.097 mmol) in DCM (1.5 mL) was treated with trifluoroacetic acid (0.747 mL, 9.69 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with aqueous saturated Na2CO3 and extracted with DCM. The organic extract was washed with brine and dried over Na2SO4. The solution was concentrated under reduced pressure and the title compound was obtained as a white solid (40 mg, 95% yield). MS m/z=437 [M+H]+. Calculated for C19H16F4N6O2: 436.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[CH2:14][CH2:13][CH2:12][O:11][C:10]=12)=[O:5])C.O>O1CCCC1.C(O)C.[OH-].[Li+]>[N:8]1[N:9]2[C:10]([O:11][CH2:12][CH2:13][CH2:14]2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=1
Reactant: CCOC(=O)c1cnn2c1OCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn2c1OCCC2
Yield: 98.2 %

Procedure:
A solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester (9.67 g, 49.3 mmol) in tetrahydrofuran (150 mL), ethanol (50 mL) and 1M of lithium hydroxide in water (148 mL, 148 mmol) was stirred at 60° C. for 2 days. After cooling, the volatiles were removed. The residue was transferred to an Erlenmeyer flask and ice was added. The reaction was acidified to pH 2 with 10M HCl. The aqueous layer was extracted several times with 3/1 chloroform/IPA. The combined organic layers were dried (Na2SO4), filtered, concentrated to afford the acid as a solid (8.14 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ7.57 (s, 1H), 4.37 (t, 2H, J=5.29 Hz), 4.07 (t, 2H, J=6.11 Hz), 2.20-2.15 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:39])=[C:7]([CH3:38])[C:8]2[O:12][C:11]([CH3:35])([C:13]([NH:15][C:16]3[CH:17]=[N:18][C:19]4[C:24]([C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:23][C:22]([CH3:33])=[CH:21][C:20]=4[CH3:34])=[O:14])[CH2:10][C:9]=2[C:36]=1[CH3:37])(=O)C.Cl.CO>O>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[C:24]2[C:19](=[C:20]([CH3:34])[CH:21]=[C:22]([CH3:33])[CH:23]=2)[N:18]=[CH:17][C:16]=1[NH:15][C:13]([C:11]1([CH3:35])[CH2:10][C:9]2[C:36]([CH3:37])=[C:5]([OH:4])[C:6]([CH3:39])=[C:7]([CH3:38])[C:8]=2[O:12]1)=[O:14]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(C(=O)Nc1cnc3c(C)cc(C)cc3c1-c1ccccc1Cl)O2
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc(C)c2ncc(NC(=O)C3(C)Cc4c(C)c(O)c(C)c(C)c4O3)c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
A mixture of 3-(5-acetoxy-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-ylcarbonyl)amino-4-(2-chlorophenyl) -6,8-dimethylquinoline (400 ml) and 6.92N-hydrochloric acid-methanol solution (10 ml) was stirred at room temperature for eight hours. After addition of water, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then concentrated. The residue was purified by a silica gel column chromatography with hexane-ethyl acetate (3:1,V/V), and then crystallized from isopropyl ether to give 4-(2-chlorophenyl)-3-(2,3-dihydro-5-hydroxy-2,4,6,7-tetramethylbenzofuran-2-ylcarbonyl) amino-6,8-dimethylquinoline (104 mg, 28.2%) as colorless prisms.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33]O)=[NH:32])=[CH:29][N:28]=1>>[F:25][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:13][N:33]=[C:31]([C:30]4[CH:35]=[CH:36][C:27]([NH2:26])=[N:28][CH:29]=4)[N:32]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) (179 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/hexane) as a yellow solid (84 mg, 35%). MS (ISP) 474.0 [(M+H)+]; mp 242° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.O[C@@H:30]1CCCNC1>>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:30][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: O[C@@H]1CCCNC1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35) and (R)-(+)-3-hydroxypiperidine hydrochloride to afford a brown oil. UPLC-MS (condition 1) tR=3.38 min, m/z=460.0-462.0 [M+H]+, m/z=458.0-461.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.41 (m, 1H) 1.49-1.63 (m, 1H) 1.75-1.85 (m, 1H) 1.90-1.98 (m, 1H) 2.73 (dd, J=12.23, 9.29 Hz, 1H) 2.87-2.96 (m, 1H) 3.56-3.69 (m, 1H) 3.75 (d, J=12.72 Hz, 1H) 3.91 (dd, J=12.10, 3.55 Hz, 1H) 4.88 (s, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.82-7.89 (m, 2H) 8.42 (d, J=2.20 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.37 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27](O)=[O:28])=[CH:23][NH:24]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27]([N:12]3[CH2:11][CH2:10][CH:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:15])[F:16])[CH2:14][CH2:13]3)=[O:28])=[CH:23][NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Reactant: FC(F)(F)c1ccccc1C1CCNCC1
Product: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2C(F)(F)F)CC1

Procedure:
Following general procedure I, the coupling of (commercially available) 4-(2-trifluoromethyl-phenyl)-piperidine (described herein) with 6-chloro-1H-indole-3-carboxylic acid gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[F:9].[CH2:10]([N:12]([CH2:34][CH3:35])[CH:13]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[C:24]([CH3:25])=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[CH:33])[CH:27]=3)[NH:22][N:21]=2)=[O:19])[CH2:14]1)[CH3:11]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:33]#[C:32][C:28]2[CH:27]=[C:26]([C:23]3[NH:22][N:21]=[C:20]([C:18]([N:15]4[CH2:16][CH2:17][CH:13]([N:12]([CH2:34][CH3:35])[CH2:10][CH3:11])[CH2:14]4)=[O:19])[C:24]=3[CH3:25])[CH:31]=[CH:30][CH:29]=2)[CH:5]=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(I)cc1Cl
Reactant: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#Cc4ccc(F)c(Cl)c4)c3)c2C)C1
Yield: 68 %

Procedure:
In analogy to the procedure described in Example 31F], 2-chloro-1-fluoro-4-iodobenzene and (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone (Example 31E]) gave the title compound in 68% yield light yellow foam. MS: 479.2 (MH+, 1 Cl).
Reaction SMILES: [CH:1]1([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:13][C:12]=2[F:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Sm].II.Cl>O.CO.O1CCCC1>[CH:1]1([O:10][C:11]2[C:12]([F:24])=[CH:13][C:14]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:16]=2[F:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)/C=C/c1cc(F)c(OC2CCc3ccccc32)c(F)c1
Agent: Cl
Agent: II
Agent: [Sm]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1cc(F)c(OC2CCc3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a mixture of methyl (E)-3-[4-[(2,3-dihydro-1H-inden-1-yl) oxy]-3,5-difluorophenyl]-2-propenoate (0.52 g, 1.6 mmol), samarium (1.2 g, 7.9 mmol), tetrahydrofuran (3 mL) and methanol (7 mL) was added iodine (0.80 g, 3.2 mmol), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid (20 mL) was added and the mixture was stirred for 20 min. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10:1) to give the title compound. yield 60%, oil.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16]3[C:11](=[C:12]4[CH:21]=[C:20]5[O:22][CH2:23][O:24][C:19]5=[CH:18][C:13]4=[N:14][CH:15]=3)[N:10]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:9](=[O:30])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[C:17]2[C:16]3[C:11](=[C:12]4[CH:21]=[C:20]5[O:22][CH2:23][O:24][C:19]5=[CH:18][C:13]4=[N:14][CH:15]=3)[N:10]([CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])[C:9](=[O:30])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)CCn1c(=O)c2cccc([N+](=O)[O-])c2c2cnc3cc4c(cc3c21)OCO4
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCn1c(=O)c2cccc(N)c2c2cnc3cc4c(cc3c21)OCO4
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a solution of compound 6a (40 mg, 0.1 mmol) in ethanol (10 mL), Ra—Ni (˜50 mg) and then hydrazine hydrate (0.2 mL) were added and reaction was stirred at room temperature for 3 h. The catalyst was filtered through the Celite and filtrate was concentrated in vacuo to provide 28 mg of a solid (74.4% yield); mp 223–224° C.; 1H NMR (CDCl3) δ 2.31 (s, 6H), 2.90 (t, 2H, J=7), 4.34 (s, 2H), 4.65 (t, 2H, J=7.4), 6.18 (s, 2H,), 7.16 (d, 1H, J=8), 7.4 (dd, 2H, J=7.6, 9.8) 7.74 (s, 1H), 8.02 (d, 1H, J=7.8), 10.03 (s, 1H); HRMS m/z calcd for C21H20N4O3H: 377.1614. found 377.1631.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=NC#N)[C:12]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1)#[N:2].C(NCC)C>C1COCC1>[C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=NC#N)N2
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(C=N2)CCCCC1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
Crude 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide (95.0 g; purity 78% HPLC area) in THF (250 mL) was treated with diethylamine (105 g) and refluxed with a concomitant addition of THF (3.35 L) until dissolved. The solvent was distilled off (2.5 L) during which a precipitate was formed. The flask was cooled to ambient temperature and the white precipitate was filtered, washed with ether and dried to give 58.0 g (61% yield) of purified 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol])-2′-ylidenecyanamide (purity >99% HPLC area).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)O[C:10](=[O:11])[C:5]=2[CH:4]=1.CC#N.[NH2:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:30][CH2:29]2)=[O:27])[CH2:22][CH2:21]1>>[NH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([NH:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH2:30][CH2:29]2)=[O:27])[CH2:22][CH2:21]1)=[O:11]
Reactant: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CN)CC2)CC1
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: CC#N
Product: COc1ccc(N)c(C(=O)NC[C@H]2CC[C@H](C(=O)N3CCN(C(=O)C(C)C)CC3)CC2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 6-Methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (96 mg, 0.5 mmol) in CH3CN (5 mL) K2CO3 (140 mg, 1 mmol) and 1-[trans-4-(4-Aminomethyl-cyclohexanecarbonyl)-piperazin-1-yl]-2-methyl-propan-1-one (148 mg, 0.5 mmol) were added and the reaction was heated at 50° C. for 16 h. The solvent was removed under reduced pressure, 5 mL of 0.4M Na2CO3 solution were added and the mixture was stirred for 1 h. Then 5 mL of DCM were added, the organic phase collected, dried over Na2SO4 and the solvent removed under reduced pressure. 156 mg of the titled product were obtained (yield=68%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][C@@H:14]([CH3:28])[C@@H:15]([CH3:27])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].C[O-].[Na+].[N+:32]([C:35]1[N:36]=[CH:37][NH:38][CH:39]=1)([O-:34])=[O:33]>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([CH2:16][C@H:15]([CH3:27])[C@H:14]([CH3:28])[CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH2:3][CH2:2][N:38]3[CH:39]=[C:35]([N+:32]([O-:34])=[O:33])[N:36]=[CH:37]3)[CH:6]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCBr)c2)cc1OC
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCn3cnc([N+](=O)[O-])c3)c2)cc1OC
Yield: 61.2 %

Procedure:
The Standard Procedure 2 was followed by use of 5a (58.2 mg, 0.129 mmol, 1.0 equiv), sodium methoxide (15.4 mg, 0.285 mmol, 2.2 equiv), and 4-nitroimidazole (6a, 29.3 mg, 0.259 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 7a (38.1 mg, 0.0789 mmol) was obtained in 61% yield as white solids: mp (recrystallized from methanol) 80.4-81.0° C.; 1H NMR (CDCl3, 400 MHz) δ 0.79 (d, J=6.8 Hz, 3H, CH3), 0.83 (d, J=6.4 Hz, 3H, CH3), 1.59-1.76 (m, 2H, 2×CH), 2.17-2.35 (m, 2H, 2×ArCH), 2.67-2.71 (m, 2H, 2×ArCH), 3.82 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.18-4.22 (m, 2H, CH2N), 4.36 (t, J=4.6 Hz, 2H, CH2O), 6.51 (s, 1H, ArH), 6.65-6.68 (m, 2H, 2×ArH), 6.73-6.78 (m, 3H, 3×ArH), 7.60 (s, 1H, nitroimidazole C5-H), 8.12 (s, 1H, nitroimidazole C2-H); 13C NMR (CDCl3, 100 MHz) δ 16.06, 16.20, 38.25, 38.95, 39.04, 39.06, 47.92, 55.77, 55.81, 55.92, 68.08, 111.17, 111.66, 112.45, 115.50, 120.60, 120.90, 123.10, 134.34, 134.58, 136.56, 146.66, 146.99, 147.82, 148.03, 148.60; IR (neat) 2957 (s), 2933 (s), 1589 (w), 1543 (s), 1516 (s), 1455 (w), 1337 (s), 1261 (s), 1236 (s), 1029 (s) cm−1; HRMS (FAB) m/z calcd for C26H34N3O6 (M+H)+: 484.2448. found: 484.2444.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=1)[C:9]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:8]2)=[O:4].C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=1)[C:9]([C:26]([OH:28])=[O:27])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)cc(C(=O)OC(C)(C)C)n2Cc1cc(-c2ccc(Cl)s2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)cc(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.5 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid 2-tert-butyl ester 5-methyl ester were dissolved in 300 ml trifluoro-acetic acid and stirred for 1 h at RT. Then 200 ml toluene were added and the solvents were removed under reduced pressure. This procedure was repeated three times, then the residue was dried in vacuo. Yield: 8.4 g.