Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[C:13](Cl)(Cl)=[S:14]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[N:4]=[C:13]=[S:14]
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1C
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(N=C=S)c1C
Yield: 95 %

Procedure:
To a solution of 2,3-dimethyl-6-nitroaniline (3.0 g, 1.0 equiv.) in toluene (150 mL) was added thiophosgene (2.5 mL, 1.8 equiv.) and the reaction mixture was heated at the reflux temp. overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (10% CH2Cl2/hex) to afford 2,3-dimethyl-6-nitrophenyl isothiocyanate as a light yellow solid (3.63 g, 95%): 1H NMR (CDCl3) δ2.39 (s, 3H), 2.40 (s, 3H), 7.17 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, light grey solid (75 mg, 92%), MS (ISP) m/z=327.4 [(M+H)+], mp 257° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9]([Li])[CH2:10][CH2:11]C.C(I)CC.Cl>CCCCCC.O>[O:4]=[C:3]([CH2:5][CH2:9][CH2:10][CH3:11])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: [Li]CCCC
Agent: Cl
Solvent: O
Solvent: CCCI
Solvent: CCCCCC
Product: CCCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
After stirring for 20 minutes, 9.3 ml of methyl acetoacetate were dropped, stirring was continued for 30 minutes at 0° C. and further 54 ml of butyllithium 1.6M in hexane were dropped. After further 30 minutes 8.4 ml of propyl iodide were dropped into the dark orange solution. The temperature was allowed to raise to room temperature and after 30 minutes, 50 ml of 37% HCl diluted with 100 ml of H2O were continuously dropped while keeping the temperature under 15° C. The reaction mixture was extracted with Et2O. The organic phase was washed with a NaCl saturated solution, dried on Na2SO4 and evaporated to dryness. The residue was purified by FC (eluent: AcOEt/hexane 1:9). 8.3 g of a clear oil were obtained (yield 61%); 1H-NMR (200 MHz, CDCl3)δ: 0.90 (t, 3H), 1.22-1.65 (m, 4H), 2.53 (t, 2H), 3.44 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]2([OH:14])[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:5][CH:6]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2([OH:14])[CH2:12][CH2:11][CH:10]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:9][CH2:8]2)[S:5][CH:6]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2cc(Br)cs2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cc(Br)cs3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reductive amination of 4-(4-bromo-thiophen-2-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:11][C:12]1[CH:13]=[C:14]([C@@H:18]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=2)[CH3:19])[CH:15]=[CH:16][CH:17]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C@@H:18]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=2)[CH3:19])[CH:13]=1)=[O:9]
Reactant: Nc1cncc(C(=O)O)c1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(NC(=O)c2cncc(N)c2)c1
Yield: 38 %

Procedure:
To a mixture of 5-aminonicotinic acid (35 mg, 0.25 mmol), N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (125 mg, 0.5 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol) in N,N-dimethylformamide (2 mL) was added 1-hydroy-7-azabenzotriazole (1 mL, 0.5-0.7M in N,N-dimethylformamide, 0.5 mmol) then N-methylmorpholine (0.055 mL, 0.5 mmol) and the mixture was stirred at room temperature for 16 hours. After this time the mixture was diluted with ethyl acetate (40 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/methanol) to give 5-amino-N-(3-{(1S)-1-[(6-chloropyrazin-2-yl)amino]ethyl}phenyl)nicotinamide (35 mg, 38%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]=[C:4]([CH3:6])[CH:3]([O:7][CH3:8])[O:2][CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COC(OC)C(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: COC(OC)C(C)=NCc1ccccc1
Temperature: 25 °C

Procedure:
12.9 mL 1,1-dimethoxyacetone was added to 10 mL benzylamine in 100 mL petrolether. Magnesiumsulfate was added and the reaction was stirred over night at RT. The mixture was filtered and evaporated to give 18.9 g of the desired product. (M+H)+: 209
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:7][C:8]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:20]=2)=[C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)[N:10]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[C:26]([NH:25][C:21]1[CH:20]=[C:19]([C:8]2[S:7][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[N:10][C:9]=2[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)[CH:24]=[CH:23][N:22]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccnc(NC(=O)c3ccccc3)c2)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccnc(NC(=O)c3ccccc3)c2)s1
Temperature: 70 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
Acetyl chloride (0.26 mL, 3.7 mmol) and 4-dimethylaminopyridine (0.09 g, 0.76 mmol) were added to a solution of N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (0.96 g, 2.4 mmol) in N,N-dimethylacetamide (20 mL) and the mixture was stirred at 70° C. for 16 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethyl acetate to obtain 0.32 g (yield 30%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:14]=O>>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:14]=[C:6](/[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)\[C:7]#[N:8])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1cccs1
Product: COc1ccc(/C=C(\C#N)c2cccs2)cc1OC
Yield: 48.3 %

Procedure:
2-Thiopheneacetonitrile (246 mg) was condensed with 3,4-dimethoxybenzaldehyde (332 mg) through Method B (production step 2), to thereby yield the target product (yield: 262 mg, 48%).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([N+:13]([O-])=O)=[CH:5][N:4]=1)#[N:2]>[Au].CCOCC>[NH2:13][C:6]1[CH:7]=[C:8]([C:9]([F:12])([F:10])[F:11])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Au]
Solvent: CCOCC
Product: N#Cc1ncc(N)cc1C(F)(F)F
Yield: 81.9 %

Procedure:
2-Cyano-5-nitro-3-trifluoromethylpyridine (0.065 g, 0.3 mmol) was reacted in the same manner as described in example 762D to give the desired compound 763E (0.046 g, 82%) as a gold colored solid after trituration with ether. HPLC: 100% at 2.07 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 187.82 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH:31]=2)O1.N#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:30]3[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH:31]=3)=[CH:10][C:3]=12
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)ccnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)C1CC=C(c2cc3c(Cl)ccnc3n2S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 100 °C

Procedure:
A solution of 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (2.0 g, 4.4 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (1.6 g, 5.5 mmol) and bis(triphenylphosphine)palladium(ii) chloride (324 mg, 0.5 mmol) in a mixed solvent of 1,2-dimethoxyethane/ethanol/water with ratio of 7/3/2 (200 mL) was purged with N2 and heated at 100° C. overnight. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was concentrated and purified by flash chromatography on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (50%) to give desired product. MS (ESI+) m/z 460 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25]OS(C)(=O)=O)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:33]=[N+:34]=[N-:35])[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Reaction time: 5 h
Yield: 64.4 %

Procedure:
(5R)-3-(4-((3R)-3-(t-butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluorophenyl)-5-methane-sulfonyloxymethyloxazolidin-2-one (1.25 g, 2.64 mM) was dissolved in N,N-dimethyl-formamide (20 ml), treated with sodium azide (275 mg, 4.23 mM), and heated with stirring at 50° for 5 hours. After cooling the mixture was diluted with water (100 ml), and extracted into ethyl acetate (3×75 ml). The combined organics were dried (magnesium sulfate), and evaporated to give a yellow solid, which 5:19 PM was recrystallised from isopropanol to give the required product (715 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]>O1CCCC1.[Pd]>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C=Cc2ccc(-c3ccc(F)cc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1ccc(CCc2ccc(-c3ccc(F)cc3)cc2)cc1

Procedure:
A solution of 10.6 g of 1-(p-n-propylphenyl)-2-(4'-fluorobiphenyl-4-yl)ethene [obtained by Heck coupling of 4-propylstyrene with 4-bromo-4'-n-fluorobiphenyl] in 200 ml of tetrahydrofuran is hydrogenated in the presence of Pd/C until the take-up H of is complete. Customary work-up gives 1-(p-propylphenyl)-2-(4'-fluorobiphenyl-4-yl)ethane, mp. 97°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[CH2:16])[CH2:13][CH:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27](Br)[CH:28]=3)[CH:23]=2)=[CH:20][N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:34]([O:38][C:39]([N:41]1[CH2:45][CH:44]([C:46]#[N:47])[CH2:43][CH:42]1[C:48]1[NH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56](B3OC(C)(C)C(C)(C)O3)=[CH:55][CH:54]=2)=[CH:51][N:52]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH:44]([C:46]#[N:47])[CH2:43][CH:42]1[C:48]1[NH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56]([C:27]3[CH:26]=[CH:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([C:19]5[NH:18][C:17]([CH:12]6[CH2:13][C:14](=[CH2:16])[CH2:15][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:33])[CH:6]([CH3:8])[CH3:7])=[N:21][CH:20]=5)[CH:23]=4)[CH:28]=3)=[CH:55][CH:54]=2)=[CH:51][N:52]=1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: C=C1CC(c2ncc(-c3ccc4cc(Br)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CC(C#N)CN7C(=O)OC(C)(C)C)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1

Procedure:
(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-methylene-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (202 mg, 0.392 mmol), 4-Cyano-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (181 mg, 0.392 mmol), Pd[PPh3] (45.6 mg, 0.0392 mmol), potassium carbonate (108 mg, 0.784 mmol) were heated in DME (3 mL)/water (0.4 mL) at 120° C. for 20 minutes under microwave conditions. The volatiles were removed in vacuo and the crude was partitioned between EtOAc and brine/aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate. Filtration and evaporation of solvents yielded the crude material, which was purified via flash chromatography on silica gel to yield the product. (161 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH2:21])(=O)=[O:19].[NH3:22]>O1CCOCC1>[NH2:22][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH2:21])=[O:19]
Reactant: N
Reactant: COc1ccc(C(=O)c2ccc(F)c(S(N)(=O)=O)c2)cc1
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2ccc(N)c(S(N)=O)c2)cc1
Temperature: 100 °C
Yield: 81 %

Procedure:
To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide (0.25 g, 0.81 mmol) dissolved in dioxane (3 mL) is added aqueous ammonia solution (1 mL). The reaction mixture is heated at 100° C. for 6 h in sealed tube and then cooled to room temperature and concentrated in vacuo. The residue is partitioned between water and ethyl acetate, and the aqueous phase is extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to provide 0.2 g (81%) of the title compound as a pale yellow solid. 1H NMR (DMSO): δ 8.05 (d, J=2 Hz, 1H), 7.70 (m, 3H), 7.40 (s, 2H), 7.05 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH2:14][C:15](=[O:18])[CH2:16][CH3:17].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]=[O:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]([OH:33])[CH:14]([CH3:13])[C:15](=[O:18])[CH2:16][CH3:17])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCC(=O)CC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(=O)C(C)C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
A solution of diisopropylamine (0.63 mL, 4.5 mmol) in THF (16 mL) at 0° C. was treated with 1.6 M n-butyllithium in sol'n in hexanes (2.8 mL). The resulting solution was stirred at 0° C. for 10 min, then cooled to −78° C. 3-Pentanone (0.41 mL, 4.1 mmol) was added and the resulting mixture was stirred cold for 1 h. A solution of 1-(t-butoxycarbonyl)-4-formylpiperidine (435 mg, 2.05 mmol) (from Step B) in THF (3 mL) was then added. After 15 min, the reaction was quenched with sat'd ammonium chloride (25 mL) and extracted with ether (100 mL). The extract was dried over magnesium sulfate and concentrated. MPLC (Biotage) on a 40S silica cartridge using 4:1 v/v, then 3:2 v/v hexanes/ethyl acetate as the eluent afforded 517 mg (85%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=[O:19])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: O=C(O)c1ccccc1N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 20.9 %

Procedure:
3-nitrophthalic anhydride (1.0 g, 0.0052 mol) and o-aminobenzoic acid (0.71 g, 0.0052 mol) were refluxed as above for four days. The clear solution was purified as per 120 to yield 0.34 g (21%) 127 as pale orange grains: mp=190-192° C.; Rf0.74 (A): Rf0.87 (C): Rf0.62 (E): IR (cm−1): 2700-3300 (OH), 3093 (C═CH), 2620 (C—H), 1718 (C═O), 1681 (bs, C═O), 1609 (C═C), 1592 (C═O), 1534 (N═O), 1482 (C═C), 1451 (C═C), 1360 (N═O), 1316 (C—O), 1257 (C—O), 771 (C═CH); MS m/z (rel intensity) 311 (50), 285 (100), 241 (55), 122 (45).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)[CH2:3]1.I.[NH:44]1[CH2:48][CH2:47][N:46]=[C:45]1S>C(O)C.CN(C1C=CN=CC=1)C>[NH:46]1[CH2:47][CH2:48][N:44]=[C:45]1[NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:8]=2)[CH2:3]1
Reactant: SC1=NCCN1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: I
Solvent: CCO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC5=NCCN5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A mixture comprising N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Example 18 step 2) (30 mg, 0.053 mmol) and 4,5-dihydro-1H-imidazole-2-thiol hydroiodide (24 mg, 0.106 mmol) in absolute ethanol (2 ml) is treated with DMAP (catalytic amount) and TEA (29 μl, 0.212 mmol). The resulting mixture is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 150° C. for 4000 s. The solvent is removed in vacuo and purification of the crude product by preparative HPLC ((30-95% acetonitrile in water—0.1% TFA) affords the title compound. (MH+ 639.63)
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([C:23]#[CH:24])[C:19](=[O:25])[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[CH3:32])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([CH2:23][CH3:24])[C:19](=[O:25])[N:18]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:17]=2[CH3:32])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1c(C)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c1=O
Solvent: CO
Product: CCc1c(C)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c1=O
Reaction time: 1.5 h

Procedure:
To a solution of 5-ethynyl-2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (12.6 mg, 0.0294 mmol) in methanol (2 mL) 10% palladium on charcoal (9.1 mg) was added, It was degassed in vacuo and filled with hydrogen for 3 times then stirred vigorously for 90 min. It was evaporated, sonicated with ethyl acetate, filtered through a 2 g plug of silica gel, eluted with ethyl acetate and evaporated to give the title compound as a pale yellow solid residue (11.3 mg, yield=89%). LC-MS (m/z) 433.6 (MH+); tR=1.67 (method C). 1H NMR (T=+70° C., 500 MHz, DMSO-d6, DMSO-d5=2.50 ppm): 1.02 (t, J=7.3 Hz, 3H, Me of Et), 1.72 (overlapping s, 3H, Me), 1.74-1.85 (overlapping m, 4H), 1.89 (overlapping m, 1H), 2.04 (overlapping s, 3H, Me), 2.06 (overlapping br. m, 1H), 2.52 (overlapping with DMSO-d5 m, 2H, CH2 of Et), 2.68 (m, 1H, CH of Cb), 4.94 (t (unresolved dd), J=9.0; 9.5 Hz, CH—N), 7.01 (dt, J(d)=2 Hz, J(t)=8 Hz, 1H), 7.11-7.20 (m, 4H), 7.34 (q (unresolved dt), J(d)=6.3 Hz, J(t)=7.8 Hz, 1H), 7.45 (t, J=7.4 Hz, 1H, para-H of Ph), 7.52 (br. t, 2H, two meta-H of Ph), 8.60 (br. d, J=8.3 Hz, 1H, NH).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH2:10]1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][C:34](O)=[O:35])=[CH:25]1>>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]3[NH:1][C:34](=[O:35])[CH2:33][C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]([CH3:23])[CH:25]=3)[CH2:10]2)=[CH:16][CH:17]=1)#[N:20]
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: N#Cc1ccc(N2CCCC(N[C@@H]3CCCC[C@H]3N)C2)cc1
Product: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Yield: 31 %

Procedure:
N-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-2-(1-methyl-1H-indol-3-yl)acetamide (15 mg, 0.031 mmol) was synthesized in 32% yield using the procedures described in General Procedure I using 4-(3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (30 mg, 0.10 mmol) and 2-(1-methyl-1H-indol-3-yl)acetic acid (19.02 mg, 0.10 mmol). Anal. Calcd. for C29H35N5O m/z 469.6, found: 470.3 (M+H)+; 1H NMR (500 MHz, MeOH-d3) δ ppm 7.61-7.47 (m, 3H), 7.23 (d, J=8.25 Hz, 1H), 7.14 (t, J=7.70 Hz, 1H), 7.07-6.97 (m, 2H), 6.89 (d, J=8.80 Hz, 2H), 3.80 (dd, J=11.00, 6.60 Hz, 1H), 3.58 (s, 3H), 3.48 (s, 2H), 3.28-3.11 (m, 4H), 3.00-2.91 (m, 1H), 2.87 (dd, J=13.20, 7.15 Hz, 1H), 2.19 (d, J=13.75 Hz, 1H), 2.05-1.92 (m, 2H), 1.90-1.71 (m, 3H), 1.67-1.49 (m, 4H), 1.44-1.34 (m, 2H).