Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)C(Cl)=O)([O-])=O.Cl.[C:14]([O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=1)=[O:25])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1c1cccc(N)c1

Procedure:
3-Nitrobenzoyl chloride was reacted with L-proline tert-butyl ester hydrochloride, then hydrogenated to produce (S)-1-(3-amino-phenyl)-pyrrolidin-2-carboxylic acid tert-butyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The tert-butyl ester was deprotected by treating the chloroform solution of the ester with 4.0 M solution of hydrogen chloride in dioxan to afford the title compound as the hydrochloride salt. 1H NMR (300 MHz, d6-DMSO) (mixture of tautomers) 14.10 (1H, br s), 10.95 (1H, br m), 8.00 and 7.79 (1H, 2×m), 7.88 (1H, m), 7.41 (1H, m), 7.26 and 7.11 (1H, 2×), 4.43 (1H, m), 4.12 (1H, m), 3.48 (1H,m), 2.97 (3H, m), 2.28-1.29 (31H, m). Found: C, 64.88; H, 7.78; N, 8.92%; C34H45ClN4O4.1.0 mol H2O requires: C, 65.11; H, 7.55; N, 8.93%.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4](C2CCCCO2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=2.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>CO>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH3:1][O:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=2
Reactant: COCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1nc(N)c2nc(OC)[nH]c2n1
Reaction time: 48 h

Procedure:
8-(Methoxy)-2-{[2-(methyloxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.2032 g) was dissolved in methanol (10 mL) which was treated with neat trifluoroacetic acid (1 mL) and then stirred for 2 days. The reaction mixture was evaporated under reduced pressure and the resultant solid suspended in ethyl acetate (25 mL) before being filtered to give the title compound (1.1310 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[O:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[O:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:3]=1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: Clc1cc(N2CC3CCC(C2)O3)nc(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3CC4CCC(C3)O4)n2)cc1
Temperature: 100 °C
Yield: 77.5 %

Procedure:
In a 0.5-2 mL microwave vial was placed 3-(6-chloro-2-iodopyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (16, 50 mg, 0.142 mmol) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (35.4 mg, 0.142 mmol) in DME (1.5 ml) to give an orange solution. Na2CO3 (2M solution in water) (0.284 ml, 0.569 mmol) was added. The mixture was degassed by bubbling nitrogen through the solution. Pd(PPh3)4 (16.43 mg, 0.014 mmol) was added and the mixture was heated under microwave irradiation for 60 min at 100° C. The mixture was diluted with ethyl acetate and washed with a saturated solution of NaHCO3. The organic phase was dried (MgSO4) and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (10-25%). Collected fractions were concentrated to give 39 mg (0.11 mmol, 79%) of the title compound as an off-white/yellow solid. The thus obtained compound was identical to the same compound prepared according to Scheme 5.
Reaction SMILES: C([O:8][CH2:9][CH:10]([CH2:26][O:27]CC1C=CC=CC=1)[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([NH:23]C=O)=[N:17][C:18]=2Cl)C1C=CC=CC=1.C(O)=[O:36].N>[Pd].O>[OH:8][CH2:9][CH:10]([CH2:26][OH:27])[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:36])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2
Reactant: O=CNc1nc(Cl)c2ncn(OCC(COCc3ccccc3)COCc3ccccc3)c2n1
Reactant: O=CO
Agent: [Pd]
Agent: N
Solvent: O
Product: Nc1nc2c(ncn2OCC(CO)CO)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 9-(3-benzyloxy-2-benzyloxymethylprop-1-oxy)-2-formamido-6-chloropurine (2.5 g, 5.2 mmol) and 80% formic acid (100 ml) was stirred at 100° C. for 1 hour, cooled and 10% palladium on charcoal (2.0 g) added. The mixture was then stirred under an atmosphere of hydrogen for 45 minutes. The catalyst was removed and the solution evaporated under reduced pressure. The residue obtained was heated in water (100 ml) until boiling commenced. Concentrated aqueous ammonia (4 ml) was added and the solution was then heated for a further 15 minutes, cooled and evaporated under reduced pressure. Recrystallisation from water (charcoal) afforded 9-(3-hydroxy-2-hydroxymethylprop-1-oxy)guanine (430 mg, 32%). IR: υmax (KBr) 3380, 3183, 1679, 1637, 1605, 1541, 1479, 1395 cm-1. 1H NMR: δH [(CD3)2SO] 1.94 (1H, m, CH), 3.53 (4H, m, 2×CH2OH), 4.26 (2H, d, J=6.3 Hz), 4.57 (2H, t, J=5.2 Hz, D2O exchangeable, 2×OH), 6.58 (2H, br.s, NH2), 7.92 (1H, s, H-8), 10.64 (1H, br.s, D2O exchangeable, H-1). Found: C, 42.08; H, 5.15; N, 27.41%. C9H13N5O4 requires: C, 42.34; H, 5.14; N, 27.44%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].C(O)C>[NH2:15][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9]
Reactant: [H][H]
Reactant: Cc1cccc(S(=O)(=O)NC(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(S(=O)(=O)NC(C)C)c1N
Yield: 100 %

Procedure:
To a mixture of 4.13 g of the material from Step A and 0.25 g of 10% palladium on carbon was added 150 mL of ethanol. The reaction mixture was stirred under a balloon of hydrogen for three days. The mixture was filtered through celite and the solvent was removed with a rotary evaporator to afford 3.65 g of the title compound as a brown oil. 1H NMR (CDCl3) δ 1.03 (d, 6H), 2.21 (s, 1H), 3.60 (m, 1H), 4.57 (br d, 1H), 4.86 (br s, 2H), 6.73 (dd, 1H), 7.24 (d, 1H), 7.64 (d, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].Br[CH2:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1)=O>>[CH3:21][C:17]1([CH3:22])[CH2:16][CH2:15][C:14]([CH3:23])([CH3:24])[C:13]2[CH:12]=[C:11]([C:9]3[N:6]=[C:4]([CH2:3][C:1]#[N:2])[S:5][CH:8]=3)[CH:20]=[CH:19][C:18]1=2
Reactant: N#CCC(N)=S
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(CC#N)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 576 mg (5.75 mmol) of 2-cyanothioacetamide and 2 g (4.72 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[N:25][NH:26][CH:27]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1c2cc(-c3cn[nH]c3)sc2C(=O)NC1(C)C
Yield: 45.7 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (291 mg, 1.50 mmol), sodium carbonate (265 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (2.5 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL), and the mixture was shaken well. The insoluble materials were filtered off. From the filtrate, the organic layer was collected, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc, then EtOAc to 90:10 EtOAc/MeOH) to afford a white solid (60 mg). This solid was triturated with EtOAc/hexane and collected by filtration to afford the title compound (50.3 mg, 38%) as a white solid:
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][N:7]=1.C1C(=O)N([Cl:27])C(=O)C1>>[Cl:27][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][N:7]=[CH:6]2
Reactant: COC(=O)c1cncc2ccccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cncc2cccc(Cl)c12
Temperature: 60 °C
Yield: 77.7 %

Procedure:
To a well stirred solution of conc. H2SO4 (28.5 mL) and methyl isoquinoline-4-carboxylate (5.0 g, 26.7 mmol) at 0° C. was added, NCS (35.7 g, 267 mmol) slowly and the reaction mixture was allowed to come to RT and then heated to 60° C. overnight. After completion (TLC), it was quenched with ice, neutralized (NaHCO3) and extracted with EtOAc (100 mL×3). The organic phase was separated, dried (Na2SO4) and concentrated to give dark brown oil (4.6 g) as crude product that was purified by flash column chromatography (15% EtOAc in Hexanes) to furnish the desired compound (3.8 g, 64%) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](F)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:16][NH2:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:17][CH3:16])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: Fc1cc(-c2cccnc2Cl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-c2cccnc2Cl)ccn1
Temperature: 80 °C

Procedure:
To 2-chloro-2′-fluoro-[3,4′]bipyridinyl (5.30 g, 25.4 mmol), methylamine hydrochloride (9.00 g, 133 mmol) and K2CO3 (28.1 g, 203 mmol) was added DMSO (70 mL). The mixture was heated overnight at 80° C. in a sealed tube. The cooled mixture was diluted with water (300 mL) and the resulting solid was filtered, washed with water and dried to yield (2-chloro-[3,4′]bipyridinyl-2′-yl)-methyl-amine. MS m/z=220 [M+1]+. Calc'd for C11H10ClN3: 219.68.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.[NH2:15][NH2:16]>C(O)C>[C:3]([NH:15][NH2:16])(=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC(=O)OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCCCCCCC(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
17.5 g of decanoic acid methyl ester is dissolved in 1 l of absolute ethanol and mixed with 350 ml of hydrazine hydrate. It is refluxed for 3 hours and then stirred overnight at room temperature. The solution is concentrated by evaporation to about 300 ml and allowed to stand until the product is crystallized out. After it is filtered off and dried, 16.6 g (=94% of theory) of decanoic acid hydrazide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[NH:11][C:12]2[C:13]3[N:26]=[N:25][N:24]([CH:27]4[CH2:31][CH2:30][CH:29]([OH:32])[CH:28]4[OH:33])[C:14]=3[N:15]=[C:16]([S:18]([CH2:21][CH2:22][CH3:23])(=O)=O)[N:17]=2)=[CH:4][CH:3]=1.[CH2:34](S)CCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[NH:11][C:12]2[C:13]3[N:26]=[N:25][N:24]([CH:27]4[CH2:31][CH2:30][CH:29]([OH:32])[CH:28]4[OH:33])[C:14]=3[N:15]=[C:16]([S:18][CH2:21][CH2:22][CH2:23][CH3:34])[N:17]=2)=[CH:4][CH:3]=1
Reactant: CCCCS
Reactant: CCCS(=O)(=O)c1nc(NC2CC2c2ccc(Cl)cc2)c2nnn(C3CCC(O)C3O)c2n1
Product: CCCCSc1nc(NC2CC2c2ccc(Cl)cc2)c2nnn(C3CCC(O)C3O)c2n1

Procedure:
The title compound was prepared as described in Example 8 using the product from step b) and butanethiol.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1)[CH3:9]
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)O
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(Oc1ccc(Cl)cc1Cl)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 250 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser, was charged with 28.2 grams (0.120 mole) of 2-(2,4-dichlorophenoxy)propanoic acid, (10.9 grams, 0.120 mole) of thiosemicarbazide and 90 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (20.2 grams, 0.13 mole) was slowly added (for 38 minutes) while maintaining the temperature within 90°-95° C. The resulting mixture was refluxed for 115 minutes, and then evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane). One hundred (100) milliliters of water was added and 50 percent NaOH solution was also added until the pH of the solution was 10. An oil formed, which was extracted with a mixture of CH2Cl2, CHCl3 and diethyl ether, and the organic phase was dried over anhydrous MgSO 4, filtered and topped on a roto-vac at 70° C. to a grey sludge. Upon addition of diethylether, a first crop of crystals formed which were removed by filtration and then dried in a vacuum oven at 80° C. to crystals containing 5-[1-(2,4-dichlorophenoxy)ethyl-2-amino-1,3,4-thiadiazole (9.7 grams). Addition of hexane to the filtrate produced a second crop of crystals which were filtered off, dried in a vacuum oven at 80° C. to 10.1 grams of crystals. The first and second crop of crystals were combined, and recrystallized from the minimum amount of an ethanol water mixture, suction filtered, and dried in a vacuum oven at 80° C. to 17.1 grams of a grey powder of 5-[1-(2,4-dichlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole. (Melting point 119°-123° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)Cl)=[CH:5][CH:4]=1.[NH2:21][C:22]([NH2:27])=[N:23][C:24]([NH2:26])=[S:25].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:26]=[C:24]([NH:23][C:22]([NH2:27])=[NH:21])[S:25][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Reactant: NC(=S)N=C(N)N
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc(NC(=N)N)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A mixture of 1,2-bis(4-methoxyphenyl)-2-chloroethanone (1.00 g) and N-diaminomethylenethiourea (0.65 g) in ethanol (20 ml) was refluxed for 12 hours. After allowing to cool to ambient temperature, then the reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed n alumina, eluting with a mixture of chloroform and methanol. The desired fractions were combined and concentrated in vacuo. The residue was washed with isopropy ether to give 4,5-bis(4methoxyphenyl)-2-guanidinothiazole (0.65 g).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].I[C:8]1[CH:9]=[N:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]1([C:8]2[CH:9]=[N:10][N:11]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Ic1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Yield: 59.6 %

Procedure:
Trityl chloride (1.58 g, 5.67 mmol) was added to a stirred cold (0-5° C.) solution of 4-iodo pyrazole (1 g, 5.15 mmol) and triethylamine (1.04 g, 10.3 mmol) in DCM (12 mL). Stirring was continued at room temperature overnight. Cold water was then added and the product was extracted with DCM and the organic layer was washed with saturated sodium bicarbonate solution followed by brine. The organic phase collected was dried over Na2SO4 and concentrated under reduced pressure The residue was purified by column chromatography (using neutral alumina and 2% EtOAc in hexane as eluent) to afford 1.9 g (84.4% Yield) of 4-iodo-1-trityl-1H-pyrazole. Na2CO3 (727 mg, 6.86 mmol) was added to a stirred solution of 4-iodo-1-trityl-1H-pyrazole (1.5 g, 3.43 mmol) in toluene: H2O (4:1, 20 mL). Pd(PPh3)4 (790 mg, 0.686 mmol) and phenylboronic acid (838 mg, 6.86 mmol) were then added and the reaction mixture was heated to reflux for 2 hrs. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated to in vacuo. Purification by column chromatography (using neutral alumina and 5% EtOAc in hexane as eluent) afforded 790 mg (59.4% Yield) of 4-phenyl-1-trityl-1H-pyrazole. 1H NMR (300 MHz, CDCl3): δ 7.96-7.94 (s, 1H), 7.64-7.6 (s, 1H), 7.46-7.4 (d, 2H), 7.36-7.0 (m, 11H), 7.24-7.16 (m, 7H). A solution of 4-phenyl-1-trityl-1H-pyrazole (785 mg, 2.03 mmol) in ether.HCl (15 mL) was stirred for 1 hr. The reaction mixture was then concentrated under reduced pressure and washed with hexane to afford 320 mg (87.4% Yield) of 4-phenyl-1H-pyrazole hydrochloride. 1H NMR (300 MHz, DMSO-d6): δ 8.1-8.08 (s, 2H), 7.64 (d, 2H), 7.38 (t, 2H), 7.22 (t, 1H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13](/[CH:17]=[CH:18]/[CH2:19][CH3:20])C(=O)C)[C:7]1[CH:12]=CC=CC=1.[ClH:21]>CN(C=O)C>[Cl:21][C:6]1[CH:7]=[CH:12][C:18]([CH2:19][CH3:20])=[CH:17][N:13]=1
Reactant: CC/C=C/N(Cc1ccccc1)C(C)=O
Reactant: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(Cl)nc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 19 %

Procedure:
To DMF (3.8 mL) at 5° C., was added POCl3 (1.4 mL) dropwise. After 5 minutes, 62b (1 g, 4.9 mmol) was added dropwise in 2 mL of DMF. The mixture was heated to 100° C. overnight. The mixture was allowed to cool to room temperature and was added dropwise to 50 mL of 1N HCl. The solution was extracted 3 times with ethyl acetate. The combined organic layer was dried, evaporated, then purified by column chromatography (eluent: 0 to 30% EtOAc in hexane) to give 0.13 g of 62c (19% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][C@@H:17]([C:19]([N:21]1[C@H:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[NH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:37]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:38]([OH:40])=[O:39]>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][C@@H:17]([C:19]([N:21]1[C@H:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[NH:18][CH:37]([C:38]([OH:40])=[O:39])[CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2CN1C(=O)[C@@H](N)CCSCCNC(=O)OCc1ccccc1
Solvent: CO
Product: CCOC(=O)[C@@H]1Cc2ccccc2CN1C(=O)[C@H](CCSCCNC(=O)OCc1ccccc1)NC(CCc1ccccc1)C(=O)O
Yield: 25 %

Procedure:
S-(2-Benzyloxycarbonylaminoethyl)-N-tert-butoxy-carbonyl-L-homocysteine (2.14 g., 0.00518 mole) and ethyl 1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (1.12 g., 0.00545 mole) were coupled via the procedure described in Example 5 to give 2.24 g. (72%) of ethyl N-[S-(2-benzyloxycarbonylaminoethyl)-N-tert-butoxycarbonyl-L-homocysteinyl]-1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (1); an oil. Compound 1 (1.10 g., 0.00183 mole) was stirred for 50 minutes at room temperature with 25 ml of trifluoroacetate acid. Concentration in vacuo gave ethyl N-[S-(2-benzyloxycarbonylaminoethyl)-L-homocysteinyl]1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (2) as a crude orange oil. This intermediate (2) was reductively alkylated with 2-oxo-4-phenylbutyric acid (3.00 g., 0.0068 mole) according to the procedure described in Example 5. After chromatography on an LH-20 column with methanol, 0.30 g. (25%) of ethyl N-[S-(2-benzyloxycarbonylaminoethyl)-N-(1-carboxy-3-phenylpropyl)-L-homocysteinyl]-1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (3) was obtained; a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:15]3([CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]3)[C:8]3([NH:12][C:11](=S)[C:10]([CH3:14])=[N:9]3)[C:6]=2[CH:7]=1.[NH3:24].CO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:15]3([CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]3)[C:8]3([N:12]=[C:11]([NH2:24])[C:10]([CH3:14])=[N:9]3)[C:6]=2[CH:7]=1
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(=S)N1
Reactant: N
Solvent: CO
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(N)=N1
Temperature: 120 °C
Yield: 27 %

Procedure:
A mixture of 5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazole]-4″(3″H)-thione (Example 29 Step 3, 365 mg, 0.92 mmol) and 7M ammonia in MeOH (10 mL, 70.00 mmol) was prepared in a microwave vial. The vial was sealed and the reaction was heated at 120° C. for 30 min in a microwave reactor. The mixture was concentrated and the residue was dissolved in 7M ammonia in MeOH (4 mL) and heated once more at 120° C. for 30 min using MW. Again, the mixture was concentrated, 7M ammonia in MeOH (10 mL, 70.00 mmol) was added and the mixture was heated at 120° C. The mixture was concentrated and the crude product was dissolved in 20% MeOH in DCM and filtered through a silica pad and eluted with 20% MeOH in DCM. After concentration of the organic layer, DCM was added to the residue. A solid was formed which was filtered off and washed with DCM, yielding 94 mg of the title compound (27% yield). The mother liquor was concentrated, Et2O was added and the solid was filtered off and dried, yielding a second crop of the title compound (85 mg, 24% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 (d, 1 H), 1.43 (m, 3 H), 1.80 (d, 2 H), 1.95 (m, 2 H), 2.20 (s, 3 H), 3.07 (d, 1 H), 3.21 (s, 3 H), 6.68 (d, 1 H), 6.74 (br. s., 2 H), 6.87 (d, 1 H), 7.31 (dd, 1 H); MS (ES+) m/z 379 [M+H]|.