Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[NH:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[C:10]([NH:12][CH2:13][CH:14]=[CH2:15])=[O:11])([O-:3])=[O:2].[O:23]1CCC[CH2:24]1.[H-].[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[N:12]([CH2:13][CH:14]=[CH2:15])[C:24]2=[O:23])[CH:20]=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: C=CCNC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Agent: O=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g of 2-(m-nitroanilino)-N-allylbenzamide and 25 ml of tetrahydrofuran was added 1.1 g of 50 % sodium hydride, and the whole was stirred for 30 minutes at room temperature. To this was added dropwise under cooling 16 g of 30 % phosgene-toluene solution, and the mixture was stirred for one hour at room temperature and then refluxed for 2 hours. After the reaction was finished, the solvent was distilled off from the resulting mixture, and to the residue obtained was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.8 g of 1-(m-nitrophenyl)-3-allylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 164°-166° C.
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]3[N:18]=[N:19][N:20]([CH:22]([CH3:28])[C:23]([O:25]CC)=[O:24])[CH:21]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Li+].O.OP([O-])(O)=O.[K+]>CO.C1COCC1>[Br:1][C:2]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]3[N:18]=[N:19][N:20]([CH:22]([CH3:28])[C:23]([OH:25])=[O:24])[CH:21]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)C(C)n1cc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)nc2)nn1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C(=O)O)n1cc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)nc2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 25 mL round-bottom flask equipped with a magnetic stirbar was added ethyl 2-(4-{2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)propanate (55 mg, 0.11 mmol), 1 mL of THF and 0.5 mL of MeOH. A 1.0 M lithium hydroxide solution in water (0.53 mL, 0.53 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into a 125 mL separatory funnel containing saturated aqueous KH2PO4 solution (75 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to yield a beige crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>CN(C=O)C.O.CCN(CC)CC>[NH2:1][C:2]1[C:3]([C:9]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[C:34]([F:33])[CH:35]=2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: Nc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncc(Br)nc1C(=O)Nc1cccc(F)c1
Reaction time: 6 h
Yield: 70.2 %

Procedure:
3-amino-6-bromopyrazine-2-carboxylic acid (500 mg, 2.29 mmol), HOBT (464 mg, 3.44 mmol) and EDCI (660 mg, 3.44 mmol) were dissolved in dry DMF (20 mL), and the resulting solution was stirred for 6 hours. Then 3-fluoroaniline (305 mg, 2.75 mmol) and Et3N (0.43 mL) was added to the mixture. After being stirred overnight, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by prep-TLC (PE:EtOAc=6:1) to give the pure product of 3-amino-6-bromo-N-(3-fluorophenyl)pyrazine-2-carboxamide (500 mg, yield: 68%). 1H-NMR (CDCl3, 400 MHz) δ 9.44 (s, 1H), 8.22 (s, 1H), 7.59 (d, J=11.2 Hz, 1H), 7.24˜7.27 (m, 2H), 6.79˜6.82 (m, 1H), 3.21 (s, 2H). MS (M+H)+: 311/313.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6]2.ClS([N:20]=[C:21]=O)(=O)=O.CN(C)C=O.O>C(#N)C>[C:21]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]=1[C:12]([F:15])([F:13])[F:14])#[N:20]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc2[nH]c(C(F)(F)F)cc2c1
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(C(F)(F)F)c(C#N)c2c1
Reaction time: 2.5 h
Yield: 25 %

Procedure:
A solution of 5-methoxy-2-(trifluoromethyl)indole (3.0 g, 13.0 mmole) in acetonitrile is treated dropwise with chlorosulfonyl isocyanate (2.02 g, 14.3 mmole) at 0° C., stirred at ambient temperatures for 2.5 hours, treated with dimethylformamide (DMF) (2.1 g, 28.6 mmole), stirred at ambient temperatures for 0.75 hour and poured into water. The resultant mixture is extracted with diethyl ether. The combined extracts are washed sequentially with water and brine, dried over MgSO4 and concentrate in vacuo to give a brown oil residue. The oil is crystallized in ether/hexanes to give the title product as brown crystals, 0.78 g (25% yield), mp 189°-190° C., identified by IR, 1HNMR, 13CNMR and 19FNMR.
Reaction SMILES: [CH2:1]([N:3]([CH2:43][CH3:44])[C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][C:29]=4[O:30][C:6]=2[CH:5]=1)[N:26]=[C:25]([CH:31]=CC1C=CC(N(C)C)=CC=1)[CH:24]=[C:23]5[CH3:42])[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:12](=[O:19])[O:11]3)[CH3:2].[N+:45]([C:48]1[CH:55]=[CH:54][C:51]([CH:52]=O)=[CH:50][CH:49]=1)([O-:47])=[O:46].C(OC(=O)C)(=O)C.N>O>[CH2:43]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][C:29]=4[O:30][C:6]=2[CH:5]=1)[N:26]=[C:25]([CH:31]=[CH:52][C:51]1[CH:54]=[CH:55][C:48]([N+:45]([O-:47])=[O:46])=[CH:49][CH:50]=1)[CH:24]=[C:23]5[CH3:42])[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:12](=[O:19])[O:11]3)[CH3:44]
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc3nc(C=Cc4ccc(N(C)C)cc4)cc(C)c3cc1C21OC(=O)c2ccccc21
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCN(CC)c1ccc2c(c1)Oc1cc3nc(C=Cc4ccc([N+](=O)[O-])cc4)cc(C)c3cc1C21OC(=O)c2ccccc21
Temperature: 160 °C
Yield: 51.4 %

Procedure:
2.3 grams (0.005 moles) of 9-(diethylamino)-2-(4-dimethylaminostyryl)-4-methylspiro [6H-[1] benzopyrano [3,2-g] quinoline-6,1'(3'H)-isobenzofuran]-3'-one, 0.6 grams (0.005 moles) of p-nitrobenzaldehyde and 0.5 grams (0.005 moles) of acetic anhydride were mixed in a flask fitted with a reflux condensor, then heated in an oil bath at 160° C. for 4 hours. The bath was cooled and 50 ml of water was added. The mixture was then made alkaline with ammonia, extracted with 100 ml of toluene, dried over sodium sulfate, treated with activated charcoal (DARCO) and filtered. The volume of the solution was reduced to 25 ml by evaporation of the toluene. Ligroine was added to precipitate the product. The yellow-orange solids were filtered off and dried to yield 1.5 grams of product. The reaction sequence was as follows: ##STR15##
Reaction SMILES: [I-:1].[Na+].[C:3]([CH:5]1[CH2:8][N:7]([C:9](=[O:33])[C@H:10]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21](Br)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH3:11])[CH2:6]1)#[N:4].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[C:3]([CH:5]1[CH2:8][N:7]([C:9](=[O:33])[C@H:10]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([I:1])[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH3:11])[CH2:6]1)#[N:4]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(I)nc12)C(=O)N1CC(C#N)C1
Temperature: 110 °C

Procedure:
In a 5 mL microwave vial were placed copper(I) iodide (6 mg, 0.03 mmol), sodium iodide (133 mg, 0.89 mmol), 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (150 mg, 0.30 mmol), 1,4-dioxane (1 mL) and trans-N,N′-dimethylcyclohexane-1,2-diamine (9 mg, 0.06 mmol). The vial was purged with a stream of nitrogen then sealed and heated in an oil bath at 110° C. for 48 h. The reaction mixture was cooled to room temperature and quenched with sat'd aqueous NH4OH (3 mL) then diluted with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated to afford 2-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a maroon oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:20])[CH3:19])([C:15](O)=[O:16])[CH2:10]1.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[CH:35]([O:38][C:39]1[CH:40]=[C:41]([NH2:49])[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)([CH3:37])[CH3:36]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:19])[CH3:20])([C:15]([NH:49][C:41]2[CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:44]=[C:39]([O:38][CH:35]([CH3:37])[CH3:36])[CH:40]=2)=[O:16])[CH2:10]1
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Reactant: CC(C)Oc1cc(N)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(OC(C)C)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxopyrrolidine-3-carboxylic acid (25 mg, 0.091 mmol) and methanesulfonyl chloride (9 μL, 0.12 mmol) in THF (0.9 mL) at 0° C. was added diisopropylethylamine (0.047 mL, 0.27 mmol). The solution was stirred 15 min at 0° C., warmed to ambient temperature, and 3-isopropoxy-5-(trifluoromethyl)benzenamine (39 mg, 0.18 mmol) was subsequently added and the solution was heated at 55° C. overnight. The following day, the reaction mixture was purified via preparative HPLC to afford the desired amide as a white solid. 1H NMR (400 MHZ, CDCl): δ 9.91 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 7.04-7.16 (m, 3H), 6.90-6.94 (m, 1H), 4.65 (septet, J=6.0 Hz, 1H), 3.97 (d, J=10.4 Hz, 1H), 3.66 (d, J=10.8 Hz, 1H), 3.04 (d, J=17.2 Hz, 1H), 2.66 (d, J=17.2 Hz, 1H), 2.36 (septet, J=6.8 Hz, 1H), 2.16 (s, 3H), 2.00 (s, 3H), 1.29 (d, J=6.0 Hz, 6H), 0.96 (t, J=6.4 Hz, 6H). LC-MS Rt (retention time): 3.08 min; MS: (ES) m/z 477 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:10][C:11]([OH:13])=[O:12])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(Br)cs1
Temperature: 25 °C

Procedure:
25 g (131 mmol) of 4-bromo-thiophene-2-carbaldehyde were dissolved in 180 ml of pyridine, and 16.34 g (157 mmol) of malonic acid and 1.11 g (13.1 mmol) of piperidine were added. The reaction mix was boiled under reflux for 6 h. After cooling to room temperature, the mixture was poured onto a mixture of ice and concentrated hydrochloric acid. The precipitated product was isolated by filtration. Yield: 21.15 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Br[C:17]1[CH:18]=[N:19][C:20]([Cl:25])=[C:21]([CH:24]=1)[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:20]1[N:19]=[CH:18][C:17]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: N#Cc1cc(Br)cnc1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnc(Cl)c(C#N)c2)cn1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
A 48 mL tube was charged with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.42 g, 40.5 mmol), 5-bromo-2-chloronicotinonitrile (8.00 g, 36.8 mmol), potassium carbonate (15.3 g, 110 mmol), PdCl2(dppf) (2.69 g, 3.68 mmol), 1,4-dioxane (135 mL, 1582 mmol) and water (23.9 mL, 1324 mmol), flushed with argon, sealed and then heated to 60° C. for 8 h. The reaction mixture was concentrated, adsorbed onto silica gel, and purified via MPLC eluting with 3% MeOH in DCM. 2-chloro-5-(1-methyl-1H-pyrazol-4-yl)nicotinonitrile (4.962 g, 61.7%) was obtained (with a small impurity). The material was taken forward crude.
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:10])[CH2:4][CH2:5][C:6](OC)=[O:7])#[N:2]>C(O)C.[Ni]>[CH3:10][C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:1][NH:2][C:6](=[O:7])[CH2:5][CH2:4]1
Reactant: COC(=O)CCC(C)(C#N)c1ccccn1
Agent: [Ni]
Solvent: CCO
Product: CC1(c2ccccn2)CCC(=O)NC1
Reaction time: 78 h
Yield: 50.7 %

Procedure:
To methyl 4-cyano-4-(2-pyridinyl)pentanoate (Preparation 42, 2.5 g, 11.4 mmol) in ethanol (30 ml) was added Raney nickel (3 g) and the reaction mixture was hydrogenated for 78 h. The reaction mixture was filtered through Celite® washing with ethanol (3.20 ml). The combined organic extracts were concentrated in vacuo to give the crude desired product (2.2 g) which was purified by flash chromatography eluting with dichloromethane:methanol (96:7) to give the pure product as an oil (1.1 g, 5.1%).
Reaction SMILES: [I:1]I.[CH3:3][C@:4]12[CH2:21][CH2:20][C@H:19]3[C@@H:9]([CH2:10][CH2:11][C:12]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:14](=[O:22])[CH:13]=4)[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23]>C(O)(=O)C>[I:1][CH:15]1[CH2:16][C@@:17]2([CH3:18])[C:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:3])[C@H:8]3[CH2:7][CH2:6][C:5]2=[O:23])=[CH:13][C:14]1=[O:22]
Reactant: II
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CC(=O)O
Product: C[C@]12CC(I)C(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Yield: 109.1 %

Procedure:
2.79 g (11 mmol) of iodine is added to 2.86 g (10 mmol) of androst-4-ene-3,17-dione and 0.875 g (11 mmol) of CuO in 30 ml of glacial acetic acid with stirring at room temperature. The reaction mixture is stirred under nitrogen atmosphere for 24 hours at 60° C. Under reduced pressure, acetic acid is distilled off and the residue is mixed with 50 ml of water. The water phase is extracted 3 times with 50 ml of ethyl acetate each, the combined ethyl acetate phases are washed with sodium thiosulfate solution and dried on sodium sulfate. After concentration by evaporation of the solution, 4.5 g of crude product is obtained. After recrystallization from ethyl acetate, 2.9 g of 2-iodo-androst-4-ene-3,17-dione (70% of theory) of melting point 92° C. is obtained.
Reaction SMILES: O1[C:5]2([CH2:9][CH:8]([N:10]([C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])[N:11]=[CH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:7]=[CH:6]2)[O:4]CC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(C)=O>[CH:12](=[N:11][N:10]1[CH:8]2[CH2:9][C:5](=[O:4])[CH2:6][CH:7]2[N:21]([CH2:22][CH2:23][CH3:24])[C:19]1=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCNC(=O)N(N=Cc1ccccc1)C1C=CC2(C1)OCCO2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Product: CCCN1C(=O)N(N=Cc2ccccc2)C2CC(=O)CC21
Reaction time: 4 h
Yield: 115.4 %

Procedure:
An acetone solution (150 ml) of the compound of step (d) (21 g) was stirred at 15° C. while camphorsulphonic acid (2.5 g) was added portionwise over 10 minutes. After 4 hours, the mixture was concentrated in vacuo, water (150 ml) and chloroform (100 ml) added and the organic phase separated. The latter was washed with dilute sodium bicarbonate (100 ml), separated and concentrated in vacuo to give the desired product as a brown oil (21.0 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C@H:3]([NH:34][C:35](=[O:38])[O:36][CH3:37])[C:4](=[O:33])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([C:30]#[C:31][CH3:32])[CH:16]=2)=[CH:13][N:14]=1.Br[C:41]1[CH:42]=[C:43]2[C:66](=[CH:67][CH:68]=1)[C:47]1[NH:48][C:49]([C@@H:51]3[CH2:55][C@H:54]([CH2:56][O:57][CH3:58])[CH2:53][N:52]3[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[N:50][C:46]=1[CH:45]=[CH:44]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.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.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:37][O:36][C:35]([NH:34][C@@H:3]([CH:2]([CH3:39])[CH3:1])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:42]3[CH:41]=[C:68]4[C:45](=[CH:44][CH:43]=3)[C:46]3[NH:50][C:49]([C@@H:51]5[CH2:55][C@H:54]([CH2:56][O:57][CH3:58])[CH2:53][N:52]5[C:59]([O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:60])=[N:48][C:47]=3[CH:66]=[CH:67]4)=[C:17]([C:30]#[C:31][CH3:32])[CH:16]=2)=[CH:13][N:14]=1)=[O:33])=[O:38]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(Br)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: CC#Cc1cc(-c2cnc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CC#Cc1cc(-c2cnc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]2)ccc1-c1ccc2c(ccc3nc([C@@H]4C[C@H](COC)CN4C(=O)OC(C)(C)C)[nH]c32)c1
Temperature: 85 °C
Yield: 29.9 %

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(3-(prop-1-ynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (153 mg, 0.28 mmol), (2S,4S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (158 mg, 0.34 mmol), Pd(PPh3)4 (32 mg, 0.028 mmol), Pd(dppf)2Cl2 (20 mg, 0.028 mmol), and K2CO3 (2M in H2O, 0.46 mL, 0.92 mmoL) were combined in DME (4 mL). The mixture was degassed with bubbling N2 for 10 min the heated to 85° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford (2S,4S)-tert-butyl 2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-2-(prop-1-ynyl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (66 mg, 30%).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=O)[C:13]([C:16]#[N:17])=[C:12]2[C:7]([CH:8](O)[CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1.CO>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:14](=[S:28])[C:13]([C:16]#[N:17])=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc2c(c(C#N)c1=O)CCCC2O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCn1cc2c(c(C#N)c1=S)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
2-Butyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-013) (80 mg, 0.35 mmol) was dissolved in toluene (8 mL), and to the reaction mixture was added Lawesson's reagent (169 mg, 0.42 mmol), the reaction mixture was heated under reflux for 12 h. The reaction mixture was cooled to room temperature, and methanol was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 h, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 2-butyl-3-thioxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-014) (63 mg, 73%) as a pale brown powder.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[C:37]2[CH:38]=[CH:39][C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])=[CH:41][C:36]=2[S:35][N:34]=1>C(Cl)Cl>[C:46]([NH:45][S:42]([C:40]1[CH:39]=[CH:38][C:37]2[C:33]([NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)=[N:34][S:35][C:36]=2[CH:41]=1)(=[O:44])=[O:43])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(NCCCN)nsc2c1
Reactant: O=C(O)c1ccc(I)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(NCCCNC(=O)c3ccc(I)cc3)nsc2c1
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
To a solution of 4-iodobenzoic acid (181 mg, 0.7 mmol) in methylene chloride (2 mL), diethyl cyanophosphonate (115 μL, 0.8 mmol) and 4-methylmorpholine (160 μL, 1.5 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-tert-butylbenzo[d]isothiazole-6-sulfonamide (238 mg, 0.7 mmol) in methylene chloride (4 mL) was then added and the resulting reaction mixture was allowed to stir overnight. The reaction mixture with diluted with methylene chloride (20 mL), washed with 10% HCl aqueous solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 1:1 ethyl acetate:hexanes provided N-(3-(6-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4-iodobenzamide (252 mg). 1H NMR (300 MZh, CDCl3): 8.47 (d, 1H), 7.96 (dd, 1H), 7.86 (d, 1H), 7.82 (d, 2H), 7.60 (d, 2H), 7.37 (t, 1H), 6.19 (br s, 1H), 4.98 (s, 1H), 3.75 (t, 2H), 3.60 (dd, 2H), 2.02 (q, 2H), 1.29 ppm (s, 9H). 13C NMR (CDCl3): 167.25, 159.79, 154.96, 139.87, 138.01, 134.16, 128.91, 126.28, 121.54, 121.19, 98.76, 55.46, 43.08, 40.33, 37.32, 30.66, 30.06. MW=572 confirmed by LC-MS, tr=14.28 min (Method Y) MH+=573.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C@H:18]([OH:34])[CH2:19][NH:20][C:21]([CH3:33])([CH3:32])[CH2:22][CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)[CH:12]=[CH:11][C:10]=1[CH:35]([CH2:39][CH:40]=[CH2:41])[C:36]([OH:38])=[O:37].S(=O)(=O)(O)O>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:2]([O:37][C:36](=[O:38])[CH:35]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:34])[CH2:19][NH:20][C:21]([CH3:33])([CH3:32])[CH2:22][CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[C:14]([Cl:15])[C:9]=1[Cl:8])[CH2:39][CH:40]=[CH2:41])[CH3:3]
Reactant: C=CCC(C(=O)O)c1ccc(OC[C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(C(=O)OCC)c1ccc(OC[C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c(Cl)c1Cl
Yield: 81 %

Procedure:
The acid of Example 19 (0.5 g) was dissolved in absolute ethanol (10 mL) and catalytic amount of conc.sulfuric acid was added. The reaction was stirred and heated to reflux overnight. Next day the reaction was concentrated and diluted with ethyl acetate and washed with 2.5N NaOH (2×20 mL), brine (20 mL) and dried over sodium sulfate. The crude mixture was purified by HPLC (eluted with CH3CN/H2O containing 0.1% TFA) to produce the desired product in 81% yield (0.43 g). MS(ES) m/e 536 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ: 8.35-8.48 (brs, 2H), 7.31-7.10 (m, 6H), 4.17-4.01 (m, 5H), 3.26-3.05 (m, 4H), 2.69-2.50 (m, 7H), 2.32 (t, 2H), 1.94 (d, 2H), 1.58-1.54 (t, 2H), 1.33 (s, 3H), 1.35 (s, 3H), 1.18 (t, 3H).