Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7](I)[C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[NH:18]1[CH:22]=[CH:21][N:20]=[N:19]1>CCOC(C)=O.[Cu](I)I.O.CC(OC)(C)C.O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:19]2[N:20]=[CH:21][CH:22]=[N:18]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: c1c[nH]nn1
Reactant: O=C(O)c1c(F)cccc1I
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: O=C(O)c1c(F)cccc1-n1nccn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a 2 L, 3-necked, round-bottomed flask equipped with an overhead mechanical stirrer, thermocouple probe, heating mantle, reflux condenser, and nitrogen inlet were added 2-fluoro-6-iodobenzoic acid (127.6 g, 480 mmol), copper iodide (4.57 g, 24 mmol), and Cs2CO3 (312.6 g, 959 mmol). To these solids were added dioxane (640 mL), then water (2.6 mL, 144 mmol), then 1H-1,2,3-triazole (55.6 mL, 959 mmol), and finally trans-1,2-dimethylcyclohexane-1,2-diamine (15.1 mL, 96 mmol). The mixture was then warmed to 60° C. for 30 min, then to 83° C. for 30 min, and then to 100° C. for 3 h. After the 3 h at 100° C., the mixture was cooled and then 1 L of MTBE and 1 L of water were added. After vigorous mixing, the layers were separated and the bottom aqueous layer was acidified to pH 1.72 with ˜148 mL of concentrated hydrochloric acid. The aqueous was then extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide a dark oil. The oil was stirred overnight in EtOAc (450 mL) and the resulting precipitate was removed by filtration. The mother-liquors were concentrated to a brown solid (106.21 g, 75 wt % by quantitative HPLC, 79.7 g, 80%). 1H NMR (400 MHz, DMSO-d6): 8.22-8.13 (bs, 2H), 7.84-7.80 (m, 1H), 7.74-7.65 (m, 1H), 7.50-7.41 (m, 1H).
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][CH:4]=1)C.Cl[CH2:14][C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C>CN(C=O)C>[CH3:30][C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[S:19][C:15]=1[CH2:14][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]=[CH:3]2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: CCc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
A suspension of 3-ethyl-1H-indol-5-ol (235 mg, 1.46 mmol), 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [425 mg, 1.46 mmol; PCT Int. Appl. (2002), WO 0292590 A1] and cesium carbonate (712 mg, 2.19 mmol) in DMF (3 ml) was stirred for 1.5 h at ambient temperature. Diethyl ether was added and the mixture was washed with 1N HCl and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/heptane 1:3) to give 522 mg (1.34 mmol, 86%) 5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([C@@:19]([N:23]([CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[O:25])([CH3:22])[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:44])=[O:4].CO.[OH-].[K+]>C1COCC1>[CH2:12]([N:9]1[C:10](=[O:11])[C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:44])[N:7]=[C:8]1[C@@:19]([N:23]([CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)=[O:25])([CH3:22])[CH2:20][CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC[C@](C)(c1nc(C)c(C(=O)OC)c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@](C)(c1nc(C)c(C(=O)O)c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Yield: 100.1 %

Procedure:
To a solution of 1-benzyl-2-{(R)-[(3-tert-butoxycarbonylamino-propyl)-(1-p-tolyl-methanoyl)-amino]-methyl-propyl}-4-methyl-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid methyl ester (2.75 g, 4.55 mmol) in THF (60 mL) was added MeOH (30 mL) followed by 1N KOH (18.2 mL, 18.2 mmol). The resultant solution was heated to 60° C. for 3 h, then concentrated under reduced pressure. The residue was diluted with H2O (75 mL), adjusted to pH ˜7 with 1N HCl, and extracted with EtOAc (3×75 mL). The extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give 2.69 g (100%) of 1-benzyl-2-{(R)-[(3-tert-butoxycarbonylamino-propyl)-(1-p-tolyl-methanoyl)-amino]-methyl-propyl}-4-methyl-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid as an oil which was used in the subsequent step without purification: MS (ES) m/e 591.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:37][C:38]2[C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:37][C:38]4[C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=3)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 44.4 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(ethylamino)piperidine-1-carboxylate obtained in Example (207a) (23.0 mg, 0.058 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (20 mg, 0.069 mmol) and sodium carbonate (61 mg, 0.575 mmol), to obtain 13 mg of the title compound (45%) as a colorless solid.
Reaction SMILES: B#B.[F:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1.C(Cl)(Cl)Cl>O1CCCC1>[F:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1
Reactant: O=C(O)COc1ccc(F)cc1
Agent: B#B
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: OCCOc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To 200 ml of 1 Molar diborane in tetrahydrofuran (chilled to 5°-10° C.) is added dropwise 17.0 g of 2-(p-fluorophenoxy)acetic acid in 100 ml of tetrahydrofuran. The mixture is stirred overnight and poured into 100 g of ice and 250 ml of chloroform. The organic layer is separated and the aqueous layer extracted with chloroform. The organic layer and extracts are combined, dried (MgSO4) and the solvent removed under vacuum. The residual pale yellow oil is distilled to give the product (14.8 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([NH:9][CH3:10])[C:5]([NH2:8])=[CH:6][CH:7]=1.[NH:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:18]([C:20](O)=O)[CH3:19].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:26]([O:25][C:23](=[O:24])[NH:17][C@H:18]([C:20]1[N:9]([CH3:10])[C:4]2[C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:19])([CH3:29])([CH3:28])[CH3:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNc1c(N)ccc(F)c1-c1ccccn1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
A solution of 4-fluoro-N2-methyl-3-pyridin-2-yl-benzene-1,2-diamine (0.75 g, 3.44 mmol), Boc-Ala (0.72 g, 3.78 mmol), HOAt (0.52 g, 3.78 mmol) in DCM (10 mL) was cooled to 0° C. EDC (0.73 g, 3.78 mmol) was added portion wise and the resulting mixture was stirred for 1 h. The mixture was diluted with DCM (20 mL) and the organic layer was washed with citric acid, brine, dried (MgSO4) and evaporated. The resulting residue was purified by chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to afford the title compound as a white solid (0.3 g, 24%). LCMS (Method J): RT 2.42 min [M+H]+ 371
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Br[C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:26]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:31][CH:30]=3)=[N:25][O:24][N:23]=2)[CH:12]=[CH:13][C:14]=1[F:15].[CH3:44][N:45](C)C=O>C(#N)C.O.[C-]#N.[Zn+2].[C-]#N.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>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:42]=[S:39]1(=[O:43])[CH2:40][CH2:41][N:36]([CH2:35][C:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:26]3[C:22]([C:17]4[N:16]([C:11]5[CH:12]=[CH:13][C:14]([F:15])=[C:9]([CH:10]=5)[C:44]#[N:45])[C:20](=[O:21])[O:19][N:18]=4)=[N:23][O:24][N:25]=3)=[CH:30][CH:31]=2)[CH2:37][CH2:38]1
Reactant: CN(C)C=O
Reactant: O=c1onc(-c2nonc2NCc2ccc(CN3CCS(=O)(=O)CC3)cc2)n1-c1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(-n2c(-c3nonc3NCc3ccc(CN4CCS(=O)(=O)CC4)cc3)noc2=O)ccc1F

Procedure:
A solution of 4-(3-bromo-4-fluorophenyl)-3-[4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (10 mg, 14 μmol), zinc cyanide (5 mg, 43 μmol), and tetrakis(triphenylphosphine)palladium(0) (8 mg, 7 μmol) in N,N-dimethylformamide (0.25 mL) was heated in the microwave at 150° C. for 5 min. The reaction mixture was diluted with 3:1 acetonitrile/water (2 mL), filtered, and purified by preparative LCMS to give the intermediate 5-[3-[4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-1,2,5-oxadiazol-3-yl]-5-oxo-1,2,4-oxadiazol-4(5H)-yl]-2-fluorobenzonitrile trifluoroacetate. This material was diluted with ethanol (1 mL), treated with 2.0 M sodium hydroxide in water (0.1 mL), and stirred for 45 min. The reaction mixture was quenched with acetic acid (50 μL, 0.9 mmol), filtered, and purified by preparative LCMS to give the desired product (1 mg, 11%). LCMS for C22H23FN7O4S (M+H)+: m/z=500.0.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[N:16][C:15]([Br:30])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>C(Cl)Cl.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:30][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[NH:5][C:19]3[CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=[CH:23][C:18]=3[C:17]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCCl
Solvent: CCCCCCCC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 85 °C
Yield: 1040 %

Procedure:
1,2-Dichloroethane (14 mL) was added to a mixture of methyl 3-azido-6-bromo-2-(4-morpholinophenyl)isonicotinate (4.66 g, 11 1 mmol), rhodium octanoate dimer (0.521 g, 0.669 mmol) and crushed 4A° molecular sieves (4.66 g) and this was heated at 85° C. for 26 hr. It was diluted with DCM, filtered, and the solid was washed with multiple portions of DCM. The solvent was removed from the combined filtrate and the residue was suspended in MeOH. The solid was collected by filtration, washed with MeOH, and dried to leave methyl 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxylate (4.05 g, 10.4 mmol, 93% yield) as a yellow solid. MS (ESI) m/z 390.11 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 9.43 (1H, br. s.), 8.20 (1H, d, J=8.85 Hz), 7.86 (1H, s), 7.00 (1H, dd, J=8.70, 1.68 Hz), 6.89 (1H, s), 4.06 (3H, s), 3.91-3.96 (4H, m), 3.32-3.37 (4H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([N:20]3[CH2:29][C@H:28]4[N:24]([CH2:25][CH2:26][CH2:27]4)[C:23]4[N:30]=[C:31]([NH:34][CH2:35][CH3:36])[N:32]=[CH:33][C:22]=4[C:21]3=[O:37])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(O)C>C(O)C>[CH2:35]([NH:34][C:31]1[N:32]=[CH:33][C:22]2[C:21](=[O:37])[N:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:15]=3)[CH2:29][C@H:28]3[N:24]([CH2:25][CH2:26][CH2:27]3)[C:23]=2[N:30]=1)[CH3:36]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c1)C2=O
Agent: Cl
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(N3CCNCC3)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
(S)-5-[3-(4-Tert-butoxycarbonylpiperazine-1-yl)phenyl]-9-ethylamino-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (0.235 g, 0.643 mmol) obtained in Step 3 was dissolved in ethanol (3 mL), and the mixture was stirred at room temperature for 1 hour after adding 4 mol/L hydrochloric acid-ethanol (3 mL). The mixture was concentrated, and extracted with chloroform after adding a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by concentrating the organic layer was purified by silica gel column chromatography to give (S)-9-ethylamino-5-[3-(piperazine-1-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (0.185 g, quantitative).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Br:20])=[N:9][CH2:10][C:11](=S)[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=O>C(O)CCC>[F:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Br:20])=[N:9][CH2:10][C:11]3[N:12]([C:24]([CH2:23][O:22][CH3:21])=[N:26][N:27]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCC(=O)NN
Reactant: Fc1cccc2c1C(c1ccccc1Br)=NCC(=S)N2
Solvent: CCCCO
Product: COCc1nnc2n1-c1cccc(F)c1C(c1ccccc1Br)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-6-fluoro-5-(o-bromophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with methoxyacetic acid hydrazide to give 7-fluoro-1-(methoxymethyl)-6-(o-bromophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3].[Br:12]Br>ClCCl>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][Br:12])=[CH:5][CH:6]=1)#[N:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C#N)cc1
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)CBr)cc1
Yield: 101.5 %

Procedure:
To a solution of 4-cyanoacetophenone (11.32 g, 77.98 mmol) in dichloromethane (200 mL) was added bromine (4.00 mL, 78.0 mmol) dropwise at room temperature. After stirring several minutes, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 4-cyanophenacyl bromide (17.73 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([OH:9])[C:4](=[NH:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>CS(C)=O>[NH:10]=[C:4]1[N:3]=[C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)[CH:7]=[C:6]([CH3:8])[N:5]1[OH:9]
Reactant: Cc1cc(Cl)nc(=N)n1O
Reactant: C1CSCCN1
Solvent: CS(C)=O
Product: Cc1cc(N2CCSCC2)nc(=N)n1O
Temperature: 100 °C
Yield: 50.7 %

Procedure:
A mixture of 32 g of 4-chloro-1,2-dihydro-2-imino-6-methyl-1-pyrimidinol, 46 g of thiomorphline, and 200 ml of dimethyl sulfoxide was heated at 100°C in a nitrogen atmosphere for 17 hours. The solvent is removed under high vacuum. The residue is shaken with 5% ammonium hydroxide solution and with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent removed. Trituration of the residue with ether gives 23 g of a solid mp 208°-210°C. Recrystallization from acetone-methanol gives a white crystalline solid, mp 243°-245°C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:32](=[O:57])[NH:33][CH:34]([C:43](=[O:56])[N:44]([CH2:48][CH:49]([O:53][CH2:54][CH3:55])[O:50][CH2:51][CH3:52])[CH:45]([CH3:47])[CH3:46])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[CH2:13][NH:14]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NCC)C>>[NH2:14][CH2:13][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:32](=[O:57])[NH:33][CH:34]([C:43](=[O:56])[N:44]([CH2:48][CH:49]([O:53][CH2:54][CH3:55])[O:50][CH2:51][CH3:52])[CH:45]([CH3:46])[CH3:47])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OCc1ccccc1)C(C)C)OCC
Solvent: CCNCC
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CN)NC(=O)OCc1ccccc1)C(C)C)OCC

Procedure:
The Fmoc protective group is eliminated from 9H-fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate using diethylamine and employing the method as described under b). The desired product is obtained with MW=576.27 (calculated, monoisotopic); measured value (M+H)+=577.22
Reaction SMILES: Br.[CH:2]([NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(=O)CC>[CH:2]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:28](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:30])[CH2:18][CH2:17]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(NC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
The mixture of benzhydryl-piperidin-4-yl-amine hydrogen bromide salt (1.74 g, 5 mmol, 1.0 eq.), N-(2-bromoethyl)phthalimide (1.27 g, 5 mmol, 1.0 eq.), K2CO3 (1.73 g, 12.5 mmol, 2.5 eq.), and NaI (1.05 g, 7.0 mmol, 1.4 eq.) in 2-butanone (20 ml) was refluxed for 2-3 hours. The mixture was then cooled to room temperature. The white solid was filtered off and was washed with small amount of CHCl3. The filtrates were combined and concentrated. The resulted residue was dissolved in CHCl3 (100 ml). The solution was washed with water (3×20 ml), then dried over anhydrous Na2SO4. After removed all solvent, the crude product 2-{2-[4-(benzhydryl-amino)-piperidin-1-yl]-ethyl} -isoindole-1,3-dione was yielded (2.70 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:13][CH:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[CH:11]([OH:25])[CH:10]1[OH:26].CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([NH:8][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([Cl:23])[N:18]=1
Reactant: NC1CC(n2cnc3c(Cl)nc(Cl)nc32)C(O)C1O
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1S,2R,3S,5R)-3-amino-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate (0.304 g, 1.00 mmol) in THF (10 ml) is treated with DIPEA (0.387 g, 3.00 mmol) followed by propionyl chloride (0.093 g, 1.00 mmol). The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). MS (ES+) m/e 360 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[C-:10]#[N:11].[Na+].CS(C)=O>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][C:10]#[N:11])[CH3:2]
Reactant: [C-]#N
Reactant: CCOC(CBr)OCC
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(CC#N)OCC
Reaction time: 5 h

Procedure:
A mixture of 8 g of bromo-acetaldehyde diethyl-acetal, 3 g of sodium-cyanide and 20 ml of dimethyl-sulfoxide is admixed at a temperature of 80° C. for 5 hours. The reaction mixture is poured on 80 ml of water, then twice extracted with 50 ml of chloroform. The chloroform extract is washed twice with 30 ml of water, dried on magnesium sulfate, then distilled in vacuo.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][Mg]Br.[O:11]=[C:12]1[CH2:18][CH:17]2[N:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]#[N:31])=[CH:22][CH:21]=3)[CH:14]([CH2:15][CH2:16]2)[CH2:13]1>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][C:12]1([OH:11])[CH2:13][CH:14]2[N:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]#[N:31])=[CH:22][CH:21]=3)[CH:17]([CH2:16][CH2:15]2)[CH2:18]1
Reactant: Br[Mg]CCC1OCCCO1
Reactant: N#Cc1ccc(N2C3CCC2CC(=O)C3)c2ccccc12
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C3CCC2CC(O)(CCC2OCCCO2)C3)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,3-Dioxane-2-ylethyl magnesium bromide reagent (0.5 M solution in anhydrous THF: 860 μL, 0.43 mmol) was added dropwise to a solution of 156AF03-217 (80 mg, 0.29 mmol) in anhydrous THF (2 mL) at rt. After 48 h stirring at rt the reaction was quenched with saturated ammonium chloride. The mixture was partitioned between ammonium chloride and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a stepwise gradient of 40-100% ethyl acetate in n-heptane, afforded the desired compound as a diastereomeric mixture, ratio 85:15 (37 mg, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]([CH:13]=[CH2:14])[C:9]1=[O:15])=[O:7])([CH3:4])(C)C.[H-].[Na+].Cl[CH:19]1[CH2:23]CC[O:20]1>O1CCCC1.C(OCC)C>[O:20]1[CH2:19][CH2:23][CH2:4][CH:1]1[O:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]([CH:13]=[CH2:14])[C:9]1=[O:15])=[O:7]
Reactant: C=CN1CCC(C(=O)OC(C)(C)C)C1=O
Reactant: ClC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CN1CCC(C(=O)OC2CCCO2)C1=O
Yield: 100 %

Procedure:
8.9 g of 3-(t-butoxycarbonyl)-1-vinyl-2-pyrrolidinone (BCVP) was dissolved in 50 ml of tetrahydrofuran free of moisture. To this solution 1.0 g of sodium hydride and 4.4 g of 2-chlorotetrahydrofuran were added and allowed to react at room temperature for 1 hour. This solution was diluted with diethylether and washed many times with pure water. The organic solvent of the organic phase was evaporated and the residue was subjected to silica gel column chromatography, to obtain 9.3 g of pure 3-(tetrahydrofuranyloxycarbonyl)-1-vinyl-2-pyrrolidinone (hereinafter referred to as "TFVP"). Its chemical structure was determined by IR spectra and NMR.