Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:17][CH2:16][C:8]2(OCC(C)(C)C[O:9]2)[CH2:7][C:6]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)O)[CH3:3].[ClH:27].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[ClH:27].[CH3:3][N:2]([CH2:4][CH:5]1[CH2:17][CH2:16][C:8](=[O:9])[CH:7]=[C:6]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH3:1]
Reactant: COc1cccc(C2(O)CC3(CCC2CN(C)C)OCC(C)(C)CO3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(C2=CC(=O)CCC2CN(C)C)c1
Temperature: 5 °C
Reaction time: 72 h
Yield: 78.9 %

Procedure:
182 g 9-dimethylaminomethyl-8-(3-methoxy-phenyl)-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-8-ol were dissolved in 1,200 ml tetrahydrofuran and the reaction mixture was cooled to 5° C. A mixture of 600 ml 32% hydrochloric acid solution and 600 ml water was added at this temperature. The mixture was stirred at room temperature for 72 hours. When the reaction had ended 500 ml ethyl acetate were added at 5° C. and the reaction mixture was then brought to pH 12 with 32% sodium hydroxide solution. The phases were separated and the aqueous phase was washed three times with 300 ml ethyl acetate each time. The combined organic phases were then washed twice with 100 ml saturated sodium chloride solution each time, dried over magnesium sulfate and then freed from the solvent. Purification was carried out via hydrochloride formation. For this, 4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enone base was dissolved in 500 ml acetone and an equimolar amount of water and trimethylchlorosilane was added. The hydrochloride which had precipitated out was filtered off with suction and dried in vacuo. 63.6 g (78.9% of theory) 4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enone hydrochloride were obtained in this way. b) rac-cis-[4-Dimethylaminomethyl-3-hydroxy-3-(3-methoxy-phenyl)-cyclohexanone]hydrochloride (compound 1)
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13](O)=O)[C@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C.CC(O)=O.O.CCOC(C)=O>[C:16]([C:20]1[CH:25]=[CH:24][C:23]2[NH:26][C:13]([C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C@@H:10]([OH:11])[CH3:12])=[N:27][C:22]=2[CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Product: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
N-Boc-L-allo-threonine (Preparation 54, 67.12 g, 306 mmol), 4-tert-butyl-diaminobenzene (60.3 g, 367 mmol) and HOBt (56.3 g, 367 mmol) were dissolved in DMF (500 mL). NMM (67 mL, 612 mmol) was added and the mixture cooled to 0° C. EDCI (65.6 g, 336 mmol) was added portionwise over 1.5 hours and the reaction was stirred at room temperature for 18 hours. EtOAc (2 L) was added followed by water (10 and the mixture stirred vigorously for 15 minutes. The aqueous layer was removed and washed further with EtOAc (2×30 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was sonicated in pentane/DCM 10/1 twice and filtered to afford a pale pink solid that was dissolved in AcOH (500 mL) and stirred at 40° C. for 24 hours followed by room temperature for 2 days. The solvent was removed in vacuo and the residue dissolved in EtOAc (1.5 L). Saturated aqueous NaHCO3 (500 mL) was added and the mixture stirred vigorously. The organic layer was collected, washed with NaHCO3 solution (2×200 mL), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DCM (500 mL) and purified using silica gel column chromatography eluting with 0-20% acetone in cyclohexaneto afford the title compound as an off-white solid (89 g, quant).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([Cl:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([Cl:21])([F:20])[F:19])=[O:41])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:29])([F:30])[F:28])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)Cl)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)Cl)c(C)cc1F
Reaction time: 0.5 h
Yield: 97 %

Procedure:
0.6 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2-chloro-2,2-difluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 20mL of chloroform, and 0.3 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.6 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C:13](=[O:19])[N:12]([CH2:20][CH2:21][N:22](C(OCC3C=CC=CC=3)=O)[CH3:23])[C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[BrH:38].C(O)(=O)C>C(O)(=O)C>[BrH:38].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C:13](=[O:19])[N:12]([CH2:20][CH2:21][NH:22][CH3:23])[C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)O[C@H]1C(=O)N(CCN(C)C(=O)OCc2ccccc2)c2ccccc2S[C@H]1c1ccc(C)cc1
Agent: Br
Solvent: CC(=O)O
Product: CNCCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(C)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.1 g of (±)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 5 ml of acetic acid and 10 ml of 25% hydrogen bromide-acetic acid is stirred at room temperature for 2 hours. After the reaction is completed, the mixture is concentrated under reduced pressure. Toluene is added to the residue, and the mixture is evaporated to remove solvent. Crystalline precipitates are collected by filtration and washed with ether. Then, the crystals are recrystallized from isopropanol. 0.7 g of (±)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(N-methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide is obtained as prisms.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[CH:8]=[CH:9][C:10]=1[CH3:11])[C:2]([NH2:4])=[NH:3].[CH3:29][NH:30][CH3:31]>C(O)CCC>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:7]3[CH:8]=[CH:9][C:10]([CH3:11])=[C:5]([NH:1][C:2]4[N:4]=[C:5]([C:10]5[CH:29]=[N:30][CH:31]=[CH:8][CH:9]=5)[CH:6]=[CH:7][N:3]=4)[CH:6]=3)=[O:28])=[CH:19][CH:18]=2)[CH2:22][CH2:23]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=N)N
Reactant: CNC
Solvent: CCCCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A suspension of N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide (30 g, 79 mmol) in n-butanol (150 ml) at 120° C. under an atmosphere of nitrogen is treated with 3-dimethylamino-1-pyridin-3-yl-propenone (15.3 g, 87 mmol). The resulting suspension is heated at 150° C. for 5 hrs. The reaction mixtures becomes a homogeneous deep orange solution and dimethylamine is removed by the distillation of n-butanol (130 ml). n-Butanol (20 ml) is added during the distillation. Butyl acetate (60 ml) is added dropwise at 100° C. and the solution is cooled to 0° C. within 1 hr and stirred at 0° C. for 16 hrs. The resulting deep orange suspension is filtered off with suction, the isolated solid is washed with n-butanol (2×50 ml) and water (2×50 ml) and dried in vacuo at 60° C. Yield: 36.4 g of the title compound, 93% based on theory, as off-whitecrystals. (99.6% area by HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2[OH:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([N+:13]([O-:15])=[O:14])=[C:5]2[OH:12]
Reactant: Oc1cnnc2ccc(Br)cc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1nnc2ccc(Br)cc2c1O
Temperature: 60 °C
Yield: 58.7 %

Procedure:
Under N2, an orange solution of 6-bromocinnolin-4-ol (18.5 g, 82 mmol) in HNO3 (90 mL, 82 mmol) was cooled to 0° C., and H2SO4 (30 mL) was added. The resulting mixture was then heated at 60° C. for 3 h. After the reaction went to completion as monitored by LC-MS, the reaction mixture was cooled to 0° C., and was then quenched with H2O (20 mL). The mixture was diluted with EtOAc (25 mL). Following general workup procedures, the crude residue was added to silica gel, and eluted with PE/EtOAc to give 6-bromo-3-nitrocinnolin-4-ol as a pale yellow solid (13 g, yield 58.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.[CH2:18]([O:20][C:21]([C:23]1[C:27]2[CH:28]=[CH:29][C:30](Br)=[CH:31][C:26]=2[O:25][N:24]=1)=[O:22])[CH3:19]>O1CCOCC1>[CH2:18]([O:20][C:21]([C:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:7]3[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=3[CH3:1])=[CH:31][C:26]=2[O:25][N:24]=1)=[O:22])[CH3:19]
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1noc2cc(Br)ccc12
Solvent: C1COCCO1
Product: CCOC(=O)c1noc2cc(-c3ccc(O)cc3C)ccc12
Temperature: 50 °C
Yield: 92.6 %

Procedure:
A solution of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.624 g, 2.67 mmol) and 6-bromo-benzo[d]isoxazole-3-carboxylic acid ethyl ester (0.360 g, 1.33 mmol) in 1,4-dioxane (20 mL) is added to a flask. The flask is evacuated and re-filled with N2 3 times. To this solution, Pd2(dba)3 (0.010 g), tricyclohexyl phosphine (10 mg), and aqueous K3PO4 (1.5 mL, 1.30 M) are added. The resulting mixture is heated to 50° C. for 2 hours under N2. The reaction mixture is cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate is concentrated under reduced pressure. The residue is purified via silica gel chromatography eluting with 25% ethyl acetate in hexanes to give the title compound (0.366 g, 93%). ES/MS m/e 298.0 (M+1); 296.0 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:22](=[O:23])[C:13]3[N:14]=[N:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[NH:11]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:22](=[O:23])[C:13]3[N:14]=[N:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[NH:11]2)=[CH:8][CH:9]=1
Reactant: O=c1c2nnc3ccccc3c2[nH]n1-c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 80 °C

Procedure:
2-(4-nitrophenyl)-1,2-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one (11.4 g, 37.2 mmol) was suspended in a mixture of ethanol (100 ml) and water (100 ml). Iron powder (11.1 g, 200 mmol) and ammonium chloride (5.34 g, 100 mmol) were added. The mixture was heated to 80° C. overnight, cooled to room temperature and basified with potassium carbonate to pH 9-10. The solids were removed by filtration through a pad of Celite®. The filtrate was extracted with n-butanol (2×200 ml). The combined organic phases were concentrated under vacuum to give a dark red solid. The solid was triturated with methanol (100 ml), filtered and dried under vacuum. The title compound was isolated as a dark red powder (5.58 g, 20.1 mmol, 57%). LCMS: m/z 278 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:10])[CH2:5][CH:6]([OH:9])[CH2:7]O.CS([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>CCCCCC>[CH2:16]([O:15][CH:5]([N:4]([CH3:10])[CH3:3])[CH:6]([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:7])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CN(C)CC(O)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(C)C(OCCCCCCCC/C=C\C/C=C\CCCCC)N(C)C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, hexane (30 mL) and potassium hydroxide (6.1 g, 108.7 mmol) were put into a four-necked flask, and 3-(dimethylamino)-1,2-propanediol (0.72 g, 6.04 mmol: DAP) was dropped under agitation. Thereafter, linoleyl methane sulfonate (5.0 g, 14.5 mmol) was added, and agitation was performed at room temperature for 3 hours. The reaction was terminated because remaining linoleyl methane sulfonate became 0.2% (degree of conversion: 59.2%, integrated value of isomer: 0.027).
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44].O>C1(C)C=CC=CC=1>[CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([NH:34][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
A solution of 5 g of (2S)-2-(N,N-dibenzylamino)-5-amino-1,6-diphenyl-4-hexene-3-one in toluene (100 ml) was chilled with ice water. To the solution, 5 ml of pyridine and 5 ml of ethyl chloroformate were gradually added. The reaction mixture was stirred at 70° C. for 12 hours, and then chilled with ice water. 5 ml of water was added to the reaction mixture, and the mixture was held at the same temperature for 1 hour. The reaction mixture was then washed with 50 ml of water and 50 ml of a dilute solution of potassium hydrogensulfate, and further with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane-ethyl acetate (10:1) as an eluent, thereby obtaining 1.65 g (28.5%) of the title compound as pale yellow powder from the eluate.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C[O:15][CH2:14]C1>CCOC(C)=O>[N+:1]([C:4]1[C:5]2[NH:11][C:14](=[O:15])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2[nH]1
Yield: 88 %

Procedure:
To 3-nitro-1,2-phenylenediamine 3a (2 g, 13.06 mmol) dissolved in THF (50 ml) was added in one portion DCI (1.5 equiv., 19.6 mmol, 3.176 g) and the reaction was refluxed for 2 hours. (TLC AcOEt 1/petroleum ether 1). The reaction was filtrated and the yellow solid material was washed with THF and diethyl ether obtaining 2 g of the product that was used for the following step without further purification. Yield=88% 1HNMR (DMSO, 200 MHz) δ 7.11 (1H, t, J=7.6 Hz), 7.31 (1H, dd, J=7.8 Hz, J′=1.2 Hz), 7.74 (1H, dd, J=8.6 Hz, J′=1 Hz), 11.45 (2H, bs)
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C(=O)([O-])[O-].[Na+].[Na+].[CH2:11]([N:13]1[C:17](=[O:18])[NH:16][N:15]=[N:14]1)[CH3:12]>CN(C)C=O.O>[Br:1][CH2:2][CH2:3][N:16]1[C:17](=[O:18])[N:13]([CH2:11][CH3:12])[N:14]=[N:15]1
Reactant: CCn1nn[nH]c1=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nnn(CCBr)c1=O
Reaction time: 8 h
Yield: 22 %

Procedure:
To a stirred solution of 109 parts of 1,2-dibromoethane and 21.2 parts of sodium carbonate in 5 parts of water and 18 parts of N,N-dimethylformamide were added dropwise a solution of 22.5 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one in 5 parts of water and 27 parts of N,N-dimethylformamide at about 40° C. Upon completion, stirring was continued overnight at 40° C. The organic phase was separated, dried and distilled, yielding 9.8 parts (22%) of 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one; bp. 110° C. at 0.1 mm pressure (interm. 47).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:59]1[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=1>CN(C=O)C>[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:59]1[CH:64]=[CH:63][C:62]([NH:65][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])=[CH:61][CH:60]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3ccc(-c4nc5ccccc5[nH]4)cc3)c(=O)oc12
Temperature: 25 °C
Yield: 75 %

Procedure:
DIEA (43.5 μL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (95.0 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4-(1H-benzoimidazol-2-yl)-phenylamine (47.5 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 71.0 mg of product in 75% yield: LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl>CN(C=O)C>[C:3]([C:5]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[N:4]
Reactant: ClCCOCCCl
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C#N)CCOCC1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a suspension of NaH (22.11 g, 552.1 mmol) in DMF (350 mL) is added ethyl cyanoacetate (23.5 mL, 195 mmol) at 0° C. over 25 min. The reaction mixture is warmed to room temperature for 2 h and it is cooled down to 0° C. again. A solution of 1-chloro-2-(2-chloroethoxy)ethane (31.1 mL, 265.4 mmol) in DMF (50 mL) is added and the reaction mixture is warmed to room temperature for 1 h. Then the reaction mixture is heated at 90° C. for 16 h before the reaction is quenched with ice cold water (180 mL). The mixture is extracted with EtOAc (2×200 mL) and the organic layers are combined, dried (Na2SO4) and concentrated. The crude compound is purified by fractional distillation under high vacuum to afford the title compound (10 g, 25%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11](=[S:13])[NH2:12].Cl[CH2:15][C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[Br:1][C:2]1[N:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[N:5]=[CH:4][C:3]=1[C:11]1[S:13][CH:15]=[C:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:12]=1
Reactant: CC(C)(C)n1ncc(C(N)=S)c1Br
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2Br)n1
Yield: 64.1 %

Procedure:
A solution of the compound (2.80 g, 10.68 mmol) obtained in step 5 and ethyl 4-chloroacetoacetate (1.588 mL, 11.75 mmol) in ethanol (30 mL) was stirred at 80° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give ethyl 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)acetate (2.55 g, 6.85 mmol, 64%) as a colorless oil
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[CH2:8][NH2:9])[CH3:5]>CCOCC>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[CH2:8][NH:9][C:2]#[N:1])[CH3:5]
Reactant: N#CBr
Reactant: CCOC(CN)OCC
Solvent: CCOCC
Product: CCOC(CNC#N)OCC
Temperature: 0 °C
Yield: 109.6 %

Procedure:
A solution of cyanogen bromide (2.12 g.), in ether (20 ml.) was added dropwise over 35 minutes to a stirred ice-cooled solution of 2,2-diethoxyethylamine (5.32 g.) in ether (20 ml.). During this addition a white precipitate was formed. The resulting suspension was stirred at 0° for a further hour, filtered and the filtrate evaporated to dryness under reduced pressure to give 2,2-diethoxyethylcyanamide (3.47 g.) as a colourless oily liquid having the following n.m.r. spectrum in CDC13: 1.24 (t, 6H); 3.1 (d, 2H); 3.65 (m, 4H); 4.0 (br s, 1H); 4.57 (t, 1H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:11][C:12]1[N:20]=[C:19](Cl)[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[C@@H:22]1[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][OH:30])[C@@H:24]([OH:32])[C@H:23]1[OH:33])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:34]([C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)([O-:36])=[O:35]>>[OH:32][C@H:24]1[C@@H:23]([OH:33])[C@H:22]([N:16]2[CH:15]=[N:14][C:13]3[C:17]2=[N:18][C:19]([N:40]2[CH:41]=[C:37]([N+:34]([O-:36])=[O:35])[N:38]=[CH:39]2)=[N:20][C:12]=3[NH:11][C@H:8]([CH2:9][OH:10])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:26][C@@H:25]1[NH:27][C:28](=[O:31])[CH2:29][OH:30]
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=[N+]([O-])c1c[nH]cn1
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(-n4cnc([N+](=O)[O-])c4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound can be prepared from N-{(1S,2R,3S,4R)-4-[6-((S)-1-benzyl-2-hydroxy-ethylamino)-2-chloro-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate GC) and 4-nitro-imidazole, as described for N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate QD).
Reaction SMILES: [CH:1]1([N:4]2[CH2:16][C@@H:7]3[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1.[C:18](N)(C)(C)C>>[C:1]([N:4]1[CH2:16][CH:7]2[CH:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:17])([CH3:2])([CH3:3])[CH3:18]
Reactant: COC(=O)[C@@H]1NCCN2C(=O)N(C3CC3)C[C@H]12
Reactant: CC(C)(C)N
Product: COC(=O)C1NCCN2C(=O)N(C(C)(C)C)CC12

Procedure:
Compound 86-C was prepared in analogy to compound 82-C by using tert-butylamine instead of cyclopropylamine.