Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C(CC)C[N:4]1[CH:8]=[C:7](C2C=CC=CC=2)[N:6]=[CH:5]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:6]1[C:7]2=[N:4][CH:8]=[CH:7][NH:6][CH:8]2[NH:4][CH2:5]1
Reactant: CCC(=O)Cn1cnc(-c2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=CNC2NCNC2=N1
Temperature: 20 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
2-[1(S)-{1,1-Dimethylethoxy)carbonylamino}-2-phenylethyl]-1-(2-oxo-butyl)-4-phenyl-1H-imidazole (60 mg) in a mixture of 10% TFA in DCM was stirred at about 20° C. for about 3 hours and then concentrated under reduced pressure. The resulting intermediate dihydro-imidazo-pyrazine was dissolved in methanol and borohydride supported on resin (AMBERLITE® IRA 400, Aldrich. 2.5 mmol BH4−/g; 4 eq) was added. The pH was maintained at about 5 by addition of drops of TFA. After about 2 hours of stirring at about 20° C., the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/Heptane 7:3; Rf=0.30). The tetrahydro-imidazo-pyrazine was obtained as a single diastereoisomer in 86% yield (38 mg). NMR (1H, 400 MHz, CDCl3) δ: 7.80-7.10 (m, 11H, arom. H), 4.28 (dd, 1H, 3J=10 Hz, 3J=3 Hz, H8), 3.95 (dd, 1H, 2J=11.5 Hz, 3J=3.6 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=3.0 Hz), 3.60 (t, 1H, 2J=3J=11.5 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=10 Hz), 2.98 (m, 2H), 1.85 (s, 1H, NH), 1.55 (m, 2H, CH2), 0.95 (t, 3H, CH3). NMR (13C, 100 MHz, CDCl3): 146.3, 140.9, 138.0, 134.4, 129.4, 128.6, 128.5, 126.6, 126.5, 124.8, 113.8, 55.9, 54.4, 50.2, 40.0, 26.6, 10.0.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH2:36]([O:38][C:39]([C:41]1([C:44]2[CH:49]=[C:48](Br)[CH:47]=[CH:46][N:45]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39]([C:41]1([C:44]2[CH:49]=[C:48]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)[CH:47]=[CH:46][N:45]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CCOC(=O)C1(c2cc(Br)ccn2)CC1
Product: CCOC(=O)C1(c2cc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)ccn2)CC1
Yield: 81 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(4-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid ethyl ester following a procedure analogous to that described in Example 1. Yield: 81% of theory; LC (method 3): tR=2.99 min; Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1.C([O-])(O)=O.[Na+]>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:3]([F:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][O:16]1)[N:6]=[CH:5]2
Reactant: C1=COCCC1
Reactant: Fc1c(Br)ccc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1c(Br)ccc2c1cnn2C1CCCCO1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a mixture of 5-bromo-4-fluoro-1H-indazole (50 g, 0.23 mol) and DHP (23 g, 0.28 mol) in dry dichloromethane (1000 mL) was added PTSA (2.2 g, 11.5 mmol) at room temperature. The resulting mixture was stirred overnight at that temperature. Upon completion, saturated aqueous NaHCO3 (100 mL) was added slowly into the reaction mixture. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜2% EtOAc in petroleum ether) and then re-crystallized from petroleum ether to afford the title compound (55 g). 1H NMR (300 MHz, DMSO-d6): δ 8.28 (s, 1H), 7.58-7.66 (m, 2H), 5.89 (dd, 1H), 3.90-3.85 (m, 1H), 3.79-3.70 (m, 1H), 2.42-2.29 (m, 1H), 2.06-1.94 (m, 2H), 1.77-1.68 (m, 1H), 1.60-1.53 (m, 2H); LCMS: 299 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([NH:30][CH2:31][CH2:32][CH3:33])[CH3:29]>C(#N)C>[CH2:28]([N:30]([CH2:12][CH:8]1[O:7][C:6]2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=[C:2]([F:1])[C:11]=2[O:10][CH2:9]1)[CH2:31][CH2:32][CH3:33])[CH3:29]
Reactant: CCCNCC
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCN(CC)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-ethylpropan-1-amine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 331 (M+, 0.5), 101 (7), 100 (bp), 98 (8), 58 (8).
Reaction SMILES: [OH-].[Na+].COC([N:7]1[C:17]2[CH2:16][CH:15]3[N:18]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH:11]([CH2:12][N:13]([C:29]([O:31][CH3:32])=[O:30])[CH2:14]3)[C:10]=2[CH:9]=[N:8]1)=O>C1COCC1.C(Cl)Cl.O>[CH3:32][O:31][C:29]([N:13]1[CH2:12][CH:11]2[N:18]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]([CH2:16][C:17]3[NH:7][N:8]=[CH:9][C:10]=32)[CH2:14]1)=[O:30]
Reactant: COC(=O)N1CC2Cc3c(cnn3C(=O)OC)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)N1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Aqueous sodium hydroxide (3 N, 0.39 mL, 1.18 mmol) was added to a stirring solution of 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-5,10-dicarboxylic acid dimethyl ester (270 mg, 0.594 mmol) in THF (1 mL). The reaction mixture was stirred for 3 h at room temperature and subsequently diluted with methylene chloride (10 mL) and water (5 mL). The phases were separated and the aqueous layer was extracted with methylene chloride (2×5 mL). The organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid methyl ester as a white solid. Retention time (min)=1.435, method [1], MS(ESI) 397.13 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.2 Hz, 2H), 7.50 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 5.21 (s, 1H), 4.41 (s, 1H), 4.19-4.01 (m, 1H), 3.90 (d, J=13.2 Hz, 1H), 3.60-3.40 (m, 3H), 3.35-3.14 (m, 2H), 2.85-2.80 (m, 1H), 2.71 (d, J=17.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([CH3:28])=[N:10][C:11]2[N:12]([CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.CCN(CC)CC.[BH4-].[Na+]>C1COCC1.O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[N:12]2[CH:22]=[C:23]([CH2:25][OH:26])[N:24]=[C:11]2[N:10]=[C:9]([CH3:28])[C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: Cc1nc2nc(C(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2nc(CO)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 103.1 %

Procedure:
To a stirred solution of 6-(tert-butoxycarbonyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid (400 mg, 0.95 mmol) in THF (6 mL) at room temperature was added ClCOOEt (0.14 mL, 1.42 mmol) and Et3N (0.26 mL, 1.9 mmol). After 1.5 h, the reaction was filtered to remove the insolubles and to the filtrate at 0° C. was added NaBH4 (72 mg, 1.9 mmol) in H2O (0.2 mL). After 30 min, the reaction was quenched with 1N HCl and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration and concentration under reduced pressure afforded the crude tert-butyl 5-(2,4-dichlorophenyl)-2-(hydroxymethyl)-7-methylimidazo[1,2-a]pyrimidine-6-carboxylate (400 mg, 100% crude yield) which was moved on to next step without further purification.
Reaction SMILES: NC1CC[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)CC1.C(N(CC)CC)C.ClC(OC[C:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1)=O>O1CCCC1>[CH3:29][CH2:28][CH2:27][CH2:32][CH2:31][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:9][CH2:8][NH2:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
To a 0° C. solution of 4-amino-1-benzylpiperidine 11 (41.2 g, 216.5 mmol) and triethylamine (51.3 mL, 369 mmol) in 600 mL of tetrahydrofuran was added benzyl chloroformate (31 mL, 217 mmol) dropwise over a period of 30 to 45 min. at such a rate that the reaction temperature was kept between 5° C. and 10° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stir for 12 hours. The solvent and volatiles were removed under reduced pressure. Water (500 mL) and ethyl acetate (1.2 L) were then added and the reaction was partitioned between the two phases. The organic layer was washed with saturated aqueous sodium bicarbonate solution (2×, 150 mL) and then dried (brine, MgSO4). Evaporation of the solvent yielded a tan liquid which was purified via column chromatography (SiO2, EtOAc/Hexane—30/70 to EtOAc—100) to provide 27.8 g of the amine 12 as a white solid (mass spec. M+=324, MP=79.1-79.6° C.).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][C:21]([CH2:24][NH2:25])=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-]>C1COCC1.O>[NH2:25][CH2:24][C:21]1[N:22]=[CH:23][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(CN)cn3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2cnc(CN)cn2)cc2c1C(CC(=O)O)OB2O
Yield: 33.9 %

Procedure:
A solution of [6-(5-aminomethyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (700 mg, 2.24 mmol) in THF (16 mL) was treated with LiOH (470 mg, 11.2 mmol) in water (8 mL) at room temperature for 2 h. The reaction was concentrated to dryness. The residue was diluted with water and adjusted to pH 3. The mixture was purified by preparative HPLC to give the title compound (250 mg). 1H NMR (300 MHz, CD3OD) δ 8.48 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.18 (s, 1H), 7.07 (s, 1H), 5.70-5.63 (m, 1H), 4.29 (s, 2H), 3.18-3.12 (m, 1H), 2.40 (s, 3H), 2.36-2.28 (m, 1H). MS found: (M+H)+=330.1.
Reaction SMILES: I([O-])(=O)=O.[Na+].[I:6]I.[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([I:6])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: II
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+2]([O-])[O-]
Product: O=C(O)c1cc(I)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.2 %

Procedure:
Sodium iodate (4.4 g) and iodine (11.1 g) were added to 90% sulfuric acid (330 mL), and stirred at room temperature for 8 hours. 2,4-Dichlorobenzoic acid (21 g) commercially available was added and stirred at the same temperature for 24 hours. The reaction solution was poured into ice water (3 L), and the precipitated solid material was collected by filtration. Further, the solid material was washed with water, and dried under reduced pressure. 2,4-Dichloro-5-iodobenzoic acid (16.8 g) was obtained by recrystallization (acetic acid-water). The resulting 2,4-dichloro-5-iodobenzoic acid (2 g) was dissolved in a mixture of dichloromethane (20 mL) and methanol (20 mL). Trimethylsilyldiazomethane (hexane solution, 2 M) was added dropwise until the solution became yellow. A small amount of acetic acid was added, and then the resulting mixture was concentrated under reduced pressure. The resulting residue was recrystallized using hexane to give the title compound 2,4-dichloro-5-iodobenzoic acid methyl ester as white solid (2 g).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[Br:11]Br>CO>[CH:4]1([C:2]([CH2:1][Br:11])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(=O)C1CCCCCC1
Reactant: BrBr
Solvent: CO
Product: O=C(CBr)C1CCCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
An ice cold solution of 19.0 g of cycloheptyl methyl ketone in 100 ml of methyl alcohol was treated dropwise with 7 ml of bromine. After 5 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then diluted with 500 ml of water and extracted with ethyl ether (3×75 ml). The combined extracts were washed with saturated sodium bicarbonate, brine, dried (MgSO4) and condensed in vacuo to yield 29.9 g of bromomethyl cycloheptyl ketone as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH2:25][NH:24][CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C=O.[C:35](O)(=O)C.C([BH3-])#N>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH2:25][N:24]([CH3:35])[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc3c(c(CCC4CCCO4)n2)CNCC3)ccc1-n1cnc(C)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Solvent: CO
Product: COc1cc(Nc2nc(CCC3CCCO3)c3c(n2)CCN(C)C3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
N-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-(2-(tetrahydrofuran-2-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.133 g, 0.31 mmol, Example 114a), formaldehyde (8.43 μL, 0.31 mmol) and acetic acid (8.76 μL, 0.15 mmol) in methanol (4 mL) was stirred at room temperature for 20 minutes. Polymer supported cyanoborohydride (0.46 g, 0.92 mmol) was added and the reaction mixture was stirred at room temperature overnight. The polymer supported cyanoborohyride was filtered off and the filtrated was purified by preparative chromatography. The product containing fractions were pooled and the solvent was evaporated. The residue was dissolved in water/acetonitrile-mixture (50:50) and freezedried giving N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-methyl-4-(2-(tetrahydrofuran-2-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.055 g, 40.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12]Br)=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[Br:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][O:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Br:20])[CH:22]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1OCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-(2-bromoethoxy)benzaldehyde (170 mg, 0.55 mol) obtained in step 1) was dissolved in DMF (20 ml), and K2CO3 (229.43 mg, 1.66 mmol), KI (9.96 mg, 0.06 mmol), and 3-bromophenol (95.46 mg, 0.55 mmol) were added to the solution, followed by stirring for 2 hours at an elevated temperature. After completion of the reaction, the reaction solution was cooled to room temperature, washed with an aqueous saturated NH4Cl solution and extracted with ethyl acetate. The organic layer thus obtained was washed one more time with an aqueous saturated NH4Cl solution. Then, the organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/n-hexane=1/9) to afford the object compound (pale yellowish solid, 161 mg, 72.7%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[S:9])[CH:2]=1.[CH2:10]([NH2:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([NH:15][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[S:9])[CH:2]=1
Reactant: CC(C)(C)CN
Reactant: S=C=Nc1cccnc1
Solvent: C1CCOC1
Product: CC(C)(C)CNC(=S)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of 3-pyridyl-isothiocyanate (1.50 mL, 13.3 mmol) in THF (30 mL) at room temperature was added neopentylamine (2.35 mL, 19.8 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 2.64 g (89%) of 1-(3-pyridyl)-3-(2,2-dimethylpropyl)-thiourea as an off-white solid which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([OH:15])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.Cl.[CH3:17]O>O1CCOCC1>[NH2:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([O:15][CH3:17])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: NCC12CC3CC(C1)CC(C(=O)O)(C3)C2
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C12CC3CC(CC(CN)(C3)C1)C2
Yield: 82 %

Procedure:
73 mg (0.30 mmol) of 3-(aminomethyl)adamantane-1-carboxylic acid were initially charged in 1.48 ml of methanol, and 1.48 ml of 4 N hydrogen chloride solution in dioxane were added. The mixture was stirred under reflux for 5 h. The mixture was concentrated by evaporation and the residue was admixed with saturated sodium hydrogencarbonate solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulphate and then concentrated by evaporation and dried. 55 mg of the target compound (82% of theory) were obtained, which were used in the subsequent stage without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:41][NH:42][CH2:43][CH:44]1[O:48][CH2:47][CH2:46][O:45]1.C(OCC)(=O)C>O1CCCC1.CCO.CCCCCC>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:42]([CH2:43][CH:44]2[O:48][CH2:47][CH2:46][O:45]2)[CH3:41])=[O:7])=[CH:4][CH:3]=1
Reactant: CNCC1OCCO1
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN(C)CC3OCCO3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 43 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and 2-methylaminomethyl-1, 3 dioxolane (0.91 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a kelly green compound CC-36. Mol. Wt.: 513.5412 (C29H27N3O6); Rf: 0.31 (ethyl acetate:n-hexane=1:2); Yield: 43%; Mp.: 156-157° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 513.1900 (C29H27N3O6+); found, 513.1902; 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 2.18 (s, 3H, —CH3), 2.44 (s, 3H, —CH3), 2.54 (d, J=8.7 Hz, 2H, —NCH2—), 3.26 (s, 2H, —CH2N—), 3.52-3.55 (m, 2H, —OCH2—), 3.72-3.77 (m, 2H, —OCH2—), 4.58 (t, J=4.5 Hz, 1H, —OCHO—), 7.43 (d, J=7.8 Hz, 2H, Ar—H), 7.88-7.92 (m, 2H, Ar—H), 8.04 (d, J=8.1 Hz, 2H, Ar—H), 8.10-8.19 (m, 2H, Ar—H), 8.27 (d, J=8.4 Hz, 1H, Ar—H), 8.70 (d, J=8.7 Hz, 1H, Ar—H), 10.15 (s, 1H, Ar—NH—), 10.53 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.87, 43.49, 59.43, 61.73, 63.91, 102.61, 125.50, 126.31, 126.48, 126.90, 127.89, 128.06, 129.06, 129.31, 130.75, 132.33, 134.16, 134.38, 134.45, 140.42, 142.29, 166.25 (NCO), 169.59 (NCO), 181.46 (CO), 183.70 (CO).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.FC(F)(F)C(O)=O.[N+:18]([O-])([OH:20])=[O:19]>O>[OH:1][C:2]1[C:7]([N+:18]([O-:20])=[O:19])=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
A solution of 4,6-dihydroxy-2-methylthiopyrimidine (42 g, 0.257 mol) in trifluoroacetic acid (91 ml, 1.186 mol) was stirred at 23° C. and warmed until all solid had gone into solution. The reaction was stirred for five hours at 23° C. Next, fuming HNO3 (15 ml, 350 mmol) was added portion wise to the reaction mixture over 25 minutes at 0° C. The reaction was stirred for twenty hours at 23° C., and treated with H2O (at 23° C.) at 80% conversion (according LC-MS). The solid precipitate was captured via filteration giving 4,6-dihydroxy-2-methylthio-5-nitropyrimidine as a tan-colored solid. The crude solid was azeotroped with toluene to give 35 g of pale tan powdery solid. 1H-NMR: 300 MHz, (CD3OD, 300 MHz) δ (ppm) 2.63 (s, 3H). LCMS-ESI−: calc'd for C5H4N3O4S: 202.0 (M−H−). Found: 202.0 (M−H−).
Reaction SMILES: [OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl.[CH3:17]O>>[OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:17])=[O:4]
Reactant: CO
Reactant: O=C(O)C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COC(=O)C(O)Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of the product from step (a) (3.0 g) and c.HCl (0.5 ml) in methanol (100 ml) was refluxed for 1 hour. The solvents were evaporated in vacuo and the residue flash chromatographed through a silica column using methanol/chloroform (3:100 v/v) to give the desired product as a pale yellow solid (2.7 g). The 200 MHz 1H NMR was consistent with the proposed structure.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:23][NH:22][CH2:21][CH2:20][N:19]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.C(OCC)(=O)C>C1COCC1>[C:31]1([S:37]([N:22]2[CH2:21][CH2:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH:18]([C:14]3[CH:13]=[C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH:7]=4)[CH:17]=[CH:16][CH:15]=3)[CH2:23]2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccccc1N1CCNCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1N1CCN(S(=O)(=O)c2ccccc2)CC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 2-(3′-methanesulfonyl-biphenyl-3-yl)-1-o-tolyl-piperazine hydrochloride (58 mg) in THF (1 mL) sodium hydride (12.3 mg, 60% in mineral oil) was added. After stirring for 30 min at room temperature, benzenesulfonyl chloride was added at 0° C. and stirring was continued at room temperature overnight. Water and ethyl acetate was added, the phases were separated and the inorganic one was extracted with ethyl acetate (×3). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane/ethyl acetate 2:1,) yielded 4-benzenesulfonyl-2-(3′-methanesulfonyl-biphenyl-3-yl)-1-o-tolyl-piperazine (55 mg, 42%) as colorless oil, MS: 547.1 (M+H)+.