Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg].[CH2:16]([NH:23][CH2:24][CH:25]1[CH2:27][O:26]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:16]([N:23]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:24][CH:25]([OH:26])[CH2:27][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cccc(CN2CCCCC2)c1
Reactant: c1ccc(CNCC2CO2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1cccc(CN2CCCCC2)c1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
10.2 g (0.04 mol) of 3-(1-piperidylmethyl)-bromobenzene in 20 ml of tetrahydrofuran are added dropwise to 0.97 g (0.04 mol) of magnesium filings in 5 ml of tetrahydrofuran at a reaction temperature of 60° C. This operation is followed by 30 minutes' stirring at 60° C., and the solution is then cooled to 10° C. 10.2 g (0.04 mol) of 2-benzylaminomethyl-oxirane in 20 ml of tetrahydrofurane are slowly added dropwise and the solution obtained is stirred at room temperature for 2 hours. After the addition of 20 ml of ice water and 4.5 g of ammonium chloride, the aqueous phase is separated and extracted with 25 ml of methylene chloride. The combined organic phases are dehydrated with sodium sulphate and concentrated by evaporation to yield a yellow resin which is chromatographed with methylene chloride/methanol (9:1) against silica gel. After concentration by evaporation, the second fraction yields the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1)([OH:9])[CH:6]([CH3:8])[CH3:7].C>[Pd].C1COCC1.CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@@:5]([OH:9])([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)CC(O)(CCc1ccc(OCc2ccccc2)cc1)C(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C[C@@](O)(CCc1ccc(O)cc1)C(C)C

Procedure:
The title compound was prepared as described in General Method 4 using 3-[2-(4-benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid methyl ester (8.6 g, 24.2 mmol) from Example SSSS. Three grams of 20% Pd over charcoal and THF:MeOH 1:1 (100 mL). The crude compound was recrystallized from hexanes-ethyl acetate to give racemic title compound (m.p. 89-91° C.). The title compound was obtained by resolution on a semi-preparative Chiralcel OD column eluting with 90% hexanes, 10% isopropanol and 0.1% trifluoroacetic acid. 1H-NMR (CDCl3) δ 0.93 (d, 3H), 0.95 (d, 3H), 1.68-1.85 (m, 2H), 1.93 (m, 1H), 2.53 (dd, 2H), 2.62 (m, 2H), 3.63 (br s, 1H), 3.71 (s, 3H), 4.97 (br s, 1H), 6.73 (d, 2H), 7.03 (d, 2H).
Reaction SMILES: [CH3:1][C:2]([S:8][CH:9](O)[C:10]([O:12][CH3:13])=[O:11])(O)[C:3]([O:5]C)=O.C(OC)(=O)[C:16](OC)=[O:17].[Na]>CO>[OH:17][C:16]1[C:3]([OH:5])=[C:2]([CH3:1])[S:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(=O)OC
Reactant: COC(=O)C(O)SC(C)(O)C(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sc(C)c(O)c1O
Yield: 68.2 %

Procedure:
A mixture of dimethyl α-methyl-thiodiglycolate (Solladie-Cavallo, Bull. Soc. Chim. Fr., 437 (1968)) (10.2 g, 53 mmoles) and dimethyl oxalate (9.4 g, 79 mmoles) in methanol (25 mL) is added slowly to a solution of sodium (3.8 g, 165 mmoles) in methanol (35 mL) under argon and maintained at 10°-15° C. with an ice bath. After the addition, the mixture is slowly heated to reflux for 1 hour, then cooled and concentrated under reduced pressure. The precipitate is filtered off, rinsed with ether, air dried, dissolved in water and acidified with 4N hydrochloric acid. The precipitate is filtered off, rinsed with water and dried to afford the product (6.8 g); mp 116°-117° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:9][C:10]1[N:11]=[C:12]([S:21][CH3:22])[N:13]=[N:14][C:15]=1[C:16](OCC)=[O:17])[CH3:8].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C1COCC1>[CH2:7]([NH:9][C:10]1[N:11]=[C:12]([S:21][CH3:22])[N:13]=[N:14][C:15]=1[CH2:16][OH:17])[CH3:8]
Reactant: CCNc1nc(SC)nnc1C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCNc1nc(SC)nnc1CO
Reaction time: 0.5 h

Procedure:
To a room temperature suspension of 5.1 g (133.7 mmol) of lithium aluminum hydride in 400 mL of anhydrous THF was added a solution of 16.2 g (66.9 mmol) of 5-ethylamino-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester in 150 mL of THF. The reaction was stirred for 6 hours at room temperature, at which time approximately 16 mL of a saturated solution of ammonium sulfate was added dropwise while keeping the reaction temperature below 25° C. with an ice bath. The reaction mixture becomes heavy with precipitate, and 200 mL of THF was added followed by 5 mL more of saturated ammonium sulfate. The reaction mixture was stirred for another 30 minutes and decanted. The remaining solids were filtered and washed several times with a total of 1 L of hot THF. The combined THF solution was concentrated and twice dissolved in dichloromethane and concentrated to give a pale orange semi-solid, (5-ethylamino-3-methylsulfanyl-1,2,4-triazin-6-yl)-methanol.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH3:17])=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1)[CH3:2].CN(CCN(C)C)C.[Li]CCCC.ClCC[I:44]>C1COCC1>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([I:44])[N:14]3[CH3:17])=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1)[CH3:2]
Reactant: ClCCI
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2ncn(C)c2n1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(I)n(C)c2n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A suspension of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (1.67 g, 4.58 mmol) and TMEDA (1.0 mL, 799 mg, 6.88 mmol) in THF (25 mL) was cooled to −78° C. before the drop wise addition of n-BuLi (2.8 mL, 6.88 mmol, 2.5 M solution in hexanes). The resulting mixture was stirred for 40 mins before the addition of 1-chloro-2-iodoethane (629 μL, 1.3 g, 6.88 mmol). The resulting mixture was stirred at −78° C. for 1 h then quenched with H2O and warmed to r.t. The pale yellow precipitate was collected by filtration washing with further H2O and dried under vacuum at 50° C. 2-(2-Ethylbenzoimidazol-1-yl)-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine was afforded as a pale yellow powder (2.0 g, 90%). LCMS (method H): RT 2.74 min [M+H]+ 490.2
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH2:20][C:21](O)=[O:22])[CH:14]=[CH:13][C:12]=2[CH2:11]1)(=[O:8])=[O:7].S(Cl)(Cl)=O.[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH2:20][C:21]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=3)=[O:22])[CH:14]=[CH:13][C:12]=2[CH2:11]1)(=[O:8])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)Cc1ccc2c(c1)CCC(NS(=O)(=O)c1cccs1)C2
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)Cc2ccc3c(c2)CCC(NS(=O)(=O)c2cccs2)C3)cc1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A mixture of 1.51 g of 6-(2-thienyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetic acid, 20 ml of methylene chloride, one drop of dimethylformamide and 3.3 ml of thionyl chloride is refluxed for 2 hours, and the solvent is removed to give yellow oil. A solution of the oil in 20 ml of methylene chloride is added dropwise to a solution of 1.30 g of methyl 4-aminobenzoate and 1.31 g of triethylamine in 15 ml of methylene chloride under stirring at room temperature. After the mixture is stirred overnight, the solvent is distilled off. Ethyl acetate and 10% hydrochloric acid are added to the residue, and the organic layer is separated therefrom, washed, dried and evaporated to remove the solvent. The resulting solid is recrystallized from a mixture of tetrahydrofuran and isopropyl ether to give 1.58 g of methyl 4-{[6-(2-thienyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino}benzoate as pale yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[CH:12]=[N:11][C:10]([C:13]#[N:14])=[N:9]1>>[C:13]([C:10]1[N:11]=[CH:12][N:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:9]=1)#[N:14]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1nc[nH]n1
Product: CCOC(=O)Cn1cnc(C#N)n1
Yield: 83.5 %

Procedure:
Ethyl 2-bromoacetate (8.88 g, 53.15 mmol) was reacted with 1H-1,2,4-triazole-3-carbonitrile (5 g, 53.15 mmol) according to the procedure as described in Example 48, Step A to give the title compound as a white solid (8 g, 84%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=O)[CH2:12]1)=[O:10].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:30][C:31]1[C:32]([C:37]([NH:39][NH2:40])=O)=[N:33][CH:34]=[CH:35][CH:36]=1.Cl>ClCCl.CO.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:37]([C:32]3[C:31]([CH3:30])=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:39][N:40]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C1CN(C(=O)c2ccc(F)cc2Cl)CCN1
Reactant: Cc1cccnc1C(=O)NN
Agent: CC[O+](CC)CC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: Cc1cccnc1-c1nnc2n1CCN(C(=O)c1ccc(F)cc1Cl)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
A solution of 4-[(2-chloro-4-fluorophenyl)carbonyl]-2-piperazinone (0.257 g, 1 mmol, e.g. prepared as described in Intermediate 2) in dry Dichloromethane (DCM) (2 ml) was stirred at room temperature under argon. Triethyloxonium tetrafluoroborate (0.190 g, 1.000 mmol) was added and the reaction solution was stirred for 3 hours. 3-Methyl-2-pyridinecarbohydrazide (0.166 g, 1.100 mmol, e.g. prepared as described in Intermediate 22) was added to the solution and stirred for 1 h. The solvent was then evaporated in vacuo and n-butanol (2.000 ml) was added to the residue. The solution was heated at reflux for 18 hours and then allowed to cool to room temperature. The solvent was then evaporated in vacuo and the residue was partitioned between Dichloromethane and brine. The organic layer was dried over sodium sulphate, filtered and the solvent was evaporated in vacuo to give a yellow solid. The solid was then purified by flash chromatography (Biotage SP4, 25+M cartridge) using a gradient of 0 to 10% MeOH/NH3 in Dichloromethane as the eluent. The solvent was then evaporated in vacuo and the remaining residue was purified by mass-directed automated (preparative) HPLC (MDAP) to yield the crude product. The product was then dissolved in methanol (2 mL) and to this was added HCl in diethyl ether (1 mL), the solvent was then evaporated in vacuo and dried in a vacuum-oven yielding 7-[(2-chloro-4-fluorophenyl)carbonyl]-3-(3-methyl-2-pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.108 g).
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:11])C1C=CC=CC=1.C[OH:38]>[Pd]>[OH:18][C@H:17]1[C@H:16]([OH:19])[C@H:15]([OH:20])[CH2:14][N:13]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][CH:29]=2)(=[O:22])=[O:23])[C@H:12]1[C:10]([OH:11])=[O:38]
Reactant: CO
Reactant: O=C(NOCc1ccccc1)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Product: O=C(O)[C@H]1[C@@H](O)[C@H](O)[C@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
The above compound (6) (6.0 g) was dissolved in methanol (180 mL) and 10% Pd—C (1.3 g) was added, and then the mixture was stirred under a hydrogen atmosphere at 45° C. for 2 hours and 30 minutes. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=20:1→10:1→5:1) to obtain the titled compound (3.76 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:28]([NH2:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C1COCC1.CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][CH:22]([NH:34][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)cc2)CC1
Reactant: CCCCCCN
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCNC1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)cc2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-chloro-N-{4-[(4-oxo-1-piperidinyl)sulfonyl]benzyl}benzamide 7d (500 mg, 1.23 mmol) was suspended in THF/methanol (10 ml/20 ml), N-hexylamine (149 mg, 1.48 mmol) and Cyanoborohydride-IRA400 (1.0 g, 3.0 mmol) were added and the reaction mixture was stirred at 50° C. overnight. Excess amine was scavenged with Ameba-PS (415 mg, 0.50 mmol) by shaking for 2 h. The resins were filtered off, solvent removed in vacuo and the obtained residue purified by column chromatography on silica gel using a step gradient of 2.5% methanol in DCM and 5% methanol in DCM. Fractions with Rf=0.28 (5% methanol in DCM,) were collected and evaporated to dryness (Note: Up to 1% conc. NH3 (13.5 M) may be added during the chromatography to reduce loss of material). The residue was dissolved in DCM (10 ml) and 1 N HCl in ether (3 ml) added. After aging at room temp for 1 h the precipitate was filtered off and dried in vacuo. The hydrochloric salt of sulfonamide 4-chloro-N-(4-{[4-(hexylamino)-1-piperidinyl]sulfonyl}benzyl)benzamide 7 was isolated as off-white powder (260 mg, 36%) in >95% purity. M/Z APCI 492.0 (M+1), 490.2 (M−1). 1H-NMR (DMSO-d6) (HCl salt) δ 9.39 (t, 1H, H—N5, 3J=5.92 Hz), 8.97 (m, br, 2H, H—N16), 7.99 (d, 2H, 3J=8.65 Hz, H—C2, 3), 7.75 (d, 2H, 3J=8.20 Hz, H—C8, 9), 7.61 (m, 4H, H—C1, 4, 7, 10), 4.61 (d, 2H, 3J=5.92 Hz, H—C6), 3.73* (d, 2H, 2J=11.84 Hz, Heq—C11, 15), 3.07 (m, br, 1H, H—C13), 2.83 (m, br, 2H, H—C17), 2.29* (m, 2H, Hax—C12, 14), 2.10* (d, br, 2H, 2J=11.90 Hz, Hax—C11, 15), 1.71-1.54* (m, 4H, Heq—C12, 14 and H—C18), 1.36-1.23 (m, 6H, H—C19, 20, 21), 0.89 (t, 3H, 3J=6.60 Hz, H—C22)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[N:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:14][C:12]1[N:13]=[C:8]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: OCc1cccc(Nc2ccncc2)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccc(Nc2ccncc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At 0° C., 50 mg (0.22 mmol) of the compound from example 8A and 53 mg (0.44 mmol) of thionyl chloride are initially charged in 1.5 ml of dichloromethane and, after warming to RT, stirred at this temperature for 12 h. The solvent is removed on a rotary evaporator and the product that remains is directly reacted further.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=2)[C:12]([OH:14])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:51]1[CH2:56][CH2:55][O:54][CH2:53][CH:52]1[C:57]1[C:65]2[S:64][C:63]([NH2:66])=[N:62][C:61]=2[C:60]([O:67][CH3:68])=[CH:59][CH:58]=1>C1COCC1.C(Cl)(Cl)Cl>[O:51]1[CH2:56][CH2:55][O:54][CH2:53][CH:52]1[C:57]1[C:65]2[S:64][C:63]([NH:66][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][N:17]=[C:9]([CH2:8][O:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:10]=3)=[N:62][C:61]=2[C:60]([O:67][CH3:68])=[CH:59][CH:58]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(COC2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(COC4CCOCC4)c3)nc12

Procedure:
From 2-(tetrahydro-pyran-4-yloxymethyl)-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+84.9° (c=1.05, CHCl3), ES-MS m/e (%): 486 (M+H+, 100).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(2-ethoxy-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 86) (500 mg, 1.08 mmol) in dichloromethane (7 ml) was treated with trifluoroacetic acid (3 ml) and stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene and dichloromethane. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0:0 (dichloromethane:methanol:acetic acid) gradually changing to 90:10:1 (dichloromethane:methanol:acetic acid) to afford the title compound as a colourless oil (374 mg).
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:32])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]([NH2:31])=[O:30])[O:24][CH2:23]2)[CH:17]([CH:33]([OH:35])[CH3:34])[C:16]3=[O:36])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:41].O.[H][H]>[Pd].O1CCOCC1>[Na+:41].[NH2:31][C:29]([O:28][CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:32])[CH:18]3[N:15]([C:16](=[O:36])[CH:17]3[CH:33]([OH:35])[CH3:34])[C:14]=2[C:12]([O-:13])=[O:11])[CH2:26]1)=[O:30]
Reactant: [H][H]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COC(N)=O)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COC(N)=O)C3)C(C)C12
Yield: 67 %

Procedure:
A mixture of 0.181 g of product from Example 17, 0.032 g of sodium bicarbonate, 2 ml of water, 11 ml of dioxane and 0.100 g of 10% palladium/carbon is reduced in a Parr apparatus at 42 psi of hydrogen for 3 hours. The reaction mixture is filtered through a pad of diatomaceous earth, washed with water and concentrated to 1/2 volume. The solution is extracted with ethyl acetate and the aqueous layer is freeze-dried. The product is purified using C18 reverse phase chromatography (95/5 water/ethyl alcohol) to give 0.095 g of the desired product as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH2:36][OH:37])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[N:11]/[C:12]2[S:13][C:14]([CH:23]=[C:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:16]=2)=[CH:6][CH:5]=1)[CH3:2].Cl[S:39]([OH:42])(=[O:41])=[O:40]>C1COCC1>[S:39]([OH:42])([O:37][CH2:36][CH2:35][N:3]([C:4]1[CH:5]=[CH:6][C:7](/[N:10]=[N:11]/[C:12]2[S:13][C:14]([CH:23]=[C:24]3[C:25](=[O:34])[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:32]3=[O:33])=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:16]=2)=[CH:8][CH:9]=1)[CH2:1][CH3:2])(=[O:41])=[O:40]
Reactant: O=S(=O)(O)Cl
Reactant: CCN(CCO)c1ccc(/N=N/c2nc(N3CCCCC3)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Solvent: C1CCOC1
Product: CCN(CCOS(=O)(=O)O)c1ccc(/N=N/c2nc(N3CCCCC3)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Temperature: 0 °C

Procedure:
0.32 g (0.62 mmol) 2-{[2-((E)-{4-[ethyl(2-hydroxyethyl)amino]phenyl}-diazenyl)-4-(1-piperidinyl)-1,3-thiazol-5-yl]methylene}-1H-indene-1,3(2H)-dione were dissolved in 33 ml THF and cooled to 0° C. Then 0.11 g (0.93 mmol) chlorosulfonic acid were added slowly drop by drop with stirring. After the addition was completed, the reaction mixture was heated under reflux for 4 hours, allowed to cool to room temperature and stirred overnight. After further cooling in an ice bath the formed precipitate was filtered off, washed with a little cold THF and dried at 40° C. in vacuum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[NH:11][C:12]([I:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CO>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[C:12]([I:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(I)ccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CO
Product: Cn1c(I)ccc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a solution of 3-(benzyloxy)-6-iodopyridin-2(1H)-one (20.48 g, 62.6 mmol) in methanol (626 mL) was added potassium carbonate (8.56 g, 62.6 mmol) and iodomethane (3.91 mL, 62.6 mmol), and the resulting mixture was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure, and the resulting residue was partitioned between water and ethyl acetate. The aqueous layer was removed and discarded. The organic layer was collected, dried over anhydrous magnesium sulfate, and purified using silica gel chromatography to afford 3-(benzyloxy)-6-iodo-1-methylpyridin-2(1H)-one (15.4 g, 45.1 mmol, 72% yield). ES-MS (M+H)+=342.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[S:14])([CH3:4])([CH3:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([N:15]=[CH:19][N:20]([CH3:22])[CH3:21])=[S:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCNC(N)=S
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=S)NCCCCNC(=O)OC(C)(C)C
Yield: 76 %

Procedure:
The title compound was synthesised from (4-Thioureido-butyl)-carbamic acid tert-butyl ester and Dimethylformamide dimethyl acetal according to the procedure described for Example C in 76% yield. MS (m/e): 303.3 (MH+, 100%).
Reaction SMILES: Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([C:25](Cl)=[O:26])=[N:23][CH:24]=4)[CH2:15][CH2:14]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.[CH3:28][NH2:29]>ClCCl.O1CCCC1>[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:29][CH3:28])=[O:26])=[N:23][CH:24]=4)[CH2:15][CH2:14]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1ccc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5-{4-[(1-Cyclobutyl-4-piperidinyl)methyl]-1-piperidinyl}-2-pyridinecarbonyl chloride hydrochloride (may be prepared as described in Example 11, step 1) was dissolved in dichloromethane (10 ml) and added dropwise to a stirred solution of methylamine (1.57 ml of a 2M solution in tetrahydrofuran) in dichloromethane (10 ml) cooled to 0° C. over 1 h. The reaction was allowed to stir for a further 3 h before the mixture was evaporated. Chromatography (silica gel, eluting with methanol/dichloromethane, 0-20%) afforded the title compound (E11) (0.13 g). MS electrospray (+ion) 371 (MH+).1H NMR δ (CDCl3): 8.14 (1H, d, J=2.8 Hz), 8.01 (1H, d, J=8.8 Hz), 7.75 (1H, m), 7.19 (1H, dd, J=2.8, 8.8 Hz), 3.80 (2H, m), 3.00 (4H, m), 2.82 (3H, m), 2.19-1.21 (21H, m obscured by H2O)