Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([CH2:7][CH:8]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:22]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23]2)[CH:9]([OH:13])[C:10]([OH:12])=O)C=CC=CC=1.[C:34]1([CH2:40][CH2:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[OH:13][CH:9]([C:10](=[O:12])[NH:42][CH2:41][CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:8]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCCc1ccccc1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCCc1ccccc1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 4-phenyl-2-hydroxy-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with 2-phenylethylamine; ESI-MS [M+H]+: 546.2
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1([CH3:11])[CH2:8][C:7]([CH:9]=[O:10])=[CH:6][CH2:5]1.Cl>CI.C(OCC)C>[CH3:3][C:4]1([CH3:11])[CH2:5][CH2:6][CH:7]([C:9](=[O:10])[CH3:1])[CH2:8]1.[CH3:3][C:4]1([CH3:11])[CH2:8][C:7]([CH:9]([OH:10])[CH3:1])=[CH:6][CH2:5]1
Reactant: CI
Reactant: CC1(C)CC=C(C=O)C1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)C1CCC(C)(C)C1
Product: CC(O)C1=CCC(C)(C)C1
Temperature: 25 °C
Yield: 107 %

Procedure:
The starting 1-(3,3-dimethyl-1-cyclopentyl)-1-ethanone was prepared thus: 2.1 g (0.088 mol) of Mg, to which a few ml of ether had been added so as to cover it, were charged into a 250 ml vessel kept under nitrogen and around ten drops of CH3I were added thereto to trigger the reaction. Once the latter had started, what was left of 11.9 g of CH3I (0.084 mol) in 30 ml of ethyl ether was introduced while maintaining a slight reflux. The mixture was then heated to reflux for 1/2 h, cooled to room temperature and 10 g (0.08 mol) of 4,4-dimethyl-1-cyclopentene-1-carbaldehyde [prepared according to Magnusson et al., J. Org. Chem. 38, 1380 (1973)], in solution in 30 ml of ether, were added thereto. It was then re-heated to reflux for 1 h. After cooling, it was poured on ice and HCl, washed to neutrality with saturated NaCl, dried, filtered and concentrated under reduced pressure. After bulb-to-bulb distillation, 6 g (yield: 53.6%) of 1-(4,4-dimethyl-1-cyclopenten-1-yl)-1-ethanol were obtained, whose analytical data were the following:
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][CH:10]([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[C:9]1=[O:38])=O)(C)(C)C.[I-:39].[Na+]>C(#N)C>[C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@H:12]2[NH:8][C:9](=[O:38])[CH:10]([CH2:26][I:39])[CH2:11]2)=[CH:15][CH:16]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCC2C[C@@H](Cc3ccc(-c4ccccc4)cc3)N(C(=O)OC(C)(C)C)C2=O)cc1
Agent: [Na+]
Solvent: CC#N
Product: O=C1N[C@H](Cc2ccc(-c3ccccc3)cc2)CC1CI

Procedure:
122 mg (3R/S,5S)-5-Biphenyl-4-ylmethyl-2-oxo-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (11-a, R1=Boc, R4=Tosyl) prepared according to Example 49, Method 2 is added to acetonitrile (3 ml). Sodium iodide (105 mg) is then added to the mixture. The resulting mixture is heated at reflux overnight. The mixture is then concentrated under reduced pressure. Purification by column chromatography, eluting with ethyl acetate-heptane (1:1) gives (3R/S,5S)-5-biphenyl-4-ylmethyl-3-iodomethyl-pyrrolidin-2-one (12-a, R1=H, R5=I). 1H NMR (CDCl3): 2.13 (2H), 2.69 (2H), 2.82 (1H), 3.28 (1H), 3.35 (1H), 3.85 (1H), 5.84 (1H), 7.17 (2H), 7.28 (1H), 7.37 (2H), 7.49 (4H).
Reaction SMILES: [CH2:1]([C:4]1([CH:19]=[CH:20][CH2:21][OH:22])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[CH2:1]([C:4]1([CH2:19][CH2:20][CH2:21][OH:22])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH2:2][CH3:3]
Reactant: C=CCC1(C=CCO)c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC1(CCCO)c2ccccc2CCc2ccccc21
Yield: 90.1 %

Procedure:
Dissolved 3-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-prop-2-en-1-ol (4.85 g, 16.70 mmol) in 75 mL of absolute ethanol. Added 10% palladium on carbon catalyst (1.20 g), and hydrogenated on Paar shaker at 58 psi of hydrogen pressure for 16 hours. Filtered to remove catalyst, and evaporated filtrate to give 4.43 g (90% yield) of 3-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanol as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[C:35]=O.[CH3:47][O:48][C:49]1[C:50]2[CH:51]=[C:52]3[CH2:61][NH:60][CH2:59][CH2:58][N:53]3[C:54]=2[CH:55]=[CH:56][CH:57]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:35]([N:60]1[CH2:59][CH2:58][N:53]3[C:54]4[CH:55]=[CH:56][CH:57]=[C:49]([O:48][CH3:47])[C:50]=4[CH:51]=[C:52]3[CH2:61]1)[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1cccc2c1cc1n2CCNC1
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCn3c(cc4c(OC)cccc43)C2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting with 281 mg (0.6 mmol) of the iminophosphorane from Example 12A, 134 mg (0.6 mmol) of 1-isocyanato-3-(trifluoromethyl)benzene and 129 mg (0.6 mmol) of 9-methoxy-1,2,3,4-tetrahydropyrazino[1,2-a]indole from Example 34A, the general procedure [M] gives 239 mg (66% of theory) of product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([CH3:38])[CH:30]=1>CN(C)C=O.C(#N)C>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([CH3:38])[CH:30]=4)[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: CC(=O)c1ccc(OCCCBr)cc1C
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1C
Temperature: 120 °C
Yield: 39.8 %

Procedure:
A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.5 g, 21.6 mmol), K2CO3 (3.5 g), 1-[4-(3bromopropoxy)-2-methylphenyl]-ethanone (4.83 g, 17.8 mmol) in dimethylformamide (25 ml) and acetonitrile (75 ml) was heated at 120° C. for 5 hours. At the end of the reaction, the solvent was removed and the residue was extracted into dichloromethane (300 ml) and the solution was washed with water and brine. The organic solution was dried and evaporated to a crude oil. The purification was done by flash chromatography over a silica gel column (80 g, eluted with dichloromethane, 1 1; 1% methanol: dichloromethane, 1.2 1; 2% methanol:dichloromethane, 1.2 1). The purest fractions were combined and afforded 2.91 g of solid. Recrystallization from dichloromethane and ethanol gave 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-methylphenyl]ethanone as off-white crystals: 2.42 g, m.p.=113°-114° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:41])[C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=3[NH:26][C:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:31][CH2:30]3)=[O:28])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:42](Cl)(=[O:44])[CH3:43]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:41])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:42](=[O:44])[CH3:43])=[CH:21][C:20]=3[NH:26][C:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=4)[CH2:31][CH2:30]3)=[O:28])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(NC(=O)c3ccc(N)cc3NC(=O)C3CCN(c4ccncc4)CC3)cc21
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc3ccn(C(=O)OC(C)(C)C)c3c2)c(NC(=O)C2CCN(c3ccncc3)CC2)c1
Yield: 77 %

Procedure:
Using the procedure described in Example 24, Part E, N-(1-tert-butoxycarbonyl-6-indolyl)-2-[1-(4-pyridyl)piperidin-4 ylcarbonylamino]-4-aminobenzamide (0.18 mmol) was reacted with acetyl chloride to yield 83 mg (77%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O)=CC=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:28][C:29]([F:32])([F:31])[F:30])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OCC(F)(F)F
Temperature: 100 °C
Reaction time: 40 h
Yield: 32 %

Procedure:
A stirred mixture of 3.14 g of 4-fluoro-2-nitrophenol, 13 g of cesium carbonate and 20 mL of anhydrous dimethylformamide was heated at 100° C. for 4 hours. After this period, 6.65 g of 2,2,2-trifluoroethyl p-toluenesulphonate was added and the mixture was stirred at the same temperature for 40 hours. Afterwards, the solvent was removed under reduced pressure at 35° C. and 50 mL of water was added to the residue. The mixture was acidified with 37% hydrochloric acid and extracted with 3×40 mL of ethyl acetate. The organic layer was washed with 20 mL of brine, dried over sodium sulphate and evaporated to dryness in vacuo. The residue was purified by flash chromatography (petroleum ether:ethyl acetate 100:7) to afford 1.53 g (32%) of Compound 5A as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][CH3:20])[C:7]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][CH3:20])[C:7](=[O:21])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 105 °C
Yield: 15 %

Procedure:
4-[6-(8-Cyclopentyl-6-ethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared by addition of 8-cyclopentyl-6-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.80 g, 2.62 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.82 g, 6.55 mmol) to toluene (10 ml) followed by heating to 105° C. over 10 hours. The resulting suspension was filtered, the solid washed with toluene and dried in vacuo yielding 4-[6-(8-Cyclopentyl-6-ethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.204 g). MS (APCI); M++1; Calc'd 520.3, Found 520.1
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[C:17]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:33]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[N:32][N:31]=4)=[CH:25][CH:24]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:4][C:5]([NH:8]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:8][C:5]1[N:4]=[C:3]([C:16]2[C:17]([O:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:33]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[N:32][N:31]=4)=[CH:27][CH:28]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[C:2]([F:1])=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(F)c(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(F)c(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a RBF, tert-butyl 5-fluoro-4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylcarbamate (1.46 g, 2.43 mmol) was dissolved in DCM (4.86 ml, 2.43 mmol). TFA (749 μl, 9.72 mmol) was added at RT. The reaction was stirred at RT. After 20 min, LCMS showed mainly starting material. 1 mL of TFA was added and the reaction was allowed to stir at RT overnight. After 16 h, the reaction was concentrated and the residue dissolved in DCM. The solution was cooled to 0° C. and neutralized with 2N NaOH. At pH=5-7, the product as a white solid precipitated out. At pH>7, the product dissolves in DCM. The precipitate was filtered with aid of DCM. The solid product was set aside, while the filtrate was concentrated. The residue was diluted with a bit of DCM. Water was added. Ether was added and the whole solution was triturated to precipitate out additional product. The solid was filtered off with an aid of Et2O. This crop was combined with the first crop of solid. The product was purified by column chromatography on 120 g silica gel using 70:30 DCM:(90:10:1 DCM:MeOH:NH4OH). Fractions containing the product were combined, and concentrated, to afford an off white solid, which was triturated in Et2O. The resulting yellow solid was filtered off with an aid of Et2O and air dried. The solids were purified further via RPLC on the acidic Gilson Only fractions containing the product were combined, diluted with DCM, and washed with sat. NaHCO3. The organic was dried over MgSO4, filtered, and concentrated to afford N-(4-(3-(2-amino-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)4-phenylphthalazin-1-amine. MS Calcd for C29H20FN7O: [M]+=501. Found: [M+1]+=502.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[OH:6][CH:7]([CH3:40])[CH2:8][S:9]([C:12]1[CH:13]=[C:14]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:15]=[C:16]([OH:22])[C:17]=1[O:18][CH2:19][CH2:20][CH3:21])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:6][CH:7]([CH3:40])[CH2:8][S:9]([C:12]1[CH:13]=[C:14]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=3)[O:24]2)[CH:15]=[C:16]([O:22][CH2:4][CH2:3][CH2:2][Br:1])[C:17]=1[O:18][CH2:19][CH2:20][CH3:21])(=[O:10])=[O:11]
Reactant: BrCCCBr
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
1,3-Dibromopropane (0.105 mL, 1.0 mol) was added to a solution of trans-2-[3-(2-hydroxypropylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (102 mg, 0.20 mmol) in DMF (1 mL) containing potassium carbonate (105 mg, 0.76 mmol). The reaction mixture was heated with stirring under nitrogen at 70° C. for 2 h, cooled, and partitioned between ethyl ether and water. The ethereal layer was separated and the aqueous layer was re-extracted twice with ether. The organic extracts were combined, dried, and evaporated to a residue (143 mg). Purification by preparative TLC (hexane-ethyl acetate; 1:1, v/v) gave the title compound (89 mg, 70%) as a colorless foam: Rf 0.5; NMR (CDCl3) δ 1.26 (d, CH2CHOHCH3), 3.66 (t, CH2Br).
Reaction SMILES: [C:1](=[S:3])=[S:2].[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([C:25]([NH:27][NH2:28])=N)[CH:11]=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:7])[CH3:6]>C(O)C.C(OC(C)C)(C)C>[CH3:7][C:5]([C:8]1[CH:9]=[C:10]([C:25]2[S:2][C:1](=[S:3])[NH:28][N:27]=2)[CH:11]=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:4])[CH3:6]
Reactant: S=C=S
Reactant: COCCOCOc1c(C(C)(C)C)cc(C(=N)NN)cc1C(C)(C)C
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: COCCOCOc1c(C(C)(C)C)cc(-c2n[nH]c(=S)s2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
Carbon disulfide (1.6 g, 0 021 mole) is added dropwise to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzene carboximidic acid hydrazide (3.0 g, 0.085 mole) in absolute ethanol (36 ml). The mixture is allowed to warm to room temperature and stir three hours. The mixture is stripped of volatiles under reduced pressure and the residue is dissolved in isopropyl ether and the solvent removed under reduced pressure. The resulting solid is recrystallized from isopropyl ether/hexane to give 2.8 g of 5-[3,5-bis(1,1-dimethylethyl)- 4-[(2-methoxyethoxy)methoxy]phenyl]-1,3,4-thiadiazole-2(3H)-thione (3.5 g theor., 80%); mp 134°-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]([O-])([O-])OCC>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:13]=[N:12][S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: CCOC([O-])[O-]
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Product: O=S1(=O)N=CNc2ccc(Cl)cc21
Temperature: 110 °C

Procedure:
40 ml of ethyl orthoformate are added to 4.75 g of 2-amino-5-chlorobenzenesulphonamide, the preparation of which is described in the journal J. Chem. Soc. Perkin I 1979, 1043-1047. The mixture is heated at 110° C. for 30 minutes in an open vessel. Dissolution is observed, and then the appearance of a precipitate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O.[I-]>[CH2:18]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([F:1])[CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Yield: 96.5 %

Procedure:
A solution of 2-fluoro-4-hydroxynitrobenzene (5.08 g, 32.36 mmol), cesium carbonate (11.71 g, 36.24 mmol), benzyl bromide (4.31 mL, 36.24 mmol), and tetrabutylamunonium iodide (50 mg) in N,N-dimethylformamide (50 mL) was stirred at 25° C. for 24 hours, diluted with water (200 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (7.72 g, 97%). 1H NMR (300 MHz, CDCl3): δ 8.10 (m, 1 H), 7.40 (m, 5 H), 6.82 (m, 2 H), 5.15 (s, 2 H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]([NH2:14])=[S:13].O>CO>[NH2:14][C:12]1[S:13][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(N)=S
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccccc2)cs1
Yield: 85.1 %

Procedure:
A solution of 19.9 g (0.10 mol) of α-bromo-acetophenone and 11.4 g (0.15 mol) of thiourea in 75 ml of methanol is refluxed for 2 h. It is evaporated to dryness under reduced pressure and the evaporation residue is taken up with water. The resulting solution, heated to the reflux temperature, is treated with CXA charcoal and then rendered alkaline with aqueous ammonia. The precipitate formed is isolated by filtration and purified by recrystallization from isopropanol, with CXA charcoal treatment. to give 15 g (yield: 85.15%) of the expected product in the form of water-insoluble white needles. M.p. (inst.)=150° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[ClH:1].[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH:18]([CH3:19])[CH3:20])[C:14]4[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccc2c1NC(=O)C2(CCCCCl)CC(C)C
Reactant: Clc1cccc(N2CCNCC2)c1
Product: Cc1cccc2c1NC(=O)C2(CCCCN1CCN(c2cccc(Cl)c2)CC1)CC(C)C
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 3-(4-chlorobutyl)-3-isobutyl-7-methyl-1,3-dihydro-2H-indol-2-one and 1-(3-chlorophenyl)-piperazine.
Reaction SMILES: [C:1](OC(OC(C)(C)C)N(C)C)(C)([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:40]=[CH:39][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([S:28]([NH:31][C@H:32]([CH:36]([CH3:38])[CH3:37])[C:33]([OH:35])=[O:34])(=[O:30])=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1.[C:41]1(C)C=CC=CC=1>>[C:36]([C@:32]([NH:31][S:28]([N:25]1[CH2:26][CH2:27][CH:22]([C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:40][CH:39]=2)[CH2:23][CH2:24]1)(=[O:30])=[O:29])([CH:1]([CH3:3])[CH3:2])[C:33]([OH:35])=[O:34])([CH3:41])([CH3:38])[CH3:37]
Reactant: CC(C)[C@@H](NS(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1)C(=O)O
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: Cc1ccccc1
Product: CC(C)[C@](NS(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1)(C(=O)O)C(C)(C)C
Reaction time: 3 h

Procedure:
N,N-dimethylformamide di-tert-butyl acetal (134 mg, 0.66 mmol) was added to a solution of 2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyric acid (90 mg, 0.22 mmol) in toluene (2.5 ml) at 90° C. The reaction was stirred for 3 h and concentrated to give tert-butyl 2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyric acid that was used in the next step with no further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[CH:7]=1.[C:15]1([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN1C(=O)CCC1>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:22])[CH2:24][CH2:25]2)=[CH:7][C:6]=1[NH:8][CH2:9][CH2:10][CH3:11])([O-:14])=[O:13]
Reactant: CCCNc1cc(Br)ccc1[N+](=O)[O-]
Reactant: O=C(c1ccccc1)N1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCNc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 213.7 %

Procedure:
A solution of 5-bromo-2-nitro-N-propylbenzenamine (250 mg, 1.02 mmol) and phenyl(piperazin-1-yl)methanone (578 mg, 3.06 mmol) in NMP (2 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish (4-(4-nitro-3-(propylamino)phenyl)piperazin-1-yl)(phenyl)methanone (520 mg, 2.18 mmol), 56% yield. 1H NMR (500 MHz, DMSO-D6) d (ppm) 8.83 (m, 1H), 7.93 (d, J=9.5 Hz, 1H), 7.50-7.45 (m, 5H), 6.41 (dd, J=2.5 Hz, 10 Hz, 1H), 6.00 (d, J=2.5 Hz, 1H), 3.72-3.40 (m, 8H), 3.29 (q, J=7 Hz, 2H), 1.66 (m, 2H), 0.96 (t, J=7 Hz, 3H).+ESI HRMS (calcd for C20H24N4NaO, M+Na) 391.1746. found 391.1741
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O1CCOCC1>[I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(I)c1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=C(Nc1cccc(I)c1)N1CCOCC1

Procedure:
A solution of 3-iodophenylisocyanate (0.1 g, 0.41 mmol) and morpholine (0.04 mL, 0.45 mmol) in 2 mL dioxane were heated at 100° C. overnight. The solvent was evaporated and the resulting product was used without purification.