Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[N:18]=[C:17]([OH:28])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(=O)(OC)OC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[N:18]=[C:17]([O:28][CH3:29])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: COc1ccc(-n2nc(OC)cc2-c2ccc(OCc3ccccc3)cc2)cn1
Temperature: 120 °C
Reaction time: 5 h
Yield: 128.8 %

Procedure:
A suspension of 5-{5-[4-(benzyloxy)phenyl]-3-hydroxy-1H-pyrazol-1-yl}-2-methoxypyridine (800 mg), dimethyl carbonate (0.9 mg) and potassium carbonate (888 mg) in DMF (8 ml) was stirred at 120° C. for 5 hours. The mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with H2O, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=30% to give 5-{5-[4-(benzyloxy)phenyl]-3-methoxy-1H-pyrazol-1-yl}-2-methoxy-pyridine (1.069 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.ClC1C=CC(O)=CC=1.C1(O)C=CC=CC=1.O(CCC(O)=O)C1C=CC=CC=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:53][CH2:54][CH2:55][CH2:56][N:57]1[CH:61]=[CH:60][N:59]=[CH:58]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]([NH:53][CH2:54][CH2:55][CH2:56][N:57]2[CH:61]=[CH:60][N:59]=[CH:58]2)=[O:11])=[CH:12][CH:13]=1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)CCOc1ccc(Cl)cc1
Agent: O=C(O)CCOc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: Oc1ccc(Cl)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(CCOc1ccc(Cl)cc1)NCCCn1ccnc1

Procedure:
A solution of 3-(4-chlorophenoxy)propionic acid (5.0 g, prepared from 4-chlorophenol by the process described in J.A.C.S. 1923, 2708 for the conversion of phenol into 3-phenoxypropionic acid) in THF (90 ml) was treated with 1,1′-carbonyldiimidazole (4.05 g) at room temperature with stirring. The mixture was stirred at ambient temperature for two hours. 1-(3-Aminopropyl)imidazole (3.12 g) was added and the mixture was stirred at ambient temperature for 18 hours. The solvent was distilled off and the residue was dissolved in dichloromethane, washed with water, dried and then evaporated to give a solid which was recrystallised from ethyl acetate to give 3-(4-chlorophenoxy)-N-[3-(imidazol-1-yl)propyl]propionamide, m.p. 114-115.5° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2.Cl>>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2
Reactant: FC(F)(F)c1cccc2ccncc12
Agent: Cl
Product: FC(F)(F)c1cccc2c1CNCC2

Procedure:
Converting 8-trifluoromethylisoquinoline to the hydrochloride, m.p. 213°-216.5° C., then treating by the procedure of Example 9 gives 8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:9]
Reactant: O=C(O)c1cc(F)cnc1N1CC(Oc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(F)cnc3N3CC(Oc4cccc(F)c4)C3)CC2)cc1
Yield: 41.2 %

Procedure:
The title compound (D187) (45 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-fluoro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D132) (50 mg, 0.228 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (52.04 mg, 0.228 mmol).
Reaction SMILES: C[NH:2][CH:3]1[CH2:21][CH2:20][N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]2[CH2:4]1>CO.CC(C)=O>[NH2:2][CH:3]1[CH2:21][CH2:20][N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]2[CH2:4]1
Reactant: CNC1CCN2c3ccccc3Cc3ccccc3C2C1
Solvent: CO
Solvent: CC(C)=O
Product: NC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
2-methylamino-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine, oil; Rf in methanol:acetone (9:1) = 0.35 on SiO2.
Reaction SMILES: C[NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:13]C1C=CC(C(Cl)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:13][C:7]1[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=1[S:3]([NH2:2])(=[O:5])=[O:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(N)(=O)=O)c(C)c1

Procedure:
N-Methyl-4-methylbenzene sulfonamide (3.70 g, 0.02 mol) and 4-methylbenzoyl chloride (3.08 g, 0.02 mol) were dissolved in xylene and refluxed for 72 hrs. After evaporation of the xylene, the residue was dissolved in ethyl acetate and washed with dilute sodium carbonate solution. After separation, drying over anhydrous magnesium sulfate and evaporation of the solvent in vacuo, the residue was recrystallized from hexane-ethyl acetate to give N-4-methylbenzoyl-N*-methyl-4-methylbenzene sulfonamide mp 90–92° C. MS m/z 303. (M+ calcd for C16H17NO3S=303). H NMR (300 Mhz, CDCl3) d 2.30 (s, 3, CH3), 2.46 (s, 3, CH3), 7.21 (m, 2, aromatic), 7.35 (m, 2, aromatic), 7.49 (m, 2, aromatic), 7.84 (m, 2, aromatic).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH:19]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1)([CH3:21])[CH3:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH:19]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)([CH3:21])[CH3:20]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC(C)C1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)C1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 62 %

Procedure:
The product is prepared by following the procedure described in example 1c using 0.30 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.17 g of (−)-2-isopropylindoline and 0.27 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.26 ml of pyridine and 4.4 ml of N,N-dimethylformamide. 0.25 g of (−)-2-[2-(2-isopropyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (reference example 11c) is thus obtained in the form of a very pale pink solid, the characteristics of which are the following:
Reaction SMILES: Br.[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH2:29])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1.[CH2:37](O)[CH2:38][CH2:39]C.C(=O)([O-])[O-].[K+].[K+].BrCCCBr>O>[N:29]1([CH:15]2[C:14](=[O:30])[N:13]3[CH:8]([CH2:7][C:6]4[CH:35]=[CH:36][C:3]([Cl:2])=[CH:4][CH:5]=4)[C:9](=[O:34])[N:10]([CH:31]([CH3:33])[CH3:32])[CH2:11][CH:12]3[N:17]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])(=[O:20])=[O:19])[CH2:16]2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: CCCCO
Agent: Br
Agent: BrCCCBr
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(C)N1CC2N(C(=O)C(N3CCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
32 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were suspended in 1 ml of water, and 2 ml of 1-butanol were added. 1 mmol of potassium carbonate and 200 μl of 1,3-dibromopropane were added to this mixture. The reaction mixture was stirred at 90° C. for 16 hours and evaporated. The residue was suspended in 5% Et3N/ethyl acetate, filtered and evaporated. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=598.10 (calculated, monoisotopic); measured value (M+H)+: 599.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:15]=2)[C:11]#[N:12])[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:34]=[CH:33][N:32]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:31]=2)[CH2:26][CH2:25]1>>[CH3:22][O:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:34]=[CH:33][N:32]([C:35]3[CH:41]=[CH:40][C:38]([NH:39][C:2]4[N:7]=[C:6]([C:8]5[CH:9]=[C:10]([CH:13]=[C:14]([N:16]6[CH2:21][CH2:20][O:19][CH2:18][CH2:17]6)[CH:15]=5)[C:11]#[N:12])[CH:5]=[CH:4][N:3]=4)=[CH:37][CH:36]=3)[N:31]=2)[CH2:26][CH2:25]1
Reactant: COC1CCN(c2ncn(-c3ccc(N)cc3)n2)CC1
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)cc(N2CCOCC2)c1
Product: COC1CCN(c2ncn(-c3ccc(Nc4nccc(-c5cc(C#N)cc(N6CCOCC6)c5)n4)cc3)n2)CC1

Procedure:
3-(2-(4-(3-(4-methoxypiperidin-1-yl)-1H-1,2,4-triazol-1-yl)phenylamino)pyrimidin-4-yl-5-morpholinobenzonitrile was obtained by following procedure E using 3-(2-chloropyrimidin-4-yl)-5-morpholinobenzonitrile and 4-(3-(4-methoxypiperidin-1-yl)-1H-1,2,4-triazol-1-yl)aniline. MS (ESI) 538.23 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[O:37])[NH:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[C:15]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[N:14]=2)[CH2:8]1.[H-].[Na+]>CN(C=O)C>[N:31]1([C:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:15]3[N:14]=[C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:7]([N:6]5[CH2:2][CH2:3][NH:4][C:5]5=[O:37])[CH2:8]4)[CH:21]=[CH:20][C:16]=3[C:17]([NH2:19])=[O:18])=[CH:24][CH:25]=2)=[O:30])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)NCCCl)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCC[C@@H](N3CCNC3=O)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
To a solution of (R)-6-(3-(3-(2-chloroethyl)ureido)piperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (86 mg, 0.162 mmol) in DMF (1 mL) was added NaH (32.4 mg, 0.811 mmol) and stirred at rt for 1 h. The reaction mixture was quenched with water, extracted twice into CH2Cl2 twice. The combined organic extracts were washed with 10% LiCl and concentrated. The residue was purified by MPLC chromatography (ISCO, 6% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) and further purified by HPLC. The product containing fractions were collected, basified with 1N NaOH, and extracted with CH2Cl2 twice. The combined organic layers were concentrated to give 13 mg of (R)-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(3-(2-oxoimidazolidin-1-yl)piperidin-1-yl)nicotinamide as a light yellow solid. LCMS: (M+H)+=494.23. 1H NMR (400 MHz, CDCl3) δ ppm 11.17 (1H, s), 7.66-7.71 (2H, m), 7.52 (1H, d, J=8.79 Hz), 7.34-7.39 (2H, m), 6.07 (1H, d, J=8.79 Hz), 5.62-5.84 (2H, m), 4.54 (1H, s), 4.26-4.38 (2H, m), 3.76-3.88 (2H, m), 3.57-3.75 (8H, m), 3.43 (4H, d, J=4.39 Hz), 2.94-3.03 (1H, m), 1.92-2.02 (1H, m), 1.80-1.89 (1H, m), 1.68 (2H, m).
Reaction SMILES: [CH3:1]C(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(C)=O.[Br:18][C@H:19]1[C@@H:24]([OH:25])[CH2:23][C@@H:22]([C:26]([O-:28])=[O:27])[C@H:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Br:35])[CH2:20]1>O>[Br:18][C@H:19]1[C:24](=[O:25])[CH2:23][C@@H:22]([C:26]([O:28][CH3:1])=[O:27])[C@H:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Br:35])[CH2:20]1
Reactant: O=C([O-])[C@@H]1C[C@H](O)[C@H](Br)C[C@H]1c1ccccc1Br
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@@H]1CC(=O)[C@H](Br)C[C@H]1c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Freshly prepared Jones reagent (2.7 M, 7.0 mL) was added at 0° C. to an acetone (25 mL) solution of (1R,2R,4R,5S)-4-bromo-2-(2-bromophenyl)-5-hydroxycyclohexanecarboxylate (2.50 g, 6.38 mmol) with stirring at room temperature for 40 minutes. The mixture was then diluted with water and extracted with ether (3×). The combined extracts were washed with water, saturated aqueous sodium bicarbonate and brine solutions, and dried (Na2SO4). Concentration in vacuo gave methyl (1R,2R,4R)-4-bromo-2-(2-bromophenyl)-5-oxocyclohexanecarboxylate as a colorless, thick syrup.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.ClC(OCC(C)C)=O.Cl.[NH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl.C(Cl)(Cl)Cl.CCOCC>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
8.3 g (3.45 mmol) of Boc-Pro-OH were dissolved in 50 ml of CH2Cl2, cooled down to 5° C.; then, 38.45 mmol (5.38 ml) of TEA were added. The reaction mixture was cooled down to −25÷−30° C. At this temperature, 38.45 mmol (4.84 ml) of isobutyl chloroformate were added using a pipette. The reaction mixture temperature was kept in the range of −18÷−20° C. for 20 minutes. Simultaneously, a solution of 5.9 g (42.3 mmol) of 1.1-fold excess of HCl.H-Gly-OEt in 75 ml of chloroform, containing 5.92 ml of TEA. The solution was cooled down to −25° C. and, after formation of mixed anhydride in the first flask, its contents were poured to the ether solution right away. The reaction mixture was incubated for 1 hour at −10° C. and then stirred for 12 hours at 4° C. on a magnetic stirrer. The reaction mixture was evaporated, then 250 ml of ethyl acetate were added; then, ethyl acetate solution was washed 3 times with 25 ml of 0.1N HCl, 3 times with 25 ml H2O, and once with saturated solution of NaCl. The organic layer was dried over MgSO4, filtered and evaporated. The residue was dried under vacuum over P2O5/KOH and paraffin.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[CH:13]=[C:12]([C:14]3([S:17]([CH3:20])(=[NH:19])=[O:18])[CH2:16][CH2:15]3)[N:11]=[C:10]([C:21]3[CH:26]=[N:25][CH:24]=[C:23]4[N:27](C(OC(C)(C)C)=O)[CH:28]=[CH:29][C:22]=34)[N:9]=2)[CH2:6][CH2:5][O:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:13]=[C:12]([C:14]2([S:17]([CH3:20])(=[NH:19])=[O:18])[CH2:16][CH2:15]2)[N:11]=[C:10]([C:21]2[CH:26]=[N:25][CH:24]=[C:23]3[NH:27][CH:28]=[CH:29][C:22]=23)[N:9]=1
Reactant: C[C@@H]1COCCN1c1cc(C2(S(C)(=N)=O)CC2)nc(-c2cncc3c2ccn3C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1COCCN1c1cc(C2(S(C)(=N)=O)CC2)nc(-c2cncc3[nH]ccc23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
Tert-butyl 4-(4-((R)-3-methylmorpholino)-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.223 g, 0.44 mmol) was added to TFA (5 ml) and DCM (5.00 ml). The resulting solution was stirred at RT for 1 hour. The reaction mixture was evaporated and the residue was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated and the residue was triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to afford the title compound (0.086 g, 48%); 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.40-1.60 (3H, m), 1.76 (1H, d), 3.11 (3H, s), 3.12-3.21 (1H, m), 3.53 (1H, t), 3.68 (1H, d), 3.80 (2H, d), 4.01 (1H, d), 4.20 (1H, s), 4.58 (1H, s), 6.95 (1H, d), 7.28 (1H, s), 7.71 (1H, s), 8.83 (1H, s), 9.08 (1H, s), 11.75 (1H, s); m/z: (ES+) MH+, 413.16.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NC(=O)NCC(=O)O)ccn1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCC(=O)N2CCC(Cc3ccccc3)CC2)ccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a cooled (0° C.) mixture of [3-(2-methyl-pyridin-4-yl)-ureido]-acetic acid (Example D3., 105 mg, 0.5 mmol), 4-benzylpiperidine (Example A1., 105 mg, 0.6 mmol), HOBt (81 mg, 0.6 mmol), TEA (0.14 mL, 1 mmol) and a cat. amount of DMAP in CH2Cl2 (20 mL) are added, followed by EDC (115 mg, 0.6 mmol). The mixture is stirred at r.t. for 15 h. The mixture is quenched with sat. aq. Na2CO3 (25 mL), the phases are separated, and the aq. phase is extracted with CH2Cl2 (3×30 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated to provide the crude title compound.
Reaction SMILES: [CH:1]1([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][NH:17][CH2:18][CH2:19][CH:20]=[O:21]>C1C=CC=CC=1>[CH3:16][N:17]([CH2:18][CH2:19][CH:20]=[O:21])[C:14]([NH:13][C:11]1[S:12][C:8]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[N:9][N:10]=1)=[O:15]
Reactant: O=C=Nc1nnc(C2CCCCCC2)s1
Reactant: CNCCC=O
Solvent: c1ccccc1
Product: CN(CCC=O)C(=O)Nc1nnc(C2CCCCCC2)s1

Procedure:
A mixture of 5-cycloheptyl-1,3,4-thiadiazol-2-yl isocyanate dimmer (9.5 grams), the dimethyl acetal of 3-methylaminopropionaldehyde (5.8 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This product is recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[N:18][CH:17]=1.[N+:30]([O-])([OH:32])=[O:31].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[N:18][CH:17]=1)[N+:30]([O-:32])=[O:31]
Reactant: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO[N+](=O)[O-])cn2)CC1
Reaction time: 6 h
Yield: 69 %

Procedure:
2.00 g of N-(12-hydroxy-1-dodecanyl)-6-(4-methyl-1-piperazinyl)nicotinamide were suspended in 40 ml of acetonitrile and to the suspension was added dropwise under ice-cooling a mixed solution of 0.8 ml of fuming nitric acid and 1.9 ml of acetic anhydride and stirred for 6 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give 1.54 g (69%) of the title compound. m.p. 74°-76° C.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:22]([NH:24][N:25]([C:30](=[O:34])[CH:31]([OH:33])[CH3:32])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:22]([NH:24][N:25]([C:30](=[O:34])[CH:31]([OH:33])[CH3:32])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C(C)O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C(C)O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of 0.71 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(2(RS)-hydroxypropionyl)-2′-isobutyl-4-methylvalerohydrazide in 8 ml of methanol was treated with 0.071 g of p-toluenesulphonic acid. The mixture was stirred for 1 hour at room temperature and evaporated to give a foam. This foam was triturated with diethyl ether, filtered off and dried to give 0.425 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2(RS)-hydroxypropionyl)-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:5]2[CH2:21][N:22](C)[CH2:23][CH2:24][O:25][C:4]=12.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[C:5]2[CH2:21][NH:22][CH2:23][CH2:24][O:25][C:4]=12
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c2c1OCCN(C)C2
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c2c1OCCNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.3 %

Procedure:
To 6-methoxy-2-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Example 48, 0.030 g, 0.081 mmol), 1,8-Bis(dimethylamino)-naphthalene (0.010 g, 0.048 mmol) and 1-chloroethyl chloroformate (25 mg, 0.18 mmol) were added followed by dry DCM (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the crude material was dissolved in dry MeOH (3 mL). The reaction mixture was heated at reflux for 2 hours, cooled and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (3 mg). MS m/z 359 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][CH3:10])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH:19]=[O:20]
Reactant: CSc1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(Cl)c(C=O)c(Cl)c1
Reaction time: 1 h

Procedure:
To a stirred solution of (3,5-dichlorophenyl)(methyl)sulfane (1.0 g, 5.1 mmol) in THF (15 mL), n-BuLi (1.6 M in THF, 4.8 mL, 7.7 mmol) was added dropwise at −78° C. and stirred for 1 h at the same temperature. A solution of DMF (0.6 mL, 7.7 mmol) in THF (3 mL) was added slowly at −78° C. and stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl aq. (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to afford compound A57-1 (1.4 g, 99%) as colorless oil.