Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].OS(O)(=O)=O.[CH3:23]O>>[CH3:23][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:3]([O:2][CH3:1])=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=1
Reactant: CO
Reactant: COc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of crude 4-methoxy-3,5-dinitro-benzoic acid (D24) (4.43 g, 17.3 mmol, 1 equiv) in MeOH (60 ml) was added concentrated H2SO4 (4 ml). The resulting mixture was refluxed for 3 h, cooled to room temperature and concentrated in vacuo. The residue was partitioned between H2O and AcOEt. The two layers were separated and the organic phase was washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (iso-hexane/AcOEt: 85/15) gave 4-methoxy-3,5-dinitro-benzoic acid methyl ester (D25) (2.84 g, 65%) as an off white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]5[S:27][C:26]([CH2:28][N:29]6[CH2:33][CH2:32][CH2:31][C@H:30]6CC(N)=O)=[CH:25][CH:24]=5)=[CH:21][N:22]=4)[CH:19]=3)=[CH:12][N:11]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:10]=2)=[CH:5][CH:4]=1)#[N:2].[N:57]1C=CC=C[CH:58]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]5[S:27][C:26]([CH2:28][N:29]6[CH2:33][CH2:32][CH2:31][C@H:30]6[C:58]#[N:57])=[CH:25][CH:24]=5)=[CH:21][N:22]=4)[CH:19]=3)=[CH:12][N:11]([C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(CN5CCC[C@H]5CC(N)=O)s4)n3c2)cc1
Reactant: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(CN5CCC[C@H]5C#N)s4)n3c2)cc1
Reaction time: 0.5 h

Procedure:
While 144 mg of (2S)-1-[(5-{6-[3-(4-cyanophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}-2-thienyl)methyl]tetrahydro-1H-2-pyrrole carboxyamide obtained in Example 35 was cooled in 1 mL tetrahydrofuran under ice-cooling, 0.05 mL pyridine and 0.57 mL trifluoroacetic anhydride were added thereto, and the mixture was stirred for 30 minutes. The solvent was removed, and the residue was purified with an NH silica gel column (hexane/ethyl acetate) to give 116 mg of the title compound (film)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]([F:12])([CH3:11])[CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]1([CH2:25][CH2:26][CH2:27][CH:28]([NH2:32])[CH:29]2[CH2:31][CH2:30]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([C:9]([F:12])([CH3:11])[CH3:10])[N:5]=[C:6]([NH:32][CH:28]([CH:29]2[CH2:31][CH2:30]2)[CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: CC(C)(F)c1nc(N)nc(Cl)n1
Reactant: NC(CCCc1ccccc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(F)c1nc(N)nc(NC(CCCc2ccccc2)C2CC2)n1

Procedure:
1.52 g (0.008 mol) of 2-amino-4-chloro-6-(1-fluoro-1-methylethyl)-1,3,5-triazine and 1.64 g (0.012 mol) of potassium carbonate are introduced into 30 ml of acetonitrile. 1.50 g (0.008 mol) of 4-phenyl-1-cyclopropyl-1-butylamine, dissolved in 10 ml of acetonitrile, are added dropwise to this solution. The mixture is refluxed for three hours. The solid components are then filtered off with suction and the filtrate is evaporated on a rotary evaporator. The residue is purified by column chromatography (eluant: methyl acetate). This gives 2.36 g (86% of theory) of 2-amino-4-(1-fluoro-1-methylethyl)-6-(1-phenyl-4-cyclopropyl-4-butylamino)-1,3,5-triazine.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Br:9]Br>C(O)(=O)C>[Br:9][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: BrBr
Reactant: O=c1cc[nH]c(=O)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]cc(Br)c(=O)[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
39.4 g (0.35 mol) of uracil are dissolved in 200 ml of acetic acid, and the mixture is warmed to 70° C. The mixture is added dropwise over the course of 2 hours to a solution of 20 ml (0.38 mol) of bromine dissolved in 200 ml of acetic acid. The orange suspension is held at 70° C. overnight and then cooled to 0°-5° C. The precipitate obtained is filtered off, washed with 200 ml of cold water and dried, giving 60.2 g of 5-bromouracil (89.7% of theory).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH:46]6[CH2:49][CH2:48][CH2:47]6)[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH:46]6[CH2:49][CH2:48][CH2:47]6)[CH:42]=[CH:43][N:44]=5)=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CC4CCC4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CC4CCC4)cc2)CCN3CC(C)C)cc1
Yield: 67 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclobutylmethylimidazol-2-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (640 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (342 mg) in dichloromethane (15 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and an aqueous solution of sodium thiosulfate was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclobutylmethylimidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (439 mg) (Compound 361) as yellow amorphous.
Reaction SMILES: C([C:3]1([C:22]([O-])=[O:23])[NH:8][C:7]2[CH2:9][O:10][C:11]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:6]=2[CH:5]=[CH:4]1)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:22]([C:3]1[N:8]=[C:7]2[CH2:9][O:10][C:11]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:6]2=[CH:5][CH:4]=1)=[O:23]
Reactant: CCC1(C(=O)[O-])C=CC2=C(COC23CN(C(=O)OC(C)(C)C)C3)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1nc(C=O)ccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To the stirred solution of 1-tert-butyl 2′-ethyl-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1,2′-dicarboxylate (0.5 g, 1.5 mmol, 1 eq.) in DCM (18 mL) at −78° C. under nitrogen atmosphere was added 25% DIBAL-H in toluene (0.64 g, 2.6 mL, 4.5 mmol, 3 eq.). Resulting reaction mixture was stirred at −78° C. for 1 hour under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by methanol (1.5 mL) followed by addition of saturated solution of sodium potassium tartarate salt (10 mL) at −78° C. and extracted with DCM (3×75 mL). Combined organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford the title compound as brown solid (0.25 g, crude). Crude compound was used as such for the next reaction. LC-MS (m/z): 291.0 (M+H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Br)=O.O.O.O.O.O.O.O.O.O.[S-2:23].[Na+].[Na+].O.Cl>CCO>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[S:23][CH:1]=[N:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: O=CNc1cc([N+](=O)[O-])ccc1Br
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2scnc2c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A solution of formamide from Step 1 (5.83 g, 23.8 mmol) and sodium sulfide nonahydrate (8.60 g, 35.8 mmol) in EtOH (120 ml) was heated to reflux for 2 h under nitrogen. After this time the reaction was cooled to RT then poured into cold water (600 ml). The resulting solution was cooled in an ice bath and acidified to pH 1 with 37% HCl. The solution was cooled in an ice bath for a further 1 h, during which time an orange precipitate formed. This solid was isolated by filtration and dried under vacuum to afford 5-nitrobenzothiazole as an orange solid (2.28 g). The above filtrate was extracted with EtOAc (3×200 ml), and the combined organic extracts dried over Na2SO4, filtered and concentrated under vacuum to afford additional 5-nitrobenzothiazole (0.89 g) as an orange solid. NMR and TLC analysis indicated that both crops of product were identical; the combined yield was 3.17 g. 1H NMR (CDCl3) δ 9.19 (s, 1H), 9.02 (d, 1H), 8.35 (dd, 1H), 8.12 (d, 1H); 13C NMR (CDCl3) δ 157.3, 153.1, 147.0, 140.2, 122.5, 120.1, 119.3. MS (ESI+) for m/z 181 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Product: COc1cc(Nc2nc(Cl)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(C(N)=O)cc1OC

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-4,5-bis(methyloxy)benzamide (3.7 g, 18.9 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,5-bis(methyloxy)benzamide was isolated as a white solid (2.75 g, 62% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3 H), 3.77 (s, 3 H), 3.80 (s, 3 H), 6.60 (d, J=3.85 Hz, 1 H), 7.38 (s, 1 H), 7.44 (d, J=8.61 Hz, 2 H), 7.62 (s, 1 H), 7.71 (d, J=4.03 Hz, 1 H), 7.95 (d, J=8.42 Hz, 2 H), 8.21 (s, 1 H), 8.32 (s, 1 H), 12.70 (s, 1 H)
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[N:7]1[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[C:9]([CH3:15])=[N:8]1.Cl.[N:17]1[CH:22]=[CH:21][C:20]([C:23](N)=[NH:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[N:7]1[C:11]2=[N:24][C:23]([C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[N:14][C:12](=[O:13])[C:10]2=[C:9]([CH3:15])[NH:8]1
Reactant: Cc1nn(C2CCCC2O)cc1C(N)=O
Reactant: N=C(N)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1[nH]n(C2CCCC2O)c2nc(-c3ccncc3)nc(=O)c1-2
Yield: 23.4 %

Procedure:
A mixture of 1-(2-hydroxycyclopentyl)-3-methyl-1H-pyrazole-4-carboxamide (2.4 g, 10 mmol), 4-pyridinecarboxamidine hydrochloride (3.2 g, 20 mmol), potassium carbonate (2.8 g, 20 mmol) and DMF (50 ml) were heated under reflux for 28 hours. The solvent was removed in vacuo, the residue was dissolved in hot water (25 ml) and was filtered. The filtrate was acidified with acetic acid and the resulting white precipitate was collected by filtration and recrystallized from DMF to afford 0.73 g (21%) of 1-(2-hydroxycyclopentyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as white needles, m.p. 281°-283° C.
Reaction SMILES: Br[CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+]>C(O)C>[CH2:13]([C:2]1[S:22][C:21]([NH2:23])=[N:20][C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(Br)Cc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a 500 ml eggplant-shaped flask were added 25.00 g (78.32 mmol) 2-bromo-1-(4-methoxy-phenyl)-3-phenyl-propan-1-one prepared in the step 3 and 150 ml anhydrous ethanol, then added 5.96 g (78.32 mmol) thiourea and 6.42 g (78.32 mmol) anhydrous sodium acetate under stirring, the resulting mixture was stirred at room temperature for 1 hour, then refluxed for 2 hours, and cooled to room temperature, and a solid was precipitated, filtered, washed with water, dried to obtain 18.01 g of a product, a single spot was shown by TLC, the product was not further purified in a yield of 77.6%, mp: 177-178□. 1H-NMR (DMSO-d6, 400 MHz) δ: 3.76 (3H, s, OCH3), 4.04 (2H, s, CH2), 6.82 (2H, s, NH2), 6.93 (2H, d, J=9.00 Hz, ArH), 7.18˜7.35 (5H, m, ArH), 7.46 (2H, d, J=9.00 Hz, ArH); EI-MS m/e (%): 296.1 (M, 100), 219.0 (19); HREI-MS Calcd. for C17H16N2OS: 296.0983. found: 296.0978. Anal. Calcd. for C17H16N2OS: C, 68.89; H, 5.44; N, 9.45. found: C, 69.08; H, 5.32; N, 9.57.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:40][CH2:41][CH3:42]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:40][CH2:41][CH3:42])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 8.0 mg, 0.018 mmol) in DMF (1.0 ml) was reacted with K2CO3 (8.0 mg, 0.055 mmol) and 1-iodopropane (9.0 μl, 0.092 mmol) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][N:25]([CH3:29])[C:26]([NH2:28])=[O:27]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:28][C:26](=[O:27])[N:25]([CH3:29])[CH3:24])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CN(C)C(N)=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(NC(=O)N(C)C)cc3)CC2)c(C)c1
Yield: 11.5 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (211 mg) described in Preparation Example 113 and 1,1-dimethylurea (66 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (22 mg) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Reactant: COc1ccc(S)cc1OC
Product: COc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1OC

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxy-thiophenol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[N:6][C:7]=1[Cl:8].[C:21]1([C:27]2([NH2:31])[CH2:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN1CCOCC1>O1CCOCC1>[NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:31][C:27]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][CH2:30]2)=[N:18][C:19]#[N:20])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: N#CN=C(Nc1cnc(Cl)c(N)c1)Oc1ccccc1
Reactant: NC1(c2ccccc2)CCC1
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: N#CN=C(Nc1cnc(Cl)c(N)c1)NC1(c2ccccc2)CCC1
Yield: 34.1 %

Procedure:
A stirred mixture of the product from Step 2 (1.5 g, 0.0052 mol), 1-phenylcyclobutylamine (0.8 g, 0.00543 mol), N-methylmorpholine (1.37 ml, 0.0125 mol) and dioxane (30 ml) was refluxed, under nitrogen for 5 hours, cooled and filtered. The solid was washed with cold dioxane and Et2O and crystallized from acetonitrile to give 0.605 g of the titled product, mp 220°-221° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.[CH2:14]([O:16][C:17](=[O:31])[C:18](=[CH:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[CH3:30])[C:19]([CH3:21])=O)[CH3:15].[ClH:32].C(OCC)C>C(OCC)C>[ClH:32].[CH2:14]([O:16][C:17]([C:18]1[CH:22]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[CH3:30])[C:5]2[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[N:3][N:2]([CH3:1])[C:6]=2[NH:7][C:19]=1[CH3:21])=[O:31])[CH3:15]
Reactant: Cn1nc(-c2ccccc2)cc1N
Reactant: CCOC(=O)C(=Cc1cc(C)ccc1C)C(C)=O
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)Nc2c(c(-c3ccccc3)nn2C)C1c1cc(C)ccc1C

Procedure:
Starting from 1-methyl-3-phenyl-5-pyrazolamine and ethyl-2-(2,5-dimethylbenzyliden)acetoacetate in equimolar proportions. The crude reaction product is taken up with ethyl ether, washed with 2% H2SO4, water, and then 5% NaHCO3 until neutralization of the mother liquors. After drying over Na2SO4 the hydrochloride of the title compound is obtained by reacting with HCl/ethyl ether. Crystallization from isopropanol/ethyl ether.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:27]([Cu])#[N:28].CN1CCCC1>O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(OC3CCCCC3)cc2c1O
Agent: CN1CCCC1
Solvent: O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(OC3CCCCC3)cc2c1O
Temperature: 130 °C
Yield: 76.5 %

Procedure:
A mixture of 1-bromo-6-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (see U.S. Patent Application Publication No. 2004/0254215; 350 mg, 0.83 mmol), CuCN (149 mg, 1.66 mmol) and N-methyl-pyrrolidine (2.5 mL) was heated at 130° C. for 2 h. After cooled, reaction mixture was poured into water (50 mL) with stirring. Precipitate was collected and rinsed with water. Resulting solid was partitioned between ethyl acetate and 10% aqueous NH4OH (50 mL), and vigorously stirred for 15 min. The mixture was acidified by aqueous concentrated HCl and then 1 N HCl solution to pH=4. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title product (234 mg). MS-(+)-ion: M+1=369.43.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]([CH:15]=[N:16][OH:17])=[C:11](Cl)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OCC)(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[H-].[Na+]>[Cu]Br>[CH2:24]([O:23][C:21]([C:20]1[C:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14][CH2:13][C:12]=2[CH:15]=[N+:16]([O-:17])[C:19]=1[OH:26])=[O:22])[CH3:25]
Reactant: ON=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c2c(c[n+]([O-])c1O)CCN(Cc1ccccc1)CC2

Procedure:
Prepared from 1-benzyl-4-chloro-5-hydroxyiminomethyl-2,3,6,7-tetrahydro-1H-azepine by reaction with diethyl malonate in the presence of sodium hydride and catalytic amounts of copper(I) bromide at 100° C.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([CH3:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[NH3:26]>CO.O>[NH2:26][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([CH3:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C)n2)cc1
Reactant: N
Solvent: CO
Solvent: O
Product: Cc1nc(C(O)CNC(C)Cc2ccc(OCC(N)=O)cc2)cs1

Procedure:
1 g (0.0027 mol) of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine is dissolved in 5 ml of methanol and stirred with 5 of concentrated ammonia at room temperature for 3 hours. The mixture is then diluted with water and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using ethyl acetate/methanol =9:1 as eluant.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][NH2:4].C([O-])([O-])=O.[K+].[K+].[OH-].[K+].[CH:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:30][C:31](Cl)=[O:32])=[CH:25][CH:24]=1>O.C1COCC1>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][NH:4][C:31]([O:30][CH2:29][C:26]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1)=[O:32]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Temperature: -5 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A stirring mixture of the N-Boc-Dap-OH 1 (10.00 g, 49.02 mmol), THF (90 mL), water (30 mL), K2CO3 (13.53 g, 98.04 mmol) and KOH (2.75 g, 49.02 mmol) was cooled to −5° C. Cbz-Cl solution (50 wt % in toluene, 25 mL, 73.53 mmol) was then added dropwise over a period of an hour. The mixture was allowed to stir for 8 h before being concentrated under reduced pressure to remove the THF. The aqueous residue was extracted with diethyl ether (50 mL), acidified to pH 4 by solid citric acid and the resulting precipitate was extracted by CH2Cl2 (2 50 mL). Combined organic layers were dried (Na2SO4) and evaporated to furnish the free acid 2 (15.57 g, 94% yield) as a gummy white solid which was used without further purification. 1H NMR (300 MHz, CDCl3) δ10.76 (1H), 7.25 (5H), 6.24, 5.67 (2H), 5.85 (1H), 5.08, 5.02 (2H), 4.36-4.23 (1H), 3.63-3.35 (2H), 1.38 (9H); 13C NMR (75 MHz, CDCl3)δ 173.5, 157.5, 156.2, 136.4, 128.6, 128.2, 80.6, 67.3, 54.4, 42.9, 28.6.