Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C:12]1[S:13][C:14](Br)=[CH:15][N:16]=1)=[O:10].[F:18][C:19]1([F:38])[O:23][C:22]2[CH:24]=[C:25]([CH3:37])[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:21]=2[O:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O1CCOCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C:12]1[S:13][C:14]([C:26]2[C:25]([CH3:37])=[CH:24][C:22]3[O:23][C:19]([F:18])([F:38])[O:20][C:21]=3[CH:27]=2)=[CH:15][N:16]=1)=[O:10]
Reactant: O=C(Nc1ncc(Br)s1)c1c(F)cccc1F
Reactant: Cc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)OC(F)(F)O2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)s1)OC(F)(F)O2
Temperature: 85 °C
Yield: 9 %

Procedure:
Argon was bubbled through a mixture of (2,6-difluorophenyl)-N-(5-bromo(1,3-thiazol-2-yl))carboxamide (152) (64 mg, 0.2 mmol), 2-(2,2-difluoro-6-methylbenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (489 mg, 0.3 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (21 mg, 10% mol) and K3PO4 (64 mg) in 1 mL ACN, 1 mL dioxane, 0.5 ml H2O. The reaction mixture was heated at 85° C. for 7 h. After cooling to room temperature, the reaction mixture was taken up in ethyl acetate, washed with aqueous NaHCO3 and brine. The organic phase was dried over (Na2SO4), concentrated and then subjected to prep HPLC chromatography to give (2,6-difluorophenyl)-N-[5-(2,2-difluoro-6-methylbenzo[d]1,3-dioxolen-5-yl)(1,3-thiazol-2-yl)]carboxamide (153) (7.4 mg, yield: 9%, purity>95%) as white solid. LC-MS: calcd. for C18H10F4N2O3S: 411 (M+1).
Reaction SMILES: [S:1]1[C:5]2[NH:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH:3]=[CH:2]1.[CH2:12]1[NH:17][CH2:16][CH2:15][N:14]2[CH2:18][CH2:19][CH2:20][CH:13]12>>[CH2:12]1[N:17]([C:9]([C:7]2[NH:6][C:5]3[S:1][CH:2]=[CH:3][C:4]=3[CH:8]=2)=[O:11])[CH2:16][CH2:15][N:14]2[CH2:18][CH2:19][CH2:20][CH:13]12
Reactant: C1CC2CNCCN2C1
Reactant: O=C(O)c1cc2ccsc2[nH]1
Product: O=C(c1cc2ccsc2[nH]1)N1CCN2CCCC2C1
Yield: 35 %

Procedure:
6H-Thieno[2,3-b]pyrrole-5-carboxylic acid (60 mg, 0.35 mmol) was coupled with octahydro-pyrrolo[1,2-a]pyrazine according to Procedure C to provide the title compound (34 mg, 35%) as a light yellow solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.4. MS (electrospray): exact mass calculated for C14H17N3OS, 275.11; m/z found, 276.2 [M+H]+. 1H NMR (CDCl3, 400 MHz): 11.1 (br s, 1H), 6.96 (d, J=5.4 Hz, 1H), 6.87 (d, J=5.4 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 4.84 (d, J=12.2 Hz, 1H), 4.70 (d, J=12.2 Hz, 1H), 3.30-2.90 (m, 4H), 2.30-1.40 (m, 7H).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH3:16]>C(O)C>[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOc1ccc(N)cc1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc(OCC)cc2)[nH]c1=O
Reaction time: 17 h
Yield: 70.6 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and 4-ethoxyaniline (14.3 g) are added to ethanol (150 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(4-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (10 g). M.p. 263°-265° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:18]=[N:17][C:16]3[NH:15][C:14](=[O:19])[N:13]4[N:20]=[CH:21][N:22]=[C:12]4[C:11]=3[CH:10]=2)[CH2:5][C@@H:4]([CH3:23])[O:3]1.[F:24][C:25]([F:36])([F:35])[O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:18]=[N:17][C:16]3[N:15]([CH2:31][C:30]4[CH:33]=[CH:34][C:27]([O:26][C:25]([F:24])([F:35])[F:36])=[CH:28][CH:29]=4)[C:14](=[O:19])[N:13]4[N:20]=[CH:21][N:22]=[C:12]4[C:11]=3[CH:10]=2)[CH2:5][C@@H:4]([CH3:23])[O:3]1
Reactant: C[C@@H]1CN(Cc2cnc3[nH]c(=O)n4ncnc4c3c2)C[C@H](C)O1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2cnc3c(c2)c2ncnn2c(=O)n3Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)O1
Temperature: 55 °C
Yield: 74.2 %

Procedure:
To a mixture of 9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (50 mg, 0.16 mmol) and 4-(trifluoromethoxy)benzyl bromide (49 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) was added potassium carbonate (44 mg, 0.32 mmol). The resulting mixture was heated at 55° C. overnight. The crude mixture was filtered then purified directly via reverse phase HPLC to yield 273 (58 mg, 61%) as a white solid.
Reaction SMILES: ClC1N=CN=C(C(NC2C=CC(S(NCC(OC)=O)(=O)=O)=CC=2C)=O)C=1.C(NC(C)C)(C)C.C1(CNCCC)CC1.[CH:42]1([CH2:45][N:46]([CH2:72][CH2:73][CH3:74])[C:47]2[N:52]=[CH:51][N:50]=[C:49]([C:53]([NH:55][C:56]3[CH:61]=[CH:60][C:59]([S:62]([NH:65][CH2:66][C:67]([O:69]C)=[O:68])(=[O:64])=[O:63])=[CH:58][C:57]=3[CH3:71])=[O:54])[CH:48]=2)[CH2:44][CH2:43]1.C1(CN(CCC)C2N=CN=C(C(NC3C=CC(S(NCC(OCC)=O)(=O)=O)=CC=3C)=O)C=2)CC1>C(O)C>[CH:42]1([CH2:45][N:46]([CH2:72][CH2:73][CH3:74])[C:47]2[N:52]=[CH:51][N:50]=[C:49]([C:53]([NH:55][C:56]3[CH:61]=[CH:60][C:59]([S:62]([NH:65][CH2:66][C:67]([OH:69])=[O:68])(=[O:63])=[O:64])=[CH:58][C:57]=3[CH3:71])=[O:54])[CH:48]=2)[CH2:44][CH2:43]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCC(=O)OC)cc2C)ncn1
Agent: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCC(=O)OCC)cc2C)ncn1
Agent: CCCNCC1CC1
Agent: COC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCC(=O)O)cc2C)ncn1
Temperature: 160 °C
Reaction time: 5 h

Procedure:
A solution of methyl 2-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate (Intermediate 33, 123 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (45.3 mg; 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give a mixture of methyl 2-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate and ethyl 2-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate which was used directly without any further purification. The residue was redissolved in methanol (10 ml) and tetrahydrofuran (10 ml) and treated with 5 N NaOH solution (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with conc. HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].Cl[C:12]([CH3:16])([CH3:15])[C:13]#[CH:14].O.[OH-].[Na+]>C(Cl)Cl.CO>[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:10][C:12]([CH3:16])([CH3:15])[CH2:13][CH2:14][C:8]=2[CH:9]=1)(=[O:3])[CH3:1]
Reactant: C#CC(C)(C)Cl
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 144 h
Yield: 34.3 %

Procedure:
To a solution of 95% 4-hydroxyacetophenone (13.6 g, 100 mmol), 3-chloro-3-methyl butyne (17.4 g, 170 mmol) in methylene chloride (75 ml) was added water (75 ml), sodium hydroxide (6.4 g, 160 mmol), and Triton B (40% in methanol, 23.0 g, 52 mmol). The reaction mixture was stirred at room temperature for six days. The organic layer was separated, the aqueous phase was reextracted with methylene chloride (2×200 ml). The combined extracts were concentrated in vacuo, the residue was taken up in ethyl acetate (500 ml) washed with 1N sodium hydroxide (3×250 ml), brine (200 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was dissolved in 1,2-dichlorobenzene (40 ml) and heated at reflux temperature for four hours. The solvent was removed by distillation at atmospheric pressure using a vigreaux column and the residue was distilled under reduced pressure (b.p. 140-150° C. at 2.0 mm) to provide the title A compound (7.0 g) as a light yellow solid. 1H NMR (CDCl3) δ 7.75 (dd, J=2.3 & 8.8 Hz, 1 H), 7.73 (d, J=2.4 Hz, 1 H), 6.78 (d, J=8.8 Hz, 1 H), 6.35 (d, J=10.0 Hz, 1 H), 5.66 (d, J=9.9 Hz, 1 H), 2.53 (s, 3 H}, 1.45 (s, 6 H); 13C NMR (CDCl3) δ 196.7, 157.4, 131.1, 130.2, 126.8, 121.6, 120.6, 116.0, 77.5, 28.3, 26.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[O-:25][C:26]#[N:27].[Na+]>O>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:26]([NH2:27])=[O:25])[CH:4]=2)[NH:8][CH:7]=1
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A solution of 2-[2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3-(2H)-dione, hemisulphate, hydrate (1.01 g) in hot water (27 ml) was treated with a solution of sodium cyanate (0.25 g) in water (9 ml) and heated on a steam bath for 1.5 h. The reaction mixture was cooled and filtered, affording the title urea as a white crystalline solid (0.82 g) m.p. 230°-2°.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([NH:14][C@H:15]([C:19]([O:21]C)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:4]1.[OH-].[Na+]>CCO>[CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:4]1
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1C[C@H](OC)[C@@H](O[N+](=O)[O-])C1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CO[C@H]1C[C@@H](C(=O)N[C@H](C(=O)O)C(C)C)C[C@@H]1O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a solution of methyl N-{[(1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentyl]carbonyl}-L-valinate (1.04 g, 3.27 mmol) in EtOH (10 mL) was added NaOH (5.0 N, 1.0 mL). After stirring at rt overnight, the mixture was partitioned between Et2O/H2O. The aq layer was extracted and acidified using 5.0 N HCl until pH-3 and then extracted with Et2O (50 mL). The organic layer was washed with brine (2×50 mL), dried over Na2SO4, and concentrated to give the title compound as a white solid (810 mg, yield 81%): 1H NMR (500 MHz, CDCl3) δ 6.70 (d, J=8.4, 1H), 5.40 (d, J=6.0, 1H), 4.53 (dd, J=4.6, 8.5, 1H), 3.93 (m, 1H), 3.48 (s, 3H), 3.03-2.96 (m, 1H), 2.53-2.46 (m, 1H), 2.38-2.20 (m, 3H), 2.08-2.02 (m, 1H), 1.01 (d, J=6.9, 3H), 0.97 (d, J=6.9, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[NH:10][C:9]=2[C:17]([N:19]([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])=[CH:4][CH:3]=1.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:10]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:9]=2[C:17]([N:19]([CH2:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH3:25])=[O:18])=[CH:6][CH:7]=1
Reactant: CN(CC(C)(C)C)C(=O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CC(C)(C)C)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-chlorophenyl)-N-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide (100 mg, 0.268 mmol) in dry DMF (1.5 mL) was added 1-(bromomethyl)-4-fluorobenzene (35 μL, 0.282 mmol) and Cs2CO3(131 mg, 0.402 mmol). The white suspension was stirred at 60° C. for 1 h. The reaction mixture was poured out in saturated aqueous NaHCO3 (25 mL) and the product was extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (2×15 mL), aqueous 1M KHSO4 (2×15 mL) and brine (2×15 mL) before drying on Na2SO4 and concentration in vacuo. The product was purified using flash chromatography (silica, gradient heptane/EtOAc 95:5→7:3). The product containing fractions were combined, concentrated in vacuo and crystallised from hot i-Pr2O to give a first batch of SC-261. The mother liquor was concentrated in vacuo and crystallised from i-Pr2O/heptane (1:1) to give white crystals which were combined with the earlier obtained batch to give SC-261 (58 mg, 45%) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([OH:11])=[CH:9][C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:6]=1)=O.C(O)(=O)C.[NH3:27]>CO>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([N:7]2[C:8](=[O:12])[CH:9]=[C:10]([OH:11])[C:5]([C:3]([NH2:27])=[O:2])=[N:6]2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: N
Reactant: COC(=O)c1nn(-c2ccc(OC)c(OC)c2)c(=O)cc1O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-n2nc(C(N)=O)c(O)cc2=O)cc1OC

Procedure:
The pyridazine (29) (295 mg) was dissolved in 3 ml of 7N NH3 in methanol and heated to reflux in a sealed tube for 4 hours. The reaction was allowed to cool, neutralized with acetic acid, and concentrated to dryness to give 266 mg of desired amide (30) as a solid. MS+: m/e=292.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: COc1ccc(NC(C)=O)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(NC(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-acetamidobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound: Rf=0.18 (silica gel, 1/1 ethyl acetate/methanol).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-])=O)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[H][H]>O>[NH2:19][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])[C:6]=1[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:10]([OH:12])=[O:11]
Reactant: CCCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
A suspension of 4-butylamino-3-nitro-5-sulphamyl-benzoic acid (8.6 g) in water (175 ml) was adjusted to pH 9.5 by addition of 2N sodium hydroxide. The resulting solution was hydrogenated after additon of Pd-on-carbon catalyst (0.5 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-4-butylamino-5-sulphamyl-benzoic acid was precipitated from the filtrate by addition of 4N hyrochloric acid until pH 3. After recrystallization from aqueous methanol the melting point was 211°-211.5° C.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])[CH3:4].[OH-].[Na+]>C(O)(=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:12]=1[Br:1])=[O:7])[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Br
Temperature: 0 °C
Reaction time: 17 h

Procedure:
Bromine (3.6 ml, 0.07 mol) was added to a solution of 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (I-5c, 3.6 g, 0.01 mol) in glacial acetic acid (50 ml) at room temperature. The reaction mixture was stirred for 17 hours, poured over ice-water, and treated with 25% aq. NaOH until the orange solution turned yellow. The aqueous solution was extracted with CH2Cl2 (3×) and the combined extracts were dried and concentrated in vacuo to give the desired compound I-5d as an oil (4.7 g): +APCI MS (M+1) 441.1; 1H NMR (CD3Cl) δ 1.41 (3H, t), 4.43 (2H, q), 7.08–7.12 (2H, m), 7.20–7.40 (7H, m).
Reaction SMILES: CNN.[OH:4][C:5]1[C:6](=[O:25])[N:7]([CH3:24])[C:8]([CH2:11][O:12][N:13]2C(=O)C3=CC=CC=C3C2=O)=[N:9][CH:10]=1>CN(C)C=O>[NH2:13][O:12][CH2:11][C:8]1[N:7]([CH3:24])[C:6](=[O:25])[C:5]([OH:4])=[CH:10][N:9]=1
Reactant: Cn1c(CON2C(=O)c3ccccc3C2=O)ncc(O)c1=O
Agent: CNN
Solvent: CN(C)C=O
Product: Cn1c(CON)ncc(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
Methylhydrazine (92 mg) (2 mmol) are added at 0° C. to a suspension of 301 mg (1 mmol) of N-[(3,4-dihydro-5-hydroxy-3-methyl-4-oxo-2-pyrimidinyl)methoxy]phthalimide in 9 ml of absolute dimethylformamide. A solution gradually results and this is then stirred at room temperature for 3 hours. The solution is concentrated in a high vacuum at room temperature, the residue is washed with petroleum ether and finally 10 ml of water are added thereto. After good intermixing the mixture is filtered. The filtrate is concentrated, finally with toluene/ethanol. After crystallization from ethanol there are obtained 125 mg of 2-[(aminooxy)methyl]-5-hydroxy-3-methyl-4(3H)-pyrimidinone as white crystals of m.p. 106° C.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:52])[C@@H:8]([N:15](C(OC(C)(C)C)=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]4[CH:32]=[C:31]([C:33](=[O:43])[NH:34][O:35]C(OCC(C)C)C)[S:30][C:29]=4[CH:44]=3)[CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.C(Cl)Cl>[CH:1]1([O:6][C:7](=[O:52])[C@@H:8]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]4[CH:32]=[C:31]([C:33](=[O:43])[NH:34][OH:35])[S:30][C:29]=4[CH:44]=3)[CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(CNc3cccc(CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC4CCCC4)c4ccccc4)c3)cc2s1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NO)c1cc2ccc(CNc3cccc(CN[C@H](C(=O)OC4CCCC4)c4ccccc4)c3)cc2s1
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a solution of (S)-[tert-Butoxycarbonyl-(3-{[2-(1-isobutoxy-ethoxycarbamoyl)-benzo[b]thiophen-6-ylmethyl]-amino}-benzyl)-amino]-phenyl-acetic acid cyclopentyl ester (0.100 g, 0.14 mmol) in DCM/MeOH (1 ml:1 ml) was added TFA (8 ml). The solution was stirred for 2 h, then diluted with DCM (200 ml). The solution was washed with saturated sodium bicarbonate (100 ml). The solution was dried (Na2SO4), concentrated and purified by reverse phase HPLC to yield the desired product (8.1 mg, 11% yield). LCMS purity 98%, m/z 531 (M+H)+ 300 MHz, DMSO, δ:1.26-1.85 (8H, m), 3.47 (2H, s), 4.21 (1H, s), 4.38 (2H, d, J 5.8 Hz), 5.02-5.07 (1H, m), 6.32 (1H, t, J 6.0 Hz), 6.45 (2H, d, J 7.9 Hz), 6.57 (1H, s), 6.97 (1H, t, J 7.8 Hz), 7.23-7.35 (5H, m), 7.42 (1H, dd, J 1.2, 8.3 Hz), 7.84 (1H, s), 7.87 (1H, s), 7.93 (1H, s), 9.23 (1H, br s), 11.4 (1H, br s)
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:12]([CH:13]([C@@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])[CH3:22]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)[C@H](C[N+](=O)[O-])c1ccccc1

Procedure:
trans-β-Nitrostyrene (34.3 mg, 0.23 mmol), diethyl malonate (0.065 mL, 0.46 mmol) and the compound (10 mol %) shown in the following Table 1 as an asymmetric catalyst were stirred in toluene (0.4 mL) at room temperature. The reaction mixture was purified by silica gel column chromatography (n-hexane/ethyl acetate=95/5→90/10→80/20) to give the title compound.
Reaction SMILES: C(OC1C(C)=C([N+]([O-])=O)C=CC=1C)CCC.[CH2:17]([O:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]([N+:29]([O-])=O)[C:23]=1[CH2:32][C:33](=O)[C:34]([OH:36])=[O:35])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([O:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]2[C:23]=1[CH:32]=[C:33]([C:34]([OH:36])=[O:35])[NH:29]2)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1c(C)ccc([N+](=O)[O-])c1CC(=O)C(=O)O
Agent: CCCCOc1c(C)ccc([N+](=O)[O-])c1C
Product: CCCCOc1c(C)ccc2[nH]c(C(=O)O)cc12

Procedure:
The compound was prepared via 3-butoxy-2,4-dimethylnitrobenzene (b.p. 129°-131° C/0.4 mm Hg) and 3-(2-butoxy-3-methyl-6-nitrophenyl)-pyruvic acid (m.p. 90°-91° C).
Reaction SMILES: C(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])CC(C)C.[OH:19][C:20]1[C:29]2[C:24](=[CH:25]C=CC=2)[C:23](C=O)=CC=1.BrCCC(C)C>>[CH2:20]([O:19][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:17]=[O:18])=[CH:7][CH:16]=1)[CH2:29][CH:24]([CH3:25])[CH3:23]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Solvent: CC(C)CCBr
Product: CC(C)CCOc1ccc(C=O)c2ccccc12

Procedure:
Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 4-hydroxy-1-naphthaldehyde and 1-bromo-3-methylbutane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10](=O)[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.CN.[BH3-][C:17]#[N:18].[Na+]>CCO>[CH3:17][NH:18][CH:10]([C:6]1[N:5]=[C:4]2[CH:3]=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1)[CH3:11]
Reactant: CC(=O)c1ccc2[nH]ccc2n1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CNC(C)c1ccc2[nH]ccc2n1

Procedure:
A microwave vial was charged with 1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone (1.50 g, 9.36 mmol), methanamine hydrochloride (8.85 g, 131.1 mol), NaBH3CN (765.0 mg, 12.18 mmol), and anhydrous EtOH (31 mL) and stirred while irradiated in a microwave (300 Watts) at 130° C. for 2 min. The resulting solid was filtered and rinsed well with EtOH. The filtrate was concentrated in vacuo. The crude product was redissolved in EtOAc and twice washed with 10% aq. NaOH, water and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was triturated with DCM, and the insoluble solid was filtered through a pad of Celite®. The filtrate was concentrated in vacuo and dried under high vacuum to afford N-methyl-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine as a solid: 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.45 (d, J=3.3 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.72 (d, J=3.3 Hz, 1H), 3.95 (q, J=6.7 Hz, 1H), 2.37 (s, 3H), 1.47 (d, J=6.7 Hz, 3H).