Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Br.Br.[NH:30]1[CH2:36][CH:35]([OH:37])[CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CC(O)C>[CH3:23][C:19]1[N:18]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:30]5[CH2:36][CH:35]([OH:37])[CH2:34][NH:33][CH2:32][CH2:31]5)[C:3]([C:24]([F:27])([F:25])[F:26])=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)[CH:22]=[N:21][CH:20]=1
Reactant: OC1CNCCNC1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(F)n2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(N3CCNCC(O)C3)n2)n1
Temperature: 120 °C
Yield: 10.8 %

Procedure:
A mixture of 1-[6-fluoro-5-(trifluoromethyl)-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.213 mmol; 79.9 mg), 1,4-diazepan-6-ol dihydrobromide (1.07 mmol; 297 mg), and cesium carbonate (2.13 mmol; 696 mg) in DMSO (2 mL) and IPA (4 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was cooled to room temperature, and then filtered through Celite®. The filtrate was concentrated and the residue was purified by reverse phase HPLC to afford 219 as an off-white solid (10.8 mg, 11%). 1H NMR (400 MHz, DMSO) δ 9.59-9.53 (s, 1H), 9.48-9.43 (s, 1H), 9.38-9.33 (s, 1H), 8.79-8.75 (s, 1H), 8.66-8.62 (s, 1H), 8.22-8.17 (d, J=8.5 Hz, 1H), 7.57-7.52 (d, J=8.5 Hz, 1H), 4.76-4.67 (s, 1H), 3.98-3.88 (d, J=10.4 Hz, 3H), 3.75-3.66 (d, J=14.1 Hz, 1H), 3.65-3.55 (dd, J=15.3, 8.4 Hz, 1H), 3.15-3.07 (m, 1H), 3.06-2.99 (m, 1H), 2.87-2.79 (dd, J=13.7, 3.4 Hz, 1H), 2.76-2.68 (dd, J=13.6, 5.8 Hz, 1H), 2.69-2.62 (s, 3H); MS (ESI) m/z: 471.1 [M+H]+
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]=1)=O.Cl.[NH4+:22].[OH-]>O>[C:3]([CH2:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]=1)(=[O:2])[NH2:22]
Reactant: [NH4+]
Reactant: COC(=O)Cc1nc(-c2ccccc2)ncc1C(=O)O
Agent: Cl
Agent: [OH-]
Solvent: O
Product: NC(=O)Cc1nc(-c2ccccc2)ncc1C(=O)O
Yield: 63 %

Procedure:
A solution of 2.65 g (9.56 mmol) of 4-Methoxycarbonylmethyl-2-phenyl-pyrimidine-5-carboxylic Acid in 11.6 mL of conc NH4OH is stirred at 25° C. for 3 h. The reaction is then diluted with H2O, chilled in ice and acidified with 6M HCl. The product is collected, washed with H2O (2×) and dried in vacuo (low heat) to give 1.55 g (63%) of orange solid: 1H NMR (DMSO-d6) δ 9.17 (s, 1H), 8.44 (m, 2H), 7.67 (s, 1H), 7.60 (m, 3H), 7.02 (s, 1H), 4.12 (s, 2H); MS (ESI)) m/z 256. (M−H). Analysis for C13H11N3O3. 0.5H2O: Calcd: C, 58.63; H, 4.55; N, 15.78. Found: C, 58.88; H, 4.53; N, 15.46.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)#[N:2].[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([C:1]#[N:2])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:24][CH:23]=1
Reactant: COCCOc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3)c2cc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
6-Cyano-7-(2-methoxyethoxy)-4-(4-nitrophenoxy)quinoline (1.8 g), iron (1.8 g) and ammonium chloride (3.6 g) were suspended in an ethanol (30 ml)—water (7 ml) mixed solvent and the suspension was heated and stirred at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was filtered with celite and washed in ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained solid was washed with ether and dried to obtain 1.2 g of the title compound.
Reaction SMILES: [Br:1][C:2]([CH:4]=[N:5][C:6]([O:8][Si](C)(C)C)=[CH2:7])=[CH2:3].C(OC([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)/[C:22](=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)/[C:21]1=[O:38])=O)(C)(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]([CH:4]1[C:22]2([C:23]3[C:28](=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[NH:20][C:21]2=[O:38])[CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH2:8][C:6](=[O:7])[NH:5]1)=[CH2:3]
Reactant: C=C(Br)C=NC(=C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: C=C(Br)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 7 %

Procedure:
To a toluene solution of 1-(1-bromo-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene in toluene (1 M, 37 mL, 37 mmol) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (2.8 g, 7.2 mmol). The reaction mixture was refluxed overnight under argon protection and purified by Prep-HPLC to give product as a white solid (120 mg, 7%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=O)=[CH:29]3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.N1CCCCC1>C(O)C>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=[C:11]2[C:10]4[C:14](=[CH:15][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)[NH:13][C:12]2=[O:16])=[CH:29]3)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 71.6 %

Procedure:
A mixture of 6-phenyl-2-oxindole (44 mg, 0.21 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (58 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 70 mg (71%) of the title compound as an orange solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([NH:8][NH2:9])=[O:7]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCl)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NNC(=O)C(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.6 %

Procedure:
Oxalyl chloride (1.56 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-phenylbutyric acid (2.28 g) in methylene chloride (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid chloride. A solution of 4-chloro-2-phenylbutyric acid chloride in THF (10 mL) was added to a solution of tert-butyl carbazate (1.5 g) and triethylamine (7.8 mL) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). A solution of 4 N hydrogen chloride in ethyl acetate (50 mL) was added to tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g). A solution of 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g) and triethylamine (5.7 mL) in ethanol (40 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (3.00 g) and triethylamine (6.0 mL) in ethanol (50 mL) at room temperature, and the reaction solution was stirred at 80° C. for 24 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 231 mg of the racemic title compound. The property values of the compound are as follows.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].[C:8]1([CH2:14][SH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>O1CCCC1.ClCCl>[CH2:14]([S:15][CH2:4][C:5]([OH:7])=[O:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CBr
Reactant: SCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CSCc1ccccc1
Temperature: 100 °C
Yield: 55.2 %

Procedure:
1N aqueous sodium hydroxide solution (500 cc), cooled to a temperature of approximately 5° C., is added in the course of 1 hour to bromoacetic acid (70 g). The mixture obtained is added to a solution of phenylmethanethiol (50 g) and 1N aqueous sodium hydroxide solution (500 cc) in tetrahydrofuran (500 cc), and then heated to approximately 100° C. for 90 minutes. The mixture is cooled to a temperature in the region of 5° C. There are added 12N aqueous hydrochloric acid solution (100 cc) and then dichloromethane (3,000 cc) in the course of 30 minutes. The organic phase is separated off after settling has taken place, and the aqueous phase is extracted with dichloromethane (2×200 cc). The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallized in boiling cyclohexane (50 cc). (Benzylthio)acetic acid (40.5 g), m.p. 58°-60° C., is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:7]=1)[CH3:4].[Cl:26][C:27]1[C:28]([CH2:39]Cl)=[N:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][CH:32]=1.O>CN(C)C=O>[Cl:26][C:27]1[C:28]([CH2:39][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:8]3[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([O:5][CH2:3][CH3:4])=[N:7]3)=[CH:24][CH:23]=2)=[N:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: ClCc1nc(-c2ccccc2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)ccc3Cl)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (478 mg) and 3-chloro-2-chloromethyl-6-phenylpyridine (357 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[4-(3-chloro-6-phenyl-2-pyridylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (740 mg, yield: 95%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[C:4]([F:17])[CH:3]=1.C([O-])(=[O:20])C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][OH:20])[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1C=Cc1nc(CCl)co1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1coc(C=Cc2ccc(Cl)cc2F)n1
Temperature: 25 °C

Procedure:
A solution of 2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-4-chloromethyl-oxazole (0.800 g, 2.94 mmol) and sodium acetate (0.482 g, 5.88 mmol) in acetic acid (10 ml) is refluxed for 55 h. The reaction mixture is cooled to r.t., concentrated in vacuo and the resulting residue is dissolved in ethanol (4 ml) and 5M potassium hydroxide (KOH) (15 ml). The solution is refluxed for 5 h and cooled to r.t. Saturated ammonium chloride (NH4Cl) is added and the mixture is extracted with ethyl acetate (3×). The extract is washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 1:1) yielding {2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-yl}-methanol as a colorless solid. Yield 0.582 g (78%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:41])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:23])[F:21])[C:12]([N:14]5[CH2:15][CH2:16][S:17][CH2:18][CH2:19]5)=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[O:39][N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCSCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCSCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-thiomorpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M25) (310 mg, 0.5 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (80 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([C:34]3[CH:33]=[N:32][C:31]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:36][CH:35]=3)=[CH:7][N:6]=2)=[CH:9][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)cn1
Reactant: Clc1cnc(-c2ccc(OCc3ccccc3)cc2)cn1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCc4ccccc4)cc3)cn2)cn1

Procedure:
In accordance with scheme D, 14 g (47.2 mmol ) of 2-chloro-5-(4-benzyloxyphenyl)pyrazine are reacted analogously to Example 4a with 11.8 g (47.2 mmol) of 2-octyloxypyridine-5-boronic acid to give 2-(4-benzyloxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrazine.
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[C:12]2[C:11]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:5][CH:4]=1.[Na+].[OH-].[Na+].[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])([O-:26])=[O:25].Cl>O>[Na+:1].[Na+:1].[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:2][C:3]1[C:12]2[C:11]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:5][CH:4]=1)=[O:31])([O-:26])=[O:25]
Reactant: Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 48.3 g portion of 4-amino-1,5-naphthalenedisulfonic acid sodium salt is suspended in 150 ml of water and 160 ml of 1N sodium hydroxide is added, then 60.0 g of m-nitrobenzoyl chloride is added all at once. The mixture is shaken for about 15 minutes or until no longer basic to test paper, then another 160 ml of 1N sodium hydroxide is added with additional shaking. The latter addition of sodium hydroxide and shaking is repeated two more times and when the mixture remains basic after 1/2 hour of shaking after the last portion is added the mixture is acidified to Congo Red with 15 ml of concentrated hydrochloric acid. Additional water is added to the mixture which is then copiously extracted with ether. The ether is removed by vacuum siphoning and the aqueous phase is filtered. The filtrate is neutralized and is concentrated at 55° C. in vacuo until crystal formation then it is cooled to room temperature. The crystallized material is collected by filtration and is washed with 250 ml of saturated saline, then with two 150 ml portions of 50% ethyl alcohol followed by two 150 ml portions of absolute ethyl alcohol and two 150 ml portions of ethyl ether. The product of the example is then oven dried at 120° C. overnight.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1cccc(Cl)c1COc1cccnc1NC(=S)Nc1ccccc1

Procedure:
A mixture of 2-amino-3-(2-fluoro-6-chlorobenzyloxy)pyridine (7.6 g, 0.03 mol), phenyl isothiocyanate (3.95 ml, 0.033 mol) and toluene (25 ml) was refluxed for 2.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 8.47 g (73%), m.p. 143°-145 ° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][C:37](=[O:39])[CH3:38])[CH2:23][C:24]3[CH:29]=[CH:28][C:27](C4C=CC=CC=4)=[CH:26][CH:25]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:41](N[C@H](CC1C=CC(OC)=CC=1)C(N1CCC[C@H]1C(O)=O)=O)(=[O:43])C>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][C:37](=[O:39])[CH3:38])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:43][CH3:41])=[CH:28][CH:29]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(C[C@@H](NC(C)=O)C(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Product: COc1ccc(C[C@@H](NC(C)=O)C(=O)N2CCC[C@H]2C(=O)NCc2ccc3c(N)nccc3c2)cc1
Yield: 80 %

Procedure:
Using the procedure described for example 97f 0.140 g of 1-(2-(R)-acetylamino-3-(4-methoxyphenyl)-propionyl)-pyrrolidine-2-(S)-carboxylic acid was converted into 0.160 g (80%) of the title compound. (+)-APCI-MS: 490 (MH+).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[C:4](=O)[NH:3][CH:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:4]1[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2[nH]c3ccccc3c12
Product: Clc1ncnc2[nH]c3ccccc3c12

Procedure:
A suspension of 3H-pyrimido[4,5-b]indol-4(9H)-one (0.091 g, 0.491 mmol) in phosphorous oxychloride (8 mL) was refluxed under nitrogen for 24 hours. Phosphorous oxychloride was removed by evaporation and the residue was partitioned between water (20 mL) and chloroform (2×20 mL). The organic extracts were filtered through celite, dried (Na2SO4) and concentrated to give 4-chloro-9H-pyrimido[4,5-b]indole as a yellow solid (0.103 g, 0.50 mmol, quantitative). 1H NMR (500 MHz, CDCl3) δ 7.60 (1H, dd, J=8.8 Hz), 7.70 (1H, dd, J=8.8 Hz), 8.43 (1H, d, J=8 Hz), 8.52 (1H, d, J=8 Hz), 8.98 (1H, s); LC-MS (3) Rt: 5.59 min; m/z (ESI) 206, 204 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12](/[CH:21]=[CH:22]/[C:23]([O:25]C)=O)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH2:31][SH:32].O>CN(C=O)C>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([CH:21]3[S:32][CH2:31][CH2:30][NH:29][C:23](=[O:25])[CH2:22]3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCCS
Reactant: COC(=O)/C=C/c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)SCCN1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of methyl (2E)-3-(7-{[(4-fluorobenzyl)amino]carbonyl}-8-hydroxy[1,6]-naphthyridin-5-yl)-2-propenoate (Example 137, Step 1) (1.22 g, 3.20 mmol) and cysteamine (4.0 g) in DMF (15 mL) was heated in an oil bath at 80° C. under an atmosphere of nitrogen with stirring for 18 hours. The product mixture was treated with water and the mixture was acidified to pH 2. The resultant precipitate was filtered, dissolved in DMSO, and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([O:12][CH3:13])[CH:6]=[CH:5][C:4]=1I.[C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1)#[CH:16].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([O:12][CH3:13])[CH:6]=[CH:5][C:4]=1[C:16]#[C:15][C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1
Reactant: C#Cc1cnn(C)c1
Reactant: COc1ccc(I)c(OC)c1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C#Cc2cnn(C)c2)c(OC)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 71 %

Procedure:
To a mixture of 2,4-dimethoxy-3-nitro-iodobenzene (0.95 mmol), 0.122 g (1.15 mmol) of 4-ethynyl-1-methyl-1H-pyrazole, 0.028 g (0.04 mmol) of dichlorobis (triphenylphosphine)palladium (H) and 8 mg (0.042 mmol) of copper (I) iodide 4 mL of anhydrous acetonitrile and 2 mL of triethylamine were added under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 1 hour, when TLC indicated a consumption of the iodobenzene. The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography (silica gel; dichloromethane:ethyl acetate 9:1) to give the title compound in 71% yield as creamy crystals. H1 NMR (CDCl3) 3.88(s, 3H, Me); 3.9 (s, 3H, OMe); 4.07 (s, 3H, OMe); 6.7 (d, 1H, CH, J=8.9 Hz); 7.44 (d, 1H, CH, J=8.9 Hz); 7.56 (s, 1H, CH pyr); 7.62 (s, 1H, CH pyr).