Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].COC1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[Cl:31][C:32]1[CH:33]=[C:34]([C:2]2[CH:3]=[C:4]([O:29][CH3:30])[C:5]([N:9]3[C:18]4[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]5[CH:27]=[CH:26][O:25][N:24]=5)(=[O:21])=[O:20])=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]3=[O:28])=[CH:6][C:7]=2[F:8])[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC1CCCC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc(F)c(Cl)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 100 °C
Yield: 95.4 %

Procedure:
A vial was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.310 g, 0.627 mmol). (3-chloro-4-fluorophenyl)boronic acid (0.175 g, 1.003 mmol), Pd(Ph3P)4 (0.072 g, 0.063 mmol). The vial was sealed with a septum cap and flushed with Ar (g), then CPME (3.14 ml) and sodium carbonate 1.9 M (0.990 ml, 1.881 mmol) were added via syringe. The mixture was heated to 100° C. for 1 h and then partitioned between water (20 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was acidified with 1N HCl. The aqueous layer was extracted with EtOAc (2×20 mL) and all the organic layers were combined, dried (Na2SO4) and concentrated for purification by MPLC (Biotage Isolera). The crude residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a Redi-Sep® Gold pre-packed silica gel column (40 g) using 90:10 Heptane: EtOAc to 100% EtOAc gradient to afford racemic 1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.325 g, 0.598 mmol, 95% yield) as a light-yellow film. Racemic 1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide was subjected to chiral separation by SFC using a Regis Whelk-0 (s,$) column and 50% MeOH in CO2. Peak 1 was (P)-1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide and peak 2 was (M)-1-(3′-chloro-2,4′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. Data for peak 1: 1H NMR (500 MHz, DMSO-d6) δ 11.49-11.82 (br s, 1H), 8.71 (d, J=1.55 Hz, 1H), 8.37 (d, J=1.87 Hz, 1H), 8.17-8.28 (m, 1H), 7.94 (d, J=5.88 Hz, 1H), 7.86 (dd, J=1.98, 8.92
Reaction SMILES: [C:1]1([N:7]2[C:12](=S)[C:11]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][NH:9][C:8]2=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24]O.Cl>[OH-].[K+].CO.O>[C:1]1([N:7]2[C:12](=[O:24])[C:11]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][NH:9][C:8]2=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: O=c1[nH]nc(Cc2c(F)cccc2F)c(=S)n1-c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]nc(Cc2c(F)cccc2F)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
4-Phenyl-6-(2,6-difluorobenzyl)-5-thioxo-2H-(1,2,4)triazin-3-one (1.00 g, 3.02 mmol) was dissolved in a solution of KOH (643 mg) in MeOH (12 mL) and water (6 mL). A solution of H2O2 (1.2 mL, 30% in water) in water (5 mL) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was acidified with conc. HCl (1.1 mL) and a white solid precipitated. Filtered and washed with water to give a white solid (816 mg, 85.8%): MS (CI) m/z 380.2 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:20]CC4C=CC(OC)=CC=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cnc(NCc4ccc(OC)cc4)cc23)c1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cccc(Nc2ncnc3cnc(N)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
To a stirred homogeneous solution of compound 167 (12.3 g, 32.3 mmol) in dry DCM (325 mL) was added trifluoroacetic acid (24.5 mL, 323 mmol), followed by anisole (7.11 mL, 64.6 mmol). The resultant mixture was stirred at room temperature for 70 h and then poured into petroleum ether (1 L) and stirred at room temperature for ca. 30 min. The petroleum ether layer was decanted and discarded. This process was repeated with more petroleum ether (800 mL). The residue left behind was dissolved in acetone/water (1:1, 200 mL) and stirred with 5M NH3 (500 mL) at room temperature for 1 h. The solid was collected by filtration and washed successively with acetone/water (1:4, 5×100 mL) and then petroleum ether/ethyl acetate (3:1, 5×100 mL) before being dried in vacuo to give N4-(3-ethynylphenyl)pyrido[3,4-d]pyrimidine-4,6-diamine (169) (8.56 g, 98%), mp 220-225° C. (decomp); 1H NMR δ [(CD3)2SO] 9.69 (s, 1H), 8.70 (s, 1H), 8.38 (s, 1H), 8.08 (t, J=1.7 Hz, 1H), 7.95-7.89 (m, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.34 (br d, J=7.7 Hz, 1H), 7.16 (s, 1H), 6.25 (s, 2H), 4.17 (s, 1H). Anal. Calcd for C15H11N5.2H2O.0.2CH3COCH3: C, 60.65; H, 5.29; N, 22.67%. Found C, 60.54; H, 5.01; N, 22.56%.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>C1COCC1.O>[C:35]([O:34][C:32]([NH:31][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[CH:24][CH:25]=3)=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[C:3]([OH:39])=[O:2])=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccc(Oc3ccc(-c4nccs4)cc3)cc2)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccc(Oc3ccc(-c4nccs4)cc3)cc2)cc1)C(=O)O
Yield: 88.7 %

Procedure:
A solution of the product from step 6 (0.4 g, 0.72 mmol) and NaOH (62 mg, 1.54 mmol) in THF/water (1:1, 10 mL) was stirred at room temperature for 16 h. After the THF was removed, the aqueous solution was acidified with 10% HCl to pH=2, the solid was collected on a filter to yield the title compound (340 mg, 82%). 1HNMR (CDCl3) δ 1.42 (s, 9H), 3.15 (m, 2H), 4.57 (m, 1H), 5.00 (m, 1H), 6.95 (d, J=8.8 Hz, 2H), 7.02-7.15 (m, 6H), 7.17 (d, J=8.8 Hz, 2H), 7.30 (d, J=3.2 Hz, 1H), 7.85 (d, J=3.2 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]([CH3:30])([CH3:29])[C:5]2=[N:6][CH:7]=1.[B:31]1(B2OC(C)(C)C(C)(C)O2)[O:35]C(C)(C)C(C)(C)[O:32]1.C([O-])(=O)C.[K+]>O1CCOCC1>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([B:31]([OH:35])[OH:32])[CH:3]=4)[C:8]([CH3:29])([CH3:30])[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(B(O)O)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure O using 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (100 mg, 0.22 mmol), Pd(PCy3)2 (14.4 mg, 0.022 mmol), bis(pinacolato)diboron (60 mg, 0.24 mmol) and potassium acetate (35 mg, 0.32 mmol) in 1,4-dioxane (4.0 mL) and heating at 120° C. in the microwave for 1 h. After aqueous work up 1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid was obtained as a colorless film. Mass Spectrum (ESI) m/e=429 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=O)[C:5]=12)=[O:8])([O-:3])=[O:2].O.[NH2:16][NH2:17]>C(O)(=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:9])[NH:16][NH:17][C:7]2=[O:8])([O-:3])=[O:2]
Reactant: NN
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c([N+](=O)[O-])cccc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A glass flask of the volume 1 l provided with an agitator, a thermometer, a condenser and a capillary was filled with 600 ml of icy acetic acid and 154.5 g (0.8 mole) of 3-nitrophthalic acid anhydride, thereafter it was heated to the temperature of 110° C. and gradually 44.1 g (0.88 mole) of hydrazine hydrate was added. Next the reaction mixture was kept at the state of boiling for 30 minutes thereafter it was cooled to the temperature of 80° C., the crystals of 5-nitro-2,3-dihydrophthalazine-1,4-dione were filtered, the sediment was washed on a filter with 50 ml of acetic acid and two times with 40 ml of distilled water. The total amount of 5-nitro-2,3-dihydrophthalazine-1,4-dione was 228.7 g, the yield was 92%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[C:21]([NH2:27])=[N:22][CH:23]=[C:24](Br)[CH:25]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[C:21]([NH2:27])=[N:22][CH:23]=[C:24]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:28])[CH:34]=3)[CH:25]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1sc(-c2cc(Br)cnc2N)cc1OC(C)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2cc(-c3cccc(Cl)c3)cnc2N)cc1OC(C)c1ccccc1Cl
Yield: 42.3 %

Procedure:
5-(2-Amino-5-bromo-pyridin-3-yl)-3-[1-(2-chloro-phenyl)-ethoxy]-thiophene-2-carboxylic acid methyl ester (120 mg, 0.26 mmol, 1.0 Eq.), 3-chlorophenyl boronic acid (44 mg, 0.28 mmol, 1.1 Eq.) and Pd(PPh3)4 (30 mg, 0.03 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.5 mL, 1.0 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (40% EtOAc/petroleum Ether) to give the sub-title compound as an off-white solid (57 mg, 0.11 mmol, 45%); 1H NMR (400 MHz, CDCl3) δ 1.75 (3H, d), 3.94 (3H, s), 5.24 (2H, br s), 5.84 (1H, q), 6.86 (1H, s), 7.01-7.41 (6H, m), 7.48 (1H, s), 7.65 (1H, s), 7.68 (1H, d), 8.24 (1H, d).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](O)(=O)=O)=[CH:3][CH:2]=1.[C:12]1([CH3:18])[CH:17]=CC=[CH:14][CH:13]=1.O.[C:20](OCC)(=[O:22])C>>[CH3:20][O:22][C:2]1[CH:1]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:12]([CH3:18])([CH3:17])[CH2:13][CH2:14][S:7]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(C)=O
Reactant: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1C(C)(C)CCS2

Procedure:
62.00 g (298.0 mmol) of the compound obtained in Example 10(a), 85.00 g (446.0 mmol) of paratoluenesulphonic acid and 500 ml of toluene are introduced into a round-bottomed flask. The mixture is heated at reflux for two hours, cooled, water and ethyl acetate are then added and extraction is carried out with ethyl acetate. The organic phase is separated by settling, washed with water and then using a saturated sodium chloride solution and dried over magnesium sulphate, and the solvents are evaporated. 65.19 g of a yellow oil are obtained, which oil is distilled under reduced pressure (5×10−2 bar/120-122° C.) to produce 17.40 g (28%) of the expected compound in the form of a colourless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[CH:15]=2)[CH2:9][CH2:8]1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:47]2[CH:54]=[CH:53][C:50]([CH2:51][Cl:52])=[CH:49][CH:48]=2)[CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44]>>[ClH:52].[ClH:52].[CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]4[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=4)[CH:15]=3)[CH2:11][CH2:12]2)[CH2:51][C:50]2[CH:53]=[CH:54][C:47]([C:39]3[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:37]([O:36][CH3:35])[CH:38]=3)=[CH:48][CH:49]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(-c2ccc(CCl)cc2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4cccc(SC)c4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2ccc(CN(c3cccc(SC)c3)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)cc2)cc(OC)c1OC
Product: Cl

Procedure:
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4]([OH:6])[CH3:5].[H-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH2:12]([O:6][CH:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])[CH:11]=[CH2:10]
Reactant: COC(=O)C(C)O
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(±)-Methyl-2-hydroxypropanoate (7.6 g, 74 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0° C. and treated with sodium hydride (3.6 g, 60% dispersion, 89 mmol, 1.2 equiv) portionwise over 45 minutes. The mixture was warmed to ambient temperature, stirred for 30 minutes, and then cooled to 0° C. Allyl bromide (8.4 mL, 96 mmol, 1.3 equiv) was added, the mixture was warmed to ambient temperature and stirred for an additional 14 hours. Sodium bicarbonate (10 mL, aqueous saturated) was added slowly and the mixture was stirred for 30 minutes before being poured into water (500 mL). The aqueous layer was extracted with ethyl acetate (2×300 mL) and the combined organic extracts were washed once with brine, dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:9][CH:8]=1.C1COCC1.O>CO>[N:15]1([C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:20])=[O:5])=[CH:8][CH:9]=2)=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(C(=O)N2CCCC2)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DIPEA (1.26 g, 9.7 mmol) was added to a stirred solution of terephthalic acid monomethyl ester (500 mg, 2.77 mmol) in DMF (3 mL) followed by HOBt (410 mg, 3.0 mmol) and EDCI (1.32 g, 7.0 mmol). After 2 minutes of stirring, pyrrolidine (215 mg, 3.0 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected to afford 53 mg (81.9% Yield) of 4-(pyrrolidine-1-carbonyl)-benzoic acid methyl ester. LiOH.H2O (285 mg, 6.8 mmol) was added to a solution of 4-(pyrrolidine-1-carbonyl)-benzoic acid methyl ester (530 mg, 2.27 mmol) in a mixture of methanol (2 mL), THF (6 mL) and H2O (2 mL). The reaction mixture was stirred at ambient temperature for 3 hrs. The reaction mixture was concentrated, the residue was diluted with water, and acidified with conc. HCl. The solid was filtered and dried to afford 41 mg (82.32% Yield).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([C:9]2[C:10]([NH:12][C:13](=[O:15])[CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#C.[CH:16]([O:20]C1C=CC(N)=CC=1)=[CH:17][CH2:18][CH3:19].C1(=O)OC(=O)C=C1.C(OC(=O)C)(=O)C>C([O-])(=O)C.[Ni+2].C([O-])(=O)C.CC(C)=O>[CH:16]([O:20][C:8]1[CH:3]=[CH:4][C:5]([C:9]2[C:10]([NH:12][C:13](=[O:15])[CH:14]=2)=[O:11])=[CH:6][CH:7]=1)=[CH:17][CH2:18][CH3:19]
Reactant: CCC=COc1ccc(N)cc1
Reactant: C#Cc1cccc(C2=CC(=O)NC2=O)c1
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: O=C1C=CC(=O)O1
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCC=COc1ccc(C2=CC(=O)NC2=O)cc1

Procedure:
The procedure is the same for 3-ethynylphenyl maleimide. The following amounts of staring materials were used: 4-butenyloxyaniline (4.0 g, 24.5 mmol), maleic anhydride (2.4 g, 24.5 mmol), acetone (100 ml) triethylamine (5 ml), nickel (II) acetate (0.25 g, 3.5 mmol), and acetic anhydride (2.75 g, 27 mmol). Yield=5.0 g, (84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][C:15](OCC)=[N:14][CH2:13][CH2:12]1)=[O:10].[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]([NH:28][NH2:29])=O>C(O)CCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:12][CH2:13][N:14]2[C:26]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][N:20]=3)=[N:28][N:29]=[C:15]2[CH2:16]1)=[O:10]
Reactant: CCOC1=NCCN(C(=O)c2cccc(Cl)c2Cl)C1
Reactant: NNC(=O)c1cnccn1
Solvent: CCCCO
Product: O=C(c1cccc(Cl)c1Cl)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 25 °C

Procedure:
A mixture of 1-[(2,3-dichlorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (0.48 g, 1.594 mmol, e.g. prepared as described below) and 2-pyrazinecarbohydrazide (0.242 g, 1.753 mmol, CAS [768-05-8], commercially available e.g. from TimTec, J & W PharmLab or AKos Consulting) in anhydrous n-butanol (3.19 ml) was heated to reflux under argon atmosphere. After 2 hours the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by mass-directed automated (preparative) HPLC (MDAP) to give pure 7-[(2,3-dichlorophenyl)carbonyl]-3-(2-pyrazinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.260 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]([S:16]([CH2:19][Cl:20])(=[O:18])=[O:17])[C:13](=[O:15])[CH3:14]>C(O)C.[Ir]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]([S:16]([CH2:19][Cl:20])(=[O:18])=[O:17])[C:13](=[O:15])[CH3:14])[CH:4]=1
Reactant: CC(=O)N(c1cc([N+](=O)[O-])c(F)cc1Cl)S(=O)(=O)CCl
Agent: [Ir]
Solvent: CCO
Product: CC(=O)N(c1cc(N)c(F)cc1Cl)S(=O)(=O)CCl
Temperature: 80 °C
Yield: 70 %

Procedure:
65.7 g (0.19 mol) of N-(2-chloro-4-fluoro-5-nitrophenyl)-N[(chloromethyl)sulfonyl]acetamide were dissolved in 1200 mL of ethanol and transferred into an autoclave. 2.5 g of an iridium catalyst (5% on carbon) were added and the apparatus was purged with nitrogen and hydrogen, respectively. A hydrogen pressure of 2,000 kPa (20 atmospheres) was applied and the mixture wag heated to 80° C. After 4 hours the hot reaction mixture was filtered and cooled to room temperature whereas some of the product precipitated. The crystals were filtered off and the mother liquor was concentrated and cooled. The precipitates were combined and dried to yield 41.9 g (70.2%) of the title compound as a solid melting at 176-180° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])(=[O:25])=[O:24])=[O:21])=[CH:18][C:17]=1[O:35][CH3:36])=[O:4].[OH-].[Na+].O.Cl>C(OCCCC)(=O)C.O1CCCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])(=[O:25])=[O:24])=[O:21])=[CH:18][C:17]=1[O:35][CH3:36])([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)O)cc12
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of the product of step d) (15 g, 23.8 mmole), concentrated sodium hydroxide liquor (6.75 ml, 119 mmole), water (85 ml) and tetrahydrofuran (18 ml) was stirred for three hours at 65° C., and the now homogeneous solution cooled to 50°-55° C. and maintained at this temperature during the subsequent acidification and extraction. Concentrated hydrochloric acid was added to a pH of 7-8, followed by addition of tetrahydrofuran (44 ml) and n-butyl acetate (29 ml), and further adjustment of the pH to 1-2. The reaction mixture was allowed to settle and the lower aqueous layer separated. The organic layer was washed with 5% brine solution (2×20 ml). The tetrahydrofuran was removed by distillation (ca 40 ml distillate collected at a jacket temperature of 95° C.), and the residual mixture cooled to 15°-20° C. The product was collected by filtration, washed with butyl acetate (15 ml) and dried at 50° C. The yield of 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)-benzamide was 11.08 g (94%); m.p. 264°-267° C.; NMR (250 MHz, DMSO-d6): 2.63 (s, 3H, ArCH3), 3.78 (s, 3H, NCH3), 3.95 (s, 3H, OCH3), 4.08 (s, 2H, ArCH2Ar'), 7.18 (d, 1H), 7.22 (s, 1H), 7.38-7.65 (m, 6H), 7.79 (d, 1H), 8.06 (d, 1H), 8.20 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:21][S@:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[NH:24])=[O:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([N:24]=[S@@:22]([CH3:21])(=[O:23])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:8])=[CH:4][N:3]=1
Reactant: Nc1ncc(C(=O)O)cc1I
Reactant: C[S@](=N)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[S@@](=O)(=NC(=O)c1cnc(N)c(I)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
To a solution of 6-amino-5-iodonicotinic acid (330 mg, 1.3 mmol), N,N-diisopropylethylamine (0.44 mL, 2.5 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (291 mg, 1.9 mmol) in 7.0 mL DMF at room temperature was added BOP (608 mg, 1.4 mmol). The solution was stirred 10 minutes and then heated at 60° C. for 5 hours. The mixture was dissolved in EtOAc, washed with Na2CO3 solution, H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown oil was purified by chromatography (silica gel, hexane/acetone). The product containing fractions were purified by chromatography one additional time (silica gel, EtOAc/MeOH). To give the title compound as a white foam (354 mg, 71%).