Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].C1(C)C=CC=CC=1.[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:3][C:1]([O:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2]
Reactant: Oc1cccnc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)Oc1cccnc1

Procedure:
A 1.93M solution of phosgene in toluene (20%) (198.3 ml) (382.3 mmoles) was diluted with dry CH2Cl2 (100 ml) and the mixture was stirred at 0° under an argon atmosphere. A solution of 3-hydroxy-pyridine (7.27 grams) (76.5 mmoles) and dry pyridine (8.06 grams) (8.25 ml) (101.9 mmoles) in dry CH2Cl2 (200 ml) was added dropwise to the stirred solution at 0° over a period of 1 hour. The mixture was stirred at 0-25° for an additional 2 hours. A stream of nitrogen was passed through the solution to remove most of the phosgene and the solution was then evaporated to dryness to give the title compound which was dried in vacuo for 1 hour and then taken up in dry CH2Cl2 (60 ml) and dry pyridine (60 ml) to give a stock solution of the title compound.
Reaction SMILES: O([C:8]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])C1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].Cl>C(O)C>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:8]1[C:9](=[CH:13][C:14]([S:24](=[O:26])(=[O:27])[NH2:25])=[C:15]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COc1ccccc1CN
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Oc2ccccc2)cc1Oc1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccccc1CNc1cc(Oc2ccccc2)c(S(N)(=O)=O)cc1C(=O)O
Temperature: 80 °C

Procedure:
43 g of 2,4-diphenoxy-5-sulfamoyl-benzoic acid (0.1 mol) prepared according to Example 1 (c) were stirred with 80 ml of 2-methoxybenzylamine for 3.5 hours at 140° C. The almost colorless reaction solution which, had been cooled to about 80° C, was then diluted with 150 ml of ethanol, and the solution was introduced while stirring into 1.0 l of 1N hydrochloric acid at room temperature. The reaction product, which had precipitated in crystals, was suction-filtered and washed with water and then boiled up for a short time with 0.3 l of ethanol, during which the major part of it remained undissolved. After cooling to room temperature, it was suction-filtered and washed with ethanol and finally dried on a steam bath.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:38]([O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)=[O:39]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:39])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Cl)OC1CCCCC1
Reactant: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC3CCCCC3)cc1)n2C)c1ccccn1
Yield: 40 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and cyclohexyl chloroformate. Yield: 40% of theory, C32H35N7O5 (597.7) Rf value: 0.26 (silica gel; dichloromethane/ethanol=19:1) ##EQU85##
Reaction SMILES: [Br:1][C:2]1[C:6]2=[CH:7][NH:8][C:9](=[O:11])[CH:10]=[C:5]2[S:4][CH:3]=1.[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[CH:7][N:8]([CH3:14])[C:9](=[O:11])[CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: CI
Reactant: O=c1cc2scc(Br)c2c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc2c(Br)csc2cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a suspension of 3-bromothieno[3,2-c]pyridin-6(5H)-one (235 mg, 1.02 mmol) in DMF (3.9 mL) was added sodium hydride (25.7 mg, 1.07 mmol). The mixture stirred 1 h at room temperature, and then methyl iodide (69.9 μL, 1.12 mmol) was added. The reaction stirred a further 1 h at room temperature and then was poured into water (100 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic fractions were washed with water (3×50 mL), dried over sodium sulfate, filtered, and concentrated. Trituration with diethyl ether (˜5 mL) and filtration to collect the resultant solid afforded 120 mg (48%) of the title compound as a tan solid. 1H NMR (400 MHz, CDCl3): δ 7.84 (s, 1 H), 6.91 (s, 1 H), 6.89 (d, J=0.8 Hz, 1 H), 3.75 (s, 3 H); MS (ESI): 244.03, 245.98 [M+H]+; HPLC tR=2.76 min (ZQ3, polar—4 min).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH3:7])[CH3:6].[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:24](O)=[O:25])=[CH:18][CH:17]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH2:31]([O:30][C:28]([NH:27][C@H:23]([C:24]([NH:2][CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:5]([CH3:7])[CH3:6])=[O:25])[CH2:22][C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][CH:20]=1)=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
The (2S)-1-amino-2-tert-butyloxycarbonylamino-3-methylbutane hydrochloride was obtained from tert-butyloxycarbonyl-L-valinol in accordance with the literature procedures (Mattingly, P. G., Synthesis, 1990, 1990, 366-368. Desired Boc-protected alcohol was obtained from Boc-L-valine, in accordance with the literature procedure (Juszczyk, P. et al., Letters In Peptide Science. 2003, 10, 79-82). The solution of (2S)-1-amino-2-tert-butyloxycarbonylamino-3-methylbutane hydrochloride (0.50 g, 2.096 mmol), Z-L-phenylalanine (0.659 g, 2.20 mmol), triethylamine (611 μl, 4.4 mmol) and HOBt (0.297 g. 2.20 mmol) in 10 ml of DMF was cooled on ice bath and DCC (0.498 g, 2.42 mmol) was added in small portions, during 0.5 h. The stirring was continued during 1 hour, next the reaction mixture was left in room temperature overnight. The precipitated DCU was filtered off, washed with DMF (2×3 ml) and the combined filtrates were evaporated under reduced pressure. The solid residue was dissolved in ethyl acetate (200 ml) and the solution was washed with 1 M hydrochloric acid (3×70 ml),
Reaction SMILES: [O:1]([C@H:9]([CH3:16])[CH2:10][C:11](OCC)=[O:12])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.CO>ClCCl>[O:1]([C@H:9]([CH3:16])[CH2:10][CH2:11][OH:12])[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: C[C@H](CCO)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
The crude product from Example 545A (˜37 mmol) was dissolved in dichloromethane (100 mL). To this stirred solution, chilled to −78° C., was added dropwise a 1M solution of diisobutylaluminum hydride in dichloromethane (185 mL, 185 mmol). The reaction mixture was stirred at −78° C. for two hours, then it was allowed to warm to −30° C. and stirred an additional 0.5 hours. Methanol was then added carefully at −20° C. to quench any remaining hydride. The reaction mixture was then diluted with methyl tert-butylether (200 mL) and washed with aqueous sodium tartrate solution (4×100 mL) and brine (2×100 mL). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (6.3 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]([C:11]1[N:16]2[N:17]=[C:18]([C:20]3([CH2:23][OH:24])[CH2:22][CH2:21]3)[N:19]=[C:15]2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]([C:11]1[N:16]2[N:17]=[C:18]([C:20]3([CH:23]=[O:24])[CH2:21][CH2:22]3)[N:19]=[C:15]2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)n2nc(C3(CO)CC3)nc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)n2nc(C3(C=O)CC3)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(3,5-Dichloro-pyridin-4-yl)-1-[2-(1-hydroxymethyl-cyclopropyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-ethanone obtained in example 6 (154 mg, 0.38 mmol) was dissolved in DCM (5 mL) and treated with NaHCO3 (127 mg, 1.51 mmol) and Dess-Martin periodinane (321 mg, 0.756 mmol). The suspension was stirred for 30 min at rt and then treated with a 50 mL of a 1:1 mixture of Na2S2O3 (sat., aq.) and NaHCO3 (sat., aq.). The reaction mixture was then extracted with EtOAc (2×25 mL). The combined organic phases were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Yield 156 mg of slightly yellow solid, which was used without further purification.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](O)[CH:17]([OH:19])[CH3:18].B(F)(F)F.CCOCC.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:15][C:12]1[N:11]=[CH:10][C:9]([C:1]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:19][CH:17]([CH3:18])[CH2:16][O:8]2)=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)nc1
Reactant: CC(O)CO
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1COC(c2ccccc2)(c2ccc(Cl)nc2)O1

Procedure:
To 25 ml of a solution of 1.5 g of 3-benzoyl-6-chloropyridine and 3.2 g of 1,2-propanediol in toluene, 1.2 g of boron trifluoride etherate was added. The resulting mixture was heated under reflux for six hours while removing the water thus formed therefrom. Then the reaction mixture was cooled, poured into an aqueous solution of sodium hydroxide and extracted with ether. The organic phase was washed with water and dried over anhydrous sodium sulfate. After filtering off the sodium sulfate and distilling off the solvent in vacuo, 2-(6-chloropyridin-3-yl)-4-methyl-2-phenyl-1,3-dioxolane was obtained, m.p.: 44°-51° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([S:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:25]=3)[NH:20][N:19]=2)(=[O:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O>CN(C=O)C>[N:1]([CH2:29][CH2:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[S:15]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)(=[O:16])=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
Sodium azide (0.79 g, 12 mmol) was added to a solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (2.06 g, 3.94 mmol) in DMF (20 mL). The reaction mixture was stirred at 80° C. for 12 hours in a sealed tube. After cooling to ambient temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was washed with 10% ammonium chloride/water solution, water and brine. It was dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 72° C. in vacuo for 40 minutes to yield 5-(2-azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a amber gum/foam (1.34 g, 86.5%). Mass spectrum (−EI, [M−H]−) m/z 392. 1HNMR (400 MHz, DMSO-d6): δ8.78 (d, 1H, J=8.70 Hz), 8.56 (dd, 1H, J=7.43 Hz and 1.16 Hz), 8.29 (d, 1H, J=8.35 Hz), 8.06 (d, 1H, J=7.66 Hz), 7.72-7.76 (m, 1H), 7.57-7.67 (m, 3H), 7.31 (d, 1H, J=2.32 Hz), 7.12 (dd, 1H, J=9.16 Hz and 2.32 Hz), 4.22-4.24 (m, 2H), 3.67-3.69 ppm (m, 2H).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[C:36]([C:37]4[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH3:44])[N:38]=4)=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:26][CH:25]=2)=[N:15][N:14]=1>C1COCC1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([O-])(O)=O.[Na+].[Cl-].[Zn+2].[Cl-].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>[CH3:44][NH:43][C:39]1[N:38]=[C:37]([C:36]2[C:31]([O:30][C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:16]4[C:17]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:13]([C:9]5[S:10][CH:11]=[C:7]([CH3:6])[N:8]=5)=[N:14][N:15]=4)=[CH:29][CH:28]=3)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:42]=[CH:41][N:40]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4ccccc34)cc2)n1
Reactant: Cc1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4nc(C)cs4)c4ccccc34)cc2)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A dry 25 ml round bottom flask under nitrogen was charged with 2.5 M nBuLi in Hexanes (0.420 ml, 1.06 mmol); which was diluted with THF (1 ml). This was cooled to −78° C. and 4-methylthiazole (100 mg, 1.01 mmol) dissolved in 2 ml of THF was added slowly via syringe. This was stirred at −78° C. for 2 hours, slowly warmed up to −10° C. and stirred at this temperature for 0.5 hour. Reaction cooled back to −78° C. and 0.5M zinc(II) chloride in THF (3.03 ml, 1.51 mmol) added via syringe. Reaction stirred at −78° C. for 0.5 hour then at room temperature for 1 hour. At this time, 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (115 mg, 0.250 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) added and reaction stirred under nitrogen at 65° C. for 48 hours. Reaction stopped, cooled to room temperature, diluted with aq. EDTA/NaHCO3 solution. This was extracted with ethyl acetate. Organic portion was dried with Na2SO4, filtered, and concentrated to give light brown residue. This was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of Aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, concentrated to afford pure N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiazol-2-yl)phthalazin-1-amine as a yellow solid. MS m/z=519 [M+H]+. Calc'd for C28H22N8OS: 518.59.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[C:13](Cl)=[N:14][CH:15]=[C:16]([CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18].[O:33]1[CH2:38][CH2:37][CH:36]([C:39]#[N:40])[CH2:35][CH2:34]1>C1COCC1>[Br:11][C:12]1[C:13]([C:36]2([C:39]#[N:40])[CH2:37][CH2:38][O:33][CH2:34][CH2:35]2)=[N:14][CH:15]=[C:16]([CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18]
Reactant: N#CC1CCOCC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)CCOCC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
KHMDS 1 M in THF (0.758 mL) was added dropwise to a mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 100 mg, 0.253 mmol) and tetrahydro-2h-pyran-4-carbonitrile (42.1 mg, 0.379 mmol) in THF (2.5 mL), under a nitrogen atmosphere. The RM was stirred at −70° C. for 1 h, and allowed to warm to RT overnight. The RM was quenched with water and the solvent was evaporated off under reduced pressure to afford 5-bromo-6-(4-cyanotetrahydro-2h-pyran-4-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (50 mg, 0.106 mmol), Pd(Ph3P)4 (18 mg, 0.016 mmol), pyrimidin-5-ylboronic acid (20 mg, 0.159 mmol), K3PO4 (68 mg, 0.319 mmol) and toluene (1.3 mL) were added to a vial, which was sealed, evacuated/purged with argon. The RM was stirred at 110° C. for 3 h, diluted with MeOH, filtered through a cartridge PL-Thiol MP-Resin and concentrated the combined filtrates were evaporated to dryness under reduced pressure. The crude product was purified by preparative SFC (Column 2-EP, gradient: 6% to 11% in 6 min) and lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.2 min, m/z=469.9 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 2.00 (d, J=13.55 Hz, 2H) 2.40 (td, J=13.08, 3.95 Hz, 2H) 3.52 (t, J=12.14 Hz, 2H) 3.94 (d, J=8.66 Hz, 2H) 7.39 (d, J=8.66 Hz, 2H) 7.86 (d, J=8.85 Hz, 2H) 8.30 (s, 1H) 8.96 (s, 2H) 9.23 (d, J=1.13 Hz, 1H) 9.32 (s, 1H) 10.67 (s, 1H).
Reaction SMILES: CO[C:3](=[O:18])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:19][CH2:20]C([O-])=O.[Na+].[Cl-].[Mg+2].[Cl-].C(NC(C)C)(C)C.C([Mg]Cl)CCC.S(=O)(=O)(O)O>C(OCC)(=O)C.O1CCCC1>[CH2:11]([C@H:4]([NH:5][C:6](=[O:7])[O:8][CH2:9][CH3:10])[C:3](=[O:18])[CH2:20][Cl:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reactant: O=C([O-])CCl
Agent: CCCC[Mg]Cl
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Temperature: 40 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
In a nitrogen gas atmosphere, a solution composed of (S)-N-(ethoxycarbonyl)phenylalanine methyl ester (35.0 g, 139 mmol), sodium monochloroacetate (24.2 g, 208 mmol), magnesium chloride (19.9 g, 208 mmol) and tetrahydrofuran (125 ml) was stirred at 40° C. for 3 hours (solution A). Separately, in a nitrogen atmosphere, diisopropylamine (65.0 g, 642 mmol) was added dropwise at 40° C. over 30 minutes to n-butylmagnesium chloride (2 M THF solution, 278 ml, 556 mmol) and the resulting mixture was further stirred at 40° C. for 2 hours (solution B). Solution B was added at about 10° C. (inside temperature) over about 30 minutes to solution A. After completion of the addition, the inside temperature was raised to 40° C. and stirring was continued for further 2 hours. Then, the reaction mixture was mixed with 900 ml of an ice-cooled mixed solution composed of 10% (w/v) aqueous solution of sulfuric acid and 550 ml of ethyl acetate with stirring. After thorough mixing, the mixture was allowed to separate into layers. The organic layer was washed in sequence with a saturated aqueous solution of sodium hydrogen carbonate (300 ml) and a saturated solution of sodium chloride (300 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, 30 ml of isopropanol was added to the residue, the mixture was heated to 60 to effect dissolution, 600 ml of hexane was then added, and the mixture was gradually cooled to 5° C. for allowing crystallization. The precipitate crystals were collected by filtration, washed with hexane and dried under reduced pressure to give 28.5 g of white needle crystals. 1H NMR (400 MHz, CDCl3): δ7.35 to 7.16 (m, 5H), 5.17 (d, 1H), 4.75 (q, 1H), 4.17 to 4.08 (m, 2H), 4.00 to 3.96 (ds, 2H), 3.09 to 3.07 (m, 2H), 1.23 (t, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)OC(C)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(OC(C)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Yield: 26 %

Procedure:
A solution of ethyl 2-{1-[4-(4-chlorophenyl)-phenyl]-ethoxy}propionate (3.0 g.) in a mixture of ethanol (150 ml.) and water (5 ml.), containing sodium hydroxide (5.0 g.), was heated under reflux for 5 hours. The mixture was then evaporated and the residue diluted with water (50 ml.) and extracted with ether. The ether extract was discarded and the aqueous alkaline phase was acidified to pH 1-3 by addition of concentrated hydrochloric acid. The mixture was extracted thoroughly with ether. The combined extracts were washed with water, dried (MgSO4), and evaporated. The residue was triturated with petrol (40-60) and the solid which formed was separated and recrystallised from toluene to give 2-{1-[4-(4-chlorophenyl)phenyl]ethoxy}propionic acid, m.p. 144°-146° C. in 26% yield.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.CCN(CC)CC>C(O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-chlorophenylhydrazine hydrochloride (269 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-chlorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale brown solid (126 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl>[I:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[C:5]=1[NH:9][C:11](=[O:15])[C:12](=[O:13])[NH:10]2
Reactant: Nc1cc(Cl)cc(I)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2cc(Cl)cc(I)c2[nH]c1=O
Temperature: 25 °C
Yield: 74.2 %

Procedure:
Synthesis of 5-1-do-7-chloro-1,4-dihydro-2,3-quinoxalinedione: The procedure of Foged, C. and Journal, P. (J. of Lab. Compd. and Radiopharmac. XXXI (5):365-373 (1992)) was adapted. To a stirred mixture of 4-chloro-6-iodo-1,2-phenylenediamine (366 mg, 1.253 mMol) in 2N HCl (30 mL) was added oxalic acid (160 mg, 1.269 mMol, used as received) in one portion. The mixture was refluxed at 120°-5° C. for 3 h, then cooled to room temperature overnight. The mixture was centrifuged and the liquid layer was removed. The red solid was washed twice with cold water (2×2 mL),. collected by filtration, and dried at 60° C. with reduced pressure for 2 h, giving 300 mg of crude 5-iodo-7-chloro-1,4-dihydro-2,3-quinoxalinedione (74%), as a red powder containing some impurities (by NMR). A 300 mg sample of crude product was dissolved in 1N NaOH (10 mL). Some insoluble material was removed by filtration, and the filtrate was then acidified to pH=6, giving 260 mg of purer product. Crystallization from DMSO/H2O, gave 169 mg of pure product (42%), as red microcrystals, mp: >350° C. (dec. from 295° C.). IR (KBr, cm-1) 3443, 3212, 1750, 1706, 1606, 1587, 1393. NMR (1H DMSO-d6): δ7.133 (d, 1H, J=1.5 Hz); 7.628 (d, 1H, J=1.5 Hz); 10.386 (d, 1H, J=1.5 Hz); 12.015 (d, 1H, J=1.8 Hz). HRMS: calcd for C8H4N2O2ClI (M+) m/z: 321.9004; found: 321.8995. Potency relative to DCK: 28.4%.