Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:15]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[C:17]([NH:27][N:28]=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[N:16]=1>C1COCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[C:17]([NH:27][N:28]=[CH:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:32][CH:31]=3)[N:16]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: FC(F)(F)Oc1ccc(C=NNc2cc(-c3ccccc3)nc(Cl)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(C=NNc2cc(-c3ccccc3)nc(Nc3ccc(Cl)cc3)n2)cc1

Procedure:
To a −78° C. THF solution of 4-chloroaniline was added 1 equivalent of nBuLi to prepare the lithium anilide. The solution was allowed to come to room temperature under nitrogen atmosphere. Aliquots of the lithium anilide were added portion wise to a THF solution of 2-chloro-4-phenyl-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)pyrimidine (XX) containing 0.05 equivalents (relative to (XX)) of Bis(triphenylphosphine) palladium(II) dichloride. The reaction was followed by thin layer chromatography. When the starting material XX was consumed the reaction was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated at reduced pressure. The product, N-(4-chlorophenyl)-4-phenyl-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)pyrimidin-2-amine (Example 58) was obtained as a solid. ESI/MS 483.9728, 485.9988 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)n2)c(F)c1
Temperature: 100 °C
Yield: 52.7 %

Procedure:
A mixture of 2,4-dichloropyrimidine (Aldrich, 0.74 g, 5.0 mmol), 2-fluoro-4-nitrophenol (Avacado, 0.79 g, 5.0 mmol), K2CO3 (0.76 g, 5.5 mmol), and DMF (50 mL) was heated at 100° C. for 2 h. The mixture was cooled and diluted with saturated NaHCO3 solution (100 mL) and extracted with EtOAc. The EtOAc extract was washed with brine, dried (MgSO4) and concentrated in vacuo to give a mixture of the 2-phenoxy- and 4-phenoxypyrimidine regioisomers as a yellow solid. The regioisomers were separated by flash chromatography using 10-40% EtOAc in hexanes as the eluent to give the title compound (0.71 g, 53%) as a white solid. 1H NMR (DMSO-d6) δ 8.76 (dd, 1H, J=6.0, 1.6 Hz), 8.43 (dt, 1H, J=9.8, 2.2 Hz), 8.23 (dd, 1H, J=8.8, 1.6 Hz), 7.80 (dt, 1H, J=9.8, 2.2 Hz), 7.48 (dd, 1H, J=6.0, 2.2 Hz).
Reaction SMILES: [I:1]I.[OH-].[K+].[F:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][NH:15]2)=[CH:11][CH:10]=1.S(=O)(O)[O-].[Na+]>CN(C=O)C>[F:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([I:1])=[N:14][NH:15]2)=[CH:11][CH:10]=1
Reactant: Fc1ccccc1Oc1ccc2cn[nH]c2c1
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1Oc1ccc2c(I)n[nH]c2c1
Yield: 90.6 %

Procedure:
Iodine (1.53 g, 6.02 mmol) and potassium hydroxide pellets (805 mg, 14.3 mmol) were added successively into a DMF solution of 6-(2-Fluoro-phenoxy)-1H-indazole (1.35 g, 5.92 mmol) at room temperature under stirring. After 1.5 h the reaction was poured into sodium bisulfite solution and extracted into EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4 filtered, concentrated and the residue was purified by flash chromatography eluting with Hex:EtOAc 9:1 to yield 1.9 g of 6-(2-fluoro-phenoxy)-3-iodo-1H-indazole: MS: 355 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@H:14]([CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH2:12][C@H:11]1[O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([Mg]Br)[CH3:36].[Cl-].[Li+].Cl>O1CCCC1.C(OCC)C>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][CH2:16][CH2:35][CH3:36])[CH2:13][CH2:12][C@H:11]1[O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2CC[C@@H](OC3CCCCO3)[C@@H]2COCc2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[C@H]1CC[C@@H](OC2CCCCO2)[C@@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
In a flow of argon, to a solution cooled to -78° C., of 13.6 g of (1R,2S,3S)-2-benzyloxymethyl-1-(2-tetrahydropyranyloxy)-3-[2-(p-toluenesulphonyloxy)ethyl]cyclopentane (prepared in Reference Example 5) in 30 ml of dry tetrahydrofuran, 12.5 ml of a 3M solution of ethyl magnesium bromide in diethyl ether was added over a period of 10 min; to the solution, 5 ml of a solution of 8.4 g of lithium chloride and 13.4 g of cupric chloride in 1 l of tetrahydrofuran was added dropwise over a period of 5 min. The mixture was stirred further for 1.5 hrs at the same temperature, for 2 hrs at 0° C., and for 16 hrs at room temperature. The reaction solution was poured into a mixture of 70 ml of 1N hydrochloric acid, ice and 150 ml of diethyl ether, and the ether layer separated was washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (5:1) as eluent to give 8.63 g of the title compound having the following physical characteristics, in a 89.8% yield.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:15][C:16]1([O:19][CH2:18]1)[CH3:17]>CN(C)C=O.O>[CH3:15][C:16]([OH:19])([CH3:18])[CH2:17][O:12][C:2]1([CH3:1])[CH2:11][CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4][CH2:3]1
Reactant: CC1(C)CO1
Reactant: CC1(O)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)COC1(C)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (4.01 g) in N,N-dimethylformamide (20 mL) was added 60% sodium hydride in oil (960 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To this mixture was added isobutylene oxide (2.52 g), and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was cooled to room temperature, and diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→65/35 (volume ratio)] to give the title compound as a colorless oil (1.81 g, 32%).
Reaction SMILES: C(N1CCN(C2C3C(=CC=CC=3)C=C([C:19]3[S:23][C:22]([CH:24]4[O:29][CH2:28][CH2:27][CH2:26][O:25]4)=[N:21][CH:20]=3)N=2)CC1)C.Cl.[OH-].[Na+]>O1CCCC1>[O:29]1[CH2:28][CH2:27][CH2:26][O:25][CH:24]1[C:22]1[S:23][CH:19]=[CH:20][N:21]=1
Reactant: CCN1CCN(c2nc(-c3cnc(C4OCCCO4)s3)cc3ccccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1csc(C2OCCCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 181.3 %

Procedure:
1-(1-Ethylpiperazin-4-yl)-3-[2-(1,3-dioxan-2-yl)thiazol-5-yl]isoquinoline (205 mg) was dissolved in tetrahydrofuran (4 ml), followed by the addition of 1N hydrochloric acid (3 ml), and the resulting mixture was stirred at room temperature for 8 hr. The reaction solution was basified by adding 8N sodium hydroxide thereto, and then extracted with in ethyl acetate. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated, to give the title compound as a colorless oil (155 mg, yield; 80%).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][N:6]=[C:7]([NH2:20])[CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[Cl:19].N1C=CC=CC=1>C(Cl)Cl>[Cl:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:18][C:9]=1[CH2:8][C:7]1[NH:20][S:1](=[O:2])[O:5][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: NC(CC1=C(Cl)c2ccccc2CC1)=NO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S1NC(CC2=C(Cl)c3ccccc3CC2)=NO1
Yield: 31.8 %

Procedure:
Thionyl chloride (0.55 mL, 7.5 mmol) was added dropwise to a mixture of N'-hydroxy-(1-chloro-3,4-dihydro-2-naphthalenyl)ethanimidamide (1.6 g, 6.8 mmol) and pyridine (1.10 mL, 13.6 mmol) in dry CH2Cl2 (25 mL) at 0° C. After the addition, the reaction was concentrated under reduced pressure, diluted with water (50 mL), and extracted with ether (3×50 mL). The organics were washed with brine, dried (MgSO4), and concentrated to obtain a black froth. The froth was chromatographed on silica gel (twice: eluant 4% MeOH/CH3Cl2 and eluant 2% MeOH/CH2Cl2) to yield 612 mg (32%) of an off-white solid, m.p. 90.5°-91.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-fluorophenyl)propionic acid (4.75 g, 28.2 mmol) in toluene (130 mL) and methanol (20 mL) was added trimethylsilyldiazomethane (2M solution in hexane, 16.24 mL, 32.5 mmol). The mixture was allowed to stir for 1 hour and gas evolution was observed initially. After 1 hour, the mixture became homogeneous and was quenched via addition of 3.5 mL of acetic acid. The mixture was concentrated in vacuo, and purified via column chromatography on a Biotage 65i column eluting with 0% ethyl acetate in hexanes (1 CV) followed by a gradient to 50% ethyl acetate in hexanes (over 7 CV) to furnish the desired product. 1H NMR (CDCl3, 500 MHz) δ 7.16 (dd, J=8.0 Hz, 5.6 Hz, 2H), 6.97 (t, J=8.5 Hz, 2H), 3.66 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([Li])CCC.CI.Cl>CCCCCC.C(COC)OC>[CH3:10][O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1]
Reactant: [Li]CCCC
Reactant: C#CC(O)CCCCC
Agent: Cl
Solvent: COCCOC
Solvent: CCCCCC
Solvent: CI
Product: C#CC(CCCCC)OC
Temperature: 60 °C

Procedure:
To an ice-cooled solution of 63 g. of 1-octyne-3-ol in 300 ml. of dimethoxyethane is added under an inert atmosphere 312 ml. of 1.6 M n-butyllithium in hexane dropwise over 1 hour. To the mixture is then added 145 g. of methyl iodide and the resulting mixture is stirred at ambient temperatures for 24 hours and then heated to 60° C. for 1 hour. The mixture is cooled and poured into cold dilute hydrochloric acid. The organic phase is separated, washed with water and saturated brine, dried (Na2SO4), and evaporated to an oil, dried (Na2SO4), and evaporated to an oil. Fractional distillation of the oil in vacuo yields the product as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>CN(C)C=O.C(OC(C)C)(C)C>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CN(C)CCCl
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])c(C=O)c1

Procedure:
10 mmol of 5-hydroxy-2-nitrobenzaldehyde dissolved in dimethylformamide are added dropwise to 20 mmol of potassium carbonate suspended in a mixture of dimethyl-formamide and isopropyl ether, and then the reaction mixture is heated at reflux for 2 hours. After the mixture has returned to ambient temperature, 10 mmol of 2-chloro-N,N-dimethylethanamine hydrochloride are added dropwise, and then the reaction mixture is heated at reflux again for one night. After returning to ambient temperature, the mixture is filtered and the solvents of the filtrate are evaporated off to yield the expected product in the form of an oil.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.CN(C=O)C.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Cu]I.CO>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:5]=[N:6][NH:7][CH:28]=2)=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(OCc2ccccc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc(COc2ccc(-c3c[nH]nn3)cc2)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
Trimethylsilyl azide (415 mg, 3.6 mmol) was added to a DMF (4.3 mL) and MeOH (0.48 mL) solution containing CuI (22.9 mg, 0.12 mmol) and 1-(benzyloxy)-4-ethynylbenzene (500 mg, 2.4 mmol) under Ar in a pressure tube (caution: build-up of pressure possible; use a safety shield). The reaction mixture was stirred at 100° C. for 12 h. The mixture was cooled to room temperature and filtered through a short silica gel pad and concentrated. The residue was purified by recrystallization from DCM.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([OH:48])[CH:41]6[CH:42]([O:43][CH:44]([CH3:46])[CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:49]([CH3:51])[CH3:50])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH:44]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:49]([CH3:51])[CH3:50])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:47]([OH:48])[CH:41]1[O:40]3)[O:36]2)([CH3:45])[CH3:46]
Reactant: CC(C)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
9 mg of compound (34) was dissolved in 2 ml of ethyl acetate and allowed to react in the presence of a catalytic amount of 10% palladium-carbon under stirring under a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with chloroform-methanol (30:1). The fraction containing the desired product was concentrated to dryness to give 6.8 mg of compound (35).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[N:10]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[C:18](=O)([O-])[O-].[Cs+].[Cs+].ClCI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[O:8][CH2:18][N:13]3[C:12]4[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=4[N:10]=[C:9]3[C:4]=2[CH:3]=1
Reactant: Oc1ncc(Br)cc1-c1nc2c([nH]1)CCCC2
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cnc2c(c1)-c1nc3c(n1CO2)CCCC3
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 5-bromo-3-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)pyridin-2-ol (0.3 g, 1.02 mmol) and Cesium carbonate (0.663 g, 2.04 mmol) in DMF (10 mL), was heated to 100° C. Then chloroiodomethane (215 mg, 1.22 mmol) was added by dropwise, the react mixture was stirred at 100° C. for 30 minutes. The solvent was removed off and the resulting residue was purified using flash column (petroleum ether:EtOAc 3:1) to provide 2-bromo-8,9,10,11-tetrahydro-6H-benzo[4,5]imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (50 mg, yield 16%) as a solid. 1HNMR (400 MHz, CDCl3): δ=8.30 (d, J=2.4 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H), 5.87 (s, 2H), 2.66˜2.68 (m, 2H), 2.58˜2.61 (m, 2H), 1.87˜1.88 (m, 4H). MS (M+H)+: 306/308.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13]CC2C=CC=CC=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:21]([OH:23])=[O:22])=[N:7]2.Cl>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:21]([OH:23])=[O:22])=[N:7]2
Reactant: O=C(O)c1ccc2c(Cl)cc(Cl)c(OCc3ccccc3)c2n1
Agent: Cl
Product: O=C(O)c1ccc2c(Cl)cc(Cl)c(O)c2n1
Temperature: 25 °C

Procedure:
A mixture of 5,7-dichloro-8-benzyloxy-quinoline-2-carboxylic acid 18 (2.56 g, 7.35 mmol) and concentrated hydrochloric acid (25 mL) was stirred at RT for h, and then concentrated to dryness. The resulting residue was washed with diethyl ether (20 mL×2). This provided 5,7-dichloro-8-hydroxyquinoline-2-carboxylic acid 19 as a yellow solid (1.78 g, 94%). 1H NMR (CDCl3/DMSO-d6 (19:1), 400 MHz): δ 10.60 (br, 1 H), 8.53 (d, J=8.8, 1 H), 8.22 (d, J=8.8, 1 H), 7.60 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:13][NH:14][C:15](=[O:24])[C@@H:16]1[CH2:20][CH2:19][C:18](=[O:21])[N:17]1[CH2:22]C)#[N:2].CN1C(=O)CC[C@H]1C(O)=O>>[C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:13][NH:14][C:15](=[O:24])[C@@H:16]1[CH2:20][CH2:19][C:18](=[O:21])[N:17]1[CH3:22])#[N:2]
Reactant: CCN1C(=O)CC[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1C#N
Agent: CN1C(=O)CC[C@H]1C(=O)O
Product: CN1C(=O)CC[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1C#N

Procedure:
N-{[2-Cyano-3-(trifluoromethyl)phenyl]methyl}-1-methyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of N-{[2-cyano-3-(trifluoromethyl)phenyl]methyl}-1-ethyl-5-oxoprolinamide (E105) but using 1-methyl-5-oxo-proline in place of 1-ethyl-5-oxo-proline.
Reaction SMILES: [C:1]([N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:15])[C:10]=2[Br:14])[CH:5]1[CH2:16][C:17]([O:19]C)=O)(=[O:3])[CH3:2].BrC1C(F)=CC=C2C=1C=C[N:26]=C2.C([Si](OC(OC)=C)(C)C)(C)(C)C.Cl>C(Cl)Cl>[Br:14][C:10]1[C:9]([F:15])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:26][C:17](=[O:19])[CH:16]=[C:5]12
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2C=CN1C(C)=O
Reactant: Fc1ccc2cnccc2c1Br
Agent: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2-dihydroisoquinolin-1-yl)acetate. To a stirred solution of 5-bromo-6-fluoroisoquinoline (43.9 g, 194 mmol) in DCM (880 mL) acetyl chloride (14.49 mL, 204 mmol) was dropped at RT and the solution was stirred for 60 min. The solution was cooled to −78° C. (yellow suspension) and then a solution of tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (38.4 g, 204 mmol) in DCM (220 mL) was added in one portion. The resulting yellow solution was stirred at −78° C. for 1 h and then allowed to warm to rt overnight. 2N aqueous HCl was added and the reaction mixture was stirred for 10 min. The organic layer was separated and washed with brine (2×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether, charcoal was added and the mixture was filtrated through a pad of celite. The solvent was evaporated and the crude product was dried under high vacuo overnight to yield the title compound (70.6 g) which was used without further purification. UPLC-MS: MS 342.2/344.2 (M+H+); UPLC rt 1.05 min.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[Cl:7][C:8]1[C:13]([C:14](=O)/[CH:15]=[CH:16]/N(C)C)=[CH:12][CH:11]=[CH:10][N:9]=1>CO>[Cl:7][C:8]1[C:13]([C:14]2[CH:15]=[CH:16][N:3]=[C:4]([NH2:6])[N:5]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: N=C(N)N
Reactant: CN(C)/C=C/C(=O)c1cccnc1Cl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1nccc(-c2cccnc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an argon purged 500 mL round bottom flask placed in an isopropanol bath (used as a heat sink), added sodium metal (3.40 g, 148 mmol) slowly to methanol (180 mL). Stirred at RT for 30 minutes. Added guanidine hydrochloride (17.0 g, 182 mmol), stirred at RT for 30 minutes, added (E)-1-(2-chloropyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one (12.0 g, 57.0 mmol), attached air condenser, and heated to 50° C. for 24 hours. Removed approximately half of the methanol by rotary evaporation. Filtered solids onto side-armed flask under vacuum, then washed with saturated NaHCO3 and H2O, air dried to yield 4-(2-chloropyridin-3-yl)pyrimidin-2-amine as off-white solid. MS (M+H)+=206. Calc'd′206.63 for C9H7ClN4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:29](=[O:30])[C:28]3[CH:27]=[CH:26][C:25]([N:22]4[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]4)=[CH:33][CH:32]=3)=[CH:13][CH:12]=1)[N:6]=[CH:5]2
Reactant: Nc1ccc(-n2ncc3cc(O)ccc32)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: O=C(Nc1ccc(-n2ncc3cc(O)ccc32)cc1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 990 was prepared according to the procedure described in Scheme IV from 5-hydroxy-1-(4-aminophenyl)indazole and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C25H24N4O3: 429.18; found: 429.07.