Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1/[CH:8]=[N:20]/[NH:19][C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: O=Cc1c(Br)cncc1Br
Reactant: NNc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccc(N/N=C/c2c(Br)cncc2Br)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 3,5-dibromo-4-pyridinecarboxaldehyde (30.0 g, 113 mmol) in ethanol (1200 mL) at reflux was added 4-fluorophenylhydrazine hydrochloride (20.0 g, 123 mmol) in several portions followed by a solution of sodium acetate (31.0 g, 228 mmol) in water (200 mL). The mixture turned from a deep red to a bright yellow and over time a yellow solid precipitated. After 20 minutes, the mixture was cooled, diluted with water (1000 mL) and the yellow solid was collected by filtration. The solid was washed with water and dried to afford N-[1-(3,5-dibromopyridin-4-yl)-meth-(E)-ylidene]-N′-(4-fluorophenyl)-hydrazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.ClCCl.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C>[CH3:15][S:16]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:18])=[O:17]
Reactant: OCCCc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
3-(4-Bromophenyl)propan-1-ol (335 g) and dichloromethane (2.5 L) was charged into Reactor 1. Reactor 1 was adjusted to −10 to 0° C. Triethylamine (205 g) was charged into Reactor 1. Methanesulphonyl chloride (272.7 g) was added dropwise into Reactor 1 maintaining contents at <0° C. Reactor 1 was stirred at −5 to 5° C. for 1 h then analysed for reaction completion. The organic layer was washed with water (1 L) and saturated NaCl solution (1 L). The organic layer was evaporated down to dryness to give 3-(4-bromophenyl)propyl methanesulfonate (418 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1.C([O-])(=[O:25])C.[Cs+].CN(C=O)C>O>[OH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc(O)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A mixture of tert-butyl ((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (5.00 g), cesium acetate (7.23 g) and DMF (40 mL) was stirred at 0° C. for 10 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:19])C(=O)C1>OS(C(F)(F)F)(=O)=O>[Br:19][C:7]1[C:6]([O:10][CH3:11])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(F)c1C#N
Agent: O=S(=O)(O)C(F)(F)F
Product: COc1c(Br)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Fluoro-6-methoxybenzonitrile (8.30 g, 54.9 mmol) was dissolved in Triflic acid (75 mL) at 0° C. then NBS (10.3 g, 57.7 mmol) was added. The reaction mixture was stirred at RT for 1 h. LC-MS showed no starting material peak. The reaction mixture was poured into ice and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by chromatography through a 330 g Redi-Sep column and eluted with 10% to 50% EtOAc/hexane solvent system to yield the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH3:6])[CH3:5].N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC>>[CH3:1][N:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:8][CH2:9][NH:10][CH3:11]
Reactant: CCN1CCC[C@H]1CN
Reactant: CNCC(C)C
Product: CNCCN(C)CC(C)C

Procedure:
By using N-methylisobutylamine (1.01 g) as a starting material, the title compound (170 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Br:10]Br>C(O)(=O)C>[Br:10][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: CSc1nccc(C)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: CSc1nccc(CBr)n1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
To a solution of 4-methyl-2-methylthiopyrimidine (12.6 g, 0.09 mol) in acetic acid (50.0 mL) was added bromine (5.5 mL, 0.11 mol) and heated at 80° C. under argon atmosphere for 2 h. Acetic acid was distilled in vacuo, the residue was triturated with dichloromethane (100.0 mL) and poured into satd. sod.bicarbonate solution (200.0 mL). Additional dichloromethane (100.0 ml) was added and stirred for 15 min. The organic phase was washed with water (3×100 mL), dried (Na2SO4), and concentrated under reduced pressure. The dark colored residue was purified by flash chromatography (EtOAc/hexane 1:4 v/v) to afford 4-(bromomethyl)-2-(methylthio)pyrimidine (10.9 g, 55%) as a dark colored liquid: 1H NMR (CDCl3/400 MHz) δ 8.50 (d, 1H, J=4.8 Hz), 7.09 (d, 1H, J=4.8 Hz), 4.34 (s, 2H), and 2.56 (s, 3H); ES MS m/z 219 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=[O:6])[CH2:3]1.[OH-].[Li+].Cl>O1CCOCC1.O>[CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: CCOC(=O)C1CCCN(C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 1-methylnipecotate, 0.3 mL (1.65 mmol) in 10 mL of dioxane was added a solution of 118 mg (4.95 mmol) of lithium hydroxide in 10 mL of water. The solution was stirred for 1.5 hours at rt. then was acidified to pH=1 with 5N HCl. The mixture was concentrated to dryness and carried on without further purification. IS (MS) 144.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CCNCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(Cl)cc2C1=O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(Cl)ccc2-3)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.3 %

Procedure:
A solution of 200 mg (0.54 mmol) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 4 ml of N,N-dimethylformamide was treated with 0.17 ml (1.65 mmol) of diethylamine and stirred at room temperature under argon for 1.5 hrs. The solution was evaporated and the residue was triturated in 10 ml of water. The crystals were filtered off under suction, the filtrate was extracted once with ethyl acetate and the extract was evaporated. The combined crude products were chromatographed on 20 g of silica gel (methylene chloride/acetone 4:1, 2:1). There were obtained 124 mg of 8-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted in acetone with ethereal hydrochloric acid into the hydrochloride. By crystallization from acetonitrile there were obtained 108 mg (42%) of 8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (1:1.9) of m.p. 191°-205° (dec.).
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O)=[CH:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)#[N:2].COC(OC)[N:23]([CH3:25])C>C(Cl)Cl>[CH3:11][C:3]1[CH:1]=[C:25]([CH:6]=[C:5]([CH3:10])[CH:4]=1)[NH:23][C:13]1[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]([CH2:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[CH:1][N:2]=1
Reactant: COC(OC)N(C)C
Reactant: N#CC(=Cc1ccncc1)c1ccccc1C(=O)O
Solvent: ClCCl
Product: Cc1cc(C)cc(Nc2ncc(Cc3ccncc3)c3ccccc23)c1
Reaction time: 22 h

Procedure:
With the exclusion of moisture, 211 g (0.843 mol) of 2-[(1-cyano-2-(pyridin-4-yl)-vinyl]-benzoic acid are suspended in 3.3 liters of CH2Cl2; 169 ml (=90%, 1.1 mol) of dimethylformamide dimethylacetal (Fluka, Buchs, Switzerland) are added at room temperature, and stirring is carried out for 22 hours to complete the reaction. The reaction mixture is filtered, and the residue is washed thoroughly with CH2Cl2 and discarded. Concentration of the filtrate by evaporation, chromatography (SiO2; ethyl acetate) and crystallisation from ethyl acetate/hexane yield the title compound: m.p. 102-104° C.; FAB-MS: (M+H)+=265; 1H NMR (DMSO-d6) 8.76 (d, 2H), 7.97 (d, 1H), 7.76 (m, 3H), 7.65 (m, 2H), 7.60 (s, 1H), 3.86 (s, 3H); Anal. calc. (C16H12N2O2) C 72.72%, H 4.58%, N 10.60%; found C 72.7%, H 4.8%, N 10.5%.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].C(OC(Cl)=O)C(C)C.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=O)[CH2:31]1.C(N)C>O1CCCC1>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([NH:3][CH2:1][CH3:2])=[O:38])[CH2:31]1
Reactant: CCN(CC)CC
Reactant: COCOc1ccc(C2CCCC(C(=O)O)C2)c(OCOC)c1
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Product: CCNC(=O)C1CCCC(c2ccc(OCOC)cc2OCOC)C1
Reaction time: 0.5 h

Procedure:
Triethylamine (11 μl) and isobutylchloroformate (10 μl) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanecarboxylic acid in anhydrous tetrahydrofuran (2 ml) under argon at 0° C. After 30 min, ethylamine (0.5 ml, 2M solution in tetrahydrofuran) was added. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (24 mg, quant.) and a mixture of diastereoisomers; m/z (ES+) 352 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[NH:19][C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:22]=1[O:30][CH3:31].[H-].[Na+].I[CH3:36]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:15])([F:16])[F:14])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:36])[C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:22]=1[O:30][CH3:31]
Reactant: CI
Reactant: COc1c(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of N-[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-2-methoxy-3-nitro-benzamide (obtained in a similar way as example I 4.1) (0.482 g, 0.806 mmole) in N,N-dimethylformamide (5 ml), magnetically stirred under argon atmosphere, at 25° C., in a round-bottomed flask, was added sodium hydride (60% suspension in oil, 0.039 g, 0.967 mmole). After the gas evolution had ceased, iodomethane (0.060 ml, 0.137 g, 0.967 mmole) was added and the mixture was stirred for 15 hours. The reaction mixture was quenched by addition of two drops of methanol, then concentrated under reduced pressure on a rotatory evaporator. The residue was placed on a silica gel column. Elution with a mixture of 15% ethyl acetate and 85% cyclohexane allowed the isolation of the title compound in quantitative yield (LC-MS analysis (method 6 described after the tables): retention time 1.22 min, observed M+H+ ion 611).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:5]=2[CH:4]=[CH:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>[Fe].C(O)(=O)C>[C:16]([NH:12][C:9]1[CH:10]=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([CH3:15])([CH3:1])[O:7][C:6]=2[CH:8]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)C=Cc2ccc([N+](=O)[O-])cc2O1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)OC(C)(C)C=C2
Temperature: 120 °C

Procedure:
2,2-Dimethyl-7-nitro-2H-benzo[b]pyran (40.00 g, the preparation of which is disclosed in British Pat. No. 1,548,222), glacial acetic acid (200 ml), acetic anhydride (120 ml) and electrolytic iron powder (88 g) were stirred and heated at 120° C. for 16 hours. Dilution with water, extraction via chloroform followed by washing of the organic layer with water and sodium bicarbonate solution, drying evaporation etc., gave a crude gum which was chromatographed on a silica gel column using ethyl acetate--60°-80° petroleum ether mixtures in a gradient elution technique. Fractions homogeneous by TLC were combined and recrystallised from 60°-80° petroleum ether to give 7-acetamido-2-,2-dimethyl-2H-benzo[b]pyran (5.27 g) as white needles of mp 80°-81° C.; nmr (CDCl3) 1.39 (6H), 2.12 (3H), 5.48 (1H, d, J=10), 6.21 (1H, d, J=10), 6.76-7.34 (3H, m), 8.95 (1H). Anal. Calcd for C13H15NO2 ; C, 71.87; H, 696; N, 6.45. Found: C, 72.00; H, 7.11; N, 6.23%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].C(OC(=O)C)(=[O:14])C.CO>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:9][OH:14])[C:3]=1[O:10][CH3:11]
Reactant: COc1c(Cl)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(Cl)ccnc1CO
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
30 g (173mmol) of 4-chloro-3-methoxy-2-methylpyridine N-oxide (cf. Example 1a) were dissolved in 100 ml of glacial acetic acid, after which 150 ml of acetic anhydride were added dropwise, at 80° C. and while stirring, and the mixture was then stirred at 110° C. for 2 h. The mixture was then cooled down to 80° C. and 200 ml of methanol were added dropwise; the mixture was then heated to boiling for 15 min. and, after having been cooled down, concentrated in vacuo; the residue was taken up in methanol and this mixture was allowed to flow into 300 ml of 1.5N methanolic sodium hydroxide solution, with this mixture then being stirred at 20° C. for 30 min. and concentrated in vacuo; the residue was taken up in water, and this mixture extracted three times with dichloromethane, with the organic phase being dried and concentrated; the residue was crystallized using petroleum ether. 23 g of product were obtained, m.p. 64°-66° C.
Reaction SMILES: CN[CH:3]([C:6]1C=C[CH:9]=[CH:8][C:7]=1C)[CH2:4]N.[CH2:13]([N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][N:17]=[C:16]1[NH:26][C:27]([O:29][CH3:30])=[O:28])C>>[CH3:13][N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][C:23]([CH2:4][CH2:3][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:22][CH:21]=2)[CH2:18][N:17]=[C:16]1[NH:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: CCN1C(NC(=O)OC)=NCC1c1ccccc1
Reactant: CNC(CN)c1ccccc1C
Product: CCCCCCc1ccc(C2CN=C(NC(=O)OC)N2C)cc1

Procedure:
Similarly, by following the same procedure of part A but respectively replacing the β-methylamino-β-(2-methylphenyl)-ethylamine with other β-alkylamino-β-phenylethylamino or β-alkylamino-(substituted phenyl)-ethylamino such as β-ethylamino-β-phenylethylamine β-isopropylamino-β-(substituted phenyl)-ethylamine, β-t-butylamino-β-(substituted phenyl)-ethylamine, β-isoamylamino-β-(substituted phenyl)-ethylamine, β-2'-t-butylethylamino-β-(substituted phenyl)-ethylamine, or β-n-hexylamino-β-(substituted phenyl)-ethylamine, the corresponding 1-alkyl-4,5-dihydro-5-(substituted phenyl)-2-methoxycarbonylaminoimidazole or 1-alkyl-4,5-dihydro-5-phenyl-2-methoxycarbonylaminoimidazoles such as 1-ethyl-4,5-dihydro-5-phenyl-2-methoxycarbonylaminoimidazole, m.p. 115°-116° C;
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.O>[CH3:18][S:17][C:4]1[N:3]=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(Nc2ccccc2)c(C=O)c(-c2ccccc2)n1
Yield: 69.8 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.07 mmol) in dioxane (21 mL) and H2O (7 mL) was added anhyd K2CO3 (443 mg, 3.21 mmol, 3 eq) followed by phenylboronic acid (196 mg, 1.6 mmol, 1.5 eq). The reaction mixture was degassed and tetrakis(triphenylphophine)palladium (61 mg, 0.053 mmol, 0.05 eq) was added. The reaction mixture was then heated under reflux for 24 h and cooled 23°, the layers were separated, EtOAc (50 mL), followed by H2O (10 mL), was added, the organic layer was separated, washed with satd aq NaCl, dried (MgSO4) and filtered. The yellow solution was then evaporated. Product was purified by column chromatography or by crystallization from 10 mL of isopropanol:H2O (2:1) to give 240 mg (70% yield) of pure 2-methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde. 1H-NMR δ 2.60 (s, 3H), 7.22 (m, 1H), 7.35-7.81 (m, 9H), 9.89 (s, 1H), 11.31 (br s, 1H), LC MS (m/e)=322 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Br:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:25])[CH:15]=[CH:16][C:17]1[N:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[S:20][CH:21]=1.CC(O)=O.OP(O)(O)=O>O>[Br:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[N:18]=[C:19]([CH:22]([CH3:23])[CH3:24])[S:20][CH:21]=4)[CH2:15][C:14](=[O:25])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)C=Cc3csc(C(C)C)n3)c(N)c2c1Br
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2oc3c(c2c1Br)NC(c1csc(C(C)C)n1)CC3=O
Temperature: 90 °C
Yield: 71.9 %

Procedure:
A mixture of 15A (2.8 g, 6.6 mmol), AcOH (10 mL) and H3PO4 (10 mL) was heated to 90° C. and reacted for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15B (2 g, 71.4% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=3)[O:6][CH:7]=1.[Na+].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>CN(C)C=O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][C:13]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=4)[O:6][CH:7]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: FC(F)(F)Oc1ccc2[nH]c(-c3nc(CCl)co3)cc2c1
Reactant: O=S([O-])c1ccc(Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cc1coc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)n1)c1ccc(Br)cc1

Procedure:
A solution of 2-(4-chloromethyl-oxazol-2-yl)-5-trifluoromethoxy-1H-indole (0.3 g, 0.95 mmol) and 4-bromo-benzenesulfinic acid sodium salt (0.92 g, 3.8 mmol) in N,N-dimethyl formamide (10 ml) was stirred for 16 h at 60° C. After cooling the mixture was poured on water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (ethyl acetate/iso-hexanes 1:1) yielded the title compound as tan solid. Yield 0.28 g (59%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=O)[CH:19]=2)[NH:14][C:13]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:57]([NH:59][CH2:60][CH3:61])[CH3:58]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([C:22](=[O:24])[N:59]([CH2:60][CH3:61])[CH2:57][CH3:58])([CH3:25])[CH3:26])[CH:19]=2)[NH:14][C:13]=1[C:27]1[CH:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[CH:32]=1)[CH3:11])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCC
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
To a stirred solution of (S)-2-[3-(2-tert-butoxycarbonylamino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid in dry methylene chloride at 0° C. is added 1-hydroxybenzotriazole followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the reagents allowed to mix for 1 hour. At this time diethylamine is added followed by 1.5 mL triehtylamine and the reaction stirred at room temperature. After completion, the mixture is concentrated in vacuo and purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH2:12]([NH2:14])[CH3:13].Cl.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:14][CH2:12][CH3:13])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1ccccc1Br
Reaction time: 24 h
Yield: 56 %

Procedure:
To a 20 mL vial were added a stirbar, 2-bromobenzene-1-sulfonyl chloride (0.995 g, 3.89 mmol), and THF (5 mL). The vial was then charged with EtNH2 in THF (5 mL, 2.0 M). The mixture was stirred for 24 hours before adding it to a separatory funnel containing 1 N HCl and EtOAc. The layers were mixed thoroughly and then separated. The organic layer was then washed with water followed by sat. NaHCO3, dried over MgSO4, filtered and concentrated to dryness to give the crude product. Subjecting the oil to FCC yielded the title compound (580 mg, 56%). 1H NMR (600 MHz, CDCl3) δ 8.17-8.10 (dd, J=7.8, 1.7, 1H), 7.75-7.69 (dd, J=7.8, 1.2, 1H), 7.48-7.43 (m, 1H), 7.43-7.37 (m, 1H), 5.16-4.91 (t, J=6.7, 1H), 3.06-2.87 (m, 2H), 1.19-1.00 (t, J=7.3, 3H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Br)C.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[CH:19]=[N:18]1>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:26]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[N:17]([CH3:16])[N:18]=[CH:19]4)[OH:27])=[CH:3][N:4]=2)[N:7]=1
Reactant: Cn1ncc2cc(C=O)ccc21
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (232.0 mg, 1.00 mmol) in 5 mL THF, was added ethylmagnesium bromide (1.50 mL, 1.50 mmol) at −10° C. After stirring at −10° C. for 1 hour, 1-methyl-1H-indazole-5-carbaldehyde (240.0 mg, 1.50 mmol) was added. The mixture was allowed to warm to room temperature slowly and stirred for additional 2 hours. The reaction was quenched with Sat. NH4Cl solution and concentrated under reduced pressure. The residue was diluted with water, and extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was washed with DCM to give the title compound as a white solid (230 mg, 70%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.21 (d, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.59 (d, 1H), 7.56 (s, 1H), 7.49 (d, 1H), 7.35 (d, 1H), 6.29 (d, 1H), 6.21 (d, 1H), 4.02 (s, 3H). LCMS (method A): [MH]+=314, tR=4.44 min