Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[C:14](F)=[CH:13][CH:12]=[CH:11][C:10]=2Cl)[N:3]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C([N-]C(C)C)(C)C.[Li+].C(OCC)(=O)C.CCCCCC>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Fc1cccc(Cl)c1-c1cc(Cl)nc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ccc(Nc2cc(-c3ccccc3)nc(Cl)n2)cc1

Procedure:
To 1 mmol of 2,4-dichloro-6-phenylpyrimidine (X) and 4-chloroaniline in 4 mL of dry THF was added 1 mmol (0.5 mL, 2M in THF/heptane/ethylbenzene) of lithium diisopropylamide. The reaction was followed by TLC (30% ethyl acetate/hexane). The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The mixture was purified by chromatography on silica gel with elution by 30% ethyl acetate/hexanes to afford 70 mg of 2-chloro-N-(4-chlorophenyl)-6-phenylpyrimidin-4-amine (XII) as an amorphous solid. ESI/MS 315.883, 317.915 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].S([O-])([O-])(=O)=O.[Ca+2].[CH2:19](Br)[CH:20]=[CH2:21]>CCOC(C)=O.[Ag]=O>[CH2:21]([O:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: N#Cc1ccc(C(=O)CO)cc1
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Product: C=CCOCC(=O)c1ccc(C#N)cc1
Reaction time: 2 h

Procedure:
To a solution of 2.7 g of 4-(2-hydroxyacetyl)benzonitrile in allyl bromide (15 mL) is added 10.2 g calcium sulfate and 6.7 g of silver oxide. The mixture is stirred under argon and in the dark for 2 hours. The mixture is diluted with AcOEt, filtered on celite, concentrated and purified on silica gel (ethyl acetate/cyclohexane: 0/100 to 50/50) to give the desired compound.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:29][NH2:30].O>C1COCC1.C(O)(=O)C>[CH3:13][C:4]1([CH3:14])[O:3][B:2]([OH:1])[C:6]2[CH:7]=[C:8]([CH2:11][NH:30][CH3:29])[CH:9]=[CH:10][C:5]1=2
Reactant: CN
Reactant: CC1(C)OB(O)c2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CNCc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (370 mg, 1.95 mmol) in THF (15 mL) at rt was added NaBH(OAc)3 (827 mg, 3.9 mmol) followed by methylamine alcoholic solution (30%, 1.0 mL). Several drops of acetic acid were added to the reaction mixture to pH of 6. The mixture was continued to stir at rt overnight. Water (20 mL) was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3,3-dimethyl-6-((methylamino)methyl)benzo[c][1,2]oxaborol-1(3H)-ol (300 mg; yield 75%) as a colorless oil. MS: m/z=206.1 (M+1, ESI+).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]([Si](C)(C)C)[S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17].O1CCCC1.[C:32]1([Mg]Br)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.OS(C(F)(F)F)(=O)=O.CCOCC>[O-:18][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:17])=[O:15].[C:1]1([S+:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=S(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
2.0 g of phenyl sulfoxide dissolved in 20 mL dichloromethane was cooled to -78° C. and then, 2.3 mL trimethylsilyl triflate was slowly added to the mixture for more than 5 minutes. The reacting mixture was stirred at the same temperature for 10 minutes and with the gradual increase of reaction temperature, stirred at 0° C. for 30 minutes. The solution was again cooled to -78° C. and 10 mL tetrahydrofuran solution of 2.0 M phenyl magnesium bromide was slowly added to the reacting solution. The reacting mixture was stirred at the same temperature for 30 minutes and further stirred at 0° C. for 30 minutes. The reaction was completed in 30 mL of 3% triflic acid aqueous solution. The reactant was diluted with 200 mL ether and extracted two times with 30 mL of triflic acid aqueous solution. The aqueous solution, so extracted, was further extracted three times with 30 mL chloroform. After collection of the organic layer, the solution was dried over anhydrous Na2SO4 and filtrated to remove the solvent. Thus, 1.9 g of triphenyl sulfonium triflate (yield: 50%) was obtained as a white solid.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CN1CCCC1=O.[F:38][C:39]1[CH:44]=[CH:43][C:42]([C@@H:45]([NH2:47])[CH3:46])=[CH:41][CH:40]=1.[OH-].[K+]>C(O)(=O)C>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([NH:47][C@H:45]([C:42]4[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=4)[CH3:46])=[N:23][CH:22]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1ncc(Cc2c[nH]c3ncc(Cl)cc23)cn1)c1ccc(F)cc1

Procedure:
In a microwave vial, 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (132, 12 mg, 0.026 mmol) was mixed with 600 μL of N-methylpyrrolidinone and (S)-1-(4-fluoro-phenyl)-ethylamine (133, 25.2 mg, 0.18 mmol). The reaction was irradiated at 200° C. for 40 minutes in microwave, then potassium hydroxide (500 μL, 4.00 M in water) was added and the reaction irradiated at 90° C. for 10 minutes in microwave. The reaction was neutralized with the addition of 120 μL of acetic acid, solvents were removed under vacuum, and the resulting material was dissolved in 400 μL of dimethyl sulfoxide for purification by HPLC. The desired compound was purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H′]′=381.9.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[F:22]>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(Br)c(F)c1
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Yield: 40 %

Procedure:
Title compound was prepared according to the procedure described in example G from N-Boc-piperazine and 4-bromo-3-fluorotoluene (40% yield, yellow oil, MS (m/e): 295.2 (M+H+, 100%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].CCN(C(C)C)C(C)C.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])=O>CN1C(=O)CCC1.Cl>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:8]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH:19]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: NC(=O)c1ccco1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Clc1ccc(-c2coc(-c3ccco3)n2)c(Cl)c1
Temperature: 130 °C
Yield: 55 %

Procedure:
To the solution of furan-2-carboxamide (56 mg, 0.5 mmol. 1 eq) and DIEA (0.13 mL, 0.75 mmo, 1.5 eq) in NMP (1 mL) was added 2-bromo-1-(2,4-dichlorophenyl)ethanone (0.6 mmol, 1.2 eq). Reaction mixture was heated at 130° C. for 15 h. The mixture was cooled down, diluted with 1 M HCl (30 mL) and extracted with EtOAc (40 mL). The organic layer was washed with 1 M HCl (30 mL), 5% solution of NaHCO3 (30 mL), brine (2×40 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by HPLC purification to provide desired 4-(2,4-Dichloro-phenyl)-2-furan-2-yl-oxazole in a yield of 55% and HPLC 99.9% purity. LC-MS [M+H]−280.4 (C13H7Cl2NO2+H, requires 281.11). 1H NMR (DMSO-d6) δ 8.84 (s, 1H), 8.13 (d, 1H, J=8.5), 8.01 (s, 1H), 7.78 (s, 1H), 7.58 (d, 1H, J=8.5), 7.29 (d, 1H, J=3.5), 6.77 (m, 1H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([F:21])=[CH:12][N:11]=1.C(N(CC)CC)C>ClCCl.CN(C1C=CC=CN=1)C>[Si:1]([O:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]1[C:13]([F:21])=[CH:12][N:11]=[C:10]([Cl:9])[N:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCCNc1nc(Cl)ncc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of t-butyldimethylsilyl chloride (1.63 g, 10.70 mmol) in dichloromethane (48.63 mL) was added 3-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-1-propanol (Example 80, 2.0 g, 9.73 mmol), followed by triethylamine (1.49 mL, 10.70 mmol) and dimethylaminopyridine (0.02 g, 0.19 mmol). The resulting cloudy mixture was stirred at rt for 18 h and then diluted with dichloromethane (80 mL). The mixture was washed with water (50 mL), dried over magnesium sulfate, and concentrated. The product was purified by column chromatography (67% hexanes in EtOAc) to give the title compound as a white solid (2.68 g, 86%). 1H NMR (300 MHz, CD2Cl2) δ 7.78 (d, 1H), 3.64-3.59 (m, 2H), 3.44-3.41(m, 2H), 1.82-1.73 (m, 2H), 0.84 (s, 9H), 0.001 (s, 6H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH:14]([S:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[N:13]([CH:25]([C:39]([CH3:41])=[CH2:40])[C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])[C:12]2=[O:42])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(Cl)[Cl:44].O>C(OCCOCC)(=O)C.C(Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH:14]([S:15][S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[N:13]([CH:25]([C:39]([CH2:41][Cl:44])=[CH2:40])[C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])[C:12]2=[O:42])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)Cc2ccccc2)C1SS(=O)(=O)c1ccccc1
Reactant: ClOCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCCOC(C)=O
Product: C=C(CCl)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)Cc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 90 %

Procedure:
A 1.0 g quantity of p-nitrobenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 25 ml of ethoxyethyl acetate. The solution was cooled in an ice bath with stirring. To the mixture was added dropwise over 20 minutes 6.l ml of a 0.285M solution of Cl2O in carbon tetrachloride. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 955 mg of p-nitrobenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 90% yield.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH3:9])[CH3:7].CN([CH:20]=[O:21])C>>[CH2:6]([N:8]([C:10]1[CH:11]=[C:12]([OH:16])[C:13](=[CH:14][CH:15]=1)[CH:20]=[O:21])[CH3:9])[CH3:7]
Reactant: CCN(C)c1cccc(O)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(C)c1ccc(C=O)c(O)c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
6.14 g (0.066 mol) of phosphorus oxychloride are cautiously added to 19 ml of dry DMF at −5° C. within a period of 5 minutes, during the course of which the temperature of the reaction solution should not exceed 10° C. Subsequently, a solution of 9.9 g (0.066 mol) of 3-(N-ethyl-N-methylamino)phenol in 14 ml of dry DMF is added thereto within a period of 10 minutes, during the course of which the temperature of the reaction solution should not exceed 20° C. When the addition is complete, the reaction solution is heated for 2 hours at 90° C. and then immediately poured onto 100 g of ice. The crude mixture is stirred for 30 minutes. The reaction solution is extracted three times with 100 ml of chloroform. The combined organic phases are concentrated under a high vacuum. The oily residue which remains is purified by column chromatography on silica gel (eluant n-hexanelchloroform 95:5). Yield: 5.8 g (26%), colourless solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=2[Cl:34])[CH2:13][CH2:12][CH2:11][CH2:10]1.CN(C=O)C>O>[Br:1][C:21]1[C:22](=[O:25])[NH:23][C:24]2[C:19]([C:20]=1[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34])=[CH:18][CH:17]=[C:16]([O:35][CH3:36])[C:15]=2[O:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OC1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)c(Br)c(=O)[nH]c2c1OC1CCCC1
Reaction time: 4 h

Procedure:
N-Bromosuccinimide (0.104 g, 0.585 mmol) was added to a solution of 4-(3,5-dichloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (0.246 g, 0.585 mmol, Example 1) and anhydrous DMF (3 mL) at 0° C. After 4 h at 0° C., the mixture was poured into water, and the precipitate was filtered. Saturated sodium thiosulfate solution (1 mL) was added to a solution of the filter cake and methanol (5 mL). After the dibromo intermediate was consumed by LCMS, the mixture was diluted with water and extracted with EtOAc. The organic extract was dried, filtered, and concentrated to give 3-bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.88 (br s, 1H), 8.42 (s, 2H), 7.62 (d, 1H), 7.04 (d, 1H), 4.98 (m, 1H), 3.89 (s, 3H), 1.84-1.51 (m, 8H); MS (ESI): 497.8.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][C:21]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[C:24]1([C:21]2([C:30]3[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=3)[CH2:20][CH2:19][NH:18][CH2:23][CH2:22]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2ccccc2)(c2ccc(O)cc2)CC1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Oc1ccc(C2(c3ccccc3)CCNCC2)cc1

Procedure:
4-(4-Hydroxy-phenyl)-4-phenyl-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (270 mg, 0.57 mmol) was treated with a solution of piperidine in DMF (20%, 5 mL) for 2 h. TLC indicated full conversion of the starting material. Concentrated in vacuo to a solid. Worked-up by flash chromatography. LC-MS indicated formation of a complex mixture. The title product was isolated in an analytical amount. LC/MS purity (UV/MS): 90/90%, Rt 3.15 min. M+1: 254
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:58]=[CH:57][C:6]([CH2:7][N:8]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C@H:32]([N:34]4[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][C@H:35]4[CH3:47])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.ClCCl.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:76][S:77](Cl)(=[O:79])=[O:78]>>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=4)[CH2:7][C:6]4[CH:57]=[CH:58][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=3)=[CH:17][C:18]([C@H:32]([N:34]3[CH2:39][CH2:38][N:37]([S:77]([CH3:76])(=[O:79])=[O:78])[CH2:36][C@H:35]3[CH3:47])[CH3:33])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)C[C@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 1 h
Yield: 77 %

Procedure:
To a 100 mL round-bottomed flask was added (R)-tert-butyl 4-((R)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.200 g, 0.252 mmol), dichloromethane (5 mL, 78 mmol), trifluoroacetic acid (5 mL, 67.3 mmol). The solution was stirred for 1 hr. The solution was concentrated down and the residue was dissolved in DCM and slowly washed with NaHCO3, to get rid off the TFA. The DCM solution was dried over sodium sulfate, filtered and concentrated. The residue was dried under a high vacuum overnight. The residue was dissolved in DCM, cooled down in a dry ice/IPA cooling bath and treated with triethylamine (0.349 mL, 2.52 mmol), and methanesulfonyl chloride (0.098 mL, 1.260 mmol).The solution was stirred at −50° C. for 30 minutes. The solvent was removed under a vacuum and the crude product was washed with water (30 mL), stirred, and sonicated. The resulting suspension was collected, washed with water, and dried in a vacuum oven overnight to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((R)-1-((R)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.150 g, 0.194 mmol, 77% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:36][C:37](=[O:49])[C:38]([NH:41]C(=O)OC(C)(C)C)([CH3:40])[CH3:39])[C:11]([N:13]1[CH2:35][CH2:34][CH2:33][C:15]2([C:19](=[O:20])[N:18]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:17][CH:16]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:41][C:38]([CH3:40])([CH3:39])[C:37]([NH:36][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([N:13]1[CH2:35][CH2:34][CH2:33][C:15]2([C:19](=[O:20])[N:18]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:17][CH:16]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:14]1)=[O:12])=[O:49]
Reactant: CN(C)C(=O)CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)C2)C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A diasteromeric mixture of tert-butyl 1-((2R)-3-(benzyloxy)-1-(2-(2-(dimethylamino)-2-oxoethyl)-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (386 mg; 0.569 mmol) was solubilised in dichloromethane (3 ml) at room temperature. Trifluoroacetic acid (439 ul; 5.69 mmol) was added and mixture stirred at RT for 72 hours. The solvent was removed in vacuo and the crude product was dissolved in methanol and loaded onto a pre-wetted 10 g SCX-2 cartridge. Methanol (50 ml) was passed through the cartridge and the product was eluted with 2M NH3 in methanol. Concentration of the ammonia fraction afforded the title compound as a diastereomeric mixture. Diastereomers were separated by chiral SFC, collecting the second peak.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:34]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH2:19][Br:34])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(Cl)cc1Cl)c1oc2cc(Br)ccc2c1CBr
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a stirred solution of (6-Bromo-3-methyl-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone (4.0 g, 10.4 mmol) in carbon tetrachloride (40 mL) was added 2,2′-azobisisobutyronitrile (AIBN) (171 mg, 1.04 mmol) and N-bromosuccinimide (1.95 g, 10.9 mmol). The reaction mixture was heated at reflux for 6 h, and upon cooling to rt, the resulting precipitate was removed by filtration and the filtrate was concentrated. The crude residue was purified by column chromatography (10% ethyl acetate in hexanes) to afford the desired product (3.30 g, 65% yield) as a white solid. Rf=0.68 (10% EtOAc in hexanes). 1H-NMR (acetone): δ 7.98 (d, 1H), 7.91 (s, 1H), 7.74 (m, 2H), 7.64 (td, 2H), 5.16 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:21][CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:20])[CH3:19]>CN(C)C=O>[C:18]([O:21][CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:20])[CH3:19]
Reactant: Oc1cccc2cccnc12
Reactant: CCCCC(OC(C)=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(OC(C)=O)c1cccc(COc2cccc3cccnc23)c1
Reaction time: 8 h
Yield: 94 %

Procedure:
1.45 g of 8-hydroxyquinoline and 1.38 g of ground anhydrous potassium carbonate are stirred in 20 ml of dimethylformamide at 25° C. for 2 hours. 2.99 g of 1-(3-bromomethylphenyl)pentyl acetate, dissolved in 10 ml of dimethylformamide, are then added dropwise and the reaction mixture is stirred overnight. The solvent is distilled off in vacuo, the residue is partitioned between water/ethyl acetate and the organic phase is dried over Na2SO4 and then concentrated in vacuo. The residue is chromatographed over silica gel 60 (Merck 9385) with CH2Cl2 /methanol 100:5 (Rf =0.45). An oil is obtained in a yield of 94% of theory.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[S:8][C:7]([C:9]([F:12])([F:11])[F:10])=[N:6][CH:5]=1.[N:13]#[C:14][NH2:15].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>ClCCl>[CH3:1][S:2]([CH2:3][C:4]1[S:8][C:7]([C:9]([F:12])([F:10])[F:11])=[N:6][CH:5]=1)=[N:15][C:14]#[N:13]
Reactant: CSCc1cnc(C(F)(F)F)s1
Reactant: N#CN
Agent: C/S(Cc1cnc(C(F)(F)F)s1)=N\C#N
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(Cc1cnc(C(F)(F)F)s1)=NC#N
Temperature: 25 °C

Procedure:
A solution of 5-[(methylthio)methyl]-2-(trifluoromethyl)-1,3-thiazole (140 mg, 0.62 mmol) and cyanamide (35 mg, 0.83 mmol) in 6 mL of dichloromethane was cooled to 0° C. and treated with iodobenzene diacetate (860 mg, 2.59 mmol). A clear yellow solution was obtained. The mixture was allowed to warm to room temperature over an hour and then the solvent removed under reduced pressure and the residue further purified by flash column chromatography on silica gel using a 50% mixture of acetone and petroleum ether as the eluant. The solvents were removed under reduced pressure to yield 130 mg (83%) of (1E)-methyl{[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}-λ4-sulfanylidenecyanamide as a pale yellow syrup: 1H NMR (CDCl3) δ 8.00 (s, 1H), 4.60 (s, 2H), 2.85 (s, 3H); LCMS (ESI) m/z 254 (M+H).