Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([C@H:11]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:27][CH3:28])[NH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])C.C1COCC1>O>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:18]([C@H:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:5]([C:4]([OH:29])=[O:3])[C:6]([OH:8])=[O:7])=[CH:19][NH:20]2
Reactant: CCOC(=O)C(C(=O)OCC)[C@@H](c1ccccc1)c1c[nH]c2cccc(OC)c12
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2[nH]cc([C@H](c3ccccc3)C(C(=O)O)C(=O)O)c12
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A 200 L reactor under N2 atmosphere was loaded with 2-[(S)-(4-methoxy-1H-indol-3-yl)-phenyl-methyl]-malonic acid diethyl ester (12 kg) and THF (53 kg). A solution of EDTA tetrasodium decahydrate (8 kg) in 20 L of cold tap water was separately prepared with shaking to dissolve the solid. One half of the EDTA tetrasodium decahydrate solution was added to the reactor, and the mixture was agitated for 10 minutes. The layers were allowed to separate over 20 minutes, and the aqueous phase was drained. The remaining EDTA tetrasodium decahydrate solution was added to the reactor and the mixture was agitated for 10 minutes before allowing the phases to separate over 20 minutes. The aqueous phase was drained, and saturated aqueous NaCl solution (14.4 kg) was added to the reactor. The mixture was agitated for five minutes, after which the phases were allowed to separate over 20 minutes. The aqueous phase was drained from the reactor, and cold tap water (55 L) was added to the reactor and agitation. KOH (50 wt %, 27.2 kg) was added, and the reactor was configured for reflux. The mixture was heated at 60-65 degrees C. (jacket temperature) overnight. A 10 mL aliquot of the reaction mixture was taken, and HPLC showed the amount of starting material and monoester were <2%. The reaction mixture was then cooled to 22 degrees C. and toluene (52 kg) was added, the contents were agitated for five minutes and then the layers were allowed to separate. The aqueous product layer was separated, combined with isopropanol (37.9 kg), and then acidified with concentrated HCl (41.4 kg). Cooling and stirring were applied during addition to maintain the internal reactor temperature below 30 degrees C. The product slowly precipitated out of solution. Once a thick slurry was formed, cold tap water (72 L) was added, the reactor jacket temperature was set at 5 degrees C., and the slurry was aged one hour. The mixture was filtered on a Rosenmund filter and collected solid was washed twice with cold tap water (50 L). The product was dried in a vacuum oven at 70 degrees C. with N2 bleed to afford 2-[(S)-(4-Methoxy-1H-indol-3-yl)-phenyl-methyl]-malonic acid as an off-white crystalline solid (8.772 kg, 86% yield). 1H mm (CDCl3): 3.80 (s, 3H), 4.28 (d, 2H, J=12.4 Hz), 5.43 (d, 2H, J=12.4 Hz), 6.35 (dd, 1H, J=1.08 Hz, J=7.41), 6.86-6.96 (m, 2H), 7.07 (m, 1H), 7.17 (m, 3H), 7.37 (m, 2H). Mp=155-157° C.
Reaction SMILES: [C:1]12([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]1)[C:9]1[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:3][CH2:2]2.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[Br:31]Br>C(Cl)(Cl)Cl>[Br:31][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]2([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]2)[CH2:2]1
Reactant: O=C1NC(=O)C2(CCc3ccccc32)N1
Reactant: BrBr
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C2(CC(Br)c3ccccc32)N1
Temperature: 25 °C
Yield: 29 %

Procedure:
Spiro[imidazolidine-4,1'-indan]2,5-dione, (C.A. reg. no. 6252-98-8) (6.06 g, 30 mmol) was combined with 7.95 ml (30 mmol) bis(trimethylsilyl)trifluoroacetamide and 4.8 g (30 mmol) bromine in 50 ml chloroform and heated to reflux. Decolorization occurred during the 18 hour reaction. The reaction mixture was cooled to 25° C. and after 45 minutes stirring a solid which had crystallized was collected by filtration to give 2.45 g (29%) of crude 3'-bromo-spiro[imidazolidine-4,1'-indan]2,5-dione. The chloroform mother liquors deposited an additional 2.18 g (26% yield), mp 58°-65° C. Two grams (7.1 mmol) of material, mp 58°-65° C., was combined with 25 ml water to give a slurry. Following stirring for 22 hours the resultant solid was collected by filtration and dried to give 0.52 g (33% yield) of the title compound: mp 260°-263° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:23])([CH3:22])[S:20](=[O:25])(=[O:24])[CH2:19][C@@:18]([CH2:36][F:37])([C:26]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=2[F:35])[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:48](Br)[CH:49]=[CH2:50]>C1COCC1>[CH2:50]([CH:19]1[C@@:18]([CH2:36][F:37])([C:26]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=2[F:35])[N:17]=[C:16]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])[C:21]([CH3:23])([CH3:22])[S:20]1(=[O:25])=[O:24])[CH:49]=[CH2:48]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1[C@@](CF)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S)-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (2.79 g, 5.10 mmol) in THF (30 mL) at −78° C. under a nitrogen atmosphere was added lithium bis(trimethylsilyl)amide, (7.65 mL, 7.65 mmol, 1M in THF) dropwise. The reaction mixture was stirred at −78° C. for 1 h and then allyl bromide (1.77 mL, 20.41 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2 h and quenched by the addition of satd. aqueous NH4Cl at −78° C., then allowed to warm to RT and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude mixture was purified by silica gel chromatography on a 80 g RediSep Gold column using a 0-30% EtOAc/hexanes gradient to afford tert-butyl N-[(3S)-2-allyl-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (2.0 g, 67%) as an off-white solid and a mixture of cis and trans (2:1) isomers. LC/MS (ESI+) m/z=610 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][N:26]([CH3:31])[S:27](Cl)(=[O:29])=[O:28]>O1CCCC1>[CH3:25][N:26]([CH3:31])[S:27]([NH:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:29])=[O:28]
Reactant: CCOC(=O)C1=Cc2cccc(N)c2OCC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cccc(NS(=O)(=O)N(C)C)c2OCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 9-amino-2,3-dihydro-1-benzoxepin-4-carboxylate (1.0 g) and triethylamine (4.18 ml) in tetrahydrofuran (10 ml) was added dimethylsulfamoyl chloride (2.30 ml) at 5° C. The reaction mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 2,3-dihydro-9-dimethylsulfamoylamino-1-benzoxepin-4-carboxylate (0.89 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C@@H:9]([N:16](CS)[C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]3[N:31]4[CH2:32][CH2:33][NH:34][CH2:35][C:30]4=[N:29][N:28]=3)(=[O:25])=[O:24])=[CH:19][C:18]=2[S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])C2C=CC=CC=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([N:34]2[CH2:33][CH2:32][N:31]3[C:27]([NH:26][S:23]([C:20]4[CH:21]=[CH:22][C:17]([NH:16][C@@H:9]([CH2:39][S:36][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=5)[CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[C:18]([S:36]([C:39]([F:40])([F:41])[F:42])(=[O:38])=[O:37])[CH:19]=4)(=[O:25])=[O:24])=[N:28][N:29]=[C:30]3[CH2:35]2)[CH2:54][CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=S(=O)(Nc1nnc2n1CCNC2)c1ccc(N(CS)[C@H](CCN2CCOCC2)c2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCn3c(nnc3NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)C2)CC1
Reaction time: 0.17 h
Yield: 204.5 %

Procedure:
To a vial containing 4-((R)-3-morpholin-4-yl-1-phenyl-sulfanylmethyl-propylamino)-N-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-trifluoromethanesulfonyl-benzenesulfonamide (50 mg, 0.074 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (14.74 mg, 0.074 mmol) was added methanol (2 mL) under nitrogen. The reaction mixture was stirred in an ice bath for 10 minutes, and then acetic acid (0.424 μL, 7.40 μmol) was added. The reaction mixture was stirred for another 30 minutes. Sodium cyanoborohydride (41.85 mg, 0.666 mmol) was then added, and the reaction was stirred at ambient temperature for 72 hours. The reaction mixture was concentrated, filtered and purified via flash chromatography on silica gel (10-50% 7N NH3 in methanol in CH2Cl2) to afford 4-{3-[4-((R)-3-Morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonylamino]-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl}-piperidine-1-carboxylic acid tert-butyl ester (65 mg, 100% yield). MS [m/z; (M+1)+]: 859.7
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:17][NH2:18]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:17][NH2:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reaction time: 72 h
Yield: 93.5 %

Procedure:
1-tert-Butoxycarbonylpiperid-4-one (6.18 g, 31 mmol) was dissolved in a 2.0 M solution of methylamine in methanol (56 mL, 112 mmol). This solution was added to 10% palladium on carbon (wet, 1.3 g) and the mixture placed under an atmosphere of hydrogen for 72 h. The reaction mixture was then purged with nitrogen and filtered through a pad of Celite, which was then washed with methanol. The resulting hazy filtrate was filtered through a 0.2 μm filter and then concentrated in vacuo to afford the title intermediate (6.16 g, 29 mmol, 93.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:25][OH:26]>C1COCC1>[OH:26][NH:25][CH:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: O=S(=O)(/C=C/c1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: NO
Solvent: C1CCOC1
Product: O=S(=O)(CC(NO)c1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of 1-(4-fluorophenyl)-4-(trans-β-styrenesulfonyl)piperazine (620 mg, 1.79 mmol) in THF (20 ml) was added hydroxylamine (3 ml, 50% aqueous solution). The mixture was stirred for 18 hours. The solvent was evaporated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried on MgSO4 to give 1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine (730 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.BrC(OC)=O.[CH3:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[Na+].[Cl-]>O1CCCC1.N1C=CC=CC=1>[CH3:24][N:25]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[O:3]
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: CNC1CCCCC1
Agent: COC(=O)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 Grams of 6-(3-carboxy)propoxycarbostyril and 1.8 ml of pyridine are added to 50 ml of tetrahydrofuran, and then 1.0 ml of methyl bromoformate is added dropwise to said solution under external ice cooling and agitation while maintaining the internal temperature at 5°-15° C. after addition, the mixture is further agitated at room temperature for 1 hour and then added with 1.2 g of N-methylcyclohexylamine, followed by additional 3-hour agitation. The reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The obtained crude crystals are recrystallized from chloroform-ethanol to obtain 2.3 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals with m.p. of 184.5°-186° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[K+].[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.C(Br)C1C=CC=CC=1>CCOCC.O>[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: Cc1ccccc1CBr
Agent: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2=O
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
9-amino-3,4-dihydroacridin-1(2H)-one (7.63 g) was suspended in 75 ml of dimethylsufoxide and 5 g of pulverized 85% potassium hydroxide was added. After 45 minutes a homogeneous solution was obtained to which was added 7.0 g of 2-methylbenzyl bromide. The reaction mixture was stirred for 30 minutes and then additional 2.0 g of the benzyl bromide was added. After 60 more minutes 300 ml of water and 30 ml of ether were added to the reaction. The precipitated product was filtered off and washed with additional ether, then flushed over a short magnesium silicate column with ethyl acetate. After evaporating the solvent, the product was again washed with cold ether to give 7.21 g of product.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.CCN(C(C)C)C(C)C.[C:30]1([C:40](Cl)=[O:41])[C:39]2[C:34](=CC=CC=2)[CH:33]=[CH:32][CH:31]=1>ClCCl>[C:40]([N:3]1[CH2:4][CH2:5][C:6]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:2]1)(=[O:41])[C:30]1[CH:39]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step a): To a stirred solution of Intermediate 1 (ethyl (1,2,3,4-tetrahydro-pyrido[4,3b]indol-5-yl)-acetate hydrochloride, 25.0 mg, 0.085 mmol) and DIEA (73 μl, 0.425 mmol) in dichloromethane (0.5 ml) is added naphthoyl chloride (15 mg, 0.11 mmol). The resulting yellow solution was kept stirring at rt for 1 h and then is quenched by adding saturated aqueous NaHCO3 solution (2 ml). The organic layer is separated and washed with water (2 ml). After removal of the solvent, crude ethyl (2-benzoyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate is obtained pure as a yellow glassy solid: tR (LC-2) 2.20 min; ESI-MS (positive ion): m/z 386.31 [M+Na]+ (calcd 362.42 for C22H22N2O3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH2:19].[OH-].[Na+].Cl>O.C(O)C>[CH3:18][N:19]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]1[CH3:16]
Reactant: CN
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1C
Temperature: 25 °C
Reaction time: 144 h
Yield: 62.9 %

Procedure:
3-Benzyloxy-2-methyl-4-pyrone (4.8 g) and methylamine hydrochloride (1.56 g) are dissolved in water (200 ml) and ethanol (100 ml) containing sodium hydroxide (2 g) is added. The mixture is stirred at room temperature for 6 days and is then acidified with concentrated hydrochloric acid to pH 2, and evaporated to dryness. The resulting colourless solid is washed with water and extracted into chloroform (2×50 ml). The chloroform extracts are combined, dried over magnesium sulphate, and evaporated to yield 1,2-dimethyl-3-benzyloxypyrid-4-one (3.2 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]([CH3:18])[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.[CH3:19][C:20]1[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:19])[N:25]=2)=[O:8])=[CH:4][C:3]=1[N:11]([CH3:18])[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1
Reactant: Cc1cccc(N)n1
Reactant: CN(c1cncnc1)c1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)c2ccc(F)c(N(C)c3cncnc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
Compound 20 (300 mg, 1.15 mmol, 1.00 eq) was dissolved in Dioxane (5.0 mL), and 1N LiOH (5.0 mL) was added. The reaction was stirred at rt for 45 minutes. The reaction was quenched with 1N HCl (5.0 mL) and extracted (3×) with ether. The combined organics were dried (MgSO4), filtered, and concentrated in vacuo to afford 200 mg (70%) of crude 4-fluoro-3-(methyl(pyrimidin-5-yl)amino)benzoic acid as a yellow solid. The product was confirmed by LCMS (>90% @ 220 nm and 254 nm) and carried forward without purification. 4-fluoro-3-(methyl(pyrimidin-5-yl)amino)benzoic acid (30 mg, 0.12 mmol, 1.0 eq), 6-methylpyridin-2-amine (15 mg, 0.14 mmol, 1.2 eq), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol, 2.0 eq), and N,N-Diisopropylethylamine (85 mg, 0.66 mmol, 5.5 eq) were dissolved in DMF (0.98 mL) and stirred at rt overnight. The reaction was quenched with water, and the layers were separated via phase separation. The organic layer was dried on air concentrator and purified by mass directed preparatory HPLC to afford 15 mg (36%) of the title compound as a mono-TFA salt: 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.65 (s, 1H), 8.28 (s, 2H), 8.14 (dd, J=7.7, 2.2 Hz, 1H), 8.00-7.94 (m, 2H), 7.75 (t, J=7.9 Hz, 1H), 7.48 (dd, J=10.7, 8.7 Hz, 1H), 7.05 (dd, J=7.4, 1H), 3.39 (s, 3H), 2.45 (s, 3H); ES-MS [M+1]+:338.1.
Reaction SMILES: Br.Br.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:5].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH3:5][N:4]([CH2:6][C:7]1([C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:3]
Reactant: CN(C)CC1NCCc2c(O)cccc21
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)CC1(C(=O)Cc2ccc(Cl)c(Cl)c2)NCCc2c(O)cccc21

Procedure:
Prepared as Ex. No. 5, from 4.5 g (12.2 mmoles) of 1-dimethylaminomethyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 3.3 g (16.10 mmoles) of 3,4-dichlorophenylacetic acid, 4.3 ml (30.60 mmoles) of triethylamine and 5.1 g (24.75 mmoles) of dicyclohexylcarbodiimide in 120 ml of dry chloroform.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[F:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[CH:39][C:40]=1[F:41]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:42]([C:37]2[CH:38]=[CH:39][C:40]([F:41])=[C:35]([F:34])[CH:36]=2)(=[O:44])=[O:43])[C:6]=1[CH3:14]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(F)c2)c2ncccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.8 g, 3.92 mmol) in DMF (3 mL) is added BEMP (1.81 mL, 6.27 mmol). After 1 hour, the reaction mixture is cooled to 0° C. and a solution of 3,4-difluoro-benzenesulfonyl chloride (0.83 mL, 6.27 mmol) in DMF (3 mL) is added. The reaction mixture is allowed to warm to room temperature, stirred at room temperature overnight, then concentrated under reduced pressure to a minimum volume. The residue is loaded on a pre-packed Isolute™ silica column and eluted using a gradient eluent from 100% iso-hexane to 30% EtOAc in iso-hexane to afford [1-(3,4-difluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+=381.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([CH:18]([OH:20])[CH3:19])[CH:15]=[C:14]([CH3:21])[N:13]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([CH:18]([O:20][S:32]([CH3:31])(=[O:34])=[O:33])[CH3:19])[CH:15]=[C:14]([CH3:21])[N:13]=1
Reactant: CCN(c1nc(C)cc(C(C)O)n1)c1ccc(C(C)C)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(c1nc(C)cc(C(C)OS(C)(=O)=O)n1)c1ccc(C(C)C)cc1Br
Temperature: 0 °C
Yield: 81.2 %

Procedure:
A mixture of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-hydroxyethyl)-6-methylpyrimidinamine (1.1 g, 2.7 mmol), triethylamine (1.5 mL, 11 mmol) and dichloromethane (15 mL) was stirred at 0° C. under a nitrogen atmosphere. Methanesulfonylchloride (364 mg, 3.2 mmol) was added dropwise and the reaction mixture was then stirred for 1.5 h. The resulting turbid solution was washed successively with an ice-cold 1N HCl solution, a saturated NaHCO3 solution and a saturated NaCl solution. Drying over MgSO4, filtration and removal of solvent in vacuo gave N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-methanesulfonyloxyethyl)-6-methylpyrimidinamine as a clear colorless oil (1.0 g); NMR (CDCl3, 300 MHz): 7.5 (d, 1H, J=1), 7.25-7.1 (m, 2H), 6.55 (s, 1H), 4.3-4.05 (m, 1H), 3.85-3.6 (m, 1H), 3.0-2.5 (m, 4H), 2.5-2.05 (br m, 3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H, J=8); CI-MS: 456, 458 (M+H).