Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:13])[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:14][CH3:15].O[C:17]1[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=2[N:20]=[N:21][N:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=3[N:20]=[N:21][N:22]=2)[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: COc1cc([C@H](N)CN(C)C)ccc1Cl
Product: COc1cc([C@@H](CN(C)C)Nc2nnnc3c(C(N)=O)cccc23)ccc1Cl

Procedure:
Compound 11 was prepared following general synthetic scheme 7 wherein (S)-1-(4-chloro-3-methoxyphenyl)-N2,N2-dimethylethane-1,2-diamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [401 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 9.27 (s, 1H), 9.09 (d, 1H), 8.58 (dd, 2H), 8.08 (t, 2H), 7.44 (d, 2H), 7.18 (dd, 1H), 6.26 (t, 1H), 3.89 (s, 3H), 3.83-3.76 (m, 1H), 3.62-3.57 (m, 1H), 2.92 (d, 6H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1>CC(N(C)C)=O>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([N:15]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:10])[CH2:16]2)=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: C[C@@H]1CNCCN1
Solvent: CC(=O)N(C)C
Product: Cc1cc(Br)cnc1N1CCN[C@H](C)C1

Procedure:
Heat a solution of 2,5-dibromo-3-methyl-pyridine (Chontech Inc., Waterford, Conn.) (2.0 g, 7.97 mmol), (R)-2-methyl-piperazine (ChemPacific Corp., Baltimore, Md.; 3.2 g, 31.9 mmol) in DMA at 130° C. for 16 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([N:33]3[CH2:34][CH2:35][N:30]([C:28]4[S:27][N:26]=[C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:29]=4)[CH2:31][CH2:32]3)=[O:18])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(Nc1ccc2[nH]ccc2c1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2[nH]ccc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 23.9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl 1H-indol-5-ylcarbamate (227 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours, and then stirred at 70° C. for 18 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 71.3 mg (23.9%) of the desired product as a solid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=CC(=O)c1c[nH]c2ccccc12

Procedure:
A mixture of 3.18 g of 3-acetylindole and 5.17 ml. (4.36 g) of tert-butoxybis(dimethylamino)methane was heated on a steam bath for 4 hours. The cooled reaction mixture was triturated with n-hexanes and gave a semi-solid. The solvent was removed in vacuo and the material was triturated with dichloromethane giving 3.08 g of the desired compound as a tan crystalline solid, mp 239°-245° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Mg]Br.Br[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.[Mg].Br[C:16]1[S:20][C:19]([C:21]2[S:22][C:23](Br)=[CH:24][CH:25]=2)=[CH:18][CH:17]=1>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:11]1[S:10][C:9]([C:16]2[S:20][C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(-c2ccc(Br)s2)s1
Reactant: Br[Mg]c1cccs1
Reactant: Brc1cccs1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: c1csc(-c2ccc(-c3ccc(-c4cccs4)s3)s2)c1
Temperature: 0 °C

Procedure:
Thienylmagnesiumbromide, made from 13 gr (80 mmol) of T-Br and 2.43 gr (100 mmol) of magnesium in 50 ml of anhydrous ether, was added to a solution of 11.71 gr (36 mmol) of 5,5'-dibromo-2,2'-bithiophene and 100 mg (0.18 mmol) of Ni(dppp)Cl2 in 150 ml of ether. The reaction mixture was refluxed for 4 hours and subsequently poured on an ice/dilute hydrochloric acid mixture. The product was extracted with toluene and recrystallized from a mixture of toluene and ethanol. The resulting orange powder was dried in vacuo. Yield: 6,75 gr (20 mmol, 57%) of T4. M.p.: 203° C. (litt: 212). Elemental analysis: found% (theory%) C 56.49 (58.15), H 3.05 (3.05), S 37.0 (38.8). 1H-NMR (300 MHz, CDCl3): ∂=7.23 (2H, dd, J=5.0 and 1.0 Hz), ∂=7.19 (2H, dd, J=3.7 and 1.0 Hz), ∂=7.08 (4H, s), ∂=7.03 (2H, dd, J=5.0 and 3.7 Hz). M/z: 330 D (M.W.=330).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:7]#[N:8])([O-])=O.[Cl:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[N:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([O:22][C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[C:7]#[N:8])[CH:19]=[N:20][CH:21]=1
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: Oc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2cncc(Cl)c2)cc([N+](=O)[O-])c1
Yield: 0 %

Procedure:
A solution of 3,5-dinitro-benzonitrile (5 g, 25.9 mol), 5-chloro-pyridin-3-ol (3.35 g, 25.9 mol) and K2CO3 (7.2 g, 52 mol) in DMF (150 mL) was heated at 100° C. overnight. The mixture was concentrated in vacuo and the residue was poured into water. The aqueous layer was extracted with ethyl acetate (3×150 mL) and the combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to afford 3-(5-chloro-pyridin-3-yloxy)-5-nitro-benzonitrile (3.1 g, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 7.87 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:29](=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:29](=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (112 mg, 0.459 mmol, Compound C of Example 22) in methylene chloride (4 mL) at 0° C. was added 96 μL (0.55 mmol) of diisopropylethylamine followed by 61 μL (0.48 mmol) of ethyl 3-chloro-3-oxopropanoate. The reaction was stirred at 0° C. for 1 h and was then quenched with 10 mL of saturate NaHCO3 solution. The aqueous layer was extracted with chloroform (3×15 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a yellow oil that solidified on standing (180 mg). 1H NMR (CDCl3) δ 9.45 (br s, 1H), 7.89 (s, 1H), 7.71 (dd, 1H, J=2.5, 1.5 Hz), 7.68 (dd, 1H, J=11.8, 2.2 Hz), 7.18 (m, 2H), 6.93 (dd, 1H, J=4.4, 1.4 Hz), 6.78 (dd, 1H, J=4.4, 2.6 Hz), 4.19 (q, 2H, J=7.2 Hz), 3.41 (s, 2H), 1.25 (t, 3H, J=7.2 Hz); MS(ESI+) m/z 359.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:25]([SH:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>C(O)C>[CH2:25]([S:37][CH2:3][CH2:2][C:1]([O:5][CH:6]([CH2:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCS
Reactant: C=CC(=O)OC(CSCc1ccccc1)CSCc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCSCCC(=O)OC(CSCc1ccccc1)CSCc1ccccc1

Procedure:
A solution of 16.5 grams of 1,3-bis-(benzylthio)-2-propyl acrylate, 9.45 grams of dodecanethiol, and 1 milliliter of "Triton B" in 75 milliliters of ethanol was heated under reflux for 11 hours. The reaction mixture was allowed to cool and was then poured into water. The oil which precipitated was separated by extraction with hexane and the hexane solution was stripped on a rotary evaporator. The residue, which weighed 22.5 grams, was identified as 1,3-bis-(benzylthio)-2-propyl 3-(dodecylthio)propionate by means of its NMR spectrum.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]2[CH2:13][CH2:12]C2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:13]([CH3:12])[CH3:18])=[O:8])[CH:3]1[C:14]([OH:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(C)C(C=CC(=O)OC2CCC2)C1C(=O)O
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)C=CC1C(C(=O)O)C1(C)C

Procedure:
Into 20 cm3 of toluene are introduced 2.1 g of tertbutyl (1R cis, ΔZ) 2,2-dimethyl 3-(3-isobutoxy 3-oxo 1-propenyl) cyclopropane-1-carboxylate and 0.1 g of paratoluene sulphonic acid, the whole is taken to reflux and maintained there for 20 minutes, concentrated to dryness by distillation under reduced pressure and chromatographed on silica eluting with a mixture of hexane and ethyl acetate (7:3) containing 1% of acetic acid and 1.53 g of (1R cis, ΔZ) 2,2-dimethyl 3-(3-isobutoxy 3-oxo-1-propenyl) cyclopropane-1-carboxylic acid are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][O:34][C:35](=[O:39])[CH:36](Br)[CH3:37]>>[CH3:33][O:34][C:35](=[O:39])[CH:36]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:32])[CH3:1])[N:26]([CH:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)[CH3:37]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: COC(=O)C(C)Br
Product: COC(=O)C(C)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 38.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 2-bromo propionic acid methyl ester (31 mL, 0.28 mmol) gave 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-propionic acid methyl ester (46 mg, 39%). MS(ESI) m/z 521.4 (M+H)+
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[C:5]=1[CH2:6][N:7]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)=[O:15])[CH2:10][CH2:9][C@H:8]1[C:32]([O:34]C)=[O:33].Cl>C1COCC1.CO.CCOCC>[F:3][C:4]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[C:5]=1[CH2:6][N:7]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)=[O:15])[CH2:10][CH2:9][C@H:8]1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@@H]1CC[C@@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CN1Cc1c(F)cccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(F)c1CN1C[C@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
LiOH (1M, aqueous) (3.0 ml, 3.00 mmol) was added to a stirred mixture of (2S,5R)-methyl 1-(2-fluoro-6-methoxybenzyl)-5-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)piperidine-2-carboxylate (1 g, 1.881 mmol) in THF (30 ml) & MeOH (10 ml) and the mixture was stirred at room temperature for Overnight. The reaction LCMS showed most starting material (M+1=532), but tlc showed product, another 3 ml of LiOH was added to the r×n, stirred for one day, LCMS gave M+H at 518, tlc showed completion. The reaction was treated 1 N HCl in ether, 6 ml, 1 eq, and rotovap to dryness and the residue was purified by column chromatography on silica gel Biotage 40M, eluting with 20% MeOH/CH2Cl2 to give the titled compound as a off-white (0.67 g, 68.8% yield).
Reaction SMILES: [CH3:1][C:2]([C:9]([OH:11])=[O:10])([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[NH2:3].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>[OH-].[Na+]>[CH2:16]([O:15][C:13]([NH:3][C@:2]([CH3:1])([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(CCC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@](CCC(=O)O)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a stirred solution of α-methyl-D,L-glutamic acid (10 g, 62 mmol) in 2 N sodium hydroxide (62 mL) at 0-5° C. was added benzyl chloroformate (12.7 g, 74.4 mmol) over 30 min. After the addition was complete the reaction mixture was stirred at room temperature for 3 hours. During this time the pH was maintained at 11 by addition of 2N sodium hydroxide (33 mL). The reaction mixture was then extracted with ether (60 mL). The aqueous layer was cooled in an ice bath and then acidified with 4N hydrochloric acid (34 mL) to pH=1. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (60 mL) and dried (MgSO4). The solvent was removed in vacuo to give 15.2 g (83%) of N-benzyloxycarbonyl-α-methylglutamic acid as an oil: 1H NMR (CDCl3) δ 8.73(m, 5H), 5.77(b, 1H), 5.09(s, 2H), 2.45-2.27(m, 4H), 2.0(s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)[CH:2]=1.S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21].[OH-].[NH4+]>>[N+:20]([C:10]1[C:11](=[O:14])[NH:12][CH:13]=[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:9]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: O=c1ccc(Cc2cccnc2)c[nH]1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=c1[nH]cc(Cc2cccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-(Pyrid-3-ylmethyl)-2-pyridone (10 g) was added to concentrated sulphuric acid (20 ml) with cooling and stirring. Fuming nitric acid (4.5 ml) was then added over 10 mins. with cooling (ice-bath), allowed to warm to room temperature overnight and then poured on to ice (200 ml). Concentrated ammonium hydroxide solution was added to bring the pH to 8, when the product precipitated from solution. The solid was filtered off and recrystallised from methanol to give the title compound (7.04 g), m.p. 216°-7° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:30][CH2:31][C:32]([F:46])([F:45])[CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:46][C:32]([F:45])([CH2:31][O:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[CH2:33][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)COS(=O)(=O)c3ccc(C)cc3)c2c1
Temperature: 135 °C
Yield: 67.8 %

Procedure:
Diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 3.5 g, 13.6 mmol), 2,2-difluoropropane-1,3-diyl bis(4-methylbenzenesulfonate) (6.0 g, 14.3 mmol) and K2CO3 (3.9 g, 28.5 mmol) are mixed in DMF (36 mL) and the reaction mixture is separated into 3 fractions. Each fraction is heated in a microwave reactor at 135° C. for 1 h. The 3 fractions are combined, and water (300 mL) and EtOAc (300 mL) are added. The aqueous layer is separated and extracted with EtOAc (3×100 mL). The organic layers are combined, washed with water (3×200 mL), dried (Na2SO4) and concentrated. The crude compound is purified by flash column chromatography using EtOAc in heptane to afford the title compound (4.7 g, 59% pure, 38% yield).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:34]1([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:29])[F:30])=[CH:23][CH:22]=2)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cn2ccnc2)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a 50-mL round-bottomed flask was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (38 mg, 0.072 mmol, Intermediate B), imidazole (7 mg, 0.11 mmol, Aldrich, St. Louis, Mo.) and cesium carbonate (46 mg, 0.14 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×40 mL). The organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an off-white glass. The crude product was purified by silica gel chromatography, eluting with 5% MeOH in EtOAc to give 2-(4-((S)-2-((1H-imidazol-1-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (28 mg) as a white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:27]2[C:28]([CH3:33])=[N:29][O:30][C:31]=2[CH3:32])[C:11]2[O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:13]3[C:23](=[O:26])[NH:24][C:25]=1[C:12]=23.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>O>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]([C:27]2[C:28]([CH3:33])=[N:29][O:30][C:31]=2[CH3:32])[C:11]2[O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:13]3[C:23](=[O:26])[NH:24][C:25]=1[C:12]=23
Reactant: COc1ccc(CNCc2cc(-c3c(C)noc3C)c3c4c2[nH]c(=O)n4[C@@H](c2ccccn2)CO3)c(OC)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1-c1cc(CN)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Yield: 82 %

Procedure:
A solution of (4S)-9-{[(2,4-dimethoxybenzyl)amino]methyl}-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (70.0 mg, 0.133 mmol) in trifluoroacetic acid (5 mL) and water (30 μL) was heated in the microwave at 120° C. for 10 min. The reaction mixture was concentrated to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (66 mg, 82%) as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 8.18 (br s, 2H), 7.80 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.32 (dd, J=7.1, 5.0 Hz, 1H), 7.19 (d, J=7.9 Hz, 1H), 6.94 (s, 1H), 5.59 (s, 1H), 4.89-4.73 (m, 1H), 4.44 (dd, J=11.5, 3.0 Hz, 1H), 4.13 (d, J=5.5 Hz, 2H), 2.24 (s, 3H), 2.07 (s, 3H); LCMS calculated for C20H20N5O3 (M+H)+: m/z=378.2. found: 378.0.
Reaction SMILES: [Br:1]C1SC(Br)=CC=1Br.COC1C=C(B(O)O)C=CC=1OC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=3)=[CH:35][CH:36]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[Br:1][C:36]1[CH:35]=[C:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=2)[S:33][C:32]=1[C:26]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(OC)c(OC)c3)s2)cc1OC
Reactant: Brc1cc(Br)c(Br)s1
Agent: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cc(Br)c(-c3ccc(OC)c(OC)c3)s2)cc1OC
Yield: 77 %

Procedure:
3-bromo-2,5-bis(3′,4′-dimethoxyphenyl)thiophene (18) was prepared by the reaction of 2,3,5-tribromothiophene (17) (321 mg, 1 mmol) and (3,4-dimethoxyphenyl)boronic acid (15) (419 mg, 2.3 mmol) according to the similar procedure for compound 16. The reaction mixture was purified by column chromatography (10%-30% EtOAc in hexanes) and afforded 18 (337 mg, 77% yield) as a yellow solid. SA-60 was also isolated (97 mg, 20% yield) from the reaction above as a dark yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.C(OCC)(=O)C>[NH2:16][C:15]1[C:11]2[C:12](=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:9]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH:10]=2)[O:14][C:31]=1[C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)C(=O)CBr
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 0.5 g (1.46 mmol) of the product of Step B in 10 mL DMF was added 0.954 g Cs2CO3 and 0.197 mL of 1-bromopinacolone. The reaction was stirred 17 hours at room temperature at which point the reaction mixture was diluted with ethyl acetate and washed with saturated NaCl/NaHCO3 solution (1:1). The residue from the concentrated solution was purified via silica gel flash chromatography eluting with a gradient of 0 to 75% ethyl acetate/hexane to afford the title compound. HPLC-MS: 439.1 (M+1), 441.1 (M+3); Rt=4.53 min.