Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6]2[C:10](=[C:11]3[C:23]4=[CH:24][N:25]([CH3:28])[C:26](=[O:27])[C:22]4=[C:21]4[C:13]([NH:14][C:15]5[CH:16]=[CH:17][C:18](=[O:29])[CH2:19][C:20]=54)=[C:12]3[CH:30]=1)[N:9]=[CH:8][CH:7]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:51]>CN(C=O)C.CCOC(C)=O>[Br:51][CH2:2][CH2:3][CH2:4][C:5]1[C:6]2[C:10](=[C:11]3[C:23]4=[CH:24][N:25]([CH3:28])[C:26](=[O:27])[C:22]4=[C:21]4[C:13]([NH:14][C:15]5[CH:16]=[CH:17][C:18](=[O:29])[CH2:19][C:20]=54)=[C:12]3[CH:30]=1)[N:9]=[CH:8][CH:7]=2
Reactant: BrC(Br)(Br)Br
Reactant: CN1C=c2c(c3c4c([nH]c3c3cc(CCCO)c5c(c23)N=CC=5)C=CC(=O)C4)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C=c2c(c3c4c([nH]c3c3cc(CCCBr)c5c(c23)N=CC=5)C=CC(=O)C4)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 13-(3-hydroxypropyl)-5-methyl-7H-indolo[6,7-a]pyrrolo[3,4-c]-carbazole-6,8-dione (1.18 g, 2.97 mmol) in DMF (45 mL) was added triphenylphosphine (1.17 g, 4.45 mmol) followed by carbon tetrabromide (1.48 g, 4.45 mmol). The resulting solution was allowed to stir at room temperature for 30 min. The solution was diluted with EtOAc (200 mL) and washed with water (2×200 mL) and brine (200 mL). The combined aqueous layers were washed with EtOAc (100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to a red-orange solid. Flash chromatography (SiO2, 20% EtOAc/hexanes) gave the title compound (1.05 g, 77%) as an orange solid, mp 238 C. 1H NMR (DMSO-d6)11.15 (s, 1H), 9.16 (d, J=7.5 Hz, 1H), 8.36 (d, J=9 Hz, 1H), 8.04 (d, J=9 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.60–7.67 (m, 2H), 7.44 (dd, J=7.5, 7.5 Hz, 1H), 6.85 (d, J=3 Hz, 2H), 5.03 (t, J=7 Hz, 2H), 3.85 (s, 3H), 3.72 (t, J=7 Hz, 2H), 2.50 (m, 2H, partially buried under DMSO signal). MS (atmospheric pressure chemical ionization, m/z) 460, 462 [C24H18BrN3O2+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC(C)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: C=CCOC(=O)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Product: C=CCOC(=O)COC(=O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Temperature: 40 °C

Procedure:
25 g of indometacin, 10 g of potassium carbonate and 1.0 g of benzyltriethylammonium chloride in 140 ml of acetone are stirred for 30 minutes at 50° to 60° C. 10.1 g of allyl chloroacetate are then added dropwise over 5 minutes. The mixture is stirred at 40° C. until the reaction has ended (as checked by thin layer chromatography; about 3 hours). The mixture is filtered while warm, the filtrate is evaporated in vacuo and the residue is taken up in ether (about 90 ml) and mixed with petroleum ether (40 to 60) (about 30 ml). This mixture is left to stand over night at -10° C. and the product is then filtered off and dried in vacuo.
Reaction SMILES: BrBr.[C:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1)[C:10]([OH:12])=[O:11])(=[S:5])[NH2:4]>C(Cl)(Cl)Cl>[NH2:4][C:3]1[S:5][C:8]2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:7]=2[N:6]=1
Reactant: COc1cc(NC(N)=S)cc(C(=O)O)c1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)O)c2sc(N)nc2c1
Temperature: 25 °C
Yield: 81 %

Procedure:
Bromine (56 μl, 1.09 mmol) was added to a suspension of 3-(carbamothioylamino)-5-methoxy-benzoic acid (248 mg, 1.09 mmol) in chloroform (7 mL). The reaction was stirred at ambient temperature resulting in large granules of solid material which were pulverized with a spatula. The chloroform was removed by pipette and the remaining solid was triturated with dichloromethane to give the product as a pale yellow solid, 200 mg, 81% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:27][CH3:28])[C:22]([O:24]CC)=[O:23])[O:13][C:12]1([CH3:30])[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C(O)C.O.[OH-].[K+]>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:27][CH3:28])[C:22]([OH:24])=[O:23])[O:13][C:12]1([CH3:30])[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
517 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-ethyl-2-propenoate was dissolved in 3.10 ml of an ethanol/water (9/1) solution of 2N potassium hydroxide, and the solution was stirred at room temperature for 3 hours. Then, the reaction solution was adjusted to pH2 with 1N hydrochloric acid under cooling with ice and after an addition of 24 ml of water, extracted three times with 20 ml of ethyl acetate. The organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-ethyl-2-propenoic acid as colorless oily substance.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.O>[C:18]([NH:22][C:7](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a cold (0° C.) solution of 139.2 g (0.9 mol) of o-toluoyl chloride in 1200 mL of methylene chloride at 25° C., under nitrogen, was slowly added 180.0 g (1.8 mol) of triethylamine followed by the dropwise addition of a solution containing 73.14 g (1.0 mol) of t-butylamine in 200 mL of methylene chloride. The resulting reaction mixture was warmed to room temperature and allowed to react for 2.5 hours. The reaction mixture was then diluted with 1800 mL of water. The resulting organic and aqueous layers were separated, and the organic layer was washed sequentially with 2N sodium hydroxide, 1.0N hydrochloric acid and brine, dried over magnesium sulfate, filtered and then reduced to dryness under reduced pressure to provide 167.6 g of the desired subtitled compound as an off-white solid (mp 77°-78° C.).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH:12]=3)[C:7]([OH:22])=[C:6]([C:23](OCC)=[O:24])[C:5]2=[O:28])[CH2:3][CH2:2]1.[NH2:29][CH2:30][CH2:31][OH:32]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH:12]=3)[C:7]([OH:22])=[C:6]([C:23]([NH:29][CH2:30][CH2:31][OH:32])=[O:24])[C:5]2=[O:28])[CH2:3][CH2:2]1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C2CC2)c1=O
Solvent: CCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C2CC2)c1=O
Yield: 64 %

Procedure:
A solution of ethyl 1-cyclopropyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (24 mg, 0.06 mmol) and 2-aminoethanol (0.05 mL) in ethanol (1 mL) was heated in a microwave for 20 minutes. The reaction mixture was concentrated in vacuo and the residue taken up in water. The solution was acidified with 1 N HCl to a final pH˜4. The precipitate was filtered through a Teflon filter and the solids collected. This material was azeotroped with methanol to provide the title compound (16 mg, 64%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1 H), 8.54 (s, 1 H), 7.80 (s, 1 H), 7.17 (m, 2 H), 7.03 (m, 2 H), 4.13 (s, 2 H), 3.84 (m, 2 H), 3.62 (m, 2 H), 2.82 (m, 1 H), 1.23 (m, 2 H), 0.76 (m, 2 H); HRMS m/z calcd for C21H21N3O4F (M+H)+ 398.1517, found 398.1512.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][C:12]2[S:16][C:15]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[CH3:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][C:12]2[S:16][C:15]([CH2:17][C:18]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=4)[O:20][N:19]=3)=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(Cc2ccc(CC(Cl)=NO)s2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(Cc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)s2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (5-(4-methyl-benzyl)-thiophen-2-yl)acetohydroximoyl chloride (250 mg, 0.894 mmol) described in Manufacturing Example 92-1-5 and 3-ethynyl-pyridin-2,6-diamine (50.0 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (157 μL, 1.13 mmol) at room temperature, which was stirred for 30 minutes at 60° C. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→3:1) to obtain the title compound (49.8 mg, 35.2%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[N:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>COCCOC.CCO.O.[Cl-].[Na+].O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[N:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH:3]=1
Reactant: COc1c(C)cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)nc1C
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)nc1C
Yield: 16.5 %

Procedure:
1-(3-Bromophenyl)-4-fluoro-1-(5-methoxy-4,6-dimethylpyridin-2-yl)-1H-isoindol-3-amine (272 mg, 0.62 mmol), pyrimidin-5-ylboronic acid (92 mg, 0.74 mmol), cesium carbonate (604 mg, 1.85 mmol) and dichloro[1,1′-bis (diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (50.4 mg, 0.06 mmol) were dissolved in DME:EtOH:water (6:3:1) (5 mL) and irradiated in a microwave oven for 20 min at 150° C. EtOAc, water and brine were added and the organic phase was collected, dried (Na2SO4) and filtered. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to afford 45 mg (17%) of the title compound.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][C:15](=[O:19])[C:16]([NH2:18])=[O:17])[O:11][CH2:10]2)=[CH:5][C:4]=1[F:20].[O:23]=[C:24]1[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26][N:25]1[C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][N:32]=1.[Cl-].[Li+].O>CN1CCCC1=O>[O:23]=[C:24]1[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26][N:25]1[C:31]1[CH:36]=[CH:35][C:34]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:13][C@H:12]([CH2:14][C:15](=[O:19])[C:16]([NH2:18])=[O:17])[O:11][CH2:10]3)=[CH:5][C:4]=2[F:20])=[CH:33][N:32]=1
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Reactant: O=C1CC(CO)CN1c1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)C(=O)C[C@H]1CN(c2ccc(-c3ccc(N4CC(CO)CC4=O)nc3)c(F)c2)CO1
Temperature: 110 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
In 14 ml of 1-methyl-2-pyrrolidon was dissolved 1.8 g of (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide. The solution was added 1.03 g of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 0.55 g of lithium chloride and 0.15 g of dichlorobistriphenylphosphine palladium(II) at room temperature and then stirred at the temperature of 110° C. for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. After being washed with brine, the organic layer, thus separated, was dehydrated, filtered, concentrated in vacuo and purified by column chromatography thereby to obtain (S)-3-(4-(2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide 410 mg. Yield 21%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=1[NH:60][C:61](=[O:72])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][NH2:71])=[N:64][CH:63]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=1[NH:60][C:61](=[O:72])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][NH:71][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])=[N:64][CH:63]=1
Reactant: NCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (300 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-fluorophenyl)-6-(2-aminoethylamino)nicotinamide (303 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (457 mg, 80%) as a yellow solid. 1H NMR (DMSO-d6)δ2.41 (s, 3H, pyrrole-CH3), 2.43 (s, 3H, pyrrole-CH3), 3.43 (m, 2H, CH2), 3.48 (m, 2H, CH2), 5.18 (s, 2H, benzene-NH2), 6.33 (m, 1H), 6.53 (m, 2H), 6.84 (m, 1H), 6.91 (m, 1H), 7.07 (m, 1H), 7.25 (s, 1H), 7.71 (m, 3H), 7.92 (d, J=8.0 Hz, 1H), 8.64 (s, 1H), 9.31 (s, 1H, benzene-NH), 10.89 (s, 1H, indolinone-NH), 13.68 (s, 1H, pyrrole-NH). LC-MS (m/z) 572 (M+1).
Reaction SMILES: [Li+].C[CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[CH2:9]1[CH2:13]OC[CH2:10]1.C(#N)C(C)=O>>[NH:5]1[C:6]2[C:7](=[CH:10][CH:9]=[CH:13][CH:8]=2)[CH:4]=[CH:3]1
Reactant: CC(C)[N-]C(C)C
Reactant: C1CCOC1
Agent: CC(=O)C#N
Agent: [Li+]
Product: c1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 1 (426 mg, 1.26 mmol) in TBF (6 mL) at −78° C. was added dropwise a 1.8 M solution of LDA in THF (1.54 mL, 2.78 mmol) and the reaction stirred for 1 hour, then pyruvonitrile (0.208 mL, 2.78 mmol) was added dropwise and the reaction was stirred for 15 minutes turning homogeneous. The reaction was quenched by the addition of satd. NH4Cl (10 mL), the layers separated, and the aqueous extracted with Et2O (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on silica gel gradiently eluted with 20 to 40% EtOAc/hexanes to give 2 (230 mg, 48% yield) as an off-white solid. Rt=1.71 min using Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=380.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[OH-].[Na+]>CO.O>[ClH:1].[N:2]1([CH2:7][CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: CCOC(=O)c1ccc(NCCn2ccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(NCCn2ccnc2)cc1
Yield: 71.8 %

Procedure:
Then, a solution of 1.0 g of ethyl p-[β-(1-imidazolyl)ethylamino]benzoate hydrochloride and 1.0 g of sodium hydroxide in 30 ml of methanol-water (1:2 by volume) was stirred for 2.5 hours at room temperature. After concentration under reduced pressure, the residue was acidified with 6N hydrochloric acid to pH 1, and then concentrated under reduced pressure. To the residue was added 20 ml of tert-butanol and evaporated under reduced pressure to remove the excess of hydrochloric acid completely. The residual solid was dissolved in ethanol, the insoluble salts were filtered off, and then the filtrate was evaporated under reduced pressure. The residual solid was recrystallized from ethanol-diethyl ether to give 0.65 g of p-[β-(1-imidazolyl)ethylamino]benzoic acid hydrochloride as colorless needles. M.P.: 222° to 224° C. (dec.).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH2:27])[C:22](=[O:25])[CH2:23]Br>>[CH3:20][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH2:27])[C:22](=[O:25])[CH2:23][N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: C=C(c1ccccc1)N(C)C(=O)CBr
Product: C=C(c1ccccc1)N(C)C(=O)CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The compound (4) synthesized in Reference Example 4 and the compound (25) synthesized in Reference Example 25 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][NH:4][C:3]1=[O:7].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(O)=O.[Na+]>C(O)C.C(OCC)C>[CH2:9]([N:5]1[CH2:6][C:2]([CH3:8])([CH3:1])[C:3](=[O:7])[NH:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)CNNC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC1(C)CN(Cc2ccccc2)NC1=O
Temperature: 25 °C
Yield: 52 %

Procedure:
4,4-dimethyl-3-pyrazolidinone [1.42 g] and benzyl bromide [1.78 mL] and NaHCO3 [1.26 g] were combined in 5 mL ethanol. The mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, diluted with diethyl ether (50 mL), dried with MgSO4, filtered and evaporated. The resulting oil was chromatographed on silica gel to yield 1.22 g (52%) of 1-Benzyl-4,4-dimethyl-3-pyrazolidinone as a light oil. 1H NMR: 7.6-7.2 (5H, m), 3.8-3.4 (4H, m), 1.2 (6H, s).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][N:33]1[CH:37]=[C:36](B(O)O)[C:35]([CH3:41])=[N:34]1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:36]3[C:35]([CH3:41])=[N:34][N:33]([CH3:32])[CH:37]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cc1nn(C)cc1B(O)O
Product: Cc1nn(C)cc1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@H](F)CO2)cs1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (1,3-dimethyl-1H-pyrazol-4-yl)boronic acid gave 241. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 7.84 (s, 1H), 4.95-4.83 (m, 1H), 4.83-4.62 (m, 1H), 4.42-4.28 (m, 1H), 4.24-4.05 (m, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.48 (dd, J=17.3, 8.4 Hz, 1H), 2.47 (s, 3H), 2.15-2.06 (m, 1H), 1.87 (d, J=14.4 Hz, 4H). LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:24][NH:25][CH3:26].C[Si](Cl)(C)C.O>ClCCl>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:25]([CH3:26])[CH3:24])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)N(C)C)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
6.5 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.02 mol) is dissolved in 60 mL of dichloromethane. 1.63 g of dimethylamine HCl (0.02 mol, 1 eq) is added and the reaction mixture is cooled to 0° C. 0.43 g TMSCl (0.004 mol, 0.2 eq) is added in 5 min. The reaction mixture is heated to room temperature and stirred for 5 hours. 50 mL of water is added to the mixture, it is stirred for 15 min and the phases are separated. The organic phase is washed with 30 mL of water then it is concentrated. The residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 4.68 g of the title compound (VIb) (70%) as a yellow solid.
Reaction SMILES: [CH2:1]([C@@H:3]([CH2:6][CH2:7][CH3:8])[CH2:4][OH:5])[CH3:2].CCN(CC)CC.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH2:1]([C@@H:3]([CH2:6][CH2:7][CH3:8])[CH2:4][O:5][S:17]([CH3:16])(=[O:19])=[O:18])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC[C@H](CC)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@H](CC)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a −10° C. stirred solution of (S)-2-ethyl-pentan-1-ol (1.30 g, 11.2 mmol) in dry CH2Cl2 (35 mL) was added Et3N (2.33 mL, 16.8 mmol). The reaction was stirred at this temperature for 15 minutes and methansulfonyl chloride (0.952 mL, 12.3 mmol) was added. The reaction was allowed to warm to room temperature overnight with good stirring. The reaction was washed with 1N HCl (3×30 mL), sat. NaHCO3 (3×30 mL), and brine (2×30 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a quantitative yield of crude product.