Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.C(OC([N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1)=O)(C)(C)C.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([C:42]4[CH:43]=[N:39][NH:40][CH:41]=4)[N:22]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:5]3=[N:6][CH:7]=2)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 88 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A stirred mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (180 mg, 0.358 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (106 mg, 0.360 mmol), [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (29.2 mg, 0.0358 mmol), and potassium phosphate (153 mg, 0.719 mmol) in water (2 mL)/1,4-dioxane (5 mL) was heated at 88° C. After 1 hour, the reaction mixture was cooled to ambient temperature, quenched with water, and extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (132 mg, 75%). LCMS calculated for C25H24N5O4S (M+H)+: m/z=490.2. Found: 490.2.
Reaction SMILES: OCCO[CH:5]([CH2:9]OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:8][CH2:7][CH2:6][CH2:5][CH3:9])(=[O:40])=[O:39]
Reactant: OCCOC(CCO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOS(C)(=O)=O
Temperature: 0 °C

Procedure:
3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (14.0 g, 35.7 mmol) was dissolved in 140 mL of CH2Cl2, was cooled to 0° C. under N2, and triethylamine (10.8 g, 14.9 mL, 0.107 mol. 3.0 eq.) was added. Methanesulfonyl chloride (11.0 g, 7.46 mL, 96.4 mmol, 2.7 eq.) was then added dropwise at <5° C. The resultant reaction mixture was diluted with additional CH2Cl2 (300 mL) and was washed with 200 mL of water and 200 mL of an aqueous saturated solution of ammonium chloride. The aqueous layers were back-extracted with 50 mL of CH2Cl2 and the combined organic layer was washed with 100 mL of brine and was dried (MgSO4) and evaporated in vacuo to give 18.4 g (94%) of 3-(2-[(methylsulfonyl)oxy]ethoxy]-4-triphenylmethoxy)-1-butanol methane sulfonate as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[C:26]([CH2:32]Br)=[N:27][C:28]([Cl:31])=[CH:29][CH:30]=1>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:32][C:26]3[C:25]([Br:24])=[CH:30][CH:29]=[C:28]([Cl:31])[N:27]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Clc1ccc(Br)c(CBr)n1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (4.55 g, 14.5 mmol) in THF (165 mL) was added sodium hydride (60% dispersion in mineral oil) (968 mg, 24.2 mmol) as a powder. The mixture was stirred at room temperature for 20 min. A solution of 3-bromo-2-(bromomethyl)-6-chloropyridine (2.5 g) in THF (30 mL) was added. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to recover the unreacted 3-bromo-6-chloro-2-methylpyridine and to afford the title compound (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=517.0; found=517.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1H); 7.84 (d, J=8.2 Hz, 1H); 7.83 (s, 2H); 7.21 (d, J=8.2 Hz, 1H); 5.89 (d, J=8.3 Hz, 1H); 5.04 (d, J=17.2 Hz, 1H); 4.47-4.41 (m, 1H); 4.35 (d, J=17.2 Hz, 1H); 0.83 (d, J=6.6 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4](Br)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH3:15][O-:16].[Na+]>CO>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]=1[CH:4]([O:16][CH3:15])[C:3]([OH:2])=[O:14]
Reactant: COC(=O)C(Br)c1c(Cl)cccc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(C(=O)O)c1c(Cl)cccc1Cl

Procedure:
10 g (0.033 mols) 2 bromo-2(2,6-dichlorophenyl)-acetic acid methyl ester (Example 8) are heated with sodium methylate in methanol (1.6 g Na in 100 ml MeOH) in an autoclave for 5 hours at 150 degrees C. After evaporation of the solvent, the residue is taken up in a water-chloroform mixture. By acidification of the aqueous phase, 3.9 g 2-(2,6-dichlorophenyl)-2-methoxy-acetic acid is obtained. It melts at 119-122 degrees C. after recrystallization from diisopropyl ether.
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[N:12]1[C:17]2[CH:18]=[CH:19][S:20]C=2C(=O)[NH:14][CH:13]=1.O>ClC(Cl)C>[Cl:11][C:6]1[C:7]2[S:20][CH:19]=[CH:18][C:17]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]cnc2ccsc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Clc1ncnc2ccsc12
Temperature: 25 °C
Yield: 75.7 %

Procedure:
Dimethyl formamide (6.6 mL, 85.4 mmol) in 50 mL of dichloroethane was cooled to 0° C. and oxalyl chloride (62 mL, 124 mmol, 2M in dichloromethane) was added slowly over several minutes forming a white gel. 3H-thieno[3,2-d]pyrimidin-4-one (5.90 g, 38.8 mmol) was added and the reaction mixture was heated to reflux. After 2.5 hours the mixture was cooled to room temperature and poured into water. The product was extracted into dichloromethane (3×100 mL), dried over sodium sulfate, and concentrated in vacuo to afford 5.01 g (76%) of 4-chloro-thieno[3,2-d]pyrimidine. 1H NMR (400 MHz, DMSO) d 8.99 (s, 1H), 8.55 (d, 1H), 7.71 (d, 1H). LC-MS: 171 (MH+); HPLC RT: 2.85 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([NH2:40])[CH2:36][CH2:37][CH2:38][CH3:39].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27]([NH:40][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (50 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, amylamine (26 μl) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 21 mg (yield 30%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[C:23]1([C:29]2[N:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH2:31][CH2:32][NH:33][CH2:34]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][CH:37]=[N:38][C:29]=4[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:34]3)=[O:21])[C:4]=12.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-c2nccc3c2CCNC3)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ccnc4-c4ccccc4)C3)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.124 g, 0.413 mmol) and 5-phenyl-1,2,3,4-tetrahydro-2,6-naphthyridine, TFA (0.147 g, 0.454 mmol) in DMF (5 mL) was added Hunig's Base (0.5 mL, 2.86 mmol) followed by TBTU (0.172 g, 0.537 mmol). The solution was stirred at rt for 5 h and quenched with 5 mL of water. The solvent was removed under reduced pressure and the residue dissolved in DMF and passed through a plug of glass wool. The DMF solution was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure. The residue was further purified by BIOTAGE® flash chromatography using a 0-5% MeOH in dichloromethane gradient. The expected product, 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-phenyl-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)ethane-1,2-dione, TFA (0.192 g, 0.314 mmol, 76% yield), was isolated as an off-white solid. LC/MS: m/z 494.12 (M+H)+, 0.878 min (method 6). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.40-12.47 (m, 1H) 9.24 (s, 1H) 8.47-8.58 (m, 1H) 8.25-8.32 (m, 1H) 7.87 (s, 1H) 7.30-7.63 (m, 6H) 4.75-4.96 (m, 2H) 3.59-3.88 (m, 5H) 2.78-2.99 (m, 2H) 2.48-2.52 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.C(=O)(O)[O-].[K+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].C1C2C(=CC=CC=2)CCN1>C1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:24]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CN1CCc2c(N)cccc2C1
Agent: O=C([O-])O
Agent: [K+]
Agent: c1ccc2c(c1)CCNC2
Solvent: c1ccccc1
Product: COc1ccc(C(=O)Nc2cccc3c2CCN(C)C3)cc1OC

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (12.9 g) prepared as in Example 4 was dissolved in dry benzene (100 ml) and 0.5 g of dry potassium bicarbonate was added. A 0.1 mole excess of 3,4-dimethoxybenzoyl chloride was dissolved in dry benzene (100 ml) and this solution was added to the solution of the tetrahydroisoquinoline. A precipitate formed immediately and the mixture was refluxed for 1 hour. The precipitate was collected by filtration and washed with 10% sodium carbonate solution followed by water. The washings were discarded and the remaining residue was recrystallized from ethanol to yield 12.0 g of the desired product as a white powder, m.p. 160°-161.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:15]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[C:22]([NH:21][CH2:20][C:19]([N:16]1[CH2:17][CH2:18][CH:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:13][CH2:12]2)[CH2:15]1)=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.9 %

Procedure:
To N-(2-(3-(4-(2-aminophenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dichlorobenzamide (Example #4.149, 0.063 g, 0.13 mmol) in DCM (1 mL) was added triethylamine (0.037 mL, 0.26 mmol) and methanesulfonyl chloride (0.011 mL, 0.14 mmol). The reaction mixture was stirred at room temperature for about 16 h. The solvent was removed in vacuo and the residue was purified by RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5 for 3 min., 5% to 60% acetonitrile/0.05M aqueous ammonium acetate over 6 min at 22.5 mL/min with 2.5 mL/min. acetonitrile at-column dilution; APCI positive mode detection; Xterra prep. MS C18. 19×50 mm column) to afford 3,4-dichloro-N-(2-(3-(4-(2-(methylsulfonamido)phenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)benzamide (0.0052 g, 0.009 mmol). RP-HPLC (Table 1, Method a) Rt 2.07 min; m/z: (M+H)+ 553.
Reaction SMILES: [CH2:1]([CH:4]([C:10](OCC)=O)[C:5]([O:7]CC)=[O:6])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:18][CH2:19]CN1C(=O)C2=CC=CC=C2C1=O.C[N:33](C=O)C>>[CH2:10]([CH:4]([CH2:1][CH2:2][CH2:3][NH2:33])[C:5]([OH:7])=[O:6])[CH:18]=[CH2:19]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C=CCC(CCCN)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl allylmalonate was slowly added into a suspension of 1.1 eq. sodium hydride in DMF and stirred at RT for 5 minutes after addition. Then N-(3-bromopropyl)-phthalimide dissolved in DMF was added and the reaction mixture were stirred at 60° C. overnight. The solution was then slowly poured into 3 volumes of ice-water; alkylation product 2 precipitated, and the precipitate was collected by filtration. The filter cake was washed with water. HPLC analysis demonstrated that 2 was pure enough for use in the next step without further purification. Attempts to deprotect and decarboxylate 2 by refluxing in 6 M HCl did not yield the desired product. Instead, decarboxylation of 2 was achieved by refluxing in DMF with 1 eq of lithium bromide and 2 eq. of water for 40 hrs to yield desired intermediate 3. Compound 3 was converted into 4 by refluxing for 1 hr with 2 eq. NaOH (1M aq) in DMF, then 1 hr in water. After removing volatiles under vacuum, the residue was treated with 5 eq. of hydrazine, suspended in absolute ethanol, and refluxed overnight. Upon cooling, most of the liberated phthalhydrazide precipitated out; the precipitate was removed by filtration. After filtration, 2 eq. LiOH was added to the filtrate and the solvent was evaporated to afford crude 1 as its lithium salt. This was used directly for solid phase synthesis.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.Cl.Cl.[CH3:42][N:43]([CH3:48])[CH:44]1[CH2:47][NH:46][CH2:45]1>CC(N(C)C)=O.CO>[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:46]3[CH2:47][CH:44]([N:43]([CH3:48])[CH3:42])[CH2:45]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Reactant: CN(C)C1CNC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 100 %

Procedure:
DIPEA (0.408 mL, 2.33 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine. 0.8 toluene-4-sulfonic acid salt (Intermediate 87, 330 mg, 0.58 mmol) in DMA (3 mL). N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 121 mg, 0.70 mmol) was then added in one portion. The mixture was heated in a microwave at 100° C. for 0.5 h then the mixture was cooled and diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated in vacuo. Further purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 gave the title compound (295 mg, 100%) as a brown gum; 1H NMR: (CDCl3) 2.18 (6H, s), 3.13-3.24 (1H, m), 3.67-3.75 (2H, m), 3.89 (3H, s), 3.96 (3H, s), 4.13 (2H, t), 6.04 (1H, s), 7.21-7.29 (1H, m, partially obscured by chloroform signal), 7.29-7.41 (3H, m), 8.22 (1H, s), 8.37 (1H, s), 8.46 (1H, d), 9.05 (1H, s); m/z: ES+ MH+ 508.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([C:16]([OH:18])=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=[O:9])[N:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[K+].Cl>CN(C)C(=O)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([C:16]([OH:18])=[O:17])([CH3:15])[CH3:14])/[C:8]([O:10][S:20]([CH3:19])(=[O:22])=[O:21])=[O:9])[N:3]=1
Reactant: CC(C)(O/N=C(\C(=O)O)c1nsc(N)n1)C(=O)O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O/N=C(\C(=O)OS(C)(=O)=O)c1nsc(N)n1)C(=O)O
Temperature: 5 °C
Reaction time: 2.5 h
Yield: 31.2 %

Procedure:
To a solution of (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic acid (2.74 g) in N,N-dimethylacetamide (45 ml) were added methanesulfonyl chloride (1.15 g) and potassium bicarbonate (1.20 g) under cooling in an ice bath. The mixture was stirred for 2.5 hours at 5° C. and poured into a cold mixture of water (200 ml), ethyl acetate (200 ml) and 1N hydrochloric acid (6 ml). The mixture was stirred for 5 minutes under cooling in an ice bath. The organic layer was separated, washed with cold water (200mlx2) and with a cold saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. Toluene was added to the residue. To the mixture was added methylene chloride and the mixture was cooled for 10 minutes in an ice bath. The crystals were collected by filtration, washed with methylene chloride and air-dried to give methanesulfonyl (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetate (1.1 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[O:11].[BH4-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: O=Cc1cc2ccccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1cc2ccccc2o1
Yield: 94.5 %

Procedure:
2-Benzofurancarbaldehyde (2.2 g, 15 mmol) was dissolved in 25 mL of methanol. To this solution was added sodium borohydride (0.28 g, 7.5 mmol) in small portions over a period of 20 minutes. Then 2 mL of water were added and the mixture was evaporated. The residue was dissolved in ethyl acetate (75 mL) and washed with water (3×75 mL), dried (MgSO4) and evaporated, providing 2.1 g of benzofuran-2-yl-methanol, in 95% yield; 1H NMR (CDCl3) δ 2.03 (t, J=6.1 Hz, 1H), 4.77 (d, J=6.1 Hz, 2H), 6.66 (s, 1H), 7.19-7.32 (m, 2H), 7.45-7.50 (m, 1H), 7.53-7.57 (m, 1H).
Reaction SMILES: C([Li])C[CH2:3][CH3:4].C(OC([C:12]1[N:13]=[CH:14][C:15]2[N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:17]3[C:22]([C:23]=2[C:24]=1[CH2:25][O:26][CH3:27])=[CH:21][C:20]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:19][CH:18]=3)=O)(C)C.[OH2:46]>C1COCC1>[C:3]([C:12]1[N:13]=[CH:14][C:15]2[NH:16][C:17]3[C:22]([C:23]=2[C:24]=1[CH2:25][O:26][CH3:27])=[CH:21][C:20]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:19][CH:18]=3)(=[O:46])[CH3:4]
Reactant: O
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: COCc1c(C(C)=O)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under an N2 atmosphere, 45 mmol of n-butyl-lithium is added dropwise within 10 minutes to 3.70 g (22 mmol) of methanesulfine-p-toluidide in 100 ml of dry THF at -78° C. To this mixture is added 5.58 g (10 mmol) of 6-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid isopropyl ester, dissolved in 50 ml of dry THF. The reaction mixture assumes a dark-blue color. The mixture is stirred for one hour at -78° C., poured into water, and extracted with ether. The ether is drawn off and the remaining oil is dissolved in 100 ml of methanol. Then 5 g of KOH is added and the mixture agitated under reflux for one hour. After cooling, ice water is added and the precipitate is filtered off. Yield: 3.5 g.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28]([CH2:31][C:32](OC)=[O:33])[C:27]([CH3:37])([CH3:36])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)C>O1CCCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28]([CH2:31][CH2:32][OH:33])[C:27]([CH3:37])([CH3:36])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)CC1=CCN(C(=O)OC(C)(C)C)CC1(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(CCO)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A solution of 1 M diisobutylaluminum hydride in toluene (14.0 mL, 14.1 mmol) was slowly dropped into a cooled (−78° C.) solution of 1.6 g (5.7 mmol) of 4-methoxycarbonylmethyl-3,3-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester obtained in the above 1) of PREPARATION EXAMPLE 20 in tetrahydrofuran (70 mL) under an atmosphere of argon. After dropping, the solution was stirred for 2 hours at the same temperature. After the reaction was completed, ethanol (10 mL) was added at 0° C. and the solution was allowed to warm to room temperature gradually. The reaction mixture was then concentrated under a reduced pressure, treated with an aqueous solution of 20% sodium potassium tartrate (50 mL), and stirred for 30 minutes. After stirring, it was extracted with ether, and dried over anhydrous sodium sulfate. After drying, the extract was filtered and the filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=2:1) to obtain 1.1 g (yield 76.4%) of 4-(2-hydroxylethyl)-3,3-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester. Its physical property is shown below.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]12([CH2:30][C:31](O)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([CH2:30][C:31]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:19])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(adamantan-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.18-11.35 (bs, 1H), 8.39-8.42 (m, 1H), 7.89-8.02 (m, 2H), 7.70-7.73 (m, 1H), 7.56-7.68 (m, 4H), 2.04 (s, 2H), 1.92-1.95 (m, 3H), 1.66-1.69 (m, 6H), 1.63-1.70 (m, 3H), 1.57-1.62 (m, 3H); MS (ESI+) m/z 448 (M+H)+.