Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:11][C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1.[Br:27]N1C(=O)CCC1=O>C(#N)C>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[C:11]([Br:27])[C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(CN)c1
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CN)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
1-[3-(aminomethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one from step 3 (3.89 g, 10.93 mmol) suspended in acetonitrile (42 mL) was cooled in an ice-bath. N-bromosuccinimide (2.04 g, 11.47 mmol) was added and the ice-bath was removed. The reaction mixture was stirred for 1.5 hours at room temperature. The reaction was diluted with acetonitrile (100 mL) and the precipitate that formed was collected by filtration and washed with acetonitrile (3×30 mL) to afford an off-white solid (2.74 g, 58%). 1H NMR (400 MHz, DMSO-d6) δ 7.67-7.59 (m, 3H), 7.34-7.31 (m, 2H), 7.04 (app t, J=8.72 Hz, 2H), 7.05-6.88 (m, 2H), 6.13 (s, 1H), 5.30 (s, 2H), 3.95 (s, 1H), 2.01 (s, 3H). ES-HRMS m/z 435.0538 (M+H C20H17BrF2N2O2 requires 435.0514).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](Cl)[CH:6]=[CH:7][C:8]=1[C:9]#[N:10].COCCOCCOCCOC.[CH3:26][C:27]1([CH3:34])[NH:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:26][C:27]1([CH3:34])[C:28](=[O:33])[N:29]([C:5]2[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)[C:30](=[O:32])[NH:31]1
Reactant: N#Cc1ccc(Cl)cc1C(F)(F)F
Reactant: CC1(C)NC(=O)NC1=O
Solvent: COCCOCCOCCOC
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: -10 °C
Reaction time: 4 h
Yield: 30.7 %

Procedure:
4.47 g of the product obtained in Stage 1 above, 11.2 ml of triglyme, 2.78 g of 5,5-dimethyl hydantoin and 1.34 g of cuprous oxide are introduced then the suspension is agitated and taken to 215° C. for 4 hours. Then it is returned to ambient temperature, followed by filtering, washing with 4.5 ml of triglyme and agitating without exceeding 25° C., 4.5 ml of 22°Be concentrated ammonium hydroxide, 26 ml of water and 4.5 ml of toluene. Agitation is carried out for 15 minutes at 20° C. then the reaction medium is cooled down to -10° C., agitation is carried out for 1 hour, followed by separating, washing with 2.2 ml of toluene then 4.5 ml of water and drying. In this way 1.98 g of expected product (brown crystals) is obtained. M.p.=210° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([OH:17])(=O)=[O:15].P(Cl)(Cl)([Cl:20])=O>>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([Cl:20])(=[O:17])=[O:15]
Reactant: O=S(=O)(O)c1ccc2oc3ccccc3c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc2oc3ccccc3c2c1
Yield: 85 %

Procedure:
2-Dibenzofuransulfonic acid (12.8 mmol) was heated at 70° C. with phosphorus oxychloride (1.30 ml, 14.0 mmol) for 2 h. Excess phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to yield 2.9 g crude 2-dibenzofuransulfonyl chloride.
Reaction SMILES: N[C@H](C(O)=O)[C@H](CC)C.[BH4-].[Na+].O1CCCC1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[C:31](=[O:32])[C:30](=[O:33])[NH:29][C:28]3[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=3[S:26]2)=[CH:21][CH:20]=1>C(O)(=O)C>[OH:32][C@H:31]1[C:30](=[O:33])[NH:29][C:28]2[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=2[S:26][C@H:25]1[C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1
Reactant: COc1ccc(C2Sc3ccccc3NC(=O)C2=O)cc1
Agent: CC[C@H](C)[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: -20 °C
Reaction time: 20 h
Yield: 87.4 %

Procedure:
A mixture of L-isoleucine (289 mg), sodium borohydride (76 mg) and tetrahydrofuran (15 ml) is refluxed under nitrogen atmosphere for three hours. The mixture is cooled to -20° C., and thereto is added 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (299 mg), and the mixture is stirred at the same temperature for 20 hours. To the reaction solution is added acetic acid (600 mg), and the mixture is stirred for two hours, and then evaporated under reduced pressure to remove the solvent. Water is added to the residue, and the precipitated crystal is collected by filtration, washed with water, and dried to give (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (263 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:2]1.C(N(CC)CC)C.ClCCl.[CH3:27][CH:28]([CH3:34])/[CH:29]=[CH:30]/[C:31](Cl)=[O:32].ClCCl.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>>[CH3:27][CH:28]([CH3:34])/[CH:29]=[CH:30]/[C:31]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:2]1)=[O:32]
Reactant: c1ccc2c(N[C@H]3CCNC3)ccnc2c1
Reactant: CC(C)/C=C/C(=O)Cl
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)/C=C/C(=O)N1CC[C@H](Nc2ccnc3ccccc23)C1
Yield: 39 %

Procedure:
To N-[(3S)-Pyrrolidin-3-yl]quinolin-4-amine (32 mg, 0.15 mmol) dissolved in 1.5 ml anhydrous dichloromethane triethylamine (0.9 mmol, 91 mg) was added with stirring followed by (E)-4-methylpent-2-enoyl chloride dissolved in anhydrous dichloromethane (29.8 mg, 0.23 mmol). The mixture was stirred at room temperature for 5 minutes after which polymer-supported toluenesulfonyl chloride (600 mg, 1-2 mmol/g) was added and the mixture was shaken for 15 minutes, filtered and the filtrate evaporated to dryness under reduced pressure. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 18 mg of a solid (0.58 mmol, 39%).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][O:5][C:6]1[N:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([N:16]3[CH:24]([CH2:25][C:26](=O)[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:33])=[N:13]2)=[CH:8][CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:3][N:2]=[C:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:25][CH:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:33])[N:16]1[C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[N:15][C:6]([O:5][CH3:4])=[CH:7][CH:8]=2)[N:13]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(CCC(C)C)=NO)nc2n1
Yield: 22.4 %

Procedure:
Hydroxylamine hydrochloride (0.9 g) is added to a suspension, maintained at 0° C. with a bath of ice-cold water, of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (4.3 g) in a mixture (100 cc) of water and ethanol (50:50 by volume). The suspension obtained is allowed to return to a temperature in the region of 20° C. and a solution of sodium carbonate (0.7 g) in distilled water (10 cc) is added. The suspension obtained is heated to reflux for 22 hours. During this period, ethanol (80 cc) is added in two portions. Refluxing is maintained for 12 hours, adding in three portions further hydroxylamine hydrochloride (1.35 g) and sodium carbonate (1.05 g). The reaction mixture is then poured into water (1 litre). The aqueous phase is extracted with methylene chloride (3×300 cc). The organic phases are combined, washed with distilled water (2×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness. After recrystallization in 2-propanol, 3-(2-hydroxyimino-5-methylhexyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (1 g), m.p. 200° C., is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:40])=[CH:9][C:8]=2[N:17]=1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate (7.20 g, 16.8 mmol) in 200 mL of CH2Cl2 was treated with MCPBA (77%, 4.32 g, 19.3 mmol). After stirring 6 h, the reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed with H2O and brine then dried over Na2SO4 and concentrated to give 7.05 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH:7]([CH2:28][N:29](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].C(OCC)C>[C:1]([O:5][C:6](=[O:44])[CH:7]([CH2:28][NH2:29])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN(Cc3ccccc3)Cc3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1

Procedure:
The product from step (c) above (4.6 g, 7.62 mmole) in ethanol (75 ml) was hydrogenated in an atmosphere of hydrogen (50 p.s.i., 3.46 bar) over palladium on charcoal (200 mg), at room temperature overnight. The reaction mixture was filtered through a Solkaflok pad, and the filtrate evaporated to dryness to yield the crude product as an oil. This was dissolved in diethyl ether, and extracted into dilute hydrochloric acid (pH 2) (2x). The combined aqueous layers were washed with diethyl ether, then neutralised with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3x). The combined organic phases were dried (Na2SO4) and evaporated to yield the title amine as an oil (2.91 g, 90%). Found: C,64.80; H,9.28; N,6.76. C23H40N2O5 requires C,65.06; H,9.50; N,6.60%.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([Cl:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of 4-chlorophenoxy acetic acid (9.32 g, 0.05 mol) in CH2Cl2 (150 mL) was added oxalyl chloride (32.5 mL, of 2M in CH2Cl2) and DMF (0.2 mL). The resulting mixture was stirred at rt overnight under Ar. The mixture was concentrated in vacuo to give 10.3 g (100%) of 56a as colorless oil. 1H NMR (60 MHz, CDCl3): δ 7.0-6.7 (m, 4H), 4.8 (s, 2H) ppm.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][OH:28])=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][CH:33]=[N:34][C:16]1=2)[CH3:14].O[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:46]=[C:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[O:44][N:43]=2)=[CH:38][C:37]=1[CH3:52].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][O:28][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[CH:46]=[C:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[O:44][N:43]=4)=[CH:38][C:37]=3[CH3:52])=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][CH:33]=[N:34][C:16]1=2)[CH3:14]
Reactant: CCOC(=O)c1cc(-c2ccc(O)c(C)c2)no1
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(OCCc3cnc4c(c3)C(=O)N(C)c3cccnc3N4CC)c(C)c2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
DEAD (55 μL, 0.35 mmol) was added over 30 min to a solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (70.0 mg, 0.23 mmol), ethyl 3-(4-hydroxy-3-methylphenyl)-5-isoxazolecarboxylate (86.5 mg, 0.35 mmol) and PPh3 (91.8 mg, 0.35 mmol) in THF (2 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:EtOAc, 10:1) to give the title compound (55 mg, 45% yield).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]1[O:8][CH2:7]1.C1OC1.[N-:12]=[N+:13]=[N-:14].[Na+].C1C(N)=NC(=O)N(CCOCCP(O)(O)=O)C=1.[OH-].[Na+]>CC(N(C)C)=O>[CH2:1]([N:12]=[N+:13]=[N-:14])[CH:3]1[O:5][CH2:4]1.[CH2:7]1[O:8][CH2:6]1
Reactant: ClCC1CO1
Reactant: [N-]=[N+]=[N-]
Agent: Nc1ccn(CCOCCP(=O)(O)O)c(=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CO1
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=NCC1CO1

Procedure:
Elastomeric GEC is prepared according to the same previous procedure as in Example 1, except that commercial rubbery Epichlorohydrin-Ethylene Oxide Copolymer (PEEC) is used instead of PECH as the starting material. The copolymer contains about 70% PECH and 30% Ethylene Oxide. For this reason, a weight ratio NaN3 :PEEC of 0.55 is used in this case. Specifically, the reaction for 5 h at 120° C. of 10 g PEEC (MW~9×105) in 50 g DMA and 5 g EG with 5.5 g NaN3 and 0.9 g NaOH will yield 9.0 g (90%) of GEC azido product. This copolymer containing about 70% GAP and 30% Ethylene Oxide has a MW of about 10,000, a Tg of about -55° C. and a functionality (f) of about 3.5.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:29])[CH2:14][CH:15]([CH:22](C(O)=O)[C:23]([OH:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:7]=[CH:6]2.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:29])[CH2:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:22][C:23]([OH:25])=[O:24])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(=O)CC(c3ccccc3)C(C(=O)O)C(=O)O)ccc2c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)CC(CC(=O)c1ccc2cc(O)ccc2c1)c1ccccc1
Temperature: 150 °C
Yield: 78.2 %

Procedure:
A mixture of 2-(3-(6-methoxynaphthalen-2-yl)-3-oxo-1-phenylpropyl)malonic acid (0.15 g) in acetic acid (5 ml) was treated with 48% aqueous HBr (2 ml) and heated to 150° C. for 2 h. The solvent and acid were removed by distillation and the residue was partitioned between 10% HCl and ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, and evaporated to afford a crude, which was purified by flash chromatography on silica gel to give 5-(6-hydroxy-2-naphthalenyl)-5-oxo-3-phenylpentanoic acid (0.1 g) as pale yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=[O:18])[CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH3:27])[CH:8]=2)[CH3:2].[CH3:29][C:30](C)([O-:32])C.[K+].CCCCCC>C(OCC)(=O)C>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=[O:18])[CH2:17][C:30](=[O:32])[CH3:29])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH3:27])[CH:8]=2)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCn1c2ccc(C(C)=O)cc2c2cc(C(=O)c3ccc(F)cc3C)ccc21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCn1c2ccc(C(=O)CC(C)=O)cc2c2cc(C(=O)c3ccc(F)cc3C)ccc21
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A one liter four-necked flask equipped with a stirrer, a nitrogen inlet tube, a reflex condenser, and a thermometer was charged with 74.69 g of 1-[9-ethyl-6-(4-fluoro-2-methylbenzoyl)-9H-carbazol-3-yl]ethanone, 538.66 g of ethyl acetate, and 67.33 g of potassium t-butoxide, and the mixture was refluxed in a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, and the white solid thus precipitated was collected by filtration by suction and washed with 500 ml of ethyl acetate. The resulting solid was stirred in 500 ml of 2N hydrochloric acid and 1.5 liters of ethyl acetate. The organic phase was washed with water until neutral. The organic phase was separated, dried with 70 g of magnesium sulfate, and filtered by suction. The solvent was removed by evaporation to give a pale yellow solid. The solid was dissolved in 150 ml of ethyl acetate and refluxed, and 100 ml of n-hexane was added thereto, followed by cooling to room temperature for crystallization. The filtrate was dissolved in 50 ml of ethyl acetate, refluxed, and 100 ml of n-hexane was added, followed by cooling to room temperature for crystallization. The resulting crystals were combined, collected by filtration by suction, and dried under reduced pressure to give 8.52 g (21%) of white crystals, which had a melting point of 132° C. and was identified by various analyses to be β-diketone compound No. 2 having a carbazolyl group.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=3)[C:23]#[N:24])=[N:14][C:12]=2[N:13]=1.[OH:37]S(O)(=O)=O.[OH-].[Na+]>O>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:28])[CH3:29])=[C:22]([CH:25]=3)[C:23]([NH2:24])=[O:37])=[N:14][C:12]=2[N:13]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)Oc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)Oc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1C(N)=O
Temperature: 90 °C

Procedure:
5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzonitrile (1 equiv) was added portionwise to concentrated H2SO4 (0.1 M substrate in acid). The reaction was heated to 90° C. and maintained at this temperature until all starting material had dissolved to give a bright red solution. The mixture was cooled and water (2 reaction volumes) added dropwise, then the solution was neutralized by careful addition of solid NaOH until pH 4-5 was attained. The mixture was cooled and neutralised by addition of 2N NaOH and then extracted using EtOAc (2×10 reaction volumes). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO2) using MeOH/DCM—0:100 going to 5:95 as eluent to give the desire product as a yellow powder.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH2:26][CH2:27]O)[N:23]=[N:22]4)[O:17][C:16]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.S(Cl)([Cl:34])=O.CO>ClCCl>[O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH2:26][CH2:27][Cl:34])[N:23]=[N:22]4)[O:17][C:16]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1
Reactant: O=C1O[C@@H](Cn2cc(CCO)nn2)CN1c1cc(F)c(C2=CCS(=O)(=O)CC2)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1O[C@@H](Cn2cc(CCCl)nn2)CN1c1cc(F)c(C2=CCS(=O)(=O)CC2)c(F)c1
Yield: 91.3 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-(2-hydroxyethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 51) (300 mg, 0.66 mmol) was reacted with thionylchloride (78.5 mg, 1.98 mmol) as described for Example 52. Chromatography on silica gel with 2.5% methanol in dichloromethane gave the title compound (285 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH:19]([C:21]1[NH:22][C:23]([CH3:31])=[CH:24][C:25]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[CH:19][C:21]3[NH:22][C:23]([CH3:31])=[CH:24][C:25]=3[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1cc(CCC(=O)O)c(C=O)[nH]1
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)cc1CCC(=O)O

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (71 mg, 0.3 mmol) was condensed with 3-(2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid (54 mg) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:51][N:52]1[C:61]2[C:56](=[CH:57][N:58]=[C:59]([CH3:62])[CH:60]=2)[CH:55]=[C:54]([C:63]2[CH:64]=[C:65]([NH:70]/[C:71](/[NH2:74])=[N:72]/O)[CH:66]=[CH:67][C:68]=2[CH3:69])[C:53]1=[O:75]>CN(C=O)C>[CH3:51][N:52]1[C:61]2[C:56](=[CH:57][N:58]=[C:59]([CH3:62])[CH:60]=2)[CH:55]=[C:54]([C:63]2[CH:64]=[C:65]([NH:70][C:71]3[N:72]=[C:8]([C:5]4([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]4)[O:10][N:74]=3)[CH:66]=[CH:67][C:68]=2[CH3:69])[C:53]1=[O:75]
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(c2nc(Nc3ccc(C)c(-c4cc5cnc(C)cc5n(C)c4=O)c3)no2)CC1
Temperature: 100 °C

Procedure:
To a solution of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (56 mg, 0.39 mmol), HATU (180 mg, 0.47 mmol) and DIPEA (0.082 mL, 0.47 mmol) in dry DMF (2 mL) at rt in the presence of anhydrous Na2SO4 (284 mg, 2.0 mmol) was added 17 (130 mg, 0.39 mmol) slowly. The consumption of 17 was determined to be completed by LC/MS. The mixture was heated at 100° C. for 2 h. Solid was filtered off and the residue was dissolved in EtOAc (50 mL). The organic layer was washed with water twice, dried over Na2SO4, filtered and evaporated to yield a residue which was purified by flash chromatography on silica with 3-5% MeOH in DCM as eluant to yield methyl 1-(3-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenylamino)-1,2,4-oxadiazol-5-yl)cyclopropanecarboxylate 23. MS m/z 446.2 (M+1).