Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:26]([O:28][CH2:29][C:30]1[N:31]([CH2:65][C:66]([OH:69])([CH3:68])[CH3:67])[C:32]2[C:41]3[CH:40]=[CH:39][C:38]([CH:42]=O)=[CH:37][C:36]=3[N:35]=[C:34]([NH:44][C:45]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:33]=2[N:64]=1)[CH3:27]>ClCCl>[CH2:26]([O:28][CH2:29][C:30]1[N:31]([CH2:65][C:66]([OH:69])([CH3:68])[CH3:67])[C:32]2[C:41]3[CH:40]=[CH:39][C:38](/[CH:42]=[CH:6]/[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:37][C:36]=3[N:35]=[C:34]([NH:44][C:45]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:33]=2[N:64]=1)[CH3:27]
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C=O)ccc3c2n1CC(C)(C)O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(/C=C/C(=O)OCC)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
(Carbethoxymethylene)triphenylphosphorane (422 mg, 1.21 mmol) was added to a solution of 2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carbaldehyde (472 mg, 808 μmol) in dichloromethane (8 mL) under argon. The reaction mixture was stirred for 20 h at room temperature and concentrated in vacuo. Crystallization from dichloromethane and diethyl ether afforded the title compound (0.399 g, 75%) as white solid, LC-MS (UV peak area, ESI) 89%, 655.4 (MH+).
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1cc(Cl)cc(Cl)c1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,5-Trichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,5-trichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:16]([CH3:27])[NH:15][C:14]=1[CH:28]=O>N1CCCC1.C(O)C>[Br: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:28][C:14]1[NH:15][C:16]([CH3:27])=[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:13]=1[CH3:12]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1CCCN1CCOCC1
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixuture of 5-bromo-1,3-dihydroindol-2-one (212 mg, 1.0 mmol), 3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carbaldehyde (250 mg, 1.0 mmol) and 3 drops pyrrolidine in 2.0 ml of ethanol was refluxed at 90° C. for 4 hours and then cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane and dried in a vacuum oven overnight to give 399.8 mg (90%) of 5-bromo-3-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one as a red solid:
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]([C:18]1[CH:19]=[N:20][C:21]([NH:24][C:25]3[N:26]=[CH:27][C:28]4[CH:33]=[C:32]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[N:31]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:29]=4[N:30]=3)=[CH:22][CH:23]=1)=[O:17])[CH2:12]2)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:36][N:35]([CH3:37])[C:34]([C:32]1[N:31]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:29]2[N:30]=[C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([C:16]([N:11]4[CH2:10][CH:9]5[NH:8][CH:13]([CH2:14][CH2:15]5)[CH2:12]4)=[O:17])=[CH:19][N:20]=3)[N:26]=[CH:27][C:28]=2[CH:33]=1)=[O:38]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 150.7 %

Procedure:
To a stirring solution of 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.232 g, 1. mmol) in CH2Cl2 (4 mL) was added a solution of 4M HCl in dioxane (2.54 mL, 10.14 mmol, 10 eq) at 25° C. After 4 hours stirring at 25° C. the reaction mixture was filtered and washed with CH2Cl2 (5 mL). The residue was collected and taken up in water then basified with 1M NaOH and extracted with CH2Cl2 (2×15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to a tan solid. The crude was purified using Column Chromatography (MeOH/CH2Cl2) giving the desired product as a white solid (0.290 g, 0.594 mmol, 59%).
Reaction SMILES: O.[ClH:2].[ClH:3].Cl.[CH2:5]([N:7]([CH2:33][CH3:34])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:23]([CH:24]=1)=[N:22][C:21]1[C:16](=[CH:17][CH:18]=[C:19]([O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH:20]=1)[CH:15]=2)[CH3:6].S(=O)(=O)(O)O.ClN1C(=O)CCC1=O>>[CH2:29]([N:28]([CH2:31][CH3:32])[CH2:27][CH2:26][O:25][C:19]1[CH:18]=[CH:17][C:16]2[C:21]([C:20]=1[Cl:2])=[N:22][C:23]1[C:14](=[CH:13][CH:12]=[C:11]([O:10][CH2:9][CH2:8][N:7]([CH2:5][CH3:6])[CH2:33][CH3:34])[C:24]=1[Cl:3])[CH:15]=2)[CH3:30]
Reactant: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)cc3nc2c1
Reactant: Cl
Agent: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c(Cl)c3nc2c1Cl

Procedure:
A 2.148 g. portion of 3,6-bis(2-diethylaminoethoxy)acridine trihydrochloride monohydrate is dissolved in 8 ml. of concentrated sulfuric acid. This solution is cooled in an ice bath and 1.175 g. of N-chlorosuccinimide are added. The procedure of Example 3 is followed giving 1.5 g. of a reddish brown crude product. This product is dissolved in 100 ml. of dichloromethane and filtered through a 2 inch×21/2 inch bed of alumina. The filter bed is washed with one liter of dichloromethane, then one liter of ethyl acetate. The filtrates are combined, concentrated in vacuo and the residue is crystallized from 10 ml. of hexane giving 1.067 g. of the desired product as yellow crystals, m.p. 83°-84° C.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:14])=[C:7]2[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH3:20]O>>[NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:14])=[C:7]2[C:11]([O:13][CH3:20])=[O:12]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1=C(C)CSC2C(N)C(=O)N12
Temperature: 75 °C

Procedure:
7-Amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1 g, 4.67 mmol) was suspended in methanol (20 mL) before treating with conc. sulphuric acid (0.1 ml, 1.876 mmol) and heated at reflux (75° C.) for 16 hours, under argon. After heating for 15 minutes all the remaining solid had dissolved to form a yellow solution. The solution turned from yellow to brown overnight. LCMS run. Desired product seen. Reaction cooled to RT, amount of solvent reduced in vacuo. Residue partitioned between EtOAc (40 ml) and saturated sodium bicarbonate solution (40 ml). Layers separated and aqueous layer was extracted with EtOAc (2×30 ml). Combined extracts were washed with brine (30 ml), dried over Na2SO4, filtered and evaporated to afford a brown gum of the desired product in 801 mg.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[O:17]=[C:18]1[C:26]2([C:30]3=[CH:31][C:32]4[O:36][CH2:35][O:34][C:33]=4[CH:37]=[C:29]3[O:28][CH2:27]2)[C:25]2[C:20](=[C:21]([C:38]#[N:39])[CH:22]=[CH:23][CH:24]=2)[NH:19]1>>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[C:38]#[N:39])[C:26]3([C:30]4=[CH:31][C:32]5[O:36][CH2:35][O:34][C:33]=5[CH:37]=[C:29]4[O:28][CH2:27]3)[C:18]2=[O:17])=[CH:5][CH:6]=1
Reactant: N#Cc1cccc2c1NC(=O)C21COc2cc3c(cc21)OCO3
Reactant: ClCc1ccc(Cl)s1
Agent: BrCC1CCCCO1
Product: N#Cc1cccc2c1N(Cc1ccc(Cl)s1)C(=O)C21COc2cc3c(cc21)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(5-chloro-2-thienyl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile was obtained (78%) as a colorless solid: mp 192-193° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 7.72 (dd, J=8.0, 1.1 Hz, 1H), 7.54 (dd, J=7.4, 1.1 Hz, 1H), 7.21 (dd, J=7.7, 7.7 Hz, 1H), 7.03 (s, 2H), 6.73 (s, 1H), 6.35 (s, 1H), 5.95 (dd, J=4.0, 0.7 Hz, 2H), 5.29 (d, J=1.5 Hz, 2H), 4.78 (dd, J=20.4, 9.6 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 155.5, 148.7, 143.2, 141.8, 137.6, 133.6, 133.2, 128.8, 127.9, 126.6, 126.5, 123.7, 118.5, 116.9, 103.0, 101.5, 93.4, 92.6, 79.5, 56.4, 40.0; MS (ES+) m/z 437.3 (M+1), 439.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][NH:18][CH:19]([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CNC(C)C
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C(C)C)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (3 g, 12.57 mmol) in DMSO (20 ml) was added methyl(propan-2-yl)amine (1.3 g, 17.77 mmol), and DIEA (3.2 g, 24.76 mmol). The resulting solution was stirred overnight at 70° C. The product was precipitated by the addition of ice/water and collected by filtration to afford methyl 3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (2.5 g, 72%).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:16]2([C:40]([F:43])([F:42])[F:41])[O:20][N:19]=[C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26]3([CH2:32][N:31]([C:33]([CH:35]5[CH2:38]S(=O)[CH2:36]5)=[O:34])[CH2:30]3)[O:25][CH2:24]4)[CH2:17]2)[CH:11]=[C:12]([Cl:15])[C:13]=1[F:14]>O.CO>[Cl:15][C:12]1[CH:11]=[C:10]([C:16]2([C:40]([F:41])([F:43])[F:42])[O:20][N:19]=[C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26]3([CH2:32][N:31]([C:33]([CH:35]5[CH2:38][S:3](=[O:5])(=[O:2])[CH2:36]5)=[O:34])[CH2:30]3)[O:25][CH2:24]4)[CH2:17]2)[CH:9]=[C:8]([Cl:7])[C:13]=1[F:14]
Reactant: O=S([O-])OO
Reactant: O=C(C1CS(=O)C1)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(C1CS(=O)(=O)C1)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 0 °C
Yield: 15.9 %

Procedure:
To a 20 mL vial containing a solution of oxone (320 mg, 0.52 mmol) in water (2 mL) at 0° C. was added (5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)(1-oxidothietan-3-yl)methanone from Example 4 (100 mg, 0.17 mmol) as a solution in methanol (4 mL). The reaction was stirred at 0° C. and allowed to warm to room temperature while stirring over 2 hours. Next, the reaction mixture was concentrated to remove excess MeOH and diluted with water. The crude product was extracted with CH2Cl2 (75 mL) and the organic phase was dried (Na2SO4) and concentrated under vacuum. The residue was purified by preparative HPLC to afford the final product (16 mg, 16%) as a solid. 1HNMR (CDCl3) δ ppm: 7.69 (1H), 7.63-7.60 (3H), 7.49 (1H), 5.19 (2H), 4.61-4.45 (4H), 4.36 (2H), 4.24-4.09 (3H), 3.72 (1H), 3.30 (1H); m/z (CI) 593 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28]I)[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCC(CCCI)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCn1ccnc1

Procedure:
To a solution of 0.32 g (0.57 mmol) of t-butyl 8-(p-chlorophenylsulfonamido)-4-(3-iodopropyl)octanoate in 3 mL dry dimethylformamide is added 0.116 g (1.7 mmol) imidazole and the mixture is then refluxed with ethyl acetate and washed with water and brine. The organic layer is dried, filtered, concentrated and then subjected to chromatography using ethyl acetate as eluent to yield t-butyl 8-(p-chloro- phenylsulfonamido)-4-[3-(1-imidazolyl)propyl]octanoate; IR (neat): 1718, 1337, 1164 cm-1 ; NMR (CDCl3): delta 7.5 (br,1H), 7.1 (s,1H), 6.9 (s,1H), 4.2 (t,2H).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1F.O1CCOCC1>O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:18]=1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Br)c(-n2ccnc2)c1
Temperature: 180 °C
Yield: 53.3 %

Procedure:
A microwave vial charged with potassium tert-butoxide (1.108 g, 9.88 mmol), 1H-imidazole (0.672 g, 9.88 mmol), 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (1.180 ml, 8.23 mmol), and 10 mL dioxane was heated to 180° C. in the microwave for 2 hours. LC/MS showed mostly product, so the reaction mixture was poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography (0 to 100% EtOAc/heptane) yielding 1-(2-bromo-5-(trifluoromethyl)phenyl)-1H-imidazole (1.277 g, 4.39 mmol, 53.3% yield). m/z (ESI) 291.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:25])=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[C:10](=[O:21])[CH:9]=1)[CH3:2].[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)[CH2:29][O:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:14](=[O:16])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[CH:22]=[CH:23][CH:24]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[F:25])=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:34]2)[CH2:29][O:28]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 87.3 %

Procedure:
To a solution of (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 114, 570 mg, 1.62 mmol) in N,N-dimethylformamide (10 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 382 mg, 1.94 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.43 g, 3.23 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.417 g, 3.23 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 10% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.750 g, 87%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:5]#[CH:6].Cl[C:21]1[N:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>CN(C=O)C.CCOC(C)=O>[CH2:3]([C:7]([C:21]1[N:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:5]#[CH:6]
Reactant: C#CCCC(C(=O)OCC)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCCC(C(=O)OCC)(C(=O)OC(C)(C)C)c1ncc([N+](=O)[O-])cn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (60%, 2.5 g, 62.4 mmol) in 100 mL of DMF was added tert-butyl ethyl but-3-yn-1-ylpropanedioate (15 g, 62.4 mmol) drop-wise at 25° C. The mixture was stirred at 40° C. for 30 minutes and 2-chloro-5-nitropyrimidine (10.0 g, 62.4 mmol) in 50 mL of DMF was added dropwise. The resulting suspension was stirred at 50° C. for 2 hours and diluted with 500 mL of EtOAc. The mixture was washed with water (3×100 mL), brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (Petroleum ether:EtOAc=10:1) to afford the title compound; MS m/z 364 (M+1)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:42]=1[F:56].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:43][C:42]=1[F:56]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 83.2 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 88, 3 g, 5.75 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (prepared as in Example 95, 3.9 g, 13.9 mmol) and dichlorobis(triphenylphosphine)palladium (II) (390 mg, 0.6 mmol) in dioxane (24 mL) was added an aqueous sodium carbonate solution (2 M, 6.93 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (2.50 g, 86%) as a white solid: LC/MS m/e calcd for C28H24F2N2O4S [M+H]+ 523.58, observed 522.7.
Reaction SMILES: [OH-:1].[Na+].BrBr.[Cl:5][C:6]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[C:14](=[O:16])C.Cl>O.O1CCOCC1>[Cl:5][C:6]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[C:14]([OH:16])=[O:1]
Reactant: [OH-]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1Cl
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.9 %

Procedure:
Sodium hydroxide (45.42 g, 1.090 mol) was dissolved in water (220 ml), and while cooling with ice, bromine (16.85 ml, 0.327 mol) was dripped therein over a period of 5 minutes. After stirring the reaction solution at 0° C. for 15 minutes, a dioxane (220 ml) solution of 2′,3′,4′-trichloroacetophenone (24.40 g, 0.109 mol) was dripped therein at 0° C. over a period of 30 minutes. After stirring at room temperature for 14 hours, water (350 ml) was added and then washed with dichloromethane (350 ml). The aqueous layer obtained was gradually made acidic with concentrated hydrochloric acid while cooling with ice and the resulting crystals were filtered out. After washing the filtered-out crystals with water, the water was removed by azeotropic distillation with toluene. 22.33 g (91%) of the title compound was thereby obtained as a pale yellow powder.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:10]2[C:14](=[C:15]([CH3:19])[C:16]=1[CH2:17][CH3:18])[CH2:13][O:12][C:11]2=[O:20])[CH:4]=O)[CH3:2].C(O)(=O)C(O)=O.[CH2:34]([O:36][P:37]([CH2:42][CH2:43][NH2:44])(=[O:41])[O:38][CH2:39][CH3:40])[CH3:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH2:39]([O:38][P:37]([CH2:42][CH2:43][NH:44][CH2:4][C:3]([CH2:1][CH3:2])=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])=[C:10]2[C:14](=[C:15]([CH3:19])[C:16]=1[CH2:17][CH3:18])[CH2:13][O:12][C:11]2=[O:20])(=[O:41])[O:36][CH2:34][CH3:35])[CH3:40]
Reactant: CCOP(=O)(CCN)OCC
Reactant: CCC(C=O)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOP(=O)(CCNCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CC)OCC
Reaction time: 8 h
Yield: 66.1 %

Procedure:
2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal (26.6 mg, 0.068 mmol) and aminoethylphosphonic acid diethylester oxalate salt (20.4 mg, 0.075 mmol) were dissolved in DMF (0.8 mL). Acetic acid (20.5 mg, 0.342 mmol) was added, followed by sodium triacetoxyborohydride (27.6 mg, 0.137 mmol). After 8 hours, the crude reaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide 24.9 mg (65%) of the desired product after lyophilization. 1H NMR (300 MHz, CDCl3): δ=0.05 (s, 9H), 1.10-1.24 (m, 8H), 1.35 (t, J=7.5 Hz, 6H), 2.19 (s, 3H), 2.23 (m, 2H), 2.35 (q, J=7.8 Hz, 2H), 2.70 (q, J=7.2 Hz, 2H), 3.25 (m, 2H), 3.56 (m, 4H), 4.15 (m, 4H), 4.29 (m, 2H), 5.15 (s, 2H), 5.47 (m, 1H) ppm; 31P NMR (121 MHz, CDCl3): δ=27.71 ppm; MS=554 [M++1].