Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].C(O)(=O)C(O)=O.[C:11]([O:15][C:16](=[O:33])[CH2:17][N:18]([C:28](=[O:32])[C@H:29]([CH3:31])[NH2:30])[CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)([CH3:14])([CH3:13])[CH3:12].C([O-])(=O)C.[Na+].[CH2:39]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55][CH2:56][CH2:57][CH2:58][C:59](=O)[C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:51][CH2:50]1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(O)C.C(O)(=O)C>[C:11]([O:15][C:16](=[O:33])[CH2:17][N:18]([C:28](=[O:32])[C@H:29]([CH3:31])[NH:30][C@@H:59]([C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:58][CH2:57][CH2:56][CH2:55][CH:52]1[CH2:53][CH2:54][N:49]([C:47]([O:46][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:48])[CH2:50][CH2:51]1)[CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reaction time: 8 h
Yield: 10.5 %

Procedure:
A solution of 0.6 g of sodium cyanoborohydride in 50 ml of ethanol is added dropwise to a stirred mixture of 2 g of N-(L-alanyl)-N-(2-indanyl)glycine tert-butyl ester oxalate, 078 g of sodium acetate, 0.58 g of acetic acid, 10 g of molecular sieves 3A, 3.6 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate and 50 ml of ethanol at room temperature over a period of 3 hours. The reaction solution is allowed to stand overnight and filtered, and the filtrate is concentrated under reduced pressure. The residue is diluted with 50 ml of water and extracted with 200 ml of ethyl acetate. The extract is dried and concentrated under reduced pressure. The resulting oily material is separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 2:3), whereby the first fraction yields 0.35 g of N-[N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester as a colorless oil.
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:13]2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:13]2
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]c(-c3ccccc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cccc2[nH]c(-c3ccccc3)cc12
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
4-t-Butyldimethylsilyoxy-2-phenylindole (55 mg, 0.17 mmol) was dissolved in THF (10 ml) at 0° C. and treated with tetrabutylammonium flouride (0.5 ml, 1.0 M in THF, excess). After stirring at this temperature for 10 minutes, the reaction was quenched by addition of saturated ammonium chloride. The mixture was extracted several time with ethyl acetate, dried over magnesium sulfate, and evaporated to give a crude oil. Flash chromatography (5% ethyl acetate/hexanes) provided the desired phenol (30 mg, 84.8%) as a white solid. NMR. MS.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH:25]([CH3:27])[CH3:26])[CH:18]=1)=[C:10]([Cl:28])[CH:9]=2)=[O:5])C.[H-].[Na+].I[CH3:32]>CN(C)C=O>[CH3:1][O:3][C:4]([C:6]1[N:7]([CH3:32])[C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH:25]([CH3:26])[CH3:27])[CH:18]=1)=[C:10]([Cl:28])[CH:9]=2)=[O:5]
Reactant: CI
Reactant: CCOC(=O)c1cc2c(Cl)c(Oc3ccc(OC)c(C(C)C)c3)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)c(Oc3ccc(OC)c(C(C)C)c3)c(Cl)cc2n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a solution of 4,6-dichloro-5-(3-isopropyl-4-methoxy-phenoxy)-1H-indole-2-carboxylic acid ethyl ester (50 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 4.3 mg, 0.18 mmol) and the mixture was stirred at 0° C. for 30 minutes. To which at 0° C. was added iodomethane (15 μL, 0.24 mmol). The solution was warmed to room temperature, stirred for 19 hours, quenched with 1M hydrochloric acid (15 mL) and extracted with ethyl acetate (15 mL). The organic extract was washed with 1M hydrochloric acid (4 times 20 mL), brine (20 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative thin layer chromatography (50% CH2Cl2 in hexane) to afford the title compound (46 mg). 1H NMR (400 MHz, CDCl3) δ7.42 (s, 1H), 7.33 (s, 1H), 6.85 (d, 1H), 6.65 (d, 1H), 6.42-6.39 (dd, 1H), 4.05 (s, 3H), 3.91 (s, 3H), 3.91 (s, 3H), 3.74 (s, 3H), 3.27-3.23 (m, 1H), 1.15 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]=[CH2:11])=[CH:7][CH:6]=[CH:5][C:4]=1[O:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[C:8]([CH:9]=[CH:10][CH3:11])=[CH:7][CH:6]=[CH:5][C:4]=1[O:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CCc1cccc(Oc2ccccc2C)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC=Cc1cccc(Oc2ccccc2C)c1OC
Yield: 100 %

Procedure:
o-Tolyl 2-methoxy-3-allylphenyl ether (30 g) and a solution of potassium hydroxide (40 g) in methanol (150 ml) were treated in a similar manner to that of Example 4-(2) to give oily o-tolyl 2-methoxy-3-(1-propenyl)phenyl ether (30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:30]1[CH2:35][CH2:34][CH:33]([CH2:36][C:37]([OH:39])=O)[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:37](=[O:39])[CH2:36][CH:33]2[CH2:32][CH2:31][O:30][CH2:35][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC1CCOCC1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)CC1CCOCC1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-2-(tetrahydro-pyran-4-yl)-acetamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using tetrahydropyran-4-yl-acetic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown foam. MS m/e: 564.4 [M]+.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[CH:6]([NH2:28])[CH:7]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[NH:13][CH:12]=1)[CH2:8][O:9][CH3:10])([CH3:3])[CH3:2].[CH2:30]=O>C1(C)C(C)=CC=CC=1>[CH:1]([O:4][C:5]([CH:6]1[CH:7]([CH2:8][O:9][CH3:10])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)[NH:13][C:12]=2[CH2:30][NH:28]1)=[O:29])([CH3:3])[CH3:2]
Reactant: COCC(c1c[nH]c2ccc(OCc3ccccc3)cc12)C(N)C(=O)OC(C)C
Reactant: C=O
Solvent: Cc1ccccc1C
Product: COCC1c2c([nH]c3ccc(OCc4ccccc4)cc23)CNC1C(=O)OC(C)C
Yield: 61.2 %

Procedure:
A solution is prepared from 3.8 g of 2-amino-3-(5-benzyloxyindol-3-yl)-4-methoxybutyric acid isopropyl ester (10 mmol) in 80 ml of xylene and added dropwise to a suspension of 360 mg of paraformaldehyde in 60 ml of xylene heated for 45 minutes to 100° C. The mixture is then refluxed for 2 hours on a water trap. After concentration, the residue is chromatographed over silica gel with methylene chloride:acetone=1:1 as the eluent, yielding 2.5 g of 6-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester (65% yield as an oil); or
Reaction SMILES: [Cl:1]Cl.[C:3]([NH2:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[Cl:1][NH:11][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccccc1
Reactant: ClCl
Solvent: O
Product: O=C(NCl)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A stream of gaseous chlorine in introduced at a speed of about 33 g/h into a suspension of 111 g of 99.5% pure benzamide (0.91 mol) in 700 ml of water maintained at a temperature of 15°-20° C. After 2 h and 15 min 75 g of chlorine (1.05 mol), controlled by weighing, have been absorbed. The mass is stirred for another 15 min at a temperature of 20° C., then the chlorinated product obtained is filtered off and is washed with water until the hydrochloric acid has disappeared. 140 g of N-chlorobenzamide (yield 98.9%) containing 21.87% of active chlorine, corresponding to a titer of 96%, are obtained.
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:16])(=[O:15])[N:7]([CH3:17])[C:6]=1[C:18]1[O:22][C:21]([CH3:23])=[N:20][N:19]=1)(=O)C.C[O-].[Na+].O.Cl>CO>[OH:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:15])(=[O:16])[N:7]([CH3:17])[C:6]=1[C:18]1[O:22][C:21]([CH3:23])=[N:20][N:19]=1
Reactant: CC(=O)OC1=C(c2nnc(C)o2)N(C)S(=O)(=O)c2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nnc(C2=C(O)c3ccccc3S(=O)(=O)N2C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of product (b) (2.218 g) in methanol (20 ml) was added 28% sodium methoxide (1.28 ml). After stirring at room temperature for 30 minutes, the solvent was stripped off and water (30 ml) was added. With vigorous stirring the pH was adjusted to ca. 1.5 with 6N HCl and the resulting solid granulated for 1 hour, filtered off, washed with water, and dried in vacuo to give compound (c), 1.903 g, 98% yield.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([O:29][C:30]1[C:38]2[NH:37][CH:36]=[CH:35][C:34]=2[C:33]([CH2:39][OH:40])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:22]([O:29][C:30]1[C:38]2[NH:37][CH:36]=[CH:35][C:34]=2[C:33]([CH:39]=[O:40])=[CH:32][CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCc1ccc(OCc2ccccc2)c2[nH]ccc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(OCc2ccccc2)c2[nH]ccc12
Reaction time: 2 h

Procedure:
Solid pyridinium dichromate (5.4 g., 15.5 mmol) was added in portions over 8 hours to a stirred solution of 7-benzyloxyindole-4-methanol (1.17 g, 4.6 mmol) in dichloromethane (30 ml). The dark mixture was stirred for a further 2 hours, filtered through a bed of silica and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[C:31]2[CH:30]=[CH:29][S:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>CO>[S:28]1[CH:29]=[CH:30][C:31]2[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:15]3[CH2:14][CH2:13][CH:12]([C:7]4[CH:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[CH:8]=4)[CH2:17][CH2:16]3)=[CH:24][CH:25]=[CH:26][C:27]1=2
Reactant: Fc1ccc2cc(C3CCNCC3)ccc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2ccsc2c1
Solvent: CO
Product: O[C@H](COc1cccc2sccc12)CN1CCC(c2ccc3cc(F)ccc3c2)CC1
Yield: 50.3 %

Procedure:
A solution 4-(6-fluoronaphth-2-yl)piperidine (0.069 g, 0.301 mmol) and (S)-(+)-4-(oxiranylmethoxy)benzo[b]thiophene (0.062 g, 0.301 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient elution) to give the title compound as a white amorphous solid (0.066 g, 50%). FDMS m/e 436 (M++1). C26H26FNO2S.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:21])[CH:19]([NH2:20])[C@H:16]3[S:15][CH2:14][C:13]=2[OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25]([CH2:27][CH2:28][C:29](Cl)=[S:30])#[N:26]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:21])[CH:19]([NH:20][C:29](=[S:30])[CH2:28][CH2:27][C:25]#[N:26])[C@H:16]3[S:15][CH2:14][C:13]=2[OH:22])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: N#CCCC(=S)Cl
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Product: N#CCCC(=S)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
7-Amino-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester [J. Am. Chem. Soc. 96, 4986 (1974)]is acylated with cyanomethylthioacetyl chloride by the procedure described in Example 1 to obtain 7-cyanomethylthioacetamido-3-cephem-3-ol-4-carboxylic acid p-nitrobenzyl ester as an oil.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[C:60]([Cl:67])[C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][N:69]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:67][C:60]1[C:61]([F:66])=[CH:62][C:63]([F:65])=[C:64]2[C:59]=1[N:58]=[C:57]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][N:69]=1)[C:56]([CH3:74])=[C:55]2[NH:47][C:46]1[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[N:42][CH:43]=[C:44]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:45]=1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2c(Cl)c(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(Cl)c(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.049 mmol), 2,5-dimorpholinopyridin-3-amine (0.098 g, 0.37 mmol), 4,8-dichloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.1 g, 0.31 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.074 g, 0.77 mmol) in toluene (3.1 mL) at 120° C. for 3 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 8-chloro-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.68 (1H, d, J=4.6 Hz), 8.18 (1H, d, J=8.0 Hz), 7.93 (1H, td, J=7.7, 1.8 Hz), 7.79 (1H, br. d., J=10.4 Hz), 7.64 (1H, d, J=2.5 Hz), 7.40 (1H, dd, J=7.4, 4.6 Hz), 7.11 (1H, dd, J=13.0, 8.7 Hz), 6.45 (1H, br. s.), 3.93 (4H, s), 3.81 (4H, app. dd, J=4.1, 2.5 Hz), 3.25 (4H, br. s), 3.09 (4H, app. dd, J=5.9, 3.9 Hz), 2.32 (3H, s). Mass Spectrum (ESI) m/e=553.2 (M+1).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:16])([O:3]C)=[O:2].O.[OH-].[Na+]>CO>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:16])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCCCCC(=O)Nc1ccccc1OCCCC(=O)O
Yield: 96 %

Procedure:
To a stirred solution of (8) (1.0 g, 2.22 mM) in methanol (100 mL) is added 1 mL of water followed by dropwise addition of 2.5 N sodium hydroxide solution (4.0 mL). The walls of the reaction flask are rinsed down with 10 mL of methanol and the mixture is stirred under a nitrogen atmosphere until TLC analysis shows no ester (mono- or di-) remaining. The methanol is removed in vacuo, the residue taken up in 100 mL of water, stirred for solution, filtered (20 mL water rinses), and the stirred filtrate acidified dropwise with 2 N hydrochloric acid. Filtration of the resultant precipitate followed by copious water washing and drying gave 0.87 g (96%) of (9) as a chalk-like white solid. The compound was one component by TLC (silica gel, the eluant was 10 mL of 2% methanol in methylene chloride containing 4 drops of glacial acetic acid). mp 128.5-130° C. uncorr.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])[NH:10][C:11]1[N:16]=[C:15]([CH2:17][OH:18])[C:14]2[C:19]([O:41][CH3:42])=[N:20][N:21]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.CN(C=O)C.[C:54]([Si:58]([CH3:61])([CH3:60])Cl)([CH3:57])([CH3:56])[CH3:55]>C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:43])[NH:10][C:11]1[N:16]=[C:15]([CH2:17][O:18][Si:58]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:61])[CH3:60])[C:14]2[C:19]([O:41][CH3:42])=[N:20][N:21]([C:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)nc(CO)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)nc(CO[Si](C)(C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a 50 mL round bottom flask charged with benzyl(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (180 mg, 0.315 mmol), imidazole (42.9 mg, 0.631 mmol) and DMF (3 ml) was added tert-butyldimethylchlorosilane (57.1 mg, 0.379 mmol). The flask was capped and the contents stirred at room temperature for 2 h. LCMS analysis indicated 80% conversion to the desire product. Excess tert-butyldimethylchlorosilane (25 mg) was added, and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (2×30 mL), dried (MgSO4) and filtered. The solvent was evaporated under reduced pressure to afford crude benzyl(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (199 mg, 0.291 mmol, 92% yield) as a colorless oil. MS: [M+H]+ m/z 685.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH2:25][CH3:26])CC3C=CC(OC)=CC=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1.C([O:53][P:54]([O:64][CH:65]([CH3:69])[C:66](O)=[O:67])([O:56]CC1C=CC=CC=1)=[O:55])C1C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.ClC1C(NC2N=C(N(CC)CC3C=CC(OC)=CC=3)C3=NC=C(C#N)N3N=2)=CC(C#N)=CC=1N1CC[C@@H](NC(OC)=O)[C@H](C(OP(OCC2C=CC=CC=2)(OCC2C=CC=CC=2)=O)(C)C([O-])=O)C1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[P:54]([O:64][CH:65]([CH3:69])[C:66]([O:45][C@H:36]1[C@H:37]([NH:40][C:41]([O:42][CH3:43])=[O:44])[CH2:38][CH2:39][N:34]([C:3]2[CH:4]=[C:5]([C:32]#[N:33])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([NH:15][CH2:25][CH3:26])[C:12]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:35]1)=[O:67])([OH:56])([OH:55])=[O:53]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reactant: CC(OP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](C(C)(OP(=O)(OCc4ccccc4)OCc4ccccc4)C(=O)[O-])C3)c2Cl)nn2c(C#N)cnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)C(C)OP(=O)(O)O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (0.040 g, 0.063 mmol), 2-((bis(benzyloxy)phosphoryl)oxy)propanoic acid (0.067 g, 0.19 mmol) in DCM (2 mL) was added DCC (0.039 g, 0.190 mmol) followed DMAP (0.77 mg, 0.006 mmol) and stirred at room temperature for 30 min. After completion of starting material (by LC-MS), reaction mixture was diluted with DCM (50 mL), filtered through celite and filtrate was washed with water and brine solution (5 mL). Combined organic extracts were dried over anhydrous Na2SO4, concentrated and purified by flash chromatography on silica gel using an ISCO system (eluted with 1:1 Hexanes and EtOAc) to give diastereomeric mixture of (3R,4R) 1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4((methoxycarbonyl)amino)piperidin-3-yl-2-((bis(benzyloxy)phosphoryl)oxy)propanoate (0.060 g) as gummy liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH2:21]([CH:29]1[CH2:33][C:32](=[O:34])[O:31][C:30]1=[O:35])[CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:32]([CH2:33][CH:29]([CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:30]([OH:35])=[O:31])=[O:34]
Reactant: CCCCCC=CCC1CC(=O)OC1=O
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: Cc1ccccc1
Product: CCCCCC=CCC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.1 g, 0.37 mmol; prepared in a manner similar to that described in Example 23), 3-oct-2-enyldihydrofuran-2,5-dione (0.078 g, 0.37 mmol) and toluene (10 ml) was heated under reflux for 20 hours, then the solvent was removed in vacuo to give crude 2-{[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]methyl}dec-4-enoic acid (0.133 g) as an oil which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[Cl:6][C:7]1[C:8]([CH2:9][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: C1CCNC1
Reactant: O=Cc1cccc(O)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(CN2CCCC2)c1Cl
Yield: 54.6 %

Procedure:
Pyrrolidine (71.3 mL, 855 mmol) was added to a solution of intermediate 12, 2-chloro-3-hydroxybenzaldehyde (103 g, 658 mmol) in dichloromethane (1 L). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (209.3 g, 987 mmol) was added in portions under stirring. The reaction mixture was stirred for 12 h at room temperature. Water (500 mL) and concentrated HCl were added to attain pH˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×400 mL), then with EtOAc (400 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, and the product was extracted with CHCl3 (3×500 mL). The organic layer was dried with Na2SO4 and evaporated in vacuo. The obtained crystals were separated by filtration from Et2O/hexane mixture (1:1) and coevaporated with dioxane to give the title compound (76 g, 55%, 359 mmol). LCMS data: 214 and 212 (M+H)+ (calculated for C11H14ClNO 211.7); 1H NMR data (DMSO-d6): 9.96 (br.s, 1H, OH); 7.08 (t, 1H, J=7.8 Hz, Ar—H); 6.91 (dd, 1H, J1=1.7 Hz, J2=7.3 Hz, Ar—H); 6.86 (dd, 1H, J1=1.7 Hz, J2=8.0 Hz, Ar—H); 3.64 (s, 2H, CH2Ar); 2.43-2.52 (m, 4H+DMSO); 1.65-1.74 (m, 4H).