Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15]Cl.[OH-].[Na+].[I-].[Na+]>C(O)C.C1(C)C=CC=CC=1.O>[CH3:12][O:13][CH2:14][CH2:15][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: COCCCl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COCCOc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
In 100 g of ethanol were dissolved 50.0 g (0.0347 mol) of 1-naphthol, 34.4 g (0.0364 mol) of 2-methoxyethyl chloride, 14.6 g (0.0365 mol) of sodium hydroxide, and 2.6 g (0.017 mol) of sodium iodide. The solution was heated and stirred at 80° C. for 8 hours. After cooling, the solution was combined with 100 g of water and 200 g of toluene, from which an organic layer was separated. It was washed 5 times with 100 g of 5 wt % sodium hydroxide aqueous solution and then 4 times with 100 g of water. The organic layer was concentrated, obtaining 45 g of oily matter. On vacuum distillation (110° C./13 Pa), 41 g of the target compound was recovered (yield 58%).
Reaction SMILES: [NH2:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5].O.C(=O)(O)[O-].[C:15](O)(=[O:26])[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>COCCOC.CN(C)C=O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:15]([NH:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:26]
Reactant: NC(=O)[C@@H](N)CC(=O)O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: NC(=O)[C@H](CC(=O)O)NC(=O)c1ccc2ccccc2n1
Yield: 69.1 %

Procedure:
To a solution of 0.50 g (3.78 mmol) of L-isoasparagine in 5.0 mL H2O containing ˜45 mg (1.5 eq) of solid bicarbonate. To this was added a suspension of 1.02 g (3.78 mmol) quinaldic acid, N-hydroxysuccinamide ester in ethylene glycol dimethylether, and the suspension was solubilized by the addition of 10 mL of dimethylformamide. After 3 hours the solution was acidified by the addition of 5% HC1 (aqueous) and the product was filtered and washed with water, dried under vacuum to yield 750 mg (70% yield) of N-(2-quinolinylcarbonyl)-L-isoasparagine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:19])[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].CCO>[OH-].[Na+]>[O:19]=[C:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: COC(=O)c1ccc2c(=O)c3ccccc3oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(=O)c3ccccc3oc2c1

Procedure:
A sample of 9-Oxo-9H-xanthene-3-carboxylic acid methyl ester, compound 4a, (16.6 g, 65.3 mmol) was suspended in 250 mL of 3 N NaOH and 250 mL of EtOH and heated to reflux for 1 h. At that time the EtOH was evaporated and the reaction was poured into 6 N HCl over ice and extracted with large volumes of 1:1 THF/diethyl ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated to provide 13.35 g of Compound 5a (55.6 mmol) after drying in a vacuum oven at 50° C. overnight.
Reaction SMILES: ClC[CH2:3][CH2:4][C:5]#[N:6].[N:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]N[CH2:9][CH2:8]1.C(N(CC)CC)C.CCOCC>C1(C)C=CC=CC=1>[CH2:4]1[CH:5]([N:6]2[CH2:11][CH2:12][N:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:9]2)[CH2:3]1
Reactant: N#CCCCCl
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C2CC2)CC1
Temperature: 20 °C
Yield: 101 %

Procedure:
124 g (1.2 M) of 4-chlorobutyronitrile were dissolved in 600 ml of toluene and the mixture was refluxed under a Dean-Stark separator for 1 hour. The resultant solution was cooled and then 158 g (1 M) of ethyl piperazine-1-carboxylate and 170 ml (1.2 M) of triethylamine were added thereto and the mixture was refluxed for 24 hours. The resulting suspension was cooled to 20° C. and one liter of ether was added thereto. The precipitate of triethylamine hydrochloride was filtered off and the filtrate was decolorized with charcoal and evaporated to dryness to obtain 200 g of ethyl 4-(3-cyclopropyl)-piperazine-1-carboxylate in the form of a brown oil which was distilled under reduced pressure at a boiling point of 140°-150° C. at 0.05 mm Hg.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:34]=[CH:33][CH:32]=[C:7]2[C:8]([N:10]([CH:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:19]=3)[CH2:14][C:15](O)=[O:16])[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:48][OH:49]>C1COCC1>[C:1]([NH:4][C:5]1[CH:34]=[CH:33][CH:32]=[C:7]2[C:8]([N:10]([CH:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[CH:19]=3)[CH2:14][C:15]([NH:48][OH:49])=[O:16])[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2]
Reactant: NO
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Yield: 69.3 %

Procedure:
3-(3-Acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(3-acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)propanoic acid (3.0 g, 6.5 mmol), carbonyldiimidazole (1.16 g, 7.12 mmol) and hydroxylamine hydrochloride (0.56 g, 8.07 mmol) in THF (20 mL) to afford 3-(3-acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxypropionamide as a white solid (2.17 g, 70%): mp, 156.5–158.0° C.; 1H NMR (DMSO-d6) δ 1.55–1.87 (m, 8H, C5H8), 2.19 (s, 3H, CH3), 3.11 (d, J=7.8 Hz, 2H, CH2), 3.70 (s, 3H, OCH3), 4.50–4.84 (m, 1H, OCH), 5.64 (t, J=7.8 Hz, 1H, CH), 6.80–6.90 (m, 3H, Ar), 7.56 (d, J=7.3 Hz, 1H, Ar), 7.77 (t, J=7.9 Hz, 1H, Ar), 8.44 (d, J=8.4 Hz, 1H, Ar), 8.81 (s, 1H, NH), 9.72 (s, 1H, OH), 10.95 (s, 1H, CONH); 13C NMR (DMSO-d6) δ 23.5, 24.2, 32.2, 34.1, 50.0, 55.6, 79.6, 112.1, 114.2, 117.9, 119.7, 125.9, 130.9, 131.4, 135.8, 136.4, 146.7,;149.2, 165.9, 167.1, 168.2, 169.2; Anal. Calcd. for C25H27N3O7: C, 61.10; H, 5.76; N, 8.55. Found: C, 61.43; H, 5.62; N, 8.50.
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH2:8][CH2:9][CH2:10][C:2]1=2>O=[Mn]=O.C(Cl)(Cl)Cl>[O:1]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]2[CH2:8][CH2:9][CH2:10][C:2]1=2
Reactant: OCc1cc2c(o1)CCC2
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2c(o1)CCC2

Procedure:
Activated MnO2 (9.3 g) was added to the CHCl3 (135 mL) solution of (5,6-dihydro-4H-cyclopenta[b]furan-2-yl)methanol (1.86 g) and refluxed for 1 h under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (9/1-7/1). The titled compound was obtained as yellow crystals (1.51 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:30][C:31]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:29]=[CH:28][C:12]3[C:13]([CH3:27])([CH3:26])[CH2:14][CH:15]([NH:19]C(=O)C(F)(F)F)[C:16](=[O:18])[NH:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[NH4+].[OH-].C1COCC1.[OH-].[Na+]>CO>[NH2:19][CH:15]1[CH2:14][C:13]([CH3:26])([CH3:27])[C:12]2[CH:28]=[CH:29][C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:30][C:31]4[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=4[C:33]([NH:35][CH3:36])=[O:34])[C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:10][C:11]=2[NH:17][C:16]1=[O:18]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)C(F)(F)F)CC3(C)C)ncc1Cl
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(N)CC3(C)C)ncc1Cl
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Combined 2-{5-Chloro-2-[5,5-dimethyl-2-oxo-3-(2,2,2-trifluoro-acetylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide (355 mg, 0.000598 mol), 1 M of NH4OH in Methanol (2 mL), and THF (50 mL, 0.6 mol). Added 2 mL of 50% NaOH and stirred for 2 hr. Product isolated as a white solid (244 mg, 82%). LCMS 498.22 (M+H), HPLC purity 94%, 1H-NMR (CDCl3, 400 MHz) δ 8.90 (bs, 1H), 8.05 (s, 1H), 7.93 (bs, 1H), 7.63 (bs, 1H), 7.44-7.39 (m, 2H), 7.35-7.31 (m, 2H), 7.28-7.26 (m, 2H), 7.20 (d, J=7.5 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.71 (bs, 1H), 3.40-3.37 (m, 1H), 2.93 (d, J=4.7 Hz, 3H), 2.31-2.27 (m, 1H), 1.99-1.96 (m, 2H), 1.88-1.85 (m, 1H), 1.38 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: C1COCCN1
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(N5CCOCC5)c([N+](=O)[O-])c4)s3)cc2)CC1

Procedure:
This compound was prepared from the compound of Example 15 and morpholine by the procedure used in Example 57. Mass spectrum (ES) MH+=524.
Reaction SMILES: [OH2:1].[OH-].[Na+].[N+:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](Cl)=[O:11])([O-:6])=[O:5].C(Cl)Cl>C1COCC1>[N+:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:1])=[O:11])([O-:6])=[O:5]
Reactant: O
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)c1cccc([N+](=O)[O-])c1
Reaction time: 174 h

Procedure:
1 liter water and 60 g NaOH are added to 100 g Vulkadur RB® and a solution of 200 g 3-nitrobenzoyl chloride in 300 ml THF is then added with stirring (cooling with ice). After 174 h, 500 ml CH2Cl2 are added and the organic phase is separated off and concentrated by evaporation. The N content of the product corresponds to the theoretical.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:24][C:25](=[O:40])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:28]([CH3:39])[CH:27]=1)[CH2:19][CH2:20][C:21](O)=[O:22])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:72]1[CH2:77][CH2:76][S:75](=[O:79])(=[O:78])[CH2:74][CH2:73]1.FC(F)(F)C(O)=O.ClCl>C(#N)C.C(OCC)(=O)C.C(O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C@@H:18]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[O:33])=[C:28]([CH3:39])[CH:27]=3)[CH2:19][CH2:20][C:21]([N:72]3[CH2:77][CH2:76][S:75](=[O:79])(=[O:78])[CH2:74][CH2:73]3)=[O:22])=[N:10][C:11]=2[CH:16]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1cc(C(=O)NC(CCC(=O)O)c2nc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCO
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCS(=O)(=O)CC2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 69 %

Procedure:
Prepared analogously to Example 1g from N-[1-(1-tert-butoxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, TBTU, diisopropylethylamine, thiomorpholine-1,1-dioxide in acetonitrile, and subsequent reaction with trifluoroacetic acid analogously to Example 17. Yield: 69%; Rf value: 0.50 (silica gel; ethyl acetate/ethanol=7:3); C28H32ClN5O5S (586.11); mass spectrum: (M+H)+=586/588 (chlorine isotope).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:13]=[CH:12][N:11]([C:14]3[N:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([O-:18])=O)[N:10]=2)[CH2:5][CH:4]([CH3:23])[O:3]1.[Na+].[NH2:25][CH:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:27]([OH:31])[C:28]([NH2:30])=[O:29]>>[NH2:30][C:28](=[O:29])[CH:27]([OH:31])[CH:26]([NH:25][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[N:22][C:14]=1[N:11]1[CH:12]=[CH:13][C:9]([CH2:8][N:6]2[CH2:7][CH:2]([CH3:1])[O:3][CH:4]([CH3:23])[CH2:5]2)=[N:10]1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC1CN(Cc2ccn(-c3ncccc3C(=O)[O-])n2)CC(C)O1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [Na+]
Product: CC1CN(Cc2ccn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(O)C(N)=O)n2)CC(C)O1
Yield: 83.3 %

Procedure:
Coupling of sodium 2-(3-((2,6-dimethylmorpholino)methyl)-1H-pyrazol-1-yl)nicotinate (400 mg, 0.946 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (220 mg, 1.135 mmol) according to the procedure described for example 1.3 and work-up gave 448 mg of the crude product, which further purified by treatment with a mixture of 30 mL of n-pentane/MTB (10 mL). Filtration and drying gave 388 mg of amorphous white solid; ESI-MS [M+H]+: 493.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Cl)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-(3-(1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.93 (s, 1H), 7.72-6.68 (m, 12H), 5.06-4.98 (m, 1H), 3.66-3.50 (m, br, 2H), 3.02-2.82 (m, br, 2H), 2.80-2.57 (m, br, 4H), 2.57-2.38 (m, br, 2H), 2.02-1.76 (m, br, 6H), 1.64-1.48 (m, br, 1H), 1.48-1.36 (m, br, 3H), 1.25 (d, 6H, J=6.8 Hz); Anal. Calc. for C33H41Cl2FN2O2.0.5EtOAc: C, 66.55; H, 7.18; N, 4.43; Found: C, 66.35; H, 6.86; N, 4.46. ESMS m/e: 550.8 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=1)=O>O1CCOCC1.C(OCC)(=O)C>[CH3:20][O:19][C:15]1[N:14]=[C:13]([NH:12][CH2:10][C:9]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:8]=2[OH:7])[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(NC(=O)c2cccc(C)c2O)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(NCc2cccc(C)c2O)n1
Temperature: 80 °C

Procedure:
80 mg (2.1 mmol, 6 eq) of lithium aluminium hydride are added in small fractions to a mixture of 90 mg (0.35 mmol) of 2-hydroxy-N-(6-methoxypyridin-2-yl)-3-methylbenzamide in 10 ml of dioxane. The reaction medium is heated at 80° C. for 16 h. 80 mg (2.1 mmol, 6 eq) of lithium aluminium hydride are added again and the medium is heated at 80° C. for 4 h. The reaction medium is diluted with 50 ml of ethyl acetate and washed with 50 ml of a saturated solution of ammonium chloride, and then twice with 50 ml of water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography over silica, eluting with a heptane/ethyl acetate (1/1) mixture. 2-[(6-methoxypyridin-2-ylamino)methyl]-6-methylphenol is obtained in the form of a white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:14]2[N:18]([CH3:19])[C:17]3[C:20]([O:27][CH3:28])=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:16]=3[N:15]=2)[CH2:3][CH2:2]1.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.[C:62]([O:66][C:67](=[O:76])[NH:68][CH:69]1[CH2:74][CH2:73][CH:72]([CH3:75])[NH:71][CH2:70]1)([CH3:65])([CH3:64])[CH3:63]>CN(C=O)C.CCOCC.O>[C:62]([O:66][C:67](=[O:76])[NH:68][C@H:69]1[CH2:74][CH2:73][C@@H:72]([CH3:75])[N:71]([C:24]([C:22]2[CH:21]=[C:20]([O:27][CH3:28])[C:17]3[N:18]([CH3:19])[C:14]([C:6]4[N:5]([CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:9]5=[N:10][CH:11]=[CH:12][CH:13]=[C:8]5[CH:7]=4)=[N:15][C:16]=3[CH:23]=2)=[O:25])[CH2:70]1)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC1CCC(NC(=O)OC(C)(C)C)CN1
Reactant: COc1cc(C(=O)O)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2C[C@@H](NC(=O)OC(C)(C)C)CC[C@H]2C)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (250 mg, 0.498 mmol) in DMF (2.3 mL) was added HATU (189 mg, 0.498 mmol) followed by DIPEA (0.174 mL, 0.996 mmol) and the reaction stirred at room temperature for 15 min. tert-Butyl(6-methylpiperidin-3-yl)carbamate (107 mg, 0.498 mmol) was added in DMF (2.3 mL) and the reaction stirred at rt for 16 h. Water (20 mL) and Et2O (20 mL) were added and the layers separated. The aqueous layer was extracted with further Et2O (2×20 mL) and the combined organics washed with water (2×20 mL), dried (Na2SO4) and concentrated in vacuo to afford a yellow oil. The crude product was purified by flash chromatography on silica (25 g) using a gradient of DCM→100% (20% MeOH/DCM)/DCM. The appropriate fractions were combined and evaporated under vacuum to give the product as a yellow oil. This material was purified further by high pH MDAP (Method E). Accordingly, the sample (160 mg) was dissolved in DMSO/MeOH (1:1, 1.8 mL) and injected in two batches. The appropriate fractions were collected and concentrated in vacuo to afford a white solid—tert-butyl(1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-6-methylpiperidin-3-yl)carbamate (93 mg, 0.162 mmol, 32.6% yield). This material was sent for chiral resolution. 4 components were successfully resolved. However analysis showed only 1-2% of the presumed minor diastereomers. The mixture was submitted for chiral preparative chromatography (Chiral Method D) and only the two major components were collected:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:12][NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][N:3]=1
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NN=c1[nH]nc(Cl)c2ccccc12)c1ccccc1
Temperature: 25 °C

Procedure:
2.5 g (4-chloro-phthalazin-1-yl)-hydrazine (compound C1) are suspended in 250 ml toluene and treated with a solution of 1.7 ml benzoic acid chloride in 50 ml toluene at reflux temperature. After 2 h the reaction mixture is cooled to ambient temperature and filtered with suction. The filtrate is concentrated under reduced pressure and the residue is recrystallized from N,N-dimethylformamide to yield 1.2 g of benzoic acid (4-chloro-2H-phthalazin-1-ylidene)-hydrazide.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29]([C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)=[O:30])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccco3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-furoyl chloride (8.5 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([Sn](C)(C)C)[N:16]=3)=[C:9]([F:26])[CH:8]=1.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:31]([CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:32])[N:16]=3)=[C:9]([F:26])[CH:8]=1
Reactant: C[Sn](C)(C)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reactant: O=C(Cl)C1CCC1
Solvent: Cc1ccccc1
Product: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCC1

Procedure:
A solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(trimethylstannyl)-thiazolo[5,4-b]pyridine (515.5 mg, 1.076 mmol) and cyclobutanecarbonyl chloride (0.147 mL, 1.291 mmol) in toluene (10.0 mL) was stirred under argon at 80° C. for 22 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (0-50% EtOAc/hexanes) to provide (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-thiazolo[5,4-b]pyridin-5-yl)(cyclobutyl)methanone as an off-white solid. MS (ESI) m/z: Calculated: 398.1; Observed: 398.9 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18](Br)[CH:19]=[CH2:20]>C(=O)(O)[O-].[Na+].[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[C:15]([O:17][CH2:20][CH:19]=[CH2:18])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)O
Reactant: C=CCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: C=CCOC(=O)C1CC(F)(F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.5 %

Procedure:
4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Example 14b, 6.77 g, 26.96 mmol) was dissolved in a 5% aqueous sodium bicarbonate solution (50 mL). Allyl bromide (3.26 g, 26.96 mmol) and trioctylmethylammonium chloride (“Aliquat® 336”, 10.90 g, 26.97 mmol) were dissolved in dichloromethane (50 mL) and were added to the aqueous solution. The biphasic reaction mixture was stirred vigorously for 48 h at 25° C. The layers were separated and the aqueous layer was extracted with dichloromethane (3×70 mL). The combined organic layers were dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford the crude desired product, which was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 20% ethyl acetate in hexanes) to afford the desired product, 4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 2-allyl ester 1-tert-butyl ester (5.85 g, 20.09 mmol, 74.5% yield) as a clear, slightly yellowish oil. 1H NMR (400 MHz, CDCl3) δ: 1.44 (9H, s), 2.43-2.54 (1H, m), 2.64-2.80 (1H, m), 3.78-3.94 (2H, m), 4.46-4.73 (3H, m), 5.24-5.37 (2H, m), 5.87-5.96 (1H, m).