Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])[CH:17]=1>CC(N(C)C)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27]3)=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=C(NC1CC1)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(C(=O)NC3CC3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.578 g, 5.25 mmol) in DMA (8.75 mL) was treated with potassium tert-butoxide (0.663 g, 5.90 mmol), stirred at RT for 1 h, treated with a solution of 4-chloro-N-cyclopropylpicolinamide (0.86 g, 4.37 mmol) in DMA (8.75 mL) and stirred at RT for 20 h. The mixture was diluted with EtOAc, washed with 1N NaOH, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/EtOAc) to afford 4-((6-aminopyridin-3-yl)oxy)-N-cyclopropylpicolinamide (0.674 g, 57%). 1H NMR (400 MHz, DMSO-d6): δ 8.72 (d, J=5.0 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 7.82 (d, J=2.9 Hz, 1H), 7.31-7.30 (m, 2H), 7.11 (dd, J=5.6, 2.6 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.08 (s, 2H), 2.85-2.84 (m, 1H), 0.65-0.62 (m, 4H); MS (ESI) m/z: 271.1 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:5]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:4]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:3]1[CH:31]([OH:38])[CH2:32][C:33](OCC)=[O:34].C[O-].[Na+]>CO>[OH:38][CH:31]1[C@H:3]2[C@@H:2]([C@@H:6]([O:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C@@H:5]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:4]2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:1][C:33](=[O:34])[CH2:32]1
Reactant: CCOC(=O)CC(O)[C@H]1[C@H](N)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC(O)[C@H]2[C@H](N1)[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1

Procedure:
Dissolve [1R,2S,3R,4S,5R]-2-amino-β-hydroxy-3,4,5-tris(phenylmethoxy)cyclopentanepropanoic acid, ethyl ester (140 mg, 0.269 mmol) in methanol (15 mL) and add a catalytic amount of sodium methoxide. Heat at reflux under a nitrogen atmosphere for 90 minutes, add additional sodium methoxide and continue heating at reflux for 21/2 hours. Evaporate the solvent in vacuo and partition between ethyl ether and aqueous ammonium chloride. Separate the organic phase, wash with aqueuos sodium chloride, dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as a yellow oil which solidifies on standing (122 mg).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH2:9]([C:17]1[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[S:20][CH:21]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:22]([C:19]1[S:20][CH:21]=[C:17]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=1)(=[O:23])=[O:24]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(CCc2ccccc2)cs1
Product: Cc1noc(NS(=O)(=O)c2cc(CCc3ccccc3)cs2)c1Br
Yield: 32 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenethylthiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-phenethyl-2-thiophenesulfonyl chloride in 32% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a gum.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]C(=O)C)=[C:6]([O:12][CH3:13])[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([O:12][CH3:13])[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(NC(C)=O)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cl)c(N)c1OC
Yield: 99.4 %

Procedure:
A solution of intermediate 9-a (0.59 mol) in HCl (20% aqueous solution) (1500 ml) was stirred and refluxed for 2 hours. The mixture was cooled, alkalinized with NaOH (50% aqueous solution) and extracted twice with CH2Cl2. The combined organic layers were washed with water, dried (MgSO4), filtered, and the solvent was evaporated, yielding 110 g (100%) of 6-chloro-2,3-dimethoxybenzenamine (intermed 9-b).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:16]=1.CCO.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Methyl 2-hydroxy-5-nitrobenzoate (11.82 g, 60 mmol), triphenylphosphine (17.29 g, 66 mmol) and EtOH (3.03 g, 3.85 ml, 66 mmol) were taken up in THF (150 ml) and cooled in ice. Di-isopropyl-azodicarboxylate (8.31 g, 10 ml, 66 mmol) was added carefully, and the reaction was stirred at RT for 1 hr. The reaction was concentrated in vacuo, and the residue was triturated with EtOAc (50 ml). The solid thus formed was collected by filtration, washed with MTBE and dried in vacuo to give 12.2 g of crude methyl 2-ethoxy-5-nitrobenzoate. The filtrate was evaporated in vacuo, and the resulting residue was triturated with EtOAc (25 ml). The resulting solid was collected by filtration, washed with MTBE and dried in vacuo to give 6.31 g of a second crop of crude methyl 2-ethoxy-5-nitrobenzoate. The combined portions of methyl 2-ethoxy-5-nitrobenzoate were taken up in hot IPA (50 ml) and cooled to RT. The resulting solid was collected by filtration, washed with MTBE and dried in vacuo to give pure methyl 2-ethoxy-5-nitrobenzoate (5.49 g, 40.5%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([N:22]([CH2:32][CH2:33][CH2:34][N:35]1C(=O)C2C(=CC=CC=2)C1=O)[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C>[NH2:35][CH2:34][CH2:33][CH2:32][N:22]([C@@H:18]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]=1)[CH:19]([CH3:20])[CH3:21])[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(Br)ccc3n2Cc2ccccc2)C(C)C)cc1
Agent: NN
Solvent: CCO
Product: Cc1ccc(C(=O)N(CCCN)[C@@H](c2nc3cc(Br)ccc3n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of N-[1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-methyl-benzamide (0.302 mmol) in ethanol at room temperature, was added hydrazine (0.19 ml, 6 mmol, 20 eq). The reaction was stirred at room temperature for 1 hour. The crude product was purified via reverse phase chromatography to give N-(3-amino-propyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propyl]-4-methyl-benzamide 6 (147 mg, yield 91%).
Reaction SMILES: C([O:3][CH:4]=[CH2:5])=C.[CH:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH:4](=[O:5])[CH:3]=[CH:10][CH2:11][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: c1ccccc1
Reactant: C=COC=C
Product: CCCCCC=CC=O

Procedure:
The above vinyl ether was dissolved in benzene (100 ml.) and the solution was refluxed for 120 hours under Argon. The solvent was removed at reduced pressure to give a yellow oil (~ 1.289 g.). This was chromatographed on 25 g. of silica gel and elution with 1:9 parts by volume of ether:petroleum ether (b.p. 30°-60°) gave 792 mg. of material. This was further purified by Kugelrohr distillation at 36°/0.5 mmHg to yield 3(S),7-dimethyl-4trans)octenal as a colorless oil, [α] D25 + 30.18° (c= 3.572, CHCl3).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Br[CH2:36][CH2:37][OH:38].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[OH:38][CH2:37][CH2:36][N:32]1[CH2:31][CH2:30][CH:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CCO)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (300 mg), 2-bromoethanol (170 mg), sodium carbonate (280 mg) and ethanol (20 mL) was stirred at 80° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=35/65→0/100 (volume ratio)] to give the title compound as a colorless amorphous compound (205 mg, 63%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:12]([O:14][C:15](=[O:19])[C:16](Cl)=O)[CH3:13].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:12]([O:14][C:15]([C:16]1[O:1][N:2]=[C:3]([CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:11]=1)=[O:19])[CH3:13]
Reactant: N=C(Cc1ccccc1)NO
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of N-Hydroxy-2-phenyl-acetamidine (1 g, 6.7 mmol) in 7 mL ethyl acetate was added a solution of Chloro-oxo-acetic acid ethyl ester (1.5 g, 10.7 mmol) in 7 mL ethyl acetate at 0° C. The mixture was stirred for 1.5 h at room temperature and then heated to 80° C. for 2.5 h. The reaction mixture was treated with aq. NaHCO3-solution and extracted with ethyl acetate. The organic layers were dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min) to yield the title compound. LCMS (method A) RtA=1.938 min; [M+H]+=233.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[OH:11].[F:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>N1C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15]([S:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[OH:11])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Nc1ccc2[nH]nc(O)c2c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2[nH]nc(O)c2c1)c1cccc(F)c1
Yield: 5.7 %

Procedure:
3-Fluoro-N-(3-hydroxy-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 2 from 51 mg of 5-amino-3-hydroxy-1H-indazole, 1.5 ml of pyridine and 69 mg of 3-fluorobenzenesulfonyl chloride. 6 mg of 3-fluoro-N-(3-hydroxy-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][N:18]([C:31]3[CH:43]=[CH:42][C:34]4[O:35]C(C)(C)[O:37][C:38](=[O:39])[C:33]=4[CH:32]=3)[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CCO>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][N:18]([C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[O:20])[C:31]3[CH:43]=[CH:42][C:34]([OH:35])=[C:33]([CH:32]=3)[C:38]([OH:39])=[O:37])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc4ccccc4c3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc4ccccc4c3)c3ccc(O)c(C(=O)O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-2-naphthamide and NaOH 5M aq. in the presence of EtOH as a white powder (51%). 1H NMR (CDCl3/MeOD 35:1, 300 MHz) δ 7.92 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 1H), 7.54 (s, 1H), 7.45 (m, 6H), 7.32 (m, 3H), 7.16 (d, J=7.9 Hz, 2H), 6.94 (d, J=8.3 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 5.13 (s, 2H), 2.62 (t, J=7.7 Hz, 2H), 1.60 (m, 2H), 1.35 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). M− (ESI): 552.3; M+ (ESI): 554.2. HPLC, Rt: 5.53 min (Purity: 98.9%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:22]=[CH:21][C:20]3[NH:19][CH2:18][CH:17]4[CH2:23][CH2:24][CH2:25][C:15]=2[C:16]=34)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH2:26][CH3:27])[CH2:18][CH:17]4[CH2:23][CH2:24][CH2:25][C:15]=2[C:16]=34)=[O:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c4c2CCCC4CN3)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CC2CCCc3c(C(=O)CCC4CCN(C(C)=O)CC4)ccc1c32
Yield: 75.8 %

Procedure:
A 10 ml suspension of 1.0 g of 3-(1-acetylpiperidin-4-yl)-1-(1,2,2a,3,4,5-hexahydrobenz[cd]indol-6-yl)-1-propanone, 2.3 g of ethyl iodide and 0.53 g of potassium carbonate in ethanol was stirred at 60° to 70° C. for 12 hours. After the solvent was distilled off under reduced pressure, water was added to the residue, after which the reaction product was extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to yield 0.82 g of 3-(1-acetylpiperidin-4-yl)-1-(1-ethyl-1,2,2a,3,4,5-hexahydrobenz[cd]indol-6-yl)-1-propanone as a colorless oily substance.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:14][S:13](=[O:16])(=[O:15])[N:12]([CH2:17][CH3:18])[CH2:11]1)C1C=CC=CC=1>CO.[Pd]>[CH2:17]([N:12]1[CH2:11][CH:10]([CH2:9][OH:8])[CH2:14][S:13]1(=[O:16])=[O:15])[CH3:18]
Reactant: CCN1CC(COCc2ccccc2)CS1(=O)=O
Agent: [Pd]
Solvent: CO
Product: CCN1CC(CO)CS1(=O)=O
Reaction time: 24 h
Yield: 95.8 %

Procedure:
A mixture of 4-Benzyloxymethyl-2-ethyl-isothiazolidine 1,1-dioxide (254 mg) and Pd/C (108 mg, 0.1 equiv) in methanol was purged with H2 and left to stir under an H2 atmosphere for 24 h. As LCMS indicated completion, the reaction mixture was filtered through a pad of silica (rinsing with MeOH). The filtrate was evaporated and 162 mg of the expected alcohol were obtained. It was pure enough to be used as such in the next step. LCMS (Method E) 0.25 min, M+H 170. 1H-NMR (CDCl3, 400 MHz): 3.8-3.70 (m, 2H), 3.39-3.25 (m, 2H), 3.20-3.01 (m, 4H), 2.94-2.78 (m, 1H), 1.24 (t, 3H).
Reaction SMILES: [C:1]([O:20][CH3:21])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C/C=C\CCCCCCCC.[C:22]([OH:28])(=[O:27])[C:23](C)([CH3:25])[CH3:24]>>[CH2:1]([O:20][CH2:21][C:23]([CH3:25])([CH3:24])[C:22]([OH:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: CC(C)(C)C(=O)O
Product: CC(C)(COCc1ccccc1)C(=O)O

Procedure:
The spectroscopic data of the compound have already been reported further back in the text. Nafion SAC 13 was used as catalyst for acyloxylating methyl oleate. The following reaction conditions were selected: catalyst velocity 4 mmol/g of catalyst, molar excess of pivalic acid compared to methyl oleate=25, temperature 120° C., batch reaction under atmospheric pressure, reaction time 24 h.
Reaction SMILES: C([CH:5]1[CH:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([OH:13])=[O:12])(C)(C)C.[H-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>C1COCC1>[C:20]([O:13][C:11]([N:6]1[CH2:7][CH2:8][CH:9]([O:10][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH2:5]1)=[O:12])([CH3:23])([CH3:21])[CH3:19]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)C1C(O)CCN1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(Cl)cc2)C1
Yield: 110.6 %

Procedure:
A solution of tert-butyl 3-hydroxy-1-pyrrolidinecarboxylic acid (0.27 g, 1.44 mmol) in dry THF (4 mL) was added dropwise to a cold (0° C.), stirred suspension of sodium hydride (0.078 g, 2.17 mmol, ca. 50% suspension in oil) in THF (10 mL). After 30 min. a solution of 4-chlorobenzyl bromide (0.36 g, 1.74 mmol) in THF (2 mL) was added and the resulting suspension was stirred at R.T. overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with saturated aqueous sodium chloride, dried and concentrated. The residue was subjected to flash chromatography (heptane-ethyl acetate, 6:1) to afford the subtitle compound 3-(4-Chloro-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as an oil (0.30 g, 66.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24]2)=[N:21][CH:22]=1.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([O:52][CH3:53])[C:38]=1[OH:54]>>[NH2:28][CH:25]1[CH2:26][CH2:27][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:41]5[CH:40]=[C:39]([O:52][CH3:53])[C:38]([OH:54])=[C:37]([Cl:36])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12](=[O:15])[CH2:13][CH3:14])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(OC)c3)cc2c1Nc1ccc(N2CCC(N)C2)nc1
Yield: 25.7 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-propionylquinolin-4-ylamino) pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (80 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (24 mg, 27% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.28 (s, 1H), 8.29-8.23 (m, 2H), 8.06-7.98 (m, 2H), 7.78 (dd, J=9.1, 2.7 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 6.92 (d, J=9.1 Hz, 1H), 6.70 (d, J=2.2 Hz, 1H), 4.14-4.06 (m, 1H), 4.04-3.96 (m, 1H), 3.91 (s, 3H), 3.87-3.77 (m, 1H), 3.75-3.66 (m, 2H), 3.23 (q, J=7.1 Hz, 2H), 2.62-2.51 (m, 1H), 2.32-2.22 (m, 1H), 1.27 (t, J=7.1 Hz, 3H); ESI MS m/z 518 [C28H28ClN5O3+H]+; HPLC 98.5% (AUC), tR=9.79 min.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>CN(C=O)C>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=1)=[O:11]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CN(C)C=O
Product: CC(C)c1ccc(NC(=O)c2ccccc2N)cc1

Procedure:
A solution of 1H-benzo[d][1,3]oxazine-2,4-dione (2.0 g, 12.2 mmol) and 4-isopropylaniline (1.92 mL, 13.5 mmol) in anhydrous DMF (10 mL) was stirred at 115° C. for 6 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and dichloromethane (150 mL). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was washed with ether (50 mL) to give 2-amino-N-(4-isopropyl-phenyl)-benzamide as a solid. Yield: 0.80 g (25.8%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[N:4][C:5]([NH2:10])=[N:6][C:7]=1[S:8][CH3:9].C1(C2[O:24]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:3]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[N:4][C:5]([NH2:10])=[N:6][C:7]=1[S:8]([CH3:9])=[O:24]
Reactant: CSc1nc(N)nc(-c2ccco2)c1Br
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reaction time: 16 h
Yield: 61 %

Procedure:
To a stirred suspension of 350 mg (1.22 mmol) 5-bromo-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine in 30 ml dichloromethane was added 1.28 g (4.89 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 16 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue recrystallised from hexane/dichloromethane to afford 225 mg (61%) 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine as a beige crystalline solid. EI-MS m/e (%): 303 (M{flBr}+, 24), 301 (M{79Br}+24), 257(48), 255 (50), 198 (81), 196(84), 117(100).
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:24][C:25]([C:27]1([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:23][CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[N:20]1([S:17]([C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:24][C:25]([C:27]4([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])[C:2]#[N:1])=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(S(=O)(=O)N4CCC4)cc3)cc2)C(N)=O)CCOCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(S(=O)(=O)N4CCC4)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.1 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4′-(azetidin-1-ylsulfonyl)biphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 7, step (i), 309 mg) in dichloromethane (8 mL) was treated with Burgess' reagent (251 mg) and the mixture was stirred at room temperature for 18 h. The solvent was partially evaporated and then purified by chromatography on silica using diethyl ether and then 1:1 ethyl acetate/isohexane as eluent to yield a white solid (222 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:44](COCC[Si](C)(C)C)[CH:43]=[N:42][C:5]=2[C:6]([CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[CH:12][C:11]=1[C:29]([F:32])([F:31])[F:30])#[N:2].O.C(=O)(O)[O-:55].[Na+]>S(=O)(=O)(O)O>[Cl:41][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([Cl:40])[C:34]=1[CH2:33][C:6]1[C:5]2[N:42]=[CH:43][NH:44][C:4]=2[C:3]([C:1]([NH2:2])=[O:55])=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)=[CH:12][C:11]=2[C:29]([F:31])([F:32])[F:30])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Cc4c(Cl)cccc4Cl)c4ncn(COCC[Si](C)(C)C)c4c3C#N)c(C(F)(F)F)c2)CC1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Nc2ccc(N3CCNCC3)cc2C(F)(F)F)nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c12
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product of Example 22B (150 mg, 0.2 mmol) in concentrated sulfuric acid (5 mL) was added water (1 mL) at 0° C. and the mixture was stirred at 95° C. for 20 minutes. After cooling to ambient temperature, water (3 mL) was added. The mixture was adjusted to pH 8-9 with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3×20 mL). The organic layers were concentrated and the residue was purified by preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 13.51 (br, 1 H), 11.64 (s, 1 H), 9.52 (br, 1 H), 8.80 (s, 2 H), 8.61(s, 1 H), 7.81 (s, 1-H), 7.62 (d, J=9 Hz, 1 H), 7.56-7.53 (m, 2 H), 7.43-7.41 (m, 1 H), 7.07 (d, J=2.1 Hz, 1 H), 6.72 (dd, J=9, 2.1 Hz, 1 H), 4.83 (s, 2H), 2.75-2.67 (m, 8 H). MS: 564 (M+H+).