Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:9](=[NH:10])[S:8][N:7]([C:11]([CH3:15])([CH3:14])[CH2:12][F:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(N(CC)CC)C>C1COCC1>[CH2:1]([C:5]1=[CH:6][N:7]([C:11]([CH3:14])([CH3:15])[CH2:12][F:13])[S:8]/[C:9]/1=[N:10]\[C:20](=[O:21])[C:19]1[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:18]=1[O:17][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)Cl
Reactant: CCCCc1cn(C(C)(C)CF)sc1=N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1cn(C(C)(C)CF)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC
Temperature: 60 °C
Reaction time: 14 h
Yield: 8.7 %

Procedure:
To a solution of Example 152C (0.46 g, 2.0 mmol) in THF (10 mL) were added 2-methoxy-5-(trifluoromethyl)benzoyl chloride (0.52 g, 2.2 mmol, JRD Fluorochemicals Ltd) and triethylamine (0.84 mL, 6.0 mmol). After stirring at 60° C. for 14 hr, the reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in dichloromethane) to afford 75 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.22-1.46 (m, 2 H), 1.65 (s, 2 H), 1.65 (s, 6 H), 2.63-2.83 (m, 2 H), 3.89 (s, 3 H), 4.60 (d, J=47.1 Hz, 2 H), 7.31 (d, J=8.8 Hz, 1 H), 7.80 (dd, J=8.6, 2.5 Hz, 1 H), 8.10 (d, J=2.4 Hz, 1 H), 8.63 (s, 1 H); MS (ESI+) m/z 433 (M+H)+; Anal. Calculated C20H24F4N2O2S: C, 55.54; H, 5.59; N, 6.48. Found: C, 55.75; H, 5.23; N, 6.43.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:10]#N)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=[O:36].[Na+].[K+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH:10]=[O:36])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butanenitrile (20.2 g) (see Preparation 26) was dissolved in anhydrous toluene (300 ml) and cooled to −78° C. under a nitrogen atmosphere. Diisobutylaluminium hydride (85.6 ml of a 1.0 M solution in toluene) was then added dropwise. The mixture was stirred at −78° C. for 1.5 hours and then allowed to warm slowly to −40° C. Water (100 ml) and saturated aqueous ammonium chloride solution (50 ml) were carefully added (exothermic reaction) and the mixture allowed to warm to 10° C. before further addition of water (100 ml) and saturated aqueous ammonium chloride solution (50 ml). A 10% w/w aqueous solution of Rochelle's salt (potassium sodium tartrate tetrahydrate) (400 ml) was added and the mixture extracted with diethyl ether. The organic phase was dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a crude product. This was chromatographed on silica gel eluting with 98:2, by volume, dichloromethane:methanol to give 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butan-1-al (17.02 g) as a yellow oil and as a mixture of diastereomers.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17].Cl>CC(C)=O>[Cl:13][CH2:14][CH2:15][C:16]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)=[O:17]
Reactant: O=C(Cl)CCCl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: Cl
Solvent: CC(C)=O
Product: O=C(CCCl)N1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
8.2 g (50 mmol) of 6-nitroindoline (prepared as described in Preparation 4) were dissolved in 100 ml of acetone, and 6.35 g (50 mmol) of 3-chloropropionyl chloride were added to the solution while ice-cooling, which resulted in the reaction mixture becoming a suspension. This suspension was stirred at room temperature for 1 hour, after which it was heated under reflux for 2 hours, and formed a solution. The resulting solution was cooled to room temperature, and then 10% w/v aqueous hydrochloric acid was added, and the precipitated crystals were collected by filtration. The crystals thus obtained were dried over phosphorous pentoxide in a desiccator under reduced pressure by means of a vacuum pump overnight to obtain 12.7 g (50 mmol) of the title compound as crystals, melting at 127°-128° C. (yield: 100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH2:30])=[N:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:7][CH:8]=1.Cl[C:32](OC1C=CC=CC=1)=[O:33].CCN(CC)CC.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:20]1([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:6]3[CH:7]=[CH:8][C:3]4[CH2:2][NH:1][C:32](=[O:33])[NH:30][C:4]=4[N:5]=3)[CH2:19][CH2:18]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCc1ccc(OCCCCN2CCN(c3cccc4ccccc34)CC2)nc1N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NCc2ccc(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
A mixture of 3-aminomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-2-ylamine (0.92 g, 2.27 mmol) in THF (25 mL) was treated with phenyl chloroformate (0.40 mL, 3.18 mmol) followed by Et3N (0.46 g, 4.54 mmol). The mixture was stirred at room temperature for 1 hour, then cooled to 0° C. and treated with LDA (5.6 mL, 11.20 mmol, 2.0 M in heptane/THF/ethylbenzene). The brown mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with EtOAc. The organic extracts were washed with water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (2.5% Et3N/EtOAc) to afford the title compound as a light yellow solid (0.204 g, 21%). mp 136–138; 1H NMR (400 MHz, CDCl3): δ 8.24–8.16 (m, 1H), 7.85–7.78 (m, 1H), 7.55 (d, 1H), 7.50–7.42 (m, 2H), 7.40 (t, 1H), 7.25 (d, 1H), 7.09 (d, 1H), 6.84 (br s, 1H), 6.34 (d, 1H), 5.05 (br s, 1H), 4.48 (s, 2H), 4.45 (t, 2H), 3.30–2.05 (m, 4H), 2.93–2.60 (m, 4H), 2.55 (t, 2H), 1.90–1.70 (m, 4H). MS ES: m/z=432.11.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])C[C@H]1CO
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Heat a mixture of (2S,4S)-4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.14 mol, 31 g), 5-bromo-2-fluoronitrobenzene (0.29 mol, 64.0 g) and triethylamine (0.58 mol, 59 g) in ethyl acetate (320 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (42 g, crude) as a thick, dark, orange oil.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:1]2[CH:2]([C:10]3[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=3[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]2=[O:7])[CH:21]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 402.99 g/mol.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18][C:19]([OH:21])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:42]([O:41][C:40]([NH:39][CH2:38][CH2:37][N:36]([CH2:35][CH2:34][NH:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[C:19]([CH2:18][CH2:17][C@H:16]([NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[C:22]([O:24][CH3:25])=[O:23])=[O:21])=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of CDMT (2.22 g, 12.62 mmol) in DCM (40 mL) and cooled to 0° C. was added N-methylmorpholine (1.38 mL, 12.63 mmol). The mixture was stirred for 10 min before adding (4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentanoic acid (3.0 g, 11.48 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate X was then added and the mixture stirred at r.t. overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was crystallized from DCM/hexane to give methyl (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate XIV (4.91 g, 8.98 mmol, 72% yield). 1H NMR (DMSO-d6) 1.35-1.47 (m, 27H), 1.80-1.91 (m, 1H), 2.19-2.32 (m, 1H), 2.33-2.42 (m, 1H), 2.46-2.57 (m, 1H), 3.11-3.38 (m, 6H), 3.40-3.53 (m, 1H), 3.54-3.62 (m, 1H), 3.73 (s, 3H), 4.26-4.38 (m, 1H), 4.99-5.09 (brs, 1H), 5.31-5.46 (m, 2H); ESIMS found for C25H46N4O9 m/z 547 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(OC(=O)C)(=O)C.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([CH2:19][NH:20][C:21]([NH:23][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[O:22])=[CH:17][CH:16]=1
Reactant: N#CCC(=O)O
Reactant: NC(=O)NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)NC(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
68.7 g of 98% cyanoacetic acid and 155 ml of acetic anhydride were kept at 65° C. for 30 minutes. 4-chlorobenzylurea (132.9 g) was added in portions over 10 minutes. After 2 hr at 70-75° C., further acetic anhydride (25 ml) was added. After a further 15 minutes, 90 ml of toluene was added, cooled to room temperature, the solid collected and washed with toluene to give the title compound (155.60 g) as a white solid mp 203-6° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([S:25](Cl)(=[O:27])=[O:26])=[C:16]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[S:17][C:11]=2[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]1=[O:33]>>[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([S:25]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)(=[O:27])=[O:26])=[C:16]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[S:17][C:11]=2[N:10]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:9]1=[O:33]
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)(=O)Cl)c(Cc3cccnc3)sc21
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)(=O)N3CC[C@@H](O)C3)c(Cc3cccnc3)sc21
Reaction time: 1 h

Procedure:
(R)-3-Hydroxypyrrolidine (50 mg) was added to the solution of 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(3-pyrdinyl)methyl-2,4-dioxothieno[2,3-d]pyrimidine-5-sulfonyl chloride (20 ml). After 1 hour, the solution was dried over anhydrous magnesium sulfate and filtered through a small silica pad, washing with ethyl acetate/methanol (19:1). The filtrate was evaporated and the residue was purified by preparative HPLC with dichloromethane:ethanol gradient elution followed by crystallisation from ethyl acetate/isohexane to give the title compound (11 mg).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B(O)(O)[C:31]1[C:36]([CH:37]=[O:38])=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:36]=2[CH:37]=[O:38])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1C=O
Yield: 55 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (200 mg, 0.363 mmol), benzaldehyde-2-boronic acid (71 mg, 0.472 mmol), sodium carbonate (0.4 mL, 2M solution), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan (2 mL) were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and Brine. The Aqueous layer was extracted with EtOAc ×3. The combined extracts were dried and evaporated. The residue was purified on a 25+M column eluting with 0-50% EtOAc/Pet Et2O to afford the title compound as a yellow solid in 55% yield.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][N:12]=[N+]=[N-])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH2:12]
Reactant: [N-]=[N+]=NCCOCCOCCN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCOCCOCCN
Yield: 96.8 %

Procedure:
The diazide (17) (3.55 g, 17.85 mmol) in THF (10 mL) was added dropwise into a cold (-5° C.) stirred mixture of lithium aluminum hydride (1.83 g, 48.2 mmol) in THF (20 mL). The reaction mixture was kept at -5° C. and carefully quenched with water (10 mL). The THF layer was filtered to remove the inorganic salts, dried over Na2SO4, and evaporated in vacuo to afford the diamine (18) (2.56 g, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[O:23]1[CH2:28][CH2:27][O:26][C:25]2[CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=[CH:32][C:24]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:33]([C:30]2[CH:31]=[CH:32][C:24]3[O:23][CH2:28][CH2:27][O:26][C:25]=3[CH:29]=2)=[O:34])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc4c(c3)OCCO4)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brown solid. MS 466 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1>C1COCC1.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(CO)cc2s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Nc1nc2ccc(C=O)cc2s1

Procedure:
110.5 g (0.613 mol) of 1a are stirred in 200 ml of THF with 319.8 g (3.678 mol) of manganese (IV) oxide at room temperature for 3 days. The reaction mixture is filtered, the residue on the filter is washed with THF, and the filtrate is evaporated in vacuo.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Zn+])=[O:6])[CH3:3].[C:14]1([C:20]2([C:23](Cl)=[O:24])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]1([C:20]2([C:23]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:5]([O:4][CH2:2][CH3:3])=[O:6])=[O:24])[CH2:21][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccccc1[Zn+]
Reactant: O=C(Cl)C1(c2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1C(=O)C1(c2ccccc2)CC1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of (2-(ethoxycarbonyl)phenyl)zinc(II) bromide (2.2 mL, 1.1 mmol) was added to a mixture of 1-phenylcyclopropanecarbonyl chloride (0.200 g, 1.1 mmol) and Pd(PPh3)4 (0.0644 g, 0.056 mmol) in THF (1.1 mL), stirred for 2 hours, diluted with EtOAc, washed with 1N HCl and brine, dried (Na2SO4), filtered, and chromatographed (20% Et2O/hexanes) to give 216.2 mg of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate. A mixture of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate (0.216 g, 0.735 mmol) and hydrazine hydrate (0.13 mL, 2.298 mmol) in ethanol (3 mL) was stirred at 75° C. overnight, and concentrated to give 179.7 mg of impure 4-(1-phenylcyclopropyl)phthalazin-1(2H)-one, which was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give impure 2-amino-4-(1-phenylcyclopropyl)phthalazin-1(2H)-one.
Reaction SMILES: CCN(CC)CC.[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([OH:14])=O)[CH2:9][CH3:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46]>CN(C=O)C.O>[Br:42][C:43]1[CH:44]=[C:45]([NH:46][C:12](=[O:14])[CH:11]([CH2:8][CH2:9][CH3:10])[CH2:15][CH2:16][CH3:17])[CH:47]=[CH:48][CH:49]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCCC(CCC)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)C(=O)Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Et3N (3.24 mL, 23.25 mmol) was added to a solution of 2-propylpentanoic acid in (2 g, 11.62 mmol) in DMF. The reaction mixture was cooled to 0° C. HATU (6.63 g, 17.4 mmol) was added to the reaction mixture which was stirred for 15 min and then 3-bromoaniline (2.5 g, 17.43 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. The reaction mixture was diluted with H2O, extracted with EtOAc, and organic layer was concentrated under reduced pressure. The residue was washed with pentane to give N-(3-bromophenyl)-2-propylpentanamide as a white solid. Yield (1.6 g, 47%); 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.12 (bs, 1H), 2.21-2.14 (m, 1H), 1.73-1.63 (m, 2H), 1.51-1.45 (m, 2H), 1.43-1.25 (m, 4H), 0.92 (t, J=7.2 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[O:20][C:19]([CH2:21][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:17]=4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(F)c4)c3c2)o1
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(F)c4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{3-fluoro-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.61 (bs, 2H); 9.28 (bs, 1H); 8.80 (s, 1H); 8.34 (d, 1H); 7.87 (m, 2H); 7.59 (d, 1H); 7.44 (m, 1H); 7.2-7.38 (m, 4H); 7.18 (m, 1H); 6.83 (s, 1H); 5.25 (s, 2H); 4.42 (s, 2H); 3.60 (m, 2H); 3.45 (m, 2H, obscured by water peak); 3.16 (s, 3H); MS m/z 565 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=O.[NH2:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:20])[CH2:17][C:18]#[N:19])[CH:13]=[CH:14][CH:15]=1.[BH4-].[Na+]>CO>[OH:20][CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1)[CH2:17][C:18]#[N:19]
Reactant: COCCCCC=O
Reactant: N#CCC(O)c1cccc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCCCCNc1cccc(C(O)CC#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-methoxypentanal (0.644 g, 5.54 mmol), 3-(3-aminophenyl)-3-hydroxypropanenitrile (12) (1.0 g, 6.16 mmol) and activated molecular sieves in methanol was stirred at RT for 8 hrs. NaBH4 (0.937 g, 24.6 mmol) was added portion wise to the reaction mixture at 0° C. The reaction mixture was stirred at RT overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. Purification by column chromatography (100-200 silica, 0% to 70% EtOAc—hexanes gradient) gave 3-hydroxy-3-(3-(5-methoxypentylamino)phenyl)propanenitrile as a yellow oil. Yield (0.34 g, 21%); 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=8.0 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.62 (s, 1H), 6.56 (d, J=8.0 Hz, 1H), 4.95 (t, J=6.4 Hz, 1H), 3.39 (t, J=6.4 Hz, 2H), 3.33 (s, 3H), 3.12 (t, J=7.2 Hz, 2H), 2.75 (d, J=6.4 Hz, 2H), 1.68-1.59 (m, 4H), 1.51-1.43 (m, 2H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:18][CH2:19][C:20](C)(C)N=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.S(=O)(=O)(O)[OH:25]>C(O)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:18][CH2:19][CH3:20])=[O:25])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CC1(C)COC(c2ccc(C3CCC4(CC3)OCCO4)cc2)=N1
Reactant: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(C2CCC(=O)CC2)cc1

Procedure:
3 g of the product of step (iii) (9.51 mmol) are dissolved in 60 ml of ethanol and 4.0 ml of 96% sulphuric acid are added, and the mixture is refluxed for 22 hours. The solvent is partially evaporated off and the remaining mixture is taken up with a mixture of 300 ml of a saturated sodium bicarbonate solution and 150 ml of ethyl acetate. The organic phase is washed with a saturated aqueous NaCl solution. The organic phase is dried and, after filtration, the solvent is evaporated off under reduced pressure. The crude product is purified by chromatography on a silica gel column, eluting with an 8/2 hexane-ethyl acetate mixture. The compound of the title is obtained in the form of a solid.