Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].[N:39]1([CH2:45][C:46]2[CH:47]=[C:48]([CH:54]=[CH:55][CH:56]=2)[O:49][CH2:50][CH2:51][CH2:52][NH2:53])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:27]([NH:53][CH2:52][CH2:51][CH2:50][O:49][C:48]2[CH:54]=[CH:55][CH:56]=[C:46]([CH2:45][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:47]=2)=[O:28])[CH3:24])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(CCCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CN(CCCCCCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.50 g (1.4 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propylamine as starting materials. Chromatographic working-up analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=633 ([M+H]+, 1), 154 ([m-NO2 -benzylOH] 100); IR (KBr): 1640 cm-1 (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 65°-69° C. (ethanol/ether).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:46])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:28]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:46])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:28]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1cccc(OC)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1cccc(OC)c1

Procedure:
To a solution of 90 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-ethoxycarbonylmethoxy-1-(3-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DCM, 0.3 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 22 mg
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([NH2:18])=[C:12]2[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[Cs+].[Cs+].CI.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:21])[C:13]([NH2:18])=[C:12]2[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(N)[nH]c2ccc(OCc3ccccc3)cc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(N)c(C#N)c2cc(OCc3ccccc3)ccc21
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of 5-benzyloxy-2-amino-1H-indole-3-carbonitrile (2.96 g; 11.25 mmol) in DMF (20 ml) under argon was treated at room temperature with Cs2CO3 (4.4 g; 13.5 mmol). The mixture was stirred and treated dropwise with methyl iodide (0.84 ml; 13.48 mmol). Stirring was continued for 1 hour when the mixture was poured into water. The precipitate was filtered, washed with water and dried to give 5-benzyloxy-2-amino-1-methyl-1H-indole-3-carbonitrile as a beige solid (2.77 g).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:7]([CH2:35][CH3:36])[C:8]1[CH:34]=[CH:33][C:11]([CH:12]=[N:13][N:14](CC2C=CC(C)=CC=2)[C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH3:6].CO>C(Cl)Cl>[CH2:35]([N:7]([CH2:5][CH3:6])[C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[N:13][NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:33][CH:34]=1)[CH3:36]
Reactant: CCN(CC)c1ccc(C=NN(Cc2ccc(C)cc2)C(=O)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)c1ccc(C=NNC(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 54.2 %

Procedure:
BBr3 (2 mL, 1.0 M solution in dichloromethane) was added dropwise to a cooled (0° C.) solution of 4-Methoxy-benzoic acid N′-(4-diethylamino-benzylidene)-N-(4-methyl-benzyl)-hydrazide (compound 2) (0.33 g, 0.00077 mol) in dried CH2Cl2 (5 mL) at −78° C. under Ar. After stirring for an additional hour at 0° C., the reaction mixture was warmed to room temperature and treated with 1:1 CH3OH:CH2Cl2 (10 mL) with cooling and stirred 2 hr at ambient temperature. Concentration of the mixture gave oil, which was purified by flash chromatography 9:1 CH2Cl2/MeOH to give the desired product as a solid 0.13 g in 41% yield, mp: 228.4° C. 1H NMR (CD3OD) δ 8.16 (s, 1H), 7.81 (d, 2H), 7.63 (d, 2H), 6.88 (d, 2H), 6.72 (d, 2H), 3.87 (d, 1H), 3.46 (q, 4H), 1.19 (t, 6H). 13C NMR (CD3OD) δ 162.2, 158.2, 147.1, 146.7, 126.3, 126.2, 120.7, 117.7, 111.9, 110.6, 108.0, 41.1, 8.6. Anal. Calcd for C18H21N3O2·¼ H2O: C, 68.43; H, 6.70; N, 13.31. Found: C, 68.36; H, 6.99; N, 13.58.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14].C1COCC1.C([Li])CCC>O>[CH3:14][C:7]1([CH3:15])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:3]#[CH:2])[CH:5]=2)[S:10][CH2:9][CH2:8]1
Reactant: CC1(C)CCSc2ccc(C=C(Br)Br)cc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C

Procedure:
7.7 g (21.2 mmol) of 2,2-dibromo-1-(4,4-dimethylthiochroman-6-yl)ethylene and 80 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 17 ml (26.6 mmol) of an n-butyllithium solution (2.5M in hexane) were added dropwise at -78° C. and the mixture was permitted to heat to room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with heptane. 3.9 g (90%) of the expected acetylene derivative were recovered in the form of a yellow oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Br:24])[CH:18]=3)[C:15](=[O:25])[O:14][N:13]=2)=[N:9][O:10][N:11]=1)=[N+]=[N-].[I-:26].[Na+].Cl[Si](C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[IH:26].[NH2:1][CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Br:24])[CH:18]=3)[C:15](=[O:25])[O:14][N:13]=2)=[N:9][O:10][N:11]=1
Reactant: [I-]
Reactant: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: I
Product: NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
3-(4-(2-azidoethylamino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (80.0 g, 0.194 mol) was mixed with methanol (800 mL). Sodium iodide (175.0 g, 1.17 mol) was added. The reaction was stirred at room temperature for 10 min. Chlorotrimethylsilane (148 mL, 1.17 mol) was dissolved in methanol (100 mL) and added to the reaction over 30 min. The reaction temperature rose 42° C. The reaction was stirred at room temperature for 30 min. LCMS indicated reaction completed (M+H=386). The reaction was quenched with sodium thiosulfate (190.0 g, 1.20 mol) in water (900 mL). A large amount of solid precipitated. The product was collected by filtration (filtration speed was slow), rinsed with water (200 mL), and dried on vacuum overnight. The filter cake was slurried in ethyl acetate (500 mL) for 30 min. The product was filtered (filtration speed is slow) and dried under vacuum over weekend to give 95 g of an off-white solid. LCMS for C12H11BrFN6O3 (M+H)+: m/z=384.9, 386.9. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (m, 4H), 7.76 (m, 1H), 7.58 (t, J=8.7 Hz, 1H), 6.78 (t, J=6.1 Hz, 1H), 3.51 (dd, J=11.8, 6.1 Hz, 2H), 3.02 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][Si](C)(C)C)[CH:5]=[CH:6][CH:7]=1.[Mg].CI.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18].[SiH3]O[SiH3]>O.C1COCC1>[CH3:18][Si:17]([CH3:20])([CH3:19])[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)Oc1cccc(Br)c1
Agent: [Mg]
Agent: [SiH3]O[SiH3]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)c1cccc(O)c1
Temperature: 0 °C
Yield: 85 %

Procedure:
Next, a dry 3 l, 3-neck flask, equipped with a mechanical stirrer and reflux condenser, and connected to a mineral oil bubbler, was flushed with a stream of argon. The flask was charged with substituted phenol (B) (200 g, 800 mmol), fresh magnesium turnings (21.6 g, 0.89 mol), THF (900 ml), and maintained at about 0° C. in an ice bath. Methyl iodide (2 ml) was added as the catalyst to initiate reaction. The reaction was kept under control by carefully applying and removing the ice bath as necessary to counter the significant heat generated. The resulting mixture was gently heated to reflux for 30 min to drive the reaction to completion, as evidenced by the dissolution of the magnesium. Once again the mixture was cooled to 0° C. in an ice bath, and chlorotrimethylsilane (133.5 g, 1.2 moles) was added. The resulting mixture was gently refluxed and monitored by thin layer chromatography (TLC) to completion. The mixture was subsequently cooled to about 0° C., and 800 ml of water was slowly added to hydrolyze the silyl ether and magnesium salts. The organic layer was separated, washed with 2×100 ml portions of brine and dried over sodium sulfate. Removal of the volatile solvents provided 3-trimethylsilylphenol (C) as a yellow oil, further purified by flash chromatography (ligroin 950:ether=15:1) 116 g, 85% yield).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[N:7][C:8]([S:12][CH2:13][CH3:14])=[N:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16].N1C=CC=CC=1.C>[OH-].[Na+]>[S:16]=[C:2]1[C:11]2[C:6](=[N:7][C:8]([S:12][CH2:13][CH3:14])=[N:9][CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: CCSc1ncc2c(=O)[nH]cnc2n1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCSc1ncc2c(=S)[nH]cnc2n1
Yield: 95.9 %

Procedure:
A mixture of 4-oxo-7-ethylthio-3H-pyrimido[4,5-d]pyrimidine (1.33 g, 6.7 mmol), P2S5 (1.48 g, 6.6 mmol) and pyridine (15 mL) is refluxed under N2 for 3 h. The pyridine is then stripped under reduced pressure, and the residue is dissolved in NaOH solution (0.5 M, 75 mL) and boiled with charcoal. After filtration, the filtrate is neutralized with acetic acid to generate a gold brown solid. Buchner filtration and drying in a vacuum oven affords 4-thiono-7-ethylthio-3H-pyrimido[4,5-d]pyrimidine (1.42g, 95%). 1H NMR (DMSO) δ 9.47 (1H, s), 8.46 (1H, s), 3.20 (2H, q, J=7.3 Hz), 1.35 (3H, t, J=7.3 Hz).
Reaction SMILES: [N:1]([CH:4]([CH2:21][CH:22]=[CH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[NH2:1][CH:4]([CH2:21][CH:22]=[CH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: C=CCC(Cc1ccccc1-c1noc2ccccc12)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(N)Cc1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a stirred solution of 631 mg of 3-[2-(2-azido-4-pentenyl)phenyl]-1,2-benzisoxazole in 10 ml of anhydrous tetrahydrofuran at -40° C. under a nitrogen atmosphere was added 2.07 ml of a 1 M solution of lithium aluminium hydride in diethyl ether. The reaction mixture was warmed to room temperature then heated to 60° C. for 1 h. After cooling to room temperature and careful quenching with 4 N sodium hydroxide, 50 ml of water was added and the product extracted with 100 ml then 50 ml of dichloromethane. The combined organic extracts were dried over sodium sulfate and the solvent removed by evaporation to give crude product which was purified by chromatography on silica gel eluting with 10% methanol in dichloromethane, to give 315 mg of 3-[2-(2-amino-4-pentenyl)phenyl]-1,2-benzisoxazole. The product was dissolved in 1 ml of methanol and 131 mg of fumaric acid was added. Addition of diethyl ether and cooling to 4° C. led to crystallisation of 313 mg of 3-[2-(2-amino-4-pentenyl)phenyl]-1,2-benzisoxazole (E)-butenedioate, melting at 170-172° C.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].OCC[C:15]#[N:16]>>[O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH2:8][C:15]#[N:16])=[O:5]
Reactant: N#CCCO
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC(=O)CC(=O)OCCC#N
Temperature: 25 °C

Procedure:
A mixture of ethyl 3-oxohexanoate (33.7 mmol) and 3-hydroxypropionitrile (28.1 mmol) were placed in a round bottom flask (magnetically stirred) equipped with a short distillation path. The resulting mixture was gradually heated to 180°-205° C. in an oil bath. The distillate was collected. The mixture was then cooled to room temperature and the residue was distilled under reduced pressure to give 2-cyanoethyl 3-oxohexanoate.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.N12CCN(CC1)CC2.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:35]([CH:36]([OH:40])[CH2:37][CH:38]=[CH2:39])=[CH:34][C:33]2[C:28](=[C:29]([CH3:41])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.[H-].[Na+]>CS(C)=O.O>[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[C:2]([O:40][CH:36]([C:35]2[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:41])[CH2:37][CH:38]=[CH2:39])=[N:7][CH:6]=1
Reactant: C=CCC(O)c1cc2cccc(C)c2nc1-c1ccccc1Cl
Reactant: Clc1ncnc2[nH]ccc12
Agent: C1CN2CCN1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCC(Oc1ncnc2[nH]ccc12)c1cc2cccc(C)c2nc1-c1ccccc1Cl
Reaction time: 5 h

Procedure:
Prepared according to procedure L. A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (474 mg, 3.1 mmol) and 1,4-diazabicyclo[2.2.2]octane (694 mg, 6.2 mmol) in anhydrous DMSO (4.5 mL) was stirred at it for 5 h and then added via cannula to a mixture of 1-(2-(2-chlorophenyl)-8-methylquinolin-3-yl)but-3-en-1-ol (500 mg, 1.5 mmol) and sodium hydride, 60% dispersion in mineral oil (180 mg, 4.5 mmol) in DMSO (3 mL) that had been stirred for 30 min at rt and 30 min at 50° C. prior to the addition. The mixture was stirred at rt for 6 h before addition of water (10 mL), and the mixture was extracted with EtOAc (4×20 mL). The combined organic layers were washed with water, brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH, 50/1) to provide 3-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)but-3-enyl)-2-(2-chlorophenyl)-8-methyl-quinoline [PI3Kδ IC50=28 nM] as a white solid. 1H-NMR (CDCl3) δ 10.20 (s, br, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.15-7.64 (m, 8H), 6.59-6.62 (m, 1H), 6.34-6.37 (m, 1H), 5.64-5.79 (m, 1H), 4.93-5.01 (m, 2H), 2.74 (t, J=8.7 Hz, 2H), 2.70 (s, 3H). Mass Spectrum (ESI) m/e=441 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([CH2:15][CH2:16]C)[C:7]=1O.[OH:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].[C:30](=[O:33])([O-])[O-].[K+].[K+]>>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=1[O:19][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:30]([OH:33])[C:7]=1[CH2:8][CH2:15][CH3:16]
Reactant: COC(=O)c1ccccc1O
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(C(C)=O)ccc(OCCCBr)c1O
Agent: [K+]
Product: CCCc1c(OCCCOc2ccccc2C(=O)OC)ccc(C(C)=O)c1O
Yield: 62.5 %

Procedure:
A mixture of 1.5 g of 1-[4-(3-bromopropoxy)-3-hydroxy-2-propylphenyl]ethanone, 0.73 g of methyl 2-hydroxybenzoate and 1.0 g of potassium carbonate was allowed to react according to Example 79 to give 1.15 g (62% yield) of 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]benzoic acid methyl ester, the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[N:34]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[C:35]=[O:36].O>ClCCl>[CH2:37]([NH:34][C:35]([N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=2)[C:13]1=[O:26])=[O:36])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=C=NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)NCc3ccccc3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (18 mg, 0.18 mmol) in dichloromethane (6 ml) was added (isocyanatomethyl)benzene (24.57 mg, 0.18 mmol). The reaction mixture was stirred at RT for 2 hours. Then the reaction mixture was poured on to water. The organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 1% MeOH in chloroform) to obtain the title compound. Yield: 18 mg (20%); 1H NMR (CDCl3, 300 MHz): δ 9.89 (s, 1H), 8.95 (t, 1H), 7.978-8.008 (d, 1H, J=9 Hz), 7.762-7.790 (d, 2H, J=8.4 Hz), 7.614-7.651 (dd, 1H, J=9, 1.8 Hz), 7.500-7.529 (d, 2H, J=8.7 Hz), 7.27-7.38 (m, 5H), 7.018-7.025 (d, 1H, J=2.1 Hz), 4.642-4.611 (d, 2H, J=5.7 Hz), 1.82 (s, 6H); MS: m/z 540 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]3[C:25](=[O:26])[CH2:24][C:23]4[CH:27]=[C:28]5[O:33][CH2:32][O:31][C:29]5=[CH:30][C:22]=4[CH:21]=[CH:20]3)[CH2:14]2)=[CH:2]1.[H][H]>C(O)C.[Pd]>[OH2:26].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]3[C:25](=[O:26])[CH2:24][C:23]4[CH:27]=[C:28]5[O:33][CH2:32][O:31][C:29]5=[CH:30][C:22]=4[CH2:21][CH2:20]3)[CH2:14]2)=[CH:2]1
Reactant: [H][H]
Reactant: O=C1Cc2cc3c(cc2C=CN1CC1CCN(CCCc2c[nH]c4ccccc24)C1)OCO3
Agent: [Pd]
Solvent: CCO
Product: O
Product: O=C1Cc2cc3c(cc2CCN1CC1CCN(CCCc2c[nH]c4ccccc24)C1)OCO3

Procedure:
Prepared from 3-[(N-(3-(indol-3-yl)-propyl)-pyrrolidin-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3-dihydro-2H-3-benzazepine with 20% palladium/charcoal at 5 bar hydrogen in ethanol at 80° C. analogously to Example 5.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[O:17])=[CH:12][CH:11]=2)[N:8]=[N:7][C:6]=1[C:24]([NH2:26])=[O:25].C1(P([C:40]2[CH:45]=[CH:44]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:46]C(Br)(Br)Br>ClCCl>[Br:46][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([NH:18][CH2:19][C:20]([F:22])([F:21])[F:23])=[O:17])=[CH:14][CH:15]=2)[N:8]=[N:7][C:6]=1[C:24]([NH:26][CH:44]1[CH2:45][CH2:40]1)=[O:25]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: NC(=O)c1nnn(-c2ccc(C(=O)NCC(F)(F)F)cc2)c1CCCO
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCBr)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.7 %

Procedure:
To a solution of 5-(3-hydroxypropyl)-1-(4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxamide (381 mg, 0.93 mmol) obtained in Example 398 and triphenylphosphine (365 mg) in dichloromethane (12 ml) was added tetrabromomethane (460 mg), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column (hexane/ethyl acetate=20/1 to 2/5) to give the title compound as a colorless solid (219 mg, 50%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(N(C(C)C)CC)(C)C.[CH2:23]([O:25][C:26]([NH:28][N:29]=[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1)[CH:31](Cl)Cl)=[O:27])[CH3:24]>C(Cl)Cl>[CH2:23]([O:25][C:26]([N:28]1[CH:3]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:31][C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)=[N:29]1)=[O:27])[CH3:24]
Reactant: C1COCCN1
Reactant: C#CC(=O)OCC
Reactant: CCOC(=O)NN=C(c1cccc(C(F)(F)F)c1)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=CC(c2cccc(C(F)(F)F)c2)=NN(C(=O)OCC)C1N1CCOCC1
Temperature: 25 °C
Yield: 55 %

Procedure:
Ethyl propiolate (3.43 g, 0.035 mole) was stirred under N2 in methylene chloride (300 mL) at RT while morpholine (3.05 g, 0.035 mole) was added dropwise over 15 min. The mixture was then refluxed for 30 min. and then cooled to room temperature (RT). Diisopropylethylamine (5.65 g, 0.0437 mole) was then added to the mixture followed by the addition of [2,2-dichloro-1-[3-(trifluoromethyl)phenyl]ethylidene]hydrazinecarboxylic acid ethyl ester (10 g, 0.029 mole) which was added dropwise as a solution in methylene chloride (60 mL) over 30 min. The mixture was then refluxed for 18 h, cooled, and partitioned 2 times with water. The organic layer was dried (MgSO4), filtered and evaporated in vacuo to give a crude solid. This solid was recrystallized from cyclohexane/ethyl acetate to give 6-(4-morpholinyl)-3-[3-(trifluoromethyl)phenyl]-1,5(6H)-pyridazindicarboxylic acid diethyl ester (7.26 g, 55% yield) as a yellow solid, mp=128°-129° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:33])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][OH:32])=[CH:29][CH:30]=3)[CH:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of [5-({[1-(4-Hydroxymethyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (50 mg, 0.11 mmol), 1 mL TFA and 2 mL DCM was stirred of room temperature for 2 h. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). The product containing fractions were lyophilised, then dissolved in 1 mL MeOH and the resulting mixture was filtered over a MeOH flushed PL-HCO3 MP-resin column. The column was washed with MeOH, the solvent was removed and the product was dissolved in water/ACN and lyophilised to yield the title compound. 1H-NMR (DMSO-d6, 400 MHz) 8.24 (s, 1H), 7.93 (t, 1H), 7.88 (s, 1H), 7.28-7.30 (s, 2H), 7.21-7.23 (s, 2H), 6.15 (s, 1H), 5.78 (bs, 2H), 5.30 (s, 2H), 5.18 (t, 1H), 4.47 (d, 2H), 4.27 (d, 2H), 2.30 (s, 3H), 2.17 (s, 3H); LCMS (method A) RtA=0.128 min; [M+H]+=366.1.