Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[C:7](=[O:21])[O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[O:19][CH3:20])[CH:10]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:10][CH2:9][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[O:19][CH3:20])[C:7]([OH:21])=[O:8])=[O:4]
Reactant: COC(=O)NC1=CC(c2cccc(OC)c2OC)OC1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)NC(CCc1cccc(OC)c1OC)C(=O)O
Temperature: 64 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
150 g of 3-methoxycarbonylamino-5(2,3-dimethoxyphenyl)-2,5-dihydro-furan-2-one and 1190 ml of CH3OH are placed into 2000 ml flasks of a Parr hydrogenator, then they are heated until complete dissolution with stirring (T about 64° C.); 30 g of 5% Pd/C are added and hydrogenation is started at 35 psi until H2 is no longer absorbed (about 60 minutes). The disappearance of the starting compound is checked by TLC, then the mixture is filtered through Celite and the filtrate is evaporated to dryness, the resulting oil is precipitated with stirring by adding ethyl ether and petroleum ether, stirring is continued for about 30 minutes, then the mixture is filtered and dried under vacuum at 60° C. 141.6 g are obtained. (Yield 93%).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]2[NH:30][C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[N:27]=4)[N:22]=[CH:21][C:20]=3[O:19][CH2:18]2)[CH2:13][CH2:12]1)C1C=CC=CC=1>[Pd].CO.O1CCCC1>[CH3:32][O:31][C:26]1[N:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]1[O:19][CH2:18][CH:17]([C@H:14]3[CH2:15][CH2:16][C@H:11]([NH2:10])[CH2:12][CH2:13]3)[NH:30][C:29]2=1
Reactant: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1)CO3
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N)CC1)CO3
Temperature: 40 °C
Reaction time: 16 h

Procedure:
10% Palladium on activated carbon (285 mg, 2.68 mmol, 1.0 eq) is added at room temperature to a stirred solution of [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid benzyl ester (1.20 g, 2.68 mmol, 1.0 eq) in methanol (80 mL) and tetrahydrofuran (8 mL). The resulting mixture is stirred under hydrogen flow (1 bar) at 40° C. for 16 hours. The catalyst is then removed by filtration and the solution is concentrated to afford trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexylamine as a yellow solid (620 mg, 74% yield) which is directly engaged in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19]>>[C:18]([C@@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])[CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:19])[NH2:20]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cc(OCC2CC2)c(Br)cn1
Product: CC(C)C[C@H](NC(=O)c1cc(OCC2CC2)c(Br)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-4-(cyclopropylmethoxy)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials and isolated (16 mg, 47%) as yellow oil; MS (ESI, m/z): 385.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:14][C:6]1=2
Reactant: C#CCN(C)C
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Product: CN(C)CC#Cc1cnc2c(c1)N(Cc1cc(Cl)ccc1Cl)CCN2
Yield: 49 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (113 mg) was coupled with 1-dimethylamino-2-propyne as in General Procedure 5 to give the title compound as a yellow solid (49% yield). M.p.=168° C., LCMS: m/z=375.08 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.31 (6H, s), 3.38 (4H, m), 3.61 (2H, t, J=4.0 Hz), 4.40 (2H, s), 5.54 (1H, bs), 6.45 (1H, d, J=1.5 Hz), 7.21 (2H, m), 7.33 (1H, m), 7.61 (1H, d, J=1.5 Hz).
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][CH:13]([C:16]1[C:24]2[O:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:21][C:20]=2[CH:19]=[C:18]([OH:32])[CH:17]=1)[CH2:14]Br.Cl>C(#N)C>[Br:12][C:13]([C:16]1[C:24]2[O:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:21][C:20]=2[CH:19]=[C:18]([OH:32])[CH:17]=1)=[CH2:14]
Reactant: Oc1ccc(-c2nc3cc(O)cc(C(Br)CBr)c3o2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C=C(Br)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Reaction time: 24 h
Yield: 58 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.25 g, 1.65 mmol) was added into a solution of 7-(1,2-dibromoethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (0.4 g, 0.96 mmol) and acetonitrile (4 mL). The reaction mixture was stirred for 24 h, poured into cold (0° C.) HCl (1N, 10 mL) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (CH2Cl2/hexanes/isopropyl alcohol 15/5/1) gave a white solid (185 mg, 58% yield, m.p. 228-230° C.); MS m/e 332 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21]Cl>CN(C)C=O>[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1cccc(C)c1CCl
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Cn1ccc2ccc(C=O)cc21
Yield: 89.3 %

Procedure:
To a solution of indole-6-carboxaldehyde (457 mg) in N,N-dimethylformamide (5 mL) were added potassium carbonate (936 mg) and 2,6-dimethylbenzyl chloride (752 mg) at room temperature, and then the reaction mixture was subjected to microwave irradiation at 160° C. for 30 minutes. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (740 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][OH:14])=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:14][CH2:13][C:11]2[CH:10]=[CH:9][C:6]3[O:7][CH2:8][C:2]([CH3:15])([CH3:1])[CH2:3][O:4][C:5]=3[CH:12]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(O)cc1
Reactant: CC1(C)COc2ccc(CO)cc2OC1
Product: COc1ccc(OCc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
According to the method described in example 23, the title compound is prepared from (3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-methanol (31) and 4-methoxyphenol. MS (ESI) 332.3 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14].C(Cl)Cl.[OH2:18]>CN(C)C(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]([C:7](=[O:14])[CH2:6][CH2:5][OH:18])[C:7]2=[O:14]
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C(CCO)n1cnc2ccc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.7 %

Procedure:
To a suspension of NaH (60% in mineral oil, 199 mg) in 20 ml of N,N-dimethylacetamide was added 6-bromo-3H-quinazolin-4-one(0.9335 mg, 4.148 mmol). The mixture was stirred at room temperature for 40 mins resulting clear red solution. Acroyl chloride (471.8 ul, 5.8072 mmol) was added. The solution was heated at 70° C. for 8 hrs, cooled to room temperature, and poured into 30 ml of ice water. Methylene chloride added and product was in the water phase. The water solvent was evaporated under vacuum. The resulted residue was purified by preparative HPLC. 1.1 g product was obtained. Yield: 74.7%; 1H NMR (500 MHz, DMSO-d6): δ 2.73412–2.76135(t, J=6.805 Hz, 2H), 4.14197–4.16922(t, J=6.815 Hz, 2H), 7.62305–7.64046(d, J=8.705 Hz, 1H), 7.96596–7.98797(dd, J1=8.635 Hz, J2=2.38 Hz, 1H), 8.2287–8.2335(d, J=2.4 Hz, 1H), 8.41991(s, 1H); ESI-MS: m/z 297, 299 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[N:19][C:20](S(C)=O)=[N:21][CH:22]=1)[CH:14]=[CH:13][O:12]2.[NH2:26][NH2:27]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[N:19][C:20]([NH:26][NH2:27])=[N:21][CH:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: CS(=O)c1ncc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Reactant: NN
Solvent: CC#N
Product: NNc1ncc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A round bottomed flask was charged with 6-(2,4-difluorophenyl)-5-(2-(methylsulfinyl)pyrimidin-5-yl)imidazo[2,1-b]oxazole (0.16 g, 0.44 mmol), ACN (20 mL) and hydrazine (0.10 mL, 3.2 mmol). The reaction mixture was stirred at about 80° C. for about 2 h. The reaction mixture was concentrated to dryness and then triturated with Et2O to give the title compound (0.13 g, 89%). LC/MS (Table 1, Method o) Rt=2.56 min; MS m/z 329.1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:28]=[CH:27][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([C:19]#[C:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:15][CH:14]=4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.CO>[Pd].C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:28]=[CH:27][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:15][CH:14]=4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@@H](C)C#Cc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N[C@@H](C)CCc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37.4 %

Procedure:
Under a hydrogen atmosphere, a mixture of N-[(1S)-3-{6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]pyridin-3-yl}-1-methylprop-2-yn-1-yl]acetamide (98.0 mg), 10% palladium/carbon (containing water (50%), 19.6 mg), methanol (5 mL) and THF (1 mL) was stirred at 50° C. for 4 hr. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound as yellow crystals (37.0 mg).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([OH:6])=[O:5].[CH2:10]([C:18]1[CH:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=2)=[N:22][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>ClCCl>[CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([O:6][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[N:20]=[CH:19][C:18]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][N:22]=2)=[CH:29][CH:28]=1)=[O:5]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CC[C@H](C)[C@H](Cl)C(=O)O
Solvent: ClCCl
Product: CCCCCCCCc1cnc(-c2ccc(OC(=O)[C@@H](Cl)[C@@H](C)CC)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8 g of (S,S)-3-methyl-2-chloropentanoic acid, 16 g of p-(5-n-octylpyrimidin-2-yl)phenol, 11.6 of N,N-dicyclohexylcarbodiimide, 0.6 g of 4-N,N-dimethylaminopyridine and 300 ml of dichloromethane is stirred overnight at room temperature. After filtering off the precipitated urea derivative, the filtrate is washed with dilute hydrochloric acid and water, and the organic phase is worked up in the usual manner. p-(5-n-Octylpyrimidin-2-yl)-phenyl (S,S)-3-methyl-2-chloropentanoate is obtained.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH:17]=[CH:18][C:19](=[O:21])[CH3:20])=[C:11]([CH3:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[Si:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[C:12]([CH:17]=[CH:18][C:19](=[O:21])[CH2:20][CH2:23][CH2:24][CH2:25][CH3:26])=[C:11]([CH3:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Reactant: CCCCI
Product: CCCCCC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C

Procedure:
The entitled compound was prepared from 4-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1enyl]but-3-en-2-one and n-butyl iodide in the same manner as described in Example 2-(1).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[CH3:1][C:2]1[C:7]2[C:8](=[O:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])ccc2[nH]c(=O)oc(=O)c12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-methyl-4H-3,1-benzoxazin-2,4-dione (20 g, 113 mmol) in 150 mL of concentrated H2SO4, cooled to −15° C., was added 7.83 g of 90% w/w HNO3 (in 30 mL of conc. H2SO4) dropwise at such a rate to keep the internal temperature below 5° C. After the addition was complete, the reaction was stirred at 0° C. for an additional 20 minutes then quenched by pouring the reaction mixture over crushed ice. Following further dilution with water, the resulting precipitate was filtered, washed with water, resuspended in water then filtered and washed again with water affording 15.1 g (60%) of 5-methyl-6-nitro-4H-3,1-benzoxazin-2,4-dione, after drying: Anal. Calc'd. for C9H6N2O5: C, 48.66; H, 2.72; N, 12.61. Found: C, 48.19; H, 2.54; N, 12.51.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[O:13].[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][CH2:4][N:5]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: CNC
Reactant: O=Cc1ccccc1N(CCCCl)c1ncccc1[N+](=O)[O-]
Product: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]

Procedure:
The title compound is prepared by reacting [2-[[3-chloropropyl](3-nitro-2-pyridinyl)amino]phenyl]methanone with dimethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](O)([CH3:10])[CH3:9].S(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([CH3:10])=[CH2:9]
Reactant: CC(C)(O)c1ccncc1Br
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)c1ccncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirred solution of Intermediate 42A (1.25 g) in pyridine (38 mL) at 0° C. was added thionyl chloride (38.5 mL, 526.5 mmol). The reaction mixture was then stirred at room temperature overnight, quenched with saturated aqueous sodium bicarbonate solution and extracted with CH2Cl2 (2×20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (80 g BIOTAGE® column, eluting with hexane:CH2Cl2/4:6) to provide Intermediate 42 (705 mg, 61.5% yield). MS (ES): m/z=198.1 [M+H]+. Intermediate 42 was used in the synthesis of Example 227.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:22][CH3:23].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl.CO>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[NH:32][C:33]([N:22]([C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1)[CH3:23])=[O:34]
Reactant: CNc1ncnc2cc(OCC3CCN(C)CC3)c(OC)cc12
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(N(C)C(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1OCC1CCN(C)CC1
Temperature: 85 °C
Yield: 5.1 %

Procedure:
6-Methoxy-4-methylamino-7-(N-methylpiperidin-4-ylmethoxy)quinazoline (0.195 g) was added to 2,6-dichlorophenyl isocyanate (0.3 g) under argon and the solids were mixed together using a spatula. The mixture was heated to 85° C. with gentle mixing for 40 minutes. The mixture was cooled to ambient temperature, dissolved in a mixture of chloroform (15 ml) and methanol (5 ml) and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 1% aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.016 g); NMR Spectrum: (CDCl3) 1.5 (m, 2H), 1.98 (m, 5H), 2.3 (s, 3H), 2.91 (d, 2H), 3.6 (s, 3H), 4.02 (s, 3H), 4.03 (d, 2H), 7.1 (t, 1H), 7.28 (s, 2H), 7.37 (d, 2H), 8.61 (s, 1H), 8.96 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@H:7](Br)[C@@H:6]1[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(=[O:3])[CH3:2].[OH2:32]>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7]([OH:32])[C@@H:6]1[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(=[O:3])[CH3:2]
Reactant: O
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](NC(=O)OCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](O)[C@H](NC(=O)OCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
700 mg of 3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-α-D-glucopyranosyl bromide [Bull, Chem. Soc. Japn., 34, 183 (1963)] was dissolved in 2 ml of acetone, and with the solution cooled to 0° C, 290 mg of silver carbonate and 20 ml of water were added. The mixture was stirred for 1 hour at this temperature and filtered. The filtrate was concentrated to obtain 580 mg of 3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-β-D-glucopyranose
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (example D.f6) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>>[C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Reactant: BrCCCCBr
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OCCCCBr)CC1

Procedure:
In analogy to example 11.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester and 1,4-dibrombutane were reacted to yield trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-carbamic acid tert-butyl ester as yellowish oil, MS: 364 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][C@@H:32]([F:35])[CH2:31]3)[N:25]=[C:26](I)[C:13]=12>>[Cl:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][C@@H:32]([F:35])[CH2:31]3)[N:25]=[C:26]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:13]=12
Reactant: F[C@@H]1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)C1
Reactant: OB(O)c1cccc(F)c1
Product: Fc1cccc(-c2nn(CCN3CC[C@@H](F)C3)c3nnc(-c4ccccc4)c(Cl)c23)c1

Procedure:
Compound IIx was synthesized according to Example 1, using 3-fluorophenylboronic acid instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-chloro-1-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazine instead of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine in Step 8.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[CH2:20]=O.[OH-].[Na+]>>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH2:20][O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: C=O
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1OC)C1C(CO)COCN1CC2
Yield: 89 %

Procedure:
6 mmoles (1.6 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are stirred with 10 ml of aqueous (30-35%) formaldehyde for half an hour. The reaction mixture is alkalized with 10 ml of a 30% aqueous sodium hydroxide solution and extracted with ethyl acetate. Drying and evaporation of the extract yields the aimed compound in a yield of 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:20][CH2:21][CH:22]4[CH2:24][O:23]4)=[CH:15][CH:16]=3)[O:11][CH:10]=2)=[CH:5][CH:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31].C(N(C(C)C)CC)(C)C>C(O)C>[OH:23][CH:22]([CH2:24][NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:35])([F:36])[F:25])[CH:28]=1)[CH2:21][O:20][C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][O:11]2)=[CH:16][CH:15]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(-c2coc3cc(OCC(O)CNCc4cccc(C(F)(F)F)c4)ccc3c2=O)cc1

Procedure:
3-(4-Methoxyphenyl)-7-(oxiran-2-ylmethoxy)chromen-4-one (0.24 g, 0.74 mmol), 3-(trifluoromethyl)benzylamine (0.11 ml, 0.74 mmol) and diisopropylethylamine (0.26 g, 1.47 mmol) was stirred in ethanol (15 ml) at 78° C. overnight. The solvent was removed under reduced pressure, and the residue chromatographed on silica gel, eluting with 5% methanol/dichloromethane, followed by recrystallization from ethyl acetate/hexane to provide 7-[2-hydroxy-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propoxy]-3-(4-methoxyphenyl)chromen-4-one.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[C@@H:13]1[CH2:17][C:16](=[O:18])[C:15]([CH2:19][C:20]#[CH:21])=[C:14]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:22][C:14]1[C@H:13]([O:2][N+:1]([O-:4])=[O:3])[CH2:17][C:16](=[O:18])[C:15]=1[CH2:19][C:20]#[CH:21]
Reactant: C#CCC1=C(C)[C@H](O)CC1=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: C#CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Into a mixed solution of 8 g of fuming nitric acid and 24 g of acetic anhydride, kept at a temperature of -5° to 10° C., was added dropwise 6 g of (R)-4-hydroxy-3-methyl-2-(2-propynyl)-2-cyclopenten-1-one ([α]D23 ; -19.5° (C=1.36, in chloroform), (R)-isomer/(S)-isomer=96.7/3.3). Then, the mixture was stirred for 30 minutes at the same temperature. Thereafter, the reaction mixture was poured into 200 ml of ice water, and then subjected to a toluene extraction. The toluene layer was separated and washed with an aqueous 5% sodium hydrogencarbonate solution and then with water. The extract was dried over anhydrous magnesium sulfate and, then, concentrated to give 7.56 g of crude (R)-3-methyl-4-nitroxy-2-(2-propynyl)-2-cyclopenten-1-one.