Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][CH2:10][C:11]([N:13]([CH2:15][C@H:16]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([CH3:37])[CH:31]=1)=[N:22][CH:23]=[N:24]2)[CH3:17])[CH3:14])=[O:12]>>[OH:9][CH2:10][C:11]([N:13]([CH3:14])[CH2:15][C@H:16]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:32]([CH3:37])[CH:31]=1)=[N:22][CH:23]=[N:24]2)[CH3:17])=[O:12]
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1O
Reactant: ClCc1ccccn1
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1OCc1ccccn1
Yield: 17 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide to give the title compound as a light yellow solid in 17% yield; NMR spectrum (DMSO-d6 373K) 1.43 (d, 3H), 2.29 (s, 3H), 2.97 (s, 3H), 3.58 (m, 1H), 4.08 (m, 3H), 5.11 (m, 1H), 5.19 (s, 2H), 7.01 (d, 1H), 7.21 (d, 1H), 7.32 (m, 2H), 7.57 (m, 3H), 7.67 (t, 1H), 8.83 (td, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.81 (s, 1H); Mass spectrum MH+ 488.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]3[S:16][CH:17]=[CH:18][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][C:29]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[O:15]=[C:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:29]=3[CH3:28])=[CH:20][CH:19]=2)=[O:7])[C:9]2[CH:18]=[CH:17][S:16][C:10]1=2
Reactant: Nc1ccc(C(=O)N2CCCC(=O)c3sccc32)cc1
Reactant: Cc1c(F)cccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3sccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a mixture of 287 mg of 4,5,6,7-tetrahydro-4-(4-aminobenzoyl)-8H-thieno[3,2-b]azepin-8-one in 3 ml of methylene chloride is added 209 μl of triethylamine which is cooled to 0° C. is added 207.1 mg of 2-methyl-3-fluorobenzoyl chloride. The cooling bath is removed and the reaction mixture stirred at room temperature under argon for 18 hours. An additional 50 ml of methylene chloride and 20 ml of water is added and the separated organic layer washed with 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate and the filtrate evaporated in vacuo to a white foam which is crystallized from ethyl acetate-hexane to give 305 mg of the desired product as a white solid, 200°-202° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:35][CH2:36][C@H:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:38][CH2:39]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A80) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([C:16]([O:18]CC)=[O:17])[CH:7]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[N:9]=[C:8]([C:16]([OH:18])=[O:17])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(COC(C)=O)nc(C(F)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCc1cc(C(=O)O)nc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 6-[(acetyloxy)methyl]-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.95 g, 3.2 mmol, from Step B) in tetrahydrofuran (8.7 mL) at 0° C. was treated with lithium hydroxide, monohydrate (140 mg, 3.2 mmol) in water (1.3 mL). The reaction was stirred for 15 minutes, then was treated with 1N HCl to pH4 while still in the ice bath. THF was removed from the mixture in vacuo. The product was extracted first with ethyl acetate, then with several portions of 10% iPrOH in CHCl3, including periodic adjustment of pH as necessary. The extracts were combined and dried over sodium sulfate, filtered and concentrated to afford a yellow oil, which was used without further purification (0.86 g, 100%). 1H NMR (300 MHz, CDCl3): δ 8.25 (s, 1H), 5.35 (s, 2H), 2.23 (s, 3H); LCMS (M+H)+: 265.0.
Reaction SMILES: Br[C:2]1[C:3]([CH:20]([O:23][CH3:24])[O:21][CH3:22])=[CH:4][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[N:6][CH:7]=1.C([Li])CCC.CN([CH:33]=[O:34])C.[BH4-].[Na+]>C1COCC1>[CH3:22][O:21][CH:20]([O:23][CH3:24])[C:3]1[CH:4]=[C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:6]=[CH:7][C:2]=1[CH2:33][OH:34]
Reactant: COC(OC)c1cc(OCCCCC2CCN(C)CC2)ncc1Br
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(OC)c1cc(OCCCCC2CCN(C)CC2)ncc1CO
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
5-Bromo-4-dimethoxymethyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine (0.5 g, 1.25 mmol, 1.0 equiv) was dissolved in THF (6 mL) and cooled to −78° C. A 2.5 M solution of n-butyllithium in hexanes (0.6 mL, 1.5 mmol, 1.2 equiv) was added dropwise. The solution was stirred for 45 min, and then DMF (0.55 mL, 1.25 mmol, 1.0 equiv) was added. After 1 h, sodium borohydride (38 mg, 1.36 mmol, 1.1 equiv) was added. The mixture was allowed to warm to −40° C. for 30 min, then was quenched with satd. aq. NaHCO3 (10 mL). The mixture was extracted with chloroform (3×30 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated to afford {4-dimethoxymethyl-6-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-3-yl}-methanol as a crude mixture. This crude material (88 mg) was dissolved in THF (3 mL) and 1.0 M HCl (3 mL) was added portionwise over 3 h at 60° C. The mixture was cooled, satd. aq. NaHCO3 was added, and the mixture was extracted with chloroform (3×30 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated. A portion of the resulting crude 5-hydroxymethyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde (33 mg), 3,5-dimethyl-benzene-1,2-diamine (22 mg), and Na2S2O5 (36 mg) were stirred in DMF (2 mL) at 90° C. for 36 h. The reaction mixture was purified by Method 2 to afford 5.3 mg of the title compound. MS (electrospray): mass calculated for C25H34N4O2, 422.27; m/z found, 423.5 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.21 (s, 1H), 7.30 (s, 1H), 7.23 (br s, 1H), 6.95 (br s, 1H), 4.68 (s, 2H), 4.34 (t, J=6.4 Hz, 2H), 2.95-2.82 (m, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H), 2.11-1.98 (m, 2H), 1.86-1.68 (m, 4H), 1.57-1.44 (m, 2H), 1.39-1.15 (m, 5H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:44])([CH3:43])[CH2:7][N:8]([S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=1)(=[O:34])=[O:33])[CH2:9][C@@H:10]([OH:31])[C@@H:11]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[CH3:54][N:55]([CH3:59])[C:56](Cl)=[O:57]>C1COCC1>[CH2:12]([C@H:11]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:10]([OH:31])[CH2:9][N:8]([CH2:7][C:6]([CH3:44])([CH3:43])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:56]([N:55]([CH3:59])[CH3:54])=[O:57])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=1)(=[O:34])=[O:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C(=O)Cl
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCN)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCNC(=O)N(C)C)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 55 mg (0.087 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((6-amino-2,2-dimethylhexyl)[3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17 μL (0.091 mmol) of N,N-diisopropylethylamine in 4 mL of anhydrous THF at 0° C. was treated with 8.4 μL (0.091 mmol) of N,N-dimethylcarbamyl chloride. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 49 mg (80%) of the desired compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH:14]=[CH:13][C:12]=2[Cl:29])[CH:9]=1)[C:5]#[N:6].O.NN>CO>[NH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:12]([Cl:29])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[CH:16]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN3C(=O)c4ccccc4C3=O)ccc2Cl)c1
Agent: NN
Solvent: O
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
3-chloro-5-({2-chloro-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}oxy)benzonitrile (0.40 g, 0.94 mmol) and hydrazine monohydrate (0.11 mL, 2.3 mmol) dissolved in methanol (10 mL). The reaction was stirred at 60° C. for 1.5 h. The solvent was evaporated and the crude product was purified by column chromatography (hexane/EtOAc) to afford the title compound (0.26 g, 94%) as a solid.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.ClCCl.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:28][CH:29]=1>C(N(CC)CC)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([CH:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]([CH3:9])[CH3:8])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(c1ccc(NC(=O)Cc2cccc(Cl)c2)c([N+](=O)[O-])c1)n1ccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 13 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrobenzenamine in 195 parts of dichloromethane was added a solution of 19 parts of 3-chlorobenzeneacetyl chloride in 65 parts of dichloromethane. After stirring for 4 hours at room temperature, 10.1 parts of N,N-diethylethanamine were added. The reaction mixture was washed with water, dried, filtered and evaporated, yielding 39 parts (100%) of 3-chloro-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrophenyl]-benzeneacetamide as an oily residue (interm. 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:28][CH3:29])[C:5]([NH2:27])=[C:6]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[CH:30](OCC)(OCC)OCC>CC#N>[Br:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2[N:27]=[CH:29][N:28]([CH3:30])[C:4]=2[CH:3]=1
Reactant: CNc1cc(Br)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)c1N
Reactant: CCOC(OCC)OCC
Solvent: CC#N
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Br)cc3c2ncn3C)cc1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-N,N-bis-(4-methoxy-benzyl)-N″-methyl-benzene-1,2,3-triamine (170 mmol) was dissolved in a mixture of HC(OEt)3 (100 mol) and MeCN (500 mL). The mixture was stirred at 85° C. for 0.5 h and then at room temperature for approximately 16 h. The mixture was combined with another one obtained following the same procedure described above. The resulting mixture was concentrated and the residue was purified by flash column chromatography (SiO2, 15:85 to 60:40 EtOAc/petroleum ether) to obtain the desired product.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]=[C:12]1[C:18](=COS(C)(=O)=O)[C:17](=[O:25])[N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=[CH:14][N:13]1[CH2:32][C:33]([N:35]([CH:44]([CH3:46])[CH3:45])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:34].[CH3:47][N:48]([CH:50]=[O:51])[CH3:49]>>[O:11]=[C:12]1[C:18](=[CH:47][N:48]2[C:49]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:16][C:50]2=[O:51])[C:17](=[O:25])[N:16]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:15]=[CH:14][N:13]1[CH2:32][C:33]([N:35]([CH:44]([CH3:46])[CH3:45])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:34]
Reactant: CN(C)C=O
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=COS(C)(=O)=O)C2=O)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=Cn3c(=O)[nH]c4ccccc43)C2=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzoximidazole (10.4 mg) in anhydrous DMF (1.5 mL) under argon was cooled to 0-5° C. Sodium bis(trimethylsilyl)amide (0.6 M in toluene, 129 μL) was added via micropipette followed by 2-[2,4-dioxo-3-(methanesulfonyloxymethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide [containing approximately 40% of 2-[2,4-dioxo-3-methylene-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide](12s, 20mg). The reaction was allowed to warm to ambient temperature and stir overnight. Addition sodium bis(trimethylsilyl)amide (0.6 M in toluene, 129 μL) was added via micropipette. After approximately 10 min., the reaction mixture was quenched with several drops of glacial acetic acid and evaporated in vacuo. The residue was partitioned between ethyl acetate and aqueous 1N NaHSO4. The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 5% methanol in CH2Cl2. The product band was removed, eluted with 4:1 CH2Cl2/methanol, filtered and evaporated in vacuo. The residue was lyophilized from CH3CN/H2O to provide 2-[2,4-dioxo-3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)methylene-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (10 mg) as a white lyophilate. 1H NMR (400 MHz, CDCI3) 0.99 (m, 6H), 3.62 (d, J=16 Hz, 1H), 3.79 (s, 3H), 4.10 (d, J=16 Hz, 1H), 4.23 (t, J=6 Hz, 1H), 4.50 (m, 2H), 4.90 (m, 1H), 5.86 (d, J=6 Hz, 1H), 5.91 (d, J=6 Hz, 1H), 6.99 (m, 7H), 7.26 (m, 3H), 7.33 (m, 2H), 7.46 (d, J=8 Hz, 1H), 7.54 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:7]2[C:11]=1[CH2:10][N:9]([CH3:12])[C:8]2=[O:13])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[C:17]([O:16][C:15](=[O:21])[NH:14][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[C:11]2[C:7]=1[C:8](=[O:13])[N:9]([CH3:12])[CH2:10]2)([CH3:20])([CH3:19])[CH3:18]
Reactant: C1CCNC1
Reactant: CN1Cc2c(C=O)ccc(NC(=O)OC(C)(C)C)c2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(CN3CCCC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of tert-Butyl (7-formyl-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)carbamate (Compound 109C, 23.0 mg, 0.0792 mmol) and sodium triacetoxyborohydride (101 mg, 0.475 mmol) in THF (0.5 mL) was stirred at room temperature for 20 minutes. Pyrrolidine (39.7 uL, 0.475 mmol) was added and the resulting mixture was stirred at room temperature overnight. The THF was removed in vacuo and the crude product was partitioned between EtOAc and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to deliver the desired product. MS (ES+): m/z 346.32 (100) [MH+] HPLC: tR=0.76 min (UPLC, Analytical).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])=[CH:16][C:15]=3[CH3:27])=[CH:7][C:6]=2[C:5]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:4]=2[N:3]=1.BrCCOCCO[CH2:40][CH2:41][CH2:42][P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:40][CH2:41][CH2:42][P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=[CH:16][C:15]=3[CH3:27])=[CH:7][C:6]=2[C:5]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:4]=2[N:3]=1
Reactant: CCOP(=O)(CCCOCCOCCBr)OCC
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCO)cc3C)cc12
Product: CCOP(=O)(CCCOCCOCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC

Procedure:
Diethyl 3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)propylphosphonate was prepared from following the procedure described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 148) and diethyl 3-(2-(2-bromoethoxy)ethoxy)propylphosphonate. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.70 (s, 1H), 8.26 (d, 1H), 7.42 (s, 1H), 7.16 (d, 1H), 7.09 (d, 1H), 6.77 (s, 1H), 6.71 (d, 1H), 6.58 (br, 2H), 3.95-4.11 (m, 6H), 3.76-3.80 (m, 2H), 3.63-3.67 (m, 2H), 3.55-3.58 (m, 2H), 3.57-3.51 (m, 2H), 3.14-3.18 (m, 2H), 3.04-3.05 (m, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.71-1.87 (m, 4H), 1.22-1.29 (m, 8H). LRMS [M+H]=610.3.
Reaction SMILES: [OH-].[Na+].O1CCCC1.C[O:9][C:10]([C@@:12]12[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:18][C@@H:17]1[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11]>CO>[CH2:24]([O:23][C:21]([N:19]1[CH2:20][C@:12]2([C:10]([OH:11])=[O:9])[C@@H:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:18]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@]12CCCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@@H]2CCCC[C@]2(C(=O)O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.6 %

Procedure:
A 1 mol/L sodium hydroxide solution (70.8 mL) and tetrahydrofuran (78.8 mL) were added to a solution of [(1R*,6R*)-8-benzyloxycarbonyl-8-azabicyclo[4.3.0]nonan-1-yl]carboxylic acid methyl ester (7.50 g, 23.6 mmol) in methanol (78.8 mL) in a nitrogen atmosphere, and the mixture was stirred at room temperature for three days. The reaction solution was concentrated under reduced pressure and then washed with diethyl ether (50 mL×2). The aqueous layer was made acidic with 3 mol/L hydrochloric acid (28 mL) under ice-cooling, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with brine (250 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 6.70 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[OH:27])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:27][C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 73.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (59.4 mg), 2-hydroxy-5-methoxyacetophenone (436 mg), and 4-dimethylaminopyridine (328 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 6 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (68.6 mg, yield 73%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:27]([NH2:32])([CH2:30][CH3:31])([CH3:29])[CH3:28].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:4]=1)=[N:32][C:27]([CH3:29])([CH3:28])[CH2:30][CH3:31])#[N:24]
Reactant: CCC(C)(C)N
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(C)(C)N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 49 %

Procedure:
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.78 mmol, 290 mg), tert-amylamine (0.85 mmol, 0.100 ml) and triethylamine (0.85 mmol, 0.119 ml) in acetonitrile (2 ml) was stirred for 25 h at 75° C. followed by work-up as described in EXAMPLE 5, b) to give the title compound (140 mg, 46%) as white crystals. Mp 149-150° C.; EI SP/MS: 366 (M+); 1H-NMR (CDCl3): δ 0.85 (t, 3H),1.35 (s, 6H), 1.75 (q, 2H), 4.65 (br s,1H), 7.70 (br s, 3H), 8.95 ppm (br s, 1H); MA calc for C15H16F6N4. 0.15 H2O: C, 49.37%; H, 4.57%; N, 14.76%. Found: C, 49.72%; H, 4.56%; N, 14.76%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[N:7]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:25][CH3:26]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[N:7]3[CH2:16][CH2:15][N:14]([CH2:25][CH3:26])[CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CCNCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN1CCc2nc3cc(Br)ccc3c(=O)n2CC1

Procedure:
A solution of 8-bromo-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (100 mg, 0.34 mmol), K2CO3 (188 mg, 1.36 mmol) and excess iodoethane in acetone (20 mL) was stirred at room temperature overnight. Then the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3×70 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give 100 mg of the desired product. MS (ESI): 322, 324 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13].[Se]=[O:16]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](=[O:16])[C:4]([CH3:8])([CH3:9])[C:3]=1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13]
Reactant: CC=CC(=O)C1=C(C)C=CCC1(C)C
Reactant: O=[Se]
Solvent: C1COCCO1
Product: CC=CC(=O)C1=C(C)C=CC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
2.5 g (13 mMole) of 2,6,6-trimethyl-1-(but-2-enoyl)-cyclohexa-1,3-dien [prepared according to the method given in Helv. Chim. Acta 54, 1899 (1971)] dissolved in 50 ml of dioxane were heated, under nitrogen atmosphere, during 45 min. at 60°, in the presence of 1.8 g (16 mMole) of selenium oxide. The reaction mixture was then cooled, concentrated under reduced pressure, and the obtained residue, diluted with 50 ml of acetic acid, was finally stirred at room temperature for 2 hours in the presence of 6 g of Raney nickel. The reaction mixture was then filtered, evaporated to dryness and the obtained residue was distilled (b.p. 100°-110°/o.2 Torr) to afford 2.4 g of a material containing 80 % of the desired keto compound.