Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:15]([OH:17])=O)[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH3:19][O:20][C:21]([C@@H:23]1[CH2:31][C:26]2([S:30][CH2:29][CH2:28][S:27]2)[CH2:25][NH:24]1)=[O:22]>>[CH3:19][O:20][C:21]([C@@H:23]1[CH2:31][C:26]2([S:27][CH2:28][CH2:29][S:30]2)[CH2:25][N:24]1[C:15]([C:12]1[NH:11][C:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][N:13]=1)=[O:17])=[O:22]
Reactant: COC(=O)[C@@H]1CC2(CN1)SCCS2
Reactant: O=C(O)c1nc(CCCc2ccccc2)c[nH]1
Agent: Br
Product: COC(=O)[C@@H]1CC2(CN1C(=O)c1ncc(CCCc3ccccc3)[nH]1)SCCS2

Procedure:
4-(3-Phenylpropyl)imidazole-2-carboxylic acid (13d) was coupled to 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid methyl ester hydrobromide (Smith et. al., J. Med. Chem., 31, pp. 875-85 (1988)) by the method described for 23 to afford 140 mg (65%) as a yellow gum: 1H NMR (CDCl3) δ 7.34-7.15 (5H, m), 6.98-6.8 (1H, 3 s), 5.7-5.65 (0.5H, m), 5.2-5.1 (1H, m), 4.82-4.75 (0.5H, m), 4.4-4.35 (1H, m), 4.05 (1H, d), 3.75-3.7 (3H, 2 s), 3.4-3.3 (4H, m), 2.95-2.45 (8H, m), 2.05-1.95 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].S(OC)(O[CH3:18])(=O)=O.[I-:21].[K+]>O>[I-:21].[CH3:18][N+:9]1[C:10]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1cccc2ncccc12
Agent: [I-]
Agent: [K+]
Solvent: O
Product: C[n+]1cccc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-Nitroquinoline (4 g, 30 mmol) was melted at 85° C., prior to addition of dimethyl sulfate (2.2 ml, 30 mmol), and the resulting mixture was stirred at this temperature for 1.5 hours. The yellow gel was dissolved in water (35 ml) and cooled to room temperature. A saturated aqueous solution of potassium iodide (7.63 g, 45.9 mmol) was added, and the resulting orange precipitate was filtered, washing the residue with chilled water. After drying under vacuum at 60° C., for 2 hours, the brick-red solid was used in the next step without purification.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=4)[CH:16]=3)=[CH:13][N:12]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:10]=2)=CC=1.F[C:39](F)(F)[C:40](O)=O>C(Cl)Cl>[OH:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH2:39][CH3:40])=[O:25])=[CH:22][CH:21]=3)[CH:16]=2)=[CH:13][N:12]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3OCc3ccc(OC)cc3)on2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3O)on2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 37-k (300 mg, 0.61 mmol) in DCM (5 mL) was added trifluoroactic acid (2.5 mL) dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness to give compound 37-m, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:13]=1[C:12](=[O:14])[C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(=O)CC>[CH2:21]([N:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12](=[O:14])[C:13]2=[CH:1][CH:2]=[CH:3][N:4]12)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2ccccc2[nH]n2cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1c2ccccc2n(Cc2ccccc2)n2cccc12
Yield: 58.8 %

Procedure:
A stirred slurry containing pyrrolo[1,2-b]cinnolin-10(5H)-one (4.0 g) and potassium carbonate (11.2 g) in 100 ml of 2-butanone was treated with benzyl bromide (4.0 g) and the mixture was stirred at 60°. After 4 h the mixture was quenched with 700 ml of H2O and extracted with two 150 ml portions of dichloromethane. These organic extracts were dried over MgSO4, filtered and concentrated to a green oil. This oil was purified by flash chromatography (silica, dichloromethane) to a yellow solid which was recrystallized from dichloromethane to give 3.5 g of bright yellow crystals, mp 146°-148°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([OH:26])=[O:25])=[C:13]3[CH3:27])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.CO.[C:34]([O-])(=O)C.[Na+]>C(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26][CH3:34])=[O:25])=[C:13]3[CH3:27])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1ncnc2cc(Cl)ccc12
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: CO
Product: COC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of anhydrous 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetic acid (1.0g.) in ethanol-free chloroform (30 ml; dried over calcium chloride) was added a solution of thionyl chloride (0.19 ml.) in chloroform (2ml). The resulting dark red solution was stirred at room temperature for 30 mins., and then methanol (20 ml.) was added. The mixture was heated under reflux for 30 mins., saturated sodium acetate solution (2 ml.) was added, and the mixture was concentrated in vacuo. Water (30 ml.) was added to the residue and the mixture was extracted with ether (3 × 30 ml.). The ether extracts were washed successively with saturated sodium hydrogen carbonate solution (30 ml.) and water (30 ml.), and dried (Na2SO4). Evaporation of the solvent gave a dark yellow oil, which slowly crystallised to give methyl 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetate, m.p. 112°-114° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:40][N:41]([CH3:46])[S:42](Cl)(=[O:44])=[O:43]>ClCCl>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:42](=[O:44])(=[O:43])[N:41]([CH3:46])[CH3:40])[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CNS(=O)(=O)N(C)C)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
An ice cold solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (25 mg, 0.057 mmol) in dichloromethane (DCM) (1 mL) was treated with Et3N (0.012 mL, 0.086 mmol) and dimethylsulfamoyl chloride (7.33 μL, 0.069 mmol), stirred for 15 min, and then warmed to rt for 1 hour. Additional Et3N (25 uL) and dimethylsulfamoyl chloride (15 uL) were added, the reaction was stirred at rt overnight. The reaction was concentrated and purified by column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-(((N,N-dimethylsulfamoyl)amino)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (22.6 mg, 0.042 mmol, 72.6% yield) as clear oil. The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-(((N,N-dimethylsulfamoyl)amino)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (18.4 mg, 0.034 mmol, 82% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42 (s, 1 H), 7.54 (td, J=1.9, 8.2 Hz, 1 H), 7.41-7.30 (m, 1 H), 7.30-7.23 (m, 1 H), 7.16 (dd, J=8.4, 12.9 Hz, 1 H), 7.09-6.99 (m, 1 H), 5.35 (s, 1 H), 4.53 (br. s., 1 H), 4.36 (br. s., 2 H), 3.69 (d, J=1.0 Hz, 3 H), 2.81 (s, 3 H), 2.80 (s, 3 H), 2.36 (s, 3 H), 2.32 (s, 3 H), 1.07 (s, 4.5 H), 1.06 (s, 4.5 H); LCMS (m/z) ES+=530 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([NH:18][C:19]1[C:20](=[O:38])[N:21]([C:25]2[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=2[Cl:37])[C:28]([NH:30][CH:31]2[CH2:33][CH2:32]2)=[O:29])[CH:22]=[CH:23][N:24]=1)([CH3:17])[CH3:16])C1C=CC=CC=1.B(Br)(Br)Br.[CH2:43](Cl)Cl>O>[CH:31]([NH:30][C:28](=[O:29])[C:27]1[CH:34]=[CH:35][C:36]([Cl:37])=[C:25]([N:21]2[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[OH:8])([CH3:17])[CH3:16])[C:20]2=[O:38])[CH:26]=1)([CH2:33][CH3:32])[CH3:43]
Reactant: ClCCl
Reactant: CC(C)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O)c1ccccc1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: O
Product: CCC(C)NC(=O)c1ccc(Cl)c(-n2ccnc(NC(C)(C)c3ccccc3O)c2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-chloro-N-cyclopropylbenzamide (Example 330g, 2.23 g) dissolved in DCM (30 mL) was treated with boron tribromide (8.43 mL of a 1M solution in DCM) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with water (200 mL), and extracted with dichloromethane (250 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was triturated with diethyl ether (50 mL) to afford the subtitle compound (1.760 g).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[N:6]=1.[CH3:17][N:18]([CH2:20][CH:21]([OH:32])[CH2:22][N:23]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH3:24])[CH3:19]>>[CH3:19][N:18]([CH2:20][CH:21]([OH:32])[CH2:22][N:23]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:7]2[N:6]=[C:5]([NH:4][C:3]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)=[CH:30][CH:31]=1)[CH3:24])[CH3:17]
Reactant: CN(C)CC(O)CN(C)c1ccc(N)cc1
Reactant: Cc1ccc(F)c(Nc2ccnc(Cl)n2)c1
Product: Cc1ccc(F)c(Nc2ccnc(Nc3ccc(N(C)CC(O)CN(C)C)cc3)n2)c1
Yield: 17 %

Procedure:
By a procedure analogous to Example 96, 4-(2-fluoro-5-methylanilino)-2-chloropyrimidine (Reference Example A-10) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropyl(N-methyl)amino]aniline (Reference Example D-2) were reacted to give the title product as a brown oil (60 mg, 17%). M/z: (ES+) 425.3 (MH+). HPLC (Hypersil 10 cm base deactivated) 60% MeCN/H2O/0.2% TFA. Retention time: 2.66 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)(=[O:27])=[O:26].C([O-])=O.[NH4+]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)c(-c2ccnc(Cl)n2)s1
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)c(-c2ccncn2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 26 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (130 mg, 0.255 mmol) and ammonium formate (161 mg, 2.55 mmol), the title compound was obtained as a white solid (50 mg, 39% yield). MS (ESI): 474 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([NH:26][C:27]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH:23]=[C:22]([CH3:37])[CH:21]=3)=[CH:18][N:19]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:37][C:22]1[CH:21]=[C:20]([C:17]2[S:16][C:15]([C:2]3([OH:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]3)=[N:19][CH:18]=2)[CH:25]=[C:24]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][N:28]=2)[CH:23]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To tert-butyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (50 mg, 0.093 mmol) in DCM (1 mL) was added 144 uL TFA (20 eq) and the reaction stirred at rt for 4 h. To the mixture was added saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layer was dried, filtered. The solvent was reduced in vacuo to give 40 mg (0.092 mmol, 98%) of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol. MS ESI: [M+H]+ m/z 436.2. 1H NMR (600 MHz, DMSO-d6): δ 8.81 (d, J=4.7 Hz, 1H); 7.93 (m, 2H), 7.44 (s, 1H); 7.25 (d, J=4.9 Hz, 1H); 7.13 (s, 1H); 5.97 (br s, 1H), 2.78-2.98 (m, 4H); 2.29 (s, 3H); 1.93-1.98 (m, 2H), 1.63-1.65 (m, 2H). rhSYK activity=+++
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:5].[OH:14]S(O)(=O)=O>>[CH3:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[NH:6][C:4](=[O:5])[C:3]2=[O:14]
Reactant: Cc1ccc(NC(=O)C=NO)cc1
Reactant: O=S(=O)(O)O
Product: Cc1ccc2c(c1)C(=O)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Hydroxyimino-N-p-tolyl-acetamide (14 g, 0.0078 mol) was added portion wise to a preheated (60° C.) conc. H2SO4 (70 mL) over a period of 30 min. After the addition, the mixture was stirred at the same temperature for another 1 h. The reaction mixture was cooled to room temperature and was poured into crushed ice. The precipitate was collected by filtration and washed with chilled water several times. Finally it was dried in a vacuum oven to get the required product as brick red coloured solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:10]([NH:12][C:13]2[C:14]([CH3:28])=[C:15]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:16]=[CH:17][CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:34][C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38](=[O:45])[NH:37][N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:29]1([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:37]3[N:36]=[C:35]([CH3:34])[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:38]3=[O:45])=[CH:4][CH:5]=2)[C:10]([NH:12][C:13]2[C:14]([CH3:28])=[C:15]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:16]=[CH:17][CH:18]=2)=[O:11])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1n[nH]c(=O)c2ccccc12
Reactant: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(Cn2nc(C)c3ccccc3c2=O)cc1)C1CCCC1

Procedure:
50 mg (0.097 mmol) of tert-butyl 3-[3-({[4-(bromomethyl)phenyl](cyclopentyl)acetyl}amino)-2-methylphenyl]propanoate, 19 mg (0.12 mmol) of 4-methylphthalazin-1(2H)-one and 47 mg (0.15 mmol) of cesium carbonate were stirred in 5 ml of DMF at 60° C. for 12 h. After cooling, the reaction mixture was purified directly by preparative HPLC. This gave 43 mg (0.07 mmol, 74% of theory) of the racemic title compound.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.Cl.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:39])[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:21][CH2:20]1>ClCCl>[CH:16]1[C:3]2[CH:2]([N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:39])[CH2:31][CH2:32][C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[CH2:21][CH2:20]3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Reactant: ClC1c2ccccc2COc2ccccc21
Agent: Cl
Solvent: ClCCl
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C2c3ccccc3COc3ccccc32)CC1
Temperature: 25 °C

Procedure:
3.46 g (15 mmol) 11-chloro-6,11-dihydrodibenzo[b,e]oxepine are dissolved in 90 ml abs dichloromethane and 5.43 g (15 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide dihydrochloride are added. 5.0 g (49.5 mmol) TEA are dissolved in 20 ml abs. dichloromethane and added dropwise under ice cooling. The mixture is stirred without further cooling for two days at RT. Subsequently, the batch is washed twice each with 50 ml water. The organic phase is dried over silica gel with CHCl3/CH2OH (95/5) and crystallized twice at first, each from 10 ml 1-chlorobutane, and subsequently crystallized once from 10 ml acetic acid. Colorless crystals with a MP of 110-112° C. were isolated; yield: 0.2 g (3%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(S(=O)(=O)c1ccc(Br)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(S(=O)(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 90 °C
Yield: 114.3 %

Procedure:
A mixture of 10-[(4-bromophenyl)sulfonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Step C (0.500 g, 0.93 mmol), 2-methoxyphenylboronic acid (0.212 g, 1.40 mmol) and potassium carbonate (0.386 g, 2.79 mmol) in dimethoxyethane:water (8 mL:2 mL) was purged with nitrogen for 10 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium[II] (38 mg, 0.0465 mmol) was then added and the reaction mixture heated to 90° C. for 21 hours. The cooled reaction mixture was partitioned between ethyl acetate (100 mL) and 1 M sodium hydroxide (100 mL). The separated organic phase was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a brown syrup (0.60 g). Purification by flash chromatography using a solvent gradient of 0 to 3% methanol in dichloromethane gave the title compound (0.520 g, 99%) as a yellow foam.
Reaction SMILES: [CH2:1]([C:3]1([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[CH2:5][O:4]1)[CH3:2].[NH2:14][CH2:15][CH:16]([OH:18])[CH3:17]>C(O)C>[CH2:1]([C:3]([CH2:5][NH:14][CH2:15][CH:16]([OH:18])[CH3:17])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[OH:4])[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CO1
Reactant: CC(O)CN
Solvent: CCO
Product: CCC(O)(CNCC(C)O)c1cccc(OC)c1

Procedure:
2-Ethyl-2-(3-methoxyphenyl)oxiran (14 g, 0.079 mole) and 1-amino-2-propanol (100 g., 1.33 mole) wee refluxed with ethanol (50 ml) for 12 hours. The solvent and excess aminopropanol was removed under reduced pressure. The residue was dissolved in methanol (80 ml) and acidified with ethereal hydrogen chloride. The methanol was evaporated and the residue taken up in water (250 ml). Non-basic material was extracted by shaking the aqueous solution with three portions of 100 ml of ether. The aqueous layer was neutralised with a large excess of 0.880 ammonia, and reextracted with ether (3×100 ml). The ether layers were washed with water and dried (MgSO4). Removal of solvent left the title compound in 98% purity (12.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH:15]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[N:17]1[C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[N:17]1[C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:15][CH2:14][N:9]3[C:7]4=[N:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=[C:6]4[CH:12]=[CH:11][C:10]3=[O:13])[CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:18]=1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2n1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(nn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(nn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A suspension of [3-(methyloxy)-6-oxopyrido[2,3-b]pyrazin-5(6H)-yl]acetaldehyde (240 mg, assuming 191 mg of aldehyde) and 1,1-dimethylethyl (6,7-dihydro[1,4]dioxino[2,3-c]pyridazin-3-ylmethyl)-4-piperidinylcarbamate (305 mg) in chloroform (10 mL) and methanol (1.5 mL) was stirred at room temperature under argon for 1 h before addition of sodium triacetoxyborohydride (553 mg). The reaction was stirred at rt overnight. A saturated solution of sodium bicarbonate (20 mL) was added to the reaction and the aqueous was extracted with 10% MeOH/DCM (3×50 mL). The combined organic phases were dried (MgSO4), evaporated and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford 358 mg of the title compound (60%).
Reaction SMILES: [CH3:1][C:2]1([C:11]([O:13]C)=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.O.[OH-].[Li+].Cl>O1CCCC1.O.CO>[CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COC(=O)C1(C)Cc2ccccc2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a tetrahydrofuran/H2O/methanol (4 mL/1 mL/1 mL) solution of the methyl 2-methyl-2,3-dihydro-1H-indene-2-carboxylate (1.80 g, 9.46 mmol) was added lithium hydroxide monohydrate (1.19 g, 28.39 mmol). The reaction mixture stirred at ambient temperature for 4 hours and then the mixture was acidified to pH 3 using 1N HCl. The organics were extracted twice with 25 mL diethyl ether, the combined organics were washed with brine and then dried (Na2SO4), filtered and concentrated to as 2-Methyl-2,3-dihydro-1H-indene-2-carboxylic acid a white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:8]#[N:9])=[N+]=[N-].CP(C)C>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(CN=[N+]=[N-])cc(C(F)(F)F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Product: N#Cc1cc(CN)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of 3-azidomethyl-5-trifluoromethyl-benzonitrile (140 mg, 0.619 mmol) in THF (1 ml) was treated with trimethyl phosphine (94.2 mg, 1.24 mmol) at room temperature and stirred for 2 hours. Reaction was quenched with water and stirred for 30 minutes. Reaction was extracted with ethyl ether and organic layer was dried over anhydrous magnesium sulphate and concentrated in vacuo. The crude product (70 mg, 56%) was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.64 (s, 2H) 3.98 (s, 2H) 7.74 (s, 1H) 7.83 (s, 2H).