Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([CH2:23][OH:24])=[CH:17][C:16]=3[F:25])=[O:11])=[CH:6][CH:5]=1.Br[CH2:29][CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[C:16]([F:25])[CH:17]=[C:18]([CH2:23][OH:24])[CH:19]=3)[N:14]([CH2:29][CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:13]=2)=[O:11])=[CH:26][CH:27]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CO)cc2c1O
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCCOC2CCCCO2)c2c(F)cc(CO)cc2c1=O
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 24 %

Procedure:
To a suspension of NaH (60% dispersion in oil, 11.1 mg) in 2.5 mL anhydrous DMF is added N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Preparation No. 7 (100 mg). After stirring the reaction mixture at room temperature for 15-20 min., 2-(3-bromopropoxy)tetrahydro-2H-pyran (89.4 mg) is added. The reaction is stirred at room temperature for 3 days. The reaction mixture is treated with saturated aqueous NaHCO3, then extracted with CH2Cl2 (3×). The combined organic layers are washed with 15% K2CO3 and H2O (2×), dried over Na2SO4, and condensed to obtain a yellow residue. The residue is chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 34.0 mg (24%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Cl:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2n1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-chlorobenzimidazole (100 g, 0.65 mol) in 500 ml of dimethylformamide (DMF) was added dropwise to a stirred suspension of 60% sodium hydride-mineral oil dispersion (28 g, 0.70 mol) in 500 ml of DMF. Mild intermittent cooling was required. After the addition was completed the mixture was stirred an additional 15 min and benzylbromide (82.6 g, 0.49 mol) was added dropwise with mild intermittent cooling. The reaction mixture was stirred an additional 1.5 h and 1 L of water was added. The mixture was extracted with benzene. The extract was dried (Na2SO4), concentrated and the residue crystallized from isopropyl ether to obtain 110 g (93%), mp 102°-105° C.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.Br[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:17][CH2:16][N:1]2[C:5]3=[CH:6][N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]3[CH:3]=[CH:2]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cc2cc[nH]c2cn1
Reactant: BrCCC1CCCCC1
Product: CCOC(=O)c1cc2ccn(CCC3CCCCC3)c2cn1

Procedure:
The title compound was prepared by alkylation of ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate with (2-bromoethyl)cyclohexane in a manner similar to step 6 of example 1. 1H NMR (CDCl3) δ ppm 8.86 (s, 1H), 8.50 (s, 1H), 7.33 (d, 1H, J=3.0 Hz), 6.66 (d, 1H, J=3.0 Hz), 4.52 (q, 2H, J=6.9 Hz), 4.29 (t, 2H, J=7.5 Hz), 1.66-1.83 (m, 7H), 1.48 (t, 3H, J=7.2 Hz), 1.18-1.32 (m, 4H), 0.93-1.05 (m, 2H). LCMS (APCI, M+H+): 301.1
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[CH:16]=[C:17]([C:38]([O:40][CH3:41])=[O:39])[C:18]2[N:19]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:20]3[CH:21]=[C:22]([Cl:28])[CH:23]=[CH:24][C:25]=3[C:26]=2[N:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:28][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[N:27]=[C:15]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[N:3]=[CH:4]5)[CH:16]=[C:17]([C:38]([O:40][CH3:41])=[O:39])[C:18]=3[N:19]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:20]=2[CH:21]=1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: COC(=O)c1cc(Br)nc2c3ccc(Cl)cc3n(Cc3ccc(OC)cc3)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COC(=O)c1cc(-c2ccc3c(cnn3C)c2)nc2c3ccc(Cl)cc3n(Cc3ccc(OC)cc3)c12
Temperature: 70 °C
Yield: 54.7 %

Procedure:
A flask containing a mixture of 1-methyl-1H-indazol-5-ylboronic acid (590 mg, 3.35 mmol), methyl 2-bromo-7-chloro-5-(4-methoxybenzyl)-5H-pyrido[3,2-b]indole-4-carboxylate (1.19 g, 2.58 mmol), powdered potassium phosphate tribasic (1.31 g, 6.19 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.212 g, 0.516 mmol), and Pd(OAc)2 (0.058 g, 0.258 mmol) was flushed with nitrogen. THF (10 mL) was added and the reaction was heated at 70° C. for 15 hr. The reaction was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried with sodium sulfate, and the solvent was removed. Silica gel chromatography (step gradient elution with DCM containing 0 to 3% EtOAc) afforded methyl 7-chloro-5-(4-methoxybenzyl)-2-(1-methyl-1H-indazol-5-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (720 mg, 1.41 mmol, 55% yield) as a solid. MS (ESI) m/z 511.14 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.47 (1H, s), 8.42 (1H, d, J=8.24 Hz), 8.27 (1H, dd, J=8.55, 1.53 Hz), 8.07 (2H, d, J=2.14 Hz), 7.50 (1H, d, J=8.55 Hz), 7.46 (1H, s), 7.35 (1H, dd, J=8.24, 1.53 Hz), 6.86-6.91 (2H, m), 6.76 (2H, d, J=8.85 Hz), 5.67 (2H, s), 4.12 (3H, s), 3.82 (3H, s), 3.73 (3H, s).
Reaction SMILES: C=C[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5]C=1.[NH2-].[Li+].[CH3:11][O:12][C:13]([CH3:19])([O:15]CC#C)[CH3:14].BrCC>CCCCCC>[CH3:11][O:12][C:13]([CH3:19])([O:15][CH2:5][C:6]#[C:7][CH2:8][CH3:3])[CH3:14]
Reactant: C#CCOC(C)(C)OC
Reactant: C=Cc1ccccc1
Agent: [Li+]
Agent: [NH2-]
Solvent: CCBr
Solvent: CCCCCC
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 96.9 %

Procedure:
883 mg (126 mmol) of granulated lithium were added within 5 minutes to 107 g (6.30 mol) of liquid ammonia at −38° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 14.6 g (140 mmol) of styrene were added portion wise within 20 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 9.9 g (70 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (90.8% GC) were added with a dropping funnel to the reaction mixture at −38° C. within 20 minutes. The reaction mixture was held at −38° C. for about 1 hour. 14 g (126 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 20 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 16 hours. 70 ml of water were added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The organic layer was separated and dried over 2 g of anhydrous magnesium sulfate. The solution was concentrated under reduced pressure (40° C., 40 mbar) and the crude product was analyzed by GC. 10.6 g of 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained with a purity of 84.4% (yield 81.8%, based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]2[N:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[N:15][N:16]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](c2nnc3ccc(F)cn23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2nnc([C@H]3CCCNC3)n2c1

Procedure:
A yellow solution of Intermediate 88b (2.01 g, 6.27 mmol) and TFA (11.0 mL, 148 mmol) in DCM (50 mL) was stirred at reflux for 30 min. The cooled solution was concentrated in vacuo, redissolved in MeOH (3 mL), applied to an SCX-2 cartridge (50 g) and washed with MeOH (150 mL). The product was eluted with 2M NH3 in MeOH (100 mL); concentration in vacuo left the title compound as a pale orange solid (1.26 g, 91%). LCMS (Method 3): Rt 0.35 min, m/z 221 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][CH:7]([CH:14]1[O:19][CH2:18][CH2:17][NH:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].CO.Cl>C1COCC1>[N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][CH:7]([CH:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: O=C1NCCOC1C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1OC(c1ccccc1)C1CNCCO1
Yield: 90.5 %

Procedure:
To 33 g of 2-[α-(2-nitro-phenoxy)-benzyl]-morpholin-3-one dissolved in 60 ml of anhydrous THF there was added dropwise under stirring 16.7 ml of a 0.9 M solution of BH3 in THF. The whole was heated at reflux for 3 hours and dropwise addition under cold conditions (0°-5° C.) was then made of 3 ml of methanol and then of 3 ml of 23% HCl. The solvent was removed under reduced pressure. The residue was diluted with H2O, made alkaline and extracted with chloroform. The organic extracts were washed to neutrality, dried and evaporated to dryness, to obtain 28.6 g of 2-[α-(2-nitrophenoxy)-benzyl]-morpholine. Yield 94%.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:9]([Cu])#[N:10].CN1C(=O)CCC1>CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[C:9]#[N:10]
Reactant: N#C[Cu]
Reactant: Clc1cncc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cncc(Cl)c1
Temperature: 210 °C
Reaction time: 3 h

Procedure:
A mixture of 3,5-dichloropyridine (4.23 g, 28.6 mmol), CuCN (3.07 g, 34.3 mmol), and argon-bubbled NMP (8 mL) was placed in a 40 mL scintillation vial, flushed with argon for 1 min, and then quickly capped and stirred under argon at 210° C. for 3 h. The dark brown easily stirred solution was allowed to cool somewhat, and was then poured into concentrated NH4OH (50 mL) on an ice bath, and stirred vigorously for 5 min. DCM (50 mL) was added, the bilayer was stirred for an additional 5 min, and then filtered. The lower dark amber organic layer was saved, and the dark blue aqueous layer was extracted with DCM (2×50 mL). The organic layers were combined and washed with NH4OH (1×30 mL), 4 M NaCl (1×30 mL), dried (Na2SO4), and concentrated to give an amber oil heavily contaminated with NMP. Silica flash chromatography of this residue (90 mm×6″ column; 6:1 hex/EtOAc eluent; 100 mL fractions; fractions 15-19 combined) afforded, after rotary evaporation at 40° C., the title compound as brilliant white microcrystals (891 mg, 22%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:12]2[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[CH:15][N:16]=2)=[O:11])[CH2:6][CH2:5]1)(=O)C.C(N1CCC(C(OC(=C2CCN(C(=O)C)CC2)C2N(CCC3C=CC=CC=3)C=CN=2)=O)CC1)(=O)C>Cl>[C:19]1([CH2:18][CH2:17][N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[C:10]([CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[O:11])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)N1CCC(C(=O)c2nccn2CCc2ccccc2)CC1
Agent: CC(=O)N1CCC(=C(OC(=O)C2CCN(C(C)=O)CC2)c2nccn2CCc2ccccc2)CC1
Agent: Cl
Product: O=C(c1nccn1CCc1ccccc1)C1CCNCC1
Yield: 27 %

Procedure:
A mixture (3.87 g) of 1-acetyl-4-[[1-(2-phenylethyl)-1H-imidazol-2yl]carbonyl]piperidine (D), (1-acetyl-4-pipendinylidene)[1-(2-phenylethyl)-1H-imidazol-2-yl]methyl 1 -acetyl-4-piperidine carboxylate (H), and 6 N hydrochloric acid (100 ml) was refluxed for 20 hrs. The cooled reaction mixture was concentrated, and the residue was diluted with water. The resulting mixture was sequentially washed with ether and ethyl acetate. The acidic aqueous layer was basified with sodium hydroxide solution and was extracted with dichloromethane. The combined extracts were washed with water, dried, filtered, and concentrated to give [1-(2-phenyethyl)-1H-imidazol-2-yl](4-piperidinyl) methanone (K, 0.91 g), m.p. 230°-232° C. from dichloromethane-hexanes. ##STR31##
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11](Cl)=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[C:30]#[N:31])=[CH:24][C:23](=[O:35])O1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:24]#[C:25][C:27]2[CH:28]=[CH:29][CH:32]=[CH:33][CH:34]=2)=[CH:10][C:9]=1[NH:18][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:34]=[CH:33][CH:32]=[C:29]([C:30]#[N:31])[CH:28]=1)=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1C#Cc1ccccc1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J2) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as an orange solid (108 mg).
Reaction SMILES: [CH3:1][C:2]([NH:22]C(=O)OC(C)(C)C)([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:21][C:2]([C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)=[O:4])([CH3:1])[NH2:22]
Reactant: COc1cccc(Oc2ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(Oc2ccc(NC(=O)C(C)(C)N)cc2)c1
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a solution of 1,1-dimethylethyl {1,1-dimethyl-2-[(4-{[3-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 71, 1.89 g) in dry dichloromethane (60 mL) at 0° C. TFA (20 mL, 260 mmol) was added dropwise and the reaction mixture was stirred for 2 hours at the same temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (50 g) to afford the title compound as a light brown oil (1.34 g).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=O)[CH2:3][CH2:2]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C1COCC1>[CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]2[O:15][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccccc1NC(=O)c1snnc1C1CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1oc(-c2snnc2C2CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
2-(4-Cyclopropyl-1,2,3-thiadiazol-5-ylcarbonylamino)benzoic acid (0.77 g; 2.7 mmols), triethylamine (0.54 g; 5.3 mmols) and 2-chloro-1-methylpyridinium iodide (0.82 g; 3.2 mmols) were dissolved or suspended in THF (15 ml), followed by stirring at room temperature for 10 hours. Subsequently, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. Crystals thus formed were washed with methanol to obtain 0.63 g of 2-(4-cyclopropyl-1,2,3-thiadiazol-5-yl)-4H-3,1-benzoxazin-4-one.
Reaction SMILES: C[N:2]1[CH2:11][CH2:10][C@@:9]2(C3C=CC=C(OC)C=3)[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3]1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH2:3]1[C@H:4]2[C@@H:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:10][CH2:11][NH:2]1
Reactant: COc1cccc([C@@]23CCCC[C@H]2CN(C)CC3)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: C1CC[C@H]2CNCC[C@@H]2C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 800 mg of N-methyl-4a-(m-methoxyphenyl)-trans-decahydroisoquinoline (3.09 mmoles) in 30 ml of methylene chloride was added in portions to an ice-cold solution of 0.59 ml (1.55 g, 6.18 mmoles) of boron tribromide in 15 ml of methylene chloride. The solution, protected under nitrogen, was kept overnight at 25° C. Methanol (5 ml) was then added and the solution evaporated. The residue was treated with 15 ml of 5 N aqueous sodium hydroxide and the mixture stirred for 15 minutes. Ether (50 ml) was added and the bilayer mixture stirred for 2 hours. The aqueous and ether layers were finally separated and the aqueous portion saturated with carbon dioxide. The resulting solid precipitate was extracted with ether and the extract concentrated to give 680 mg of N-methyl-4a-(m-hydroxyphenyl)-trans-decahydroisoquinoline, mp 195°-205° C.
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=O)(C)(C)C.[CH2:17]([CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21])[CH3:18].Cl>CC(O)=O>[CH2:23]([C:19]1[C:20]([CH3:21])=[N:16][C:13]2[N:12]([N:11]=[C:10]3[CH2:9][NH:8][CH2:15][C:14]3=2)[C:17]=1[CH3:18])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: CCC(C(C)=O)C(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CCc1c(C)nc2c3c(nn2c1C)CNC3
Temperature: 25 °C
Reaction time: 32 h
Yield: 77.6 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (0.6 g; 2.68 mmol; 1 eq.) and 3-ethyl-2,4-pentanedione (0.36 mL; 2.68 mmol; 1 eq.) in AcOH (8 mL) was stirred at room temperature for 32 hours. Aq. 32% HCl (1.05 mL; 10.7 mmol; 4 eq.) was added and the resulting mixture stirred for a further 16 hours. After concentration in vacuo, the residue was triturated in MTBE and the precipitate filtered off and dried. The solid was taken up in ethyl acetate and washed with 1M aq. NaOH (2×), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (450 mg, 94%) as a beige solid. 1H NMR (DMSO-d6) δ 4.05-4.00 (m, 4H), 2.73-2.63 (m, 5H), 2.51 (s, 3H), 1.12 (t, J=7.4 Hz, 3H). UPLC/MS: (MS+) 217.3 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][NH:23][OH:24].C[Si]([N:29]=[C:30]=[O:31])(C)C.O.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][N:23]([OH:24])[C:30]([NH2:29])=[O:31]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCNO)c3cc(F)ccc32)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(/C=C2/C(C)=C(CCN(O)C(N)=O)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the hydroxylamine intermediate from Step 4 (1.62 g, 4.7 mmol) in THF (15 mL) there was added 85% trimethylsilyl isocyanate (954 mg, 7.25 mmol). The mixture was stirred at room temperature for 30 minutes. Water (10 mL) was added and stirring was continued for a further 10 minutes. Ethyl acetate was then added, the organic layer was decanted, washed with brine, dried over MgSO4 and evaporated to dryness. The residue was triturated with ether and filtered to afford the pure title product as a yellow solid, mp: 149° C. dec.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH3:12])[N:6]=1)[CH3:3].[NH:13]1C=CN=[CH:14]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:4][C:5]2[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH3:12])[N:6]=2)[CH:1]=[CH:14][N:13]=[CH:3]1
Reactant: Cc1ccc(O)c(CN(C)C)n1
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Product: Cc1ccc(O)c(Cn2ccnc2)n1
Yield: 76.3 %

Procedure:
The procedure described in Example 1 was repeated except that 2-dimethylaminomethyl-3-hydroxy-6-methylpyridine (16.6 g.) and imidazole (6.8 g.) were reacted in xylene (50 ml.) to afford 2-(imidazol-1-ylmethyl)-3-hydroxy-6-methylpyridine (yield, 14.42 g.), m.p. 153°-155° C. after recrystallization from isopropanol/petroleum ether (b.p. 60°-80° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]2=[O:12].CN1CCOCC1.[C:27]12([CH2:37][C:38](Cl)=[O:39])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>O1CCOCC1>[C:27]12([CH2:37][C:38]([NH:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][N:6]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]4=[O:12])=[O:39])[CH2:34][CH:33]3[CH2:32][CH:31]([CH2:30][CH:29]([CH2:35]3)[CH2:28]1)[CH2:36]2
Reactant: Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 5-amino-2-benzylisoquinolin-1(2H)-one (50 mg, 0.2 mmol) and NMM (0.022 mL, 0.2 mmol) in 1,4-dioxane (3 mL) was added dropwise at room temperature a solution of 1-adamantaneacetic acid chloride (43 mg, 0.2 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 1 h. The volatiles were removed on a rotary evaporator. The crude product was purified by prep. HPLC affording 2-Adamantan-1-yl-N-(2-benzyl-1-oxo-1,2-dihydro-isoquinolin-5-yl)-acetamide (45.5 mg, 0.11 mmol, 53% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[CH:13][CH:14]=4)=[C:4]2[CH:3]=1.C[C:25]([N:27](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N>[CH3:23][N:16]1[C:15]2[C:10]3[C:11](=[C:4]4[C:5](=[N:8][C:9]=3[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]1=3)[CH:6]=[CH:7][C:2]([C:25]#[N:27])=[CH:3]4)[CH:12]=[CH:13][CH:14]=2
Reactant: CC(=O)N(C)C
Reactant: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cccc1c23
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN1c2ccccc2-c2nc3ccc(C#N)cc3c3cccc1c23
Temperature: 100 °C
Yield: 99 %

Procedure:
(Method T) 3-Chloro-8-methyl-8H-quino[4,3,2-kl]acridine, 28 (150 mg, 0.47 mmol), tris(dibenzylideneacetone)dipalladium (0) (9 mg), bisdiphenylphosphino ferrocene (17 mg), zinc powder (5 mg), zinc cyanide (33 mg) and DMA were mixed in a sealed tube, flushed with nitrogen, the tube sealed and the mixture heated to 100° C. for 3 days. The cooled mixture was taken up in dichloromethane (50 mL), washed with 2M ammonium hydroxide (20 mL) and water (20 mL), dried, filtered, evaporated and purified by column chromatography to the title compound (147 mg, 0.46 mmol, 99%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[O:28]=[S:29]1(=[O:43])[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[O:43]=[S:29]1(=[O:28])[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:33][CH2:34]1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cn1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-(1,1-dioxothiomorpholin-4-ylmethyl)-pyridin-2-ylamine (Step 104.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 585.9 [M+H]+; tR=3.96 min (System 1); TLC: Rf=0.39 (DCM/MeOH/NH3aq, 94:5:1).