Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[C:20](Br)[C:5]2[N:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:21]=[C:20]([C:28]([O:30][CH2:31][CH3:32])=[CH2:29])[C:5]2[N:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)Oc2cc(N)cc(Br)c2N(c2ccc(F)cc2)C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cc(N)cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2
Temperature: 100 °C

Procedure:
A mixture of 7-amino-5-bromo-4-(4-fluorophenyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 53(7); 100 mg), tributyl(1-ethoxyvinyl)tin (278 μL), dichlorobis(triphenylphosphine)palladium(II) (19 mg) and toluene was heated at 100° C. under argon atmosphere for 4 hours. After cooling, the reaction mixture was filtered through a NH-silica gel pad, and the filtrate was concentrated in vacuo to give 7-amino-5-(1-ethoxyvinyl)-4-(4-fluorophenyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.N([O-])=[O:27].[Na+]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([OH:27])=[CH:6][C:5]=1[NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(O)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 82.6 %

Procedure:
This compound was produced using similar methods as those used in Step 3, example 27, starting with 4-amino-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (1.80 g, 5.08 mmol), trifluoroacetic acid (30 mL) and sodium nitrite (0.42 g, 6.15 mmol in 10 mL of water). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 20/80) to give 4-hydroxy-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (1.49 g, 83%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6); δ 11.98 (s, 1H), 10.62 (s, 1H), 8.21 (d, 1H), 8.06 (d, 2H), 7.90 (d, 1H), 7.61 (d, 2H), 6.61 (dd, 1H), 3.84 (s, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16](=[O:32])[CH2:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].Br[CH2:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[F:43]>C1(C)C=CC=CC=1.C1COCC1.CCOCC.CCCCC>[C:11]([O:15][C:16](=[O:32])[CH:17]([N:18]=[C:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[F:43])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1ccc(F)c(CBr)c1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(F)c(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
KHMDS (550 μl of a 0.5 M solution in toluene, 0.55 mmol) diluted with dry THF (1.5 mL) was added to a solution of t-butylglycinate Schiff base 3 (68 mg, 0.23 mmol) in THF (1.5 mL). A mixture containing 2-fluoro-5-methoxybenzyl bromide (35, 50 mg, 0.23 mmol) in THF (1.0 mL) was immediately added to the resulting enolate solution at −78° C. The combined mixture was warmed to room temperature, stirred for 2 h, diluted with 1:1 ether/pentane (20 mL), washed with brine (3×10 mL), dried (sodium sulfate), filtered and then concentrated to afford 40 as a crude yellow oil (115%). Interestingly, a lower yield of 22% (40 mg) was obtained compared to using LiHMDS.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[N:15]([CH3:22])[C:14]=2[CH:23]=1.[CH2:24](I)[CH3:25]>O>[CH2:24]([N:19]1[C:18](=[O:20])[CH2:17][C:16](=[O:21])[N:15]([CH3:22])[C:14]2[CH:23]=[C:10]([O:9][CH3:8])[CH:11]=[CH:12][C:13]1=2)[CH3:25]
Reactant: CCI
Reactant: COc1ccc2c(c1)N(C)C(=O)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)CC(=O)N(C)c2cc(OC)ccc21
Temperature: 0 °C
Yield: 76.7 %

Procedure:
Sodium hydride (60% in oil, 44 mg) was suspended in of DMF (8 ml), and was cooled to 0° C. in an ice water bath. 8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Ethyl iodide (187 mg) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1). The purified product was condensed to dryness to give the title compound (190.2 mg) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[CH:2]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=[O:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 80.5 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (5.6 g, 9.32 mmol) in dichloromethane (100 ml) was added PCC (3.01 g, 13.98 mmol). The mixture was stirred at rt for 6.5 h then was filtered through a pad of celite and silica gel which was washed with dichloromethane then 1:1 ethyl acetate:hexanes. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography using a 0-10% EtOAc in hexanes gradient to afford the title compound as a white solid (4.49 g, 7.50 mmol, 80% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.68 (1H, d, J=1.5 Hz), 7.87 (2H, d, J=8.2 Hz), 7.16 (2H, d, J=8.2 Hz), 5.26 (1H, dd, J=6.4, 1.8 Hz), 4.76 (1H, d, J=1.8 Hz), 4.63 (1H, s), 2.88 (1H, td, J=11.1, 5.8 Hz), 2.02-2.15 (3H, m), 1.70 (3H, s), 1.58 (9H, s), 1.00 (3H, s), 0.97 (3H, s), 0.97 (3H, s), 0.91 (6H, s), 0.83-1.94 (19H, m).
Reaction SMILES: [CH:1]1([S:4]([N:7]2[C:11]3=[CH:12][C:13]4[C:17]([C:18]([F:19])=[C:10]3[N:9]([C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])C2=O)=[N:16][N:15]([CH3:20])[C:14]=4[CH3:21])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[F:29][C:23]1[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=1[NH:9][C:10]1[C:11]([NH:7][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:5])=[O:6])=[CH:12][C:13]2[C:17]([C:18]=1[F:19])=[N:16][N:15]([CH3:20])[C:14]=2[CH3:21]
Reactant: Cc1c2cc3c(c(F)c2nn1C)n(-c1ccc(I)cc1F)c(=O)n3S(=O)(=O)C1CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c2cc(NS(=O)(=O)C3CC3)c(Nc3ccc(I)cc3F)c(F)c2nn1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
To a solution of 5-cyclopropanesulfonyl-8-fluoro-7-(2-fluoro-4-iodophenyl)-2,3-dimethyl-2,7-dihydro-5H-imidazo[4,5-f]indazol-6-one (24 mg, 0.044 mmol) in THF (3 ml) was added potassium trimethylsilanolate (11 mg, 0.088 mmol). The reaction was stirred at room temperature for 5 h, quenched with saturated aqueous NH4Cl solution (5 ml), and extracted with EtOAc (2×10 ml). The combined organic solution was washed with brine (15 ml), dried over MgSO4, and concentrated. Silica gel chromatography (EtOAc:Hexanes=50:50) yielded 19 mg (83%) of the title compound. m/z=517 [M−1]−. 1H NMR (DMSO-d6, 400 MHz): δ 0.78 (m, 4H), 2.48 (m, 1H), 2.68 (s, 3H), 4.13 (s, 3H), 6.38 (m, 1H), 7.32 (d, J=8 Hz, 1H), 7.41 (s, 1H), 7.59 (m, 2H), 9.23 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]=[C:6]1[C:5]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:24]3[N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[NH:7]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=C1Nc2ccc(Br)cc2C12CCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCC1)C(=O)N2
Temperature: 80 °C
Yield: 83.2 %

Procedure:
A solution of 5′-bromospiro[cylopentane-1,3′-[3H]indol]-2′(1′H)-one (2.0 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.3 mmol) in ethylene glycol dimethyl ether (50 mL) was stirred under a flow of nitrogen for 15 min. To the solution was added sequentially 1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassium carbonate (2.4 g, 17 mmol) in water (10 mL). The mixture was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (30 mL) and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. Crystallization from 20% ethyl acetate/hexane gave 2-(1′,2′-dihydro-2′-oxospiro[cyclopentane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (2.2 g, 83%) as a white powder, mp 179-180.5° C. 1H NMR (DMSO-d6, 400 MHz) δ1.30 (s, 9H), 1.75-1.98 (m, 8 H), 6.16 (dd, 1 H, J=1.8, 3.3 Hz), 6.22 (‘t’, 1 H, J=3.3, 3.3 Hz), 6.79 (d, 1 H, J=7.9 Hz), 7.08 (dd, 1 H, J=1.8, 7.9 Hz), 7.14 (‘d’, 1 H, J=1.5 Hz), 7.28 (dd, J=1.9, 3.3 Hz),10.30 (s, 1 H). MS (EI) m/z 352 [M+]. Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.08; H, 6.83; N, 7.74.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=[O:13])[CH2:11][Cl:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:14](O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:16][CH2:15][CH2:14][O:13]1)[CH2:11][Cl:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NOC)C1(CCl)OCCO1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A mixture of ethyl 2-methoxyimino-3-oxo-4-chlorobutyrate (syn isomer, 41 g), ethylene glycol (24.6 g), p-toluenesulfonic acid (2.0 g) and toluene (250 ml) was heated for 20 hours under reflux while removing water. The reaction mixture was cooled to ambient temperature, washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and then the solvents were removed. The residue was distilled under reduced pressure to give ethyl 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer, 24.4 g), bp 103°-110° C./2 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]2=[N:17][CH:18]=[C:19]([NH:21]C(=O)OC(C)(C)C)[N:20]=[C:15]2[CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[C:16]2=[N:17][CH:18]=[C:19]([NH2:21])[N:20]=[C:15]2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(NC(=O)OC(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(-c1cc3nc(N)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 30 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
In a flask was added tert-butyl 6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.200 g, 0.382 mmol) and TFA (0.088 mL, 1.15 mmol) in DCM (1 mL). The mixture was stirred for about 2 h at about 30° C. Additional TFA (0.100 mL, 1.29 mmol) was added and the mixture was stirred at about 40° C. overnight. The mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous Na2CO3 (5 mL) and dried over MgSO4, filtered and concentrated in vacuo. The material was purified by 4 g silica column eluting with 10 to 100% EtOAc/DCM to provide 6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-amine (0.065 g, 40%): LC/MS (Table 2, c) Rt=1.62 min; MS m/z 424 (M+H)+.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>C(O)(=O)C>[CH3:1][S:2][CH:3]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]3[C:15]2=[O:20])=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)C(SC)c1ccc(N)cc1
Solvent: CC(=O)O
Product: COC(=O)C(SC)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Yield: 99.5 %

Procedure:
Methyl α-methylthio(p-aminophenyl)acetate (760 mg) and 533 mg of phthalic anhydride were dissolved in 8 ml of acetic acid, and the solution was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and 100 ml of an aqueous solution of sodium bicarbonate was added. The mixture was extracted once with 20 ml of methylene chloride, and then twice with 10 ml of methylene chloride each time. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 1.222 g of methyl α-methylthio(p-phthalimidophenyl)acetate as colorless crystals in a yield of 99.5%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)#[N:16]>>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Product: N#Cc1ccc(CN(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-cyanobenzyl bromide
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=Cc1cccnc1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1cccnc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with nicotinaldehyde (0.5 g, 4.7 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.102 g, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:47]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:47][CH2:50][NH:51][C:52](=[O:54])[CH2:53]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cncc(F)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cncc(F)c3)n2)CCN1

Procedure:
75 mg (0.17 mmol) of the compound of Example 44A is reacted analogously to the synthesis of the compound of Example 1 with 19 mg (0.19 mmol) of 2-oxopiperazine. 80 mg (90% of theory) of the title compound is obtained.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](=[O:20])[CH2:6]1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:3][CH2:4][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:7](=[O:20])[CH2:6]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1CC(CO)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)OC(C)(C)C)N1CC(COCc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
In a 100 ml 3 necked flask, fitted with magnetic stirrer and reflux condenser under inert atmosphere, 1.1 g (60%, 27.5 mmoles, 1.1 eq) of sodium hydride are suspended in 60 ml of DMF and the mixture cooled down to 0° C. 6.37 g (24.8 mmoles, 1 eq) of tert-butyl (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398 in 10 ml of DMF are added cautiously. After 10 min, 3.3 ml (4.75 g, 27.8 mmoles, 1 eq) of benzyl bromide in 10 ml of DMF are added, and stirring continued for 30 min at 0° C., followed by 3 hours at room temperature. The mixture is concentrated to dryness, the residue is suspended in brine/CH2Cl2, decanted and extracted with CH2Cl2. The combined organic phases are dried over MgSO4, concentrated to dryness and the residue is purified by Prep LC (1 kg SiO2, hexane/MTBE, 40:60->0:100) to give 3.2 g of a mixture of t-Bu and Benzyl esters in two fractions, 37% total yields. It is used as such for the next step 7.3.1.b. 1H NMR (250 MHz, (CDCl3): 0.85 (t, 3H), 1.44 (s, 9H), 1.55-1.95 (m, 2H), 2.10 (dd, 1H), 2.45 (dd, 1H), 2.55-2.70 (m, 1H), 3.45-3.55 (m, 1H), 4.40 (dd, 1H), 4.55 (s, 2H), 7.20-7.40 (m, 5H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][OH:10].Cl>>[Br:7][CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCBr
Agent: Cl
Product: BrCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
3,4-Dihydro-2H-pyran (92.5 g, 1.1 mol) was added dropwise to 2-bromoethanol (125 g, 1.0 mol) on an ice-bath. The temperature was kept between 25-30° C. during addition. When addition was complete a concentrated hydrochloric acid solution (1 ml) was added and the reaction mixture was stirred overnight at room temperature. The mixture was fractionated in vacuo to give 147 g (70%) of 2-bromoethyl- tetrahydropyran-2-yl ether.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl>CO>[N:8]1([C:5]([CH3:7])([CH3:6])[C:4]([OH:13])=[O:3])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CCOC(=O)C(C)(C)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)n1ccnc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
1.54 g of 2-imidazol-1-yl-2-methyl-propionic acid ethyl ester (73828-88-3) are dissolved in 20 ml of methanol. 20 ml of a 3M NaOH are added and the mixture is stirred for 16 hours at 60° C. The reaction mixture is then neutralised with 1M HCl and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60 F) based on its Rf value.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][N:5]2[CH2:6][C@@H:7]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[C:8]3[C:13]([C@@H:4]2[CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[ClH:25]>CO.O.[Pd]>[ClH:25].[ClH:25].[CH3:1][N:2]1[CH2:24][CH2:23][N:5]2[CH2:6][C@@H:7]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[C:8]3[C:13]([C@@H:4]2[CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CN1CCN2C[C@@H](c3ccc([N+](=O)[O-])cc3)c3ccccc3[C@@H]2C1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CN1CCN2C[C@@H](c3ccc(N)cc3)c3ccccc3[C@@H]2C1

Procedure:
A solution of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-(4-nitrophenyl)-2H-pyrazino[2,1-a)isoquinoline (5.2 g, 0.014 m) in methanol (500 ml), water (100 ml) and conc HCl (5 ml) was hydrogenated on a Parr apparatus over 2.0 g of palladium on carbon catalyst of 40 psi for 1 hour. The catalyst was removed by filtration and the solvents evaporated to a solid residue. This was dissolved in water (500 ml), basified to pH 11 with 50% NaOH, and extracted with ether (3×200 ml). The extracts were dried over MgSO4 and evaporated to an oil, 4.04 g. This crude product was purified by chromatography on silica gel with a Prep 500 HPLC, eluting with 2% ammoniated methanol/chloroform. Pure fractions were combined and evaporated to give an oil, 1.12 g. This was dissolved in methanol (30 ml) and acidified with HCl gas. Upon standing, a white solid crystallized, which was collected by filtration and vacuum dried at 95% for 24 hours to give 1.08 g of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-(4-aminophenyl)-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, m.p. 274°-276°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4](Cl)[CH:3]=1.[CH3:24][O-:25].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4]([O:25][CH3:24])[CH:3]=1
Reactant: Cc1c(Cn2cnc3c(Cl)cc(Cl)nc32)cccc1C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc2c1ncn2Cc1cccc(C(F)(F)F)c1C

Procedure:
5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (200 mg, 0.555 mmol) was suspended in Methanol (1.5 mL), sodium methoxide (0.150 mL, 0.656 mmol) was added and the mixture was irradiated in a microwave oven for 90 min at 110° C. Conversion to desired product was observed by LC/MS (5,7-dimethoxy product, 5-methoxy isomer and 7-OH-5-Cl derivative observed by mass as well). The mixture was diluted with water and the precipitate formed was collected by filtration, washed with water and dried. The solid was purified on silica gel (ISCO 0-60% EtOAc in hexanes) to give 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (125 mg, 0.351 mmol, 63.3% yield) as a white powder. Additional material was prepared from 120 mg of 5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine, irradiated in a microwave for 30 min at 110° C. in the presence of NaOMe. After work-up, 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (109 mg, 0.306 mmol, 55.2% yield) was obtained and carried on without further purification to the next step. MS (ES+) m/e 356 (MH+).