Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:34])=[C:18]([NH:20][C:21](=[O:33])[CH2:22][C:23]23[CH2:32][CH:27]4[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]4)[CH2:24]2)[CH2:30]3)[CH:19]=1.O[CH2:36][CH2:37][CH2:38][N:39](C)[C:40](=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:67]>O1CCCC1.CO>[ClH:67].[CH3:40][NH:39][CH2:38][CH2:37][CH2:36][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:34])=[C:18]([NH:20][C:21](=[O:33])[CH2:22][C:23]23[CH2:32][CH:27]4[CH2:26][CH:25]([CH2:31][CH:29]([CH2:28]4)[CH2:30]2)[CH2:24]3)[CH:19]=1
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Reactant: Cc1ccc(O)cc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CNCCCOc1ccc(C)c(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1
Reaction time: 72 h

Procedure:
Diethyl azodicarboxylate (0.50 ml) was added to a solution of N-(5-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.50 g, Example 12), tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (0.60 g, J. Org. Chem., 1988, 53(10), 2229) and triphenylphosphine (0.88 g) in tetrahydrofuran (5 ml). After stirring for 19 hours at room temperature further triphenylphosphine (0.90 g) and diethyl azodicarboxylate (0.50 ml) were added. After stirring for 4 hours at room temperature further triphenylphosphine (0.90 g) and diethyl azodicarboxylate (0.50 ml) were added and the reaction mixture was stirred for 3 days. The reaction was then concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give material that was further purified by chromatography over a Dynamax® column using a Gilson automated chromatography machine eluting with iso-hexane:ethyl acetate (4:1) to give the Mitsunobu reaction product (0.29 g) which was dissolved in methanol (10 ml). A solution of hydrogen chloride (generated by slow addition of acetyl chloride (12 ml) to methanol (10 ml) at 0° C. CARE—Very Exothermic) was then added to the latter solution and the reaction stirred at room temperature for 1 hour. The reaction was then concentrated under reduced pressure to give the title compound as a yellow solid (0.13 g).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1.[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH2:29]>>[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH:29][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1
Reactant: COc1cccc(Cc2nnc(SC)[nH]c2=O)c1
Reactant: Cc1[nH]cnc1CSCCN
Product: COc1cccc(Cc2nnc(NCCSCc3nc[nH]c3C)[nH]c2=O)c1
Reaction time: 0.08 h
Yield: 41.4 %

Procedure:
3-Methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (1.07 g) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.77 g) were heated together on an oil bath (160°-70° ) for 3/4 hour. The solidified mass was broken up under methanol (ca 15 ml) and boiled for 5 minutes. After cooling the white solid was filtered off and recrystallised from dimethylformamide to give the title compound as a colourless solid (0.65 g) m.p. 203°-4°.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:20]=[CH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24][N:25]([CH3:30])[C:26](=[O:29])[CH2:27]Cl>CN(C=O)C>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:27][C:26]([N:25]([CH3:30])[CH3:24])=[O:29])[C:8]=2[CH:20]=[CH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(=O)CCl
Reactant: C=Cc1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1c(C2CCCCC2)c2ccc(C(=O)OC)cc2n1CC(=O)N(C)C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-vinyl-1H-indole-6-carboxylate (from Step 1) in DMF, NaH (1.2 eq.; 60% in mineral oil) was added. After evolution of gas had ceased, N,N-dimethyl chloroacetamide (1.3 eq.) was added dropwise. The mixture was stirred overnight, then all volatiles were evaporated and the residual material was taken up in DCM. The solution was washed with 1N HCl (1×), brine (2×) and then dried over Na2SO4. The solvent was evaporated and the residual material crystallised from DCM with PE. The product was obtained as a yellow solid (68%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.36-1.38 (m, 3H); 1.69-1.96 (3m, 7H); 2.85 (s, 3H); 2.91-2.95 (m, 1H); 3.13 (s, 3H); 3.85 (s, 3H); 5.15 (s, 2H); 5.41 (d, J 17.8, 1H); 5.61 (d, J 11.6, 1H); 6.71-6.78 (dd, Ja 11.6, Jb 17.8, 1H); 7.61 (d, J 78.3, 1H); 7.81 (d, J 8.5, 1H); 7.94 (s, 1H). MS (ES+) m/z 369.6 (M+H)+.
Reaction SMILES: C(#N)C.[NH:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]#[N:14])=[N:5]1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])[CH2:24][CH2:25]I>CCOC(C)=O>[F:27][C:23]([F:28])([C:22]([F:30])([F:29])[F:21])[CH2:24][CH2:25][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]#[N:14])=[N:5]1
Reactant: N#Cc1n[nH]c2ncccc12
Reactant: FC(F)(F)C(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Temperature: 75 °C

Procedure:
An acetonitrile solution (150 mL) containing the intermediate from Step C above (10.5 g, 43.7 mmol), potassium carbonate (30.2 g, 219 mmol) and 1,1,1,2,2-pentafluoro-4-iodobutane (23.95 g, 87 mmol) was heated at 75° C. for 48 hours. The reaction solution was cooled to room temperature and diluted with EtOAc. The solution was washed with water, brine and concentrated in vacuo. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the title compound. 1H NMR (400 MHz, CH3CN-d3): δ 8.71 (dd, J=4.47, 1.51 Hz, 1H); 8.31 (dd, J=8.22, 1.52 Hz, 1H); 7.44 (dd, J=8.24, 4.48 Hz, 1H); 4.92 (t, J=6.98 Hz, 3H); 3.00-2.82 (m, 2H). m/z=291.0 (M+H).
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([O:24][CH3:25])[N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl>[NH2:2][CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([O:24][CH3:25])[N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cc(CBr)nc(OC)c1
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(CN)nc(OC)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
6.72 g (47.9 mmol) of hexamethylenetetramine (urotropin) were initially introduced in 250 ml of chloroform and a solution of 10.95 g (39.95 mmol) of ethyl 2-bromomethyl-6-methoxyisonicotinate (20c) in chloroform was added dropwise at 0° C. The mixture was stirred at RT for 4.5 hours and after this a further 3.36 g (24.0 mmol) of hexamethylenetetramine (urotropin) was added. After standing at RT for a further 60 hours, the solvent was distilled off under reduced pressure and the residue was dissolved in 500 ml of ethanol. 50 ml of concentrated HCl were added and the mixture was stirred at RT for two hours. After addition of a further 30 ml of concentrated HCl and stirring at RT overnight, it was freed from the solvent under reduced pressure. The residue was taken up in DCM and carefully treated with K2CO3 until evolution of gas was no longer observed. Subsequently, it was washed twice with saturated K2CO3 solution, and the organic phase was dried with MgSO4 and concentrated. The crude product thus obtained (7.60 g) was reacted further without further purification. LCMS-Rt: 0.74 min [M+H+]: 211.2
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26](O)(=[O:29])[CH2:27][CH3:28]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (17.9 mg, 57.9%), MS (ISP) m/z=387.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and propionic acid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:11][CH3:12])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1Cl

Procedure:
2-Chloronicotinic acid (5.90 g, 37.5 mmol), ethanol (120 mL), toluene (35 mL) and 98% sulfuric acid (2 mL) were heated together under reflux for 48 hours. After evaporation of the ethanol and toluene, the residue was dissolved in water, neutralized with sodium bicarbonate, and extracted with chloroform. The organic layer was dried through MgSO4, and then the solvent was evaporated to give a dark-brown oil-like residue, which was purified by flash chromatography using a gradient of 10-20% hexane/ethyl acetate as the eluant to give ethyl 2-chloronicotinate (4.60 g) as a light-brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13](S(C)(=O)=O)[C:12]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26]OS(C)(=O)=O)[CH2:22][CH2:21]2)=[N:11][C:10]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:26][CH:23]3[CH2:24][CH2:25][N:20]([C:12]2=[N:11][C:10]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:21][CH2:22]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(N2CCC(COS(C)(=O)=O)CC2)n(S(C)(=O)=O)c(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCN2CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
A mixture of ethyl 5-(benzyloxy)-1-(methylsulfonyl)-2-(4-((methylsulfonyloxy)methyl)piperidin-1-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate and K2CO3 (0.051 g, 0.368 mmol) in ethanol (10 mL) was stirred at 60° C. for 4 h and cooled to room temperature. Water was added and the product was extracted with ethyl acetate. The organic phase was washed with brine then dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (Biotage flash chromatography system; 0%-10% methanol/CH2Cl2, 25 CV; 10% methanol/CH2Cl2, 5 CV) to give the title compound as a white glass (0.0248 g, 37% yield). 1H NMR (500 MHz, CDCl3) δ: 7.44 (2H, dd, J=7.3 Hz), 7.30-7.22 (3H, m), 5.27 (2H, s), 4.22 (2H, q, J=7.1 Hz), 4.01-3.94 (2H, m), 3.77-3.70 (2H, m), 3.67 (2H, brs), 3.02 (1H, brs), 2.29-2.24 (2H, m), 1.93-1.88 (2H, m), 1.22 (3H, t, J=7.0 Hz). LCMS (M+H) calcd for C20H24N3O4: 370.17; found: 370.30.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([N:13]2[C:12]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Clc1ccc(-n2nc3c(c2-c2ccccc2)CCNCC3)cc1
Yield: 38.4 %

Procedure:
The title compound (50.4 mg) was prepared from 201.1 mg of 2-(4-chloro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (made from (4-chloro-phenyl)-hydrazine as in Example 176, Steps A and B), and 65.1 mg of phenylboronic acid as described in Example 204. MS (ESI): exact mass calculated for C19H18ClN3, 323.12; found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.39-7.34 (m, 3H), 7.22-7.19 (m, 2H), 7.15-7.11 (m, 4H), 3.11-3.07 (m, 2H), 3.04-3.00 (m, 2H), 2.99-2.96 (m, 2H), 2.67-2.64 (m, 2H).
Reaction SMILES: B(F)(F)F.CCOCC.[N+:10](=[CH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N-].C(=O)(O)[O-].[Na+].[Cl:24][CH2:25][C:26]#N>>[Cl:24][CH2:25][C:26]1[O:18][C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][N:10]=1
Reactant: N#CCCl
Reactant: CC(C)(C)C(=O)C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)c1cnc(CCl)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2 mL (2.3 g, 16 mmol) of boron trifluoride etherate in 20 mL of chloroacetonitrile at 0° C. was added a solution of 1.33 g (10 mmol) of 1-diazo-3,3-dimethyl-2-butanone in 5 mL of chloroacetonitrile dropwise. The resulting solution was stirred at 0° C. for 0.5 h. The reaction mixture was added to saturated aqueous sodium bicarbonate solution to neutralize the acid and the product was extracted three times with dichloromethane. The combined extracts was dried (sodium sulfate), concentrated and purified by flash column chromatography (Merck silica, 25×200 mm, dichloromethane) to give 1.1 g of 2-(chloromethyl)-5-t-butyloxazole as a yellow liquid (6.4 mmol, 64% overall from the acid chloride).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[Cl:18][C:19]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:20]=1[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#N.[OH2:35]>C1COCC1>[Cl:18][C:19]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:20]=1[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:35]
Reactant: N#Cc1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., a 1.2 M solution of diisobutylaluminum hydride in toluene (12.3 ml, 14.8 mmol) was added dropwise to a solution of 2-(2,4-dichlorophenoxy)benzonitrile (3.0 g, 11.3 mmol) in THF (30 ml). The reaction mixture was warmed to room temperature and stirred for 16 hours. It was cooled to 0° C. Water (10 ml) was added dropwise. It was warmed to room temperature. The solid was removed by filtration through a plug of celite. The solvent was removed from the filtrate in vacuo. The crude product was purified by flash chromatography on silica (130 g), using ethyl acetate/heptane 1:3 as eluent, to give 800 mg of 2-(2,4-dichlorophenoxy)benzaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[S:11]1[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cnccc3s2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2nc3cnccc3s2)cc1
Yield: 60.3 %

Procedure:
2-(4-nitrophenyl)thiazolo[4,5-c]pyridine (2.57 g, 0.01 mol), iron powder (2.8 g, 0.05 mmol) and NH4Cl (4.32 g, 0.08 mol) were refluxed in CH3OH/H2O (4:1, 200 mL) for 6 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was washed with water (30 ml) to give 4-(thiazolo[4,5-c]pyridin-2-yl)benzenamine as a white solid (1.37 g, Yield: 60%).
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([Br:18])=[C:13]3[CH2:19][C@@H:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][C@H:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[Br:18][C:14]1[CH:15]=[CH:16][C:17]2[NH:9][CH2:10][C@@H:11]3[CH2:21][C@H:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:19][C:13]=1[C:12]=23
Reactant: CCCN(CCC)[C@@H]1Cc2c(Br)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN(CCC)[C@@H]1Cc2c(Br)ccc3c2[C@H](CN3)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a stirred solution of 12.8 g (29 mmol) of (+)(2aR,4S)-1-benzoyl-6-bromo-4-(di-n-propylamino)-1,2,2a, 3,4,5-hexahydrobenz[cd]indole in 200 ml of tetrahydrofuran cooled to -78° C. under a nitrogen atmosphere was added 20 ml (32 mmol) of a 1.6M solution of n-butyllithium in hexane. The reaction mixture was stirred at -78° C. for 30 minutes and then allowed to warm to -20° C. To the reaction mixture was added 50 ml of a 1N hydrochloric acid solution. The mixture was extracted once with diethyl ether. The acidic solution was made alkaline with the addition of cold 5N sodium hydroxide solution. The basic mixture was extracted twice with methylene chloride. The combined organic solution was washed with a saturated sodium chloride solution. The methylene chloride solution was dried over magnesium sulfate and evaporated to give 9.6 g of (-)(2aR,4S)-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.
Reaction SMILES: [CH2:1]1[O:12][CH:4]([C:5]2[S:6][CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=2)[O:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH2:2]1[O:3][CH:4]([C:5]2[S:6][CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=2)[O:12][CH2:1]1
Reactant: O=Cc1csc(C2OCCO2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1csc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
228 m9 of 2,4-thiophenedicarboxaldehyde 2-ethylene acetal was dissolved in 3 ml of ethanol, and 57 mg of sodium borohydride was added. The mixture was stirred for 30 minutes at room temperature. The solvent was evaporated, and water and ethyl ether were added to the residue to extract it. The organic layer was separated, and dried over anhydrous magnesium sulfate. The desiccant was separated, and the solvent was evaporated. The residue was purified by silica gel column chromatography Wakogel C-200, 10 g; eluting solvent: hexane/ethyl acetate =1/1] to give 130 mg of 4-hydroxymethyl-2-thiophenecarboxaldehyde ethylene acetal as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1.[F:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([F:22])[C:20]=1F>CN(C=O)C>[F:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([F:22])[C:20]=1[N:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a suspension of anhydrous potassium carbonate (11.80 g, 85.90 mmol) in DMF (30 ml) was added a solution of 4-piperidinone (7.20 g, 47.2 mmol) in DMF (5 ml) followed by the addition of 3,4,5-trifluoronitrobenzene (7.00 g, 42.8 mmol) and stirred at room temperature for 3 h. The reaction mixture was poured onto ice water and the resulting solid was filtered off. Drying the solid under vacuum yielded the title compound as yellow powder (4.50 g, 45%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH:6]=[CH2:7].[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:32]=[CH:31][C:27]([CH:28]=[N:29][OH:30])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH:6]1[O:30][N:29]=[C:28]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([CH3:11])[CH:21]=3)=[CH:32][CH:31]=2)[CH2:7]1)[CH3:8]
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Reactant: C=CC(C)(C)CC(=O)OC
Product: COC(=O)CC(C)(C)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 100 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using 3,3-dimethyl-pent-4-enoic acid methyl ester and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 3-methyl-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-butyric acid methyl ester (0.14 g, 100%) as a crude oil. MS found: (M+H)+=433.
Reaction SMILES: C(OCC)(=O)CC(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:8]=1)=O.S(=O)(=O)(O)O.O.[C:32]([OH:35])(=[O:34])[CH3:33]>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH2:33][C:32]([OH:35])=[O:34])[CH:12]=[CH:11][CH:10]=2)=[O:21])=[CH:19][CH:18]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)OCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C

Procedure:
A solution of 15.2 g of ethyl 3-(p-chlorobenzoyl)-benzyl malonate in 50 ml of acetic acid was added to a solution of 50 ml of sulfuric acid and 50 ml of water and the mixture was refluxed under a nitrogen atmosphere for 20 hours and then cooled to room temperature. The mixture was poured into water and then extracted with methylene chloride. The organic phase was extracted with N sodium hydroxide and the alkaline phase was treated with activated carbon, filtered and acidified by addition at 10°C with stirring of 270 ml of N hydrochloric acid. The mixture was vacuum filtered and the precipitate was washed with water and dried under reduced pressure to obtain 3.11 g of 3-(3'-p-chlorobenzoyl-phenyl)-propionic acid which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:8][C:4]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([Cl:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)cccc1Cl
Product: CCOC(=O)c1c(Cl)cccc1CBr

Procedure:
Reaction of ethyl 3-chloro-o-toluate with N-bromosuccinimide as described in Example 1a provides ethyl α-bromo-3-chloro-o-toluate as an oil.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc(Nc2cccc(OC)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(Nc2cccc(C(=O)O)c2C(=O)O)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 3-(3-methoxy-phenylamino)-phthalic acid dimethyl ester (0.43 g, 1.4 mmol) and 3N NaOH (25 mL) in ethanol (50 mL) was heated to reflux for 2 hours and cooled to room temperature. The solvent was removed under vacuum and the residue was dissolved in water (50 mL), washed with CH2Cl2 (2×50 mL), and acidified with 6N HCl to pH 1-2. The resulting mixture was extracted with ethyl acetate (2×50 mL). The organic extracts were washed with water (2×50 mL) and dried (MgSO4). After filtration of the MgSO4, the solvent was evaporated in vacuo to give the product, 0.32 g, 82% yield; 1H NMR (DMSO-d6) δ 3.70 (s, 3H), 6.48 (dd, J=7.9 Hz, J=1.7 Hz, 1H), 6.62-6.64 (m, 2H), 7.11-7.44 (m, 4H), 7.92 (s, 1H), 13.12 (br, 2H).
Reaction SMILES: C(OC(=O)[N:7]([CH3:25])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:25][NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: C1COCCN1
Reactant: CSc1nccc(-c2cnc3c(N(C)C(=O)OC(C)(C)C)nccn23)n1
Product: CNc1nccn2c(-c3ccnc(N4CCOCC4)n3)cnc12

Procedure:
Methyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from methyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 8 supra), and morpholine. LC-MS: [M+H]+ 312.3.