Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([F:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][CH:14]([C:20]([CH3:22])=O)[C:15](OCC)=[O:16].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:22][C:20]1[C:14]([CH3:13])=[C:15]([OH:16])[C:10]2[C:8](=[C:7]([F:12])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=2)[N:9]=1
Reactant: CC(C)(C)c1ccc(N)c(F)c1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Yield: 23.4 %

Procedure:
4-t-Butyl-2-fluoroaniline (4.79 g) prepared according to the above process and ethyl 2-methyl-acetoacetate (4.96 g) were refluxed in toluene (60 ml) in the presence of trifluoroboron etherate (0.3 ml) for 3 hr to obtain a reaction solution. The reaction solution thus obtained was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The reaction product was refluxed in diphenyl ether (80 ml) for one hr and was allowed to stand for cooling. The precipitated product was then collected by filtration under the reduced pressure to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-hydroxyquinoline (compound 1, 1.66 g). 1H-NMR data on this compound in deutro-DMSO (dimethyl sulfoxide) were as shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([F:28])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(Cl)cc(Cl)c2)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2cc(Cl)cc(Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(3,5-dichlorophenyl)-3-hydroxypyrrolidin-1-carboxylate (0.88 g, 2.65 mmol) in dichloromethane (50 mL) was added dropwise diethylaminosulphurtrifluoride (0.35 mL, 2.65 mmol) dissolved in dichloromethane (20 mL) and the mixture was stirred at 0° C. for 20 minutes and at ambient temperature for 10 minutes. Aqueous sodium carbonate (10%, 50 mL) was added and the phases separated. The aqueous phase was extracted with dichloromethane (2×50 mL) and the pooled organic phase was dried (Na2SO4) and evaporated. Purification by flash column chromatography gave the title compound (0.45 g). MS m/z (rel. intensity, 70 eV) 334 (M+, 1), 278 (8), 277 (6), 260 (8), 57 (bp).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:22][NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.7 %

Procedure:
(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (300 mg, 1.1 mmol) was dissolved in 1,2-dichloroethane (30 mL) and cooled to 0° C. Formaline solution (˜0.1 mL, 35%) was added to the solution, followed by sodiumtriacetoxy borohydride (0.16 g, 0.76 mmol). The reaction mixture was further stirred for 45 min maintaining the same temperature. The reaction mixture was then quenched with 10% NaHCO3 solution and diluted with CH2Cl2. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica 60-120 mesh, eluent 10-20% MeOH in CHCl3) to afford N-methyl-1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (120 mg, yield 38%). 1H NMR (300 MHz, CDCl3) δ 7.90-7.88 (m, 2H), 7.48 (s, 1H), 7.44-7.34 (m, 3H), 3.93-3.86 (m, 2H), 3.75-3.67 (ddd, J=12.0 Hz, 8.9 Hz, 3.0 Hz, 2H), 3.01 (s, 2H), 2.49 (s, 3H), 2.36-2.39 (m, 2H), 2.09-2.01 (m, 2H). MS (ESI) m/z: Calculated for C16H20N2OS: 288.13. found: 289.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.[CH3:17][C:18]1[C:19](=O)[CH2:20][CH:21]([CH3:24])[C:22]=1[CH3:23].Cl.N>O1CCCC1>[CH3:17][C:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[CH2:20][C:19]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cccnc12
Reactant: CC1=C(C)C(C)CC1=O
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C(C)=C(c2cccc3cccnc23)C1
Temperature: -80 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
A solution of 8.3 g (40 mmol) of 8-bromoquinoline in 100 ml of tetrahydrofuran was cooled to −80° C. and 16 ml of n-butyllithium (2.5 M in hexane, 40 mmol) were subsequently added dropwise. After the addition was complete, the mixture was stirred for a further 15 minutes at −80° C. and 4.96 g (40 mmol) of 2,3,4-trimethylcyclopent-2-enone were then added. The mixture was allowed to come to room temperature and was then refluxed for 30 minutes. After cooling to room temperature, the reaction mixture was admixed with ice water and 10 ml of concentrated hydrochloric acid and stirred for 30 minutes. A dilute aqueous ammonia solution was then added until a pH of 12 had been reached. The aqueous phase was then separated off from the organic phase and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the solvent was distilled off. Distillation at 117-132° C. and 2×10−2 mbar gave 4.02 g (17.1 mmol, 43%) of 2,3,4-trimethyl-1-(8-quinolyl)cyclopentadiene.
Reaction SMILES: CC(C)=O.[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOC(C)=O>[CH2:27]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C1CCc2ccc(OCc3ccccc3)cc2O1
Yield: 85.7 %

Procedure:
To a 5 L acetone solution of ethyl 7-hydroxy-chromane-2-carboxylate (630.1 g, 2.84 mol) was added potassium carbonate powder (785 g, 5.68 mol) and benzyl bromide (405 ml, 3.41 mol). The resulting suspension was heated to reflux for 16 hr. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give solid material, which was re-dissolved in AcOEt, washed with water to remove residual salt, dried over MgSO4, filtered, concentrated to a small volume. Addition of hexanes caused precipitation of the title compound, which was collected by suction-filtration. The filtrate was triturated from dichloromethane-hexanes to give more precipitates. Finally the filtrate was concentrated and chromatographed on silica gel eluting with 20 to 80% dichloromethane/hexanes. Combination of all crops yielded the title compound 760.2 g as off-white solid (86%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH3:16])[CH:8]=1)(=[O:5])=[O:4].[CH2:19]([Mg]Br)[CH:20]=C.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:18])([F:17])[S:3]([O:6][C:7]1[CH:12]=[C:11]2[C:10](=[C:9]([CH3:16])[CH:8]=1)[NH:13][CH:20]=[CH:19]2)(=[O:5])=[O:4]
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)cc2cc[nH]c12
Reaction time: 2 h

Procedure:
A solution of 3-methyl-4-nitrophenyl trifluoromethanesulfonate (8.96 g, 31.4 mmol) in THF (200 mL) at 0° C. was treated dropwise with 1M allylmagnesium bromide in THF (110 mL 110 mmol), stirred for 2 hours, transferred into saturated NH4Cl (200 mL), and extracted with ethyl acetate (200 mL). The extract was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography with 9:1 hexanes/ethyl acetate to provide 3.19 g of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][Sn](CCCC)(CCCC)CCCC.C([Li])CCC.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:43]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[O:51][CH3:52])=[C:42]([O:53][CH2:54][CH2:55][OH:56])[N:41]=[C:40](S(C)(=O)=O)[N:39]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:43]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[O:51][CH3:52])=[C:42]([O:53][CH2:54][CH2:55][OH:56])[N:41]=[C:40]([CH2:5][O:4][CH2:3][O:2][CH3:1])[N:39]=2)(=[O:35])=[O:36])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(S(C)(=O)=O)nc1OCCO
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2ccccc2OC)c(OCCO)n1
Reaction time: 0.07 h

Procedure:
##STR150## (1) To a solution of methoxymethyloxymethyltributyltin (655 mg) in tetrahydrofuran (6 ml) is added dropwise a 1.63M solution of n-butyl lithium in n-hexane (1.09 ml) at -78° C. The mixture is stirred at the same temperature for four minutes, and thereto is added a solution of 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxyphenoxy)-2-methylsulfonylpyrimidin-4-yl]benzenesulfonamide obtained in Reference Example 10-(1) (200 mg) in tetrahydrofuran (2 ml), and the mixture is stirred for 40 minutes. To the mixture is added an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1~50:1) to give 4-tert-butyl-N-[6-(2-hydroxyethoxy)-2-methoxymethyloxymethyl-5-(2-methoxy-phenoxy)pyrimidin-4-yl]benzenesulfonamide (111 mg) as a colorless caramel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:19](=O)[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH:19]([NH2:28])[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1nc2cccc(C)n2c1-c1cc(F)cc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc2nc(C(C)N)c(-c3cc(F)cc(F)c3)n12
Temperature: 65 °C
Yield: 55.2 %

Procedure:
A solution of 1-[3-(3,5-difluorophenyl)-5-methylimidazo[1,2-a]pyridin-2-yl]ethanone (0.23 g, 0.82 mmol) in methanol (9.5 mL) was treated with ammonium acetate (0.63 g, 8.2 mmol) and heated at 65° C. for 1 h. The reaction mixture was treated with sodium cyanoborohydride (0.15 g, 2.5 mmol) and heated at 65° C. for 4 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (0.13 g, 56%) as a colorless oil. LCMS for C16H16F2N3 (M+H)+: m/z=288.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([NH2:20])=[CH:18][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:11][C:5]=2[CH:4]=1.CS([C:24]1[N:29]=[CH:28][C:27]2=[CH:30][CH:31]=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])[N:26]2[N:25]=1)=O.C(O)(C(F)(F)F)=O>>[CH3:1][O:2][C:3]1[C:19]([NH:20][C:24]2[N:29]=[CH:28][C:27]3=[CH:30][CH:31]=[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])[N:26]3[N:25]=2)=[CH:18][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1N)CCCC(N1CCOCC1)C2
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n1)CCCC(N1CCOCC1)C2
Yield: 13.2 %

Procedure:
Following a procedure analogous to 251c, 3-Methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (0.095 g, 0.34 mmol) and N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (63 mg, 0.17 mol) were converted to the title compound (25.89 mgs) as a TFA salt. H-NMR (CDCl3) δ 9.59 (broad s, 1H-TFA), 8.96 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 7.68-7.49 (m, 4H), 6.98-6.95 (m, 3H), 4.06-4.00 (m, 2H), 3.85 (s, 3H), 3.78-3.69 (m, 2H), 3.44-3.14 (complex series of m, 7H), 3.90-3.04 (m, 5H), 2.86 (s, 3H), 2.68-2.58 (m, 1H), 2.39-2.19 (m, 3H) 2.09-1.87 (m, 2H); LC/MS (ESI+): 577.2 (M+H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=O.[CH2:12]([CH2:14][NH2:15])[OH:13]>CO>[SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[CH2:6][CH2:7][C:8]([NH:15][CH2:14][CH2:12][OH:13])=[O:10]
Reactant: O=C(O)CCC(=O)NCCS
Reactant: NCCO
Solvent: CO
Product: O=C(CCC(=O)NCCS)NCCO

Procedure:
A solution of 4.4 g (23 mmol) of methyl ester of N-(2-mercaptoethyl)succinamic acid obtained in Example 1a) in 20 cm3 of methanol, and 1.68 g (27 mmol) of ethanolamine was stirred for 5 hours at 60° C. under argon atmosphere.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=1.C(O)C.[OH-].[K+].Cl>O>[CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCC(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)CCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A solution of 5 g. of ethyl 4-(13,13-dimethyltetradecyl)aminobenzoate in 75 ml. 95% ethanol is saponified with 2.5 g. of 85% potassium hydroxide by refluxing for 5 hours. The warm solution is diluted with 150 ml. water and adjusted to pH 5 with 37% hydrochloric acid. The precipitate is filtered, washed with water, dried in vacuo and crystallized from acetic acid to yield the title compound as a creamcolored, amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C@H:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CS([C:20]1[N:21]([CH3:33])[C:22]([C:25]2[CH:30]=[CH:29][N:28]([CH3:31])[C:27](=[O:32])[CH:26]=2)=[N:23][N:24]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C@H:13]([O:15][C:20]3[N:21]([CH3:33])[C:22]([C:25]4[CH:30]=[CH:29][N:28]([CH3:31])[C:27](=[O:32])[CH:26]=4)=[N:23][N:24]=3)[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O)c1cc(-c2cccc(Cl)c2)on1
Reactant: Cn1c(-c2ccn(C)c(=O)c2)nnc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@H](Oc1nnc(-c2ccn(C)c(=O)c2)n1C)c1cc(-c2cccc(Cl)c2)on1
Temperature: 60 °C

Procedure:
The title compound from example 17.1 (96 mg, 0.43 mmol), the title compound from example 34.1 (100 mg, 0.36 mmol) and cesium carbonate (419 mg, 1.29 mmol) were combined with a stir bar in a screw cap vial which was purged with nitrogen. The combined reagents were stirred in DMF and heated to 60° C. overnight. The reaction mixture was then diluted with water and extracted three times with chloroform. The organic phase was dried over magnesium sulfate, filtered and concentrated then chromatographed in 0-10% methanol in ethyl acetate (pale solid, 105 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:25]([Mg]Cl)([CH3:27])[CH3:26]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[CH:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (150.0 mg, 0.394 mmol) in tetrahydrofuran (3.0 mL) was added i-propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.59 mL, 0.591 mmol). The reaction mixture was stirred at 0° C. for 2 hrs. To the mixture was added i-propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.59 mL, 0.591 mmol). The mixture was stirred at 0° C. for 1 hr. After cooling, the mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (78.8 mg, 0.186 mmol, 47%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[N:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[N:10]([C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:11][CH2:12]2
Reactant: O=[N+]([O-])c1ccc(N2CCN3CCC2CC3)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCN3CCC2CC3)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 4-(4-nitro-phenyl)-1,4-diaza-bicyclo[3.2.2]nonane (0.50 g, 2.0 mmol), palladium on carbon (100 mg, 10%) and methanol (60 ml) was stirred for 15 minutes under hydrogen (130 ml of hydrogen was consumed). The crude mixture was filtered through celite and the product was isolated as an oil in quantitative yield.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:16]O>>[NH2:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:16])=[O:10]
Reactant: Nc1ncccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
Concentrated H2SO4 (20 mL, 360 mmole) was added dropwise over 5 minutes to a suspension of 2-aminonicotinic acid (25 g, 181 mmole) in MeOH (400 mL), and the mixture was heated at reflux; a homogeneous solution formed within 5 min. After 72 h, the reaction was cooled to room temperature and concentrated under vacuum. The residue was basified with 1.0 N Na2CO3 (500 mL) (Gas evolution!) and extracted with EtOAc (500 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated to dryness to give the title compound (19.6 g, 71%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, 1 H), 8.13 (dd, 1 H), 6.63 (dd, 1 H), 6.30 (br s, 2 H), 3.89 (s, 3 H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:40])[CH2:22][N:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[O:26])[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:40])[CH2:22][N:23]([C:25]([CH:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)=[O:26])[CH3:24])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 138 %

Procedure:
N-(N-tert-Butoxycarbonyl-piperidine-4-carbonyl)-(N-methyl)-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (67) (1.46 g; 2.66 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 2 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.65 g) as a clear oil. ESMS:MH+ 450.2
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)=[CH:3][CH:2]=1.[C:21]([C:29](O)=[O:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[OH:28][C@H:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:29]([N:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=1)[CH2:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1)=[O:30]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@H](O)c2ccccc2)cc1
Yield: 32.8 %

Procedure:
In analogy to example 7, steps 1 and 2, p-tolyl-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (200 mg, 0.714 mmol) was coupled to benzoylformic acid (112 mg, 0.746 mmol) and reduced to give the title compound (97 mg, 32.2%) MS m/e: 415.1 [M+H]+ after separation on a chiral column.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH2:27]([N:9]1[CH2:10][CH2:11][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[C:3]([N:12]3[CH2:17][CH2:16][CH:15]([O:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH2:14][CH2:13]3)[N:4]=2)[CH2:8]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc(OC2CCN(c3nc4c(nc3Cl)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
Benzyl bromide was purified by passage through a plug of basic alumina prior to use. A solution of 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (736.2 mg, 1.954 mmol) in ACN (9.77 mL) was divided into two equal portions. Each solution was treated with a half portion of benzyl bromide (232 μL, 1.954 mmol) and stirred at 80° C. for 3 h. The reaction mixtures were allowed to cool to room temperature, and Each solution was treated with a half portion of sodium triacetoxyborohydride (1.242 g, 5.86 mmol). The reaction mixtures were stirred at room temperature for 1 h, then were quenched with saturated aqueous NaCl. The reaction mixtures were combined and partitioned between EtOAc with Et2O added to assist in phase separation and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a 20% to 60% gradient of EtOAc in heptanes gave the title compound (522.2 mg, 56.8%). ESI-MS m/z [M+H]+ 471.4.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.[CH2:25]([NH:33][NH2:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:16][C:15]1[CH:14]=[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])[N:33]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:34]=1
Reactant: NNCCc1ccccc1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Agent: O=S(=O)(O)O
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(CCc2ccccc2)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and phenethyl hydrazine sulfate according to the procedure of Example 28.