Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][OH:2].[C:3]1([C:9]2([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[O:14][CH2:13]C=[CH:11][O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C>C(O)C>[OH:2][N:1]=[C:19]([C:18]1[CH:17]=[CH:16][C:15]([C:9]2([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:14][CH2:13][CH2:11][O:10]2)=[CH:22][CH:21]=1)[NH2:20]
Reactant: N#Cc1ccc(C2(c3ccccc3)OC=CCO2)cc1
Reactant: NO
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1ccc(C2(c3ccccc3)OCCO2)cc1
Yield: 102 %

Procedure:
) Hydroxylamine (0.0449 mol) was added to a mixture of 4-(2-phenyl-1,3-dioxin-2-yl)benzonitrile (0.022 mol) in ethanol (88 ml). Then, N,N-diethylethanamine (0.0449 mol) was added dropwise and the resulting reaction mixture was stirred and refluxed for 3.5 hours. The solvent was evaporated. The residue was washed with water and this mixture was extracted with EtOAc. The separated organic layer was dried (Na2SO4), filtered and the solvent was evaporated, yielding 6.38 g of N′-hydroxy-4-(2-phenyl-1,3-dioxolan-2-yl)benzenecarboimidamide (interm. 10)
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1)(=[O:3])[NH2:2].[ClH:34]>O1CCOCC1>[ClH:34].[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[CH:6]=[C:5]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=2)[C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=1
Reactant: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C(N)=O)c1
Reaction time: 0.5 h

Procedure:
tert-Butyl [(1S,2R)-2-({6-carbamoyl-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl]amino)cyclohexyl}carbamate (22.5 g, 49.5 mmol) was diluted with dioxane (140 mL). To this solution was added hydrochloric acid (4.0 M in dioxane, 62 mL, 250 mmol). After 30 minutes, the reaction mixture was diluted with hexanes (400 mL) and filtered. The collected solids were dried in a nitrogen bag. The solids were diluted with dioxane (140 mL) followed by hydrochloric acid (4.0 M in dioxane, 62 mL, 250 mmol). After 1 hour, the reaction mixture was diluted with hexanes (400 mL), filtered, and washed with hexanes (2×150 mL). The isolated solids were dried under reduced pressure, and then suspended in dichloromethane (300 mL). After stirring for 3 hours, the mixture was filtered and dried in a nitrogen bag to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide hydrochloric acid salt.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[C:27]([O:29]C(C)(C)C)=[O:28])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[C:27]([OH:29])=[O:28])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 46.7 %

Procedure:
tert-Butyl 1-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}-2-pyrrolidinecarboxylate (0.25 g, 0.68 mmol) was dissolved in trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 2.5 hrs. Isopropyl ether was added to the reaction mixture to precipitate crystals, which were collected by filtration and recrystallized from ethanol-hexane to give the titled compound (0.13 g, 45%) as white crystals.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]#N)=[CH:14][N:13]3[CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][Si](C#C)(C)C.N1CCCCC1>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.[Cl-].[NH4+]>[C:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:20]=[C:10]([C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[N:11]=2)[CH:14]=1)#[CH:21]
Reactant: N#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNCC1
Product: C#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.2 g of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2), 156 μL of trimethylsilylacetylene, 20 mg of dichlorobis(triphenylphosphine)palladium and 2 mL of piperidine are placed in a 20 mL microwave tube. The mixture is heated for 15 minutes in a microwave machine set at 130° C. After cooling, the mixture is poured into 50 mL of saturated aqueous ammonium chloride solution. The resulting mixture is extracted twice with 70 mL of ethyl ether. The combined organic phases are separated out by settling, dried and concentrated to dryness under reduced pressure. The residue is taken up in 4 mL of a 1M solution of tetrabutylammonium fluoride in THF and stirred for 16 hours at 25° C. After evaporating the reaction medium to dryness, the residue is chromatographed on silica, eluting with a mixture of cyclohexane and ethyl acetate (gradient from 0 to 35%) to give 30 mg of 6-ethynyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a beige-coloured solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17])([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([S:2][CH3:1])[CH:4]=1)=[O:17])([O-:12])=[O:11]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: CSc1cccc(N)c1
Product: CSc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 94.6 %

Procedure:
Using 3-methylthioaniline (2.1 ml, 16.5 mmol) and 3-nitrobenzoic acid (2.64 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 4.09 g (94.6%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:8]([CH3:17])[C:7]=2[CH:18]=1.[Li+].CC([N-]C(C)C)C.C(C1C=CC=CC=1)C.[CH3:35][C:36]([CH3:41])([CH2:39][CH3:40])[CH:37]=[O:38]>C1COCC1.CCCCCCC>[OH:38][CH:37]([C:36]([CH3:41])([CH3:35])[CH2:39][CH3:40])[CH2:17][C:8]1[C:7]2[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:10][C:9]=1[C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(C)c2c1
Reactant: CCC(C)(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CCC(C)(C)C(O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 0.493 g 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one from Step A Example 1 in 20 mL anhydrous THF at −78° C. under nitrogen was added 2.0 mL 2 M LDA in heptane, THF, and ethylbenzene. After 50 minutes, 0.40 g 2,2-dimethylbutanal was added. Remove the cooling bath and let the reaction mixture warm up to room temperature. After 70 minutes, the reaction was quenched by adding 2 mL saturated ammonium chloride and the reaction mixture was evaporated under reduced pressure to remove solvents. Dilute the residue with ether, wash with 1 M HCl (2×) and saturated brine, dry over anhydrous Na2SO4, and evaporate to give a crude product. It was purified on RP-HPLC using 65˜100% MeCN in water without TFA to give the title compound as colorless solid after lyophilization. 1H NMR (CDCl3, 500 MHz) 7.44 (d, 9.1 Hz, 1H), 7.20 (d, 2.0 Hz, 1H), 7.10 (dd, 2.5 & 9.1 Hz, 1H), 3.86 (s, 3H), 3.58 (dd, 1.6 & 10.6 Hz, 1H), 3.29˜3.34 (m, 1H), 2.90˜2.95 (m, 1H), 1.51˜1.59 (m, 1H), 1.39˜1.46 (m, 1H), 1.40 (s, 9H), 1.02 (s, 3H), 1.01 (s, 3H), 0.92 (t, 7.6 Hz, 3H). LC-MS: 4.47 min. (m/Z=329.3, 369.2, 347). A faster-eluting isomeric side-product was also isolated during purification and was identified as 1-[2-(1-hydroxy-2,2-dimethylpropyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylpentan-2-one. 1H NMR (CDCl3, 500 MHz) 7.30 (d, 9.0 Hz, 1H), 6.84 (dd, 2.5 & 8.9 Hz, 1H), 6.75 (d, 2.5 Hz, 1H), 4.44 (s, 1H), 4.07 (AB d, 18.5 Hz, 1H), 4.04 (AB d, 18.5 Hz, 1H), 3.78 (s, 3H). 1.74 (q, 7.6 Hz, 2H), 1.263 (s, 3H), 1.260 (s, 3H), 0.99 (s, 9H), 0.91 (t, 7.4 Hz, 3H). LC-MS: 3.95 min. (m/Z=369.3=M+Na, 329.3,).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([F:13])[CH:6]=1.CSC.[B].C1COCC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:35].Cl>>[ClH:35].[ClH:35].[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][NH2:1])=[CH:6][C:7]=1[F:13]
Reactant: N#Cc1ccc(CCCN)cc1F
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [B]
Solvent: CSC
Solvent: C1CCOC1
Product: NCCCc1ccc(CN)c(F)c1
Yield: 73 %

Procedure:
Scheme IIIb, step C: 4-(3-Aminopropyl)-2-fluorobenzenecarbonitrile (1.1 g, 6.17 mmol) and boron dimethylsulfide 2M in THF (6.2 mL, 12.34 mmol) were combined and reduction was carried out in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, 3-[4-(aminomethyl)-3-fluorophenyl]propylamine dihydrochlorde, (1.15 g, 73%) as a dihydrochloride salt. Electron spray M.S. 183 (M*+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:2]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C:30]1([C:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1>[C:30]1([C:36]2[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][CH2:12][CH2:11][C:3]3[CH:2]=[N:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: OCCCCc1cnc2ccccc2c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Product: C1=C(c2ccccc2)CCN(CCCCc2cnc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
A solution of 4-(3-quinolinyl)butan-1-ol (Example E) (2.0 g, 0.01 mol), N,N diisopropyl-ethylamine (3.5 mL, 0.02 mol) and a catalytic amount of 4-dimethylaminopyridine is cooled to 0° C. and methanesulfonyl chloride (0.8 mL, 0.0105 mol) is added dropwise. The solution is stirred at 0° C. for 18 hours, and concentrated under reduced pressure. The residue is taken up in dimethylformamide (20 mL), and to this solution is added 4-phenyl-1,2,3,6-tetrahydropyridine (2.41 g, 0.015 mol) and sodium bicarbonate (3.4 g, 0.04 mol). The mixture is heated at 40° C. for 5 hours and the solvent removed under reduced pressure. The residue is partitioned between 50 mL of ethyl acetate and 50 mL of water. The aqueous layer is extracted with 50 mL of ethyl acetate and the organic extracts are dried (sodium sulfate) and the solvent removed in vacuo. The residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give 2.15 g of the title compound; mp 92.8°-93.9° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([C:21](=[O:24])[CH2:22][CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([OH:24])[CH2:22][CH3:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-propan-1-one (211 mg, 0.5825 mmol) in THF (5 mL) was added LAH (1M in THF, 0.58 mL, 0.58 mmol) at 0° C. and stirred for 30 minutes. The reaction was quenched by an addition of aq. KF solution (135 mg in 0.5 mL of water). The mixture was stirred vigorously for 10 minutes followed by an addition of anhydrous sodium sulfate. The insoluves were removed by filtration through a cotton pad and the cake was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (heptane/ethyl acetate 3:1 to 1:1) yielding (RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-propan-1-ol as a light yellow oil with ES-MS m/e: 364.1 (M'H+) and (SR)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-propan-1-ol as a light yellow oil. ES-MS m/e: 364.1 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[C:19]1([CH3:30])[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[CH:21][CH:20]=1>>[CH3:30][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH2:27][NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[CH2:4][CH2:3]2)=[O:29])=[CH:21][CH:20]=1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: Cc1ccc(NC(=O)CCl)cc1
Product: Cc1ccc(NC(=O)CNC2CCN(CCCC(=O)c3ccccc3)CC2)cc1

Procedure:
Using a procedure analogous to Example 1 4-amino-1-(4-phenyl-4-oxobutyl) piperidine may be reacted with N-(p-tolyl) chloro-acetamide to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[F:11][C:12]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:13]=1[C:14](N(OC)C)=[O:15]>C1COCC1>[F:11][C:12]1[C:23]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:21]=[CH:20][C:13]=1[C:14]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:15]
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)cc1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
1 milliliter of a 1M THF solution of 4-methoxyphenylmagnesium bromide (1 mmol) was added to a solution of 126 mg (0.5 mmol) of 2-fluoro-N-methoxy-N-methyl-3-trifluoromethyl-benzamide in 2 ml of THF at 0° C. The reaction mixture was stirred for 2 hrs. at this temperature and then quenched with saturated NH4Cl solution and the phases were separated. The aqueous phase was extracted twice with CH2Cl2 and the combined organic phases were washed with brine and dried over Na2SO4. The resulting ketone (135 mg) was obtained after flash chromatographic purification using 5% EtOAc in heptane as an eluent.
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:23][N:3]1[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=[C:2]1[N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc(-c3ccccc3)c(-c3nc4c(N)ncnc4s3)n2C)CC1
Temperature: 195 °C
Yield: 48 %

Procedure:
A mixture of 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (0.02 g) and N-methylpiperazine (1 mL) were heated under microwave conditions (CEM explorer, 195° C., 1 hour). The solvent was evaporated in vacuo and the residue dissolved in EtOAc (10 mL), washed with water (2×10 mL), dried and the solvent evaporated in vacuo to give the title compound as a yellow solid (10 mg, 48%)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.N1C=CC=C[C:19]=1[O:24]C(=O)OC1C=CC=CN=1>ClCCl.C(OCC)(=O)C>[O:10]1[C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:3][NH:2][C:19]1=[O:24]
Reactant: NCC1(O)CCCCC1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1NCC2(CCCCC2)O1
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
1-Aminomethyl-cyclohexanol hydrogen chloride (250 mg, 1.5 mmol) and triethylamine (0.21 mL, 1.5 mmol) were mixed in dichloromethane (5 mL), and the mixture was stirred for 15 min. Carbonic acid dipyridin-2-yl ester (326 mg, 1.5 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (2×4 mL), brine (2×4 mL); dried over anhydrous sodium sulfate and concentrated to give the title compound as a white powder (174 mg, 74%). 1H NMR (300 MHz, CDCl3): δ 6.42 (br, 1H), 3.31 (s, 2H), 1.86 (m, 2H), 1.76 (m, 2H), 1.65 (m, 2H), 1.47 (m, 4H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([C:30]([O:32]C)=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][C:18]3=[O:29])[CH3:12])[CH:7]=[CH:8][CH:9]=1.C1COCC1.Cl>CO>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([C:30]([OH:32])=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:19][C:18]3=[O:29])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(C(C)Nc2cccc(Cl)c2F)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Sodium hydroxide (0.217 mL, 0.43 mmol) was added to a stirred solution of methyl 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (200 mg, 0.43 mmol) dissolved in MeOH (2 mL). The resulting solution was stirred at room temperature for 16 hrs. THF was added and the resulting solution was stirred at 50° C. for 8 hrs. The pH was adjusted to 3 with HCl 2N, the solvent was removed under vacuum and the residue diluted with H2O. The solid was collected by filtration, washed with water and dried to give 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (171 mg, 88%) as a white solid. Mass Spectrum: M+H+ 447.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)cc1
Yield: 72.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-methylphenylboronic acid (106 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 17 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), followed by recrystallization from ethyl acetate, to give 150 mg (72%) of the title compound as a white solid. mp 178°. FDMS: m/e=319. α[D]589 =+77.14 (c=1.00, chloroform).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)=O.[CH2:8]([O:11][C:12](=[O:28])[C@@H:13]([O:18][C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][S:22][C:23](=[O:25])[CH3:24])[CH2:14][C:15]([NH2:17])=O)[CH:9]=[CH2:10].C(N(CC)CC)C>ClCCl>[CH2:8]([O:11][C:12](=[O:28])[C@@H:13]([O:18][C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][S:22][C:23](=[O:25])[CH3:24])[CH2:14][C:15]#[N:17])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)[C@H](CC(N)=O)OC(=O)[C@H](C)CSC(C)=O
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)[C@H](CC#N)OC(=O)[C@H](C)CSC(C)=O
Reaction time: 8 h
Yield: 109.1 %

Procedure:
Trichloroacetyl chloride (0.3 g, 1.7 mmol) in dichloromethane (20 ml) was added at 0°-5° to a stirred solution of 2(S)-(3-(acetylthio)-2(S)-methyl-1-oxopropoxy)-4-amino-4-oxobutanoic acid 2-propenyl ester (0.48 g, 1.5 mmol) and triethylamine (0.31 g, 3 mmol) in dichloromethane (50 ml). The mixture was stirred overnight, the organic solution washed with water, dried (MgSO4) and the solvent evaporated to give the sub-title ester (0.49 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[CH:16][C:11]3=[N:10][C:9]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:19][CH2:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=3)=[C:9]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[N:10]=[C:11]2[CH:16]=1)([CH3:20])[CH3:21]
Reactant: CC(C)(C#N)c1ccn2c(-c3ccnc(N)n3)c(-c3ccc(F)cc3)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CN)c1ccn2c(-c3ccnc(N)n3)c(-c3ccc(F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 100 mL round bottom flask containing nitrile 27 (700 mg, 1.88 mmol) in THF (25 mL) was charged with lithium aluminum hydride (285 mg, 7.52 mmol). After stirring at room temperature for 45 minutes, the reaction mixture was poured into an 1.0 L Erlenmeyer flask and quenched with 200 mL ethyl acetate, 10 mL water, sodium sulfate, and an excess of 2:1 Na2SO4 10H2O:celite. The mixture was filtered, then concentrated under reduced pressure, and then dissolved in a minimum volume of CH2Cl2, then loaded onto a 40 g Isco RediSep normal phase silica cartridge, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% methylene chloride and ended at 90% methylene chloride, 9% methanol, 1% concentrated ammonium hydroxide. Fractions containing desired product were pooled and concentrated under reduced pressure. Yield of 28: 196 mg (28%). 1H NMR (500 MHz, CDCl3) δ 1.38 (s, 6H), 2.89 (s, 2H), 5.14 (bs, 2H), 6.54 (d, J=5.5 Hz, 1H), 6.97 (dd, J=7.5, 2.0 Hz, 1H), 7.14 (m, 2H), 7.65 (m, 3H), 8.13 (d, J=5.5 Hz, 1H), 9.46 (dd, J=7.5, 0.5 Hz, 1H). MS (ESI+) 377.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:28][N:29]2[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)([O-])=O.C(N(CC)C(C)C)(C)C.[H][H]>[Pd].O>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:28][N:29]2[CH2:30][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:32]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2
Reactant: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c([N+](=O)[O-])c2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(N)c2)C1
Reaction time: 2 h

Procedure:
A slurry of methyl 1-((3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate (0.390 g, 0.78 mmol) and 10% palladium on carbon, 50% water, (0.41 g) and N,N-diisopropylethylamine (0.27 mL, 1.6 mmol) was treated with a hydrogen balloon and stirred rapidly for 2 h, then was flushed with nitrogen, filtered through celite, rinsing with MeOH/DCM. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography 40 g, 20-100% EA/hexanes to give methyl 1-((3-amino-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate as a yellow solid. MS (ESI) m/z: Calculated: 470.2; Observed: 470.8 (M++1).