Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@:11]1([C:25]([O:27]C(C)(C)C)=[O:26])[CH2:16][C:15](=[O:17])[C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20]C(C)(C)C)=[O:19])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.C(O)C>[C:3]([O:7][C:8]([NH:10][C@@:11]1([C:25]([OH:27])=[O:26])[CH2:16][C:15](=[O:17])[C@@H:14]2[C@@H:12]1[C@H:13]2[C:18]([OH:20])=[O:19])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)CC(=O)[C@H]2[C@H](C(=O)O)[C@@H]21
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Add 2.5M sodium hydroxide (15.55 mL, 38.88 mmol) to a stirred solution of the ditert-butyl (1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.0 g, 4.86 mmol) in tetrahydrofuran (24.3 mL) and ethanol (9.72 mL). Heat the reaction mixture to 60° C. and maintain stirring overnight. Continue heating for 4 hours then wash with ethyl acetate. Cool the aqueous phase in an ice bath and acidify to pH=2-3 with 1N hydrochloric acid solution. Extract with ethyl acetate (3 times), dry the organic on sodium sulfate, filter and concentrate to give the title compound as an orange solid (1.4 g, 96%). MS (m/z): 322 (M+23).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]#[N:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[OH:18][CH2:19][C:20](=O)[CH3:21].O>C1COCC1.C(OCC)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[O:18][CH:19]=[C:20]([CH3:21])[N:17]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Reactant: CC(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1coc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
17 mL 2 mol/L aqueous sodium hydroxide solution was dropped to 6.7 g 4-cyano-piperazine-1-carboxylic acid tert-butyl ester and 2.5 mL 1-hydroxy-propan-2-one in 10 mL THF. The reaction was stirred 12 h at RT and over night at 75° C. The reaction was cooled, water was added and the mixture was diluted with diethylether. The precipitate was filtered to give 1.32 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12]OS(C)(=O)=O)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1)[CH2:22][C:23]#[CH:24].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[CH:36][CH:37]=1)[CH2:22][C:23]#[CH:24]
Reactant: C1COCCN1
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(COS(C)(=O)=O)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: C#CCN(Cc1cc2c(=O)n(C)c(CN3CCOCC3)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl 4-[N-[7-chloro-2-methanesulphonyloxymethyl-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl )amino]benzoate (0.193 g, 0.35 mmol), dichloromethane (7 ml), and morpholine (0.304 g, 3.5 mmol) was stirred at room temperature for 6 h under argon. The cloudy reaction mixture was then partitioned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate (80 ml). The organic layer was washed more 5% sodium carbonate (2×80 ml), and brine (80 ml), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography, on elution with 10% ethyl acetate in dichloromethane, afforded a solid which was triturated with 5% dichloromethane in hexanes. The white solid was collected by filtration, dried in vacuo over P2O5 (0.174 g, 82%), mp 140-143° C.; 1H-NMR (DMSO-d6) 1.50 (s, 9H, But), 2.48, (br s obscured) and 3.55 (br s) (8H, N(CH2CH2)2O), 3.62 (s, 5H, 2-CH2, N3-Me), 3.20 (s(poorly resolved triplet), 1H, C≡CH), 4.39 (s, 2H, CH2C≡C), 4.79 (s, 2H, 6-CH2), 6.78 (d, J=8.7 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.7 Hz, 2H, 2′,6′-ArH), 7.80, 7.89 (2×s, 2H, 5-H, 8-H). MS (ESI, m/z) 537, 539 [(M+H)+, 100%, 38% respectively; Cl isotopic pattern].
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[C:16](=[O:29])[C:17]4[N:18]=[CH:19][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:21]=4[N:22]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:38].[Na+].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:15]2[C:16](=[O:29])[C:17]3[N:18]=[CH:19][N:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:21]=3[N:22]=[C:14]2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:38])[NH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:31][CH:32]=1
Reactant: Nc1ccc(-c2ccc(-c3nc4c(ncn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)cn1
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1ccc(-c2ccc(-c3nc4c(ncn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)c[nH]1
Temperature: 100 °C

Procedure:
A solution of 2-[4-(6-amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (10 mg, 0.02 mmol) in acetonitrile (0.4 mL) and H2O (0.4 mL) was treated with NaNO2 and 5 μL of concentrated H2SO4. The reaction mixture was heated at 100° C. for 1 h. The reaction was allowed to cool to room temperature and neutralized with aqueous Na2CO3. The reaction was diluted with H2O and extracted with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated. The resulting crude material was purified by preparative LCMS to provide the title compound 1-(4-chloro-phenyl)-2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one_as a white solid. 1H NMR (CDCl3) δ (ppm) 8.21 (s, 1H), 8.01 (dd, 1H), 7.81 (d, 1H), 7.58 (apparent t, 2H), 7.49 (m, 1H), 7.39 (d, 2H), 7.33 (m, 3H), 7.14 (d, 2H), 6.98 (d, 1H); HPLC-MS calculated for C28H18ClN5O2 (M+H+): 492.1. Found: 492.1.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH3:28][NH:29][CH2:30][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1)[OH:32].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:29]([CH2:30][CH:31]([OH:32])[C:33]4[CH:34]=[CH:35][C:36]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[CH:37][CH:38]=4)[CH3:28])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc(N2CCOCC2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN(C)CC(O)c2ccc(N3CCOCC3)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-(4-morpholin-4-ylphenyl)ethanol dihydrochloride (Preparation 89) (118 mg, 0.38 mmol) and diisopropylethylamine (180 μL, 1.0 mmol) in dry DMF (5.0 mL) was stirred for 48 hours at room temperature. The solution was diluted with water (10 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (76 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:34]=[CH:33][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH:61]2[CH2:63][O:62]2)=[CH:55][CH:54]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:27]([NH:26][C:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:7]3[CH:33]=[CH:34][C:4]([CH2:3][CH2:2][NH:1][CH2:63][C@H:61]([OH:62])[CH2:60][O:59][C:56]4[CH:57]=[CH:58][C:53]([OH:52])=[CH:54][CH:55]=4)=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1)=[O:25])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCNC(=O)Nc1ccc(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: CCCCCCNC(=O)Nc1ccc(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 34.2 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}carbonyl)phenyl]-N′-hexylurea (0.394 g, 0.846 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.308 g, 0.761 mmol) according to Procedure G to give the title compound (0.232 g, 0.26 mmol).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C1CSCCN1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCSCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and thiomorpholine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [N:1]1([C:7]2[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:15][C:16]1[C:24]2[N:23]=[C:22](Cl)[NH:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1>>[Br:15][C:16]1[C:24]2[NH:23][C:22]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:6][CH2:5]3)=[N:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1
Reactant: OCc1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Product: OCc1cccnc1N1CCN(c2nc3cc(C(F)(F)F)cc(Br)c3[nH]2)CC1

Procedure:
(2-Piperazin-1-ylpyridin-3-yl)methanol (0.48 g, 2.5 mmol, Example 46a) reacted with 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.60 g, 2 mmol, Example 6b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 456 (M+1).
Reaction SMILES: O1CCCC1.C([O:8][C:9]([C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][C:14]=2[CH:15]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:13]2[O:12][C:11]([CH2:9][OH:8])=[CH:15][C:14]=2[CH:16]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2cc(OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To a tetrahydrofuran (20 mL) solution of 5-benzyloxy-benzofuran-2-carboxylic acid ethyl ester (890 mg, 3.00 mmol) described in Production Example 7-1-3 was added lithium aluminum hydride (342 mg, 9.00 mmol) at 0° C., which was stirred at room temperature for 3 hours. To the reaction solution were added water (342 μL), 5 N aqueous sodium hydroxide solution (342 μL) and water (1.03 mL) at 0° C. followed by filtering through Celite. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (561 mg, 74%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C1([Li])C=CC=CC=1.[CH2:17]([N:20]=[C:21]=[S:22])[CH:18]=[CH2:19].Cl>O.C1C=CC=CC=1>[CH2:17]([NH:20][C:21](=[S:22])[CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH:18]=[CH2:19]
Reactant: COCc1ccccn1
Reactant: C=CCN=C=S
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: C=CCNC(=S)C(OC)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 9.95 g. (0.081 mole) of 2-(methoxymethyl)pyridine in 80 ml. of dry benzene is added dropwise to a chilled solution of 40 ml. (0.084 mole) of phenyl lithium in 80 ml. of dry benzene. The mixture is stirred at 0°C. for 1 hour after the addition is complete. Then 8.02 g. of allyl isothiocyanate in 50 ml. of benzene is added dropwise and the mixture is allowed to come to room temperature gradually. The mixture is the diluted with 500 ml. of water and acidified with 10% hydrochloric acid. The layers are separated and the organic layer is washed several times with water. The aqueous layers are combined, neutralized with 10% aqueous sodium hydroxide solution and then brought to pH 9 with 5% aqueous sodium bicarbonate solution, then extracted with chloroform. The chloroform extracts are washed once with brine and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a silica gel column, eluting with ethyl acetate. The fractions containing the product are combined and evaporated and the residue is recrystallized from ethyl acetate/hexane to give N-allyl-2-methoxy-2-(2-pyridyl)thioacetamide, m.p. 59.5°-60°C.
Reaction SMILES: Cl.Cl[C:3]1C=CC=CC=1C(OC1CNC1)C1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][C:44]([CH3:47])([CH3:46])C)=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:28]([O:36][CH:37]1[CH2:38][N:39]([C:41]([NH:43][CH:44]([CH2:46][CH3:3])[CH3:47])=[O:42])[CH2:40]1)[C:27]1[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=1[Cl:25]
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Agent: Cl
Agent: [N-]=C=O
Product: CCC(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=1[N+:22]([O-])=O)([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:22]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1-c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Product: Nc1cccc(N)c1-c1c(N)cccc1N

Procedure:
The reaction of Step 2 is specifically performed as follows. The Pd/C of 5-15%, and preferably 10%, relative to the mass of the substrate, is added as the catalyst to the 2,2′,6,6′-tetranitrobiphenyl. The hydrogen gas of 5-20 atm, and preferably 10 atm, is added to the autoclave. Upon completion of the reaction, the solid is filtered off, and the filtrate is concentrated, to afford the 2,2′,6,6′-tetraminobiphenyl.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:12][Si](C=[N+]=[N-])(C)C.C1(C)C=CC=CC=1>CO.C1C=CC=CC=1>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:3]1([NH2:2])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NC1(CC(=O)O)CCCC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC1(N)CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A stirred solution of (1-amino-cyclopentyl)-acetic acid hydrochloride (363 mg, 2.02 mmol) in a 1:1 mixture of anhydrous methanol/benzene (20 mL) cooled to 0° C. under a nitrogen environment was treated dropwise via syringe with a 2.0 M solution of trimethylsilyldiazomethane in toluene (2.0 mL, 4.0 mmol). The reaction mixture was allowed to warm to 25° C., stirred for 1 h, and concentrated in vacuo to give (1-amino-cyclopentyl)-acetic acid methyl ester (311 mg, 98%) as a colorless oil. LC-MS (ESI) calculated for C8H15FNO2: 157.2, found 158.2 [M+H+].
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:18]([F:20])[F:19])[O:7][C@H:6]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][CH:33]=[N:34][C:35]=2[NH:39]C(=O)C1C=CC=CC=1)(=O)C.CO>N>[NH2:39][C:35]1[N:34]=[CH:33][N:32]=[C:31]2[C:36]=1[N:37]=[CH:38][N:30]2[C@H:6]1[C@H:5]([OH:4])[C@H:9]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:18]([F:20])[F:19])[O:7]1
Reactant: CC(=O)O[C@H]1[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Agent: N
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@](COCc2ccccc2)(C(F)F)[C@@H](OCc2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A mixture of compound 25 (0.225 g, 0.35 mmol) in NH3.MeOH (40 mL) was stirred in a sealed tube at 65° C. for 16 hrs, warmed to 25° C. and stirred for 3 hrs. TLC showed the reaction was completed, the reaction solution was concentrated and the crude compound was purified by silica gel chromatography column [dichloromethan:methanol (30:1)] to give product 26 as an colorless oil (0.16 g, 92%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:43]=[C:44]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:45][NH:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1)=[O:48]>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([N:64]1[CH2:63][CH2:62][N:61]([C:44](=[O:43])[CH2:45][NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:51][CH:50]=2)=[O:48])[CH2:66][CH2:65]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(F)cc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-chloro-4-fluoro-benzoic acid (44.9 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 26 mg (21.0% yield) of biphenyl-4-carboxylicacid {2-[4-(2-chloro-4-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 99.27%, 1H NMR: (CDCl3) δ 7.94 (d, 2H), 7.74-7.6 (q, 4H), 7.54-7.46 (t, 2H), 7.44-7.38 (t, 1H), 7.38-7.3 (m, 2H), 7.24-7.2 (m, 1H), 7.16-7.06 (tt, 1H), 4.4-4.26 (td, 2H), 4.1-3.84 (m, 2H), 3.78-3.6 (m, 3H), 3.54-3.24 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][O-:13].[Na+]>C1COCC1>[Br:1][C:2]1[CH:9]=[C:8]([O:13][CH3:12])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Br)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a solution of 4-bromo-2,6-difluorobenzonitrile (1, 15.0 g, 69 mmol) in THF (100 mL) at 0° C. was slowly added sodium methoxide (25% wt in methanol, 14.9 g, 69 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated and partitioned between dichloromethane (500 mL) and water (250 mL). The organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (15.2 g, 99%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.01-6.99 (m, 1H), 6.94 (s, 1H), 3.96 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:16][C:3]=1[CH2:4][N:5]([CH:13]1[CH2:15][CH2:14]1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH3:28]B1OB(C)OB(C)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH:13]1([N:5]([CH2:4][C:3]2[CH:16]=[C:17]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:18]([O:20][CH3:21])=[CH:19][C:2]=2[CH3:28])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:15][CH2:14]1
Reactant: COCCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c(Br)cc1OC
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COCCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c(C)cc1OC
Temperature: 100 °C
Reaction time: 23 h

Procedure:
A mixture of tert-butyl [2-bromo-4-methoxy-5-(3-methoxypropoxy)benzyl]cyclopropylcarbamate (200 mg), trimethylboroxin (94 μL), tris(dibenzylideneacetone)dipalladium (8.2 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-phos) (21.5 mg) and potassium phosphate (191 mg) in dioxane (7.0 ml) was stirred under argon atmosphere at 100° C. for 23 hours. After being stand to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a NH-silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1 to 3/1) to give tert-butyl cyclopropyl[4-methoxy-5-(3-methoxypropoxy)-2-methylbenzyl]carbamate (103 mg) as a pale yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)[CH:54]=[N:55][CH:56]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)[CH:54]=[N:55][CH:56]=1
Reactant: COc1cncc(-c2cccc(N)c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cncc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(5-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.014 g of product in 56% yield: LCMS (ESI) m/z 389 (MH+).