Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O.CCCCCC>[Cl:15][C:16]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:17]=1[CH2:18][N:10]1[C:9]([CH3:14])=[C:8]2[C:12]([CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7]2)=[N:11]1
Reactant: COC(=O)c1ccc2c(C)n[nH]c2c1
Reactant: Clc1cc(-c2ccccc2)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1ccc2c(C)n(Cc3ccc(-c4ccccc4)cc3Cl)nc2c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 26.1 %

Procedure:
A mixture of 6-(methoxycarbonyl)-3-methyl-1H-indazole (1.90 g), 2-chloro-4-phenylbenzyl bromide (3.37 g), potassium carbonate (2.76 g), ethyl acetate(10 ml) and water (5 ml) was stirred for 14 hr at 70° C. Hexane and water were added, and the precipitated solid was collected by filtration and washed with a mixed solvent of ethyl acetate and hexane (2/3). This was dried under reduced pressure to give the objective compound (1.02 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[CH3:13].CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:24])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
2-(4-Bromo-phenyl)-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid ethyl ester (XXXI) is prepared by alkylation of the corresponding potassium enolate with XXX. The reaction is typically carried out by deprotonating (4-bromo-phenyl)-acetic acid ethyl ester with potassium tert-butoxide in dimethylformamide at room temperature for one hour, then cooling the reaction to zero degrees Celsius and slowly adding XXX, followed by stirring at room temperature for twelve hours.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:13]=C([CH:17]=[CH:18][N:19]=3)C#N)[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:20].[Na+].[CH3:22][CH2:23][OH:24]>O>[C:1]1([C:7]2[N:11]([C:12]3[CH:13]=[C:22]([CH:17]=[CH:18][N:19]=3)[C:23]([OH:20])=[O:24])[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: CCO
Reactant: N#Cc1ccnc(-n2nccc2-c2ccccc2)c1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccnc(-n2nccc2-c2ccccc2)c1
Temperature: 80 °C
Yield: 55 %

Procedure:
To a stirred solution of 2-(5-phenyl-1H-pyrazol-1-yl)isonicotinonitrile (100 mg, 0.41 mmol) in EtOH (10 mL) was added a solution of 25% NaOH in water (1.0 mL). The reaction mixture was heated under reflux conditions at 80° C. for 1 h. After reaction completion, the solvent was removed, and the resultant mixture was diluted with water, and the pH was adjusted to pH=4-5 with 2.0 N HCl. The mixture was extracted with EtOAc (3×15 mL), the combined organic layers were dried over Na2SO4, and the solvent was removed to obtain pale yellow solid, which was washed with hexane and dried under reduced pressure to afford the title compound (60 mg, 55% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.5 (S, 1H), 8.2 (d, 1H, J=2.1 Hz), 7.9 (s, 1H), 7.78 (s, 1H), 7.7 (d, 1H, J=2.7 Hz), 7.3 (m, 2H), 7.2 (m, 1H), 6.65 (s, 2H). [M+H] Calc'd for C15H11N3O2, 266. Found, 266.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[C:4](CC)[C:3]=1I.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[C@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C@@H:21]2[C@@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([C:3]4[CH:4]=[C:5]([CH:9]=[CH:10][CH:2]=4)[C:6]([OH:8])=[O:7])[C:24]3=[O:32])[CH2:22]2)=[CH:19][CH:20]=1
Reactant: CCc1c(C(=O)[O-])ccc(C)c1I
Reactant: O=C1Nc2ccccc2[C@@]12C[C@H]2c1ccc(Cl)cc1
Product: O=C(O)c1cccc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 81 starting from methyl-ethyl-3-iodobenzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro [cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1 LC/MS m/e calcd. for C23H16ClNO3 389, observed (M+H)+: 390.1. 1H NMR (400 MHz, DMSO-d6) δppm 2.31-2.42 (m, 2 H) 3.42 (t, J=8.72 Hz, 1 H) 6.88 (d, J=7.58 Hz, 1 H) 7.15 (t, J=7.20 Hz, 1 H) 7.22-7.28 (m, 1 H) 7.28-7.36 (m, 3 H) 7.36-7.41 (m, 2 H) 7.60-7.70 (m, 2 H) 7.86 (s, 1 H) 7.93-8.00 (m, 1 H) 13.24 (br. s, 1 H).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([P:20](=[O:27])([O:24]CC)[O:21]CC)[P:12](=[O:19])([O:16]CC)[O:13]CC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[Si](C)(C)C.O.C(Cl)(Cl)Cl>C(Cl)Cl>[C:1]1([S:7]([NH:10][CH:11]([P:20](=[O:21])([OH:27])[OH:24])[P:12](=[O:13])([OH:19])[OH:16])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(OCC)C(NS(=O)(=O)c1ccccc1)P(=O)(OCC)OCC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=P(O)(O)C(NS(=O)(=O)c1ccccc1)P(=O)(O)O
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a solution of tetraethyl (phenylsulfonylaminomethylene)bis(phosphonate) (400 mg) in methylene chloride (4 ml), was added iodotrimethylsilane (0.8 ml) dropwise with stirring under nitrogen gas atmosphere in an ice-water bath. The mixture was stirred for 30 minutes at the same condition and then at ambient temperature for 1.5 hours. To the reaction mixture were added water (10 ml) and chloroform (8 ml) under ice-water bath cooling. The separated aqueous layer was washed with chloroform until its color disappeared and then evaporated in reduced pressure. The residue was washed with ethanol to give white powder of (phenylsulfonylaminomethylene)bis(phosphonic acid) (194 mg).
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=[O:4])=[O:3].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([C@@H:6]([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[N+:23]=[N-:24].[CH3:1][S:2]([O:5][C@H:6]([CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=[O:3])=[O:4]
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)C1CCOCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N=[N+]=[N-])C1CCOCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of (1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-tetrahydro-2H-pyran-4-ylethyl methanesulfonate (4.29 g, 12.7 mmol) in 40 mL of DMF was treated with sodium azide (1.00 g, 15.2 mmol) and the mixture was heated to 60° C. for 12 hours and then to 80° C. for 8 hours. The reaction mixture was concentrated under reduced pressure and the resulting material was dissolved in 50 mL of ethyl acetate and washed successively with H2O (3×25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10-25% ethyl acetate/hexanes) gave 1.60 g of {[(2S)-2-azido-2-tetrahydro-2H-pyran-4-ylethyl]oxy}(tert-butyl)dimethylsilane as a colorless oil and 1.50 g of recovered (1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-tetrahydro-2H-pyran-4-ylethyl methanesulfonate. The recovered starting material was again subjected to the reaction conditions to afford an additional 0.59 g of product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([C:24](OC)=[O:25])=[CH:23][C:4]=2[N:3]=1>C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([CH2:24][OH:25])=[CH:23][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)nc(N)c1ncc(CCc3ccccc3)cc12
Solvent: C1CCOC1
Product: Nc1nc2cc(CO)ccc2c2cc(CCc3ccccc3)cnc12
Temperature: 25 °C

Procedure:
To a solution of methyl 5-amino-2-phenethylbenzo[f][1,7]naphthyridine-8-carboxylate (from the previous step) (1.0 eq.) in THF (0.03M) was added Super-H (10 eq.) at 0° C. The solution was allowed to warm to ambient temperature over 30 min. The reaction was quenched by water until no bubbling. The layers were separated and aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give (5-amino-2-phenethylbenzo[f][1,7]naphthyridin-8-yl)methanol as an off white solid: 1H NMR (methanol-d4): δ 8.63 (dd, 1H), 8.56 (dd, 1H), 8.24 (d, 1H), 7.57 (d, 1H), 7.35 (dd, 1H), 7.27-7.15 (m, 5H), 4.75 (s, 2H), 3.20 (t, 2H), 3.06 (t, 2H). LRMS [M+H]=330.1.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.S1(CCCC1)(=O)=O.[C:22]([C:25]1[CH:43]=[CH:42][CH:41]=[CH:40][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:39])C(O)=O)=[CH:31][CH:30]=1)([OH:24])=O.[OH-:44].[Na+].[CH2:46]([OH:48])C>>[O:24]=[C:22]1[C:25]2[CH:43]=[CH:42][CH:41]=[CH:40][C:26]=2[CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH2:39][C:46]([OH:48])=[O:44])=[CH:33][C:34]1=2
Reactant: [OH-]
Reactant: CC(C(=O)O)c1ccc(OCc2ccccc2C(=O)O)cc1
Reactant: CCO
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: O=C(O)CCc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 110 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Phosphorus pentoxide (10.4 g, 0.073 mole) was cautiously added to 7.4 ml of absolute ethanol under a nitrogen atmosphere and stirred at 110° C. for 1 hour; 53.1 ml of sulfolane was added and the temperature adjusted to 85° C. After adding 4-(2-carboxybenzyloxy)phenylpropanoic acid of Example 6a (5.0 g, 0.017 mole), the reaction was stirred at 85° C. for 3.5 hours. The mixture was poured into 1 liter of ice water, made basic by addition of NaOH pellets, extracted with toluene and the aqueous phase was then acidified with concentrated HCl. The resulting precipitate was filtered, triturated with isopropanol and dried giving 3.22 g of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-propanoic acid (68% yield), m.p. 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[N:43]1[CH:48]=[N:47][CH:46]=[N:45][C:44]=1[N:49]1[CH2:54][CH2:53][CH:52]([NH2:55])[CH2:51][CH2:50]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:55][CH:52]1[CH2:53][CH2:54][N:49]([C:44]2[N:43]=[CH:48][N:47]=[CH:46][N:45]=2)[CH2:50][CH2:51]1)=[O:24]
Reactant: NC1CCN(c2ncncn2)CC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NC1CCN(c2ncncn2)CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 1-[1,3,5]triazin-2-yl-piperidin-4-ylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH:19]([C:21]3[C:22]([O:47][CH3:48])=[C:23]([C:29]4[CH:30]=[N:31][N:32]([CH:34]5[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]5)[CH:33]=4)[C:24]([CH3:28])=[C:25]([Cl:27])[CH:26]=3)[CH3:20])[N:16]=[C:17]([CH3:18])[C:10]=12>C(Cl)Cl>[Cl:27][C:25]1[C:24]([CH3:28])=[C:23]([C:29]2[CH:30]=[N:31][N:32]([CH:34]3[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]3)[CH:33]=2)[C:22]([O:47][CH3:48])=[C:21]([CH:19]([N:15]2[C:11]3=[N:12][CH:13]=[N:14][C:9]([NH2:8])=[C:10]3[C:17]([CH3:18])=[N:16]2)[CH3:20])[CH:26]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(C2CCNCC2)c1
Reaction time: 1 h

Procedure:
TFA (0.3 mL, 4 mmol) was added to a solution of tert-butyl 4-(4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (30 mg, 0.052 mmol) in methylene chloride (0.2 mL) at room temperature and the mixture was stirred for 1 h. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C24H30ClN8O (M+H)+: m/z=481.2; Found: 481.1
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[O:17][C:16]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[NH:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:15][CH:14]=1>CO>[CH3:12][C:13]1[O:17][C:16]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:11][CH:9]([CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[OH:10])[CH2:31][CH2:30]2)=[CH:15][CH:14]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Cc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1
Solvent: CO
Product: Cc1ccc(Cn2c(NC3CCN(CC(O)COc4ccccc4)CC3)nc3ccccc32)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A mixture of 4.5 parts of 2-(phenoxymethyl)oxirane, 4.65 parts of 1-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine and 120 parts of methanol was stirred overnight at room temperature. The precipitated product was filtered off and dried, yielding 3.1 parts (44.8%) of 4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-α-(phenoxymethyl)-1-piperidineethanol; mp. 164.8° C. (compound 25).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.[CH:27]([C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])=O.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>C(O)C>[CH2:9]([NH:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:27][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([O:33][CH3:34])=[O:32])=[CH:22][CH:21]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(N)cc1
Reactant: COC(=O)c1ccccc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCCCCCCNC(=O)c1ccc(NCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 4-amino-N-dodecylbenzamide (0.304 g, 1.0 mmol), acetic acid (0.060 g, 1.0 mmol) and methyl 2-formylbenzoate (0.164 g, 1.0 mmol) in ethanol (2 mL) was added at once NaBH3CN (0.075 g, 1.20 mmol). The resulting mixture was stirred overnight at rt. A saturated solution of NaHCO3 (10 mL) was added to the reaction mixture, the aqueous layer was separated and extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to give a colorless oil. This crude product was purified by column chromatography over silica gel to give the title compound as a colorless oil (0.212 g, 47%). M+(LC/MS(ESI)): 453.6. HPLC (Condition A), Rt: 6.64 min (HPLC purity: 100%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[Cl:26])=[CH:14][N:13]([CH2:27][C:28]2[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:29]=2[F:38])[C:12]1=[O:39])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[Cl:26])=[CH:14][N:13]([CH2:27][C:28]2[C:33]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:31]=[CH:30][C:29]=2[F:38])[C:12]1=[O:39]
Reactant: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@@H](CC(C)C)NC(=O)OC(C)(C)C)c2=O)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)CC(C)C)c2=O)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of compound 8a (30 mg, 0.048 mmol) in DCM (1 mL) was added TFA (0.1 mL, 1.3 mmol) and stirred at room temperature for 1.5 hours. After concentration, the residue was taken up in DCM and sat'd aq. NaHCO3 was added. The aq. layer was extracted with DCM. Combined organic extracts were dried over Na2SO4 and concentrated to give compound 8b . MS (CI) m/z 528.0, 530.0 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[S:20][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3].CS(O[CH:26]([C:28]1[C:33]([F:34])=[CH:32][C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH3:27])(=O)=O>>[F:34][C:33]1[CH:32]=[C:31]([F:35])[CH:30]=[C:29]([F:36])[C:28]=1[CH:26]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[C:7]3[CH:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:20][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1)[CH3:27]
Reactant: CC(OS(C)(=O)=O)c1c(F)cc(F)cc1F
Reactant: CC(C)Cc1cc2c(NC3CCNCC3)ncnc2s1
Product: CC(C)Cc1cc2c(NC3CCN(C(C)c4c(F)cc(F)cc4F)CC3)ncnc2s1

Procedure:
The title compound was prepared (110 mg, 55%) from 6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine(130 mg, 0.45 m. mol) and 1-(2,4,6-trifluorophenyl)ethyl methanesulfonate (228 mg, 0.9 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3):δ 8.40 (s, 1H), 6.75 (s, 1H), 6.65 (m, 2H), 4.95 (d, 1H), 4.15 9q, 1H), 4.05 (m, 1H), 3.00 (m, 2H), 2.70 (d, 2H), 2.20 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H), 1.55 (d, 3H), 1.25–1.65 (m, 2H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 448.55; Observed: 449.2 (M++1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C@H:29]([CH2:35][CH3:36])[CH2:30][C:31](OC)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C@H:29]([OH:28])[CH2:35][CH3:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC[C@@H](O)CC(=O)OC
Agent: Cl
Product: CC[C@@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (58 mg, 54%), MS (ISP) m/z=431.5 [(M+H)+], mp 161° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl (R)-3-hydroxy-pentanoate.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:27]=1[C:28](O)=[O:29]>>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[C:27]=1[C:28]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)=[O:29]
Reactant: O=C(O)c1c(F)cccc1C(F)(F)F
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3C(F)(F)F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
N-[(2-fluoro-6-(trifluoromethyl)phenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2-fluoro-6-(trifluoromethyl)benzoic acid using the general procedures described in example 7 and was obtained as a white solid: mp 218-220° C. ES-HRMS m/e calcd for C25H23F4N3O5 (M+Na) 530.1310, found 530.1317.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[C:29]=3[F:36])=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:42]>C(O)C>[ClH:42].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[C:29]=2[F:36])=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(F)c(F)c3F)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(F)c(F)c2F)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 70-4 (700 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (520 mg) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[C:2]#[CH:3].C([N-]C(C)C)(C)C.[Li+].C([O-])(=O)C#C.[Li+].[C:24]([O:28][C:29]([N:31]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@@H:32]([CH2:40][CH2:41][CH:42]=[O:43])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:47]([O:46][C:44]([N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[C@H:32]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:40][CH2:41][CH:42]([OH:43])[C:3]#[C:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)[C@H](CCC=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C#CC(=O)OC(C)(C)C
Agent: C#CC(=O)[O-]
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C#CC(O)CC[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.4 %

Procedure:
To a solution of tert-butyl propiolate (42.7 mg, 0.34 mmol) in a dry THF (1.5 mL) was slowly added lithium diisopropylamide (2.0 M in THF/ethyl benzene, 0.15 mL, 0.29 mmol) at −78° C. under nitrogen atmosphere. The resulting reaction mixture was continued stirring at the same temperature for 1.0 hour (to generate lithium propiolate anion), then slowly added (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (0.075 g, 0.193 mmol) in 1.0 mL THF solution. The mixture was stirred at the same temperature for 90 minutes (until finished by TLC). Then, the reaction was quenched with saturated aqueous NH4Cl (0.5 mL) solution and warmed to room temperature by removing the external acetone/dry ice bath. The reaction solution was diluted with ethyl acetate (20 mL) and an aqueous saturated solution of NH4Cl (15 mL) was added with stirring. The aqueous phase was extracted with ethyl acetate (50 mL) and the combined organic layers dried and concentrated under reduced pressure. The resulting residue was purified on 12 g silica gel column (eluent, hexanes to 40% ethyl acetate in hexanes) to afford (7S)-di-tert-butyl 7-(bis(tert-butoxycarbonyl)amino)-4-hydroxyoct-2-ynedioate (diastereomeric mixture, 40 mg, 40.3% yield) as an oil. 1H NMR (CDCl3) δ ppm: 4.76 (dt, J=9.2, 5.2 Hz, 1H), 4.53 (m, 1H), 2.27 (m, 1H), 2.04 (m, 1H), 1.83 (m, 2H), 1.52 (s, 18H), 1.50 (s, 9H), 1.46 (s, 9H). 13C NMR (CDCl3) δ ppm: 169.63, 169.52, 152.47, 152.40, 152.34, 84.96, 84.94, 83.63, 83.09, 83.04, 81.48, 81.46, 77.89, 77.84, 61.90, 61.37, 58.47, 58.31, 33.75, 33.70, 28.02, 27.96, 27.93, 25.13 and 24.72. MS (ESI+): 536 (M+Na)+.