Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13]2)=[CH:8][N:7]=1)[CH3:4].[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[CH:8]1[C:9]2[CH2:10][CH2:11][NH:12][CH2:13][C:14]=2[CH:15]=[C:6]([NH:5][C@@H:3]([CH3:4])[CH2:2][OH:1])[N:7]=1
Reactant: C[C@@H](CO)Nc1cc2c(cn1)CCN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](CO)Nc1cc2c(cn1)CCNC2

Procedure:
A solution of 326 (56 mg, 0.18 mmol) and TFA (2 mL) and was stirred at RT for 45 min. The reaction was concentrated to provide crude (S)-2-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylamino)propan-1-ol 2,2,2-trifluoroacetate (328) which was used in the nest step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>>[O:16]=[C:12]1[C:11](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:10]2[C:14](=[CH:15][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2cc(-c3cccnc3)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-Pyridin-3-yl-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [Cl:1]/[C:2](/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:3]\[C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].S(Cl)([Cl:21])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1]/[C:2](/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:3]\[C@H:4]1[C@H:6]([C:7]([Cl:21])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)Cl
Yield: 96.9 %

Procedure:
1.0 g (0.0035 mol) of (±)-trans-3-(Z-2-chloro-2-(4-chloro-phenyl)-vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid were dissolved in 20 ml of carbon tetrachloride, and 5 ml of thionyl chloride were added dropwise slowly at 25° C., while stirring. The mixture was then heated to the reflux temperature for 4 hours. After this reaction time, excess thionyl chloride and carbon tetrachloride were distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./2 mm Hg. 1.03 g (96.9% of theory) of (±)-trans-3-(Z-2-chloro-2-(4-chloro-phenyl)-vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid chloride were obtained as an oily liquid. ##STR21##
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([Si](C(C)C)(C(C)C)C(C)C)[CH:28]=[C:29]([C:37]3([OH:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[C:30]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:22][CH:21]=1>O1CCCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[NH:27][CH:28]=[C:29]([C:37]3([OH:43])[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]3)[C:30]=2[C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[CH:22][CH:21]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2(O)CCNCC2)c(-c2ccncc2)c1-c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC1(c2c[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
2.73 ml (2.73 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran were added to a solution of 675 mg (1.37 mmol) of 2-(4-fluorophenyl)-4-(4-hydroxypiperidin-4-yl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole [prepared as described in Example 9(iii) above] in 14 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, the solvent was distilled off under reduced pressure. Water was added to the resulting residue and the precipitate thus obtained was collected by filtration and then washed with ethyl acetate to give 363 mg (yield 79%) of the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-:14].[K+].Cl>O>[OH:14][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Yield: 150.2 %

Procedure:
A mixture of 3-chloro-2-nitrobenzoic acid (40 g, 0.20 mol) and KOH (160 g, 2.86 mol) in water (200 mL) was heated to reflux for 16 hr. 6N aqueous hydrochloric acid was added to the mixture to pH=3, then extracted with ethyl acetate (500 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 3-hydroxy-2-nitrobenzoic acid (55 g), LC-MS (ESI) m/z 184 [M+1]−.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:4]=2[CH:3]=1.[H][H]>CN(C)C=O.CO.[Ni]>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]2[O:18][C:17](=[O:19])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[C:5]=2[CH:6]=1
Reactant: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2oc(=O)c3c(c2cc1N)CCNC3
Yield: 81.2 %

Procedure:
A solution of 1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (6.0 g, 0.023 moles) in N,N-dimethylformamide (100 ml) and methanol (50 ml) is hydrogenated at 50 psi in the presence of Raney Nickel (0.5 g) at room temperature for 20 hours. Additional Raney Nickel (0.5 g) in N,N-dimethylformamide (50 ml) is then added, and hydrogenation resumed until hydrogen uptake ceases. The catalyst is filtered off and rinsed with warm N,N-dimethylformamide. The filtrate is concentrated under reduced pressure and filtered to afford the product (4.3 g), mp 283°-284° C.
Reaction SMILES: [CH:1]([CH:4]1[C:8](=[O:9])[O:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[N:5]1[C:46](=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50])([CH3:3])[CH3:2].C(OC(C)C)(C)C>C1COCC1.[Pd]>[CH3:50][CH2:49][CH2:48][CH2:47][C:46]([N:5]([C@H:4]([C:8]([OH:9])=[O:7])[CH:1]([CH3:3])[CH3:2])[CH2:6][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:23][N:24]=[N:25][N:26]=2)=[CH:14][CH:15]=1)=[O:51]
Reactant: CCCCC(=O)N1C(c2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)OC(=O)C1C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Yield: 50.5 %

Procedure:
A solution of the 4-isopropyl-3-pentanoyl-2-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-yl]oxazolidin-5-one (1.0 g, 1.5 mmoles) in 20 ml of THF is hydrogenated under 5 bars, at 60° C., in the presence of Pd(5%)/C (100 mg). After completion of the reaction, the mixture is cooled and the catalyst is filtered off. After working up the reaction mixture as in Example 4, valsartan (0.33 g, molar yield: 53%) is isolated by crystallization from isopropyl ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[NH:64]1[CH:68]=[N:67][C:66]([NH2:69])=[N:65]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:4]1[N:3]=[C:2]([NH:69][C:66]2[N:67]=[CH:68][NH:64][N:65]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccccc3n2)nc1
Reactant: Nc1nc[nH]n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Fc1ccc(C(F)(F)c2nc(Nc3nc[nH]n3)c3ccccc3n2)nc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a mixture of 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline from Example 4 Step A (100 mg, 0.32 mmol), Pd2(dibenzylideneacetone)3 (12 mg, 0.013 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol), SEM protected 1,2,4-triazol-3-amine (97 mg, 0.45 mmol), and Na2CO3 (48 mg, 0.45 mmol) was added toluene (3 mL), and the mixture was evacuated and flushed with argon three times. The mixture was heated at 110° C. for 2 h, and then diluted with DCM and filtered. To the filtrate was added TFA (3 mL) and the mixture was stirred at rt for 2 h and then concentrated under reduced pressured. To the residue was added MeOH and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex C-18 reverse phase column eluting with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O). The obtained material was triturated with diethyl ether to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(1H-1,2,4-triazol-3-yl)quinazolin-4-amine (16 mg, 14%). 1H NMR (300 MHz, methanol-d4) δ 8.68 (br s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.90-8.15 (m, 4H), 7.71-7.88 (m, 2H). LCMS (ESI) m/z 358 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]2=[O:23])=[CH:4][C:3]=1[CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:34]([C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:35]([CH:34]([C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]2=[O:23])=[CH:4][C:3]=1[CH2:24][CH2:25][CH3:26])([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)ccc1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
To a solution of 0.105 g (0.30 mmol) of the product of step C in 1.0 mL of DMF was added 0.115 g (0.33 mmol) of cesium carbonate and the resulting suspension was stirred under a nitrogen atmosphere for 15 minutes. A solution of 0.094 g (0.33 mmol) ethyl α-bromo-3,4-methylenedioxyphenylacetate in 0.5 mL of DMF was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then suspended in 10% aqueous citric acid and extracted into ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane; combination of the product fractions and evaporation in vacuo afforded 0.137 g (83%) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O.C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1OCC(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccccc1OCC(F)F
Yield: 90 %

Procedure:
The 1-(2,2-difluoro-ethoxy)-2-nitro-benzene (2.16 mmol) was dissolved in a 1:1-mixture of ethanol and ethyl acetate in order to obtain a final concentration of 0.05M. Hydrogenation was performed at 60° C., 1 bar of hydrogen and with palladium on charcoal (10%) as the catalyst. After evaporation of the solvent the title compound was obtained in 90% yield and could be used in the next step without further purification; (calculated) C8H9F2NO [173.16]; (found) [M+H]+=174.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18](O)=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.C1C=C2N=NN(O)C2=CC=1.O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:54][C@H:55]([C:65]([C:67]([O:69][CH3:70])=[O:68])=[O:66])[CH2:56][O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.FC(C(O)=O)(F)F.CCN(CC)CC>CCOC(C)=O>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([NH:54][C@H:55]([C:65]([C:67]([O:69][CH3:70])=[O:68])=[O:66])[CH2:56][O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C(=O)[C@@H](N)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of Boc-Tyr(OBn) (1.88 g, 6.50 mmol) in EtOAc (30 mL) at 0° C. was added HOBT hydrate (1.19 g, 7.80 mmol) followed by DCC (1.61 g, 7.80 mmol). A solution of Ser(OBn)-CO2Me.TFA (2.1 g, 6.50 mmol) in EtOAc (20 mL) was added followed by Et3N (1.09 mL, 7.80 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered, diluted with EtOAc, and washed twice with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography (40% EtOAc/hexane) gave 2.67 g (73%) of the title compound as a white solid, mp 81°-84° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][CH3:30])=[CH:4][C:5]([O:27][CH3:28])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][N:14]([CH2:22][C:23](O)=[O:24])[C:13]2=[O:26])=[O:10])[CH:7]=1.CN(C(ON1N=N[C:41]2[CH:42]=[CH:43][CH:44]=[N:45][C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1>CS(C)=O>[Cl:1][C:2]1[C:3]([O:29][CH3:30])=[CH:4][C:5]([O:27][CH3:28])=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][N:14]([CH2:22][C:23](=[O:24])[NH:45][CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)[C:13]2=[O:26])[CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(OC)c(NC(=O)CN2C(=O)N(CC(=O)O)Cc3ccccc32)cc1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CS(C)=O
Product: COc1cc(OC)c(NC(=O)CN2C(=O)N(CC(=O)NC3CCCC3)Cc3ccccc32)cc1Cl
Reaction time: 8 h

Procedure:
A solution of {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2-oxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (Example 5-1) (20 mg, 0.046 mmol) in DMSO (1 ml) is treated with a solution of HATU (19.3 mg, 0.05 mmol) in DMSO (2 ml). The reaction mixture is then treated with cyclopentylamine (4.12 mg, 0.048 mmol) and the reaction left to stand at RT overnight. The reactions are analysed by HPLC/LCMS and concentrated in vacuo. The residue is taken up in DCM and washed with 1M HCl The organic phase is washed with saturated NaHCO3 and concentrated in vacuo to give the title compound; [M+H]+ 501
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:21][CH2:20][C@H:19]1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=2)[CH2:33][NH:34]C(=O)OC(C)(C)C)[CH:27]=[N:28][CH:29]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+].CCOC(C)=O.N>C(Cl)Cl.C(Cl)Cl.CO.CCOC(C)=O.O>[CH2:8]([O:15][C:16]([N:18]1[CH2:21][CH2:20][C@H:19]1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=2)[CH2:33][NH2:34])[CH:27]=[N:28][CH:29]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2cncc(OC[C@@H]3CCN3C(=O)OCc3ccccc3)c2)c1
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: NCc1cccc(-c2cncc(OC[C@@H]3CCN3C(=O)OCc3ccccc3)c2)c1
Reaction time: 7 h
Yield: 288.5 %

Procedure:
In a 100 mL round-bottom flask, a mixture of trifluoroacetic acid (1.2 mL) and water (0.12 mL) was added to a solution of tert-butyl 3-[5-[[1-(benzyloxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]benzylcarbamate (329 mg, 653 μmol) in CH2Cl2 (6 mL). The flask was loosely stoppered, and the mixture was stirred magnetically for 7 h. Shortly before, a small aliquot was worked up with aq. NaHCO3/EtOAc and analyzed by TLC (UV detection; SiO2, EtOAc: Rf 0; SiO2, CH2Cl2/MeOH/conc. aq. NH3 87:13:3: Rf approx. 0.55), indicating complete conversion of the starting material. The mixture was evaporated (40° C./14 torr) to obtain a colorless glass (0.76 g), which was taken up in MeOH (3 mL). The pH was adjusted to approx. 8-9 (indicator paper) by adding a few drops of conc. NH3, and the solution was evaporated again. The residue was chromatographed on SiO2 (20×1.9 cm, CH2Cl2/MeOH/conc. aq. NH3 87:13:3), and the product-containing fractions were evaporated and dried (40° C./oil pump) to obtain 262 mg (99.5%) of the free primary amine as a slightly yellowish glass. 1H NMR (CDCl3, 500 MHz) δ 8.50 (s, 1H), 8.32 (br, 1H), 7.56 (s, 1H), 7.51-7.45 (m, 2H), approx. 7.43 (br and overlapping, 1H), 7.40 (m, 1H), 7.32 (br s, 5H), 5.13, 5.08 (ABq, 2H, J=12.3 Hz), 4.67 (m, 1H), approx. 4.5 (br, 1H), 4.22 (br s, 1H), 4.09-4.00 (m, 2H), 3.99 (s, 2H), 2.51-2.37 (m, 2H), 1.64 (br, NH2 and H2O). MS (EI) m/z 403 (M+, 5.8%), 312 (6.4%), 200 (5.4%), 199 (4.0%), 91 (100%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.CO.[BH4-].[Na+]>O1CCCC1>[OH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:30][CH2:31]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (5 g), methanol (20 mL) and tetrahydrofuran (20 mL) was added sodium borohydride (0.61 g) at 0° C., and the mixture was stirred at the same temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3 g, 58%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][C@@H:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[C:20]([NH2:25])[N:19]=1.C([O-])(O)=O.[Na+].O>O1CCOCC1.CCOC(C)=O.ClC1C=C(Cl)N=C(N)N=1>[NH2:25][C:20]1[N:21]=[C:22]([N:7]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]([C:8]([NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:9])[CH2:6]2)[CH:23]=[C:18]([Cl:17])[N:19]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1c1cc(Cl)nc(N)n1
Yield: 116.8 %

Procedure:
To a solution of (3S,6R)-6-methyl-N-phenyl-3-piperidinecarboxamide (12 g, 55 mmol) in 1,4-dioxane (250 mL) was added 4,6-dichloro-2-pyrimidinamine (8.11 g, 49.5 mmol) and sat. aqueous NaHCO3 (125 mL), and the reaction mixture was then refluxed overnight. The reaction was not completed. The reaction mixture was cooled, added 4,6-dichloro-2-pyrimidinamine (0.9 g, 5.5 mmol), and refluxed overnight. When the reaction was completed, the mixture was cooled down. To the mixture was added about 500 mL of H2O to form a precipitate, and then filtered to obtain a gummy solid. The gummy solid was then dissolved in EtOAc (˜800 mL). The organic solution was washed with water (2×200 mL), brine (200 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford the crude title compound (20 g). LC-MS (ES) m/z=346 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: Oc1ccc(F)cc1F
Reactant: C1=COCCC1
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc(OC2CCCCO2)c(F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
260.2 g (2.0 mol) of 2,4-difluorophenol and 252.4 g (3.0 mol) of 3,4-dihydro-2H-pyran are introduced into a 750 ml sulfation flask and cooled to 0° C. One drop of polyphosphoric acid is carefully added to the solution, and the mixture is stirred for a further 16 hours at 0° to 5° C. (check using GC and TLC). The mixture is then reduced alkaline using a little powdered sodium hydroxide. The product is distilled at 119°-120° C. in vacuo (22 mbar). 377 g (88% of theory) of a clear, colourless liquid are obtained.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[BH4-].[Na+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21](=[O:25])[C:22]([OH:24])=[O:23])([O-:13])=[O:12]>O1CCCC1>[OH:25][CH:21]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])[C:22]([OH:24])=[O:23]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: O=C(O)[C@@H]1CCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 144 h

Procedure:
L-(-)-proline (7.50 g., 65.1 mmol) and sodium borohydride (2.46 g., 65.1 mmol) were stirred in tetrahydrofuran under nitrogen for sixteen hours. Recrystallized o-nitrophenylpyruvic acid (14.17 g., 76.5 mmol) in tetrahydrofuran (50 ml.) was added dropwise, and the resulting solution was stirred at room temperature for six days. The solvent was evaporated and the resulting gum was stirred with 10% aqueous HCl (200 ml.) for 4.5 hours. A small amount of solid was filtered to provide nearly racemic α-hydroxy-2-nitrobenzenepropanoic acid, 1.25 g., m.p. 98°-102° C., [α]D25 -4.21° (c 2.045, EtOH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([CH2:12][CH3:13])[CH2:8][CH2:7]2.[CH3:19][N:20]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:39].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:39])[N:20]([CH3:19])[CH:29]=3)[CH:3]=[C:4]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=2)[O:10]1)[CH3:13]
Reactant: CCC1CCc2cc(NS(C)(=O)=O)cc(Br)c2O1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCC1CCc2cc(NS(C)(=O)=O)cc(-c3cn(C)c(=O)c4ccccc34)c2O1
Temperature: 85 °C
Yield: 19.2 %

Procedure:
A mixture of the title compound from Step 6 (105 mg, 0.315 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (108 mg, 0.379 mmol), K2CO3 (131 mg, 0.949 mmol) and Pd(dppf)Cl2 (23.1 mg, 0.032 mmol) in dioxane/H2O (10 mL/3 mL) was heated to 85° C. for 2 h. It was then filtered and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA 50:1 to 20:1 to 10:1) to give the title compound (25 mg, 19%). 1H NMR (400 MHz, CD3OD) δ 8.31 (d, J=8.4 Hz, 1H), 7.59-7.55 (m, 1H), 7.47-7.43 (m, 1H), 7.31-7.23 (m, 2H), 7.05 (s, 1H), 6.95 (d, J=2.8 Hz, 1H), 3.77-3.71 (m, 1H), 3.60 (s, 3H), 2.95-2.75 (m, 5H), 1.95-1.92 (m, 1H), 1.66-1.54 (m, 1H), 1.38-1.22 (m, 2H), 0.59-0.55 (m, 1.25H), 0.42-0.38 (m, 1.75H). LCMS: 413.0 (M+1)+.