Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C([Li])CCC.[CH3:14][N:15]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C1COCC1>[CH3:14][N:15]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:36])([C:5]2[N:4]([CH2:3][O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=1)[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Reactant: COCn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 14 h

Procedure:
To a solution of 55 mg (0.49 mmol) of 1-methoxymethyl-1H-imidazole in 5 ml of THF at −78° C. was added 0.20 ml (0.50 mmol) of a 2.5 M solution of n-butyllithium in hexanes and the resultant mixture was stirred at −78° C. for 30 mins. After this time, a solution of 160 mg (0.47 mmol) of N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide (Example 22, Step A) in 2 ml of THF was added and the resultant mixture stirred at −78° C. for a further 2 h, and then at room temperature for 14 h. After this time the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 4:1) to give the title compound. 1H-NMR (CDCl3) δ 3.09 (s, 3H), 3.19 (s, 3H), 4.90 (s, 2H), 5.16 (brs, 1H), 7.07–7.16 (m, 4H), 7.42–7.62 (m, 7H). Mass Spectrum (CI+) m/e=456.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:21]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=2)=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:33]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]([C:21]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=2)=[O:22])[CH3:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NC(=O)c2ccnc(Cl)c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccnc(Cl)c1)c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-{2-[(2-chloro-pyridine-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (100 mg, prepared as described in Example 1, Steps A-C) was added to a suspension of sodium hydride (50% in oil, 24 mg) in tetrahydrofuran at 0° C. and the resulting mixture was stirred at 0° C. for 1 hour at which time iodomethane (0.03 ml) was added. The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, washed three times with water, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (cyclohexane:ethyl acetate 7:3) to afford 4-{2-[(2-Chloro-pyridine-4-carbonyl)-methyl-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester as white crystals. M.p. 59-61° C.; 1H NMR (400 MHz, CDCl3) 1.5 (s, 9H), 2.2 (m, 2H), 2.8 (m, 2H), 3.4 (m, 2H), 3.4 (s, 3H), 3.5 (m, 2H), 6.7 (m, 1H), 6.9 (m, 1H), 7.0-7.3 (m, 4H), 8.1 (m, 1H); MS (ES+) 331 (M+H+—CO2-isobutene), 375 (M+H+-isobutene), 431 (M+H+). This compound was treated according to Example 1 Step D to afford the title product as yellow crystals. M.p. 117-120° C.; 1H NMR (400 MHz, CDCl3) 2.4 (m, 2H), 2.5 (m, 2H), 2.6 (m, 2H), 2.9 (m, 2H), 3.2 (m, 2H), 3.5 (s, 3H), 3.5 (m, 2H), 6.2 (dt, J=18, 9 Hz, 1H), 6.5 (d, J=18 Hz, 1H), 6.8 (d, J=9 Hz, 1H), 6.9 (d, J=5 Hz, 1H), 7.0-7.3 (m, 6H), 8.1 (d, J=5 Hz, 1H); retention Time HPLC 2.17 min; MS (ES+) 481/483 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]2([CH3:14])[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:7]=1>C(O)C.ClCCl.CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C@:8]2([CH3:14])[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:7]=1
Reactant: CC1(c2cc(Br)ccc2F)COC(=O)N1
Solvent: CCCCCCC
Solvent: CCO
Solvent: ClCCl
Product: C[C@@]1(c2cc(Br)ccc2F)COC(=O)N1

Procedure:
A solution of the (RS)-4-(5-bromo-2-fluoro-phenyl)-4-methyl-oxazolidin-2-one (20.2 g) in ethanol/dichloromethane/heptane (4/2/2) was divided in 1 g aliquots which were separated on chiral HPLC (Chiralpak AD) using a 90:10-mixture of ethanol and heptane as the eluent. The first eluting enantiomer (retention time: 7.98 min), the (R)-(−)-4-(5-bromo-2-fluoro-phenyl)-4-methyl-oxazolidin-2-one (intermediate C5A), was obtained as a brownish crystalline solid (9.154 g, 45.3% of theory), and the second eluting enantiomer (retention time: 12.19 min), the (S)-(+)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide, was also obtained as a light brown crystalline solid (9.25 g, 45.8% of theory), with e.e. >99.5% each.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH:35]=2)O1.C([O-])(=O)C.[K+].O>[Pd].CC#N>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:34]3[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH:35]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CC=C(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 90 °C

Procedure:
(1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)phenyl)methanone (0.895 g, 2.270 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.60 g, 2.39 mmol), potassium acetate (1.06 g, 17.9 mmol), and palladium catalyst (0.13 g, 0.18 mmol) were taken up in 24 mL of 3:1 MeCN:water. The mixture was purged with nitrogen and heated to 90° C. for 15 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The organics were washed with 30 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel [10 to 100% EtOAc (contains 5% MeOH)/hexane] afforded 1-(4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2([OH:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[CH:5][N:4]=1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2([OH:18])[CH2:16][CH2:15][CH:14]([N:19]3[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=4)=[O:25])[CH2:20]3)[CH2:13][CH2:12]2)=[CH:5][N:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ncc(C2(O)CCC(=O)CC2)c(OC)n1
Product: COc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c(OC)n1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(2,4-dimethoxy-pyrimidin-5-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].C(Cl)(Cl)Cl.BrBr.[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[S:28])[CH:23]=[CH:24][CH:25]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(N(CC)CC)C.CC(C)=O.O1CCOCC1>[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[S:28][C:2]([CH3:3])=[CH:1][N:29]=2)[CH:23]=[CH:24][CH:25]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=S)c1
Reactant: CCC=O
Agent: BrBr
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cnc(Nc2cccc(CNC(=O)OC(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a mixture of propionaldehyde (72 μl), chloroform (1 ml) and 1,4-dioxane (1 ml), bromine (52 μl) was added. The reaction mixture was stirred at room temperature for 30 min and then N-(3-(t-butoxycarbonylaminomethyl)phenyl)thiourea (262 mg), acetone (2 ml) and triethylamine (0.14 ml) were added. The reaction mixture was heated under reflux for 3.5 h and concentrated under reduced pressure. To the resulting residue, water was added and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride:methanol=99:1) to give 79.2 mg of the titled compound (yield, 27%).
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[NH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:32]([F:35])([F:34])[F:33])[N:16]=2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:21]([C:20]1[C:15]([NH:14][CH2:13][C@H:10]2[CH2:9][CH2:8][C@H:7]([NH:6][CH2:2][C:3]([NH2:5])=[O:4])[CH2:12][CH2:11]2)=[N:16][C:17]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][C:32]([F:33])([F:34])[F:35])=[N:18][CH:19]=1)#[N:22]
Reactant: NC(=O)CBr
Reactant: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](NCC(N)=O)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 2-bromoacetamide (30 mg, 0.21 mmol), 4-{[(trans-4-aminocyclohexyl)methyl]amino}-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidine-5-carbonitrile (117 mg, 0.28 mmol) and DIPEA (74 mL, 0.43 mmol) in DMF (1 mL) was stirred at 50° C. for 4 h. The reaction mixture was then diluted with EtOAc (30 mL) and washed with water (3×3 mL) and brine. The organic phase was dried over Na2SO4 and concentrated. Silica gel preparative TLC of the crude product using 10:1:0.05 CH2Cl2:MeOH:NH4OH as an eluent afforded 28 mg (27%) of the title compound as a white solid, m/z 476.5 [M−1]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[S:8])[NH:6][NH2:7].[CH3:12][CH:13]([C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>C(O)C.C(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[S:8][C:24]([CH:13]([CH3:12])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:7][N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(CCNC(=O)OC(C)(C)C)C(=O)c1ccccc1
Reactant: NNC(=S)c1cccc(F)c1
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(CCNC(=O)OC(C)(C)C)C1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a solution of 3-fluorobenzothiohydrazide (300 mg, 1.76 mmol) in ethanol/DCM (6 mL/2 mL) was added tert-butyl 3-methyl-4-oxo-4-phenylbutylcarbamate (538 mg, 1.94 mmol). After stirring at room temperature for 16 hours, acetic acid (3 drops) was added and the mixture stirred for another 48 hours. The reaction mixture was then concentrated under reduced pressure and chromatographed (9:1 hexanes/ethyl acetate) to provide the product (366 mg, 48%) as a mixture of diastereomers as a yellow foam.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].ClCCl.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13]>C(N(CC)CC)C>[CH3:1][C:2]([CH3:7])([CH2:5][O:6][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH2:3][O:4][Si:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(CO)CO
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CO[Si](C)(C)C)CO[Si](C)(C)C
Temperature: 0 °C

Procedure:
0.6 g of 2,2-dimethyl-1,3-propandiol was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, thereto was added 2.09 ml of triethyl amine, followed by the addition of 1.76 ml of trimethylsilyl chloride. The mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.23 g of concentrate. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:40]2[CH2:44][CH2:43][C:42](=[O:45])[CH:41]=2)O1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:40]4[CH2:44][CH2:43][C:42](=[O:45])[CH:41]=4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC1(C)OB(C2=CC(=O)CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1C=C(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)CC1

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclo hexyl methyl)-amide, cesium carbonate, 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopent-2-enone and tetrakis(triphenyl phosphine)palladium(0). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83-8.86 (bs, 1H), 8.27-8.29 (m, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.12-8.14 (m, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.12 (s, 1H), 4.72 (s, 1H), 3.42-3.44 (m, 2H), 3.20-3.22 (m, 2H), 2.55-2.57 (m, 2H), 2.07-2.10 (m, 2H), 1.89-2.01 (m, 2H), 1.70-1.77 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].C1CCCCC1.O.C([O-])([O-])=[O:17].[Na+].[Na+]>CCCCCC>[CH3:1][CH:2]1[O:17][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: CC1CCCCC1=O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCCCCC
Solvent: O
Product: CC1CCCCC(=O)O1
Reaction time: 3 h

Procedure:
3.15 g of 2-methylcyclohexanone and 3.85 g of cyclohexane percarboxylic acid, dissolved in n-hexane, are kept at 50° C. for 3 hours under agitation. The reaction product is treated with H2O, then neutralized with a solution of Na2CO3 and finally extracted with ethyl acetate. After solvent distillation, one obtains 3.3 g of 7-methyl-2-oxepanone, identified by mass spectrometry (EI, 70 eV), yielding the following m/e values: 128, 98, 80, 69, 55, 42.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:12]([C:13](O)=O)=[C:11]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[C:4]#[CH:5])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:13][C:12]1[C:11]([O:16][C:17]2[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])=[N:10][C:9]([CH3:26])=[CH:8][C:7]=1[NH:6][CH:3]([CH2:4][CH3:5])[CH:1]=[CH2:2]
Reactant: C#CC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: C=CC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C

Procedure:
The title compound was prepared as a clear oil by reduction of 4-(1-Ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid with lithium aluminum hydride and aluminum chloride. 1H NMR(CDCl3) d 6.87(s,2H), 6.08(s,1H), 5.7–5.9(m,1H), 5.1–5.3(m,2H), 3.75–4.0(m,2H), 2.30(s,3H), 2.16(s,3H), 2.15(s,3H), 2.08(s,6H), 1.70(m,2H), 1.03(t,3H)ppm.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13](O)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.C([N:25]1CCOCC1)C.C(OC(Cl)=O)C(C)C.N>O1CCCC1.C(OCC)(=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([NH2:25])=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1
Reactant: Cc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Reaction time: 0.17 h

Procedure:
5 g of BOC-D-Cys(MBzl)-OH are dissolved in 60 cc of dry tetrahydrofuran, the solution is cooled to -15°, 1.85 cc of N-ethylmorpholine are added, and then 1.92 cc of chloroformic acid isobutyl ester are added, and the mixture is stirred for 10 minutes. Dry ammonia gas is subsequently passed through the solution at -15° while stirring, stirring is continued for 2 hours, whereby the temperature rises to room temperature. The reaction mixture is diluted with approximately 800 cc of ethyl acetate, is washed with water, and the organic phase is dried over sodium sulphate. Concentration, filtration, washing with ethyl acetate/ether and drying are effected, and the title compound is obtained. M.P. 140°; [α]D20 = +26° in dimethyl formamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].Cl.[CH3:29][NH2:30]>>[CH3:29][NH:30][C:24]([C:21]1[O:22][C:23]2[C:15]([N:12]3[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:10][CH2:11]3)=[CH:16][CH:17]=[CH:18][C:19]=2[CH:20]=1)=[O:25]
Reactant: CN
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: Cl
Agent: [Li+]
Product: CNC(=O)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and methylamine hydrochloride (90 mg, 1.3 mmol). Yield: 50 mg (62%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([OH:23])=[C:8]([C:20](=[O:22])[CH3:21])[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1.Cl>N1C=CC=CC=1>[C:20]([C:8]1[C:7]2[O:23][C:1](=[O:2])[NH:5][C:6]=2[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)(=[O:22])[CH3:21]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)oc12
Temperature: 50 °C

Procedure:
52 g (0.53 mol) phosgene are piped into a solution of 121 g (0.47 mol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 800 mL pyridine at 20 to 40° C. The reaction mixture is heated to 50° C. for 2 hours, then poured onto ice and acidified with conc. hydrochloric acid. A reddish-brown solid is isolated which is repeatedly recrystallised from ethanol with the addition of activated charcoal.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:12][C:13]([N:15]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]([CH3:20])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:48]([O:50][C:51](=[O:69])[CH2:52][C@H:53]([NH2:68])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([Cl:67])[CH:62]=2)=[CH:57][CH:56]=1)[CH3:49]>C1COCC1.C(#N)C.O>[CH2:48]([O:50][C:51](=[O:69])[CH2:52][C@H:53]([NH:68][C:17](=[O:19])[CH:16]([N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:20])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([Cl:67])[CH:62]=2)=[CH:57][CH:56]=1)[CH3:49]
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)C(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(C)N(CC(=O)OCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
To a suspension of 2-(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-propionic acid TFA salt (197 mg, 0.714 mmol) in THF (10 ml) at room temperature is added EDCI (219 mg, 1.142 mmol) and HOBT (164 mg, 1.071 mmol). The mixture is stirred at room temperature for 10 mins and then was added a solution of (R)-3-amino-4-(3′-chloro-biphenyl-4-yl)-butyric acid ethyl ester (202 mg, 0.571 mmol) in THF and TEA (0.199 ml, 1.428 mmol). The mixture is stirred at room temperature. Reverse phase HPLC [30 to 90% ACN—H2O (0.1% TFA) over 10 min by X-Bridge phenyl column] give the title compound (290 mg, 71% yield). LCMS (condition B): 575 (M+1); retention time=1.52 min.
Reaction SMILES: O=[C:2]1[NH:19][CH2:18][CH2:17][S:16][CH2:15][CH2:14][S:13][CH2:12][CH2:11][NH:10][C:9](=O)[CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3]1.B#B.O>O1CCCC1>[O:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][S:16][CH2:17][CH2:18][NH:19][CH2:2][CH2:3]1
Reactant: O=C1COCCOCC(=O)NCCSCCSCCN1
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: C1COCCOCCNCCSCCSCCN1

Procedure:
A solution of 7 g. of the cyclic diamide obtained in Example 28 in 100 ml. anhydrous tetrahydrofurane is added slowly to 50 ml. of a freshly prepared solution (1.5 M) of diborane in anhydrous tetrahydrofuran under nitrogen atmosphere and at a temperature of 0° C. The mixture is then heated to reflux for two hours. The excess reagent is destroyed by adding 10 ml. of water and the solution is evaporated to dryness on a rotatory evaporator under vacuum. 100 ml. 6N hydrochloric acid are added to the residue and the mixture is refluxed for two hours; a clear solution is obtained. This solution is then evaporated to dryness under vacuum. The residue is dissolved in 30 ml. water and the solution is pressed through a column of an anion exchange resin (Dowex 1, Trade Mark). The column is washed with water until there is no basic reaction. The combined water solutions obtained are evaporated to dryness under vacuum on a water bath (80° C.-100° C.). The residue is recrystallized.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1CCCCC1>CO.C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:37])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cnc(Nc2ccc(C3CCNCC3)nc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Agent: C=O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2ccc(C3CCN(C)CC3)nc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A solution of 1-(2-(2-(5-methyl-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A46 (0.121 g, 0.265 mmol) in MeOH (10 mL) was treated with formaldehyde solution (37% in water, 59 μL, 0.80 mmol) and sodium triacetoxyborohydride (0.225 g, 1.06 mmol) and stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, aq. NaOH (2 M, ˜30 mL) was added and the aqueous phase was extracted with EtOAc (3×30 mL). The organics were combined, washed with brine, dried (MgSO4) and the solvent evaporated under reduced pressure to give a colourless oil. The oil was taken up in DCM and cyclohexane was added until a white precipitate formed. The suspension was sonicated for 10 minutes and the solid was isolated by vacuum filtration and dried under high vacuum for 4 hours to give the title compound 49 as a white solid (0.051 g, 41%). LCMS-D: rt 3.13 min; m/z 471 [M+H]+.