Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([O:20][CH3:21])[C:10]2([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])[C:30](O)=[O:31])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([O:20][CH3:21])[C:10]2([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12]2)=[CH:3][C:2]=1[NH:1][C:30](=[O:31])[C@H:29]([C:26]1[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=1)[C@@H:33]([CH3:38])[C:34]([F:35])([F:36])[F:37]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: COC(c1ccc(Cl)c(N)c1)C1(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.641 mmol) of (+/−)-tert-butyl 1-[(3-amino-4-chlorophenyl)(methoxy)methyl]cyclopropanecarboxylate and 188 mg (0.706 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 2.3 ml of DMF and 0.7 ml of pyridine, and 293 mg (0.770 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight. Another 0.6 eq. of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid was then added, and the reaction mixture was stirred at 45° C. for 14 h. After cooling, the mixture was diluted with ethyl acetate and the solution was washed with 1 N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 30:1). This gave 168 mg of the target compound (39.9% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH3:36])[C:34]=1[NH2:35])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[CH:7]=1.[CH:37]1([CH2:40][C:41](O)=O)[CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C>CN(C=O)C>[CH:37]1([CH2:40][C:41]2[NH:1][C:2]3[CH:3]=[C:4]([O:5][C:6]4[N:11]=[CH:10][N:9]=[C:8]([N:12]5[CH2:13][CH2:14][CH:15]([N:18]6[CH2:24][CH2:23][C:22]7[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=7[NH:20][C:19]6=[O:31])[CH2:16][CH2:17]5)[CH:7]=4)[CH:32]=[C:33]([CH3:36])[C:34]=3[N:35]=2)[CH2:39][CH2:38]1
Reactant: O=C(O)CC1CC1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c(N)c4)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(CC6CC6)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g (0.42 mmol) 3-{1-[6-(3,4-diamino-5-methyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 46 mg (0.46 mmol) cyclopropyl-acetic acid, 151 mg (0.47 mmol) TBTU and 0.14 mL (1.00 mmol) TEA in 2.00 mL DMF were stirred for 4 h at RT. Then 2.00 mL glacial acetic acid was added and the mixture was stirred overnight at RT. In addition the reaction mixture was stirred for 1 h at 100° C., then cooled and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [OH-].[Li+].[F:3][CH:4]([F:29])[C:5]1[N:6]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH2:27][CH3:28])=[CH:19][CH:18]=2)[C:7]([S:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:8][N:9]=1>C1COCC1.O>[F:29][CH:4]([F:3])[C:5]1[N:6]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH2:27][CH3:28])=[CH:19][CH:18]=2)[C:7]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[N:8][N:9]=1
Reactant: CCOC(=O)CSc1nnc(C(F)F)n1-c1ccc(CC)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(-n2c(SCC(=O)O)nnc2C(F)F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Lithium hydroxide solution (1M aqueous, 0.77 mL, 0.77 mmol) was added to a solution of ethyl 2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate (0.15 g, 0.38 mmol) in THF/water (3:1, 1.5 mL) and the mixture stirred for 8 h at room temperature. The crude reaction mixture was then concentrated and acidified with HCl (1N, 3 mL) and extracted with ethyl acetate (3×2 mL). The combined organic extracts were concentrated to afford 2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off-white foam (0.136 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:28]2[C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:29]2[C:28]3[O:24][CH2:25][CH2:26][C:27]=3[CH:32]=[CH:31][CH:30]=2)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cccc2c1OCC2
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCC3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,3-Dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=494.3.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23][C:24]([CH3:35])([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])[CH3:25].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:32]4[CH2:33][CH2:34][C@H:30]([NH:29][C:27]([O:26][C:24]([CH3:35])([CH3:25])[CH3:23])=[O:28])[CH2:31]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Yield: 99.5 %

Procedure:
A solution of 12.5 g (40 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester, 8.9 g (48 mmol) of (S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]pyrrolidine, 8.1 g (80 mmol) of triethylamine and 75 ml of acetonitrile was heated at reflux for 18 hours. The reaction mixture was cooled to 5° and the solid was removed by filtration, washed with acetonitrile, ether and dried in vacuo to give 19.0 g of the title compounds, mp 148°-151°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:23][C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:24]([Cl:23])=[O:26])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Cl)CC4)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 1M solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.84 g, 2.88 mmol) in anhydrous THF was added dropwise triphosgene (1.28 g, 4.32 mmol) and triethylamine (0.92 mL, 6.62 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure to give the desired product, 3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carbonyl chloride as an orange solid was used immediately in the next step without any further purification.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=1>[Li]CCCC.[Zn+2].[Br-].[Br-]>[Br:19][C:20]1[N:21]=[C:22]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(I)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Brc1cccc(Br)n1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Zn+2]
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)n2)c1

Procedure:
The title compound was prepared from 2-iodo-4-methyl-6-(4-trifluoromethyl-phenyl)pyridine (example A.58) (5.81 g, 16 mmol), n-BuLi/ZnBr2 and commercially available 2,6-dibromopyridine (5.31 g, 22.4 mmol) according to Tetrahedron Letters 1996, 37(15), 2537 and the general procedure IVc protocol b. Obtained as a white solid (2.34 g, 37%). MS (ISP) 393.0 [(M+H)+] and 395.0 [(M+2+H)+].
Reaction SMILES: Cl.[CH:2]1([CH2:5][NH:6][C:7]([C:9]2[C:13]3[CH2:14][NH:15][CH2:16][CH2:17][C:12]=3[O:11][N:10]=2)=[O:8])[CH2:4][CH2:3]1.C1(CN[C:23]([C:25]2[C:29]3CNC[CH2:33][C:28]=3ON=2)=[O:24])CC1.C(Cl)(=O)CCC=C>>[CH:2]1([CH2:5][NH:6][C:7]([C:9]2[C:13]3[CH2:14][N:15]([C:23](=[O:24])[CH2:25][CH2:29][CH:28]=[CH2:33])[CH2:16][CH2:17][C:12]=3[O:11][N:10]=2)=[O:8])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CC1)c1noc2c1CNCC2
Agent: C=CCCC(=O)Cl
Agent: Cl
Product: C=CCCC(=O)N1CCc2onc(C(=O)NCC3CC3)c2C1
Yield: 84 %

Procedure:
The corresponding base was released from 4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid cyclopropylmethyl amide hydrochloride. In a manner similar to general method 3, 170 mg (0.42 mmol) of 4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid cyclopropylmethyl amide were reacted with 89 μL (0.89 mmol) of 4-pentenoyl chloride to yield 150 mg (84% of theoretical) of 5-pent-4-enoyl-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid cyclopropylmethyl amide (66), which were obtained in the form of a brown oil.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)=[CH:5][S:4][CH:3]=1.[C:13](C1C(Br)=CSC=1)(=[O:15])[CH3:14]>>[C:13]([C:2]1[C:6]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)=[CH:5][S:4][CH:3]=1)(=[O:15])[CH3:14]
Reactant: Brc1cscc1C1=CCCCC1
Reactant: CC(=O)c1cscc1Br
Product: CC(=O)c1cscc1C1=CCCCC1
Yield: 31 %

Procedure:
Prepared from 3-bromo-4-cyclohex-1-enyl-thiophene (See MacDowell; Jeffries J. Org. Chem., 1970, 35, 871-875 incorporated herein by reference), in 31% yield analogous to the procedure for the preparation of 4-acetyl-3-bromo-thiophene. 1H NMR (300 MHz, CDCl3) δ7.90(d, 1H, J=2.7 Hz), 6.97 (d, 1H, J=2.7 Hz), 5.66 (q, 1H, J=1.8 Hz), 2.49 (s, 3H), 2.15-2.19 (m, 4H), 1.64-1.79 (m, 4H).
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].S(Cl)([Cl:21])=O>>[C:1]([Cl:21])(=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)CCCCCCCCCCCCC(=O)Cl

Procedure:
Isohexadecanoic acid (20 g, 0.078 mol) and thionyl chloride (7.2 ml, 0.0984 mol) were refluxed together gently for 1 hour to produce isohexadecanoyl chloride and the reaction was monitored by infra-red spectroscopy. Excess thionyl chloride was distilled away under rotary pump vacuum at reflux temperature. The acyl chloride was dissolved in n-hexane (50 ml) and slowly added to a chilled stirred solution of n-propylamine (7.05 ml, 0.0858 mol, m 0.1 excess). The solution also contained triethylamine (12 ml, 0.0858 mol, 0.1 excess) in n-hexane (200 ml) to ensure base conditions. After the addition was completed the reaction mixture was stirred at room temperature for 3 hours until all the acyl chloride was consumed. This was detected by monitoring the shift in the carbonyl frequency by infra-red spectroscopy. A product mixture was produced which consisted of N-(n-propyl)-isohexadecamide. The produce mixture was washed with water (2×200 ml), 6M hydrochloric acid (4×100 ml), water (100 ml), saturated aqueous sodium bicarbonate (1×100 ml), saturated aqueous sodium chloride (1×100 ml) and dried over MgSO4 before being filtered and rotary evaporated to yield a yellow oil (22.4 g, 96.5%). Infra-red spectroscopy (liquid film) detected absorption peaks at 3280 cm-1 (broad, strong), 3080 cm-1 strong, 1630 cm-1 (strong) and 1540 cm-1 (strong).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C(=O)=O.CC(C)=O.C(O[C:20](=[O:30])[NH:21][C@H:22]([C:25]([CH:27]1[CH2:29][CH2:28]1)=[O:26])[CH2:23][CH3:24])(C)(C)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH:27]1([C@@:25]2([OH:26])[C@H:22]([CH2:23][CH3:24])[NH:21][C:20](=[O:30])[CH2:1]2)[CH2:28][CH2:29]1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)C1CC1
Reactant: CC(C)NC(C)C
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC[C@@H]1NC(=O)C[C@@]1(O)C1CC1
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
A solution of diisopropylamine (7.28 g) in tetrahydrofuran (110 mL) was ice-cooled under a nitrogen atmosphere, and 1.6 mol/L n-butyllithium-hexane solution (44.1 mL) was added. The mixture was stirred at the same temperature for 20 min, and the reaction solution was cooled with dry ice/acetone. Ethyl acetate (6.96 mL) was added to the reaction solution, the mixture was stirred at the same temperature for 1 hr, and a solution of tert-butyl[(1S)-1-(cyclopropylcarbonyl)propyl]carbamate (10.7 g) in tetrahydrofuran (60 mL) was added. The mixture was stirred at the same temperature for 5 hr, saturated aqueous ammonium chloride solution (300 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=5→25%), the obtained oil was dissolved in 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (300 mL), and diisopropylethylamine (22.7 mL) was added. The reaction solution was refluxed under heating for 4 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/ethyl acetate=3→10%), and the obtained solid was recrystallized from ethyl acetate/diethyl ether/hexane to give the title compound as colorless crystals (yield: 2.80 g, 39%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:17].ClC(Cl)C>C(O)(C)(C)C>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:17][C:16]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([CH3:13])[CH:15]=1
Reactant: Cc1cc(N)ccc1Oc1ccccc1
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc(Nc2ncnc3ccc(I)cc23)ccc1Oc1ccccc1
Temperature: 90 °C

Procedure:
The 4-chloro-6-iodo-quinazoline (5.0 g, 17.2 mmol) and the 3-methyl-4-phenoxyaniline (17.2 mmol) were mixed together in 1:1 dichloroethane and t-butanol (50 ml). The reaction mixture was heated at 90° C. for 4 hours whereupon a yellow precipitate was observed. The reaction was cooled down and the precipitate was collected and afforded (6-iodo-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine. (8.0 g, 94%). M/z, 454. 1H NMR (CD3OD): δ: 9.12(s, 1H), 8.83(s, 1H), 8.39 (d, 1H, J=8.8 Hz), 7.63(d, 1H, J=8.8 Hz), 7.55 (d, 1H, J=2.1 Hz), 7.35(dd,1H, J1=J2=8.5 Hz), 7.28(t, 2H, J=8.1 Hz, ), 7.05 (t, J=8.5 Hz), 6.87(d, 1H, J=8.1 Hz), 3.81 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN1CCOCC1>C(Cl)Cl>[CH2:33]([O:40][NH:41][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)=[CH:19][CH:18]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h

Procedure:
A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzoic acid (which was obtained in Example 150) (1.58 g, 6 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) and O-benzylhydroxyamine hydrochloride (1.05 g, 6.6 mmol) was stirred in methylene chloride (150 mL). N-methylmorpholine (1.82 g, 18 mol) was added dropwise and the mixture was stirred overnight. The mixture was then washed with 0.05 N hydrochloric acid and water. The resulting solution was dried with magnesium sulfate and concentrated. The residue was crystallized from methylene chloride/hexanes to give the title compound as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.67 (t, J=5.6 Hz, 4H), 3.42 (t, J=5.6 Hz, 4H), 3.91 (s, 4H), 4.89 (s, 2H), 6.97 (d, J=9.0 Hz, 2H), 7.30-7.50 (m, 5H), 7.62 (d, J=9.0 Hz, 2H); MS (ES) m/z: 369.3 (MH+); HRMS Calcd. for C21H24N2O4 (M+): 368.1736. Found: 368.1744.
Reaction SMILES: [C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:7](O)=[O:8])(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl>[C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:6][C:7]([N:46]1[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]1)=[O:8])(=[O:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)N1CCN(C)CC1)SC(C)=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]-carbonyl]heptanoic acid (E5, Isomer A; 226 mg, 0.5 mmol), N,N1 -dicyclohexylcarbodiimide (103 mg, 0.5 mmol), 1-hydroxybenzotriazole (76 mg, 0.5 mmol) and N-methylpiperazine (0.05 ml, 0.5 mmol) in dichloromethane (8 ml) was stirred at 5° C. for 1 h, then at room temperature overnight. After cooling, the precipitated solid was filtered off. The solution was diluted with dichloromethane and extracted with 0.25M citric acid. The extracts were washed with dichloromethane then basified with 10% sodium carbonate, and extracted with ether. The ether extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. Trituration of the oily residue with ether, followed by recrystallisation of the resulting solid from ethyl acetate/hexane gave the title compound as a single isomer (Isomer A), 98 mg (37%) mp 133°-138° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].Cl[C:38]1N=C(N2CCOC[C@@H]2C)C2CCN(C)CC=2N=1.CC1C=C(C=CC=1B1OC(C)(C)C(C)(C)O1)N>>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][C:16]=3[N:17]=2)=[C:10]([CH3:38])[CH:11]=1)=[O:36])[CH3:2]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C)C2
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: Cc1cc(N)ccc1B1OC(C)(C)C(C)(C)O1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C)C3)c(C)c1

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 13) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by triturating with a (9:1) mixture of petrol ether (40-60)/ethyl acetate, yielding the title compound after filtration and drying of the solid obtained (85 mg, 0.24 mmol, 68%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19]C)[OH:12])[CH3:4].[Cl:21]CCl.[OH-].[Na+].C([Al]CC(C)C)C(C)C>CCOCC>[ClH:21].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[OH:12])[CH3:2]
Reactant: ClCCl
Reactant: COc1ccccc1C1(O)CCCCC1CN(C)C
Agent: CC(C)C[Al]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: CN(C)CC1CCCCC1(O)c1ccccc1O

Procedure:
Starting from (RS)-2-dimethylaminomethyl-cyclohexanone and 1-bromo-2-methoxy-benzene, (1RS,2RS)-2-dimethylaminomethyl-1-(2-methoxy-phenyl)-cyclohexanol hydrochloride (30) was obtained, under the conditions given in Example 1 (1st step) and using ether as a solvent, in a yield of 47%. The base was released from (30) with dichloromethane/sodium hydroxide solution. After drying the solution, the dichloromethane was distilled off under vacuum. 30.0 g (0.1 mole) of the base were reacted with diisobutylaluminium as in Example 2. 22.7 g (78% theoretical) (1RS,2RS)-2-(2-dimethylaminomethyl-1-hydroxy-cyclo-hexyl-phenol hydrochloride (31) were obtained, with a melting point of 168°-170° C. 28.6 g (0.1 mole) of compound (31) were reacted with 450 ml of concentrated formic acid as in Example 5. The crude base obtained was introduced on to a column packed with silica gel and eluted with 7:1 diisopropyl ether/methanol. 21 g base were obtained, from which 18.6 g (69% theoretical) of hydrochloride (29), which had a melting point of 168° C., was obtained with concentrated hydrochloric acid in acetone.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:12]=1)(C)(C)C.[ClH:28].C(O)(C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl>[ClH:28].[NH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:12]=1
Reactant: Cc1cccc(Nc2nccc(-c3ccc(NC(=O)OC(C)(C)C)s3)n2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(Nc2nccc(-c3ccc(N)s3)n2)c1

Procedure:
[5-(2-m-Tolylamino-pyrimidin-4-yl)-thiophen-2-yl]-carbamic acid tert-butyl ester was treated with 4 N HCl in 1,4-dioxane for 6 hours or 20% TFA in DCM for 2 hours. The solution was dried in vacuo to afford [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine HCl salt. The amine salt was also neutralized by drying down the HCl/dioxane solution, redissolving in EtOAc and washing with saturated NaHCO3 (2×) and brine (1×) and dried over Na2SO4. Concentrated and redissolved and dried down 2× from DCM to obtain an orange foam [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine (quantitative). MS: m/z 283 (M+H+).