Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]3[CH:9]([CH2:10][CH2:11][N:12](C)[CH2:13]3)[CH2:8][C:7](=[O:16])[C:6]=2[CH:17]=1.N#CBr>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:8][C:7](=[O:16])[C:6]=2[CH:17]=1
Reactant: CN1CCC2CC(=O)c3cc(F)ccc3C2C1
Agent: N#CBr
Solvent: ClC(Cl)Cl
Product: O=C1C[C@H]2CCNC[C@H]2c2ccc(F)cc21
Yield: 68.9 %

Procedure:
0.45 g (1.92 mmol) of 8-fluoro-2-methyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one was dissolved in 6 ml of anhydrous chloroform and added dropwise at room temperature over 15 minutes to a solution of 244 mg (2.3 mmol) of cyanogen bromide in 2 ml of anhydrous chloroform. Subsequently, the mixture was heated under reflux for a further 75 minutes, concentrated in a vacuum, taken up with 12 ml of 2N hydrochloric acid and heated under reflux over 6 hours. Subsequently, the mixture was made basic with 3N sodium hydroxide solution and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed once with 70 ml of saturated sodium chloride solution, dried (MgSO4) and concentrated in a vacuum. 0.29 g (69%) of cis-8-fluoro-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one was obtained as a yellow oil.
Reaction SMILES: OC1CCC(C)(C)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2.[CH3:27][C:28]1([CH3:52])[C:37]2[CH:36]=[CH:35][C:34]([C:38]#[C:39][C:40]3[CH:50]=[CH:49][C:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:42][CH:41]=3)=[CH:33][C:32]=2[C:31](=[O:51])[CH2:30][CH2:29]1>>[OH:51][CH:31]1[CH2:30][CH2:29][C:28]([CH3:27])([CH3:52])[C:37]2[CH:36]=[CH:35][C:34]([C:38]#[C:39][C:40]3[CH:41]=[CH:42][C:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:49][CH:50]=3)=[CH:33][C:32]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(O)CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9), 1 g (2.88 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound using 60 mg (1.6 mmol) of sodium borohydride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=1>CCOC(C)=O.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2F)CC1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-(2-fluoro-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (A27) (0.391 g, 1.20 mmol) in EtOAc (10 mL) was added 10% Pd/C (0.118 g) in EtOAc (1 mL) and the resulting suspension was stirred at 30° C. under a hydrogen atmosphere for 16 hours. The resulting mixture was filtered through Celite and the filtrate concentrated under reduced pressure to give the title compound A28 (0.339 g, 96%); 1H NMR (400 MHz, CDCl3) δ 6.94 (dd, J=8.3 Hz, 1H), 6.41 (dd, J=8.2, 2.4 Hz, 1H), 6.36 (dd, J=12.1, 2.3 Hz, 1H), 4.21 (brs, 2H), 3.65 (s, 2H), 2.84 (m, 3H), 1.75 (bd, J=13.3 Hz, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1)[CH3:2].[CH3:11][N:12]1[C@H:26]2[C@@H:16]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:27]=3[C:24]([CH2:25]2)=[CH:23][NH:22]4)[CH2:15][C:14](=O)[CH2:13]1>[Pd]>[CH3:11][N:12]1[C@H:26]2[C@@H:16]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:27]=3[C:24]([CH2:25]2)=[CH:23][NH:22]4)[CH2:15][CH:14]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=2)[CH2:13]1
Reactant: CCOc1ccc(N)cn1
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Pd]
Product: CCOc1ccc(NC2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cn1

Procedure:
The following compounds (isomers Ia and Ib) are obtained in a manner analogous to that described in Example 3, from 2-ethoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium:
Reaction SMILES: FC(S(O[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([NH:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:10]=1)(=O)=O)(F)F.O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C>[C:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][NH:23][C:11]1[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NCCNc1nc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C#N)cc2)n1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1nc(-c2ccc(C#N)cc2)cc(N2CCOCC2)n1
Temperature: 90 °C

Procedure:
2-({2-[(tert-butoxy)carbonylamino]ethyl}amino)-6-(4-cyanophenyl)pyrimidin-4-yl (trifluoromethyl)sulfonate (134 mg, 0.275 mmol) was dissolved in a 2M solution of morpholine in acetonitrile and the resulting solution heated to 90° C. for 18 h. The solution was cooled, water added and the suspension extracted thoroughly with ethyl acetate. Concentration of the combined organic layers gave a crude solid which was chromatographed (silica gel, 2% methanol/methylene chloride) to afford 234 mg of (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-6-morpholin-4-ylpyrimidin-2-yl]amino}ethyl)carboxamide as a off white solid. Removal of the tert-butoxy protecting group was accomplished in the following manner: the (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-6-morpholin-4-ylpyrimidin-2-yl]amino}ethyl)carboxamide produced as described above was dissolved in anhydrous hydrogen chloride in dioxane (2 mL of a 2M solution) and stirred at room temperature for 2 h. Concentration gave 134 mg of 4-{2-[(2-aminoethyl)amino]-6-imidazolyl-4-ylpyrimidin-4-yl}benzenecarbonitrile as its (2×) hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[NH:5][CH2:6][CH2:7][F:8].C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>>[F:12][C:11]1[CH:10]=[C:9]2[C:4](=[C:3]([O:13][CH3:14])[C:2]=1[F:1])[N:5]([CH2:6][CH2:7][F:8])[CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1c(NCCF)ccc(F)c1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(CCF)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of the whole (0.0022 mole) of the 3,4-difluoro-N-(2-fluoroethyl)-2-methoxyaniline prepared as described in step (C3) and 0.57 g (0.0026 mole) of diethyl ethoxymethylenemalonate was heated at 140°-150° C. for 6 hours, after which it was allowed to cool to room temperature. 2 ml of acetic anhydride and 1 ml of concentrated sulfuric acid were added in that order to the mixture, and it was then allowed to stand at room temperature. The reaction mixture was then poured into ice-water to precipitate crystals, which were collected by filtration to give 0.18 g of ethyl 6,7-difluoro-1-(2-fluoroethyl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (X, R9' =2-fluoroethyl) as colorless crystals.
Reaction SMILES: [BrH:1].N[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.N([O-])=O.[Na+]>O>[Br:1][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: Nc1ccc2c(C(F)(F)F)cc(=O)oc2c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1cc(C(F)(F)F)c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of 48% HBr (4.5 g, 26.7 mmol) (3 mL) containing 7-amino-4-trifluoromethylcoumarin (Aldrich) (2.0 g, 8.8 mmol) at -10° C. was added NaNO2 (670 mg in 1 mL of H2O) then Cu powder 35 mg was added. The reaction mixture was stirred at r.t. for 30 min., then heated to 100° C. for 30 min.. The reaction mixture was cooled to 0° C. and H2O (25 mL) was added. The mixture was extracted with EtOAc (400 mL) and the combined organic phase was washed with brine (200 mL) dried over MgSO4 and evaporated. The crude solid was purified by chromatography on silica gel using hexane:EtOAc 8:2 as eluent, to give 1.5 g (58%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:27])=[CH:16][CH:17]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:3]=1
Reactant: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccc(O)cc3)coc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccc(OC)cc3)coc2c1
Yield: 87.6 %

Procedure:
In 150 ml of acetone was dissolved 5.5 g of ethyl {[5-chloro-3-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl]oxy}acetate under heating, and 4.8 g of anhydrous potassium carbonate was added thereto. To the solution was added 3.4 ml of methyl iodide, followed by refluxing for 2 hours. After cooling, the solvent was removed by distillation under reduced pressure. Water was added to the residue, and the insoluble material was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethanol-chloroform to obtain 5.0 g of the entitled compound having a melting point of 121° to 122° C.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(NC3CCN(Cc4ccccc4)CC3)ccc12
Yield: 50.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (400 mg, 1.73 mmol) and 1-benzyl-piperidin-4-amine (1.31 mL, 6.94 mmol) to provide 457 (337 mg, 50% yield) as a white powder. LC-MS (M+H=385, obsd.=385).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[Cl:27][C:28]1[C:29]([CH3:41])=[N:30][N:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=2I)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:28]1[C:29]([CH3:41])=[N:30][N:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH2:26])[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16]3)[CH:32]=1
Reactant: Cc1cccc(-n2cc(Cl)c(C)n2)c1I
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-n2cc(Cl)c(C)n2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.150 g, 0.422 mmol, prepared as in Example 2, Step 1-2) and 4-chloro-1-(2-iodo-3-methylphenyl)-3-methyl-1H-pyrazole (0.281 g, 0.845 mmol) in dioxane (3 mL) and 2 M aqueous sodium carbonate (1.0 mL, 2.0 mmol). The vessel was capped with a septum and the solution was degassed by bubbling nitrogen gas through the solution for 10 min. Next, Pd (PPh3)4 (0.049 g, 0.042 mmol) was added and the vessel was sealed. The reaction mixture was stirred and heated in a microwave reactor at 140° C. for 15 min. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase preparative HPLC with 0.1% TFA in CH3CN/H2O, gradient 5-70% over 20 min to provide 6-(2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as a white solid. The purified compound was portioned between DCM and saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give 6-(2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as a white solid. MS (ESI, pos. ion) m/z: 434 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11].O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])=[O:8]
Reactant: CCNCC
Reactant: O=C(Cl)CCCCCBr
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)CCCCCBr
Yield: 95.3 %

Procedure:
A solution of 6-bromohexanoyl chloride (100 g, 468 mmol) in 350 ml of tetrahydrofuran was poured into a solution of diethylamine (1.08 moles, 79 g, 112 ml) in 800 ml of rapidly stirring water. The mixture was then extracted with 2×200 ml of CH2Cl2 and the pooled extracts were washed with 250 ml of brine. Drying over Na2SO4 and concentration under recuced pressure afforded 111.6 g (446 mmol, 100% yield) of product as a pale yellow oil: 1H NMR (Me2SO-d6, 300 MHz) δ3.5 (t, J=6.7 Hz, 2H), 3.2-3.3 (m, 4H), 2.3 (t, J=7.5 Hz, 2H), 1.8 (m, 2H), 1.3-1.6 (m, 4H), 1.1 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:41][CH2:40][CH2:39][CH:38]([NH2:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:41][CH2:40][CH2:39][CH:38]([NH:42][C:19]([C:16]2[S:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[O:22][C@H:23]4[CH2:27][CH2:26][O:25][CH2:24]4)[C:10]=3[C:17]=2[CH3:18])=[O:20])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Product: Cc1c(C(=O)NC2CCCN(C(=O)OC(C)(C)C)CC2)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12

Procedure:
Prepared analogously to example 1.4 from 4-{4-fluoro-2-[(S)-(tetrahydro-furan-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 4-amino-azepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][N:6]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[C:16]([NH2:22])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=1)#[N:26].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][N:6]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[C:16]([NH:22][C:35](=[O:36])[CH2:34][NH:33][C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Reactant: CNc1ccc(C(=O)N(CCC(=O)OC)c2ccccc2)cc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)N(CCC(=O)OC)c2ccccc2)cc1NC(=O)CNc1ccc(C#N)cc1

Procedure:
The product of 1b (23.2 mmol) and N-(4-cyano-phenyl)-glycine (23.2 mmol) were coupled with CDI (23.2 mmol) in dry THF at room temperature. After completion of the reaction the mixture was evaporated to dryness and the crude product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]([CH3:22])[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[CH:17]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1>O1CCCC1.ClCCl.CN=C=O>[CH3:22][N:21]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:18]([NH:19][CH3:20])=[O:25])=[CH:3][CH:4]=3)[CH2:15][CH2:14]2)=[CH:17][C:18](=[O:25])[N:19]([CH3:24])[C:20]1=[O:23]
Reactant: Cn1c(N2CCN(CCCOc3ccc(N)cc3)CC2)cc(=O)n(C)c1=O
Agent: CN=C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(OCCCN2CCN(c3cc(=O)n(C)c(=O)n3C)CC2)cc1
Reaction time: 20 h
Yield: 179.3 %

Procedure:
1.5 g of 6-[4-(3-[4-aminophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione obtained in Example 6 was dissolved in a mixed solvent of tetrahydorfuran/dichloromethane (15 ml/10 ml), and 0.26 ml of methyl isocyanate was added to the solution at room temperature, followed by stirring for 20 hours. The precipitated crystals were collected by filtration, and then washed with a small amount of cooled dichloromethane, thereby obtaining 1.55 g (yield: 90%) of 1,3-dimethyl-6-[4-(3-[4-(N'-methylureido)phenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]1[N:19]=[C:20]([CH3:23])[S:21][CH:22]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:19]=[C:20]([CH3:23])[S:21][CH:22]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2csc(C)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (772 mg, 5.4 mmol) was dissolved in anhydrous DMF (30 mL), then potassium carbonate (2.25 g, 16.3 mmol) and 4-(chloromethyl)-2-methyl-1,3-thiazole (1.50 g, 8.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 6-methyl-2-{[(2-methyl-1,3-thiazol-4-yl)methyl]sulfanyl}pyrimidin-4-ol (244 mg, 18% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 2.59 (s, 3H), 4.40 (s, 2H), 5.98 (bs, 1H), 7.36 (s, 1H); LRMS (ES+) m/z 254 (80%, M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:35])[CH:22]([C:26]2[C:31]([F:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[F:34])[O:23][CH2:24][CH3:25])=[CH:15][CH:14]=1)=[NH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:36])[NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:35])[CH:22]([C:26]2[C:31]([F:32])=[CH:30][C:29]([O:33][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:28][C:27]=2[F:34])[O:23][CH2:24][CH3:25])=[CH:15][CH:14]=1)=[NH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCN1CCOCC1
Reactant: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)cc(O)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)cc(OCCN2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 22.8 %

Procedure:
To a mixture of (RS)-[(4-{[2-(2,6-difluoro-4-hydroxy-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester (100 mg), N-(2-hydroxyethyl)morpholine (29 mg) and polymer bound triphenylphosphine (˜3 mmol/g, 167 mg) in CH2Cl2 (2 ml) was added di-tert-butyl azodicarboxylate (93 mg) before shaking 22 h at rt. After filtration of the polymer the solvent was evaporated and the residue was purified by HPLC to obtain 28 mg of (23%) (RS)-{[4-({2-[2,6-difluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-ethoxy-acetylamino}-methyl)-phenyl]-imino-methyl}-carbamic acid benzyl ester.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([N:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:15][CH:14]=[C:13]([C:11]([N:1]3[C@@H:10]4[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]4)[CH2:4][CH2:3][CH2:2]3)=[O:12])[CH:17]=2)[CH2:23][CH2:22]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 2 h
Yield: 44.7 %

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.04 g, 0.12 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (0.37 mmol). Methylsulphonyl chloride (0.25 mmol) was added and the mixture stirred for 2 hours and then the solvent removed by evaporation. The residue was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.022 g). LCMS m/z 411.11 min [M+H]+ RT=10.84 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 4.6 (m, 1H), 3.9-3.6 (m, 3H), 3.1-2.7 (m, 2H), 2.7 (s, 3H), 2.1-1.1 (m, 19H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C1C=C(Cl)C=C(C(OO)=[O:17])C=1>ClCCl>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:17])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccncc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc[n+]([O-])cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
To a solution of 3,4-dimethylpyridine (100.0 g, 0.93 mol) in dichloromethane was added m-CPBA (320.0 g, 1.87 mol) at the room temperature. The reaction mixture was stirred at room temperature overnight, and then quenched with saturated solution of Na2S2O3 (100 mL). The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to yield a residue that was purified by column chromatography on silica gel (10-100% MeOH in EtOAc) to give 3,4-dimethylpyridine 1-oxide (70.0 g, 61%).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[CH3:9][O:10][C:11](Cl)=[O:12]>C(OCC)C>[CH3:9][O:10][C:11]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:12]
Reactant: C[C@@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COC(=O)N[C@H](C)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of D-alanine (5 g, 56.1 mmol) in 1 N NaOH (152 mL, 152 mmol) at 0° C. is added a solution of MeOC(O)Cl (6.5 mL, 84.2 mmol) in diethyl ether (30 mL). The mixture is stirred in ice bath for 3 hours and then adjusted to pH 9 with 1 N NaOH. After stirring at room temperature for 1 hour, the mixture is washed with ether (3×50 mL), acidified to pH ˜2 with 5 N HCl, extracted with EtOAc (5×50 mL). The organic extract is washed with water, brine, and then dried (MgSO4). The solvent is removed to yield compound cxxxiv, N-methoxycarbonyl-D-alanine, as colorless oil (6.48 g, 79%).