Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C1COCC1>[N:36]1([C:33]2[CH:32]=[CH:31][C:30]([NH:29][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[S:24][CH:25]=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:28])=[CH:35][CH:34]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CNc1ccc(N2CCOCC2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 100 mg, 0.256 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (55 mg, 0.3086 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 82% yield (0.116 g, 0.2107 mmol).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1>>[Cl:38][C:39]1[CH:44]=[C:43]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N4CCCCC4)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 5, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 2) and 3-chlorophenylboronic acid to afford the desired product as a colorless foam (54%). MS (ISP): 641.5 (M+H)+.
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6](OCC)=[O:7])=O.Cl.[NH2:16][NH2:17]>C(O)C.O.Cl>[CH2:13]([O:12][C:2]([C:3]1[NH:16][N:17]=[C:6]([OH:7])[CH:4]=1)=[O:11])[CH3:14]
Reactant: NN
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(O)n[nH]1
Temperature: 80 °C

Procedure:
To a solution of 5 g Diethyl Oxalacetate sodium salt in 100 ml ethanol, 1.5 g hydrazine monohydrochloride were added and the reaction mixture was heated to 80° C. for 3 h. Then the solution was diluted with 100 ml of water containing 3 ml of halfconcentrated HCl and extracted with DCM (3×100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was subjected to the next reaction step without further purification; Yield: 3.4 g
Reaction SMILES: OS(O)(=O)=O.[OH:6][CH2:7][CH:8]1[CH:13]2[CH2:14][CH:10]([CH2:11][CH2:12]2)[CH:9]1[CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C([O-])(O)=[O:25].[Na+]>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6].O.CC(O)C>[C:7]([CH:8]1[CH:13]2[CH2:14][CH:10]([CH2:11][CH2:12]2)[CH:9]1[CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])([OH:25])=[O:6]
Reactant: O=C([O-])O
Reactant: COC(=O)CCCC=CC1C2CCC(C2)C1CO
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)CCCC=CC1C2CCC(C2)C1C(=O)O
Temperature: -20 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
14.5 ml of Jones solution (26.7 g of chromium trioxide and 23 ml of concentrated H2SO4 made up to 100 ml with water) are allowed to run into a solution of 1.2 g (5 mmol) of methyl 6-(3-hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-hex-5-enoate in 250 ml of absolute acetone at -20° C. The mixture is stirred at -20° C. for 3 hours and 40 ml of 2-propanol, followed by 30 ml of water, are then added and the pH is brought to 4 with solid NaHCO3. The precipitate is decanted off, the solution is evaporated in vacuo and the residue is extracted 3 times with ethyl acetate. After the ethyl acetate phase has been dried over sodium sulphate, it is evaporated in vacuo and the methyl 6-(3-carboxybicyclo[2.2.1]hept-2-yl)-hex-5-enoate is purified as described under (a). 1.0 g (yield: 75%).
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([CH2:7][NH2:8])[C:5]([CH3:10])([CH3:9])[CH2:4][CH:3]1[CH3:11].[CH3:12][C:13]1[O:19]C(C)(C)[O:17][C:15](=O)[CH:14]=1>C1(C)C(C)=CC=CC=1>[C:15]([NH:1][CH:2]1[CH:3]([CH3:11])[CH2:4][C:5]([CH3:10])([CH3:9])[CH:6]1[CH2:7][NH:8][C:15](=[O:17])[CH2:14][C:13]([CH3:12])=[O:19])(=[O:17])[CH2:14][C:13]([CH3:12])=[O:19]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CC1CC(C)(C)C(CN)C1N
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)NCC1C(NC(=O)CC(C)=O)C(C)CC1(C)C
Temperature: 113 °C
Yield: 89.3 %

Procedure:
To 5-amino-2,2,4-trimethylcyclopentylmethylamine (127.72 g, 0.819 mol) in xylene (525 ml) at 122° C. was added with stirring 2,2,6-trimethyl-1,3-dioxen-4-one (232.51 g, 1.637 mol) in xylene (525 mol) over 10 minutes, during which the temperature decreased to 104° C. After heating to 113° C. over 5 minutes, vigorous effervescence and distillation of acetone (through a Vigreux column) commenced. Pot temperature was increased to 127° C. over 5 minutes and to 140° C. over a further 30 minutes, with collection of acetone distillate. After cooling to 39° C., dichloromethane was added, and removal of solvent and drying (93° C./100 Pa) gave 1-acetoacetamido-2-acetoacetamidomethyl-3,3,5-trimethylcyclopentane (237.03 g, 89%), (AAMTCP), which was crushed to a light yellow powder, mp 94-114° C. (mixture of stereoisomers), and identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].O.[Cl-].[Na+]>N1C=CC=CC=1>[C:13]([O:1][CH:2]1[C:10]2[C:5](=[C:6]([C:11]#[N:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:15])[CH3:14]
Reactant: N#Cc1cccc2c1CCC2O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1CCc2c(C#N)cccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
3.89 g of (RS) 1-hydroxy-4-indanecarbonitrile in 39 ml of pyridine is cooled to 0° C., 3.45 ml of acetic anhydride is added drop by drop, and the whole is agitated for 16 hours at 20° C. The reaction mixture is poured into 300 ml of water containing sodium chloride and extracted with isopropyl ether; the ethereal phase is washed with 2N hydrochloric acid and then with water until pH 7 is obtained. The ethereal phase is dried and brought to dryness, and the residue is taken up in 1,2-dichloroethane, and again concentrated to dryness under reduced pressure. The residue is taken up in 40 ml of hexane, agitated for one hour, filtered, and 4.46 g of expected product is recovered. M.p.=65° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[Cl:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12]([F:32])=[C:13]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH2:27][CH2:28][CH2:29][Cl:30])[C:21]=2[F:31])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]>C(Cl)Cl>[Cl:30][CH2:29][CH2:28][CH:27]([C:22]1[C:21]([F:31])=[C:20]([C:18]([C:13]2[CH:14]=[CH:15][C:16]([F:17])=[C:11]([CH:10]([S:3][C:2]([F:6])([F:5])[F:1])[CH2:9][CH2:8][Cl:7])[C:12]=2[F:32])=[O:19])[CH:25]=[CH:24][C:23]=1[F:26])[S:3][C:2]([F:6])([F:5])[F:1]
Reactant: FC(F)(F)SCl
Reactant: O=C(c1ccc(F)c(CCCCl)c1F)c1ccc(F)c(CCCCl)c1F
Solvent: ClCCl
Product: O=C(c1ccc(F)c(C(CCCl)SC(F)(F)F)c1F)c1ccc(F)c(C(CCCl)SC(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 108 h
Yield: 51.9 %

Procedure:
75 g (0.55 mol) of trifluoromethylsulphenyl chloride are added at 20 to 25° C. with stirring to a solution of 43 g (0.2 mol) of 3-chloropropyl-2,4-difluorophenyl ketone in 100 ml of methylene chloride. The mixture is stirred at room temperature for 108 hours and then concentrated by stripping off the solvent under reduced pressure. 63 g of (3-chloro-1-trifluoromethylmercapto-propyl)-2,4-difluorophenyl ketone are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]#[C:25][Si](CC)(CC)CC)[CH:23]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C.[N:59]([CH2:62][CH2:63][N:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1)=[N+:60]=[N-:61]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]4[N:61]=[N:60][N:59]([CH2:62][CH2:63][N:64]5[CH2:65][CH2:66][O:67][CH2:68][CH2:69]5)[CH:25]=4)[CH:23]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: [N-]=[N+]=NCCN1CCOCC1
Reactant: CC[Si](C#Cc1cncc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)c1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3cn(CCN4CCOCC4)nn3)c2)c2cccnc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 471 mg (0.994 mmol) 2-(5-chloro-2-fluoro-phenyl)-4-(5-triethylsilanylethynyl-pyridin-3-yl)-[1,8]naphthyridine in 6 ml THF was treated with 1.19 ml of a 1 M solution of tetra-n-butylammonium fluoride in THF and stirred for 1 hour at room temperature. Then 276 μl (1.99 mmol) triethylamine, 190 mg (1.21 mmol) 4-(2-azido-ethyl)-morpholine and 9.5 mg (0.05 mmol) cuprous iodide were added. The reaction mixture was stirred for 66 hours at 70° C. The reaction mixture was cooled to room temperature and partitioned between ethylacetate and brine. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-(5-chloro-2-fluoro-phenyl)-4-{5-[1-(2-morpholin-4-yl-ethyl)-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-[1,8]naphthyridine as colourless solid; HPLC-MS: 1.50 min, [M+H] 516.
Reaction SMILES: [ClH:1].Cl.[Cl:3]C1C=C([CH:10]([C:27]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)C=CC=1.[Cl:34][C:35]1[CH:36]=[C:37](C(C2(O)CCCCC2)CN2CCNCC2)[CH:38]=[CH:39][CH:40]=1.C1(C(C)C=O)C=CC=CC=1.Cl>>[ClH:3].[ClH:34].[Cl:1][C:35]1[CH:40]=[C:39]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][C:27]2([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:14][CH2:13]2)[OH:33])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(CN1CCN(CC(c2cccc(Cl)c2)C2(O)CCCCC2)CC1)c1ccccc1
Reactant: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCCC1
Agent: CC(C=O)c1ccccc1
Agent: Cl
Product: CC(CN1CCN(CCC2(O)CCCCC2c2cccc(Cl)c2)CC1)c1ccccc1

Procedure:
In an analogous manner to Example 117, 1-{1-(3-chlorophenyl)-2-[4-(2-phenylpropyl)piperazin-1-yl]ethyl}cyclohexanol dihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol (see Example 1) and 2-phenylpropionaldehyde. MS (ESI) m/z 441/443 ([M+H]+); HRMS: calcd for C27H37ClN2O.2.00 HCl, 512.2128; found (ESI), 441.2662.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:8][CH2:7]1
Reactant: COc1ccccc1N1CCN(CC#CCN)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1N1CCN(C/C=C/CN)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.1 %

Procedure:
A solution of 1-amino-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-butyne (13.4 g) in tetrahydrofuran (150 ml) was added dropwise over 45 mins to a suspension of lithium aluminum hydride (3.91 g) in tetrahydrofuran (500 ml), while the reaction temperature was maintained below 5° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 20 hrs. Water (3.9 ml), 15% aqueous sodium hydroxide (3.9 ml) and water (12 ml) were added sequentially, while the reaction temperature was kept below 30° C. The precipitate was filtered through a bed of celite, washed three times with diethyl ether (100 ml), filtered, and the filtrate was concentrated. Recrystallization of the residue from hexane gave 7.31 g (54%) of product, mp 63°-67° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:21][N:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNCc1ccccc1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(N(C)Cc3ccccc3)c2)c1
Temperature: 180 °C
Yield: 66 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 1.0 g, 0.0036 mol) and N-methylbenzylamine (20 mL) was heated at 180° C. for 24 hours. The excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 0.88 g (66% yield) of product as a yellow oil: Anal. Calc'd. for C24H24N4: C, 78.23; H, 6.56; N, 15.20. Found: C, 78.55; H, 6.51; N, 15.21.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:25][CH2:26][C:27]2[C:32]([N+:33]([O-])=O)=[CH:31][N:30]=[C:29]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:28]=2)[CH2:8][CH2:9][C:10]([N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:43]#[C:44]Br>C(O)C.C1COCC1.[Pd]>[NH2:43][C:44]1[N:25]([C@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9][C:10]([N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:11])[CH2:26][C:27]2[CH:28]=[C:29]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:30]=[CH:31][C:32]=2[N:33]=1
Reactant: O=C(CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1)N(Cc1nnn[nH]1)C1CCCCC1
Reactant: N#CBr
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1=Nc2cnc(Oc3ccccc3)cc2CN1[C@@H](CCC(=O)N(Cc1nnn[nH]1)C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(S),N-dicyclohexy-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-N-(1H-tetrazol-5-ylmethyl)-butyramide (0.75 g, 1.3 mmole) in ethanol (30 mL) and THF (20 mL) was added palladium on carbon (10%, 0.48 g). The reaction mixture was hydrogenated for 1 hour at 20 psi. The reaction mixture was then filtered. Cyanogen bromide (3 M in dichloromethane, 0.65 ml, 1.9 mmole) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the resulting residue was purified by reverse phase HPLC to yield 4-{[4-(2-amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-4-(S),N-dicyclohexyl-N-(1H-tetrazol-5-ylmethyl)-butyramide as a white solid, as its corresponding TFA salt.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](S(C)(=O)=O)=[N:9][C:8]=2[C:7]([C:20]#[N:21])=[C:6]1[N:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1.[CH3:41][Mg]Br.C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:41])=[N:9][C:8]=2[C:7]([C:20]#[N:21])=[C:6]1[N:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1
Reactant: Cn1c(S(C)(=O)=O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (890 mg) in tetrahydrofuran (2 ml) was cooled to 0° C. and a 3M methylmagnesium bromide/diethyl ether solution (333 μl) was added dropwise thereto. After 30 minutes, the reaction solution was warmed to room temperature and stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (64 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([N:29]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][C:31]([OH:33])=[O:32])[CH2:12][N:13]([CH2:18][CH2:19][N:20]([CH2:25][C:26]([OH:28])=[O:27])[CH2:21][C:22]([OH:24])=[O:23])[CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.[C:38](Cl)(Cl)=[S:39].C(Cl)(Cl)Cl>O>[C:31]([CH2:30][N:29]([CH2:34][C:35]([OH:37])=[O:36])[CH:11]([CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:38]=[S:39])=[CH:3][CH:4]=1)[CH2:12][N:13]([CH2:18][CH2:19][N:20]([CH2:21][C:22]([OH:24])=[O:23])[CH2:25][C:26]([OH:28])=[O:27])[CH2:14][C:15]([OH:17])=[O:16])([OH:33])=[O:32]
Reactant: Nc1ccc(CCCC(CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O)cc1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CN(CCN(CC(=O)O)CC(CCCc1ccc(N=C=S)cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 6b (10.2 mg, 0.0152 mmol) in water (100 μL) was added dropwise 1M thiophosgene in CHCl3 (18.2 μL, 0.0182 mmol). The resulting mixture was stirred at room temperature for 3 h. The aqueous layer was concentrated in vacuo to provide pure 7b (10 mg, 97%) as a light yellowish solid. 1H NMR (MeOD, 300 MHz) δ 2.40-4.51 (m, 28H), 7.05-7.70 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-].O.Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2ncccc2F)c(F)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ncccc2F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a mixture of methyl 2-chloro-4-fluoro-5-(3-fluoropyridin-2-yl)benzoate (Preparation 36, 240 mg, 0.85 mmol) in ethanol (5 mL) was added 2M LiOH in water (2.1 mL, 4.23 mmol). The reaction was stirred at room temperature for 1 hour before neutralising with 2M HCl (aq). The resulting precipitate was collected, washed with water and dried to afford the title compound as a white solid (160 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1)(=[O:24])=[O:23]
Reactant: Nc1nc(-c2ccc(Cl)s2)cs1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: O=S(=O)(Nc1nc(-c2ccc(Cl)s2)cs1)c1c(Cl)cc(Cl)cc1Cl

Procedure:
The title compound was prepared from 4-(5-chloro-2-thienyl)-1,3-thiazol-2-amine and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (24.0 mg) with purity >90%. MS (pos) m/z 461.0, 463.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30](Cl)(=[O:33])[CH2:31]C>>[C:30]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:33])[CH3:31]
Reactant: CCC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)C3)cc1

Procedure:
Compound dr was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with propionyl chloride. LC-MS: m/z=+439 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)([CH3:4])[CH3:3].C(N1C=C(B2OC(C)(C)C(C)(C)O2)[C:32]([C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-])=O)=[CH:46][CH:45]=2)=[N:31]1)C>>[CH3:4][C:2]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[C:8]([C:45]2[CH:46]=[CH:47][N:50]=[C:32]3[NH:31][CH:48]=[CH:49][C:44]=23)[CH:7]=[N:6]1)([CH3:3])[CH3:1]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)n1ncc(B2OC(C)(C)C(C)(C)O2)c1-c1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)n1ncc(-c2ccnc3[nH]ccc23)c1-c1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure described for Intermediate 6 with 1-(1,1-dimethylethyl)-5-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, provided the title compound. ESMS [M+H]+: 362.2
Reaction SMILES: [ClH:1].[CH:2]1[C:14]2[CH:13]([CH2:15][CH2:16][N:17]([CH3:23])[CH2:18][CH2:19][C:20]([Cl:22])=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[F:31].C([O-])([O-])=O.[K+].[K+].Cl>CO.C(OCC)C.ClCCl>[ClH:22].[ClH:1].[F:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][N:35]([C:20](=[O:21])[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:6]4[C:14]3=[CH:2][CH:3]=[CH:4][CH:5]=4)[CH3:23])[CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: Fc1ccc(N2CCNCC2)cc1F
Reactant: CN(CCC(=O)Cl)CCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CN(CCC(=O)N1CCN(c2ccc(F)c(F)c2)CC1)CCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A mixture of 3-{[2-(9H-fluoren-9-yl)-ethyl]-methyl-amino}-propionic acid chloride hydrochloride (1.14 g), 4-(3,4-Difluoro-phenyl)-piperazine (587 mg), dichloromethane (25 ml) and 1 M aq. K2CO3 (25 ml) is stirred at room temperature for 1 hour. The phases are separated, the organic phase dried over sodium sulfate, filtered and evaporated. Purification by chromatography on silicagel (EtOAc/MeOH 7:3) afforded 1.2 g (100%) of a slightly colored oil. It is dissolved in 4 ml MeOH and acidified with 6 ml 1 M HCl in diethyl ether. More ether is added until the solution gets cloudy (ca. 3 ml). Crystallization at 5° afford 1.01 g (74%) of the desired product as dihydrochloride. M.p. 144°-154°. Anal: Calculated. for C29H33Cl2F2N3O.H2O: C, 61.48%; H, 6.22%; N, 7.41%. Found: C, 61.52%; H, 6.36%; N, 7.37%.