Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[NH2:53][CH2:54][C@H:55]([OH:58])[CH2:56][OH:57]>CN(C=O)C.CCOCC>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:53][CH2:54][C@H:55]([OH:58])[CH2:56][OH:57])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: NC[C@H](O)CO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC[C@H](O)CO)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.5 %

Procedure:
A solution of 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 23) (70 mg, 0.174 mmol) in DMF (2 mL) was treated with EDC (40.1 mg, 0.209 mmol), HOBT (32.0 mg, 0.209 mmol) and N-ethylmorpholine (0.066 mL, 0.523 mmol) and after 3 min with (S)-3-aminopropane-1,2-diol (15.89 mg, 0.174 mmol). The resulting mixture was stirred at room temperature for 5 h then further EDC (40.1 mg, 0.209 mmol), N-ethylmorpholine (0.066 mL, 0.523 mmol), HOBT (32.0 mg, 0.209 mmol) and (S)-3-aminopropane-1,2-diol (15.89 mg, 0.174 mmol) were added and the mixture stirred for 16 h before concentrating in vacuo. The residue was partitioned between water and EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with saturated aqueous NaHCO3 (×3) then brine, dried over MgSO4 and concentrated in vacuo. Trituration of the residue with Et2O gave 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N—((S)-2,3-dihydroxypropyl)benzamide (36 mg, 0.076 mmol, 43.5% yield) as a pale yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=O)[CH2:6][NH2:7].C[N:15](C)[CH:16]=[CH:17][C:18]#N.CC[O-].[Na+].[Na]>C(O)C>[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]1[C:17]([C:16]#[N:15])=[CH:18][NH:7][CH:6]=1
Reactant: NCC(=O)c1cccc(Cl)c1Cl
Reactant: CN(C)C=CC#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
20.0 g of 2,3-dichlorophenacylamine hydrochloride and 10.0 g of 3-dimethylaminoacrylonitrile are heated for 1 hour under reflux in 300 ml of ethanol. Then an ethanolic solution of sodium ethylate, prepared from 2.1 g of sodium and 30 ml of ethanol, is rapidly added dropwise and the reaction mixture is stirred for another 10 minutes under reflux. The reaction mixture is cooled to room temperature and then poured into ice/hydrochloric acid and the resultant mixture is stirred for 11/2 hours. The precipitate is isolated by filtration, washed with water and dried, affording 15.4 g (78% of theory) of title compound with a melting point of 152°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[C:27]([O:32][CH3:33])[CH:26]=2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[C:27]([O:32][CH3:33])[CH:26]=2
Reactant: COc1ccc2cc(CCl)cnc2c1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(Cc3c(O)nc(C)c4cc(OC)c(OC)cc34)cnc2c1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (200 mg, 912 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.95 mL, 1.90 mmol) at RT followed by 3-(chloromethyl)-7-methoxyquinoline hydrochloride MDE 32012 (245 mg, 1.00 mmol) and the mixture was stirred at 150° C. for 20 min under microwave irradiation. After cooling to RT, another portion of a 2 N aq. KOH solution (0.30 mL, 0.60 mmol) was added and the mixture was stirred at 150° C. for 20 min under microwave irradiation. After cooling to RT, the mixture was diluted with EtOAc (50 mL) and acidified by a 10% aqueous citric acid solution (5 mL) before neutralisation with a saturated aqueous NaHCO3 solution. The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7N NH3 in MeOH=100:0 to 94:6) gave 23 mg of 6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (4 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)-1-methylisoquinolin-3-ol dihydrochloride 29 as a brown solid (27 mg, 6% yield).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9](=S)[NH:10][CH3:11])[C:6]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.[I-].ClC1C=CC=C[N+]=1C.[N:31]#[C:32][NH2:33].[H-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:32]([NH:33][C:9]([C:7]1[C:6]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4][C:3]([CH2:20][F:21])([CH2:2][F:1])[CH:8]=1)=[N:10][CH3:11])#[N:31]
Reactant: N#CN
Reactant: CNC(=S)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: C[n+]1ccccc1Cl
Agent: [H-]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN=C(NC#N)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 25 %

Procedure:
A mixture of 84 mg of 2,2-bis(fluoromethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 140 mg of 2-chloro-1-methylpyridinium iodide, 0.06 ml of triethylamine and 2 ml of dried tetrahydrofuran was refluxed with heating for 2 hours. After the reaction solution was cooled to room temperature, 42 mg of cyanamide and 38 mg of sodium hydride (60%) were added therein and the resultant mixture was refluxed with heating for 4 hours. Ice water was added therein and the mixture was extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The obtained residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99). The resultant product was recrystallized by a mixed solvent of ethyl acetate and hexane to obtain 21.5 mg of N-cyano-2,2-bis(fluoromethyl)-N'-methyl-6-nitro-2H-1-benzopyran-4-amidine with a melting point of 259°-261° C.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].C(N(C(C)C)CC)(C)C.[CH2:18]([O:25][CH2:26]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl.C(OCC)(=O)C>[CH2:18]([O:25][CH2:26][O:8][CH2:7][C@H:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](C)CO
Reactant: ClCOCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](C)COCOCc1ccccc1
Reaction time: 1 h

Procedure:
Methyl (S)-(+)-2-methyl-3-hydroxypropionate (2.0 g; 16.9 mmole) and diisopropylethylamine (2.2 g; 17.1 mmole) were dissolved in dry dichloromethane (2 ml), and benzyloxymethyl chloride (2.7 g; 17.3 mmole) was dropwise added thereto, followed by stirring for 1 hour. 1N Hydrochloric acid (10 ml) and ethyl acetate (20 ml) were added thereto, and the aqueous layer was extracted with ethyl acetate. The extract was combined with the organic layer, washed with a sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give methyl (S)-3-benzyloxymethyloxy-2-methylpropionate.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Br:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:28])=[N:26][CH:27]=1>O1CCOCC1>[Br:21][C:22]1[C:23]([NH:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[N:24][C:25]([Cl:28])=[N:26][CH:27]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2Br)C1
Reaction time: 20 h
Yield: 66.7 %

Procedure:
(S)-(−)-1-Boc-3-aminopyrrolidine (0.817 g, 4.39 mmol) and triethylamine (1.22 mL, 8.78 mmol) were added to a solution of 5-bromo-2,4-dichloropyrimidine (1.00 g, 4.39 mmol) in dioxane (22 mL) at 10° C. After 20 hours at room temperature, the solution was concentrated, dissolved in CH2Cl2 (50 mL) and washed with 2 M aqueous K2CO3 (50 mL). The aqueous layer was further extracted with CH2Cl2 (50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (50% ethyl acetate/hexanes) to give the title compound as an oil (1.106 g, 67%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[NH:17][C:16]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=1[O:45][CH3:46]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]([CH2:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=2[O:45][CH3:46])[C:16]1=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Product: COC(=O)c1ccc(CN2C(=O)C(NCCCCCNC(=O)OC(C)(C)C)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Yield: 75 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 89 from 2 g of 3-[[5-(tert-butoxycarbonylamino)pentyl]amino]-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1.19 g of methyl 4-bromomethyl-3-methoxybenzoate. 2.06 g of the expected product are obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][NH:4][CH2:5][C@@H:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(CC)CC.[C:31](Cl)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].O>C(Cl)Cl>[C:17]([O:16][C:15]([NH:14][C@@H:6]([CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:5][N:4]([CH2:3][C:2]([F:22])([F:23])[F:1])[C:31](=[O:32])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:21])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CNCC(F)(F)F)CC1CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)CN(CC(F)(F)F)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 10.6 %

Procedure:
To a solution of tert-butyl (S)-1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-ylcarbamate (1.7 g, 5 mmol) and Et3N (2 mL, 15 mmol) in CH2Cl2 (20 mL) was added dropwise a solution of CbzCl (1.02 g, 6 mmol) in CH2Cl2 (10 mL) at 0° C. After stirring for an additional 2 h, water (30 mL) was added. The mixture was extracted with CH2Cl2 (2×20 mL), the organic layers were washed with brine, dried over MgSO4, and evaporated. The residue was purified by silica chromatography to obtain benzyl (S)-2-(t-butoxycarbonylamino)-3-cyclohexyl-propyl-2,2,2-trifluoroethylcarbamate (250 mg, yield 10% for 2 steps) as an oil. 1H NMR (CDCl3, 400 MHZ) δ 0.90 (m, 2 H), 1.25 (m, 4 H), 1.44 (s, 9 H), 1.70 (m, 7 H), 3.33 (m, 2 H), 3.85 (m, 3 H), 4.45 (brs, 1 H), 5.20 (s, 2 H), 7.36 (m, 5 H).
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:10][C:11]1[C:12]([NH2:21])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH3:9].[C:22]([CH:25]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:26](OCC)=[O:27])(=O)[CH3:23].C(OCC)(=O)C>CCCCCC>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:25]2[C:26](=[O:27])[C:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=[C:11]([O:10][CH2:7][CH2:8][CH3:9])[C:12]=3[NH:21][C:22]=2[CH3:23])=[CH:32][CH:33]=1
Reactant: CCCOc1cc2ccccc2cc1N
Reactant: CCOC(=O)C(C(C)=O)c1ccc(OC)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCCOc1cc2ccccc2c2c(=O)c(-c3ccc(OC)cc3)c(C)[nH]c12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 26.1 %

Procedure:
To a benzene solution (38 ml) containing 3-propoxynaphthalen-2-ylamine (600 mg, 2.98 mmol) and ethyl α-acetyl-4-methoxyphenylacetate (1.41 g, 5.96 mmol) was added 85 mg of Amberlyst 15 (Sigma-Aldrich). The resulting mixture was heated under reflux for 20 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, filtered to remove resin, and then the filtrate was concentrated under reduced pressure. Diphenyl ether (2.8 ml) was added to the residue, and the mixture was then heated with a mantle heater and stirred for 70 minutes under reflux. The resulting reaction mixture was cooled to room temperature, and then directly purified using silica gel column chromatography (dichloromethane:methanol=80:1→70:1). The purified product was concentrated under reduced pressure, giving an oily substance (800 mg, yield: 72%). Ethyl acetate and n-hexane were added to the thus-obtained oily substance to crystallize and then recrystallized from ethyl acetate, giving a pale yellow powder of 2-(4-methoxyphenyl)-3-methyl-5-propoxy-4H-benzo[f]quinolin-1-one (290 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][O:9][Si:14]([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
(3-Bromophenyl)methanol (5.0 g) was mixed with THF (60 ml), and TBSCl (5.0 g) and imidazole (3 g) were added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water and EtOAc were added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain [(3-bromobenzyl)oxy](tert-butyl)dimethylsilane (8.0 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:24][N:25]1[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]1>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([NH:30][C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)n1
Reactant: Cn1cc(N)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)Cc2cccc(Br)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (6-bromopyridin-2-yl)acetic acid (Example 235, Step 2) (30 mg, 0.39 mmol) in dimethylformamide (3 mL) was charged with carbonyldiimidazole (338 mg, 2.08 mmol) and maintained at room temperature for 1 hour. A solution of 1-methyl-1H-pyrazol-4-amine (175 mg, 1.81 mmol) in dimethylformamide (2 mL) was added and the reaction was stirred overnight at room temperature. The reaction was then directly purified by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to yield the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7](C)=[C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29](=[O:39])[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[S:27])=[CH:21][C:20]=3[F:40])[CH:10]=2)[N:5]=[CH:4]1)[CH3:2].FC1C=C(N)C=C[C:47]=1[O:48]C1C=CN=C2C=C(C3N=CN(CCOC)C=3)SC=12.COC1C=CC=CC=1CC(N=C=S)=O>>[F:40][C:20]1[CH:21]=[C:22]([NH:25][C:26]([NH:28][C:29](=[O:39])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])=[S:27])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[N:5]=[CH:4][N:3]([CH2:1][CH2:2][O:48][CH3:47])[CH:7]=3)[S:17][C:16]=12
Reactant: COCCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1C
Agent: COc1ccccc1CC(=O)N=C=S
Product: COCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1

Procedure:
Following the procedure described above for the compound 90 (scheme 17) but replacing the amine 89 with the amine 95 and using 2-(2-methoxyphenyl)acetyl isothiocyanate instead of 2-phenylacetyl isothiocyanate, title compound 96 was obtained as a beige solid (6 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.57 (1H, s), 11.77 (1H, s), 8.53 (1H, d, J=5.48 Hz), 8.08 (1H, d, J=12.03 Hz), 8.02 (1H, s), 7.91 (1H, s), 7.76 (1H, s), 7.59-7.52 (2H, m), 7.28-7.21 (2H, m), 6.98 (1H, d, J=8.22 Hz), 6.91 (1H, d, J=7.44 Hz), 6.71 (1H, d, J=5.67 Hz), 4.21 (2H, t, J=4.89 Hz), 3.80 (2H, s), 3.77 (3H, s), 3.65 (2H, t, J=4.89 Hz), 3.26 (3H, s). MS (m/z) 592.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Li+].[Li+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(O)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
To a solution of 2,5-dihydroxybenzaldehyde (10.41 g, 75.4 mmol) in 100 mL of DMF was added lithium carbonate (16.71 g, 226 mmol), followed by benzyl bromide (13.5 mL, 113 mmol). The solution was warmed to 60° C. and stirred for 30 hours. The reaction was poured into EtOAc and washed with water, saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown oil which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH2:12][CH2:13][N:14]=[N+:15]=[N-:16])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[N:14]([CH2:13][CH2:12][N:9]1[C:8]2[CH:17]=[CH:18][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[CH:10]1)=[N+:15]=[N-:16]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCN=[N+]=[N-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester (5.0 g, 0.0204 mol) in THF/water 1:1 (100 mL) was added with stirring LiOH (0.73 g, 0.0306 mol) and the mixture was stirred for 5 h at ambient temperature. The solvent was evaporated and to the residue was added ice water (100 mL). The pH of the reaction mixture was adjusted to 5 with 1N HCl and the mixture extracted with EtOAc (5×100 mL). The combined organic phases were washed with saturated brine solution (100 mL), dried (Na2SO4) and the solvent evaporated affording 4.2 g (89%) of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid as an ash coloured solid. MS-ESI m/z 232 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 3.8 (t, 2H), 4.5 (t, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 8.25 (s, 1H), 8.4 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[N:23][C:24]([NH:27][C:28]3[N:29]=[CH:30][C:31]4[CH:37]=[C:36](F)[C:35](=[O:39])[N:34]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[C:32]=4[N:33]=3)=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CCCCCC>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:22]=[N:23][C:24]([NH:27][C:28]3[N:29]=[CH:30][C:31]4[CH:37]=[C:36]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[C:35](=[O:39])[N:34]([CH:40]5[CH2:41][CH2:42][CH2:43][CH2:44]5)[C:32]=4[N:33]=3)=[CH:25][CH:26]=2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)CO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(F)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC(C)COc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 95 °C
Yield: 37 %

Procedure:
60% Sodium hydride in oil (0.182 g, 4.4 mmol) was washed with hexane and added to 2-methyl-1-propanol (10 ml). This mixture effervesced and formed a solution. To this solution was added 4-[6-(8-cyclopentyl-6-fluoro-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.225 g, 0.44 mmol, prepared as in Example 17) and the mixture was heated at 95° C. for 72 hours. The solvents were evaporated, and the residue was dissolved in diethyl ether then filtered. The filtrate was evaporated to provide 4-[6-(8-cyclopentyl-6-isobutoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a crystalline solid (0.092 g, 37%). MS (APCI) M++1: Calc'd, 564.3, Found 564.3.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]2[CH:12]3[CH2:13][CH2:14][CH:9]2[C:10](=O)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]2[CH:12]3[CH2:13][CH2:14][CH:9]2[C:10](=[N:23][OH:24])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC2CCC1C2=C(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: ON=C1CC2CCC1C2=C(c1ccccc1)c1ccccc1
Yield: 84.9 %

Procedure:
33.7 g (129 mmol) of 7-diphenylmethylenebicyclo[2.2.1]-heptane-2-one were stirred with 9.9 g (142 mmol) of hydroxylamine hydrochloride and 17.8 g (129 mmol) of potassium carbonate in 50 ml of ethanol at room temperature for four hours. Then 200 ml of water were added, and the mixture was extracted three times wit 100 ml of methylene chloride. The combined methylene chloride phases were washed three times with 300 ml of water, dried over sodium sulfate and concentrated in vacuo. 31.7 g of 7-diphenylmethylenebicyclo[2.2.1]heptane-2-one oxime were obtained as an amorphous solid. ##STR17##
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][C:5](=[CH2:15])[CH2:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:16]([O:1][CH2:2][C@@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][C:5](=[CH2:15])[CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: C=C1C[C@H](CO)[C@H](c2cccc(F)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C1C[C@H](COCc2ccccc2)[C@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a solution of 3-(S)-(hydroxymethyl)-4-(R)-(3-fluorophenyl)-1-methylenecyclopentane (3.11 g, 16.5 mmol) from Example 65, Step C in DMF (100 mL) was added benzyl bromide (4.24 g, 24.8 mmol) and then sodium hydride (60% in mineral oil, 0.73 g, 18.2 mmol) portionwise over 5 min. The reaction was stirred at rt for 16 h, then diluted with ether (100 mL) and quenched slowly into aq. sodium bicarbonate (200 mL). The layers were separated and the aqueous was extracted with ether. The organic layers were washed 3× with water, then brine, dried over sodium sulfate and concentrated. The residue (7 g) was purified by FC using 0.5-1% ethyl acetate in hexanes to afford the title compound (2.32 g).