Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Br:12]Br>CC(O)=O>[NH2:11][C:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]([Br:12])=[CH:8][N:9]=1
Reactant: BrBr
Reactant: COC(=O)c1nccnc1N
Solvent: CC(=O)O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
3-Aminopyrazine-2-carboxylic acid methyl ester (200 g, 1.3 mol, 3B Scientific Corporation) was dissolved in AcOH (1 L). The solution was warmed to 50° C. and Br2 (312 g, 1.9 mol) added dropwise. When the addition was completed, the mixture was stirred at 50° C. for additional 3 hours. The reaction mixture was poured slowly to ice-water (4 L). The precipitate was filtered, washed with water and dried under a reduced pressure to afford the subtitle compound (iii) as a red brown solid (300 g).
Reaction SMILES: [CH:1]1([C:4]2[NH:13][C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.[O:14]1CCOCC1.O>>[CH:1]1([C:4]2[NH:13][C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH:12]=[O:14])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccnc2[nH]c(C3CC3)nc12
Reactant: C1COCCO1
Solvent: O
Product: O=Cc1ccnc2[nH]c(C3CC3)nc12

Procedure:
2-Cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine (100 mg, 0.58 mmol; from EP0420237 A1) was treated with SeO2 (160 mg, 1.44 mmol) in 6 ml of dioxane:water (4:1) and subjected to microwave irradiation (300 W, normal absorbance) at 180° C. for three 20 min interyals. The mixture was subsequently treated with satd. aq. NaHCO3 (25 ml) and water (25 ml) and the solids were removed by filtration through Celite, rinsing with DCM. The filtrate was extracted with DCM (4×50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated to dryness to yield the crude title compound. MS (ESI+) for m/z 188 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Cl[C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:13]1[C:8]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC1CNC1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OC1CN(c2ncccc2C(F)(F)F)C1
Temperature: 50 °C
Reaction time: 12 h
Yield: 23.5 %

Procedure:
A suspension of azetidin-3-ol hydrochloride (500 mg), 2-chloro-3-(trifluoromethyl)pyridine (425 mg) and cesium carbonate (1.14 g) in DMF (5 ml) was stirred at 50° C. for 12 hr, and water was added. The reaction mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(S(C)(=O)=O)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a stirring solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (Example 149) (115 mg, 0.279 mmol) and NEt3 (43 μL, 0.307 mmol) in DMF (2 ml) was added methanesulfonyl chloride (24 μL, 0.307 mmol). Reation mixture was stirred at room temperature (20° C.) overnight before being concentrated in vacuo and purified by prep. HPLC at high pH to afford a white solid (75 mg, 55%).
Reaction SMILES: [ClH:1].[CH3:2][C@:3]([NH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=O.CSC.B>C1COCC1>[ClH:1].[ClH:1].[CH3:2][C@:3]([NH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][N:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: C[C@@](N)(C(=O)N1CCOCC1)c1ccccc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@](N)(CN1CCOCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0.2 %

Procedure:
Under an argon atmosphere 412 mg of (1S)-1-methyl-2-morpholin-4-yl-2-oxo-1-phenylethylamine hydrochloride (1.522 mol) were dissolved in 30 mL of dry THF. A 2 M solution of borane dimethylsulfide (4.4 mL, 5.78 mmol) was added dropwise at 0° C. and the mixture stirred for 10 minutes at 0° C. and then allowed to reach room temperature (gas evolution). After 4 hours the reaction was quenched with methanol (added very carefully) and diluted with methanol when effervescence ceased. THF was removed under vacuo and the methanolic solution was heated at 60° C. for 30 minutes. The solvent was at last completely removed recovering 330 mg of the amine that was subsequently dissolved in 15 mL of dioxane and treated with 1.35 mL of HCl 4 N in dioxane. After 1 hour the solvent was evaporated and the product was triturated with diethylether to yield 350 mg of the expected salt.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[C@H:5]1[S:22][CH2:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9].[SH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>C(#N)C.[Cl-].[Zn+2].[Cl-]>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[CH2:21][S:22][C@H:5]1[S:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Reactant: N#Cc1ccc(S)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2)SC[C@H]1OC(C)=O
Yield: 23 %

Procedure:
A suspension of 192 mg (0.44.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate, 71 mg (0.52.10-3 mol) of 4-mercaptobenzonitrile, 20 mg (0.15.10-3 mol) of zinc chloride and a 400 pm sieve in 2 ml of acetonitrile is stirred for 4 h under an inert atmosphere. The reaction mixture is then filtered on Celite® in ethyl acetate and subsequently washed with a 1N solution of sodium hydroxide, water and finally a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. After precipitation in ether, 42 mg (yield: 23%) of the expected product are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH:9]C(=O)OCC1C=CC=CC=1)([CH3:8])[CH3:7].[H][H]>[Pd].C(O)C>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]([NH2:9])([CH3:8])[CH3:7]
Reactant: [H][H]
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1ncco1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)C1=NCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
A mixture of benzyl 2-(oxazol-2-yl)propan-2-ylcarbamate (Example 8 d, 0.63 g) and palladium on carbon (10% w/w, 0.06 g) in ethanol (20 mL) was charged with hydrogen balloon and stirred at room temperature for 2 h. TLC showed the reaction was complete; it was filtered and concentrated to give the product as yellow oil (0.1 g, 33%); MS (EI): m/e=129.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[C:4]([CH3:9])[N:3]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)cc(C)n1
Product: Cc1cc(Cl)cc(C)n1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
2,6-dimethyl-4-hydroxypyridine (1 g) was added to phosphoryl chloride (5 mL). The solution was stirred at 100° C. for six hours. The reaction mixture was partitioned by adding water, a 5 N aqueous sodium hydroxide solution and ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.15 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[O:22]=[C:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=2)[NH:24]1>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:31]3\[C:23](=[O:22])[NH:24][C:25]4[C:30]\3=[CH:29][C:28]([NH:32][C:33](=[O:35])[CH3:34])=[CH:27][CH:26]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(NC(C)=O)cc43)c(C)c2C1=O
Yield: 18.9 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide 30d obtained from step 3 of Example 30 as starting materials to obtain (Z)—N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide 51 (12 mg, yield 18.9%) as an orange solid.
Reaction SMILES: [C:1]([CH:5]([N:10]([C:23](=[O:35])[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([CH3:32])=[C:26]([O:33][CH3:34])[CH:25]=1)[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH3:21])[CH2:6][CH2:7][CH2:8]C)([CH3:4])([CH3:3])[CH3:2].[C:36](OCC)(=O)C>CCCCCC>[C:1]([CH:5]([N:10]([C:23](=[O:35])[C:24]1[CH:25]=[C:26]([O:33][CH3:34])[C:27]([CH3:32])=[C:28]([O:30][CH3:31])[CH:29]=1)[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][CH3:36])[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(N(NC(=O)c1cccc(OC)c1C)C(=O)c1cc(OC)c(C)c(OC)c1)C(C)(C)C
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC(N(NC(=O)c1cccc(OC)c1CC)C(=O)c1cc(OC)c(C)c(OC)c1)C(C)(C)C

Procedure:
RG-115852, 3,5-dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-pentyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide. 1H NMR (CDCl3, 500 MHz), δ (ppm): 7.05 (t, 1H), 7.0 (s, 1H), 6.85 (d, 1H), 6.65 (s, 2H), 6.25 (d, 1H), 4.7 (d, 1H), 3.89 (s, 3H), 3.78 (s, 6H), 2.10 (s, 3H), 1.86 (s, 3H), 1.3-1.6 (br m, 6H), 1.06, 0.99 (2 s, 9H), 0.94 (t, 3H); TLC Rf=0.55 (1:1 ethyl acetate:hexane).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25]O>C(O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]2[O:25][CH:2]12
Reactant: C1=Cc2ccccc2C1
Reactant: OO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Product: c1ccc2c(c1)CC1OC21
Temperature: 25 °C
Yield: 19.4 %

Procedure:
To a mixture of indene (426 mg, 3.67 mmol), dicyclohexylcarbodiimide (150 mg, 0.73 mmol), hydrogen peroxide (1 mL of 30% aqueous, 9.8 mmol) and ethanol (5 mL) was added 10 mg of cation exchange resin (mild) beads. The reaction mixture was stirred at room temperature for twenty-four hours. Filtration removed the dicyclohexylurea and the resin beads. The filtrate was partitioned in a separatory funnel between ether (30 mL) and water (20 mL). Standard ethereal workup, followed by column chromatography on silica gel (elution with hexanes:ether, 10:1) afforded indene epoxide (94 mg, 98%).
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:20]1([CH3:23])[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)OC(C)(C)C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Reaction time: 4 h
Yield: 70.9 %

Procedure:
1.60 g of (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3yl]-acrylic acid tert-butyl ester (compound C1) are dissolved in 70 ml of dichloromethane at ambient temperature. Then 7 ml of trifluoroacetic acid (TFA) are added and stirred for 4 hours. The solvent is evaporated to dryness and to the residue are added 30 ml of water. The water phase is extracted exhaustively with ethyl acetate. Then the organic phase is dried over sodium sulfate. The filtrate is evaporated and dried under vacuo to give 0.951 g of the title compound as a pale grey solid.
Reaction SMILES: [CH2:1]([P:4]([CH:9]([P:34]([CH2:39][CH:40]=[CH2:41])([CH2:36][CH:37]=[CH2:38])=[O:35])[NH:10][C:11](=[O:33])[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:17])([CH2:6][CH:7]=[CH2:8])=[O:5])[CH:2]=[CH2:3].N1CCCCC1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([P:4]([CH:9]([P:34]([CH2:36][CH:37]=[CH2:38])([CH2:39][CH:40]=[CH2:41])=[O:35])[NH:10][C:11](=[O:33])[NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH2:6][CH:7]=[CH2:8])=[O:5])[CH:2]=[CH2:3]
Reactant: C=CCP(=O)(CC=C)C(NC(=O)NCCCC(=O)OCC1c2ccccc2-c2ccccc21)P(=O)(CC=C)CC=C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: C=CCP(=O)(CC=C)C(NC(=O)NCCCC(=O)O)P(=O)(CC=C)CC=C
Reaction time: 0.83 h
Yield: 105.8 %

Procedure:
Ester 152 (778 mg, 1.18 mmol) was treated with a 5% v/v solution of piperidine in DMF (6 mL). After stirring for 50 min, the reaction mixture was diluted with saturated NaHCO3 solution and washed once with Et2O. The aqueous layer was acidified to pH 2 with conc. HCl solution and extracted with a 4:1 mixture of CHCl3/i-PrOH (3×). The organic layers were combined, dried over MgSO4, filtered and concentrated to dryness, yielding acid 153 as yellowish oil (520 mg, 92%) which was used without purification. 1H NMR (400 MHz, CDCl3) δ 1.84 (quint, J=6.4 Hz, 2H), 2.35 (t, J=6.6 Hz, 2H), 3.26-3.29 (m, 2H), 4.52-4.67 (m, 8H), 5.04 (dt, J=22.2, 10.1 Hz, 1H), 5.20-5.27 (m, 4H), 5.30-5.40 (m, 4H), 5.751 (bs, 1H), 5.84-5.98 (m, 4H), 6.90 (d, J=10.3 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[C:10]([F:22])=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6].CCN(CC)CC>CCO>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[C:10]([F:22])=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(NS(=O)(=O)CCCCl)c1F
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cc([N+](=O)[O-])cc(N2CCCS2(=O)=O)c1F
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a solution of methyl 3-{[(3-chloropropyl)sulfonyl]amino}-2-fluoro-5-nitrobenzoate (D145) (300 mg, 0.85 mmol, 1 equiv) in EtOH (30 ml) was added NEt3 (280 μl, 2 mmol, 2.3 equiv) and the resulting solution was refluxed for 1.5 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with AcOEt/Et2O to give methyl 3-(1,1-dioxido-2-isothiazolidinyl)-2-fluoro-5-nitrobenzoate (D147) (150 mg, 55%) as a light tan solid which was used in the next step without further purification. [M+H+ NH3]+=336.3, RT=2.50 min.
Reaction SMILES: C([C@H:5]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:33])[CH:17]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28]([NH2:32])=[N:27][CH:26]=[CH:25]3)=[O:21])[CH3:18])[CH2:12][CH2:11]1)[C:6]([OH:8])=[O:7])(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:32][C:28]1[C:29]2[C:24](=[CH:23][C:22]([C:20]([NH:19][C@@H:17]([CH3:18])[C:16]([N:13]3[CH2:12][CH2:11][CH:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])[CH2:15][CH2:14]3)=[O:33])=[O:21])=[CH:31][CH:30]=2)[CH:25]=[CH:26][N:27]=1
Reactant: CC(NC(=O)c1ccc2c(N)nccc2c1)C(=O)N1CCC(O[C@H](C(=O)O)C(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1ccc2c(N)nccc2c1)C(=O)N1CCC(OCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 594 mg of tert-butyl (S)-[[1-(2-[[(1-amino-6-isoquinolinyl)carbonyl]amino]-1-oxopropyl)piperidin-4-yl]oxy]acetic acid in 8 mL of dioxane was added 3 mL 36% hydrochloric acid and stirred at room temperature for two hours. The solution was concentrated and trituration of the residue with diethyl ether yielded 560 mg of the title compound. HPLC Supelcosil LC-18-DB column using a gradient elution system of 20% A/80% B to 20% A/20% B/60% C over 40 min at a flow of 0.25 ml/min(A: 0.5M phosphate buffer pH 2.1, B: water, C acetonitril/water 3/2 v/v). Rt=22.4 min.
Reaction SMILES: C[O:2][C:3](=[O:32])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[N:21])=[C:14]([C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)[CH:13]=2)=[CH:8][CH:7]=1.O[Li].O>C1COCC1.O>[C:22]12([C:14]3[CH:13]=[C:12]([C:9]4[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]([OH:32])=[O:2])=[CH:11][CH:10]=4)[CH:17]=[CH:16][C:15]=3[O:18][CH2:19][C:20]#[N:21])[CH2:23][CH:24]3[CH2:25][CH:26]([CH2:27][CH:28]([CH2:30]3)[CH2:29]1)[CH2:31]2
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(OCC#N)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#CCOc1ccc(-c2ccc(/C=C/C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(E)-3-(3′-Adamantan-1-yl-4′-cyanomethoxybiphenyl-4-yl)-acrylic acid methyl ester (240 mg, 0.56 mmol) was added to a solution of LiOH.H2O (117 mg, 2.8 mmol) in 24 ml of THF:H2O 1:1. The solution thus obtained was kept under stirring at RT overnight. THF was removed under reduced pressure and the resulting aqueous layer acidified with 1N HCl to allow the formation of the title compound as a white precipitate that was filtered (216 mg, 93%).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]([Cl:15])=[C:13]2[C:8]([N:9]=[CH:10][CH:11]=[CH:12]2)=[N:7]1)C.[OH-].[Li+]>CO>[Cl:15][C:14]1[N:6]([CH2:5][C:4]([OH:16])=[O:3])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[N:9]2
Reactant: CCOC(=O)Cn1nc2ncccc2c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1nc2ncccc2c1Cl

Procedure:
(3-Chloro-pyrazolo[3,4-b]pyridin-2-yl)-acetic acid ethyl ester was treated with 1N lithium hydroxide (LiOH) (1 equiv) in 1 mL of MeOH to provide 2-(3-Chloro-pyrazolo[3,4-b]pyridine-2-yl)-acetic acid, which was used as directly in subsequent reactions without further purification: LCMS (ES) M+H 212.0, Rf 0.34 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[N:11]([O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[N:29][CH:30]=4)[C:7]=3[C:8]=2[CH3:20])[N:3]=1.C=O.[C:37](O)(=O)C.C([BH3-])#N.[Na+]>O>[CH3:37][N:24]([C:25]1[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[N:29][CH:30]=1)[CH:21]1[C:7]2[C:8]([CH3:20])=[C:9]3[C:4](=[CH:5][C:6]=2[CH2:23][CH2:22]1)[N:3]=[C:2]([CH3:1])[N:11]([O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])[C:10]3=[O:19]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(NC2CCc3cc4nc(C)n(OC(=O)C(C)(C)C)c(=O)c4c(C)c32)cn1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(N(C)C2CCc3cc4nc(C)n(OC(=O)C(C)(C)C)c(=O)c4c(C)c32)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 5-[-((6RS)-2-methyl-4-oxo-3-pivaloyloxy-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-pyridine-2-carboxylate (0.24 g), an aqueous solution of formaldehyde (37% weight/volume, 0.52 ml) and glacial acetic acid (5 ml) was stirred at ambient temperature for 30 minutes. Sodium cyanoborohydride (0.05 g) was added portionwise during 5 minutes and the mixture was stirred at ambient temperature for 30 minutes. The mixture was poured onto a mixture of ice and water (20 ml) and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using ethyl acetate as eluant. There was thus obtained methyl 5-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]pyridine-2-carboxylate as a gum (0.185 g);
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:9]=2[CH3:16])[S:4][C:3]=1[CH:17]1[O:21]CCO1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[O:29]C>>[F:22][C:23]1[CH:24]=[C:25]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=3[CH3:16])[S:4][C:3]=2[CH:17]=[O:21])[CH:26]=[CH:27][C:28]=1[OH:29]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)c(C)c1
Product: Cc1cc(O)ccc1-c1sc(C=O)c(-c2ccc(O)c(F)c2)c1C
Yield: 44.9 %

Procedure:
Starting from 2-[3-bromo-5-(4-methoxy-2-methylphenyl)-4-methylthien-2-yl]-1,3-dioxolane (0.96 g, 2.6 mmol, made in Example 11, Step 1) and substituting 3-fluoro-4-methoxyphenylboronic acid (0.57 g, 3.4 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.40 g, 67%) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](O)=[O:40])[CH:34]=1)C1C=CC=CC=1.[NH2:42][CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>>[N:46]1([CH2:45][CH2:44][CH2:43][NH:42][C:39]([C:35]2[CH:34]=[C:33]([C:10]3[CH:11]=[C:12]([C:23]4[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=4)[C:13]([OH:15])=[CH:14][C:9]=3[OH:8])[CH:38]=[CH:37][CH:36]=2)=[O:40])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NCCCN1CCOCC1
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)NCCCN3CCOCC3)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid and N-(3-aminopropyl) morpholine as described in general procedure D. LCMS: 497 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:17])[C@@H:12]([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:20](=[O:26])[NH:21][C:22]([Br:25])=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([C@H:12]([C:13](=[O:15])[NH:18][C:19]1[C:20](=[O:26])[NH:21][C:22]([Br:25])=[CH:23][CH:24]=1)[CH3:16])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: Nc1ccc(Br)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C(=O)Nc1ccc(Br)[nH]c1=O)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
To a solution of (S)-2-(benzyloxycarbonyl-methyl-amino)-propionic acid (2.7 g, 11.4 mmol) in 10 mL of CH2Cl2 at 0° C., is added 1-chloro-N,N-2-trimethyl-1-propenylamine (1.5 g, 11.4 mmol) drop wise. After being stirred at 0° C. for 20 minutes, the solution is added to a solution of 3-amino-6-bromo-1H-pyridin-2-one (1B) (1.8 g, 9.5 mmol) in 40 mL of CH2Cl2 at 0° C. slowly. Triethyl amine (3.2 ml, 22.8 mmol) is then added slowly. The reaction mixture is stirred at 0° C. for 1 hour, then washed with 2×15 ml of water, and concentrated. The crude product is purified by chromatography (CH2Cl2 95%, MeOH 5%) to give [(S)-1-(6-bromo-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl)-ethyl]-methyl-carbamic acid benzyl ester (1C) (3.0 g, yield 79%) as purple solid. MS (ESI) m/e 408, 410 (M+H+).