Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([NH:23][CH:24]3[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:26]1[CH2:25][CH:24]([NH:23][C:21]([C:18]2[N:17]=[C:16]([C@@H:10]([CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[O:20][N:19]=2)=[O:22])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NC2CNC2)no1)NO
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of tert-butyl 3-{[(5-{(1R)-4-cyclohexyl-1 -[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)carbonyl]amino}-1-azetidinecarboxylate (Example 43) (160 mg, 0.33 mmol) in dichloromethane (10 ml) was cooled to 0° C. and treated with trifluoroacetic acid (7 ml) and the resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 45 minutes. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane (×2).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][SH:17].[Na]>O1CCOCC1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([S:17][CH3:16])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS
Reactant: CC(C)(C)n1ncc([N+](=O)[O-])c(Cl)c1=O
Agent: [Na]
Solvent: C1COCCO1
Product: CSc1c([N+](=O)[O-])cnn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
Into 20 ml of a dioxane solution of 2.31 g of 2-tert-butyl-4-chloro-5-nitropyridazin-3-(2H)-one, 5 ml of an aqueous solution of 0.7 g of sodium methylmercaptan was dropwise added over a period of 4 minutes under cooling with ice. The mixture was stirred at room temperature for 10 minutes and then extracted with ethyl acetate. The extract was washed with water and then with saturated sodium chloride aqueous solution, and then it was dried over anhydrous sodium sulfate and concentrated. The residual oil was subjected to column chromatography, and using an eluent (n-hexane:ethyl acetate=20:1), 1.5 g of oily 2-tert-butyl-4-methylthio-5-nitropyridazin-3-(2H)-one was obtained.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), 1-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[CH:9].[OH:11][C:12]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]2[C:13]=1[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([CH3:23])[O:17]2>CC(CC)=O.[I-].[K+]>[OH:11][C:12]1[CH:21]=[C:20]([O:22][CH2:9][C:8]#[CH:7])[CH:19]=[C:18]2[C:13]=1[C:14](=[O:25])[CH2:15][C:16]([CH3:23])([CH3:24])[O:17]2
Reactant: C#CCBr
Reactant: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1cc(O)c2c(c1)OC(C)(C)CC2=O
Temperature: 0 °C
Yield: 75 %

Procedure:
In 60 ml of methyl-ethyl-ketone 4.2 g of 5,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 3.0 g (22 millimoles) of potassium carbonate, 0.2 g of potassium iodide, and 3.0 g (2.3 ml, 25 millimoles) of propargyl bromide are added and the reaction mixture is refluxed for 4 hours. The inorganic salt is filtered off, the residue is taken up in 100 ml of carbon tetrachloride and extracted twice with 25 ml of a 5% sodium hydroxide solution each. The aqueous-alkaline layer is cooled to 0° C. The precipitated sodium phenolate salt is filtered off, washed twice with 20 ml of acetone each, and suspended in 25% hydrochloric acid (50 ml). The mixture is stirred at 5° C. for an hour. The precipitated white product is filtered off, washed twice with 20 ml of water each and dried to constant weight. The crude product thus obtained can be directly subjected to further reactions. Thus 3.7 g of the desired compound are obtained, yield 75%, Mp.: 122°-124° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:24][O:25][CH2:26]Cl>CS(C)=O.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][CH2:24][O:25][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCOc1cc(C#N)ccc1OCc1ccccc1
Yield: 62.3 %

Procedure:
To a solution of the resulting 4-benzyloxy-3-hydroxy-benzonitrile (300 mg, 1.33 mmol) and potassium tert-butoxide (300 mg, 2.66 mmol) in dimethylsulfoxide (4 mL) was added chloromethyl methyl ether (0.204 mL, 2.66 mmol) portionwise under nitrogen atmosphere stirring on an ice bath, and the solution was stirred for 2 days. NH silica gel (25 mL) was added to the reaction solution, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=7:3) then silica gel column chromatography (hexane:ethyl acetate=7:3), and the title compound (306 mg, 0.829 mmol, 85.3%) was obtained as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C>[OH:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1cc([N+](=O)[O-])ccc1C#N
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc([N+](=O)[O-])cc1O
Temperature: 160 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
To a solution of 2-methoxy-4-nitrobenzonitrile (5.0 g, 28.1 mmol) in N,N-dimethylformamide (28 mL) was added lithium chloride (2.38 g, 56.2 mmol), and the mixture was stirred at 160° C. for 16 hr. The reaction solution was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with 1% aqueous citric acid solution (150 mL), water (150 mL) and saturated brine (150 mL×2), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→30/70), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate to give the title compound (3.98 g, 86%) as a yellow-brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1>CO.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1NCC1CC1
Agent: [Pt]
Solvent: CO
Product: Nc1cc(Br)cnc1NCC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of 5-bromo-N-(cyclopropylmethyl)-3-nitropyridin-2-amine (Step C, 5.5 g, 20.3 mmol) and 3% platinum on sulfide carbon (N.E.CHEMCAT, 1 g) in methanol (250 mL) was stirred at room temperature for 3 h under hydrogen. The mixture was filtered through a pad of celite and the filtrate was concentrated to afford the title compound (4.9 g, 100%) as black oil.
Reaction SMILES: [H][H].[OH:3][C:4]1[CH:23]=[C:22]([O:24][CH2:25][O:26][CH3:27])[CH:21]=[C:20]([O:28][CH2:29][O:30][CH3:31])[C:5]=1[C:6](=[O:19])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][CH:10]=1>C(OCC)(=O)C.[Pd]>[OH:3][C:4]1[CH:23]=[C:22]([O:24][CH2:25][O:26][CH3:27])[CH:21]=[C:20]([O:28][CH2:29][O:30][CH3:31])[C:5]=1[C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:13][CH:14]=1
Reactant: COCOc1ccc(C=CC(=O)c2c(O)cc(OCOC)cc2OCOC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCC(=O)c2c(O)cc(OCOC)cc2OCOC)cc1
Yield: 91.8 %

Procedure:
Then, a suspension of 4.10 g of 5% palladium/carbon in 50 ml of ethyl acetate was saturated with hydrogen, and 60 ml of an ethyl acetate solution of 6.61 g of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)chalcone was added to the suspension and hydrogenation was carried out. After the reaction, the reaction liquid was filtered and concentrated under a reduced pressure to obtain 6.10 g (yield=91.8%) of 1-[2-hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-(4-methoxymethoxyphenyl)-1-propanone.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([C:29]([O:31][CH3:32])=[O:30])=[N:12][C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[N:14][C:15]=1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:1]([O:9][C:10]1[C:11]([C:29]([O:31][CH3:32])=[O:30])=[N:12][C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[N:14][C:15]=1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2CCCN2C(=O)OC(C)(C)C)nc(O)c1OC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(C2CCCN2)nc(O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 5-(benzoyloxy)-2-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-6-hydroxypyrimidine-4-carboxylate C-15 was treated with TFA:CH2Cl2 (3:7) at 0° C. The solution was warmed to room temperature and the progress of the reaction was monitored by MS analysis. After 1 h the reaction was complete and the solvent was removed under reduced pressure using a rotatory evaporator. The product C-16 was precipitated with Et2O and collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C@H:10]([NH:23]C(=O)OC(C)(C)C)[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].Cl.O1CCOCC1>C(Cl)(Cl)Cl.CO>[NH2:23][C@@H:10]([CH2:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])[CH2:11][N:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c(F)cccc1F)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N[C@@H](Cc1c(F)cccc1F)CN1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 118.6 %

Procedure:
In a 200 mL round-bottomed flask was added 1,1-dimethylethyl {(1S)-2-(2,6-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (2.72 g, 6.40 mmol) in Chloroform (75 ml) and Methanol (10 ml). HCl/1,4-Dioxane (40.0 ml, 160 mmol) was added and the mixture stirred overnight. The solvents were removed affording the title compound (2.4 g, quant.) as the HCl salt: LC-MS (ES) m/z=317 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][NH2:6].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][NH:6][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C(C)(C)CN
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)CNC1CCCC1
Reaction time: 22 h
Yield: 95.5 %

Procedure:
To a solution of 21.98 g (0.167 mole) of 3-amino-2,2-dimethyl-propanoic acid methyl ester (from method 6) in 500 mL of dichloromethane cooled to 0 degrees, was added 14.1 g (0.167 mole) of cyclopentanone, 16.0 g (0.181 mole) of sodium acetate and 52.0 g (0.025 mole) of sodium triacetoxyborohydride. The mixture stirred at room temp. for 22 hours, and then quenched by the addition of 500 mL of saturated sodium bicarbonate solution. The mixture was stirred for 1 hour and then extracted twice 400 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 31.8 g of 3-cyclopentylamino-2,2-dimethyl-propanoic acid methyl ester which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH:14]([NH:16][C:17]([O:19]CC1C=CC=CC=1)=O)[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:37]=[CH:36][C:32](C(O)=O)=[CH:31][C:30]=1[Cl:38].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CO.CCOC(C)=O.C(Cl)Cl.[Pd].CN(C=O)C>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH:14]([NH:16][C:17](=[O:19])[C:32]1[CH:36]=[CH:37][C:29]([NH2:28])=[C:30]([Cl:38])[CH:31]=1)[CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Reactant: Nc1ccc(C(=O)O)cc1Cl
Agent: [Pd]
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a solution of 95 (10.50 g, 27.9 mmol) in MeOH (100 ml) was added a suspension of 10% Pd/C (5.00 g) in EtOAc (50 ml). The mixture was stirred under H2 for 48 hours, filtered through celite and the solvent evaporated to yield a waxy solid. This was dissolved in CH2Cl2 (100 ml) and DMF (50 ml) and the solution cooled to 0° C. 4-Amino-3-chlorobenzoic acid (5.82 g, 27.2 mmol), DIEA (14.58 ml, 83.7 mmol), HOBT (3.77 g, 27.9 mmol) and EDC 6.68 g, 34.8 mmol) were added and the solution stirred at 0° C. for 15 mins then at room temperature for 24 hours. The reaction mixture was diluted with EtOAc, washed with NaHSO4 (2×), 10% NaHCO3 (2×) and brine then dried over MgSO4, filtered and evaporated. The crude product was purified by flash column chromatography, using CH2Cl2/MeOH (99/1 to 97/3%) to yield the title compound as a white solid (7.75 g, 70% yield). 1H-NMR (500 MHz, CD3OD) δ 1.27-1.67 (m, 12H), 1.8-2.14 (m, 4H) 3.48-3.85 (m, 2H), 4.26-4.53 (m, 3H), 4.81-4.98 (m, 1H), 6.71 (d, 1H), 7.15 (m, 1H), 7.50 (dd, 1H), 7.75 (d, 1H). Analytical HPLC 10.83 min. LC-MS (ES+) m/e=396.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([NH:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]2.[C:19]([S:22][CH2:23][CH:24]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[C:25](Cl)=[O:26])(=[O:21])[CH3:20].O>CC(N(C)C)=O>[C:19]([S:22][CH2:23][CH:24]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[C:25]([N:14]([CH:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[CH2:6][CH2:7]1)[CH2:15][C:16]([OH:18])=[O:17])=[O:26])(=[O:21])[CH3:20]
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)Cl
Reactant: COc1cc2c(cc1OC)C(NCC(=O)O)CC2
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1OC)C(N(CC(=O)O)C(=O)C(CSC(C)=O)CSC(C)=O)CC2
Temperature: 25 °C
Yield: 45.5 %

Procedure:
N-(5,6-Dimethoxy-1-indanyl)glycine (4.0 g) is suspended in 40 ml of dimethylacetamide, then 4.4 g of 3-acetylthio-2-acetylthiomethylpropionyl chloride is added dropwise with stirring at room temperature, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into 400 ml of water and extracted with 300 ml of ethyl acetate. The extract is washed with 30 ml of 10% hydrochloric acid and with water, and dried. After ethyl acetate is distilled off under reduced pressure, ethyl ether is added to the residue and the mixture is allowed to stand at room temperature. The resulting crystalline precipitates are collected by filtration to give 3.4 g of N-(3-acetylthio-2-acetylthiomethylpropionyl)-N-(5,6-dimethoxy-1-indanyl)glycine as colorless needles melting at 140°-143° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=N/NC2C3C(=CC=CC=3)C=NN=2)=[CH:5][CH:4]=1.[NH2:22][C@H:23]([C:31]([OH:33])=[O:32])CC1C=CC=CC=1.CS(C)=O.C(S)[C@@H](O)[C@H](O)CS>C1N(CCO)CCN(CCS(O)(=O)=O)C1>[NH2:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COc1ccc(/C=N/Nc2nncc3ccccc23)cc1
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CS(C)=O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 0.02 h

Procedure:
PAH activity was measured at 25° C. for 1 min essentially as described (BjØrgo E, et al., Eur. J. Biochem. 1988; 257(1):1-10). Tetrameric hPAH (1-2 μg) was incubated in 20 mM Hepes 0.2 M NaCl pH 7.0, containing catalase (0.04 mg/ml), 0.1-1 mM L-Phe, DMSO 2.5% and 0-100 μM of each compound. After 4 min incubation at 25° C., ferrous ammonium sulphate (100 μM) was added, and the reaction was triggered after 1 min by adding BH4 (10-200 μM) in the presence of 5 mM DTT. In some experiments, the preincubation step with L-Phe was omitted and L-Phe was added together with BH4 to analyze the L-Phe induced activation of the enzyme. To determine the kinetic parameters for BH4 and L-Phe, BH4 was used at 0-200 μM (at fixed 1 mM L-Phe) and L-Phe at 0-1 mM (BH4 was fixed at 75 μM). L-Tyr formed was quantified by HPLC and fluorimetric detection (DØskeland A P, et al., J. Biol. Chem. 1984; 259:11242-11248). The saturation curves were fitted to hyperbolic (for BH4) or sigmoidal (for L-Phe) kinetic models by using Sigma Plot v.9.0 (SPSS Inc).
Reaction SMILES: [C:1]([CH:9]=[C:10]([CH3:14])[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18]>>[C:1]([CH:9]=[C:10]([CH3:14])[C:11]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=CC(=O)c1ccccc1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Product: CC(=CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
As for Example 8, 3-(benzoyl)-2-methylacrylic acid is coupled to L-proline to give 1-[3-benzoyl-2-methylacryloyl]-L-proline. The preceding compound is reacted with thiolacetic acid in carbontetrachloride to give the product of the example as a glass.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:10][C:9]([CH2:33][C:34]#[N:35])([N:11]3[CH:15]=[C:14]([C:16]4[C:17]5[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[C:18]=5[N:19]=[CH:20][N:21]=4)[CH:13]=[N:12]3)[CH2:8]2)[CH2:3][CH2:2]1.Cl[C:37]([O:39][CH2:40][CH2:41][CH3:42])=[O:38].C(Cl)Cl.C(O)(C(F)(F)F)=O.C(N)CN>CO>[C:34]([CH2:33][C:9]1([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:8][N:7]([CH:4]2[CH2:3][CH2:2][N:1]([C:37]([O:39][CH2:40][CH2:41][CH3:42])=[O:38])[CH2:6][CH2:5]2)[CH2:10]1)#[N:35]
Reactant: CCCOC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)N1CCC(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)CC1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (0.010 g, 0.020 mmol) and propyl chloroformate (3.0 μL, 0.026 mmol) in methylene chloride (1 mL, 20 mmol) was stirred for 1.5 h. TFA, 1 mL, was added. After 1 hour, the solvent was removed by rotary evaporation to give an oil. The oil was dissolved in 1 mL MeOH and 50 microL ethylenediamine was added. After 1 hour, the reaction was purified by prep-HPLC (pH10) using a Waters XBridge C18, 5 μm particle size, 19×100 mm; mobile phase system: aqueous (0.1% NH4OH)/acetonitrile; flow rate: 30 mL/min; separation gradient: 40-60% B in 5 min to give 5.3 mg white solid (58%). 1H NMR (400 MHz, DMSO): δ 12.13 (1H, br); 8.83 (1H, s); 8.7 (1H, s); 8.42 (1H, s); 7.61 (1H, m); 7.05 (1H, m); 3.95 (2H, t); 3.75 (4H, m); 3.55 (4H, m); 3.0 (2H, br); 2.43 (1H, m); 1.65 (2H, m); 1.58 (2H, m); 1.15 (2H, m); 0.95 (3H, t). LCMS (M+1): 449.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NCCCCN
Product: N#Cc1ccc(NCCCCN)nc1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
6-Chloro-3-pyridinecarbonitrile (5.0 g) was dissolved in 1,4-diaminobutane (50 ml), and the solution was stirred at 170° C. for 2 hours with heating. Diethyl ether and distilled water were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with diethyl ether. The aqueous layer was saturated with sodium chloride, and the resulting mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (4.77 g).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10][C:9]=3[S:22][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][C:9]=4[S:22][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2sc3ncnc(Cl)c3c2CC1
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCNCC4)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 12A from tert-butyl 4-chloro-5,6,8,9-tetrahydro-7H-pyrimido[5′,4′:4,5]thieno[2,3-d]azepine-7-carboxylate from Example 84A (680 mg, 2.00 mmol) and 3-chloro-4-fluoroaniline (306 mg, 2.10 mmol) to yield 419 mg (60%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19](OC)=[O:20])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[NH2:1][C:2]1[N:3]([C:16]2[CH:25]=[CH:24][CH:23]=[C:18]([CH2:19][OH:20])[CH:17]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12
Reactant: COC(=O)c1cccc(-n2nc3c(c2N)c(=O)[nH]c2ccccc23)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1c2c(=O)[nH]c3ccccc3c2nn1-c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
A mixture of methyl 3-(3-amino-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzoate (80 mg), lithium aluminum hydride (12 mg) and tetrahydrofuran (5 ml) was stirred at room temperature for 3 hours. Diethyl ether and then saturated aqueous sodium sulfate solution were added to the reaction mixture, and the organic layer was separated by decantation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Diisopropy ether was added to the residue. The precipitated solid was collected by filtration, washed with diisopropyl ether, and dried to obtain the target compound (60 mg).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH3:12][C:13]([O:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21](NCOC)=[O:22])([CH3:15])[CH3:14].C(OCC)(=O)C>O1CCCC1.CCCC(C)C>[CH3:15][C:13]([O:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21](=[O:22])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([CH3:12])[CH3:14]
Reactant: COCNC(=O)CCNC(=O)OC(C)(C)C
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCC(=O)c1nccs1
Temperature: 0 °C
Yield: 67.1 %

Procedure:
To a solution of 2-bromothiazole (5.035 g, 30.7 mmol) in dry tetrahydrofuran (125 ml) at −78° C. under nitrogen was added a solution of n-butyllithium in hexanes (1.6 M, 17.6 ml, 28.2 mmol) over a period of 30 minutes, followed by a solution of [3-(methoxymethylamino)-3-oxopropyl]carbamic acid 1,1-dimethylethyl ester (2.976 g, 12.8 mmol) in dry tetrahydrofuran (30 ml) added over 30 minutes. The reaction mixture was allowed to warm up to 0° C., quenched with saturated ammonium chloride and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (3×50 ml) and saturated brine solution (1×100 ml), dried (magnesium sulphate) and concentrated in vacuo to leave a crude orange oil. Flash chromatography (silica, 25% ethyl acetate in isohexane) gave 2.2 g of a pale yellow oil (67%).